Each recommendation is identified as falling into one of three
categories of endorsement, indicated by a bracketed Roman numeral
following the statement. The three categories represent varying
levels of clinical confidence:
[I] Recommended with substantial clinical
confidence
[II] Recommended with moderate clinical
confidence
[III] May be recommended on the basis of
individual circumstances
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B. Summary of Recommendations
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1. Psychiatric management
Psychiatric management consists of a broad array of interventions
and activities that psychiatrists should initiate and continue to
provide to patients with major depressive disorder through all phases
of treatment [I].
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a. Establish and
maintain a therapeutic alliance
In establishing and maintaining a therapeutic alliance, it
is important to collaborate with the patient in decision making and
attend to the patient's preferences and concerns about treatment [I].
Management of the therapeutic alliance should include awareness
of transference and countertransference issues, even if these are
not directly addressed in treatment [II]. Severe
or persistent problems of poor alliance or nonadherence to treatment
may be caused by the depressive symptoms themselves or may represent psychological
conflicts or psychopathology for which psychotherapy should be considered [II].
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b. Complete the psychiatric
assessment
Patients should receive a thorough diagnostic assessment in order
to establish the diagnosis of major depressive disorder, identify
other psychiatric or general medical conditions that may require
attention, and develop a comprehensive plan for treatment [I].
This evaluation generally includes a history of the present illness
and current symptoms; a psychiatric history, including identification
of past symptoms of mania, hypomania, or mixed episodes and responses
to previous treatments; a general medical history; a personal history
including information about psychological development and responses
to life transitions and major life events; a social, occupational,
and family history (including mood disorders and suicide); review of
the patient's prescribed and over-the-counter medications;
a review of systems; a mental status examination; a physical examination;
and appropriate diagnostic tests as indicated to rule out possible
general medical causes of depressive symptoms [I].
Assessment of substance use should evaluate past and current use
of illicit drugs and other substances that may trigger or exacerbate
depressive symptoms [I].
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c. Evaluate the safety
of the patient
A careful and ongoing evaluation of suicide risk is necessary for
all patients with major depressive disorder [I].
Such an assessment includes specific inquiry about suicidal thoughts, intent,
plans, means, and behaviors; identification of specific psychiatric
symptoms (e.g., psychosis, severe anxiety, substance use) or general
medical conditions that may increase the likelihood of acting on
suicidal ideas; assessment of past and, particularly, recent suicidal
behavior; delineation of current stressors and potential protective
factors (e.g., positive reasons for living, strong social support);
and identification of any family history of suicide or mental illness [I].
In addition to assessing suicide risk per se, it is important to
assess the patient's level of self-care, hydration, and
nutrition, each of which can be compromised by severe depressive
symptoms [I]. As part of the assessment process,
impulsivity and potential for risk to others should also be evaluated,
including any history of violence or violent or homicidal ideas, plans,
or intentions [I]. An evaluation of the impact
of the depression on the patient's ability to care for
dependents is an important component of the safety evaluation [I].
The patient's risk of harm to him- or herself and to others
should also be monitored as treatment proceeds [I].
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d. Establish the
appropriate setting for treatment
The psychiatrist should determine the least restrictive setting for
treatment that will be most likely not only to address the patient's
safety, but also to promote improvement in the patient's
condition [I]. The determination of an appropriate
setting for treatment should include consideration of the patient's
symptom severity, co-occurring psychiatric or general medical conditions,
available support system, and level of functioning [I].
The determination of a treatment setting should also include consideration
of the patient's ability to adequately care for him- or
herself, to provide reliable feedback to the psychiatrist, and to
cooperate with treatment of the major depressive disorder [I].
Measures such as hospitalization should be considered for patients
who pose a serious threat of harm to themselves or others [I].
Patients who refuse inpatient treatment can be hospitalized involuntarily
if their condition meets the criteria of the local jurisdiction
for involuntary admission [I]. Admission to a
hospital or, if available, an intensive day program, may also be
indicated for severely ill patients who lack adequate social support
outside of a hospital setting, who have complicating psychiatric
or general medical conditions, or who have not responded adequately
to outpatient treatment [I]. The optimal treatment
setting and the patient's likelihood of benefit from a
different level of care should be reevaluated on an ongoing basis
throughout the course of treatment [I].
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e. Evaluate functional
impairment and quality of life
Major depressive disorder can alter functioning in numerous spheres
of life including work, school, family, social relationships, leisure
activities, or maintenance of health and hygiene. The psychiatrist
should evaluate the patient's activity in each of these
domains and determine the presence, type, severity, and chronicity
of any dysfunction [I]. In developing a treatment
plan, interventions should be aimed at maximizing the patient's
level of functioning as well as helping the patient to set specific
goals appropriate to his or her functional impairments and symptom
severity [I].
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f. Coordinate the
patient's care with other clinicians
Many patients with major depressive disorder will be evaluated
by or receive treatment from other health care professionals in
addition to the psychiatrist. If more than one clinician is involved
in providing the care, all treating clinicians should have sufficient
ongoing contact with the patient and with each other to ensure that
care is coordinated, relevant information is available to guide
treatment decisions, and treatments are synchronized [I].
In ruling out general medical causes of depressive symptoms,
it is important to ensure that a general medical evaluation has
been done [I], either by the psychiatrist or by
another health care professional. Extensive or specialized testing
for general medical causes of depressive symptoms may be conducted
based on individual characteristics of the patient [III].
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g. Monitor the patient's
psychiatric status
The patient's response to treatment should be carefully
monitored [I]. Continued monitoring of co-occurring
psychiatric and/or medical conditions is also essential
to developing and refining a treatment plan for an individual patient [I].
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h. Integrate measurements
into psychiatric management
Tailoring the treatment plan to match the needs of the particular
patient requires a careful and systematic assessment of the type,
frequency, and magnitude of psychiatric symptoms as well as ongoing
determination of the therapeutic benefits and side effects of treatment [I].
Such assessments can be facilitated by integrating clinician- and/or patient-administered rating
scale measurements into initial and ongoing evaluation [II].
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i. Enhance treatment
adherence
The psychiatrist should assess and acknowledge potential barriers
to treatment adherence (e.g., lack of motivation or excessive pessimism
due to depression; side effects of treatment; problems in the therapeutic
relationship; logistical, economic, or cultural barriers to treatment)
and collaborate with the patient (and if possible, the family) to minimize
the impact of these potential barriers [I]. In
addition, the psychiatrist should encourage patients to articulate
any fears or concerns about treatment or its side effects [I].
Patients should be given a realistic notion of what can be expected
during the different phases of treatment, including the likely time course
of symptom response and the importance of adherence for successful
treatment and prophylaxis [I].
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j. Provide education
to the patient and the family
Education about the symptoms and treatment of major depressive
disorder should be provided in language that is readily understandable
to the patient [I]. With the patient's permission,
family members and others involved in the patient's day-to-day
life may also benefit from education about the illness, its effects
on functioning (including family and other interpersonal relationships),
and its treatment [I]. Common misperceptions about
antidepressants (e.g., they are addictive) should be clarified [I].
In addition, education about major depressive disorder should address
the need for a full acute course of treatment, the risk of relapse,
the early recognition of recurrent symptoms, and the need to seek
treatment as early as possible to reduce the risk of complications
or a full-blown episode of major depression [I].
Patients should also be told about the need to taper antidepressants,
rather than discontinuing them precipitously, to minimize the risk of
withdrawal symptoms or symptom recurrence [I].
Patient education also includes general promotion of healthy behaviors
such as exercise, good sleep hygiene, good nutrition, and decreased use
of tobacco, alcohol, and other potentially deleterious substances [I].
Educational tools such as books, pamphlets, and trusted web sites
can augment the face-to-face education provided by the clinician [I].
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a. Choice of an initial
treatment modality
Treatment in the acute phase should be aimed at inducing remission
of the major depressive episode and achieving a full return to the
patient's baseline level of functioning [I].
Acute phase treatment may include pharmacotherapy, depression-focused
psychotherapy, the combination of medications and psychotherapy,
or other somatic therapies such as electroconvulsive therapy (ECT),
transcranial magnetic stimulation (TMS), or light therapy, as described in
the sections that follow. Selection of an initial treatment modality
should be influenced by clinical features (e.g., severity of symptoms, presence
of co-occurring disorders or psychosocial stressors) as well as
other factors (e.g., patient preference, prior treatment experiences) [I].
Any treatment should be integrated with psychiatric management and
any other treatments being provided for other diagnoses [I].
An antidepressant medication
is recommended as an initial treatment choice for patients with
mild to moderate major depressive disorder [I] and
definitely should be provided for those with severe major depressive
disorder unless ECT is planned [I]. Because the
effectiveness of antidepressant medications is generally comparable
between classes and within classes of medications, the initial selection
of an antidepressant medication will largely be based on the anticipated
side effects, the safety or tolerability of these side effects for
the individual patient, pharmacological properties of the medication
(e.g., half-life, actions on cytochrome P450 enzymes, other drug
interactions), and additional factors such as medication response
in prior episodes, cost, and patient preference [I].
For most patients, a selective serotonin reuptake inhibitor (SSRI),
serotonin norepinephrine reuptake inhibitor (SNRI), mirtazapine, or
bupropion is optimal [I]. In general, the use
of nonselective monoamine oxidase inhibitors (MAOIs) (e.g., phenelzine,
tranylcypromine, isocarboxazid) should be restricted to patients
who do not respond to other treatments [I], given
the necessity for dietary restrictions with these medications and
the potential for deleterious drug-drug interactions. In patients
who prefer complementary and alternative therapies, S-adenosyl
methionine (SAMe) [III] or St. John's
wort [III] might be considered, although evidence for their
efficacy is modest at best, and careful attention to drug-drug interactions
is needed with St. John's wort [I].
Once an antidepressant medication has been initiated, the rate
at which it is titrated to a full therapeutic dose should depend
upon the patient's age, the treatment setting, and the presence
of co-occurring illnesses, concomitant pharmacotherapy, or medication
side effects [I]. During the acute phase of treatment,
patients should be carefully and systematically monitored on a regular
basis to assess their response to pharmacotherapy, identify the
emergence of side effects (e.g., gastrointestinal symptoms, sedation,
insomnia, activation, changes in weight, and cardiovascular, neurological,
anticholinergic, or sexual side effects), and assess patient safety [I]. The
frequency of patient monitoring should be determined based upon
the patient's symptom severity (including suicidal ideas),
co-occurring disorders (including general medical conditions), cooperation
with treatment, availability of social supports, and the frequency
and severity of side effects with the chosen treatment [II].
If antidepressant side effects do occur, an initial strategy is
to lower the dose of the antidepressant or to change to an antidepressant
that is not associated with that side effect [I].
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2. Other somatic therapies
ECT is recommended as a treatment of choice for patients with
severe major depressive disorder that is not responsive to psychotherapeutic
and/or pharmacological interventions, particularly in those
who have significant functional impairment or have not responded
to numerous medication trials [I]. ECT is also
recommended for individuals with major depressive disorder who have
associated psychotic or catatonic features [I],
for those with an urgent need for response (e.g., patients who are
suicidal or nutritionally compromised due to refusal of food or
fluids) [I], and for those who prefer ECT or have
had a previous positive response to ECT [II].
Bright light therapy might be used to treat seasonal affective
disorder as well as nonseasonal depression [III].
Use of a depression-focused psychotherapy alone is recommended
as an initial treatment choice for patients with mild to moderate
major depressive disorder [I], with clinical evidence
supporting the use of cognitive-behavioral therapy (CBT) [I],
interpersonal psychotherapy [I], psychodynamic therapy [II],
and problem-solving therapy [III] in individual [I] and
in group [III] formats. Factors that may suggest
the use of psychotherapeutic interventions include the presence of
significant psychosocial stressors, intrapsychic conflict, interpersonal
difficulties, a co-occurring axis II disorder, treatment availability,
ormost importantpatient preference [II].
In women who are pregnant, wish to become pregnant, or are breast-feeding,
a depression-focused psychotherapy alone is recommended [II] and
depending on the severity of symptoms, should be considered as an
initial option [I]. Considerations in the choice
of a specific type of psychotherapy include the goals of treatment
(in addition to resolving major depressive symptoms), prior positive
response to a specific type of psychotherapy, patient preference,
and the availability of clinicians skilled in the specific psychotherapeutic
approach [II]. As with patients who are receiving pharmacotherapy,
patients receiving psychotherapy should be carefully and systematically
monitored on a regular basis to assess their response to treatment
and assess patient safety [I]. When determining
the frequency of psychotherapy sessions for an individual patient,
the psychiatrist should consider multiple factors, including the
specific type and goals of psychotherapy, symptom severity (including suicidal ideas),
co-occurring disorders, cooperation with treatment, availability
of social supports, and the frequency of visits necessary to create
and maintain a therapeutic relationship, ensure treatment adherence,
and monitor and address depressive symptoms and suicide risk [II].
Marital and family problems are common in the course of major depressive
disorder, and such problems should be identified and addressed,
using marital or family therapy when indicated [II].
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4. Psychotherapy plus antidepressant medication
The combination of psychotherapy and antidepressant medication
may be used as an initial treatment for patients with moderate to
severe major depressive disorder [I]. In addition, combining
psychotherapy and medication may be a useful initial treatment even
in milder cases for patients with psychosocial or interpersonal
problems, intrapsychic conflict, or co-occurring Axis II disorder [II].
In general, when choosing an antidepressant or psychotherapeutic
approach for combination treatment, the same issues should be considered
as when selecting a medication or psychotherapy for use alone [I].
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b. Assessing the
adequacy of treatment response
In assessing the adequacy
of a therapeutic intervention, it is important to establish that
treatment has been administered for a sufficient duration and at
a sufficient frequency or, in the case of medication, dose [I]. Onset
of benefit from psychotherapy tends to be a bit more gradual than
that from medication, but no treatment should continue unmodified
if there has been no symptomatic improvement after 1 month [I].
Generally, 4–8 weeks of treatment are needed before concluding that
a patient is partially responsive or unresponsive to a specific
intervention [II].
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c. Strategies to
address nonresponse
For individuals who have not responded fully to treatment, the
acute phase of treatment should not be concluded prematurely [I],
as an incomplete response to treatment is often associated with
poor functional outcomes. If at least a moderate improvement in
symptoms is not observed within 4–8 weeks of treatment
initiation, the diagnosis should be reappraised, side effects assessed,
complicating co-occurring conditions and psychosocial factors reviewed,
and the treatment plan adjusted [I]. It is also
important to assess the quality of the therapeutic alliance and
treatment adherence [I]. For patients in psychotherapy,
additional factors to be assessed include the frequency of sessions
and whether the specific approach to psychotherapy is adequately
addressing the patient's needs [I]. If
medications are prescribed, the psychiatrist should determine whether
pharmacokinetic [I] or pharmacodynamic [III] factors
suggest a need to adjust medication doses. With some TCAs, a drug
blood level can help determine if additional dose adjustments are
required [I].
After an additional 4–8 weeks of treatment, if the
patient continues to show minimal or no improvement in symptoms, the
psychiatrist should conduct another thorough review of possible
contributory factors and make additional changes in the treatment
plan [I]. Consultation should also be considered [II].
A number of strategies are available when a change in the treatment
plan seems necessary. For patients treated with an antidepressant,
optimizing the medication dose is a reasonable first step if the
side effect burden is tolerable and the upper limit of a medication
dose has not been reached [II]. Particularly for
those who have shown minimal improvement or experienced significant
medication side effects, other options include augmenting the antidepressant
with a depression-focused psychotherapy [I] or
with other agents [II] or changing to another
non-MAOI antidepressant [I]. Patients may be changed
to an antidepressant from the same pharmacological class (e.g.,
from one SSRI to another SSRI) or to one from a different class (e.g.,
from an SSRI to a tricyclic antidepressant [TCA]) [II]. For
patients who have not responded to trials of SSRIs, a trial of an
SNRI may be helpful [II]. Augmentation of antidepressant
medications can utilize another non-MAOI antidepressant [II],
generally from a different pharmacological class, or a non-antidepressant
medication such as lithium [II], thyroid hormone [II],
or a second-generation antipsychotic [II]. Additional
strategies with less evidence for efficacy include augmentation
using an anticonvulsant [III], omega-3 fatty acids [III],
folate [III], or a psychostimulant medication [III],
including modafinil [III]. If anxiety or insomnia
are prominent features, consideration can be given to anxiolytic
and sedative-hypnotic medications [III], including
buspirone, benzodiazepines, and selective 
-aminobutyric
acid (GABA) agonist hypnotics (e.g., zolpidem, eszopiclone). For
patients whose symptoms have not responded adequately to medication,
ECT remains the most effective form of therapy and should be considered [I].
In patients capable of adhering to dietary and medication restrictions,
an additional option is changing to a nonselective MAOI [II] after
allowing sufficient time between medications to avoid deleterious
interactions [I]. Transdermal selegiline, a relatively
selective MAO B inhibitor with fewer dietary and medication restrictions,
or transcranial magnetic stimulation could also be considered [II].
Vagus nerve stimulation (VNS) may be an additional option for individuals
who have not responded to at least four adequate trials of antidepressant
treatment, including ECT [III].
For patients treated with psychotherapy, consideration should
be given to increasing the intensity of treatment or changing the
type of therapy [II]. If psychotherapy is used alone,
the possible need for medications in addition to or in lieu of psychotherapy
should be assessed [I]. Patients who have a history
of poor treatment adherence or incomplete response to adequate trials
of single treatment modalities may benefit from combined treatment
with medication and a depression-focused psychotherapy [II].
During the continuation phase
of treatment, the patient should be carefully monitored for signs
of possible relapse [I]. Systematic assessment
of symptoms, side effects, adherence, and functional status is essential [I] and
may be facilitated through the use of clinician- and/or
patient-administered rating scales [II]. To reduce
the risk of relapse, patients who have been treated successfully
with antidepressant medications in the acute phase should continue
treatment with these agents for 4–9 months [I]. In general,
the dose used in the acute phase should be used in the continuation
phase [II]. To prevent a relapse of depression
in the continuation phase, depression-focused psychotherapy is recommended [I],
with the best evidence available for CBT.
Patients who respond to an acute course of ECT should receive
continuation pharmacotherapy [I], with the best
evidence available for the combination of lithium and nortriptyline.
Alternatively, patients who have responded to an acute course of
ECT may be given continuation ECT, particularly if medication or
psychotherapy has been ineffective in maintaining remission [II].
In order to reduce the risk of a recurrent depressive episode, patients
who have had three or more prior major depressive episodes or who
have chronic major depressive disorder should proceed to the maintenance
phase of treatment after completing the continuation phase [I]. Maintenance
therapy should also be considered for patients with additional risk
factors for recurrence, such as the presence of residual symptoms,
ongoing psychosocial stressors, early age at onset, and family history
of mood disorders [II]. Additional considerations
that may play a role in the decision to use maintenance therapy
include patient preference, the type of treatment received, the
presence of side effects during continuation therapy, the probability
of recurrence, the frequency and severity of prior depressive episodes (including
factors such as psychosis or suicide risk), the persistence of depressive
symptoms after recovery, and the presence of co-occurring disorders [II].
Such factors also contribute to decisions about the duration of
the maintenance phase [II]. For many patients,
particularly for those with chronic and recurrent major depressive
disorder or co-occurring medical and/or psychiatric disorders,
some form of maintenance treatment will be required indefinitely [I].
During the maintenance phase, an antidepressant medication
that produced symptom remission during the acute phase and maintained
remission during the continuation phase should be continued at a
full therapeutic dose [II]. If a depression-focused
psychotherapy has been used during the acute and continuation phases
of treatment, maintenance treatment should be considered, with a
reduced frequency of sessions [II]. For patients
whose depressive episodes have not previously responded to acute
or continuation treatment with medications or a depression-focused
psychotherapy but who have shown a response to ECT, maintenance
ECT may be considered [III]. Maintenance treatment
with VNS is also appropriate for individuals whose symptoms have
responded to this treatment modality [III].
Due to the risk of recurrence, patients should be monitored
systematically and at regular intervals during the maintenance phase [I].
Use of standardized measurement aids in the early detection of recurrent
symptoms [II].
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5. Discontinuation
of treatment
When pharmacotherapy is being discontinued, it is best to taper
the medication over the course of at least several weeks [I].
To minimize the likelihood of discontinuation symptoms, patients
should be advised not to stop medications abruptly and to take medications
with them when they travel or are away from home [I].
A slow taper or temporary change to a longer half-life antidepressant
may reduce the risk of discontinuation syndrome [II] when
discontinuing antidepressants or reducing antidepressant doses.
Before the discontinuation of active treatment, patients should
be informed of the potential for a depressive relapse and a plan
should be established for seeking treatment in the event of recurrent
symptoms [I]. After discontinuation of medications,
patients should continue to be monitored over the next several months
and should receive another course of adequate acute phase treatment
if symptoms recur [I].
For patients receiving psychotherapy, it is important to raise
the issue of treatment discontinuation well in advance of the final
session [I], although the exact process by which this
occurs will vary with the type of therapy.
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6. Clinical factors
influencing treatment
For suicidal patients, psychiatrists should consider an increased
intensity of treatment, including hospitalization when warranted [I] and/or
combined treatment with pharmacotherapy and psychotherapy [II].
Factors to consider in determining the nature and intensity of treatment
include (but are not limited to) the nature of the doctor-patient
alliance, the availability and adequacy of social supports, access
to and lethality of suicide means, the presence of a co-occurring
substance use disorder, and past and family history of suicidal behavior [I].
For patients who exhibit psychotic symptoms during an episode
of major depressive disorder, treatment should include a combination
of antipsychotic and antidepressant medications or ECT [I].
When patients exhibit cognitive dysfunction during a major depressive
episode, they may have an increased likelihood of future dementia,
making it important to assess cognition in a systematic fashion
over the course of treatment [I].
Catatonic features that occur as part of a major depressive episode
should be treated with a benzodiazepine [I] or barbiturate [II],
typically in conjunction with an antidepressant [II].
If catatonic symptoms persist, ECT is recommended [I].
To reduce the likelihood of general medical complications, patients
with catatonia may also require supportive medical interventions,
such as hydration, nutritional support, prophylaxis against deep
vein thrombosis, turning to reduce risks of decubitus ulcers, and
passive range of motion to reduce risk of contractures [I].
If antipsychotic medication is needed, it is important to monitor
for signs of neuroleptic malignant syndrome, to which patients with
catatonia may have a heightened sensitivity [II].
When patients with a major depressive disorder also have a co-occurring
psychiatric illness, the clinician should address each disorder
as part of the treatment plan [I]. Benzodiazepines
may be used adjunctively in individuals with major depressive disorder
and co-occurring anxiety [II], although these agents
do not treat depressive symptoms, and careful selection and monitoring
is needed in individuals with co-occurring substance use disorders [I].
In patients who smoke, bupropion [I] or
nortriptyline [II] may be options to simultaneously
treat depression and assist with smoking cessation. When possible,
a period of substance abstinence can help determine whether the
depressive episode is related to substance intoxication or withdrawal [II].
Factors that suggest a need for antidepressant treatment soon after
cessation of substance use include a family history of major depressive
disorder and a history of major depressive disorder preceding the
onset of the substance use disorder or during periods of sobriety [II].
For patients who have a personality disorder as well as major
depressive disorder, psychiatrists should institute treatment for
the major depressive disorder [I] and consider psychotherapeutic
and adjunctive pharmacotherapeutic treatment for personality disorder
symptoms [II].
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b. Demographic and
psychosocial factors
Several aspects of assessment and treatment differ between women
and men. Because the symptoms of some women may fluctuate with gonadal
hormone levels, the evaluation should include a detailed assessment
of mood changes across the reproductive life history (e.g., menstruation,
pregnancy, birth control including oral contraception use, abortions, menopause) [I].
When prescribing medications to women who are taking oral contraceptives,
the potential effects of drug-drug interactions must be considered [I].
For women in the perimenopausal period, SSRI and SNRI antidepressants are
useful in ameliorating depression as well as in reducing somatic
symptoms such as hot flashes [II]. Both men and women
who are taking antidepressants should be asked whether sexual side
effects are occurring with these medications [I].
Men for whom trazodone is prescribed should be warned of the risk
of priapism [I].
The treatment of major depressive disorder in women who are
pregnant or planning to become pregnant requires a careful consideration
of the benefits and risks of available treatment options for the
patient and the fetus [I]. For women who are currently
receiving treatment for depression, a pregnancy should be planned,
whenever possible, in consultation with the treating psychiatrist,
who may wish to consult with a specialist in perinatal psychiatry [I].
In women who are pregnant, planning to become pregnant, or breast-feeding,
depression-focused psychotherapy alone is recommended [II] and
should always be considered as an initial option, particularly for
mild to moderate depression, for patients who prefer psychotherapy,
or for those with a prior positive response to psychotherapy [I].
Antidepressant medication should be considered for pregnant women
who have moderate to severe major depressive disorder as well as
for those who are in remission from major depressive disorder, are
receiving maintenance medication, and are deemed to be at high risk
for a recurrence if the medication is discontinued [II]. When
antidepressants are prescribed to a pregnant woman, changes in pharmacokinetics
during pregnancy may require adjustments in medication doses [I].
Electroconvulsive therapy may be considered for the treatment of
depression during pregnancy in patients who have psychotic or catatonic
features, whose symptoms are severe or have not responded to medications,
or who prefer treatment with ECT [II]. When a woman
decides to nurse, the potential benefits of antidepressant medications
for the mother should be balanced against the potential risks to the
newborn from receiving antidepressant in the mother's milk [I].
For women who are depressed during the postpartum period, it is
important to evaluate for the presence of suicidal ideas, homicidal
ideas, and psychotic symptoms [I]. The evaluation
should also assess parenting skills for the newborn and for other
children in the patient's care [I].
In individuals with late-life depression, identification of co-occurring
general medical conditions is essential, as these disorders may
mimic depression or affect choice or dosing of medications [I].
Older individuals may also be particularly sensitive to medication
side effects (e.g., hypotension, anticholinergic effects) and require
adjustment of medication doses for hepatic or renal dysfunction [I].
In other respects, treatment for depression should parallel that
used in younger age groups [I].
The assessment and treatment of major depressive disorder
should consider the impact of language barriers, as well as cultural
variables that may influence symptom presentation, treatment preferences,
and the degree to which psychiatric illness is stigmatized [I].
When antidepressants are prescribed, the psychiatrist should recognize
that ethnic groups may differ in their metabolism and response to
medications [II].
Issues relating to the family situation and family history, including
mood disorders and suicide, can also affect treatment planning and
are an important element of the initial evaluation [I].
A family history of bipolar disorder or acute psychosis suggests
a need for increased attention to possible signs of bipolar illness
in the patient (e.g., with antidepressant treatment) [I].
A family history of recurrent major depressive disorder increases
the likelihood of recurrent episodes in the patient and supports
a need for maintenance treatment [II]. Family
history of a response to a particular antidepressant may sometimes
help in choosing a specific antidepressant for the patient [III].
Because problems within the family may become an ongoing stressor
that hampers the patient's response to treatment, and because
depression in a family is a major stress in itself, such factors
should be identified and strong consideration given to educating
the family about the nature of the illness, enlisting the family's
support, and providing family therapy, when indicated [II].
For patients who have experienced a recent bereavement, psychotherapy
or antidepressant treatment should be used when the reaction to
a loss is particularly prolonged or accompanied by significant psychopathology
and functional impairment [I]. Support groups
may be helpful for some bereaved individuals [III].
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c. Co-occurring general
medical conditions
In patients with major depressive disorder, it is important
to recognize and address the potential interplay between major depressive
disorder and any co-occurring general medical conditions [I].
Communication with other clinicians who are providing treatment
for general medical conditions is recommended [I].
The clinical assessment should include identifying any potential
interactions between medications used to treat depression and those
used to treat general medical conditions [I].
Assessment of pain is also important as it can contribute to and
co-occur with depression [I]. In addition, the psychiatrist
should consider the effects of prescribed psychotropic medications
on the patient's general medical conditions, as well as
the effects of interventions for such disorders on the patient's
psychiatric condition [I].
In patients with preexisting hypertension or cardiac conditions,
treatment with specific antidepressant agents may suggest a need
for monitoring of vital signs or cardiac rhythm (e.g., electrocardiogram [ECG] with
TCA treatment; heart rate and blood pressure assessment with SNRIs and TCAs) [I].
When using antidepressant medications with anticholinergic side
effects, it is important to consider the potential for increases
in heart rate in individuals with cardiac disease, worsening cognition
in individuals with dementia, development of bladder outlet obstruction
in men with prostatic hypertrophy, and precipitation or worsening of
narrow angle glaucoma [I]. Some antidepressant
drugs (e.g., bupropion, clomipramine, maprotiline) reduce the seizure
threshold and should be used with caution in individuals with preexisting
seizure disorders [II]. In individuals with Parkinson's
disease, the choice of an antidepressant should consider that serotonergic
agents may worsen symptoms of the disease [II],
that bupropion has potential dopamine agonist effects (benefitting symptoms
of Parkinson's disease but potentially worsening psychosis) [II],
and that selegiline has antiparkinsonian and antidepressant effects
but may interact with L-dopa and
with other antidepressant agents [I]. In treating
the depressive syndrome that commonly occurs following a stroke,
consideration should be given to the potential for interactions
between antidepressants and anticoagulating (including antiplatelet)
medications [I]. Given the health risks associated with
obesity and the tendency of some antidepressant medications to contribute
to weight gain, longitudinal monitoring of weight (either by direct
measurement or patient report) is recommended [I],
as well as calculation of body mass index (BMI) [II].
If significant increases are noted in the patient's weight
or BMI, the clinician and patient should discuss potential approaches
to weight control such as diet, exercise, change in medication,
nutrition consultation, or collaboration with the patient's
primary care physician [I]. In patients who have undergone
bariatric surgery to treat obesity, adjustment of medication formulations
or doses may be required because of altered medication absorption [I].
For diabetic patients, it is useful to collaborate with the patient's
primary care physician in monitoring diabetic control when initiating
antidepressant therapy or making significant dosing adjustments [II].
Clinicians should be alert to the possibility of sleep apnea in
patients with depression, particularly those who present with daytime
sleepiness, fatigue, or treatment-resistant symptoms [II].
In patients with known sleep apnea, treatment choice should consider
the sedative side effects of medication, with minimally sedating
options chosen whenever possible [I]. Given the
significant numbers of individuals with unrecognized human immunodeficiency
virus (HIV) infection and the availability of effective treatment,
consideration should be given to HIV risk assessment and screening [I].
For patients with HIV infection who are receiving antiretroviral
therapy, the potential for drug-drug interactions needs to be assessed
before initiating any psychotropic medications [I].
Patients who are being treated with antiretroviral medications should
be cautioned about drug-drug interactions with St. John's
wort that can reduce the effectiveness of HIV treatments [I].
In patients with hepatitis C infection, interferon can exacerbate depressive
symptoms, making it important to monitor patients carefully for
worsening depressive symptoms during the course of interferon treatment [I].
Because tamoxifen requires active 2D6 enzyme function to be clinically
efficacious, patients who receive tamoxifen for breast cancer or other
indications should generally be treated with an antidepressant (e.g.,
citalopram, escitalopram, venlafaxine, desvenlafaxine) that has
minimal effect on metabolism through the cytochrome P450 2D6 isoenzyme [I].
When depression occurs in the context of chronic pain, SNRIs and
TCAs may be preferable to other antidepressive agents [II].
When ECT is used to treat major depressive disorder in an individual
with a co-occurring general medical condition, the evaluation should
identify conditions that could require modifications in ECT technique
(e.g., cardiac conditions, hypertension, central nervous system
lesions) [I]; these should be addressed insofar
as possible and discussed with the patient as part of the informed
consent process [I].
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II. Formulation and
Implementation of a Treatment Plan
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A. Psychiatric Management
For all patients with major depressive disorder, psychiatric management
includes a broad array of possible interventions and activities.
Essential components include educating the patient and when appropriate
the family about depression, discussing treatment options and interventions,
and enhancing adherence to treatment. Developing a successful plan
of treatment for individuals with major depressive disorder is also
promoted by an initial, thorough assessment of the patient. In addition,
the psychiatrist must determine the treatment setting that will
be most likely to enhance the patient's safety as well
as promote improvement in the patient's condition. These
elements of psychiatric management are described in more detail
below.
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1. Establish and
maintain a therapeutic alliance
A psychiatric assessment begins with establishing therapeutic
rapport and developing an alliance with the patient, regardless
of the treatment modalities ultimately selected. The alliance itself
may be the primary active therapeutic agent even for patients who
receive monotherapy with medication (4). To establish
and maintain a therapeutic alliance, it is important for the psychiatrist
to be sensitive to the patient's concerns. By virtue of
their depressed state, patients often view themselves in a negative
light. They may feel unworthy of help, embarrassed or ashamed of
having an illness, guilty about placing burdens on family members
or the clinician, and distant or alienated from others. Individuals
may also have a negative view of prior treatment experiences or
have misconceptions about psychiatric treatment, which can color the
therapeutic relationship. Such issues require open discussion to
educate the patient about the goals and framework of treatment and
to provide an empathic and trusting environment in which the patient
feels comfortable expressing his or her self-doubts, fears, and
other concerns. Cultural and religious factors may influence the
patient's view of the depressive illness, his or her receptiveness
to psychiatric treatment, and his or her preference of treatment
modalities (5–7). Establishing a therapeutic
alliance with a clinician of a different background may present
additional challenges for some patients. Management of the therapeutic
alliance should also include awareness of transference and countertransference issues, even
if these are not directly addressed in treatment.
Because patients frequently have strong preferences about
treatment options, the psychiatrist should identify the patient's
wishes for treatment and collaborate with the patient in choosing
among effective treatments. In addition, treatment adherence can
be enhanced by the delivery of patient-centered care and by a strong
treatment alliance with the psychiatrist. Severe or persistent problems
of poor alliance or nonadherence to treatment may be caused by the
depressive symptoms themselves. They may also represent psychological
conflicts or a psychopathological condition for which psychotherapy
should be considered.
If possible and appropriate, the family should be included in
discussions about the patient's illness and plans for treatment.
When family members are involved, they can also be encouraged to
play a helpful role in improving the patient's adherence
to treatment and supporting the therapeutic alliance.
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2. Complete the psychiatric
assessment
Patients with symptoms of depression should receive a thorough
biopsychosocial assessment, both to determine whether a diagnosis
of major depressive disorder is warranted and to identify the presence
of other psychiatric or general medical conditions. The general
principles and components of a complete psychiatric evaluation have
been outlined in APA's Practice Guideline
for Psychiatric Evaluation of Adults, Second Edition (8).
The evaluation includes a history of the present illness and current
symptoms, including vegetative symptoms and symptoms of mania or
psychosis, as well as a psychiatric history that particularly notes
current treatments, responses to previous treatments, past hospitalizations
or suicide attempts, and the presence of co-occurring psychiatric disorders.
Assessing the severity of the specific symptoms of depression may
be aided by the use of standardized clinician- or patient-administered
rating scales such as those described in Section II.A.8.
Many individuals with depression attempt to alleviate symptoms
through the use of alternative or complementary treatments, over-the-counter
or prescription medications or dietary regimens, or through use
of caffeine, tobacco, alcohol, or other substances, which may precipitate
or exacerbate depressive symptoms. Consequently, each of these factors should
be carefully assessed. The personal history will include an assessment
of psychological development; a sexual history, including history
of sexual abuse or assault; identification of early life trauma,
including physical, sexual, or emotional abuse or neglect; determination
of responses to life transitions, major life events, or significant
traumas; a social history; and an occupational history, including
history of military service. Co-occurring general medical conditions are
common and can influence the diagnosis of major depressive disorder
as well as choices of treatment. Thus, a general medical history
is essential, along with a review of the patient's current medications;
a review of systems, including assessment for pain; and any indicated
diagnostic tests or physical examinations. The latter may be done
by the psychiatrist or by another physician or medically trained
clinician. A mental status examination is crucial in identifying
signs of depression, associated psychosis, cognitive deficits, and
factors influencing suicide risk (e.g., suicidal ideas, anxiety),
as well as in identifying co-occurring psychiatric disorders. Because
major depressive disorder is associated with functional impairment,
the presence, type, and severity of the dysfunction should be evaluated.
Impairments can include deficits in interpersonal relationships
and family functioning, work performance, maintenance of health
and hygiene, and deficits in quality of life. Whenever feasible, assessment
should also include input from family members in order to determine
the impact of the patient's condition on his or her family.
Family members and significant others can also report key elements of
the patient's history or recent status that the patient
may minimize or be unable to recall or report accurately. In addition,
family functioning may affect the outcome of the patient's
depressive illness (9, 10).
A family history is also important to obtain and involves the
collection of the family pedigree including parents, grandparents,
and number and sex of siblings and children. For patients with children
at home, information on their symptom state may be useful because
of the high possibility of psychiatric problems in the offspring
of a depressed parent (11, 12). Such problems
may require intervention or may be an added stressor for the patient.
The family history includes history of depression or other mood disorders,
substance use disorders, psychosis, suicide, and unusual behaviors
in the patient's relatives along with any associated impairments. Because
family history is a potent and consistent risk factor for mental
disorders, formulating diagnosis and treatment decisions for the
patient can be aided by knowing the age of onset and severity of psychiatric
symptoms in the patient's family, as well as relatives' psychiatric
treatment history, especially the tolerability and effectiveness
of those treatments.
In establishing a diagnosis of major depressive disorder as part
of the initial assessment, other differential diagnostic possibilities
are important to consider. An initial consideration in the differential
diagnosis is mood disorder due to a general medical condition. Specific
medical conditions that are important to consider and that may be
associated with a major depressive episode include neurological
conditions (e.g., stroke, Parkinson's disease, dementia, multiple
sclerosis), thyroid disorders, metabolic conditions (e.g., hypercalcemia),
malignancy, and infectious diseases (13–15).
Depressive symptoms that would otherwise be diagnosable as major depressive
disorder are diagnosed instead as a mood disorder due to a general
medical condition if the mood disturbance is judged to be the direct physiological
consequence of a specific general medical condition. Similarly,
medications used to treat general medical conditions may induce
depressive syndromes. Such medications include transplant anti-rejection agents,
chemotherapy agents, interferon, steroids, some antibiotics, and
others. Depression caused by medications is classified in the DSM-IV-TR
as other (or unknown) substance-induced mood disorder (DSM-IV-TR
code 292.84) (16).
Psychosocial stressors and other antecedent events, and their
possible contribution to the generation of depressive symptoms,
should be explored in the course of a psychiatric assessment. Depressive
symptoms are a common response to psychosocial stressors, particularly
bereavement. Symptoms characteristic of a major depressive episode
may arise after a significant loss; however, the diagnosis of major
depressive disorder is generally not given unless depressive symptoms are
still present 2 months after the loss, are particularly severe,
or are uncharacteristic of or unrelated to bereavement, such as
persistent suicidal ideation or morbid preoccupation with worthlessness
or guilt (16). Following a stressor, depressive symptoms
that do not reach sufficient number or severity to be classified
as a major depressive episode may be better described as an adjustment
disorder. Despite the possible presence of antecedent stressors,
psychiatrists should not dismiss potentially disabling depressive
symptoms as "normal," thereby depriving patients
of needed therapeutic attention.
A thorough assessment of depression also includes the evaluation
of psychotic symptoms. Major depressive disorder may be associated
with mood-congruent and mood-incongruent hallucinations and delusions.
Depressed patients may not initially present with psychotic symptoms,
and patients may wish to hide shaming or distressing thoughts. Therefore, psychiatrists
should carefully query patients about such symptoms in order to
provide appropriate treatments for them (see Section III.A.2.a).
Identifying the presence of atypical, melancholic, or catatonic
features of depression is also important, as such features may influence
the choice of treatments (see Sections III.A.2.b, III.A.2.c, and
III.A.2.d). Considering that major depressive episodes are common
in the course of bipolar I disorder and that recurrent major depressive
episodes are characteristic of bipolar II disorder (17),
it is important to consider bipolar disorders as part of the differential diagnosis
of major depressive disorder. This distinction is especially important
because the treatments for bipolar disorders often differ from those
for major depressive disorder.
All patients who present for treatment for a major depressive
episode should be screened for a past history of manic or hypomanic
episodes and for past adverse reactions to antidepressants that
might be consistent with a "switch" into hypomania
or mania. Screening instruments for manic and hypomanic episodes
include the Mood Disorders Questionnaire (18) and the
Screening Assessment of Depression–Polarity, which includes
three easily administered dichotomous questions (19).
However, since patients are often unaware of prior hypomanic or
manic episodes, even when questioned carefully, collateral sources
of information, such as family members living with the patient,
may be crucial in uncovering such episodes. Clinical assessment
should also include whether or not the patient is experiencing a
mixed episode, which is characterized by symptoms of both a major
depressive episode and a manic episode that occur nearly every day for
at least 1 week.
It is also important to consider the frequency and chronicity
of prior episodes of major depressive disorder. Chronic forms of
depressionsuch as dysthymic disorder, "double depression" (dysthymic
disorder and major depressive disorder), and major depressive disorder
with the "chronic" specifierare all
depressions with a duration of at least 2 years. In clinical studies,
chronic depression has a lower response rate than nonchronic depression,
but because the placebo-response rate is also lower, the relative
clinical benefit is comparable. The onset of benefit in chronic
depression appears more gradual than in nonchronic depression. However,
despite a smaller response rate and slower response, it is important
to recognize that chronic depression is not treatment refractory
(20). Unfortunately, however, in many patients, chronic
depression remains undiagnosed or, if diagnosed, undertreated (21).
The presence of a family history of a mood disorder should
also be determined. Family histories of major depressive disorder
and bipolar disorder are common in those with major depressive disorder,
but a family history of bipolar disorder may indicate increased
risk of bipolar disorder in the patient. A family history of suicide
is relevant in determining a patient's suicide risk (22)
and may also signal the presence of an unrecognized mood disorder
in a relative.
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3. Evaluate the safety
of the patient
Addressing safety concerns may take precedence over establishing
a full differential diagnosis or completing the psychiatric assessment.
Because of the increased rates of suicide in depressed patients
(22–24), a thorough and ongoing evaluation
of the patient's suicide risk is essential. Some components of
an evaluation for suicidal risk are summarized in Table 1. The psychiatrist
should evaluate the presence of suicidal ideation and behaviors,
the extent to which the patient has made plans for or begun to prepare
for suicide, the availability and lethality of the means for suicide,
and the degree to which the patient intends to act on suicidal plans.
A complete assessment also includes clinical factors that may increase
the likelihood of a patient's acting on suicidal ideation,
including a history of prior suicide attempts and the presence of
psychotic symptoms, severe anxiety, panic attacks, impulsivity,
and substance use. Patients should also be asked about a family
history of suicide and recent exposure to suicide or suicide attempts
by others. A suicide risk assessment should be individualized to the
particular circumstances of the patient by including an evaluation
of the patient's strengths, motivation to seek help, social
support systems, and physical health.
Despite the best efforts of the psychiatrist, some patients may
engage in self-harm (22). Even with careful assessments of
suicide risk, the ability to predict suicidal behavior is poor, with
many false positives (i.e., patients who appear more likely to make
attempts or die by suicide but who do not) as well as false negatives
(i.e., patients who appear less likely to make attempts or die by
suicide but who do). The assessment of suicide risk is complicated
by the fact that suicidal individuals often conceal their thoughts
and plans or act impulsively on short-lived suicidal thoughts, making
their response to direct questions an unreliable predictor of dangerousness
to self. For this reason, in addition to using direct questioning,
the psychiatrist should also obtain information through observation
and collateral history whenever possible (22, 25).
The risk of suicide should also be monitored as treatment proceeds,
since variations in depressive symptoms may be associated with fluctuations
in suicide risk. In youth and young adults, increases in suicidal
thoughts and attempts have been reported early in the course of
treatment with antidepressants, although no increases in mortality
rates were seen in clinical trials (26). Family members can
provide information that increases the likelihood of early detection
of harmful behaviors. It is also useful to convey the expectation that
family members will call the psychiatrist if concerns for safety
emerge (27). For information about how suicidal ideation or
behaviors affect the treatment plan, see Section III.A.1.a.
Although the greatest risk surrounding depression involves
the patient's health, a rare but also potentially disastrous
outcome of depression is violence toward others, including homicide
(28, 29). Psychosis, substance abuse,
impulsivity, and a history of aggression increase this risk (30–32).
Psychiatrists accordingly should assess not only suicidal risk but
also history of violence, homicidal ideation, and plans of violence
toward others. Additional assessment may be necessary under specific
circumstances. For example, it is important to assess the impact
of parental depression (including peripartum depression) on children
in the home, with specific attention given to the parent's
vulnerability to neglect or harm the children (33).
Whenever suicidal or violent ideas are expressed or suspected, careful
documentation of the decision-making process is essential. In addition,
patients who exhibit suicidal or violent ideas or intent require
close monitoring.
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4. Establish the
appropriate setting for treatment
Treatment settings for patients with major depressive disorder
include a continuum of possible levels of care, from involuntary
hospitalizations to partial hospital programs, skilled nursing homes,
and in-home care. In general, patients should be treated in the
least restrictive setting that is most likely to prove safe and
effective. The psychiatrist should choose an appropriate site of
treatment after evaluating the patient's clinical condition,
including symptom severity, co-occurring conditions, level of functioning,
and available support system. The estimated degree of risk to self
and to others is another significant determinant of treatment setting.
Decisions about treatment setting should also include consideration
of the patient's ability to adequately care for him- or herself,
provide reliable feedback to the psychiatrist, and cooperate with
treatment of the major depressive disorder.
Patients with suicidal or homicidal ideation, intention, or plans
require close monitoring. For those at significant risk, measures
such as hospitalization should be considered; hospitalization is
usually indicated for patients who are considered to pose a serious
threat of harm to themselves or others. Patients who refuse can
be hospitalized involuntarily if their condition meets the criteria
of the local jurisdiction for involuntary admission. Severely ill
patients who lack or reject adequate social support outside of a
hospital setting should be considered for admission to a hospital
or intensive day program, if available. In addition, patients who
also have complicating psychiatric or general medical conditions
or who have not responded adequately to outpatient treatment may need
to be hospitalized.
The optimal treatment setting and the patient's likelihood of
benefit from a different level of care should be reevaluated on
an ongoing basis throughout the course of treatment. Unfortunately,
the spectrum of treatment settings available to patients is often
limited by lack of availability of options in the geographic setting,
lack of ability to pay for care, and/or limitations imposed
by third party payers.
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5. Evaluate functional
impairment and quality of life
The assessment of a patient with major depressive disorder
includes a determination of the severity and chronicity of symptoms.
Even mild depression can impair function and threaten life and the
quality of life. In the extreme, depressed people may be totally
unable to function socially or occupationally or even to feed and
clothe themselves and maintain minimal personal hygiene. Severely
depressed patients may be immobilized to the point of being bedridden,
with associated medical complications.
The psychiatrist should address impairments in functioning and
help the patient to set specific goals appropriate to his or her
functional impairments and symptom severity. This will likely involve
helping the patient to establish intermediate, pragmatic steps in
the course of recovery. For example, the psychiatrist may help patients
who are having difficulty meeting commitments to develop a reasonable
plan to fulfill their obligations (e.g., work, family obligations),
potentially by making alternative arrangements. The psychiatrist
may advise other patients not to make major life changes while in
the midst of a major depressive episode. Impairments in the patient's
overall quality of life should also be assessed, which can be done
by asking patients what bothers them the most about their depression
and determining how their current activities and enjoyment of life
have been altered by their depressive symptoms. The overall goals
of treatment of major depressive disorder should focus on alleviating
functional impairments and improving quality of life in addition
to achieving symptom resolution and episode remission.
+
6. Coordinate the
patient's care with other clinicians
The psychiatrist should assure that a comprehensive assessment
of general medical conditions is performed in order to identify
factors that may precipitate or exacerbate depressive symptoms.
He or she may initiate the medical evaluations or coordinate care
with other appropriate clinicians. In some situations, review of
medical records provided by the patient will suffice. In other situations,
particularly when medical treatment is indicated, the psychiatrist
should, with the patient's permission, arrange for collaborative
care with other clinicians. Such collaboration may incorporate discussion
of prescribed medication, including dose changes and possible drug
interactions as well as necessary diagnostic procedures and medical monitoring,
which may include laboratory measures and ECG (34).
In treating the patient's depressive illness, a multifaceted approach
is typically required that may include provision of depression-focused
psychotherapy, pharmacotherapy, ECT, or other therapeutic approaches.
Under some circumstances, all aspects of treatment will be administered
by one psychiatrist, and this model of care may improve integration
of treatment components (35) or reduce overall treatment
cost (36). In other situations, treatment may require
the coordinated effort of several clinicians. This decision is frequently influenced
by the clinicians' expertise in providing the indicated
therapeutic modality, economic factors, availability of treatment,
and by the patient's preferences. When this treatment model
is used, one team member must assume the primary overall responsibility
for the patient's care. This individual serves as the coordinator
of the treatment plan, advocates for the appropriate level of care,
oversees the family involvement, makes decisions regarding which
potential treatment modalities are useful and which should be discontinued,
helps assess the effects of medications, and monitors the patient's
safety. Because of the diversity and depth of medical knowledge
and expertise required for this oversight function, a psychiatrist
is generally optimal for this role, although this staffing pattern
may not be possible in some health care settings. If the treatment
is split, the psychiatrist who is providing the psychiatric management
and the medication treatment should meet with the patient frequently enough
to monitor his or her care. Ongoing coordination of the overall
treatment plan is essential and is enhanced by clear role definitions,
plans for the management of crises or relapses, and regular communication
among the clinicians who are involved in the treatment.
Psychiatrists may at times serve as consultants to ongoing treatment
of depression by other prescribers. Health care professionals other
than psychiatrists may prescribe antidepressant medication for their
patients for a variety of reasons, including convenience, financial
reasons, stigma, and access to care issues (37). Primary
care doctors, obstetricians, and physicians of other disciplines
may screen for depression and initiate treatment for patients. In
fact, at least one-fourth of patients presenting to primary care
settings may have major depressive disorder, and 70%–80% of
antidepressants are prescribed by a primary care physician or medical
subspecialist (38, 39). Regardless of
whether the psychiatrist is acting as a consultant or transferring
ongoing care to another clinician (e.g., with transition from an
inpatient to outpatient setting), communication and coordination
of treatment are essential. Optimal communication with other health
care professionals can improve overall treatment by assuring that
medical conditions and psychosocial issues are appropriately addressed. Good
communication also decreases the risk that patients will receive
inconsistent information about treatment options and risks and benefits.
Furthermore, communication among clinicians improves vigilance against
relapse, side effects, and risk to self or others.
+
7. Monitor the patient's
psychiatric status
As treatment progresses, different features and symptoms of the
patient's illness may emerge or subside. The psychiatrist should
carefully and systematically monitor changes in the patient's
psychiatric status, including major depressive disorder symptoms,
as well as symptoms of other potential co-occurring conditions (Table
2). Monitoring the patient's status for the emergence of
or changes in destructive impulses toward self or others is especially
crucial; additional measures such as hospitalization or more intensive
treatment should be considered for patients found to be at higher
risk. In addition, the patient should be monitored for treatment-emergent
side effects, some of which may be difficult to distinguish from
symptoms of the underlying depressive disorder or co-occurring medical conditions.
Significant changes in a patient's psychiatric status or
the emergence of new symptoms may warrant a diagnostic reevaluation
of the patient. For example, patients who note worsening irritability,
increased difficulty sleeping, racing thoughts, growing impulsivity,
euphoria, or rapid shifts in mood should be monitored more closely
and may warrant re-evaluation and consideration of a possible bipolar
disorder diagnosis. Often family members or caregivers notice changes
in the status of the patient first and are therefore able to provide valuable
input to the psychiatrist.
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8. Integrate measurements
into psychiatric management
The integration of measurement tools into psychiatric management,
which has been referred to as measurement-based care, may enhance
the quality of care and improve clinical outcomes (40).
Clinician-rated and/or self-rated scales can help determine
the trajectory of disease course and effects of treatment. Many
such scales are available in several versions that vary by number
of items. Self-rated scales are convenient to use but require review,
interpretation, and discussion with the patient. In research studies,
commonly used tools include the Inventory of Depressive Symptoms
(IDS), which is available in clinician-rated and self-rated versions (http://www.ids-qids.org/),
the clinician-rated Hamilton Rating Scale for Depression (HAM-D) (http://healthnet.umassmed.edu/mhealth/HAMD.pdf)
(41, 42), the clinician-rated Montgomery
Asberg Depression Rating Scale (MADRS) (http://www.cnsforum.com/streamfile.aspx?filename=MADRS.pdfandpath=pdf)
(43), and the self-rated 9-item Patient Health Questionnaire
(PHQ-9) (http://www.depression-primarycare.org/clinicians/toolkits/materials/forms/phq9/) (44, 45).
The Beck Depression Inventory (BDI, BDI-II) is another commonly
used, copyrighted, 21-question multiple-choice self-rated instrument
(46).
Systematic measurement of side effects can also assist in
the provision of treatment. Several self-report rating scales have been
developed for assessing side effects of antidepressant treatment
and are available in English and Spanish versions (http://www.edc.pitt.edu/stard/public/assessment_forms.html).
The Frequency, Intensity, and Burden of Side Effects Rating Scale
(FIBSER), which has also been referred to as the Frequency and Intensity
of Side Effects Rating/Global Rating of Side Effect Burden,
uses three global Likert scale ratings to assess side effects experienced over
the preceding week (47, 48). The Patient
Rated Inventory of Side Effects (PRISE) is a 9-item scale that asks patients
about the presence of side effects in eight organ system domains,
as well as about other side effects (47, 48).
A clinician-administered scale, the Toronto Side Effects Scale,
that focuses on antidepressant medication side effects is also available (http://ww1.cpa-apc.org:8080/publications/archives/cjp/2002/march/orAntidepressantsAppendix.asp)
(49). The Udvalg for Kliniske Undersøgelser (UKU)
side effect rating scale (50) (available at http://www.cnsforum.com/streamfile.aspx?filename=UKU.pdf&path=pdf) is often used in research studies and may
offer clinicians additional questions that could be asked about
side effects, but it is likely to be too detailed for routine clinical
use.
Although the use of rating scales is not yet common practice
in clinical settings, in part due to pragmatic concerns (51),
the use of such scales can be valuable in monitoring symptoms and
treatment progress. In addition, electronic monitoring is becoming
more feasible, as electronic health records are more commonly utilized
and patients and psychiatrists have increased access to technological
tools that can help monitor and record symptoms. Baseline data and
information about treatment-emergent changes can be collected systematically
from the patient and electronically transmitted via telephone or
the Internet. In addition to providing secure electronic capture
of patient data, computerized decision support systems can be useful
in implementing evidence-based treatment for major depressive disorder
(52).
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9. Enhance treatment
adherence
For treatment to be successful, it is essential to support
the patient's adherence to all details of the regimen by
providing education about the illness and its treatment, maintaining
a strong therapeutic alliance, mobilizing family and other supports
(including eliciting questions and clarifying common misconceptions),
evaluating factors affecting adherence, and addressing barriers
to adherence as they arise. Major depressive disorder is often a
chronic or recurrent condition that requires patients to participate
actively in and adhere to treatment plans for long periods, despite
the fact that side effects or requirements of treatments may be
burdensome. Patients may have strong preferences for modality of
treatment or medication choice, particularly if they or a family
member have had past experience with the treatment or medication.
When feasible, factoring in these preferences may improve adherence
to treatment. During the acute phase, patients with major depressive
disorder may be poorly motivated, unduly pessimistic about their
chances of recovery with treatment, suffering from deficits in memory,
or poorly caring for themselves. During the maintenance phase, euthymic
patients may undervalue the benefits of and focus on the burdens
of treatment. The psychiatrist should recognize these possibilities,
emphasize the importance of adherence for successful treatment and
prophylaxis, and encourage the patient to articulate any concerns regarding
adherence (e.g., side effects, costs of treatment, scheduling conflicts,
lack of transportation or child care). Patient and family attitudes
about depression and its treatment can also influence adherence.
Family members can play an important role in promoting optimism
about treatment, assisting patients with adherence and providing
the psychiatrist with input on side effects or other treatment-related
concerns that may influence adherence.
Some aspects of adherence will vary with the type of treatment
being used. For example, patients in psychotherapy may experience
increased anxiety as they confront fearful or difficult topics.
This anxiety, in turn, may decrease adherence to psychotherapy,
and patients may begin to arrive late to or miss therapy sessions.
In patients who are beginning treatment with a medication, common
side effects of medication options should be discussed. Patients
should be involved in treatment decisions and encouraged to convey
input on side effects that they consider reasonable or unbearable.
Side effects such as weight gain, cognitive dulling, sexual side
effects, sedation or fatigue, and agitation may represent different
burdens to different individuals. Emphasizing the following specific
topics improves adherence: 1) explaining when and how often to take
the medicine; 2) suggesting reminder systems, such as pill boxes,
alarms, etc.; 3) discussing the need to take medication for at least
2–4 weeks before beneficial effects may be noticed; 4)
emphasizing the need to take medication even after feeling better;
5) reviewing the need to consult with the psychiatrist before discontinuing medication;
6) giving the patient an opportunity to express his or her understanding
of the medication, hearing his or her concerns, and correcting any
misconceptions, and 7) explaining what to do if problems or questions
arise (53). Behavioral tailoring, which involves developing
an individualized approach to incorporating medication into the
daily routine and can also include simplifying the medication regimen,
has demonstrated efficacy for individuals with schizophrenia and may
also be applicable to individuals with other psychiatric illnesses
(54). Adherence may also be improved by minimizing
the cost and complexity of medication regimens. Most antidepressant
medications are available in generic forms, which are generally
less costly. For individuals who cannot afford needed medications,
some pharmaceutical companies offer patient assistance programs.
Information on such programs is available from pharmaceutical company
Web sites, from the Web site of the Partnership for Prescription
Assistance (http://www.helpingpatients.org), and
from Rx Assist (http://www.rxassist.org).
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10. Provide education
to the patient and the family
Education concerning major depressive disorder and its treatments
should be provided to all patients. Education is an essential element
of obtaining informed consent to treatment. Whenever possible, education
should also be provided to involved family members and significant
others, although generally the patient's consent is required
before such information can be shared. Specific topics to discuss
may include that major depressive disorder is a medical illness
and that effective treatments are both necessary and available. This
information may be especially important for patients who attribute
their illness to a moral defect, or for family members who are convinced
that there is nothing wrong with the patient. Education regarding
available treatment options will help patients make informed decisions,
anticipate side effects, and adhere to treatments. Patients with
depression can become easily discouraged in treatment, especially
if there is less than a full initial response. The psychiatrist should
encourage and educate patients to distinguish between the hopelessness
that is a symptom of depression and the relatively hopeful actual
prognosis. In addition, for patients treated with antidepressant
medication or ECT, psychiatrists may choose to discuss a predictable
progression of treatment effects: first, side effects may emerge,
then neurovegetative symptoms remit, and finally mood improves. Often
significant others notice symptomatic improvement before the patient
does.
Given the chronic, episodic nature of major depressive disorder,
exacerbations are common. Patients, as well as their families, if
appropriate, should be instructed about the significant risk of
relapse. They should be educated to identify early signs and symptoms
of new episodes and the stressors that may precede them. Patients
should also be instructed to seek adequate treatment as early in
the course of the new episode as possible to decrease the likelihood
of a full-blown exacerbation or complications.
Patient and family education also includes general promotion
of healthy behaviors such as good sleep hygiene and decreased use
of caffeine, tobacco, alcohol, and other potentially deleterious
substances. For most individuals, exercise carries benefits for
overall health. Data generally support at least a modest improvement
in mood symptoms for patients with major depressive disorder who
engage in aerobic exercise (55–61) or resistance
training (62, 63). Regular exercise may
also reduce the prevalence of depressive symptoms in the general
population, with specific benefit found in older adults (64, 65)
and individuals with co-occurring medical problems (57, 66).
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1. Choice of initial
treatment modality
The acute phase of treatment
lasts a minimum of 6–12 weeks. During this phase, the aims
of treatment are to induce remission of symptoms and achieve a full
return to the patient's baseline level of functioning.
In addition to general psychiatric management (described in Section
II.A), treatment may consist of pharmacotherapy or other somatic
therapies (e.g., ECT, light therapy), depression-focused psychotherapy,
or the combination of somatic and psychosocial therapies. Selection
of an initial treatment modality is influenced by several factors,
including the symptom profile, the presence of co-occurring disorders
or psychosocial stressors, the patient's prior treatment
experience, and the patient's preference.
Psychiatrists should present
patients with information concerning the evidence for a broad range
of treatment options, including somatic therapies and psychosocial
interventions. Antidepressant medications can be used as an initial treatment
modality by patients with mild, moderate, or severe major depressive
disorder. Clinical features that may suggest that medications are
the preferred treatment modality include a history of prior positive
response to antidepressant medications, the presence of moderate
to severe symptoms, significant sleep or appetite disturbances,
agitation, patient preference, and anticipation of the need for
maintenance therapy. Patients with major depressive disorder with
psychotic features require either the combined use of antidepressant
and antipsychotic medications or ECT.
Psychotherapy may also be considered as monotherapy for patients
with mild to moderate major depressive disorder. The availability
of clinicians with appropriate training and expertise in specific
psychotherapeutic approaches can be a factor in choosing a psychotherapy
(67). Other factors that can influence this choice
may be the psychosocial context, patient preference, prior positive
response to psychotherapy, the presence of significant psychosocial
stressors or interpersonal difficulties, co-occurring Axis II disorders,
or the stage, chronicity, and severity of the major depressive episode.
Specifically, many severely depressed patients will require both
a depression-focused psychotherapy and a somatic treatment such
as pharmacotherapy. Pregnancy, lactation, or the wish to become
pregnant may tilt a decision toward psychotherapy as an initial
treatment (see Section III.B.6). Given the lower occurrence of side
effects and suggestion of enduring benefits associated with depression-focused
psychotherapies (68), such treatments might be preferable
alternatives to pharmacotherapy for some patients with mild to moderate
depression.
Combining a depression-focused psychotherapy and pharmacotherapy
may be a useful initial treatment choice for patients with moderate
to severe major depressive disorder. Other indications for combined
treatment include chronic forms of depression, psychosocial issues,
intrapsychic conflict, interpersonal problems, or a co-occurring
Axis II disorder. In addition, patients who have had a history of
only partial response to adequate trials of single treatment modalities
may benefit from combined treatment. Poor adherence with pharmacotherapy
may also warrant combined treatment with medications and psychotherapy
focused on treatment adherence.
Electroconvulsive therapy should be considered as a potential
treatment option for all patients with major depressive disorder
who have psychotic features or catatonia and for those with an urgent
need for response, such as patients who are suicidal or who are
nutritionally compromised as a result of refusing food. Electroconvulsive
therapy may also be the treatment modality of choice for patients
with major depressive disorder who have a high degree of symptom
severity. Other considerations include the presence of co-occurring general
medical conditions that preclude the use of antidepressant medications,
a prior history of positive response to ECT, and patient preference.
Evidence for TMS is currently insufficient to support its use in
the initial treatment of major depressive disorder.
If a patient with mild depression wishes to try exercise alone for
several weeks as a first intervention, there is little to argue against
it (Section II.A.10), provided the patient is sufficiently monitored
for an abrupt worsening of mood or adverse physical effects (e.g.,
ischemia or musculoskeletal symptoms). The dose of exercise and
adherence to an exercise regimen may be particularly important to
monitor in the assessment of whether an exercise intervention is
useful for major depressive disorder (69, 70).
If mood fails to improve after a few weeks with exercise alone,
the psychiatrist should recommend medication or psychotherapy. For
patients with depression of any severity and no medical contraindication
to exercise, physical activity is a reasonable addition to a treatment
plan for major depressive disorder. The optimal regimen is one the
patient prefers and will adhere to.
Figure 1 summarizes treatment modalities that may be appropriate
during the acute phase of treatment depending on the severity of
the patient's symptoms and other associated features of
the depressive episode. It is important to note that other factors
may be relevant to treatment decisions for individual patients and
that determinations of episode severity are imprecise, although
rating scales may be helpful in assessing the magnitude of depressive
symptoms and their effects on functional status and quality of life
(see Sections II.A.7 and II.A.8).
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Antidepressant medications have been grouped as follows: 1)
TCAs, which for the purposes of this guideline also include the
tetracyclic antidepressant medication maprotiline; 2) SSRIs, which
include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram,
and escitalopram; 3) SNRIs, which include venlafaxine, desvenlafaxine,
and duloxetine; 4) other antidepressant medications, including bupropion,
nefazodone, trazodone, and mirtazapine; and 5) MAOIs, which include
phenelzine, tranylcypromine, isocarboxazid, and the transdermal
formulation of selegiline. Although some studies have suggested
superiority of one mechanism of action over another, there are no
replicable or robust findings to establish a clinically meaningful
difference. For most patients, the effectiveness of antidepressant
medications is generally comparable between classes and within classes
of medications. Response rates in clinical trials typically range
from 50% to 75% of patients, with some evidence
suggesting greater efficacy relative to placebo in individuals with
severe depressive symptoms as compared with those with mild to moderate symptoms
(71–73). Although remission rates are less
robust and selective publication of positive studies could affect
the apparent effectiveness of treatment (74, 75),
these factors do not appear specific to particular medications or
medication classes.
Nevertheless, antidepressant medications do differ in their
potential to cause particular side effects such as adverse sexual
effects, sedation, or weight gain. Therefore, the initial selection
of an antidepressant medication will largely be based on the tolerability,
safety, and cost of the medication, as well as patient preference
and history of prior medication treatment (Table 3). Other factors
include the medication half-life and potential for drug interactions
related to properties such as plasma protein binding or metabolism through
the cytochrome P450 system (Tables 4 and 5). On the basis of these
considerations, the following medications are optimal for most patients:
SSRIs, SNRIs, mirtazapine, and bupropion. Table 6 provides the starting
and usual doses of medications that have been shown to be effective for
treating major depressive disorder.
In choosing an antidepressant medication, many psychiatrists
also consider the family history of response to particular medications;
however, the impact of this factor on the likelihood of the patient's
response to these medications is unclear. Nevertheless, the medication
experiences of others close to the patient do influence the patient's
belief about particular medications and pharmacotherapy in general.
The presence of co-occurring psychiatric or general medical
conditions can be a significant factor influencing the choice of
an antidepressant medication. For example, TCAs are generally not
optimal in patients with cardiovascular conditions, cardiac conduction
defects, closed angle glaucoma, urinary retention, significant prostatic
hypertrophy, or eating disorders with significant malnutrition or
purging. In older adults and others with malnutrition, autonomic
disorders (e.g., diabetic neuropathy, Parkinson's disease),
or low blood pressure, TCAs may exacerbate hypotension and orthostasis, resulting
in syncope or falls. Selective serotonin reuptake inhibitors and SNRIs
may be inappropriate for patients who are experiencing sexual dysfunction.
Patients who are receiving tamoxifen for breast cancer or other
indications should generally be treated with an antidepressant (e.g.,
citalopram, escitalopram, venlafaxine, desvenlafaxine) that has
minimal effect on metabolism through the cytochrome P450 2D6 isoenzyme,
because reduced metabolism of tamoxifen through CYP 2D6 is likely
to be associated with lower levels of tamoxifen's active
metabolite (76–79) with the possibility of poorer patient
outcomes (80, 81).
Because of the need for dietary restrictions and the potential
for serious side effects and drug interactions, use of MAOIs is
generally limited to patients who do not respond to other treatments.
MAOIs may be particularly effective for patients with major depressive
disorder with atypical features, although many psychiatrists prefer
to prescribe SSRIs for such patients because of SSRIs' greater safety
and tolerability and more favorable adverse effect profile.
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a. Efficacy of antidepressant
medications
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1. Selective serotonin reuptake inhibitors
Selective serotonin reuptake inhibitors currently available
include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram,
and escitalopram. A large body of literature supports the superiority
of SSRIs compared with placebo in the treatment of major depressive
disorder. In more than 10 systematic reviews and meta-analyses,
the effectiveness of SSRIs has been compared with that of other antidepressant
medications, mainly TCAs. The SSRIs have demonstrated comparable
efficacy to the TCAs (84–88),
even when anxiety symptoms are considered (85, 87–90).
Although a few analyses suggest small advantages of SNRIs
over SSRIs in rates of remission (91), a preponderance
of the data finds no significant evidence of the superiority of any
other class or agents over SSRIs (84, 89, 90, 92–95).
One meta-analysis suggests a slight superiority of escitalopram compared
with other SSRIs and venlafaxine (93), and another
found significantly greater efficacy for escitalopram, sertraline,
venlafaxine, and mirtazapine as compared with duloxetine, fluoxetine,
fluvoxamine, and paroxetine (96), but other studies
show no differences in efficacy among individual SSRIs (84, 93–95, 97, 98).
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2. Serotonin norepinephrine reuptake inhibitors
The serotonin norepinephrine reuptake inhibitors currently available
are venlafaxine, desvenlafaxine (the principal metabolite of venlafaxine),
and duloxetine. An immediate-release form of venlafaxine is available,
but most clinicians prefer the extended-release formulation because
it is approved for once-daily dosing and may be less often associated
with reported withdrawal symptoms.
Each of these medications is efficacious (i.e., superior to placebo
in controlled studies and meta-analyses) (95, 99), and
venlafaxine (75–150 mg/day) and duloxetine (60 mg/day)
showed comparable efficacy in a pair of trials (100). For
venlafaxine and perhaps desvenlafaxine, clinically significant norepinephrine
reuptake inhibition may not be achieved for the average patient
at lower therapeutic doses, although desvenlafaxine has a much greater
bioavailability, resulting in a lower effective dose. In individual
studies, venlafaxine and duloxetine are generally as effective as
SSRIs (see the meta-analyses of Nemeroff et al. [101] and
Thase et al. [102] for tabulated
summaries of individual study results from the more than 40 relevant
randomized controlled trials). Results of comparative studies of
desvenlafaxine are not known at this time. Relative to SSRIs, some
analyses of pooled data sets have suggested a small advantage for
SNRIs (91), which might afford clinically modest benefits
for patients with more severe depression (102) or for
patients who have not responded to prior trials of SSRIs (103).
However, other meta-analyses have shown equivalent efficacy for
SSRIs and SNRIs (95), whereas some have shown superiority of
individual medications but no clearcut medication class effects
(96). Relative to TCAs, venlafaxine's efficacy
is comparable (91, 104, 105), whereas
the more recently introduced duloxetine and desvenlafaxine have
not been systematically compared with TCAs.
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3. Other antidepressant medications
A number of other antidepressant medications differ structurally or
in their pharmacological action from medications in the categories
just described and are included here.
Although bupropion is classified as a norepinephrine and dopamine
reuptake inhibitor, the latter effect is relatively weak, and its
mechanism of action remains unclear (106). There are
three formulations of bupropion: immediate release, sustained release,
and extended release. Bupropion is distinct from most antidepressants
in not having an indication for the treatment of any primary anxiety
disorder, and it may be less well tolerated than other antidepressants
among patients with significant anxiety. In addition, a meta-analysis
showed that SSRIs were modestly superior to bupropion for a subset
of patients with major depressive disorder and anxiety (107).
For individuals with low to moderate levels of anxiety, the same
meta-analysis showed that the efficacy of bupropion in treating
major depressive disorder was roughly comparable to that of the
SSRIs (107). Results of another meta-analysis suggested
that bupropion may be more likely to improve symptoms of fatigue
and sleepiness than at least some of the SSRIs (108).
Bupropion may be a good choice for patients who have a goal of quitting
smoking as it has U.S. Food and Drug Administration (FDA) approval for
this indication, reduces desire for nicotine, and doubles rates
of smoking cessation (109, 110). Patients
typically experience minimal weight gain or even weight loss on
bupropion (111), and for this reason it may be an appropriate
antidepressant for patients who are overweight or obese.
Mirtazapine is thought to work through noradrenergic and serotonergic
mechanisms, although this tetracyclic compound is not a reuptake
inhibitor (112). Mirtazapine has comparable efficacy
to SSRIs (113).
Trazodone is the oldest medication from this group that is still
in wide use. Although trazodone is an effective antidepressant,
relative to placebo (105, 114, 115),
in contemporary practice it is much more likely to be used in lower
doses as a sedative-hypnotic than as an antidepressant. Despite widespread
use of trazodone as a hypnotic, few data support its use for this
indication.
Nefazodone has an analogous structure to trazodone but somewhat
different pharmacological properties. In comparative trials versus
SSRIs, nefazodone showed comparable efficacy and overall tolerability
(116).
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4. Tricyclic antidepressants
Tricyclic antidepressants (amitriptyline, nortriptyline, protriptyline,
imipramine, desipramine, doxepin, and trimipramine) are effective
treatments for major depressive disorder and have comparable efficacy
to other classes of antidepressants, including SSRIs, SNRIs, and
MAOIs (85, 105). The efficacy of subclasses
of tricyclics (e.g., secondary amines or tertiary amines) appears
to be comparable. TCAs may be particularly effective in certain
populations, such as in hospitalized patients (117, 118).
Conventional wisdom is that this advantage is explained by the superiority
of TCAs (versus SSRIs) among the subset of patients with melancholia or
more severe depression, because such a specific advantage has not
been consistently documented in studies of less severely ill outpatients
(85, 105, 118).
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5. Monoamine oxidase inhibitors
MAOIs currently used as antidepressants include phenelzine,
tranylcypromine, isocarboxazid, moclobemide, and the transdermally
delivered formulation of selegiline.
MAOIs have comparable efficacy
to other antidepressants for outpatients with major depressive disorder
and may be appropriate for patients with major depressive disorder who
have not responded to safer and more easily used treatments (119, 120).
In fact, the role of MAOIs in major depressive disorder is now almost
exclusively reserved for patients who have not responded to at least
several other pharmacotherapies. Studies have demonstrated the effectiveness
of MAOIs in patients who have not responded to other antidepressant
medications, particularly TCAs (119). However, the effectiveness
of MAOIs relative to other strategies for treatment-resistant patients
in contemporary practice remains unclear, particularly for patients
who have not responded to multiple sequential trials with SSRIs
and SNRIs (121).
MAOIs have been shown to be particularly effective in treating
depressed patients with atypical features, so psychiatrists should
consider using these medications for patients with symptoms such
as reactive moods, reverse neurovegetative symptoms, and sensitivity
to rejection (119, 120, 122). There
do not appear to be any significant differences in efficacy among
the older MAOIs (119), although there are important individual
differences in responsiveness, and these medications are not interchangeable.
There are no comparative studies of the newer transdermal (skin
patch) formulation of selegiline; its efficacy has only been established
relative to placebo (123–125),
and clinical experience is limited.
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b. Side effects of
antidepressant medications
The severity of side effects from antidepressant medications in
clinical trials has been assessed both through the frequency of
reported side effects and through the frequency of treatment dropout.
The likelihood of different side effects varies among classes of
antidepressant medications, among subclasses, and among individual
agents. In addition, most newer antidepressants are better tolerated
than TCAs (84–88, 97, 117, 126)
and safer in overdose (127, 128).
When side effects occur during treatment with an antidepressant,
an initial strategy is to lower the dose of the antidepressant or
to change to an antidepressant that is not associated with that
side effect. As an example, bupropion can be used if patients encounter
sexual side effects with an SSRI medication. When lowering the dose
or discontinuing the medication is not effective, additional strategies may
be considered. These additional strategies are described in Table
7, which also lists prominent and clinically relevant side effects
associated with particular medication classes.
Serotonin syndrome, as the
name implies, is presumed to result from high levels of serotonin
in the brain. Although it can occur with administration of one or
more serotonergic medications, it is most severe when an MAOI is
coadministered with another serotonergic medication. Consequently,
great care must be taken when changing patients from another antidepressant
medication to an MAOI and from an MAOI to other antidepressant medications
because of the persistent effects of discontinued medications. A
washout period is essential before and after using an MAOI. If the
psychiatrist chooses to discontinue a monoamine-uptake-blocking
antidepressant medication (e.g., SSRI, SNRI, TCA) and substitute an
MAOI, toxic interactions can best be avoided by allowing at least
a 2-week washout period between medication trials (Table 8). The
long half-life of the SSRI fluoxetine and its metabolites necessitates
a 5- to 6-week washout period or longer before the use of an MAOI.
Additional information about serotonin syndrome with specific medication
classes can be found in Sections II.B.2.b.1.g. and II.B.2.b.5.b.
Because knowledge of potential drug-drug interactions is frequently
changing, it is useful to consult a frequently updated drug information
database before selecting an antidepressant in a patient taking
other medications.
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1. Selective serotonin reuptake inhibitors
SSRIs have comparable tolerability overall, but the specific medications
differ somewhat in their side effect profiles, which may guide selection
of an agent for an individual patient. Pharmacokinetic issues, including
half-life and effect on the CYP-450 enzyme system, are additional
considerations in the choice of an SSRI.
SSRIs commonly cause nausea, vomiting, and diarrhea (98). These
adverse events are generally dose dependent and tend to dissipate
over the first few weeks of treatment. In some patients, however,
diarrhea persists.
SSRIs sometimes precipitate or exacerbate restlessness, agitation,
and sleep disturbancesside effects that often attenuate with
time. Anxiety may be minimized by introducing the agent at a low
dose. Akathisia has also been reported in patients taking SSRIs
(129) and may contribute to reported restlessness or
activation. If akathisia does occur, a beta-blocker or benzodiazepine
can be tried to reduce symptoms. Insomnia can be treated by using
sleep hygiene techniques or CBT as a first approach or by adding
a sedative-hypnotic medication or trazodone. Some have found melatonin
to be helpful in treating SSRI-induced insomnia.
Although loss of erectile or ejaculatory function in men and loss
of libido and anorgasmia in both sexes may be complications of virtually
any antidepressant medication, these side effects appear to be more
common with SSRIs. The psychiatrist should ascertain whether the
reported sexual dysfunction is a result of the antidepressant medication,
the underlying major depressive disorder, a co-occurring medical
disorder, a disturbance in a relationship, or a need for education
about sexual functioning. If sexual dysfunction is determined to
be a side effect of the antidepressant medication, a number of strategies
are available, including continuing treatment to assess whether
the dysfunction will disappear with time, lowering the dose, discontinuing
the antidepressant, or substituting another antidepressant such
as bupropion (130). Specific pharmacological treatments
that can be added for arousal difficulties, erectile dysfunction,
or orgasm dysfunction include buspirone (131), bupropion
(132), sildenafil (133), and tadalafil
(134). Other phosphodiesterase inhibitors may be also
useful in treating sexual side effects, and a variety of other medications
have been used with anecdotal success (135, 136).
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d. Neurological effects
Selective serotonin reuptake inhibitors can initially exacerbate
both migraine headaches and tension headaches. These effects tend
to be transient and improve within the first few weeks of treatment.
With continued treatment, SSRIs may actually help prevent and treat
migraine headaches (137, 138). Selective
serotonin reuptake inhibitors have also been associated with extrapyramidal
side effects, including akathisia, dystonia, parkinsonism, and tardive
dyskinesia (139, 140). The incidence of
such side effects is very low with SSRIs but may be higher in older
patients, especially those with Parkinson's disease.
Selective serotonin reuptake
inhibitors, like other antidepressive agents, have been associated
with an increased risk of falls. In studies of nursing home residents,
SSRI use has been associated with an approximately twofold increase in
the risk of a fall (141, 142). An even
greater risk of falls in patients who were taking SSRIs was noted
in a community-based cohort study (143). Meta-analyses
have also documented an increased risk of falls in patients treated
with antidepressive agents, in general (144, 145).
The implications of this increase in fall risk are complicated by
the decrease in bone density that has been noted in depressed patients
(146) and in patients treated with SSRIs (147, 148).
An increase in the risk of hip fractures has also been noted (149).
Rarely, SSRI use has been associated with bradycardia, which could also
contribute to syncope and falls (150). In all patients,
including those treated with SSRIs, fall risk may be increased in
individuals receiving benzodiazepines or other hypnotic agents (144, 145, 151)
and in those receiving multiple medications (144, 145).
Systematically reviewing patients' medication regimens
may help to eliminate medications that may no longer be needed,
although such interventions have not been found to alter fall risk,
per se (152). Inquiring about a history of falls in
the past year and assessing for abnormalities in gait and balance
can also help in identifying patients at particular risk for falling
(153).
Weight gain, at times substantial, occurs in some patients taking
SSRIs (154). Patients who take paroxetine have a higher
incidence of weight gain than those who take other SSRIs (98, 155).
Fluoxetine causes an initial reduction in weight, which tends to
normalize with continued treatment (156).
Use of SSRIs has been associated with the rare development of
a syndrome caused by an excess of central nervous system serotonergic
activity. Features of serotonin syndrome include abdominal pain,
diarrhea, flushing, sweating, hyperthermia, lethargy, mental status
changes, tremor and myoclonus, rhabdomyolysis, renal failure, cardiovascular shock,
and possibly death (157). Although serotonin syndrome
can occur rarely with the use of SSRIs alone, it is usually associated
with the simultaneous use of multiple serotonergic agents and is
most severe when SSRIs are given together with MAOIs. Consequently,
when an SSRI is being changed to an MAOI or vice versa, particular
attention must be give to the duration of time between treatments (Section
II.B.2.b) to avoid precipitating a potentially lethal serotonin
syndrome. Serotonin syndrome has also been reported when SSRIs are used
in combination with tramadol, high-dose triptans, or the antibiotic
linezolid, which also has some ability to inhibit MAO (158, 159).
The potential for drug-drug interactions differs significantly across
the SSRIs. Selective serotonin reuptake inhibitors have variable
effects on hepatic microsomal enzymes and therefore cause both increases
and decreases in the blood levels of other medications. For example,
when SSRIs that strongly inhibit the CYP 2D6 isoenzyme (e.g., paroxetine, fluoxetine)
are administered concomitantly with tamoxifen, the metabolism of
tamoxifen to its active metabolite is reduced (76–79),
resulting in a potential decrease in its efficacy in preventing
breast cancer relapse (80, 81). Interaction
with other drugs was higher for fluoxetine, fluvoxamine, and paroxetine
than for sertraline, citalopram, and escitalopram (98, 160, 161).
As described above, there can be a potentially lethal interaction
between SSRIs and MAOIs: the serotonin syndrome. At least five half-lives
should elapse between the time an SSRI is stopped and an MAOI is
started; for fluoxetine discontinuation, this means waiting approximately
5–6 weeks before starting an MAOI; for discontinuation
of other SSRIs, approximately 2 weeks should pass before starting
an MAOI (162). A 2-week waiting period has been suggested
after discontinuing an MAOI before starting an SSRI or another MAOI
(Table 8).
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i. Discontinuation syndrome
Selective serotonin reuptake
inhibitors generally should not be abruptly discontinued after extended
therapy and, whenever possible, should be tapered over several weeks
to minimize discontinuation-emergent symptoms. Clinical experience
and a few controlled studies suggest that among the SSRIs, discontinuation-emergent
symptoms are more likely with paroxetine than sertraline, citalopram,
or escitalopram and least likely to occur with fluoxetine (due to
the long elimination half-life of its primary metabolite, norfluoxetine) (163, 164).
Discontinuation-emergent symptoms include both flu-like experiences such
as nausea, headache, light-headedness, chills, and body aches, and
neurological symptoms such as paresthesias, insomnia, and "electric
shock-like" phenomena. These symptoms typically resolve
without specific treatment over 1–2 weeks. However, some
patients do experience more protracted discontinuation syndromes,
particularly those treated with paroxetine, and may require a slower downward
titration regimen. Another strategy is to change to a brief course
of fluoxetine, e.g., 10 mg for 1–2 weeks, and then taper
and discontinue the fluoxetine (165).
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2. Serotonin norepinephrine reuptake inhibitors
The most common side effects of the SNRIs (venlafaxine, desvenlafaxine,
and duloxetine) are similar to those seen with SSRIs, including
nausea and vomiting, sexual dysfunction, and activation; like the
side effects seen with SSRIs, those with SNRIs can attenuate with
continued use. The SNRIs also are more likely to be associated with
side effects that reflect noradrenergic activity, including increased
pulse rate, dilated pupils, dry mouth, excessive sweating, and constipation.
Although all three SNRIs carry the warning of increased blood pressure,
this risk is greater during therapy with venlafaxine at doses above
150 mg/day (166) than with duloxetine at doses
of 60–120 mg/day (167) or desvenlafaxine
at doses of 50–100 mg/day (168). Because
this blood pressure increase is dose-related, SNRI-induced hypertension
may respond to dose reduction. In the absence of a reduction in
hypertension, a different antidepressant medication may be considered.
Alternatively, in a patient with well-controlled depressive symptoms,
it may be preferable to add an antihypertensive agent rather than
risk a depressive relapse or recurrence with medication tapering.
As with the SSRIs, abrupt discontinuation of SNRIs should be avoided
whenever possible. Discontinuation symptoms, which are sometimes
protracted, are more likely to occur with venlafaxine (and, by implication, desvenlafaxine)
than duloxetine (100) and may necessitate a slower
downward titration regimen or change to fluoxetine. As described
above (Section II.B.2.b), there can be a potentially lethal interaction
between SNRIs and MAOIs: the serotonin syndrome.
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3. Other antidepressant medications
Bupropion differs from other modern antidepressants by its lack
of direct effects on serotonergic neurotransmission and, as a consequence,
a virtual lack of sexual side effects (169). Neurologic
side effects with bupropion include headaches, tremors, and seizures
(106). The risk of seizures is minimized by avoiding
high doses (e.g., using no more than 450 mg/day), avoiding
rapid titration, using divided dosing schedules for the immediate-release
and sustained-release formulations, and avoiding use of bupropion in
patients with risk factors for seizures. Bupropion should also not
be used in patients who have had anorexia nervosa or bulimia nervosa because
of elevated risk of seizures (170). The risk of seizures
may also be increased by the concomitant use of inhibitors of CYP
2B6 (e.g., desipramine, sertraline, paroxetine, fluoxetine) due to
the resulting increase in bupropion blood levels. Bupropion has
been associated with a low risk of psychotic symptoms, including delusions
and hallucinations. It should therefore be used cautiously in patients
with psychotic disorders. Other side effects with bupropion include agitation,
jitteriness, mild cognitive dysfunction, insomnia, and gastrointestinal
upset.
The most common side effects of mirtazapine include dry mouth,
sedation, and weight gain. For this reason, mirtazapine is often
given at night and may be chosen for depressed patients with initial
insomnia and weight loss. Although these side effects tend to occur
early in the treatment course and may attenuate with continued use, the
weight gain associated with mirtazapine is greater than that with
other non-TCA, non-MAOI antidepressants (95) and may
make it a less attractive choice for some patients. Mirtazapine
increases serum cholesterol levels in some patients (171).
Although several patients treated with mirtazapine were observed
to have agranulocytosis in early studies, subsequent clinical experience
has not confirmed an elevated risk (172).
The most common side effect with trazodone is sedation. Because
the sedation associated with trazodone is greater than that with
other non-TCA, non-MAOI antidepressants (95), this
can be an advantage in patients with initial insomnia (173).
Trazodone can also cause cardiovascular side effects, including
orthostasis, particularly among elderly patients or those with preexisting
heart disease. Use of trazodone has also been associated with life-threatening ventricular
arrhythmias in several case reports (173). Trazodone
also can cause sexual side effects, including erectile dysfunction
in men; in rare instances, priapism occurs, which might require surgical
correction (174, 175).
Side effects with nefazodone include dry mouth, nausea, constipation,
orthostasis, and visual alterations (176). Sedation
is also common and may necessitate a gradual titration of nefazodone.
However, in patients with insomnia, the sedating properties of nefazodone
can be helpful in improving sleep (177). There appears
to be a low incidence of treatment-emergent sexual dysfunction (178, 179)
with nefazodone and, unlike trazodone, it has not been associated
with priapism. Nefazodone has also been associated with rare but potentially
fatal liver failure (180, 181), which
has limited its use in recent years. Drug-drug interactions can
also be problematic as nefazodone inhibits hepatic microsomal enzymes and
can raise levels of concurrently administered medications such as
certain antihistamines, benzodiazepines, and digoxin.
+
4. Tricyclic antidepressants
+
a. Cardiovascular effects
Cardiovascular effects, including arrhythmias, can be problematic
with TCA treatment. Consequently, a pretreatment ECG is indicated
for patients with significant cardiac risk factors and patients
older than age 50 years. Follow-up ECGs may also be indicated to
identify the development of conduction changes, typically during
the early phase of TCA use (182). Tricyclic antidepressants
act similarly to class Ia antiarrhythmic agents such as quinidine,
disopyramide, and procainamide, which increase the threshold for
excitation by depressing fast sodium channels, prolong cardiac cell
action potentials through actions on potassium channels, and prolong
cardiac refractoriness through actions on both types of channels
(183). As a result, combinations of TCAs with other class
I antiarrhythmic agents can exert additive toxic effects on cardiac
conduction; patients with ventricular arrhythmias taking another
class I antiarrhythmic agent who require TCA therapy should be under
careful medical supervision. Individuals with prolonged QT intervals,
whether preexistent or medication induced, are predisposed to develop
ventricular tachycardia (184). Even patients with normal
pretreatment ECG results may develop atrioventricular block with
TCAs that reverts to normal after discontinuation of antidepressant medication
treatment (185). Because of these effects on cardiac
conduction, TCAs (like other class Ia antiarrhythmic agents) may
carry an increased risk of serious cardiac adverse effects, including
mortality (186–189). In addition, fatal arrhythmias
can occur in the context of TCA overdose (190, 191).
In addition to causing arrhythmias,
TCAs can cause a number of other cardiovascular side effects, including
tachycardia (through muscarinic cholinergic blockade and 
-adrenergic blockade)
or orthostatic hypotension (through -adrenergic blockade).
Side effects such as orthostatic hypotension may in turn lead to
events such as dizziness, falls, or fractures, which are of particular
concern in elderly patients (192). Of the TCAs, nortriptyline
may be less likely to contribute to orthostatic blood pressure changes (185). Preexisting
orthostasis, antihypertensive treatment, dehydration, and salt depletion, whether
voluntary or a result of diuretic treatment, may contribute to symptomatic
orthostatic hypotension with TCAs. If there is no medical contraindication,
patients with symptomatic orthostatic hypotension should maintain
adequate fluid intake and be cautioned against extreme dietary salt
restriction.
+
b. Anticholinergic side effects
All TCAs have antimuscarinic effects; tertiary amine tricyclic antidepressants
produce the most anticholinergic side effects, whereas the secondary
amines desipramine and nortriptyline have less antimuscarinic activity
(193). The most common consequences of muscarinic blockade
are dry mouth, impaired ability to focus vision at close range,
constipation, urinary hesitation, tachycardia, and sexual dysfunction. Although
patients can develop some degree of tolerance to anticholinergic
side effects, these symptoms may require treatment if they cause
substantial dysfunction or interfere with adherence. Impaired visual
accommodation may be counteracted through the use of pilocarpine
eye drops. Dry mouth may be counteracted by advising the patient
to use sugarless gum or candy and ensuring adequate hydration. Constipation
can be managed by adequate hydration and the use of bulk laxatives.
Antidepressant medications with anticholinergic side effects should
be avoided in patients with cognitive impairment, narrow-angle glaucoma,
or prostatic hypertrophy. Tricyclic antidepressants can impair memory
and concentration and even precipitate anticholinergic delirium, particularly
in patients who are elderly, medically compromised, or taking other
anticholinergic medicines. Such toxic confusional states may signal
the presence of high TCA blood levels and can improve with lowering
of the dose (194).
Tricyclic antidepressants also have affinity for histaminergic receptors
and produce varying degrees of sedation. In general, tertiary amines
cause greater sedation, while secondary amines cause less (193).
Sedation often attenuates in the first weeks of treatment, and patients
experiencing only minor difficulty from this side effect should
be encouraged to allow some time to pass before changing antidepressant
medications. Patients with major depressive disorder with insomnia may
benefit from sedation when their medication is given as a single
dose before bedtime.
Tricyclic antidepressants can cause weight gain, possibly through
their histaminergic properties and/or blockade of 5-HT2 receptors
(195). The degree of weight gain appears to vary by
agent (e.g., greater weight gain with amitriptyline and less with
desipramine), is often dose dependent, and is potentially reversible
with cessation of TCA therapy. Regular monitoring of weight permits
early detection of weight gain and can allow the treating clinician
and patient to determine whether a management plan to minimize or
forestall further weight gain is clinically indicated.
+
e. Neurological effects
Tricyclic antidepressants can cause myoclonus (196).
Since this may be a sign of toxicity, the clinician may wish to
check the blood level (if available) to ensure that it is not excessive. If
the level is nontoxic and myoclonus is not bothersome to the patient,
the agent may be continued without a change in dose. If the myoclonus
is problematic and the blood level is within the recommended range,
the patient may be treated with clonazepam at a dose of 0.25 mg
t.i.d. Alternatively, the antidepressant medication may be changed.
In overdoses, TCAs can cause seizures. Some vulnerable patients
may experience seizures even on therapeutic doses of a TCAespecially
clomipramine and maprotiline (197). Amoxapine, a dibenzoxazepine-derivative
tricyclic antidepressant, also produces seizures in overdose and
has active metabolites that block dopamine receptors, conferring
a risk of extrapyramidal side effects and tardive dyskinesia (198).
Use of TCAs has been associated with an increased risk of
falls in a number of studies and meta-analyses, and the relative
risk of falling appears comparable to that with SSRI treatment (141, 144, 145).
Although systematic reviews show a relatively minor effect of orthostatic
hypotension on fall risk, TCAs may contribute to orthostasis and
falls in individual patients (153). If orthostatic
hypotension is prominent or associated with gait or balance problems,
it may require further evaluation and treatment to minimize the
likelihood of falls (199). Other aspects of fall risk
with TCAs are similar to those that have already been described for
patients treated with SSRIs (Section II.B.2.b.1.e). Other causes
of falls include bradycardia, cardiac arrhythmia, a seizure, or
ataxia.
+
g. Medication interactions
A number of medications that inhibit, induce, or are metabolized
by hepatic microsomal enzymes can interact with TCAs (200).
For example, medications that induce CYP 3A4 such as carbamazepine
or barbiturates will cause a decrease in serum levels of TCAs. Drugs
such as the antipsychotic medication perphenazine or SSRIs such
as fluoxetine or paroxetine can inhibit metabolism via CYP 2D6,
resulting in a reduced clearance and increased levels of TCAs. Tricyclic antidepressants
can also alter the pharmacokinetics or pharmacodynamics of other
medications; for example, TCAs can cause a lowering of valproate
levels and reduce the activity of clonidine. Therefore, adjustments
in medication doses may be necessary when TCAs are administered
concomitantly with other drugs for which there is an interaction.
The ability to obtain meaningful antidepressant blood levels to
guide dosing is an advantage with several of the TCAs (e.g., nortriptyline, amitriptyline,
desipramine, imipramine) (201). Potentially dangerous
interactions, including hypertensive crises and serotonin syndrome,
can develop when TCAs are administered with MAOIs (see Sections
II.B.2.b and II.B.2.b.5.b), norepinephrine, or epinephrine.
+
5. Monoamine oxidase inhibitors
A hypertensive crisis can occur when a patient taking an MAOI
ingests large amounts of tyramine or other vasoactive amines in
foods or medications (202). This reaction is characterized
by the acute onset of severe headache, nausea, neck stiffness, palpitations,
profuse perspiration, and confusion and can possibly lead to stroke
and death (119). Dietary restrictions include avoiding
foods such as aged cheeses or meats, fermented products, yeast extracts,
fava or broad beans, red wine, draft beers, and overripe or spoiled
foods (202, 203). A number of medications
including norepinephrine reuptake blocking drugs (e.g., SNRIs, TCAs),
sympathomimetic vasoconstrictive agents, and over-the-counter decongestants
can also produce a hypertensive crisis when used in combination
with MAOIs (202, 204). Individuals with
asthma who receive MAOIs should be cautioned regarding interactions
with sympathomimetic bronchodilators, although other antiasthma
agents appear to be safe. Stimulants may be added to MAOIs, but only
with caution and in selected individuals with treatment-resistant
symptoms (205, 206).
At low doses (6 mg/24 hours), selegiline differs
from the older MAOIs in selectively blocking MAO B. In addition, the
transdermal delivery of selegiline bypasses enzyme inhibition in
the gut and first-pass metabolism in the liver. As a result, a low-tyramine
diet is not needed when selegiline is prescribed at the minimum
therapeutic dose. However, few safety data are available at higher
doses at which selegiline becomes nonselective and inhibits both MAO
A and MAO B. Consequently, a low-tyramine diet is needed when doses
of 9 mg/24 hours and higher are prescribed as with other
MAOIs (207, 208). Moclobemide, which is
available in Canada but not the United States, differs from the
above MAOIs in binding reversibly to MAO and makes dietary restrictions
unnecessary with moclobemide. The potential for drug-drug interactions
with selegiline and moclobemide has not been fully studied, but
caution suggests that the same drug interactions should be considered
as when prescribing the older, nonselective, irreversible MAOIs.
Although some clinicians continue to recommend that patients
carry nifedipine as a self-administered antidote (e.g., 10 mg by
mouth at the first sign of a hypertensive crisis [209]),
this practice has not been approved by the FDA, and there are concerns
about both the safety and efficacy of this strategy, which can produce
dangerous hypotension (210). Definitive treatment of
hypertensive crises usually involves intravenous administration
of an antihypertensive agent (e.g., labetalol, sodium nitroprusside)
in an emergency department setting.
As discussed previously in Section II.B.2.b.1.g, serotonin
syndrome is caused by excess CNS serotonergic activity and is characterized
by abdominal pain, diarrhea, flushing, sweating, hyperthermia, lethargy,
mental status changes, tremor and myoclonus, rhabdomyolysis, renal
failure, cardiovascular shock, and possibly death. Serotonin syndrome
most commonly occurs when MAOIs (including reversible inhibitors
of monoamine oxidase and selegiline) are taken in close proximity
to other serotonergic agents, such as buspirone or antidepressants
(157, 204, 211). Consequently,
when patients are being changed from an SSRI other than fluoxetine
or an SNRI to an MAOI, a waiting period of at least 2 weeks is needed
between the discontinuation of one medication and the initiation of
the other. When changing from fluoxetine to an MAOI, a waiting period
of at least 5 weeks is needed before the MAOI is started (Table
8). Other medications that have been reported to produce serotonin
syndrome when used in conjunction with MAOIs include synthetic opioids (e.g.,
dextromethorphan, meperidine, tramadol, propoxyphene, methadone),
nonantidepressant tricyclic compounds (e.g., carbamazepine, cyclobenzaprine),
sibutramine, and over-the-counter cold products such as chlorpheniramine
(204).
+
c. Cardiovascular effects
Orthostatic hypotension is commonly seen during MAOI treatment.
Possible treatments for this side effect include adding dietary
salt to increase intravascular volume, or use of the mineralocorticoid
fludrocortisone. Use of MAOIs can also be associated with the development
of peripheral edema, which may be helped by the use of support stockings.
Weight gain is also commonly seen in patients treated with nonselective
MAOIs. Although clinical experience is limited, results of one 52-week
study suggested that treatment with transdermal selegiline may not
be associated with an increased risk of weight gain (212).
Sexual side effects seen with MAOI therapy include anorgasmia,
decreased libido, and erectile or ejaculatory dysfunction. Sexual
side effects may diminish over time or with reductions in MAOI doses.
The transdermal formulation of selegiline appears to have a relatively
low risk of sexual side effects (213).
+
f. Neurological effects
Treatment with MAOIs can also be accompanied by headaches
and insomnia; these side effects may diminish over time with continued
use. Other neurological effects seen with MAOIs include sedation,
myoclonic jerks, paresthesias, intense daytime drowsiness, and,
rarely, peripheral neuropathy.
+
c. Implementation
of pharmacotherapy
Improvement with pharmacotherapy can be observed as early
as the first 1–2 weeks of treatment, and improvement continues
up to 12 weeks. Many patients may show partial improvement as early
as the end of the first week (214–216). Others
achieve improvement within the first 2–4 weeks (217–220).
In short-term efficacy trials, all antidepressant medications appear
to require at least 4–6 weeks to achieve maximum therapeutic
effects (221, 222). There is also evidence
for continued accrual of benefit for an additional 4–6
weeks (223). Furthermore, longer time to therapeutic
effect has been seen with studies conducted in "real world" settings
(224), as well as in studies of patients with more
chronic illness (225, 226) or patients
with major depressive disorder complicated with co-occurring medical and/or
Axis I disorders (224, 227).
Once an antidepressant medication has been selected, it can
be started at doses suggested in Table 6. Initial doses should be
incrementally raised as tolerated until a therapeutic dose is reached
or the patient achieves remission, provided there has been at least
some improvement in symptoms in the initial weeks of treatment (217–220).
For patients who exhibit a partial response to treatment, doses
of antidepressant medications should be maximized, side effects
permitting, before changing to a different antidepressant medication.
In some instances, due to factors such as rapid metabolism of medication
(228, 229), patients may require doses
above those noted in FDA labeling. Patients who have achieved some
improvement during the initial weeks of treatment should be encouraged
to continue taking antidepressant medication for a total of at least
4–8 weeks. If at least moderate improvement is not observed
with maximally tolerated doses after 4–8 weeks of treatment,
reappraisal and adjustment of the pharmacotherapy should be considered.
Patients with no improvement in the initial weeks of treatment generally
need an earlier adjustment of treatment. For these patients, the psychiatrist
should consider changing to another antidepressant rather than increasing
the dose of the medication. For some antidepressant medications,
the exact relationships between doses and major depressive disorder
symptom response have not been rigorously investigated with fixed-dose studies,
and minimum effective doses have not been clearly established; moreover,
for other antidepressant medications, some studies have failed to
show dose-response relationships (230, 231).
Therefore, the initial doses and usual adult doses in Table 6 are
intended to serve as general guidelines, and actual doses may vary
from individual to individual.
Titration of the dose to full therapeutic doses generally
can be accomplished over the initial week(s) of treatment but may vary
depending on the development of side effects, the patient's
age, and the presence of co-occurring medical and psychiatric conditions.
In general, patients who are older, are medically compromised, or
have decreased ability to metabolize and clear antidepressant medications
will require lower doses. In such patients, reduction of initial
and therapeutic doses to 50% of usual adult doses is often
recommended, and dose escalations should be made at a slower rate
than for younger and healthier adults. Doses will also be affected
by the side effect profile of medications and the patient's
ability to tolerate these side effects. Medication doses should
also be tailored to individual patients depending on the potential
for pharmacokinetic alterations and drug-drug interactions.
Patients who have started taking an antidepressant medication
should be carefully and systematically monitored to assess their
response to treatment, the emergence of side effects, their clinical
condition, safety, and adherence to treatment. Use of clinician-
and patient-rated scales can facilitate such assessments (see Section
II.A.8). Factors to consider when determining the frequency of treatment
visits include the severity of illness, the patient's cooperation
with treatment, the availability of social supports, the presence
of co-occurring general medical illnesses, and the progression of symptom
change. Visits should also be frequent enough to monitor and address
suicide risk and to actively promote treatment adherence, since
attrition from treatment continues to be a major hurdle in maximizing
outcomes. Patients in clinical trials appear to benefit from monitoring
once a week or more. This frequency of monitoring enhances adherence rates
and likely helps patients avoid the demoralization that may occur
before the onset of beneficial effects (216). In the recently
completed STAR*D ("Sequenced Treatment Alternatives
to Relieve Depression") trial, up to six visits were recommended
during the first 12 weeks (acute phase) of measurement-based treatment
at each of the four treatment steps (40). In clinical
practice, the frequency of monitoring during the acute phase of
pharmacotherapy may vary and can be as often as multiple times per
week in more complex circumstances. The method of monitoring (e.g.,
face-to-face visits, telephone contact, or contact with another
clinician knowledgeable about the patient) may vary depending on
the clinical context and the treatment modality.
Although for most patients, monitoring of antidepressant blood
levels is not necessary, it may be useful for those taking TCAs.
For some medications, particularly nortriptyline, amitriptyline,
desipramine, and imipramine, blood drug levels correlate with both
efficacy and side effects (201, 232, 233). When
such medications are given, obtaining blood drug levels can be particularly
informative when patients have not responded to treatment with an
adequate dose of antidepressant medication for an adequate duration;
when patients are particularly vulnerable to the toxic effects of
a medication and require the lowest possible effective dose; when
there are concerns about patient adherence; and when there is concern that
drug-drug interactions are adversely affecting antidepressant medication
levels. In time, genetic testing may help guide selection or dosing
of antidepressants, but data are currently insufficient to justify
the cost of such tests (229).
Some antidepressant medications, especially TCAs, can cause
significant morbidity and mortality in overdose (190, 191).
Ingestion of a 10-day supply of a tricyclic agent administered at
a dose of 200 mg/day is often lethal. Early on in treatment,
it is prudent to dispense only small quantities of such antidepressant
medications and keep in mind the possibility that patients can hoard
medications over time. Alternatively, in patients who are suicidal,
it may be preferable to employ agents that are safer in overdose
such as the SSRIs, bupropion, or mirtazapine.
+
3. Other somatic
therapies
+
a. Electroconvulsive
therapy
Electroconvulsive therapy has the highest rates of response
and remission of any form of antidepressant treatment, with 70%–90% of
those treated showing improvement (234–236).
Although the remission rate with ECT appears to be lower when it is
used in community settings than when it is used in clinical trials
(237), the proportion of patients with major depressive
disorder who respond to ECT is still greater than the proportion who
respond to antidepressant medication. In addition, ECT has been
associated with significant improvements in health-related quality
of life (238). Consequently, ECT should be considered
for patients with severe major depressive disorder that is not responsive
to psychotherapeutic and/or pharmacological interventions,
particularly those with significant functional impairment who have
not responded to numerous medication trials (239).
Electroconvulsive therapy may be particularly beneficial and can
be considered as a first-line treatment option for severe major
depressive disorder when it is coupled with psychotic features (240, 241),
catatonia (239, 242), suicide risk (243),
or food refusal leading to nutritional compromise, as well as in
other situations when a particularly rapid antidepressant response
is required (240), such as with severely ill inpatients
(239). Electroconvulsive therapy is also indicated
as a first-line treatment for patients who have previously shown
a positive response to this treatment modality or who prefer it (239).
+
1. Side effects of electroconvulsive therapy
Electroconvulsive therapy is a very safe treatment, and there are
no absolute contraindications to its use (239). Risks
of morbidity and mortality, in general, do not exceed those associated
with anesthesia alone (239, 244, 245).
However, the presence of some medical conditions may necessitate
modifications in anesthesia or ECT administration.
Electroconvulsive therapy may have cardiovascular side effects,
mediated by changes in the autonomic nervous system with the initial
stimulus and subsequent seizure activity (239). More
specifically, ECT typically causes a transient rise in heart rate
and blood pressure, with associated increases in cardiac workload
and intracranial pressure. These effects can be managed by optimizing
blood pressure control prior to ECT and administering antihypertensive
agents (e.g., short-acting beta-blockers or calcium channel blockers)
at the time of ECT (239). Arrhythmias, which are usually
transient, can also occur in conjunction with ECT and can be managed
with usual antiarrhythmic therapies if they do not resolve spontaneously
(239).
Electroconvulsive therapy
can also be associated with cognitive effects, the most common of
which is a period of confusion following the ECT and associated
anesthesia that generally lasts between 30 and 60 minutes (246).
Electroconvulsive therapy also is associated with anterograde amnesia, which
typically resolves soon after the last ECT treatment (247).
Some degree of retrograde amnesia, particularly for recent memories,
may continue for a longer period of time after the end of the ECT
course (247) but is less pronounced for autobiographical
memories than for impersonal memories (248). These
cognitive effects of ECT are related to electrode placement, stimulus dosage,
age, and premorbid cognitive status (249–253).
Retrograde amnesia also improves over time, typically resolving
within 6 months (248, 252), although some
patients report incomplete recovery of memories, particularly for
events around the time of the treatment (247, 254). Rarely,
patients report more pervasive and persistent cognitive disruption,
the basis of which is uncertain (252, 255).
For many individuals, however, subjective memory (256)
and quality of life (238) is improved following ECT
with the resolution of the major depressive episode and its associated deficits
in memory or executive functioning (257, 258).
+
2. Implementation of electroconvulsive therapy
The evaluation preceding ECT consists of a psychiatric history
and examination to verify that ECT is indicated, a general medical
evaluation (including medical history and physical examination with
cognitive assessment, vital signs, and any specifically indicated
laboratory, radiologic, or imaging studies) to define factors that
may influence the risk of ECT, and an anesthesia evaluation to identify
and address the nature and extent of anesthetic risk and the need
for modification of medications or anesthetic technique (239).
This evaluation should include a summary of treatment indications,
treatment risks, and a suggestion of any indicated additional evaluative
procedures, alterations in treatment, or modifications in ECT technique
(239). In assessing indications for caution (e.g.,
recent myocardial infarction, cardiac arrhythmias, intracranial
space-occupying lesions), the relative risks and benefits should
be carefully weighed in collaboration with an anesthesiologist,
a general medical physician, and other specialists, as necessary.
Once completed, the pre-ECT evaluation will serve as the basis for
a specific, individualized discussion of the risks and benefits of
ECT relative to other therapeutic options as part of the informed
consent process. With the patient's permission, it is helpful
to educate the patient's family about ECT and involve them
in discussions relating to consent.
An additional aspect of decision-making prior to ECT relates
to the use of psychotropic medications during the ECT course. There
is growing use of ECT combined with antidepressant medication. Although
data supporting this practice are still few, it does not appear
to increase side effects and may augment response (259, 260).
An additional goal of combination treatment is to minimize the risk
of relapse between the end of the ECT course and the attainment of
full antidepressant effectiveness. Antipsychotic medications are typically
continued during the ECT course (239, 261),
although most data on this practice come from studies of patients
with schizophrenia who are receiving ECT. The safety of combining
lithium and ECT has been questioned, although there are conflicting
data (239, 262). Medications that have
anticonvulsant properties are often discontinued or given at decreased
doses during the ECT course to minimize effects on seizure induction
(239, 261). With benzodiazepines, there
is some evidence that concurrent use may diminish ECT effectiveness,
particularly when right unilateral electrode placement is used (263).
Electroconvulsive therapy may be administered either unilaterally
or bilaterally (using a bitemporal or bifrontal electrode placement).
Compared with patients who receive bilateral treatment, most patients
who receive right unilateral electrode placement with low stimulus
intensities experience fewer cognitive effects but less therapeutic
benefit (253). Stimuli of higher intensity (i.e., 500% above
seizure threshold) are associated with antidepressant effects more
comparable to those seen with bilateral electrode placements, although
such stimulus intensities are not always achievable with existing
ECT devices (264). Regardless of what electrode placement
is chosen, stimulus dosing should be individualized and stimulus
parameters adjusted to induce an adequate generalized seizure, which
is typically at least 20 seconds or greater in motor duration and
30 seconds in EEG duration (239). Failure to induce
an adequate seizure should be followed immediately by restimulation
at higher energies until an adequate seizure is elicited.
Electroconvulsive therapy
is typically administered 2–3 times/week; less
frequent administration has been associated with less cognitive
impairment but also a longer lag in the onset of action (265).
In clinical practice, the need for ECT to be administered at this
frequency could produce logistical barriers for some patients who
would either require hospitalization or transportation after ECT
sessions. The acute course of ECT treatment typically consists of
six to 12 treatments and generally does not exceed 20 treatments
(239, 266). It is important that treatment
continue until symptoms have remitted or clearly reached a plateau,
since relapse rates appear to be greater and overall prognosis worse
if ECT is discontinued prematurely (237). Use of a
formal rating scale may be helpful in assessing symptom response
as well as the cognitive side effects of treatment, permitting adjustments
in the treatment parameters or frequency (239, 267).
For more detail on the administration of ECT, see APA's The
Practice of Electroconvulsive Therapy: Recommendations for Treatment,
Training, and Privileging (A Task
Force Report of the American Psychiatric Association) (239).
+
b. Transcranial magnetic
stimulation
Transcranial magnetic stimulation (TMS) uses a specifically designed
magnetic coil that is placed in contact with the head to generate
rapidly alternating magnetic-resonance-imaging-strength magnetic
fields and produce electrical stimulation of superficial cortical
neurons. Based on the results of a multisite randomized sham-controlled
clinical trial of high-frequency TMS over the left dorsolateral
prefrontal cortex (268), TMS was cleared by the FDA
in 2008 for use in individuals with major depressive disorder who
have not had a satisfactory response to at least one antidepressant
trial in the current episode of illness. However, another large
randomized sham-controlled trial of TMS added to antidepressant pharmacotherapy
showed no significant benefit of left dorsolateral prefrontal cortex
TMS (269). In comparisons of actual TMS versus sham
TMS, most (270–272) but not all (273)
recent meta-analyses have found relatively small to moderate benefits
of TMS in terms of clinical response. Although the primary studies
used in these meta-analyses are highly overlapping and the variability
in TMS stimulus parameters and treatment paradigms complicates the
interpretation of research findings, these meta-analyses also support the
use of high-frequency TMS over the left dorsolateral prefrontal
cortex. Lesser degrees of treatment resistance may be associated
with a better acute response to TMS (274).
In comparison with ECT, TMS has been found in randomized studies
to be either less effective than ECT (275) or comparable
in efficacy to ECT (276–278), but in the latter studies
TMS was more effective and ECT was less effective than is typically
seen in clinical trials. A fewer number of studies have compared
cognitive effects of TMS and ECT. One randomized trial found no significant
difference between TMS and non-dominant unilateral ECT on performance
on neuropsychological tests at 2 and at 4 weeks of treatment (276),
although a small open-label trial reported a greater degree of memory
difficulties with ECT than with TMS shortly after the treatment
course (279).
Across all studies, TMS was well tolerated and was associated with
low rates of treatment dropout (270, 280).
Transient scalp discomfort and headaches were the most commonly
reported side effects (280).
In clinical practice, the need for daily TMS could produce logistical
barriers for some patients.
+
c. Vagus nerve stimulation
Vagus nerve stimulation is approved for use in patients with treatment-resistant
depression on the basis of its potential benefit with long-term
treatment. There is no indication for the use of VNS in acute phase
treatment of depression, as data showed no evidence for acute efficacy
(281, 282). Further information on the
use of VNS as an adjunct to other antidepressive treatments is provided
in Section II.B.7.c.
There has been considerable research on time-limited psychotherapies
for major depressive disorder, although the number of studies is
smaller than for pharmacotherapies. Most research has focused on
individual, in-person, outpatient treatment, in part based on the
needs and constraints of research methods. However, research has
also begun to explore psychotherapies in differing formats, including
groups, over the telephone, and with computer assistance.
When psychotherapy is part of the treatment plan, it must be
integrated with psychiatric management (Section II.A) and any other
treatments (e.g., pharmacotherapy) that are being provided. Clinical
considerations and other patient factors should be considered in
determining the nature and intensity of psychotherapy. Typically
psychotherapy is given in an ambulatory setting, although some psychotherapies
might benefit depressed inpatients, given adequate lengths of stay
and courses of treatment (283–285). Like pharmacotherapy,
the effectiveness of psychotherapy will vary with the skill and training
of the therapist. Patient factors, such as the nature and duration
of depressive symptoms, beliefs and attitudes toward psychotherapy,
and early life experiences (e.g., history of trauma) also affect
treatment response to psychotherapy. Psychotherapy is particularly
useful in addressing the psychosocial stressors and psychological
factors that have an impact on the development or maintenance of
depressive symptoms.
Cognitive-behavioral therapy, interpersonal psychotherapy (IPT),
and behavioral psychotherapies (e.g., behavioral activation) have
demonstrated acute efficacy in treating major depressive disorder.
There is less evidence for other psychotherapies. However, one meta-analysis
found no large differences in long-term efficacy between any of
the major psychotherapies, including dynamic psychotherapy, for
mild and moderate depression (286). In terms of longer
term outcomes, psychotherapy is generally found to have more prolonged
effects than pharmacotherapy after cessation of active treatment.
In particular, IPT and CBT have shown lasting benefits in maintaining
remission (287–289). These time-limited treatments
are essentially equipotent with antidepressant medications for outpatients
with mild to moderate acute depression but probably should be used
in conjunction with medication for severe or melancholic major depressive
disorder. Some research has suggested patient and illness characteristics
that might predict differential benefits of CBT over IPT, and vice versa,
for patients with major depressive disorder (e.g., see reference 290),
but such preliminary findings require replication.
Cognitive-behavioral therapy and IPT appear less effective
than pharmacotherapy for chronic depression, at least as acute monotherapy
(291–296). Nonetheless, in patients who respond
to medication, psychotherapy may foster the development of social
skills and confidence after years of depression-related impairments
(297).
Psychotherapy carries its own "side effects." A
psychotherapy that requires considerable time or patience may be poorly
tolerated. The work of psychotherapy itself may generate anxiety
or other strong feelings, which may be difficult for patients to
manage. An indirect measure of the relative side effects and tolerability
of psychotherapy can be obtained from the dropout rates in clinical
trials; however, many other factors can also affect these rates
(e.g., other burdens of the research trial, specific features of
the clinical management provided, logistical barriers in attending
appointments). Depending on what can reasonably be expected with
the given type of psychotherapy, the psychiatrist should consider
a change in the intensity or type of psychotherapy and/or
addition or change to medication if psychotherapy for major depressive
disorder has not resulted in significant improvement in 4–8
weeks.
+
a. Specific psychotherapies
+
1. Cognitive and behavioral therapies
In the treatment of depressed patients, psychotherapies that focus
primarily on aspects of cognitive patterns and those that emphasize
behavioral techniques can be used alone, but are generally used
in combination. Cognitive-behavioral therapy combines cognitive
psychotherapy with behavioral therapy and maintains that irrational beliefs
and distorted attitudes toward the self, the environment, and the
future perpetuate depressive affects and compromise functioning.
The goal of CBT is to reduce depressive symptoms by challenging
and reversing these beliefs and attitudes and encouraging patients to
change their maladaptive preconceptions and behaviors in real life
(298).
Cognitive-behavioral therapy is an effective treatment for major
depressive disorder. In meta-analyses, CBT has generally surpassed
control conditions in efficacy and has had equal efficacy compared
with other empirically supported psychotherapies (i.e., IPT and
behavior therapy) (299). Studies comparing the effectiveness
of CBT with pharmacotherapy, however, are methodologically challenging to
conduct, and results are inconsistent (296, 300).
Also unclear is whether CBT is less effective for patients with
more severe depressive symptoms.
Behavior therapy for major depressive disorder is based on
theoretical models drawn from behavior theory (301)
and social learning theory (302). Behavioral activation
is a newly articulated behavioral intervention with some positive
preliminary results that merit further study (288, 303).
Specific behavior therapy techniques include activity scheduling (304, 305),
self-control therapy (306), social skills training (307),
and problem solving (308). Behavior therapy involves graded
homework, scheduling of enjoyable activities, and minimizing unpleasant
activities (309). Behavior therapy has demonstrated
efficacy, at times superior to cognitive therapy, in treating major
depressive disorder (310).
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2. Interpersonal psychotherapy
The focus of IPT is on current life changes, including losses, role
disputes and role transitions, social isolation, deficits in social
skills, and other interpersonal factors that may interact with the
development of the depressive episode (311, 312). In
IPT the goal is to intervene by identifying the current trigger
of the depressive episode, facilitating mourning in the case of
bereavement, promoting recognition of related affects, resolving
role disputes and role transitions, and building social skills to
improve relationships and to acquire needed social supports. In
IPT, major depressive disorder is defined as a medical illness,
and the illness, rather than the patient, is blamed for the symptoms.
Interpersonal psychotherapy's medical model makes it highly
compatible with pharmacotherapy in combined treatment.
Interpersonal psychotherapy is an efficacious treatment for
major depressive disorder (296, 313).
Studies have shown efficacy of this treatment in depressed primary
care patients and patients with more severe depression (311).
The efficacy of IPT has been demonstrated for adolescents, pregnant
and postpartum women, and geriatric patients (311).
Interpersonal psychotherapy can also be used as a monthly maintenance
therapy to prevent relapse (289, 314, 315).
Some studies have also suggested possible subgroups in whom IPT may
show differential efficacy, specifically among HIV-positive patients
(316) and patients who have co-occurring obsessive
personality traits and who are single and not living with others
(317). Furthermore, for patients with severe life events,
IPT may have advantages over therapies that do not focus on such
events directly.
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3. Psychodynamic psychotherapy
The term "psychodynamic psychotherapy" encompasses
a range of brief to long-term psychotherapeutic interventions (318–320).
These interventions derive from psychodynamic theories about the
etiology of psychological vulnerability, personality development,
and symptom formation as shaped by development and conflict occurring
during the life cycle from earliest childhood forward (321–325).
Some of these theories focus on conflicts related to guilt, shame,
interpersonal relationships, the management of anxiety, and repressed
or unacceptable impulses. Others address developmental psychological
deficits produced by inadequacies or problems in the relationship
between the child and emotional caretakers, resulting in problems
of self-esteem, sense of psychological cohesiveness, and emotional
self-regulation (323, 326–330).
Psychodynamic psychotherapy may be brief but usually has a
longer duration than other psychotherapies, and its aims extend
beyond immediate symptom relief. These goals are to modify underlying
psychological conflicts and deficits, which increase the patient's
vulnerability to depressive affect and the development of major
depressive disorder. Psychodynamic psychotherapy is therefore broader than
most other psychotherapies, encompassing both current and past problems in
interpersonal relationships, self-esteem, and developmental conflicts
associated with anxiety, guilt, or shame. Time-limited, structured
psychodynamic psychotherapy may focus more on understanding the
psychological basis of the presenting symptoms or on a selected
underlying conflict. Sometimes a goal of psychodynamic psychotherapy,
brief or extended, may be to help the patient accept or adhere to
necessary pharmacotherapy (331).
Although psychodynamic psychotherapy is often used in clinical
practice, its efficacy in the acute phase of major depressive disorder
remains less well studied in controlled trials than the efficacy
in this phase of some other forms of psychotherapy. This research
is reviewed in Part B, Section V.B.3.
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4. Problem-solving therapy
Problem-solving therapy is a manual-guided, brief treatment lasting
six to 12 sessions. This therapy, often administered by nurses or
social workers, has been used to prevent depression in elderly and/or
medically ill patients, and it has also been used to treat patients
with relatively mild depressive symptoms. The approach combines elements
of cognitive therapy (addressing negative assessments of situations)
and IPT (focal problem solving). Some studies have reported modest
improvement in patients with mild depressive symptoms. Although
problem solving therapy has had limited testing for patients with
major depressive disorder, it may have a role in targeted patient
populations with mild depression (332–335).
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5. Marital therapy and family therapy
Marital and family problems are common in the course of mood
disorders, and comprehensive treatment often demands assessing and
addressing these problems. Marital and family problems may be the
consequence of major depressive disorder but may also increase vulnerability
to developing major depressive disorder or retard recovery from
it (336–339). A number of marital and family
therapies have been shown to be effective in the treatment of depression. Techniques
include behavioral approaches (338), problem-focused
approaches (340), and strategic marital therapy (341, 342).
Family therapy has also been found to be helpful in the treatment
of more severe forms of depression in conjunction with medications
and hospitalization (343).
Group psychotherapy is widely practiced, but research on its application
to major depressive disorder is limited. Specific types having some
data to support their efficacy include CBT (344–347)
and IPT (348–351). Meta-analyses of the relative effectiveness
of psychotherapeutic approaches conducted in group format versus
individual format have not involved patients with rigorously defined
major depressive disorder (352–355).
On the basis of a very limited controlled study, supportive group
therapy has been suggested to have utility in the treatment of major
depressive disorder. In a study of depressed outpatients, a mutual
support group and group CBT were found to be equally effective in
reducing depressive symptoms (346). In a study of HIV-positive
patients with mild to moderate major depressive disorder, structured
supportive group therapy plus placebo yielded similar decreases
in depressive symptoms to structured group therapy plus fluoxetine
(356). Individuals experiencing stressors such as bereavement
or chronic illness may benefit from contact with others facing similar
challenges.
Medication maintenance support groups may also offer benefits,
although data from controlled trials for patients with major depressive
disorder are lacking. Such groups inform the patient and family
members about prognosis and medication issues, providing a psychoeducational
forum that contextualizes a chronic mental illness in a medical
model.
The efficacy of self-help groups led by lay members (357) in
the treatment of major depressive disorder has not been well studied.
However, one investigation of group therapies found that a higher
proportion of depressed outpatients had remission following treatment
in groups led by professionals than had remission following participation
in groups led by nonprofessionals (346). Further study
is needed on the possibility that self-help groups may serve a useful
role in enhancing the support network and self-esteem of participating patients
with major depressive disorder and their families.
Overall, group therapy has some evidence to support its use
as well as the potential advantage of lowered cost, inasmuch as
one or two therapists can treat a larger number of patients simultaneously.
This advantage needs to be weighed against the difficulties in assembling
the group, the lesser intensity of focus patients receive relative
to individual psychotherapy, and potentially adverse effects from
interactions with other group members.
It can be useful to establish an expected duration of psychotherapy
at the start of treatment. Communicating this expectation may help
mobilize the patient and focus treatment goals, yet there are few
data available on the optimal duration of specific depression-focused
psychotherapies. In many trials, CBT and IPT have been delivered
in approximately 12–16 weekly sessions. In a subanalysis
of one clinical trial, CBT delivered in 16 weeks was more effective
than CBT delivered in 8 weeks for those with severe major depressive
disorder (358). Moreover, evidence suggests benefit
from monthly continuation phase treatment with IPT in reducing the
probability of relapse (314). In addition, patients
with chronic, treatment-resistant depression may require long-term
treatment.
The optimal frequency of psychotherapy has not been rigorously
studied in controlled trials. The psychiatrist should consider multiple
factors when determining the frequency for individual patients,
including the specific type and goals of the psychotherapy, the
frequency necessary to create and maintain a therapeutic relationship,
the frequency of visits required to ensure treatment adherence,
and the frequency necessary to monitor and address suicide risk
and other safety concerns. Time-limited brief psychotherapies may mobilize
many depressed patients to more rapid improvement. The severity
of illness, the patient's cooperation with treatment, availability
of social supports, cost, geographic accessibility, and presence
of co-occurring general medical problems may also influence visit
frequency. The frequency of outpatient visits during the acute phase
is generally weekly but may vary based on these factors. Some experienced
clinicians find that sessions are needed at least twice weekly,
at least initially, for patients with moderate to severe depression.
Regardless of the type of depression-focused psychotherapy
that is selected, the clinician should carefully and systematically
monitor the patient's response to treatment, which can be
facilitated by the use of clinician- and patient-rated scales at regular
intervals (see Section II.A.8). If 4–8 weeks of treatment
do not yield at least moderate improvement (
20% diminution
in symptoms), the clinician should thoroughly review and reappraise
the treatment plan.
+
c. Combining psychotherapy
and medication
Several meta-analyses of studies of the combination of psychotherapy
and pharmacotherapy for patients with major depressive disorder
have documented a modest advantage for the combination as compared
with one or the other modality alone (359–361).
Particularly large additive effects have been observed in individual
studies of patients with chronic depression (362),
patients with severe recurrent depression (359), and
hospitalized patients (285). Combined treatment might
therefore be considered a treatment of first choice for patients
with major depressive disorder with more severe, chronic, or complex
presentations. Combining family therapy with pharmacotherapy has
also been found to improve posthospital care for depressed patients
(343).
Dual treatment combines the unique advantages of each therapeutic
modality: while pharmacotherapy may provide earlier symptomatic
relief, psychotherapy yields broader and longer lasting improvement
(363). Psychotherapy can also be used to address issues
that arise during pharmacotherapy, such as decreased adherence.
However, the advantage of routinely combining interventions may
be modest for patients with less severe depressive symptoms (359).
There are no empirical data from clinical trials to help guide
the selection of particular antidepressant medications and particular
models of psychotherapeutic approaches for individuals who will
receive the combination of both modalities. In general, the same
issues that influence these decisions when choosing a monotherapy
will apply, and the same doses of antidepressant medication and
the same frequency and course of psychotherapy should be used for
patients receiving combination modality treatments as are used for
patients receiving them as a monotherapy.
Results from a series of recent studies provide indirect evidence
that for patients who have had only a partial response to pharmacotherapy,
adding a course of CBT may be an effective strategy for preventing
relapse (363–368). During 12 weeks of treatment
in the STAR*D study, cognitive therapy was as effective
as either augmenting with bupropion or buspirone or changing antidepressants
to bupropion, sertraline, or venlafaxine. However, patients who
did not respond to an initial course of citalopram were less likely
to accept cognitive therapy as a change or augmentation option than
they were to accept a different medication option (369),
perhaps due to the nature of the study design.
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5. Complementary
and alternative treatments
As defined by the National Center for Complementary and Alternative
Medicine, complementary and alternative medicine is "a
group of diverse medical and health care systems, practices, and
products that are not presently considered to be part of conventional
medicine." As the definitions are usually applied, "complementary" therapies
are used conjunctively with conventional medicine, "alternative" therapies
are used in place of conventional medicine, and "integrative" medicine makes
use of all therapies appropriate to an individual patient's
needs.
The use of integrative therapies is increasingly common, although
training and comfort with complementary and alternative modalities
vary greatly by practitioner. Many patients do not spontaneously
disclose use of complementary or alternative treatments to health
care professionals, so it is particularly important that direct
inquiry about such treatments be part of routine health care questions. At
this time, there are several modalities that have modest evidence
for antidepressant efficacy and deserve further study. Some of these modalities
can be recommended with enthusiasm for their general health benefits;
however, patients should be informed that evidence for their antidepressant
efficacy as monotherapy is limited or absent.
St. John's wort is a plant widely used to treat depressive
symptoms. Overall, studies of St. John's wort show greater
consensus and support for benefits in mild to moderate major depressive
disorder, as compared with less consistent findings in patients
with more severe symptoms. One review of 14 short-term, double-blind
trials conducted in outpatients with mild to moderate symptoms of
major depressive disorder concluded that St. John's wort
in doses of 300 mg/day and 1,800 mg/day had efficacy
that was superior to placebo (105). St. John's
wort had generally comparable efficacy and fewer side effects than
low-dose TCA treatment (e.g., 30–150 mg/day of amitriptyline)
(105), but doses at the low end of this range would
not be expected to produce therapeutic benefits. However, in the
two largest controlled studies conducted in the United States (370, 371),
effects of St. John's wort did not differ from placebo,
which somewhat limits confidence in the magnitude of the antidepressant
actions of St. John's wort. In addition, preparations of
St. John's wort are not regulated by the FDA as a drug
and lack standardization of their ingredients, composition, and
potency. Based on the evidence cited, St. John's wort would
not meet the FDA's minimum requirements to be declared
an effective antidepressant and is not recommended for general use
in treating depression.
Another important consideration with St. John's wort
is the potential for drug-drug interactions (372–374).
St. John's wort appears to induce the metabolism of drugs
via CYP 3A4, reducing the efficacy of medications, including antiretroviral
medications, immunosuppressants (including cyclosporine), antineoplastic
agents, anticoagulants (including warfarin), oral contraceptives,
and hormone replacement therapy (373, 374).
Unwanted pregnancies have been reported with concomitant St. John's
wort and oral contraceptive use (373, 375, 376),
and rejection of transplanted organs has been observed when St.
John's wort is taken concurrently with cyclosporin (374).
The significant decreases in antiretroviral medication levels with
concomitant St. John's wort use suggest that these medications
will be less effective in treating HIV infection (374). Effects
of St. John's wort on P-glycoprotein have also been observed,
altering the pharmacokinetics and pharmacodynamics of medications such
as digoxin that are transported by this route (374).
Apart from affecting blood levels of nonpsychiatric medications, the
safety and efficacy of the combined use of St. John's wort with
other antidepressant medications is not known. The combined use
of St. John's wort with MAOIs is contraindicated.
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b. S-adenosyl
methionine
S-adenosyl methionine is
a naturally occurring molecule. In humans, it is concentrated in
the liver and the brain and serves as a methyl donor in the synthesis
of biologically active compounds such as phospholipids, catecholamines,
and the neurotransmitters dopamine and serotonin (377).
Cerebrospinal fluid levels of SAMe are lower in individuals with severe
major depressive disorder, compared with control subjects (378),
and treatment with SAMe increases CSF SAMe and 5-hydroxyindoleacetic
acid levels (379). S-adenosyl
methionine is available for both parenteral and oral administration
(380).
Some data support the efficacy and tolerability of SAMe in patients
with major depressive disorder. Oral, intravenous, and intramuscular
formulations have been assessed and appear efficacious in at least
pilot studies (381–383). Like St. John's
wort, SAMe is not regulated by the FDA and lacks standardization
of its composition and potency. S-adenosyl methionine
has been compared with TCAs and has been reported to have greater
efficacy while being more tolerable (381). It is unclear
at present how SAMe compares to SSRIs in efficacy and cost-efficiency.
While some data support the use of SAMe as monotherapy and as augmentation
therapy, the data at this time, as with St. John's wort,
are insufficient to make a recommendation for its use in the treatment
of major depressive disorder.
Most studies of omega-3 fatty acids for major depressive disorder
have been adjunctive studies, in which patients were already receiving
antidepressant medications but still met the criteria for major
depressive disorder. Studies vary in the omega-3 fatty acids used
(eicosapentaenoic acid [EPA], docosahexaenoic
acid [DHA], or the combination), and doses and
durations of study trials have also varied. It is difficult to interpret
the literature on this treatment given the heterogeneity in study
design and outcomes.
Omega-3 fatty acids are generally recommended as an adjunctive
therapy for mood disorders, as health benefits, including those
for cardiovascular health, are well established, and individuals
with psychiatric disorders may be at greater risk for obesity, metabolic
problems, and other health problems than the general population
(384, 385). More evidence is required
to establish a definitive role in the acute treatment of major depressive
disorder. Doses of 1–9 grams have been studied in mood
disorders, with a majority of evidence supporting use of lower doses.
Adjunctive EPA or the combination of EPA and DHA (the combination found
in most commercially available brands) appears most useful, with
less evidence for DHA alone for the treatment of major depressive
disorder. Further data are needed to ascertain the role of omega-3
fatty acids as monotherapy for major depressive disorder.
Folate has been primarily assessed as a predictor of antidepressant
medication response and as an adjunctive treatment. Low folate blood
levels have been associated with lack of response and slower response
to fluoxetine for major depressive disorder (386, 387),
and higher folate levels at treatment baseline appear associated
with better response to antidepressants (388). Folate
has been studied as an adjunctive treatment compared with placebo
in addition to fluoxetine, with significantly greater improvement
in those receiving folate, especially among female patients (389).
Folate is a low-risk intervention with general health benefits.
Folate protects against neural tube defects in early pregnancy.
In general, 0.4–1 mg of folate is recommended for women
of reproductive age. Considering the modest evidence that supports
folate as an augmentation strategy and its attractive risk-benefit
profile, folate can be recommended as a reasonable adjunctive strategy
for major depressive disorder that carries little risk and may decrease
birth defects in the case of pregnancy. Data are inadequate to suggest
efficacy as a monotherapy.
Bright light therapy appears effective for seasonal affective disorder
and nonseasonal major depressive disorder, as demonstrated in generally
short-term, placebo-controlled trials (390–394),
although some studies have methodological limitations (395).
The mechanism of action for light therapy is not clear but appears
to involve the serotonergic neurotransmitter system (396, 397).
There is some evidence that light therapy may hasten the response
to treatment with antidepressant medication (398).
Open-label data also support light therapy for patients with major
depressive disorder that has not responded to antidepressant medication
(399). Greater intensity of light is associated with
efficacy (400). Light therapy also may augment the
antidepressant benefits of partial sleep deprivation (401, 402).
Monitoring for mania and hypomania may be appropriate with initiation
of light therapy, as hypomania has been reported (392).
However, in general bright light therapy is a low-risk and low-cost
option for treatment.
Acupuncture is a treatment modality that is part of traditional Chinese
medicine. Its efficacy is somewhat difficult to assess, as much
of the research is published in Asian languages and overlooked in
typical literature searches. In addition, there is significant variation
in the acupuncture techniques used as well as limited descriptions
of methodology and diagnosis (403). One randomized
trial showed comparable benefits of electroacupuncture and amitriptyline
(404), and another small randomized trial in depressed women
showed benefits of acupuncture relative to a sham control (405).
However, a subsequent larger study did not replicate these results
(406), and a recent meta-analysis concluded that acupuncture
was not associated with any benefits in treating major depression in
terms of response or remission rates (407). Assuming
needles are properly sterilized, there do not appear to be substantial
risks of acupuncture treatment. However, based on current evidence,
acupuncture is not recommended in the treatment of major depressive
disorder.
+
6. Assessing response
and adequacy of treatment
The goal of acute phase treatment for major depressive disorder,
insofar as possible, is to achieve remission and a return to full
functioning and quality of life. Remission is defined as at least
3 weeks of the absence of both sad mood and reduced interest and
no more than three remaining symptoms of the major depressive episode
(408). However, it is not uncommon for patients to
have substantial but incomplete symptom reduction or improvement
in functioning during acute phase treatment. A number of studies
have provided compelling evidence that even mild residual symptoms
at the end of a depressive episode are associated with significant
psychosocial disability, compared with asymptomatic remission (409);
a more than three times faster relapse to a subsequent major depressive episode
(410); and in first-episode patients, a more chronic future course
(410–412). The presence of mild residual symptoms has
been shown to be an even stronger predictor of a subsequent return
to a major depressive episode than a prior history of multiple episodes
of major depressive disorder (410). For this reason,
it is important not to conclude the acute phase of treatment prematurely
for partially responsive patients. Throughout treatment, both the patient's
response and the adequacy of treatment must be vigilantly and systematically monitored.
Use of structured measures of depression symptom severity, side
effects, treatment adherence, and functional status can facilitate
identification of patients who have not had a complete response
to treatment (40, 44).
If a patient is found to have an incomplete treatment response,
the treatment itself should be evaluated. Medications must be thoughtfully
selected and given at an adequate dose and for an adequate duration.
Similarly, psychotherapy must be well chosen for the patient, skillfully
executed, and conducted over an appropriate period of time with
an adequate frequency of visits. In addition to being caused by
inadequate treatment, poor response may result from multiple other
factors (413) that are enumerated in Table 9.
For pharmacotherapy, determination of the adequacy of treatment
requires ensuring that antidepressant medications have been used
for an adequate dose and duration. This can be assessed using standardized
measurement instruments (414). Generally, adequate
treatment with an antidepressant medication for at least 4–6
weeks is necessary before concluding that a patient is not responsive
or only partially responsive to a particular medication (218, 221).
For patients with no improvement in symptoms during the initial
weeks of treatment, treatment should be reevaluated and possibly changed.
Furthermore, there is little evidence to support extending antidepressant
medication trials beyond 6 weeks in patients who have shown no response.
Patients with chronic forms of depression or with co-occurring Axis
I disorders or general medical conditions may require a longer duration
of acute phase treatment before concluding that a different treatment
strategy is indicated (224).
For psychotherapy, treatment
should be reassessed if there has not been meaningful improvement
after a few months, depending on what can reasonably be expected
for the given type of psychotherapy. Patients should be reassessed
every 3–4 months to ensure adequate improvement. Regardless
of treatment modality, lack of improvement over time warrants reconsideration
of interventions, given the large number of available treatment
options.
+
7. Strategies to
address incomplete response
The psychiatrist should consider a change in treatment for patients
who have not fully responded to an adequate acute phase treatment
over a sufficient time, generally 4–8 weeks. The treatment
plan can be revised by implementing one of several therapeutic options,
including optimizing the initial treatment, changing to a different
treatment, and combining treatments. These options are outlined
in Figure 2 and described in more detail below.
+
Following any change in treatment, the patient should continue
to be closely monitored. If there is not at least a moderate improvement
in major depressive disorder symptoms after an additional 4–8
weeks of treatment, the psychiatrist should conduct another thorough
review. This reappraisal should include the following: verifying
the patient's diagnosis and adherence; uncovering and addressing
clinical factors that may be preventing improvement, such as the
presence of co-occurring general medical conditions or psychiatric
conditions (e.g., alcohol or substance abuse); evaluating for potential drug-drug
interactions; obtaining collateral information from those involved
with the patient; and uncovering and addressing psychosocial, psychological,
and personality factors that may be impeding recovery (Table 9).
If no new information is uncovered to explain the patient's
lack of adequate response, other treatment options should be considered,
including ECT and a consultation from an expert in mood disorders.
Despite optimal treatment, some patients may continue to have chronic
depressive symptoms. For these patients, the psychiatrist should
add a disease management component to the overall treatment plan.
This component involves setting realistic expectations, improving
functioning, and developing self-management skills (415, 416).
+
a. Maximizing initial
treatments
For patients who have not fully responded to treatment for depression,
an initial strategy is to optimize the intensity of psychotherapy
or maximize the dose of medication, especially if the upper limit
of the antidepressant dose has not been reached. Decisions about
pharmacotherapy will involve a balancing of efficacy, side effects,
and medication adherence. Dose escalation and management of side
effects at critical decision points are essential in order to avoid
premature discontinuation of the chosen antidepressant medication
and to maximize the dose and duration of the antidepressant therapy
(40, 218).
Because of pharmacokinetic and pharmacodynamic differences
among individuals, some patients may require doses higher than those
approved by the FDA to achieve adequate blood levels of a medication
and receive therapeutic benefits. Patients who have had their dose
increased should be monitored for increased severity of side effects;
dose increases should be considered only for patients who do not
have significant or intolerable side effects while taking the medication.
Frequent follow-up contact (either in person or via the phone) may
be necessary to address symptoms, side effects, and patient adherence
in order to personalize treatment to the specific clinical needs
of the patient. When available and clinically meaningful, therapeutic
ranges for blood levels of antidepressant medications are useful
in optimizing medication dosing (201, 232, 233).
Individual differences are common in the time to response and
the tolerability of treatments. For patients who have shown a partial
response to treatment, particularly those with features of personality
disorders and prominent psychosocial stressors, extending the antidepressant
medication trial (e.g., by 4–8 weeks) may allow up to one-third
of patients to respond more fully (417–419).
In patients who are receiving psychotherapy, similar principles
apply in terms of monitoring and adjusting treatment in the context
of nonresponse or difficulty tolerating psychotherapy (331).
Factors to be considered include the frequency of sessions, the
type of psychotherapy being used, the quality of the therapeutic
alliance, and the possible need for medications in lieu of or in
addition to psychotherapy. Whereas increasing the frequency of therapy
sessions is a reasonable approach to nonresponse, this approach
is based on clinical wisdom and has not been systematically studied.
+
b. Changing to other
treatments
Changing to a different non-MAOI antidepressant medication
is a common strategy for patients with treatment-resistant major
depressive disorder, especially those who have not shown at least
partial response to the initial medication regimen. Although there
are no specific patient characteristics that predict which medication
to choose (420), results from STAR*D suggest
that changing to a second-step treatment results in additional remission
rates of about 25%, and further changes are associated
with continued remission, albeit at lower rates (about 13%–14%).
Treatment can be changed to a non-MAOI antidepressant medication
from the same pharmacological class (e.g., from one SSRI to another
SSRI) or to one from a different class (e.g., from an SSRI to a
TCA) (369, 421–422). Adding or
changing to a depression-focused psychotherapy should also be considered
for patients with major depressive disorder who do not respond fully
to medication treatment. Other strategies for patients who do not
respond adequately to pharmacotherapy include changing to an MAOI
after allowing sufficient time between medications to avoid hazardous
interactions (see Table 8). Transcranial magnetic stimulation could
also be an option, as it appears to be safe and well tolerated (270, 280).
In addition, it has shown small to moderate benefits in most (268, 270–272)
but not all (269, 273
()
) clinical
trials and recent meta-analyses. Recent randomized trials suggest
that quetiapine monotherapy also produces a greater reduction in depressive
symptoms than placebo (423, 424), with
comparable efficacy to duloxetine (424), although the
potential side effects of second-generation antipsychotic treatment
need to be taken into consideration. ECT remains the most effective
therapy for patients with treatment-resistant symptoms (239, 425),
although results of clinical trials differ on whether patients with
medication-resistant symptoms have responses to ECT that are comparable to
those of patients without documented medication resistance (426–428).
+
c. Augmenting and
combining treatments
Pharmacotherapy can be combined with a depression-focused
psychotherapy, both as an initial treatment plan, and as a strategy
to address nonresponse to treatment in one modality or the other.
See Section II.B.4.c above for further information about combining
pharmacotherapy and psychotherapy.
Antidepressant medications can be augmented with another non-MAOI
antidepressant or with other, nonantidepressant agents. The addition
of a second non-MAOI antidepressant may be helpful, particularly
for patients who have had a partial response to antidepressant monotherapy
(429). One option is to add a second non-MAOI antidepressant
medication from a different pharmacological class, taking care to
avoid drug-drug interactions. Another option is to add an adjunctive,
nonantidepressant medicationsuch as lithium, thyroid hormone,
an anticonvulsant, a psychostimulant, or a second-generation (atypical)
antipsychotic. More information about these strategies is given
later in this section.
Some limited evidence and
clinical experience support the addition of bupropion to an SSRI.
This combination is generally well tolerated, although bupropion,
a moderately potent inhibitor of CYP 2D6, increases blood levels
of some SSRIs (430). In one study, combined treatment
with bupropion and an SSRI resulted in better outcomes than either
therapy alone (431). Another commonly used strategy
is the combination of mirtazapine and an SSRI or venlafaxine. Generally,
mirtazapine 15–30 mg at bedtime is added to the incompletely
effective antidepressant and titrated up to 45 mg/day on
the basis of response and tolerability (432).
For patients with pronounced anxiety or persistent insomnia not
adequately relieved by an SSRI or SNRI, adjunctive use of anxiolytic
and sedative-hypnotic medications is common (433, 434).
These include benzodiazepines such as clonazepam (435)
and selective GABA agonists such as zolpidem (436) and
eszopiclone (437). Buspirone has also been used adjunctively
in anxious individuals (429). Although adjunctive therapy
of anxiety or insomnia can hasten symptomatic relief, there is no
evidence of sustained benefit, and some patients have difficulty
stopping the anxiolytic or hypnotic medication (438, 439).
Lithium, thyroid hormone, and stimulants are sometimes combined
with antidepressants to augment response. Lithium is the most extensively
studied of these adjuncts (440–443) and may
also reduce the long-term risk of suicide (444). The
interval before full response to adjunctive lithium is said to be
in the range of several days to 6 weeks. The blood level required
to enhance the effects of antidepressants still has not been confirmed.
If effective and well tolerated, lithium should be continued at
least for the duration of acute treatment and perhaps beyond the
acute phase for purposes of relapse prevention.
Thyroid hormone supplementation, even in euthyroid patients,
may increase the effectiveness of antidepressant medication treatment,
whether used as an augmentation agent (445, 446)
or in combination with an antidepressant from the outset of therapy
(447). The dose typically used for this purpose is
25 mcg/day of triiodothyronine, increased to 50 mcg/day
if the response is inadequate after about a week. The duration of
treatment required has not been well studied.
Second-generation antipsychotic medications may increase the
rates of response or remission of depressive symptoms in patients
who typically have not responded to more than two medication trials
(448), even when psychotic symptoms are not present.
Generally, in clinical practice, lower doses are used for antidepressant
augmentation than for treatment of psychosis. For example, the combination
of olanzapine and fluoxetine has been extensively studied (449–452)
and is typically initiated with 6 mg of olanzapine and 25 mg of
fluoxetine daily and titrated upward as tolerated to a maximum of 18
mg of olanzapine and 75 mg of fluoxetine daily. Aripiprazole has
received FDA approval for augmentation of antidepressive agents
and is typically initiated at 2.5–5 mg/day and titrated
upward as tolerated to a maximum of 15 mg/day (453). With
quetiapine, doses of 25 to 400 mg/day have been used, with
benefits for depressive symptoms found in some (454, 455)
but not all (456) clinical trials. Risperidone augmentation,
in doses of up to 3 mg daily (457, 458)
also appears to improve the response to antidepressant agents. In
most of these trials, the onset of the effect of second-generation
antipsychotic augmentation has been rapid, although the magnitude
of the advantage relative to placebo has been relatively modest.
In the only two trials to utilize active comparison groups, the combination
of olanzapine and fluoxetine was not significantly more effective
at study endpoint than continued therapy with nortriptyline (450)
or venlafaxine (451). Naturalistic follow-up data also
suggest that long-term weight gain can be problematic for many patients
receiving second-generation antipsychotic augmentation therapy,
particularly with the olanzapine-fluoxetine combination (459).
In addition, a recent meta-analysis suggests that the rate at which
SGA augmentation is discontinued is nearly four-fold greater than
study discontinuation among subjects randomly assigned to placebo (448).
When compared with other strategies for antidepressant nonresponders,
augmentation with a second-generation antipsychotic carries disadvantages:
the high cost of many agents, the significant risk of weight gain
and other metabolic complications (e.g., dyslipidemia, hypertriglyceridemia,
glucose dysregulation, diabetes mellitus), and potential risk of hyperprolactinemia,
tardive dyskinesia, neuroleptic malignant syndrome, and QTc prolongation.
Thus, the advantages and disadvantages of antipsychotic medications
should be considered when choosing this augmentation strategy. In
addition, when augmentation with a second-generation antipsychotic is effective,
it is uncertain how long augmentation therapy should be maintained.
Many clinicians find that augmentation of antidepressants with
low doses of stimulants such as methylphenidate or dextroamphetamine
may help ameliorate otherwise suboptimally responsive depression
(460–462), although not all clinical trials
have shown benefits from this strategy (463). More
recently, the novel compound modafinil has shown modest benefit
when combined with SSRIs, related to specific effects on residual
symptoms such as fatigue and hypersomnolence (464–467).
Although there are no clear guidelines regarding the length of time
stimulants or modafinil should be coadministered, in one extension
study the effects of modafinil were maintained across 12 weeks of additional
therapy (468). Physicians prescribing modafinil for
this off-label use should become familiar with rare but dangerous
cutaneous reactions to it, including reported instances of Stevens-Johnson
syndrome, toxic epidermal necrolysis, drug rash with eosinophilia
and systemic symptoms (469), and cytochrome P450 interactions.
Modafinil can also induce CYP 3A4 and render contraceptive medications and
other medications metabolized through this route ineffective.
Although their use in this context has not been extensively evaluated,
anticonvulsants such as carbamazepine, valproic acid, and lamotrigine
may offer some benefit in the treatment of medication-resistant
major depressive disorder (121, 429, 470–473).
A rarely used strategy is the combined use of a TCA or trazodone
and an MAOI (474, 475). The combination
of a TCA and an MAOI has been used for more than three decades for
treatment of some of the most treatment-resistant depressive disorders;
however, the risk of drug-drug interactions necessitates careful
monitoring (119). Of particular concern with these
combinations is the serotonin syndrome, characterized by delirium,
hyperthermia, hyperreflexia, myoclonus, and, rarely, death (see
Section II.B.2.b.5.b). Use of an MAOI in combination with a TCA
and related antidepressants should probably not be considered until
other pharmacological strategies for patients with treatment-resistant
illness have been exhausted; psychiatrists and patients choosing
to use the combination of an MAOI and a TCA should be well acquainted
with the potential hazards and carefully weigh the relative risks
and benefits of such a strategy.
Vagus nerve stimulation was approved for use in patients whose
symptoms have not responded to at least four adequate trials of
antidepressant medications and/or ECT. Acute benefits were
not observed in the sham-controlled portion of the VNS trial (282).
When compared with a parallel treatment-as-usual arm, the long-term
(1–2 year) open-label extension showed small (476, 477)
but persistent (478) improvements in symptoms with
VNS that could be clinically significant for some patients. Other
open-label studies have also shown some benefit when VNS is used
simultaneously with pharmacotherapy (479–481).
As with any surgical device implantation, there is a small risk
of postsurgical infection (482). A majority of individuals experience
hoarseness or voice alteration during stimulation, and coughing,
dyspnea, and neck discomfort are common (281, 481)
but generally are tolerable to patients (282, 479). Patients
also need to be informed of the implications of having an implanted
VNS device for future medical care (482). For example,
with a VNS device in place, brain MRI requires the use of a special
send-receive coil. The VNS device may affect the operation of other
implanted devices such as cardiac pacemakers or defibrillators and
other procedures such as diathermy, and whole body or radiofrequency
receive-only MRI are contraindicated. VNS is also contraindicated
in the presence of bilateral or left cervical vagotomy.
Relative to other antidepressive treatments, the role of VNS
remains a subject of debate. However, it could be considered as
an option for patients with substantial symptoms that have not responded
to repeated trials of antidepressant treatment.
Continuation phase pharmacotherapy
is strongly recommended following successful acute phase antidepressant therapy,
with a recommended duration of continuation therapy of approximately
4–9 months (assuming good and consistent control of depression
symptoms). The goal of continuation treatment is to prevent relapse
(i.e., the reemergence of significant depressive symptoms or dysfunction)
in the vulnerable period immediately following remission (i.e., a
complete alleviation of symptoms) (408, 410, 411).
The possibility of relapse should be carefully monitored during the
continuation phase as this is when risk of relapse is highest (483).
Within the first 6 months following recovery from a major depressive
episode, relapse of depressive symptoms is common, with the proportion
of patients with relapse ranging from 20% of patients in
mixed samples (484–487) to as many as 85% of
severely depressed inpatients receiving treatment with ECT (234, 488, 489).
These studies also show that relapse rates are greater if antidepressant
treatment (including ECT) is discontinued or reduced in dose or
intensity following recovery (234, 489, 490).
There is evidence that patients who do not completely recover during
acute treatment have a significantly higher risk of relapse (and
a greater need for continuation treatment) than those who have no
residual symptoms (227, 491, 492).
Similarly, patients who have not fully achieved remission with psychotherapy
are at greater risk of relapse in the near term (364, 365, 367, 493, 494).
To reduce the risk of relapse during the continuation phase, treatment
should generally continue at the same dose, intensity, and frequency
that were effective during the acute phase. Although the number
of randomized controlled trials of antidepressant medications in
the continuation phase is limited, the available data indicate that
patients treated for a first episode of uncomplicated major depressive
disorder who exhibit a satisfactory response to an antidepressant
medication should continue to receive a full therapeutic dose of that
agent for at least 4–9 months after achieving full remission
(105, 225, 495).
Published studies for the continuation phase with older TCAs
as well as newer medications have consistently shown efficacy of
these medications in preventing relapse, compared with placebo.
Lithium has also been shown to have efficacy in preventing relapse
(496).
Cognitive-behavioral therapy may prevent relapse of depression
when used as augmentation to medication treatment. It may also bestow
an enduring, protective benefit that reduces the risk of relapse
after the treatment has ended (363). Cognitive group
therapy helps to prevent relapse and recurrence for patients in
remission after a major depressive episode (497). Mindfulness-based
cognitive therapy is a variant of cognitive therapy that encourages
patients to pay attention to their thoughts and feelings in the
moment and to accept them rather than judging or trying to change
or disprove them. Among patients with remitted depression, mindfulness-based
cognitive therapy groups may reduce risk of relapse for patients
who have already experienced three or more episodes (498).
Such benefits for CBT (and potentially, for other psychotherapies)
would offer an advantage over pharmacotherapy, which works only
as long as the patient continues the antidepressant medication.
Continuation therapy is also essential in reducing relapse risk
after an acute course of ECT (239). Although relapse
occurs for many patients regardless of continuation strategy (234, 488, 489),
remission of symptoms following successful treatment with ECT may
be maintained with either pharmacotherapy or continuation ECT (234).
Research shows that continuation ECT is comparable in efficacy to
the combination of nortriptyline and lithium (234)
and that the latter combination is superior to nortriptyline alone
in preventing relapse (489). Although there is limited
information regarding prognostic factors, relapse may be less likely
among patients with melancholic depression who receive continuation ECT
after remission with acute ECT than among those who receive continuation
pharmacotherapy after remission with acute ECT (499).
Given the significant risk of relapse during the continuation
phase of treatment, it is essential to assess depressive symptoms,
functional status, and quality of life in a systematic fashion,
which can be facilitated by the use of periodic, standardized measurements.
It is often helpful for patients and families to identify particular
signs (e.g., lack of engagement in specific activities that are
usually enjoyed, specific "signal" symptoms or
patterns of thought) that are typical of their earlier depressive
episodes and may suggest the beginnings of a depressive relapse.
Furthermore, any sign of symptom persistence, exacerbation, or reemergence
or of increased psychosocial dysfunction during the continuation period
should be viewed as a harbinger of possible relapse.
If a relapse does occur during the continuation phase, a return
to the acute phase of treatment is required. An initial step is
often to increase the dose of medication (500) or,
with continuation ECT, to increase the frequency of treatment (501). For
patients receiving psychotherapy, an increased frequency of sessions
or a shift in the psychotherapeutic focus may be needed. It is also
essential to determine whether any specific precipitants are contributing
to the relapse of depression. For example, the onset or worsening
of psychosocial stressors, substance use disorders, or general medical
conditions can contribute to increased depressive symptoms. In addition,
decreased treatment adherence or reductions in medication blood levels
(e.g., due to drug-drug interactions or increased cigarette use)
can also prompt a depressive relapse.
Patients with chronic and/or
recurrent major depressive disorder who complete the continuation
phase without relapse proceed to the maintenance phase of treatment,
in which the goal is to protect susceptible patients against recurrence
of subsequent depression.
Patients who have had three or more prior major depressive
episodes should receive maintenance treatment. Within the first
6 months following recovery from a major depressive episode, 20% of
patients will experience a recurrence (484). Between
50% and 85% of patients will have at least one
lifetime recurrence, usually within 2 or 3 years (502),
although there is little consistency in the time to recurrence for any
individual patient (484). Patients who have had a prior major
depressive episode also have a high risk of experiencing subsequent
affective episodes other than another major depressive episode,
such as a manic, hypomanic, or dysthymic episode (503).
The number of lifetime major depressive episodes is significantly associated
with the probability of recurrence, such that the risk of recurrence
increases by 16% with each successive episode (484).
Maintenance therapy should be considered more strongly for
patients with additional risk factors for recurrence, such as the
presence of residual symptoms, ongoing psychosocial stressors, family
history of mood disorders, and the severity of prior episodes (504)
(see Table 10). Additional considerations that may play a role in
the decision to use maintenance therapy include patient preference,
the presence of side effects during continuation therapy, and the
severity of prior depressive episodes, including factors such as
psychosis or suicide risk. Due to the risk of recurrence and the
importance of early detection of recurrent symptoms, patients should
be monitored periodically and in a systematic fashion during the maintenance
phase; such assessments can be facilitated by the use of standardized
rating scales, as described in Section II.A.8.
In general, the treatment that was effective in the acute and
continuation phases should be used in the maintenance phase.
Among the therapeutic options available for maintenance treatment,
antidepressant medications have received the most study. There have
been more than 30 trials of pharmacotherapy in the maintenance phase,
and results have generally demonstrated the effectiveness of antidepressant
medication for relapse prevention (105, 226, 314, 505–507).
Many of these trials used TCAs (314, 506),
although results of trials involving newer antidepressant medications
have been assessed in a recent meta-analysis (507).
Lithium has also been used as maintenance treatment for major depressive
disorder (441). Despite this, there is limited information
on many of the clinical decisions involving medication use in the
maintenance phase. Even though lower doses of medication are less
likely to produce side effects, results from one study suggest that full
doses are superior to lower doses in the maintenance phase (508).
Particularly if medications are well-tolerated, it is generally
advisable to prescribe the same antidepressant medication doses
for maintenance therapy that were effective in prior phases of treatment.
Even with adequate maintenance treatment, pharmacotherapy is not invariably successful
in preventing relapse and return of symptoms, which still occur
in as many as 25% of individuals (509, 510).
It is unclear whether some relapses during maintenance therapy are loss
of therapeutic efficacy, a phenomenon that has been referred to
as tachyphylaxis, but many such relapses appear related to inadequate
prophylactic effects of medication (511). When relapses
occur, clinicians typically address them using the same approaches
described to treat incomplete responses to treatment, such as increasing
the dose of medication, changing to a different medication, or adding
another medication or a depression-focused psychotherapy to augment
therapeutic response (510, 512).
There have been fewer investigations of the effectiveness of
psychotherapy in the maintenance phase. Nonetheless, several studies
have shown that acute psychotherapies for major depressive disorder
also have maintenance benefits. For example, even once-monthly maintenance
IPT has been shown to forestall relapse in patients at high risk
for relapse (289, 314, 315, 513).
Most of these studies have used once-monthly maintenance IPT, but
research has not demonstrated that frequency of sessions affects
outcome (289). In one study, maintenance cognitive
therapy delivered over 2 years was as effective as maintenance medication
for recurrent major depressive disorder (514). Combining
psychotherapysuch as CBT, cognitive therapy, or IPTwith
pharmacotherapy in the maintenance phase has also been considered
by investigators. Some results suggest that the combination of antidepressant
medications plus psychotherapy may be more effective in preventing
relapse than treatment with single modalities (314, 365, 506, 515, 516).
For patients receiving treatment with pharmacotherapy and/or
psychotherapy, the frequency of visits during the maintenance phase
should be set according to the clinical condition and the specific
treatments being used. The frequency can range from as low as once
every several months for stable patients who require only psychiatric
management and medication monitoring to as high as once or twice
per week for those receiving psychodynamic psychotherapy. For CBT
and IPT, maintenance-phase treatments usually involve a decreased
frequency of visits (e.g., once a month). The duration of the maintenance
phase will vary depending on the frequency and severity of prior
major depressive episodes, the tolerability of treatments, and patient
preferences. For many patients, some form of maintenance treatment
may be required indefinitely.
Electroconvulsive therapy has also been used in the maintenance
phase, although evidence for its benefits comes largely from case
reports (239). Patients who exhibit repeated episodes
of moderate or severe major depressive disorder despite optimal
pharmacological treatment or patients who are medically ineligible
for such treatment may be maintained with periodic ECT. Although
the optimal frequency and duration of maintenance phase ECT treatments
has not been well studied, maintenance ECT is often administered monthly;
individuals for whom this is insufficient may find treatment at
more frequent intervals to be beneficial (501).
+
E. Discontinuation
of Treatment
If maintenance-phase treatment
is not indicated, stable patients may be considered for discontinuation
of treatment after the continuation phase. The precise timing and
method of discontinuing psychotherapy and pharmacotherapy for major
depressive disorder have not been systematically studied.
The decision to discontinue treatment should be based on the
same factors considered in the decision to initiate maintenance
treatment (Table 10), including the probability of recurrence, the
frequency and severity of past episodes, the persistence of depressive
symptoms after recovery, the presence of co-occurring disorders,
and patient preferences. The type of treatment being received may
also play a role in the decision making. In general, psychotherapy
has a longer lasting treatment effect and carries a lower risk of
relapse following discontinuation than pharmacotherapy. In terms
of timing, patients should be advised not to discontinue medications
before holidays, significant events (e.g., weddings), or stressful
events.
Patients should be carefully monitored during and immediately
after treatment discontinuation to ensure that remission is stable.
The highest risk for a relapse is seen in the first 2 months after
discontinuation of treatment. Hence, it is important to schedule
a follow-up visit during this period to ensure stability.
When pharmacotherapy is being discontinued, it is best to taper
the medication over the course of at least several weeks. Such tapering
allows for the detection of recurring symptoms at a time when patients
are still partially treated and therefore more easily returned to
full therapeutic treatment if needed. In addition, such tapering
can help minimize the incidence of antidepressant medication discontinuation
syndromes, particularly with paroxetine and venlafaxine (98, 163, 164).
Discontinuation syndromes are problematic because their symptoms
include disturbances of mood, energy, sleep, and appetite and can
therefore be mistaken for or mask signs of relapse (517).
Consequently, patients should be advised not to stop medications
abruptly and to take medications with them when they travel or are
away from home. Discontinuation syndromes have been found to be
more frequent after discontinuation of medications with shorter
half-lives, and patients maintained on short-acting agents should
have their medications tapered gradually over a longer period (518, 519).
Another strategy is to change to a brief course of fluoxetine, e.g.,
10 mg for 1–2 weeks, and then discontinue the fluoxetine
(165). The psychiatrist should closely monitor patients
withdrawing from antidepressants and provide reassurance that symptoms
are time-limited and can be addressed by more gradual tapering (see
Section II.B.2.b.1.i).
How to end psychotherapy is typically dependent on the type
of therapy. For time-limited approaches, termination is usually
broached from the initiation of treatment and periodically revisited,
as the therapist-patient dyad notes which session they are in, how
many remain, and how they have progressed toward defined goals.
In dynamically oriented psychotherapy, the therapist typically raises
termination as an issue well in advance of the final session, using
the opportunity to explore remaining and unresolved issues in transference.
Before the discontinuation of active treatment, patients should
be informed of the potential for a depressive relapse. Early signs
of major depressive disorder should be reviewed, often with a family
member, and a plan established for seeking treatment in the event
of recurrent symptoms. Patients should continue to be monitored
over the next several months to identify early evidence of recurrent
symptoms. Again, systematic assessment of symptoms, side effects,
adherence, and functional status during this period of high vulnerability
is strongly recommended. If a patient does suffer a recurrence after
discontinuing medication, treatment should be promptly reinitiated.
Usually, the previous treatment regimen to which the patient responded
in the acute and continuation phases should be reinitiated (520).
Patients who have a recurrence following discontinuation of antidepressant therapy
should be considered to have experienced another major depressive
disorder episode and should receive adequate acute-phase treatment
followed by continuation-phase treatment and possibly maintenance-phase
treatment.
+
III. Specific Clinical
Features Influencing the Treatment Plan
+
a. Suicidal ideation
and behaviors
Because suicide is the worst outcome of major depressive disorder,
a patient's risk for suicide must be assessed repeatedly
over the course of treatment. For patients who report suicidal ideation,
intention, or planning, close surveillance is necessary (see Sections
II.A.3 and II.A.4). Psychiatrists should consider greater intensity
of treatment for suicidal patients, including hospitalization when
warranted and/or combined treatment with pharmacotherapy
and psychotherapy. In patients at high risk for suicide and in whom
a particularly rapid antidepressant response is required, consideration should
be given to the use of ECT (239, 243, 521).
Patients with major depressive disorder who present to an emergency department
with suicidal ideation, or who have made a suicide attempt, should
be triaged to determine their level of safety and establish the
appropriate level and setting of care. Upon entrance to the emergency
department, they should be searched to permit removal of potentially
dangerous items, such as weapons and personal belongings that could
cause harm (e.g., sharp objects, belts, shoes, medications). Factors to
consider in determining the nature and intensity of treatment include
(but are not limited to) access to and lethality of suicide means,
past and family history of suicidal behavior, co-occurring substance
abuse, the availability and adequacy of social supports, and the
nature of the doctor-patient alliance.
To lower the risk of suicide, the psychiatrist should also treat
modifiable risk factors, such as anxiety (especially panic attacks),
insomnia, agitation, psychotic symptoms, and substance abuse (22),
in addition to treating the major depressive episode. Among inpatients
who died by suicide, Busch et al. (522) observed that
a great majority were admitted for indications other than suicidal
ideation, and anxiety and agitation were common, suggesting that
such symptoms should be addressed if they are present. Family members
can also play an important role in detecting and preventing suicidal
behaviors. When permitted by the patient, the psychiatrist should educate
those close to the patient concerning appropriate interventions
and encourage communication.
There has been a growing controversy about the risk of suicidal
ideas and behaviors (sometimes referred to as "suicidality")
after initiation of antidepressant treatment. Although information
on such risk continues to evolve, a predictive relationship to suicide
has never been demonstrated. Clinical experience has long suggested
that patients may develop the energy and capacity to act on self-destructive
plans made earlier in the course of their illness if neurovegetative
and psychomotor symptoms respond to antidepressant treatment before
mood improves. More recently, meta-analyses of data from clinical
trials have shown statistically significant increases in suicidal
thoughts or behaviors in individuals age 25 years or younger who
are treated with antidepressant medication, compared with placebo, with
an approximately 1.5- to 2.5-fold increase in the relative risk
(26, 523–530). In percentage
terms, it is estimated that one to three of 100 individuals age
25 years or younger could potentially have an increase in suicidal
thoughts or behaviors with antidepressant treatment (26),
although there has been no evidence of increased mortality in the
study subjects as a result of suicide (531). To alert
clinicians to the need for vigilance and communication during the
initial phase of antidepressant treatment, the FDA has issued a
black-box warning pertaining to children, adolescents, and young
adults that advises of this increase in the risk of suicidal thinking
and behavior; information on the warning is available on the FDA Web
site at http://www.fda.gov/cder/drug/antidepressants/default.htm.
In making decisions about treatment, this awareness of a potential
increase in suicidal thinking and behavior in children, adolescents,
and young adults must be balanced against the negative effects,
including suicide, of untreated depression (532) as
well as the demonstrated benefits of antidepressant treatment (523, 533–535).
For adults age 65 years or older, a review of the evidence from
clinical trials showed a decrease in the risk of suicidal thinking
or behaviors with antidepressant treatment, with no change in risk detected
for other adults (age 25 to 64 years) (536).
For additional details about
the treatment of suicidal individuals, clinicians are encouraged
to consult APA's Practice Guideline for
the Assessment and Treatment of Patients With Suicidal Behaviors (22).
+
b. Major depressive
disorder–related cognitive dysfunction
Cognitive inefficiency and impairment are common features
of major depressive disorder. Many depressed patients report slowed
thoughts, poor concentration, distractibility, and reduced capacity
to process information. They also display diminished attention to
self-care and to their environment. Transient cognitive impairment,
especially involving attention, concentration, and memory storage
and retrieval, are demonstrable through neuropsychological testing
(537). In extreme cases, especially in elderly patients,
these deficits are so prominent that patients appear to have dementia.
For individuals who exhibit symptoms of a dementia syndrome, it
is crucial that any underlying depressive disorder be identified
and treated.
Among depressed patients, the differential diagnosis of cognitive
dysfunction includes degenerative dementias (such as Alzheimer's
disease and Pick's disease) and reversible causes (such
as vitamin B12 deficiency, folate deficiency,
testosterone deficiency, substance use). Several clinical features help
distinguish major depressive disorder–related cognitive dysfunction
from other dementia syndromes. When performing cognitive tasks,
depressed patients generally exert less effort and report greater
incapacity than do patients with dementia. The latter, especially
in more advanced stages, typically do not recognize their cognitive
failures, since insight is impaired. In contrast, depressed patients
may report being unable to think or remember. Patients with major
depressive disorder–related cognitive dysfunction lack
the signs of cortical dysfunction (i.e., aphasia, apraxia, agnosia)
encountered in dementias such as Alzheimer's disease (538, 539).
Nevertheless, distinguishing dementia from depression-related cognitive dysfunction
can be difficult, particularly as the two may coexist. For further
discussion of the co-occurrence of dementia and depression, the
reader may also wish to consult APA's Practice
Guideline for the Treatment of Patients With Alzheimer's Disease
and Other Dementias, Second Edition (539).
The detection of major depressive disorder–related
cognitive dysfunction alerts the psychiatrist to the need for treatment
of the underlying major depressive disorder, which should in turn
reduce the signs and symptoms of the cognitive dysfunction. Although
initially reversible, major depressive disorder–related
cognitive dysfunction increasingly appears to be a harbinger of
subsequent dementia (540, 541). In addition,
research suggests that certain types of executive cognitive dysfunction
predict greater disability and limited treatment response in geriatric
patients with depression (542, 543).
+
2. DSM depressive
subtypes
Major depressive disorder is sometimes accompanied by hallucinations
or delusions, which may be congruent or incongruent with the depressed
mood. Recognition of psychosis is essential among patients with
major depressive disorder as it is often undetected, resulting in
ineffective treatment (544–546). Psychotic
features constitute a risk factor for recurrent major depressive
disorder and recurrent psychosis and hence indicate the need for
maintenance treatment.
Electroconvulsive therapy is highly effective in treating psychotic
depression (241) and can be considered as a first-line
treatment option whenever major depressive disorder is associated
with psychotic features (239, 243, 547).
Pharmacotherapy can also be used as a first-line treatment option
for major depressive disorder with psychotic features. Psychotic depression
typically responds better to the combination of an antipsychotic
and an antidepressant medication rather than treatment with either
component alone (547–549), although some research
has shown comparable responses for antidepressive treatment or antipsychotic
treatment alone (550, 551). Lithium augmentation
is helpful for some patients who have not responded to combined
treatment with antidepressant and antipsychotic medication (262, 552).
A catatonic syndrome sometimes occurs in the context of major
depressive disorder (553–556) and is characterized
by at least two of the following manifestations: immobility, as evidenced
by catalepsy or stupor; extreme agitation; extreme negativism; peculiarities
of voluntary movement, as evidenced by posturing, stereotyped movements,
mannerisms, or grimacing; and echolalia or echopraxia (556, 557).
The presence of catatonia should prompt a thorough differential diagnosis
as it can also occur in association with general medical conditions
and with several other psychiatric disorders, including bipolar
disorder and schizophrenia (556, 558, 559).
Catatonic signs often dominate the clinical presentation and may
be so severe as to be life-threatening, compelling the consideration
of urgent somatic treatment. Patients with catatonic features may
also need supportive medical interventions including hydration,
nutrition, prophylaxis against deep vein thrombosis, turning to
prevent bed sores, and passive range of motion to prevent contractures.
Intravenous administration of a benzodiazepine (e.g., lorazepam,
diazepam) or a barbiturate (e.g., amobarbital) may induce rapid relief
(242, 553) and can be followed by continued
oral administration for patients who show an initial response. When such
intervention is ineffective, the clinician should consider the urgent
use of ECT (239, 242). The efficacy of
ECT in catatonia is well documented in the case series literature (239)
and is usually apparent after a few treatments. After catatonic
manifestations recede, antidepressant medication treatments may
be needed during acute and maintenance phases of treatment. In addition
to antidepressant medications, ongoing treatment may include ECT,
lithium, antipsychotics, or a combination of these approaches, depending upon
the patient's condition. Patients with catatonia may have
an increased susceptibility to neuroleptic malignant syndrome when
exposed to antipsychotic medications (560), and this
should be considered in planning treatment.
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c. Melancholic features
Melancholic features describe characteristic somatic symptoms,
such as the loss of interest or pleasure in all, or almost all,
activities or a lack of reactivity to usually pleasurable stimuli.
Other symptoms include worsened depression in the morning, early
morning awakening, and significant anorexia or weight loss, among
others (16). Major depressive disorder with melancholic
features is responsive to both pharmacotherapy and ECT. Serotonin
norepinephrine reuptake inhibitors and TCAs may have an advantage
over SSRIs for this patient population (561, 562).
Psychotherapy may be less appropriate for patients with melancholia
(563), particularly if the symptoms prevent engagement
with the therapist (e.g., lack of interest in activities). Major
depressive disorder with melancholic features may also be associated
with an added risk of suicide (564) and an increased
risk of subsequent recurrence despite the use of maintenance pharmacotherapy (509).
Major depressive disorder with atypical features is characterized
by a pattern of marked mood reactivity and at least two additional
symptoms, including leaden paralysis, a long-standing pattern of
interpersonal rejection sensitivity, significant weight gain or
increase in appetite, and hypersomnia (the latter two of which are
considered reversed vegetative symptoms) (16). The
phrase "atypical features" distinguishes this
depressive subtype from the more classical "endogenous" presentation
of depression, but it does not connote an uncommon or unusual form
of depression. Atypical features are more common in women, are associated
with an earlier age at onset of depression and a greater degree
of associated anxiety disorders, and frequently have a more chronic,
less episodic course, with only partial interepisode recovery (565, 566).
These atypical features are also common in the depressed phase of
bipolar I disorder and bipolar II disorder (567, 568),
indicating a need for careful screening for manic or hypomanic episodes
in patients who present with atypical depressive symptoms.
In the treatment of major depressive disorder with atypical
features, MAOIs have greater efficacy than TCAs (122, 569–572).
Some data also support the use of SSRIs, bupropion, and CBT in this
patient population (573–577). Electroconvulsive
therapy is also effective in treating patients with atypical features
(578). The presence and severity of specific symptoms
as well as safety considerations should help guide the choice of
treatment for major depressive disorder with atypical features.
For example, if a patient does not wish to, cannot, or appears unlikely
to adhere to the dietary and medication precautions associated with
MAOI treatment, the clinician should consider alternative antidepressant
medication or psychotherapy.
A seasonal pattern of major depressive disorder is characterized
by a regular temporal relationship between particular periods of
the year and the onset and remission of symptoms, which is not the
result of seasonally related psychosocial stressors (e.g., seasonal
unemployment, significant anniversaries). The most common presentation
in the northern hemisphere is the regular appearance of symptoms
between early October and late November and regular remission from
mid-February to mid-April. Episodes of major depressive disorder
with seasonal pattern frequently have atypical features such as
hypersomnia and overeating. Some of these patients experience manic
or hypomanic episodes as well; hence, it is important to diagnose
bipolar disorder when appropriate.
The entire range of treatments for major depressive disorder
may be used to treat major depressive disorder with seasonal pattern,
either in combination with or as an alternative to light therapy.
As a primary treatment, light therapy may be recommended as a 1-
to 2-week time-limited trial (395), primarily for outpatients
with clear seasonal patterns. For patients with more severe forms
of major depressive disorder with seasonal pattern, the use of light
therapy is considered adjunctive to pharmacological intervention.
In terms of specific antidepressive agents, the extended release
formulation of bupropion is FDA approved for use with patients who
have major depressive disorder with seasonal pattern.
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3. Co-occurring psychiatric
disorders
Co-occurring psychiatric disorders
generally complicate treatment. Patients with major depressive disorder
who also have other psychiatric disorders have greater symptom severity
and are more challenging to treat than patients with major depressive
disorder alone. Yet the presence of co-occurring Axis I or Axis
II disorders should not lead clinicians to conclude that patients
are untreatable. Furthermore, other Axis I or Axis II disorders
may masquerade as major depressive disorder or may seem to co-occur
with the depression. In these cases, the other apparent disorders
evanesce with successful treatment of the underlying major depressive
disorder.
Dysthymic disorder is a chronic mood disorder with symptoms
that fall below the threshold for major depressive disorder. Because
of this, it may escape notice and may be inadequately treated. Nonetheless,
it can cause significant suffering and disability. In some patients,
both dysthymic disorder and major depressive disorder (so-called "double depression")
may be diagnosed.
In the treatment of dysthymic disorder and chronic major depressive
disorder, there is demonstrated efficacy for antidepressant medications,
including TCAs, SSRIs, other newer agents, and MAOIs. Unfortunately,
clinical trials provide little evidence of the relative efficacies
of particular agents (105, 579). In general,
pharmacotherapy of dysthymic disorder resembles that for episodes
of major depressive disorder; responses to antidepressant medications
by patients with dysthymic and chronic major depressive disorders
have been comparable to the responses by patients with major depressive
disorder episodes (580). In "double depression," antidepressant
medication can reverse not only the acute major depressive episode
but also the co-occurring dysthymic disorder (581).
Patients with dysthymic disorder, as well as patients with chronic
and severe major depressive disorder, typically have a better response
to the combination of pharmacotherapy and psychotherapy than to
either alone (294, 295), although results
of combined treatment studies have been mixed and complicated by
methodological problems (582).
As a group, anxiety disorders are the most commonly occurring
psychiatric disorders in patients with major depressive disorder
(583). A 2005 epidemiological study found that among
individuals with major depressive disorder, 62% also met
the criteria for generalized anxiety disorder, 52% for
social phobia, 50% for posttraumatic stress disorder (PTSD), 48% for
panic disorder, 43% for specific phobia, and 42% for obsessive-compulsive
disorder (584). In addition, agitation and anxiety,
including panic attacks, are frequent co-occurring symptoms of major
depressive disorder. The appearance of anxiety and agitation in
patients in a major depressive episode, particularly when accompanied
by racing or ruminative thoughts, should alert the clinician to
the possibility of a mixed mood state of a bipolar spectrum disorder
(585).
In studies of major depressive disorder with a co-occurring
anxiety disorder, both depressive symptoms and anxiety symptoms
respond to antidepressant medication treatment (586).
However, TCAs and SSRIs may initially worsen rather than alleviate
anxiety symptoms, including panic attacks; patients should be so
advised, and these medications should be introduced at low doses
and slowly increased when treating such patients. Adjunctive antipanic
agents, such as benzodiazepines, may be necessary as well. Selective
serotonin reuptake inhibitors are beneficial for patients with co-occurring
depression and social anxiety disorder (587) and co-occurring
depression and PTSD (588). Bupropion is comparable
to SSRIs in the treatment of patients with major depressive disorder
and low to moderate levels of anxiety (82), but studies
vary as to whether bupropion is (589) or is not (590)
effective in the treatment of panic disorder. Because benzodiazepines
are not antidepressants and carry their own adverse effects and
toxicity, including abuse and dependence, benzodiazepines should
not be the primary pharmacological agents for patients with major
depressive disorder who have co-occurring anxiety symptoms. These
agents may be used adjunctively with other antidepressive treatments, however
(591). Psychotherapies such as CBT, behavioral therapy,
and IPT may also be used to treat anxiety symptoms in the context
of major depressive disorder (591, 592).
Obsessive-compulsive symptoms are also common in patients
with major depressive episodes. In addition, obsessive-compulsive
disorder may appear as a co-occurring condition in some patients
with major depressive disorder. Clomipramine and SSRIs have demonstrated
efficacy in managing obsessive-compulsive symptoms in addition to
treating depression (593–595).
Patients with dementia are predisposed to depression, and
the psychiatrist should therefore screen for depression in this population,
although this is sometimes challenging (539). One screening
tool is the Cornell Scale for Depression in Dementia, which incorporates
self-report with caregiver and clinician ratings of depressive symptoms
(596). Treatment of major depressive disorder in the
cognitively impaired patient requires careful supervision and monitoring
of the patient's pharmacotherapy; this may entail education
of home health aides, nursing home staff, and others. Antidepressants
are likely to be efficacious in treatment of depressive symptoms, but
they do not improve cognition, and data on antidepressant use in
patients with dementia are limited (597–599).
Individuals with dementia are particularly susceptible to the adverse
effects of muscarinic blockade on memory and attention. Therefore,
individuals with dementia generally do best when given antidepressant
medications with the lowest possible degree of anticholinergic effect,
e.g., bupropion, fluoxetine, sertraline, trazodone, and, of the
tricyclic agents, desipramine or nortriptyline (600).
Alternatively, some patients do well when given stimulants in small
doses. Electroconvulsive therapy is also effective in major depressive disorder
superimposed on dementia. It should be used if medications are associated
with an excessive risk of adverse effects, are not tolerated, or
if immediate resolution of the major depressive disorder episode
is medically indicated (such as when it interferes with the patient's
acceptance of food). In individuals with dementia, ECT treatment
may be associated with a transient worsening of the patient's
cognitive status (239, 601, 602).
APA's Practice Guideline for the Treatment
of Patients With Alzheimer's Disease and Other Dementias,
Second Edition (539) contains more
information about the treatment of depression and dementia.
+
d. Substance use
disorders
Major depressive disorder frequently occurs with alcohol or other
substance abuse or dependence. Therefore, the psychiatrist should
obtain a detailed history of the patient's substance use.
With the patient's permission, family members, friends,
or co-workers can be collateral sources of information. If the evaluation
reveals a substance use disorder, this should be addressed in treatment.
A patient with major depressive disorder who has a co-occurring
substance use disorder is more likely to require hospitalization,
more likely to attempt suicide, and less likely to adhere to treatment
than a patient with major depressive disorder of similar severity
uncomplicated by substance use (603–608).
Detoxifying patients before initiating antidepressant medication
therapy is advisable when possible (110). Antidepressants
may be used to treat depressive symptoms following initiation of
abstinence if symptoms do not improve over time. It is difficult
to identify patients who should begin a regimen of antidepressant
medication therapy soon after initiation of abstinence, because
depressive symptoms may have been induced by intoxication and/or
withdrawal of the substance. A family history of major depressive
disorder, a history of major depressive disorder preceding alcohol
or other substance abuse, or a history of major depressive disorder during
periods of sobriety raises the likelihood that the patient might
benefit from antidepressant medication, which may then be started
early in treatment. Comparing the temporal pattern of symptoms with
the periods of use and abstinence of the substance may help to clarify
the patient's diagnosis. Repeated, longitudinal psychiatric
assessments may be necessary to distinguish substance-induced depressive
disorder from co-occurring major depressive disorder, particularly because
some individuals with substance use disorders reduce their substance
consumption once they achieve remission of a co-occurring major
depressive disorder.
Co-occurring substance use, especially with stimulant drugs, raises
the risk of deleterious interactions with MAOIs, although few such
events have been reported (609). Benzodiazepines and
other sedative-hypnotics carry the potential for abuse or dependence
and should rarely be prescribed to patients with co-occurring substance
use disorders, except as part of a brief detoxification regimen.
Hepatic dysfunction and hepatic enzyme induction frequently complicate
pharmacotherapy of patients with alcoholism and other substance
abuse. These conditions may require careful monitoring of blood
levels (as appropriate for the medication), therapeutic effects,
and side effects to avoid the opposing risks of either psychotropic medication
intoxication or underdosing.
For individuals with nicotine dependence who wish to stop
smoking, bupropion and nortriptyline treatment increase smoking
cessation rates by about twofold (109) and would be
useful to consider when selecting a specific antidepressive agent
(110).
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e. Personality disorders
For patients who exhibit symptoms of both major depressive disorder
and a personality disorder, psychiatrists should consider appropriate
treatment for each. Major depressive disorder should generally be
the initial target; if evidence of a personality disorder persists
when the depressive symptoms have resolved, psychotherapeutic and
adjunctive pharmacotherapeutic approaches may be helpful (610–615).
Patients with virtually any personality disorder exhibit a less
satisfactory antidepressant medication treatment response, in terms of
both social functioning and residual major depressive disorder symptoms,
than do individuals without personality disorders (616).
Personality disorders tend to interfere with treatment adherence and
development of a psychotherapeutic relationship. Furthermore, many
personality disorders increase the risk of episodes and increase
time to remission of major depressive disorder (617, 618).
Patients with various personality disorders also showed high rates
of new-onset major depressive episodes in a large prospective study
(619) and were at higher risk of attempting suicide
than patients without a co-occurring personality disorder (620).
Axis II diagnoses should be made with caution during a major
depressive episode, as depressive symptoms may exaggerate or mimic
personality traits. Treatment of the depressive disorder for these
patients can cause the apparent personality disorder symptoms to
remit or greatly diminish. Depressed patients may believe that their
current symptoms have been present from early life, when in fact
they only began with the current episode. Such misperceptions often hinder
accurate diagnosis. Some Cluster C personality disorders (e.g.,
avoidant, dependent, obsessive-compulsive) may reflect the residual
impact of recurrent depressive symptoms and may remit with maintenance
therapy (621).
Patients with borderline personality disorder have a particularly
high rate of major depressive disorder: 20% in a community
sample (622) and 50% in clinical samples (623). About
10%–15% of patients with major depressive
disorder have co-occurring borderline personality disorder (624),
and the percentage increases significantly in hospital and partial hospital
samples. Patients with borderline personality disorder often exhibit
mood lability, rejection sensitivity, inappropriate intense anger,
and depressive "mood crashes." These symptoms
are also common in patients with depression, particularly with atypical
features, complicating the diagnosis of these disorders. Antidepressants
are in general less effective in treating depressive episodes in
patients with major depressive disorder and borderline personality
disorder (625–629), with an overall response
rate to all therapies of 20% (630).
For patients with major depressive disorder and borderline personality
disorder, the personality disorder must also be addressed in treatment.
Symptoms of both disorders can initially be treated with an SSRI
or SNRI. Behavioral impulsivity and dyscontrol can also be treated
with low-dose antipsychotics, lithium, and some antiepileptic medications.
Monoamine oxidase inhibitors, although efficacious, are not recommended due
to the risk of serious side effects and the difficulties with adherence
to dietary restrictions. Psychotherapeutic approaches such as dialectical
behavioral therapy and psychodynamic psychotherapy have been useful
in treatment of borderline personality disorder as well. In patients
with borderline personality disorder particular attention must be
paid to the maintenance of therapeutic rapport, which is frequently disrupted, and
to the risk of self-harm and suicide, which occurs in 8%–10% of
such individuals. More information about the treatment of borderline
personality disorder can be found in APA's Practice
Guideline for Treatment of Patients With Borderline Personality
Disorder (610).
Eating disorders are also
common in patients with major depressive disorder (631).
Selective serotonin reuptake inhibitors are the best studied medications
for treatment of eating disorders, with fluoxetine having the most
evidence for the effective treatment of bulimia nervosa (170).
Antidepressants may be less effective in patients who are severely
underweight or malnourished, and normalizing weight should take
priority in these patients. Although SSRIs and psychotherapy are
widely used for patients with anorexia nervosa, the evidence base
on which these practices rest is modest. Patients with chronic anorexia
nervosa have in general been less responsive to formal psychotherapy.
On the other hand, evidence strongly supports the use of CBT in
the treatment of bulimia nervosa. Other therapies (e.g., IPT, group
therapies, family therapy) and medications such as SSRIs have also been
studied and have demonstrated effectiveness for this disorder. Bupropion
should be avoided in individuals with eating disorders due to the
increased risk of seizures in these patients. Electroconvulsive
therapy has not generally been useful in treating eating disorder
symptoms. Although there are few data to guide treatment of co-occurring
major depressive disorder and eating disorders, it is reasonable
to optimize treatment of both disorders based on these and other considerations.
More information about the treatment of eating disorders can be
found in APA's Practice Guideline for the
Treatment of Patients With Eating Disorders, Third Edition (170).
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B. Demographic and Psychosocial
Variables
+
1. Major psychosocial
stressors
Major depressive disorder may follow a substantial adverse life
event, especially one that involves the loss of an important relationship
or life role. This is particularly true in initial episodes of depression,
with psychosocial stressors being less associated with the onset
of recurrent episodes (632). Lower socioeconomic status,
nonmarried status, unemployment, urbanization, and violent trauma
seem to increase the risk of developing major depressive disorder,
whereas religious belief may decrease it (633–635).
Among those exposed to trauma, the prevalence of major depressive
disorder seems to be higher among persons who develop PTSD than among
those who do not (636). A recent meta-analysis underlined
that among refugees, PTSD was diagnosed in one of 10 and one in
20 had major depressive disorder (637).
Marital discord has been identified as a potent risk factor
in women for the development of depression (638, 639).
Problems in the family setting may become an ongoing stressor that hampers
the patient's response to treatment. Ambivalent, abusive,
rejecting, or highly dependent family relationships may predispose
an individual to major depressive disorder. The psychiatrist should
screen for such factors and consider family therapy, as indicated,
for these patients. Family therapy may be conducted in conjunction
with individual and pharmacological therapies. Even for instances
in which there is no apparent family dysfunction, it is important
to provide the family with education about the nature of the illness
and to enlist the family's support and cooperation with
the treatment.
The psychiatrist may choose to treat a major depressive episode
with an antidepressant, even if a major stressor preceded the episode.
Nonetheless, attention to the relationship of both prior and concurrent
life events to the onset, exacerbation, or maintenance of major
depressive disorder symptoms is an important aspect of the overall
treatment approach and may enhance the therapeutic alliance, help
to prevent relapse, and guide the current treatment. A close relationship between
a life stressor and major depressive disorder suggests the potential
utility of a psychotherapeutic intervention coupled, as indicated,
with somatic treatment.
Bereavement is a particularly
severe stressor that can trigger a major depressive episode. However,
grief, the natural response to bereavement, resembles depression,
and this sometimes causes confusion. Psychiatrists treating bereaved individuals
should differentiate symptoms of normal acute grief, complicated
grief, and major depressive disorder, as each of these disorders
requires a unique management plan. Normal grief should be treated
with support and psychoeducation about symptoms and the course of
mourning; complicated grief requires a targeted psychotherapy, with
or without concomitant medication (535, 640);
and major depressive disorder should be treated with medication
and/or depression-focused psychotherapy.
Acute grief is the universal reaction to loss of a loved one, and
it is a highly dysphoric and disruptive state (641).
Acute grief is characterized by prominent yearning and longing for the
person who died, recurrent pangs of sadness and other painful emotions,
preoccupation with thoughts and memories of the person who died,
and relative lack of interest in other activities and people. Despite
the similarity with depression, only about 20% of bereaved
people meet the criteria for major depressive disorder. Successful
mourning leads to resolution of acute grief over a period of about
6 months. Integrated grief remains as a permanent state in which
there is ongoing sadness about the loss often accompanied by ongoing
feelings of yearning for the person who died. However, when the
death is accepted, and grief integrated, the person is again interested
in his or her own life and other people.
Complicated grief is a recently recognized syndrome in which
symptoms of acute grief are prolonged, associated with intense and
persistent yearning and longing for the deceased person, and complicated
by guilty or angry ruminations related to the death and/or
avoidance behavior. Studies of individuals bereaved by the attacks
of September, 11, 2001, have demonstrated that complicated grief
is a distinct condition from either major depressive disorder or
PTSD (642, 643). It is important to note
that treatment for depression is not effective in relieving symptoms
of complicated grief (640).
Although DSM-IV-TR excludes the diagnosis of major depressive
disorder during the first 2 months following bereavement, major
depressive disorder in the wake of bereavement can impede the course
of mourning. Bereavement-related depression responds to antidepressant medication
and should be treated; otherwise it is likely to become chronic
and impairing (644). There is no indication that depression
in the context of bereavement differs from other major depressive
episodes, and data indicate that chronicity of bereavement-related
depression over 13 months is similar to chronicity of depression
in other contexts (644).
+
3. Culture and ethnicity
An appreciation of cultural
and ethnic variables is important to the accurate diagnosis of major
depressive disorder and in the selection and conduct of psychotherapy
and pharmacotherapy (645–647). Although major
depressive disorder is seen across cultural and ethnic groups, and
the age at onset, gender differences, and prevalence of co-occurring
conditions are similar across cultures, the actual incidence and prevalence
of depression vary (648–656). Furthermore, some
evidence suggests that patients of different cultures express depressive
symptoms differently, particularly somatic and psychomotor symptoms
(657). Specific cultural variables may also influence
the assessment of major depressive disorder symptoms. For example,
in some cultures, depressive symptoms may be more likely to be attributed
to physical diseases (658). In addition, language barriers
can impede accurate psychiatric diagnosis and effective treatment
(659), and, even when speaking the same language, individuals
of different cultures may use different psychological terms to describe
their symptoms (6, 7). In addition, the
importance of individual experience should not be underestimated
in the therapeutic relationship (660). The assessment
and treatment process can also be influenced by religious beliefs
(5). Individuals with high levels of religious involvement
may have diminished rates of major depressive disorder (661, 662).
Differences in the utilization of psychiatric services by some
cultural and ethnic groups have been well documented. Relative to
Caucasians, African Americans and Latinos appear less likely to
receive treatment for mood disorders (663–665).
Several studies have underscored the lower frequency of use
of antidepressant drugs (and more specifically, SSRIs) (648, 666–669),
ECT (670), and psychotherapy (671, 672)
in minority groups, compared with Caucasians. If treatment for depression
is initiated, African Americans are disproportionately more likely
to receive pharmacotherapy (672), to drop out of treatment
(673), and to develop chronic symptoms (674)
than are Caucasian patients. These differences in mental health
service use by minority populations appear to have a number of potential
causes. Cultures and ethnicities may differ in the degree to which
psychiatric illness is stigmatized (675) and in the
preferences of individuals for treatment (676–678).
For example, studies have found that Hispanic individuals were more
likely to prefer counseling than whites, whereas African Americans
varied across studies in their relative preference for counseling
rather than pharmacotherapy (6, 679).
Service use by minority populations is more affected by financial
constraints (including those related to insurance) and social barriers
(e.g., stigma) than the use of comparable services by Caucasians
(664, 680, 681). In addition,
pharmacological factors may play a role in patient preferences and
adherence, as ethnic groups may differ in their relative rates of
metabolism (682–684) and side effects and response
to antidepressant medications (685–688).
The combined prevalence of major depression, dysthymic disorder,
and "minor" depression in individuals over age
60 years has been reported to be as high as 25%, and major
depressive disorder has been reported to be present in 14%–42% of
nursing home residents (689). Elderly patients typically
display more vegetative signs and cognitive disturbance but report
less subjective dysphoria than younger patients. Major depressive
disorder may consequently be misattributed to physical illness,
dementia, or the aging process itself. For older adults with chronic
illness or physical disability, including those expected to remain
in a long-term care facility, depression may be erroneously regarded
as expected or inevitable, and therefore untreatable (690).
As a result, it is common for major depressive disorder to be undiagnosed
and untreated among older adults.
As in all depressed individuals, a suicide risk assessment is
an essential element of the evaluation process in older individuals.
Although older adults constitute only 13% of the U.S. population,
they account for 19% of all suicides, with elderly white
men having the highest rates of completed suicides (691).
This increase in suicide risk with aging in some demographic groups
should be taken into consideration when estimating suicide risk
and developing a plan to reduce such risk.
Several general medical conditions common among older adults
are risk factors for depression. In addition, the presence of depression
often exacerbates the course of the co-occurring medical condition
and is a risk factor for poor outcomes. For example, elderly patients
who are depressed and recovering from hip fractures have poorer
functional outcomes from rehabilitative care and are less likely
to return to full ambulation, compared with older adults with hip
fractures who are not depressed (692–694).
There is also frequent co-occurrence of major depressive disorder
and cardiovascular disease; 25% or more of those with cardiovascular
disease also have major depressive disorder, and co-occurring depression
increases the morbidity and mortality of cardiovascular illness
(695–697). The term vascular depression has
been used to describe depression occurring in late life in patients
with clinical evidence of cerebrovascular disease (698),
although at this time it has not been established as a unique subtype
of depression. In addition, major depressive disorder is a complication
of cerebral infarction (see Section III.C.3). There is also a high
prevalence of major depressive disorder among patients with dementia,
and mood symptoms may precede cognitive symptoms and diagnosis of
dementia (see Section III.A.3.C).
Just as patients with medical conditions should be screened
for depression, patients exhibiting symptoms of depression should
be thoroughly evaluated for the presence of co-occurring medical
conditions, as major depressive disorder and general medical illnesses
frequently coexist, especially in elderly patients (696, 699).
This evaluation should include a systematic review of the patient's
medications. Some medications have been reported to induce depressive symptoms
(e.g., beta-blockers), although they may simply be producing lethargy
and fatigue that mimic depression (700, 701).
Consequently, the psychiatrist must carefully assess whether a given
medication is contributing to depressive symptoms before prematurely
altering what may be a valuable treatment. Patients undergoing their
first major depressive episode in old age should be assessed for
an undiagnosed neurological or other general medical disorder that
may be responsible for the depressive symptoms. Similarly, frequently
co-occurring symptoms of major depressive disorder, such as lassitude
or pain, may mimic symptoms of a general medical condition. Pain
in older adults, especially from orthopedic sources, may contribute
significantly to the presence of depression in this population (702).
Once the patient has been thoroughly assessed, the treatment
considerations for depressed geriatric patients are essentially
the same as for younger patients. A meta-analysis has shown that
SSRIs; TCAs; and cognitive-behavioral, behavioral, and psychodynamic
therapies are all superior to placebo in the acute treatment for
depression in subjects older than age 55 years (703–708).
In addition, treatments for depression have been shown to be effective
in nursing home populations (709, 710),
as well as in inpatient and traditional outpatient settings of care.
However, compared with younger individuals, older patients may be
more likely to experience relapses and less likely to achieve a
full response to treatment with antidepressant medications (711–714).
In contrast, ECT is not only effective as a treatment for depression
among older individuals, but those over age 65 years actually have better
response rates than younger patients (715). Consideration
should also be given to combined treatment with pharmacotherapy
and psychotherapy, as evidence for the efficacy of stand-alone psychotherapy,
such as CBT, is weak (716). Although the role of stimulants
for antidepressant monotherapy is very limited, these compounds
have some role in apathetic major depressive disorder in elderly
patients with complicating general medical conditions. Late-life
depression associated with vascular disease has also been found
to respond well to treatment with antidepressants (717)
and, in one unreplicated study, to TMS (718). Furthermore,
in a recent randomized controlled trial, administering escitalopram prophylactically
to patients who had experienced a stroke resulted in lower rates
of depression at 12 months (334). Psychosocial factors
are also frequent contributors to depression among older adults
and should be addressed as part of the treatment plan (719, 720).
There are several considerations in prescribing medications
for elderly patients. As with any patient, the psychiatrist should
attempt to use as few medications as possible, and this is especially
important given the complexity and multiplicity of issues in elderly
patients. It is often useful to use medications that address several
issues at once, such as choosing mirtazapine for a depressed, elderly
patient with weight loss and insomnia. Elderly patients typically
require a lower oral dose than younger patients to yield a particular
blood level, and they tolerate a given blood level less well. Nevertheless, the
blood levels at which antidepressant medications are maximally effective
for elderly patients appear to be the same as those for younger
patients (721, 722). Dose regimens should
be adjusted for age-related metabolic changes, with close attention
paid to hepatic and renal metabolic function. For patients who are
receiving other medications, careful attention should be paid to
potential drug interactions (160, 161, 723–725)
(Tables 4 and 5).
Elderly patients are particularly prone to orthostatic hypotension
and cholinergic blockade; for this reason, SSRIs, SNRIs, and other
antidepressants should be considered over MAOIs or TCAs. Among the
TCAs, desipramine and nortriptyline should be considered over amitriptyline,
imipramine, and doxepin, due to increasing sensitivity to side effects
and toxicity with advancing age. Treatment with SSRIs causes the
syndrome of inappropriate antidiuretic hormone secretion (SIADH)
at a higher rate in elderly patients than in younger patients (726, 727).
Patients taking SSRIs have a three times greater risk of developing
SIADH than patients taking other antidepressants, with the greatest
risk among elderly patients (728).
For maintenance treatment, one study has shown that antidepressant
medication (nortriptyline) and IPT are effective for elderly patients
with recurrent major depressive disorder (315), yet
a trend toward superior response was observed for combined pharmacotherapy
and IPT, compared with pharmacotherapy alone. Another study demonstrated
that paroxetine (but not monthly psychotherapy) was effective as maintenance
therapy for elderly patients (729). For older patients
with particularly severe or treatment-resistant depressive illness,
addition of maintenance ECT to nortriptyline appears to improve
treatment outcome (730). Among elderly patients who
have had prior depression, the risk of developing another episode
of major depressive disorder is substantially increased in those
who develop or report sleep disturbance (731). Sleep
disturbances may function as independent predictors of depression
and are not simply prodromal depressive symptoms.
A body of systematic evidence suggests a particular value for
various forms of collaborative or team-based care for elderly patients.
Such care combines, for example, specialty mental health consultation/intervention
with primary care management or community-based outreach and monitoring of
care (732, 733). Older adults with depression
can benefit from integration of mental health services in the setting where
they typically receive their general medical care. It has been shown
that support for algorithm-driven depression care processes within
the primary care outpatient practice can lead to increased treatment
adherence and improved clinical outcomes, including a reduction
in mortality (734).
As part of the diagnostic assessment of a woman with major depressive
disorder, there should be a detailed inquiry regarding reproductive
life history and mood symptoms associated with reproductive life
events, such as menses, use of oral contraceptive agents, peripartum,
infertility, menopause, and pregnancy loss due to abortions, miscarriages, and
perinatal losses. Although associations between reproductive factors
and major depressive disorder are neither widespread nor consistent,
some women may be particularly vulnerable to fluctuations in gonadal
hormone levels (735). The perimenopausal transition
has been identified as a high-risk period for new-onset major depressive
disorder, with high variability of sex hormones as a risk factor
(736, 737). Women in the perimenopausal
transition may benefit from the use of serotonergic antidepressants,
for mood and also for somatic symptoms such as hot flashes (738).
Since women are often caretakers in families, psychosocial
stresses such as caring for an ill husband, child, or parent must
be carefully assessed. Treating depressed mothers is associated
with improved prognosis for their children as well (739).
Maternal remission from depression was associated after 3 months
with significantly decreased diagnoses and symptoms in their children,
compared with children of mothers whose depression had not remitted.
Thus, treating depressed mothers may crucially benefit both the
patients and their children.
The patient's gender also factors into other treatment
considerations for major depressive disorder. For example, the risks
of certain adverse effects from treatments may also differ by gender.
When prescribing trazodone to men, it is important to provide education
about the risk of priapism (174). Older men typically
have prostatic hypertrophy, making them particularly sensitive to
anticholinergic effects of some antidepressants on the bladder outlet.
While both men and women may experience decreased libido or anorgasmia while
taking SSRIs, men may also experience ejaculatory dysfunction (740).
Some women who are taking birth control pills require higher doses
of TCA medications because of the induction of the hepatic enzymes
responsible for medication metabolism. Similarly, medications that
induce hepatic enzymes, such as anticonvulsants used as adjunctive
treatment, reduce the effectiveness of contraceptives.
+
6. Pregnancy and
postpartum
Major depressive disorder during pregnancy and postpartum presents
unique treatment considerations. During these periods, approximately
10% to 15% of perinatal women will experience
major depressive disorder, which is at least as common as rates
reported for women in nonreproductive states (741, 742).
Evaluation and communication of risks and benefits of antidepressants
during pregnancy and breast-feeding is challenging and must include
the risks of untreated maternal mood disorder, the limited body
of research that informs safety of antidepressants, and the general
lack of prospective long-term data following antidepressant exposure
in utero and through lactation.
Depression-focused psychotherapy or other nonmedication therapies
may be considered first for some women, and psychotherapy should
be considered as part of the treatment plan whenever possible. As
childbearing is a life stressor with psychosocial repercussions
that may be amenable to psychotherapy, psychotherapy may serve to
minimize medication exposure in some women. Although there is little
controlled research, psychotherapies appear efficacious in antenatal
and postpartum depression, with IPT being the best studied (743, 744).
Therefore, depression-focused psychotherapies such as IPT and CBT
should be considered in the treatment plan as a first-line treatment
or in combination with medication to minimize medication exposure,
especially if the individual has experienced a good response to
a particular psychotherapy in the past or strongly prefers to avoid medication.
+
a. Depression during
pregnancy
Psychiatrists should be familiar with the management of major
depressive disorder in the context of pregnancy (745). More
than 80% of women in the United States will have children
(746), and about half of pregnancies are unplanned (747).
Therefore, pregnanciesincluding unplanned pregnanciesare
likely to occur during the course of treatment of major depressive
disorder, as it is often a chronic and/or recurrent condition
that is a major cause of disability during the reproductive years
and disproportionately affects women, compared with men. In consideration
of the high prevalence of both unplanned pregnancy and major depressive
disorder in women, the risks and benefits of antidepressants and
untreated maternal depression during pregnancy should be discussed
with all female patients who have reproductive potential. Whenever
possible, a pregnancy should be planned in consultation with a treating
psychiatrist, who may wish to consult with a specialist in perinatal
psychiatry. For women who are pregnant or planning to become pregnant,
decisions about treatment for depression require weighing multiple benefits
and risks for the woman as well as for the fetus. Making such decisions
may require several discussions and will generally involve discussions
with the patient's partner as well as her obstetrician.
Antidepressant medications carry some reported risks in pregnancy
(see below), but so does untreated depression. Suicide risk, marital
discord, the inability to engage in appropriate obstetrical care,
and difficulty caring for other children must also be considered.
There are also serious and well-characterized risks to the fetus
of exposure to maternal major depressive disorder, including the
possibility of low birth weight secondary to poor maternal weight
gain (or frank weight loss) and increased risk of obstetrical complications such
as premature delivery (748).
Antidepressant efficacy has not been determined for pregnant
women, and questions remain as to whether medications have equivalent
efficacy during pregnancy, compared with the nonpregnant state.
Some safety data are available, but the findings often conflict,
making data interpretation challenging and difficult to apply to
the care of individual patients. Nevertheless, antidepressant medication
should be considered and discussed as an option with pregnant women
who have moderate to severe major depressive disorder.
For women who are in remission from major depressive disorder
and receiving maintenance medication and/or for women deemed
to be at high risk for a recurrence if the medication is discontinued,
the risks of treatment with medications must also be weighed against
the risks of alternative treatment options and untreated depression.
Relapse rates for women with a history of major depressive disorder
are high during pregnancy, especially if antidepressants are discontinued
(749).
+
1. Risks of antidepressants during pregnancy
The impact of the duration and timing of antidepressant exposure
during pregnancy requires further study. Wisner et al. (750)
reviewed the risks associated with the use of antidepressants during
pregnancy, and a growing body of complicated literature has followed.
Overall, risk of teratogenicity with antidepressants following first
trimester exposure appears to be low, although some rare birth defects
have been observed to occur at higher rates with use of specific
SSRIs (751, 752). First-trimester paroxetine
exposure has been associated with cardiac malformations, a finding
that resulted in changes in FDA labeling for paroxetine from C to
D (753); labeling changes have been made to all SSRI
antidepressants with regard to this possibility when used during
pregnancy. There have been conflicting results regarding whether
first-trimester paroxetine exposure and cardiac teratogenicity are associated
(754, 755). For fluoxetine, one study
(756) found a higher incidence of three or more minor
physical anomalies in infants exposed to fluoxetine than in a control
group, and fetuses exposed to fluoxetine after 25 weeks' gestation
had lower birth weights, which were associated with lower maternal
weight gain. Although one case-control study reported a potential
association between late antenatal SSRI use and the rare but serious
condition of persistent pulmonary hypertension in the newborn (PPHN)
(757), two subsequent retrospective chart review studies
showed no such association (758, 759).
An additional case-control study (760) showed a marginally
significant increase in the relative risk of PPHN with SSRI use,
but the estimated rate of PPHN occurrence was 1.5 per 1,000 births,
which is less than the rate of 2.7 per 1,000 births reported by
others (758) in non-SSRI exposed infants. Therefore,
while many physicians are concerned about the reported association
between SSRIs and PPHN, the preponderance of evidence from published
studies on this topic does not support an association. Use of SSRIs
may also be associated with prematurity (761, 762),
although untreated depression and stress during pregnancy may also
contribute to the risk of prematurity (748, 763).
Some naturalistic studies and health care utilization studies suggest that
antidepressants are associated with shorter length of gestation
(761, 762), but there have been no randomized
studies of the treatment of antenatal major depressive disorder
that would adequately control for untreated maternal depression, antidepressant
use, and confounding variables related to treatment selection. With
late pregnancy antidepressant use, some but not all studies show
a risk of medical complications such as prematurity and a transient neonatal
withdrawal/adaptation syndrome (761, 764).
The syndrome in the neonate appears to be associated with antidepressant
use in the third trimester, has been reported in babies exposed
in utero to TCAs and SSRIs, and includes transient symptoms such
as jitteriness, tremor, difficulty with feedings, and other symptoms
(764). Several studies, involving relatively small
samples, have examined effects of antidepressant exposure during
pregnancy on subsequent childhood behavior and development and found
minimal (765) or no (766–768)
effects on language, cognition, or motor or behavioral development independent
of maternal depressed mood during pregnancy and the child's
early life (766, 767).
+
2. Implementation of pharmacotherapy during pregnancy
No controlled trials inform the use of antidepressants during pregnancy.
Dose requirements may change during pregnancy because of changes
in volume of distribution, hepatic metabolism, protein binding,
and gastrointestinal absorption. Pharmacokinetic changes in late
pregnancy may result in lower blood levels, with clinical implications,
although more study is needed to develop monitoring and dosing guidelines. The
limited data in this area demonstrate that pregnant women metabolize
TCAs and SSRIs more rapidly in late pregnancy (769–774).
A number of factors influence antidepressant choice during
pregnancy. If a woman has had a history of a good response to or
is already taking a particular antidepressant, it is logical to
consider that antidepressant among first-line treatments in an effort
to minimize the number of different medication exposures. Using
a single agent is also preferable to using several medications concomitantly.
Because paroxetine use is classified as having a higher level of
risk than other SSRIs, it should not be considered a first-line
treatment when selecting a new antidepressant for a pregnant patient.
Fluoxetine has the longest half-life and is more likely to be demonstrated
at high levels in newborns after in utero exposure. Sertraline has
been demonstrated to have lower cord blood levels than other SSRIs,
although the clinical significance of this is unknown (775).
Although there are few data for bupropion and safety in pregnancy,
its benefits for smoking cessation may make it especially useful
in women who have major depressive disorder and who smoke cigarettes,
as tobacco is a known teratogen. Given these data, it is recommended
that consideration be given to using an antidepressant with some
available safety information that has been studied in pregnant women.
For women who discontinue medication during pregnancy and are deemed
at risk for postpartum depression, medication can be restarted following
delivery.
Electroconvulsive therapy is also recommended as a treatment
option for major depressive disorder during pregnancy (239).
The current literature supports the safety for mother and fetus,
as well as the efficacy of ECT during pregnancy (239).
The psychiatrist should consider ECT for pregnant patients with
moderate to severe depression who are unresponsive to or unsuitable
for pharmacotherapy, for pregnant patients with major depressive
disorder with psychotic features, and for pregnant patients electing
to use this modality as a matter of preference after having weighed
the relative risks and benefits of ECT and other treatment options.
For details on the use of ECT during pregnancy, refer to The Practice
of Electroconvulsive Therapy: Recommendations for Treatment, Training,
and Privileging (A Task Force Report of the American Psychiatric
Association) (239).
+
b. Postpartum depression
Major depressive disorder with postpartum onset is defined in
DSM-IV-TR as a major depressive episode with onset within 4 weeks
of delivery. However, the occurrence and course of major depressive
disorder in childbearing women is heterogeneous, and definitions
of postpartum depression may evolve with continued research (16, 776).
In major depressive disorder with postpartum onset, anxiety symptoms are
more prevalent than in major depressive disorder occurring at other
times (777). It is not uncommon for women with postpartum
depression to experience obsessions and/or compulsions,
and obsessions may often involve thoughts of harming the baby, which
must be differentiated from postpartum psychosis. Psychiatrists
should provide psychoeducation about major depressive disorder to
pregnant and postpartum women and their families to improve the
detection of major depressive disorder during pregnancy and the postpartum
period.
Several other psychiatric conditions may follow childbirth
(778). The transient 7- to 10-day depressive condition referred
to as "postpartum blues" is by definition too
mild to meet the criteria for major depressive disorder and does
not require medication. In addition to providing reassurance, psychiatrists
should encourage mothers who experience postpartum blues to increase
psychosocial support and obtain help with the care of the infant.
Puerperal psychosis is a more severe disorder complicating one to
two of 1,000 births. Although postpartum psychosis is rare, women
with this disorder may have homicidal impulses toward the newborn;
for this reason, careful assessment of homicidal as well as suicidal
ideation, intention, and plans is important. Postpartum psychosis
must always be treated as a psychiatric emergency, with hospitalization
considered for the safety of the mother and baby (779).
Many patients who have had episodes of this type ultimately prove
to have bipolar disorder (780).
The woman's parenting skills for both the newborn
baby and any other children in her care must be carefully assessed. Untreated
maternal major depressive disorder, and specifically postpartum
depression, have negative consequences for children, with adverse
effects on attachment and child development (781, 782).
Major depressive disorder can seriously interfere with the new mother's
ability to provide physically and emotionally appropriate care for
her baby and other children. The psychiatrist should work with the
patient to develop a plan to manage this effect, such as enlisting
family members to assist with child care.
Antidepressants are often prescribed for postpartum depression,
according to the same principles delineated for other types of major
depressive disorder, despite a limited number of controlled studies.
Two placebo-controlled trials of SSRIs (fluoxetine and paroxetine)
have been published for the treatment of postpartum depression,
with fluoxetine appearing more efficacious than placebo and paroxetine
being comparable to placebo on primary outcome measures of depressive symptoms
(783, 784). Wisner et al. (785)
did not find a difference in response and remission rates in a randomized
controlled trial of sertraline versus nortriptyline for postpartum major
depressive disorder. Open studies of other antidepressants in postpartum
women suggest efficacy, although some studies included only a small
number of participants (786). Paroxetine alone and
paroxetine plus CBT both produced a significant change from baseline
in one study, but there was no placebo-only group for comparison
(787).
Patients and clinicians are often concerned about the risks of
possible exposure to antidepressants during breast-feeding. These
risks, however, must be weighed against the well-known, and at times
profound, risks to the woman and her children of untreated postpartum
depression. Mothers should be counseled regarding the relative risks
and benefits when making these treatment decisions. Antidepressant
medications are considered compatible with breast-feeding, but long-term
data are not available regarding risks and benefits. Although there
have been some suspected case reports of adverse effects in breast-feeding
infants exposed to maternal antidepressants, most studies show low
levels of exposure via breast milk, with the exception of fluoxetine,
which appears to have a dose-related risk for detectable levels
in infant sera (788, 789). At this time,
there are no studies which have determined a "safe" amount
and duration of antidepressant exposure in the fetus and newborn.
However, exposure to antidepressants via breast milk is considered
substantially lower than in-utero exposure. Women who elect to breast-feed
while taking antidepressants should be supported in doing so, given
the widely known health benefits (e.g., immune system effects) to
infants who are breast-fed. Similarly, women who elect to bottle-feed
should also be supported in this decision. Some women will not accept
treatment with antidepressant medication while they are breast-feeding.
Depression-focused psychotherapy can be recommended instead.
Major depressive disorder is one and one-half to three times as
common among those with a first-degree biological relative affected
with the disorder as in the general population. In addition, the
rates of depression, anxiety, and other disorders are increased
more than two- to sixfold in the offspring of depressed parents.
A family history of depression is associated with an earlier age
at onset of depression (790), and children of depressed
parents are more likely to have depression with a chronic and recurrent
course (791). Furthermore, a family history of recurrent
major depressive disorder increases the chances that the patient's
own illness will be recurrent and that the patient will not fully
recover between episodes (792). A family history of
bipolar I disorder, bipolar II disorder, or acute psychosis probably
increases the chances that the patient's own major depressive
disorder is a manifestation of bipolar rather than unipolar depression,
and that antidepressant medication therapy may incite a switch to
mania (793). Patients with such a family history should
be questioned particularly closely regarding a prior history of
mania or hypomania and should be carefully observed for signs of
a switch to mania during treatment with antidepressant medication.
There are no real predictors of response to individual antidepressants,
yet in the absence of other information clinicians sometimes rely
on family history of therapeutic benefit to select a specific medication
for a family member. Although it does not have specific support
in the literature, this practice appears reasonable.
+
C. Treatment Implications
of Co-occurring General Medical Conditions
In patients with co-occurring medical conditions, there is
a higher prevalence of major depressive disorder than in the general
population. Furthermore, co-occurring medical conditions in patients
with major depressive disorder are associated with poorer outcome
(794, 795). A number of medical conditions
are known to cause mood symptoms, such as stroke, hypothyroidism,
carcinoma of the pancreas, and many others. Apart from directly
causing depressive symptoms, debilitating, painful, and chronic
medical conditions often constitute an ongoing stressor that predisposes
patients to depressive episodes. Nevertheless, a depressive episode, in
any context, is never a "normal" response to illness
and consequently warrants treatment.
In addition to the increased risk of major depressive disorder
with general medical conditions, depressive episodes increase the
risk of certain general medical conditions, such as heart disease.
(796). Due to the interrelationship between depression
and medical illness, it is very important to recognize and treat
depressive symptoms in medically ill patients, and vice versa. The
psychiatrist should also attend to the potential for interactions
between antidepressants and the co-occurring medical conditions
as well as any nonpsychiatric medications that the patient may be
taking.
The presence of treated or untreated hypertension may influence
the choice of an antidepressant, as a few antidepressant medications
have been associated with increases in blood pressure. With SNRIs
such as venlafaxine and duloxetine, dose-dependent elevations in
blood pressure are usually mild, although more severe hypertension
has also been observed (166, 797). However,
another study found no increase in hypertension with duloxetine
dosed up to 80 mg/day (798). Hypertension induced
by SNRIs may respond to a decrease in the medication dose, or an
alternative antidepressant medication may be considered. Alternatively,
for a patient with well-controlled depressive symptoms, it may be
preferable to add an antihypertensive agent rather than risk a depressive
relapse or recurrence with medication tapering.
Antihypertensive agents and antidepressant medications may
interact to either intensify or counteract the effect of the antihypertensive
therapy (799). The action of antihypertensive agents
that block alpha receptors (e.g., prazosin) may be intensified by
antidepressant medications that block these same receptors, notably
the TCAs and trazodone. Tricyclic antidepressants may antagonize
the therapeutic actions of guanethidine, clonidine, or alpha-methyldopa.
Concomitant antihypertensive treatment, especially with diuretics,
increases the likelihood that TCAs, trazodone, or MAOIs will induce
symptomatic orthostatic hypotension.
Side effects of antihypertensive agents, such as fatigue or sexual
dysfunction, may also confound the evaluation and interpretation
of depressive symptoms. It has also been thought that beta-blockers,
especially propranolol, may account for depressive symptoms in some
patients, but this association has been questioned (700, 701).
Depression increases the risk of cardiovascular disease (800).
In addition, patients who are depressed following a myocardial infarction
have an increased rate of mortality, compared with patients without
depression (801–803). Following an acute myocardial
infarction, the decreased survival rates of depressed patients may
in part be due to lower heart rate variability in these patients,
compared with nondepressed patients (804). Particularly
in patients with a history of major depressive disorder (805),
there is evidence that the depressive symptoms associated with cardiac
illness respond to antidepressants (717, 806, 807).
However, studies in which the attempt has been made to influence
cardiac-related mortality through treatment of depression have shown
mixed results (808–811).
A depressed patient with a history of a cardiac problem should
be monitored for the emergence of cardiac symptoms, ECG changes,
persistent tachycardia, or orthostatic blood pressure decrements.
Consultation with the patient's cardiologist before and
during antidepressant medication treatment may be advisable, especially
for patients who have recently had a myocardial infarction. Increases
in heart rate and blood pressure may be associated with the use
of agents with noradrenergic properties such as SNRIs and stimulants;
thus, changes in heart rate and blood pressure should be assessed
after treatment with these agents is instituted in patients with coronary
artery disease, hypertension, or congestive heart failure. Although
TCAs have been used effectively to treat major depressive disorder
in patients with some forms of ischemic heart disease (812),
psychiatrists should take particular care in using TCAs for patients
with a history of ventricular arrhythmia, subclinical sinus node
dysfunction, conduction defects (including asymptomatic conduction
defects), prolonged QT intervals, or a recent history of myocardial
infarction (184, 185, 813–818).
Selective serotonin reuptake inhibitors, SNRIs, and bupropion appear
to be safer for patients with preexisting cardiac disease; several
SSRIs have been used safely in patients with cardiac disease in
large clinical trials (807, 809, 810, 819).
Electroconvulsive therapy can also be used safely in individuals
with cardiac disease or arrhythmias, although specialist consultation
and modifications in ECT technique or anesthesia may be indicated
(239, 245, 820–822).
Monamine oxidase inhibitors do not adversely affect cardiac conduction,
rhythm, or contraction but may induce orthostatic hypotension and
have risks relating to drug-food and drug-drug interactions.
Depression is observed in approximately one-third to one-half
of individuals in the weeks to months following a stroke, with a
substantial proportion developing major depressive disorder (334, 823, 824).
Although conclusions of meta-analyses are mixed (825, 826),
some research suggests that antidepressant treatment immediately
following a stroke may reduce rates of depression (334)
and possibly mortality (827). Among psychotherapeutic
approaches to preventing depression after stroke, problem-solving
therapy has been best studied, but findings are inconsistent (334, 825).
When depression develops after a stroke, it has detrimental
effects on quality of life (823). In addition, the
presence of depression 1 month following a stroke has been associated with
an increase in subsequent mortality (828). Use of screening
tools such as the PHQ-9 may help to identify depressive episodes
after stroke (829), and care management may improve
outcomes once poststroke depression is recognized (830).
Psychotherapies have not been well studied as treatments for poststroke
depression; however, a meta-analysis of randomized trials that have
been conducted did not show efficacy (825). Findings
on the therapeutic effects of antidepressants in post-stroke depression
have been mixed, perhaps due to the substantial heterogeneity of
study populations and designs (831, 832).
Although a meta-analysis did not show any difference in the rate
of depressive remission with antidepressant treatments compared
with placebo (832), patients receiving an antidepressant
did show more improvement in depressive symptoms (831, 832)
and a greater proportion were classified as treatment responders
(831). Individual randomized controlled trials have
shown therapeutic benefits for several SSRIs, including fluoxetine,
sertraline, and citalopram (833–836), and
for the TCA nortriptyline (837, 838);
however, not all studies have shown benefit for some of these agents
(837, 839–841). Nevertheless,
for individuals with poststroke depressive symptoms, a trial of
antidepressant therapy may be considered, with SSRIs being better
tolerated and having fewer contraindications in this older and more
medically ill population (842, 843). However,
in individuals who are receiving concomitant treatment with anticoagulant
(e.g., warfarin) or antiplatelet (e.g., dipyridamole, clopidogrel,
aspirin) medications, it is important to consider the potential
for an increased bleeding risk due to drug-drug interactions with
antidepressants (844, 845).
Major depressive disorder occurs to some degree in 40%–50% of
patients with Parkinson's disease. Patients with Parkinson's
disease experience alterations of serotonergic and noradrenergic
systems that may induce depression. There is no evidence favoring
any particular antidepressant medication from the standpoint of
therapeutic efficacy and safety for patients with Parkinson's
disease complicated by major depressive disorder (846).
A meta-analysis of placebo-controlled studies identified a clear
benefit for both active treatment and placebo, but it did not find
differences between them (847). Although SSRIs can
be used, there is some risk of worsening of Parkinson's
disease symptoms (increases in "off" time and
exacerbation of tremor) with agents that are primarily serotonergic
(848). Bupropion, in contrast, exerts a beneficial
effect on the symptoms of Parkinson's disease in some patients
but may also induce psychotic symptoms, perhaps because of its agonistic
action in the dopaminergic system (849). Noradrenergic
agents and SNRIs may also be preferable to SSRIs. Nonselective MAOIs
(e.g., tranylcypromine, phenelzine, isocarboxazid) may adversely
interact with l-dopa products (850).
Selegiline, also known as l-deprenyl,
is a selective type B MAOI recommended in the treatment of Parkinson's
disease. Selegiline loses its specificity for MAO B in doses greater
than 10 mg/day. As a result, it may induce serotonin syndrome
when given in higher doses in conjunction with serotonin-enhancing
antidepressant medications. The theoretical benefits of the antimuscarinic
effects of some of the tricyclic agents in the treatment of patients
with major depressive disorder with Parkinson's disease
are offset by the memory impairment that may result. Amoxapine,
an antidepressant medication with dopamine-receptor-blocking properties,
should be avoided for patients who have Parkinson's disease.
Lithium may, in some instances, induce or exacerbate parkinsonian
symptoms. Electroconvulsive therapy exerts a transient beneficial
effect on the symptoms of idiopathic Parkinson's disease
in many patients (851, 852); however,
it might occasionally worsen l-dopa-induced
dyskinesias and induce a transient interictal delirium (853),
which necessitates reductions in doses of dopamine agonist medications
(239).
The prevalence of depression in individuals with epilepsy
appears to be increased in secondary and tertiary care center samples,
although in population-based studies this increase is not well established
(854). On the other hand, major depressive disorder
significantly increases the risk of unprovoked seizures even after
the adjustment of age, sex, length of medical follow-up, and medical
therapies for depression (855). In addition, some antidepressant
drugs, such as TCAs and bupropion, lower the seizure threshold and
have a dose-dependent epileptogenic potential. This seizure risk
is intermediate for immediate-release formulations of bupropion, maprotiline,
and TCAs (in particular, clomipramine) and low for sustained-release
formulations of bupropion (17, 197, 856).
Major depressive disorder in patients with seizure disorders
can usually be safely and effectively managed according to the same
principles outlined for patients without seizures. In particular,
SSRIs and SNRIs are not likely to increase the risk of developing
seizures (856–858). However, blood levels
of TCAs may be increased by several antiepileptic drugs, increasing
the side-effect burden of the anticholinergic and other side effects
of tricyclics (859).
Some anticonvulsants appear useful for treatment and prophylaxis
of mood disorders (e.g., carbamazepine, valproate, lamotrigine).
Thus, in patients with depression and epilepsy, consideration can
be given to concomitant prescription of an anticonvulsant (or elevating
the dose of an existing anticonvulsant). Nevertheless, anticonvulsant
compounds may also have a negative effect on mood for some patients
(859). For example, barbiturates and possibly vigabatrin
have been associated with an increased risk for depression (860).
In addition, a recent FDA statement noted that increased rates of
depression and suicide risk may be associated with anticonvulsants
(861).
Many individuals with major depressive disorder will be overweight
or obese, given the high prevalence of excess weight in the general
population (862). In addition, rates of depression
may be increased in obese individuals, particularly among women
and in those with a body mass index (BMI) greater than 40 (863).
Individuals with obesity resulting from binge eating disorder also
have higher rates of depression (170). In the subgroup
of patients with atypical depression, increased eating and weight
gain are symptomatic of the depressive disorder (864).
For other patients, the lack of motivation and energy that occur
with depression can make it difficult to maintain an exercise regimen
or nutritional dietary habits. In addition, treatment with many
antidepressant medications appears to lead to weight gain (865) and
also makes it more difficult to lose weight in a structured weight
management program (866).
In treating individuals with major depressive disorder who
are overweight or obese, the effects of treatment on weight should
be considered in selecting a therapeutic approach. If pharmacotherapy
is used, the selection of an antidepressant medication should include
consideration of its relative tendency to contribute to weight gain,
which is generally greatest with mirtazapine, TCAs (tertiary TCAs
more so than secondary TCAs), and MAOIs and less prominent with
SSRIs and SNRIs (865). Bupropion is generally weight neutral
and has been associated with modest weight reduction when used to
treat major depressive disorder in obese adults (867, 868).
Longitudinal monitoring of weight, either by direct measurement
or patient report, can permit monitoring of BMI, as well as early
intervention if weight gain becomes a problem with antidepressant
treatment. Patients' concerns about weight gain may also
contribute to poor adherence, and monitoring of weight can facilitate
such discussions. The impact of weight on medication dosing should also
be considered. In one study, greater relative body weight was associated
with a lesser likelihood of response to a fixed dose trial of an
antidepressant (869), perhaps suggesting a need for
increases in medication dose with increasing body weight.
Psychotherapeutic approaches to treatment avoid the potential
for medication-induced weight gain and may also have modest benefits
in weight management. Cognitive-behavioral therapy has shown efficacy
in the treatment of binge eating disorder (170, 870)
and could potentially be used in addressing obesity (871)
and medication-induced weight gain (872).
The increasing use of surgical treatments for obesity also has
implications for the treatment of patients with major depressive
disorder. Depression is common among bariatric surgical candidates
and, in and of itself, is not a contraindication for surgery (873–877).
Long-term follow-up studies show improvements in co-occurring general
medical conditions (878), as well as decreases in depressive
symptoms and improved quality of life with weight loss (879–881).
However, weight loss after surgery may be less pronounced in individuals
with a lifetime diagnosis of major depressive disorder (882)
or in those with severe psychiatric illness that has required hospitalization
(883). Close follow up is important following bariatric
surgery in order to assess for changes in psychiatric symptoms,
assist patients in the psychological and psychosocial adaptation
to weight loss, and adjust medication regimens. Particularly following
jejunoileal bypass or biliopancreatic diversion, but also following
gastric bypass procedures, altered dissolution (884)
and absorption of medication may require adjusting the dose of medication
or changing from a slow-release to an immediate-release formulation
(875).
Diabetes mellitus is common in the general population, particularly
in overweight or obese individuals (885). However, it
is not clear whether an association exists between diabetes and
major depressive disorder, as meta-analyses and epidemiologic studies
yield mixed results (886–888). Some patients
may have reduced adherence to diet and medications when depressed
(889), but there are inconsistent findings on whether
successful treatment of depression (with medication, psychotherapy,
and/or collaborative care) improves glycemic control (889–896).
However, when initiating antidepressant therapy or making significant
dosing adjustments, it is useful to collaborate with the patient's
primary care physician in monitoring diabetic control because fluctuations
in fasting blood glucose may occur. Some evidence suggests that
use of TCAs may be associated with worsened glycemic control, and
other antidepressants (such as SSRIs) may be preferable to TCAs
for patients with diabetes (896, 897).
The possible contribution of obstructive sleep apnea (OSA)
to depressive symptoms is an important consideration, particularly
in patients who are obese, report excessive daytime sleepiness,
or have treatment-resistant depressive symptoms. Symptoms such as
fatigue and poor sleep quality can occur in sleep apnea as well
as in major depressive disorder, requiring a careful assessment
to distinguish whether either or both disorders are present. Underrecognition
of OSA is common, and rates of OSA appear to be increasing with
the increasing prevalence of obesity (898). Although
the prototypical sleep apnea patient is likely to be obese with
a history of snoring, sleep apnea may still be present even in the
absence of these findings (899). Individuals with OSA
or excessive daytime sleepiness appear to have greater rates of depression
than comparison groups (900–902), although
the rates of depressive symptoms and major depressive disorder diagnosis
fluctuate across studies (903). In addition, epidemiological
findings suggest an increasing likelihood of depression with increasing
sleep-related breathing disorder severity (904). With
initiation of continuous positive airway pressure treatment, improvement
in OSA symptoms has been associated with decreased depressive symptoms
(905, 906), in addition to reductions
in OSA-associated health risks (898). Consequently,
recognition and treatment of OSA is important among individuals
with major depressive disorder. Identification of OSA is also important
to treatment planning, as use of sedating medications can exacerbate
OSA and worsen daytime sleepiness, with associated complications
(907).
+
9. Human immunodeficiency
virus and hepatitis C infections
According to the Centers for Disease Control and Prevention,
more than one million individuals in the United States were living
with HIV infection by the end of 2003 (908), with increased
rates among individuals with psychiatric disorders, including substance
use disorders (909). Estimates suggest that at least
one-fifth of infected individuals have unrecognized infection (910),
necessitating increased efforts to identify HIV infection (911),
given the availability of effective treatment (912).
Consequently, clinicians treating patients with major depressive
disorder should consider screening for HIV.
Rates of major depressive disorder are increased among individuals
with HIV infection, compared with HIV-negative individuals (913).
When treating major depressive disorder in patients who also have
HIV, antidepressant medications can be used safely and effectively
(914, 915), although high placebo response
rates and high study attrition rates have sometimes confounded interpretation
of research findings (916, 917). When
antidepressants are used, SSRIs are better tolerated than TCAs (918, 919).
In individuals who are receiving treatment with antiretroviral agents,
it is important to check for potential drug-drug interactions when
choosing a medication regimen (920). Significant interactions
can also occur if St. John's wort is taken by patients
receiving antiretroviral medications. Although few studies have
been conducted in patients who meet diagnostic criteria for major
depressive disorder, individual and group psychotherapies using
interpersonal, cognitive-behavioral, and psychoeducational approaches
have also been associated with reductions in depressive symptoms among
patients with HIV infection (316, 921–926).
Persons with mental illness also have elevated rates of infection
with hepatitis C (927), and infection with hepatitis
C is commonly present in individuals with HIV infection (928). Among
individuals with hepatitis C, depressive symptoms are common, and
many patients fully meet the criteria for major depressive disorder
(929). Treatment of hepatitis C with interferon appears
to be associated with a further increase in the risk for depression,
although findings vary depending upon the study population, concomitant
medications (e.g., ribavirin), and the type of interferon used for
therapy (930, 931). The increase in depressive
symptoms with interferon treatment may also be more prominent in
patients with greater levels of pretreatment depression (932).
This suggests a need for careful monitoring if patients with current
major depressive disorder are administered interferon, particularly
since many patients treated with interferon have unrecognized or
insufficiently treated depression (933). Studies in
which antidepressant medications were administered concomitantly
with interferon have shown inconsistent prophylactic effects (934, 935).
However, antidepressant therapy does seem to be effective when used
to treat depression that develops in the course of interferon therapy
for hepatitis C infection (936, 937).
Consequently, major depressive disorder should not be viewed as
a contraindication to the treatment of hepatitis C infection, particularly
given the severe long-term hepatic complications associated with chronic
infection (938).
Pain syndromes and major depressive disorder frequently co-occur.
Although the reported prevalence of pain among depressed patients
varies with cultural differences and study design, one-half to two-thirds
of depressed individuals will typically note some type of pain (702, 939–941).
Conversely, in primary care settings, individuals with pain symptoms
are about twice as likely to be depressed as those without pain, and
the rates of depression are further increased if pain is chronic
or involves multiple types of pain (940, 942).
It is important to note that individuals with co-occurring pain
and depression tend to have worse treatment outcomes and poorer
overall functioning than those with either condition alone (940, 942–944).
Consequently, every patient with depression should be assessed for
the presence, nature, location, and severity of pain complaints.
Overall, antidepressant treatment has been associated with
reductions in pain symptoms among individuals with psychogenic or
somatoform pain disorders (945). However, among trials
of second-generation antidepressants in individuals with co-occurring
pain and depression, duloxetine, venlafaxine, and paroxetine seem
to be of comparable but relatively minor benefit (939, 946, 947).
Neuropathic pain is commonly associated with diabetic peripheral
neuropathy but may also have other etiologies such as postherpetic
neuralgia. For neuropathic pain in general, evidence-based guidelines
recommend the use of TCAs or SNRIs (948, 949).
Of the antidepressant medications, TCAs have been found to be most
effective in decreasing pain associated with both postherpetic neuralgia
(950, 951) and diabetic neuropathy (949, 952)
but have no apparent effect on HIV-associated neuropathic pain (949).
Given the greater tolerability of SNRI antidepressants, these agents
may sometimes be chosen before a TCA for a patient with co-occurring depression
and neuropathic pain. In addition, if a TCA is used, therapeutic
drug monitoring may be helpful, given the wide variability of TCA
blood levels across individuals (953).
Similar effects have been found for the use of antidepressants
to prevent migraine and tension-type headaches. In patients with
and without co-occurring depression, TCAs show greater efficacy
than SSRIs (954, 955), but SNRIs also
have some evidence for efficacy (956, 957).
In individuals with tension-type headaches, addition of stress management
therapy may augment the effects of TCA treatment (958).
Antidepressant treatment is also recommended for individuals
with fibromyalgia, as it is associated with reductions in pain and
often leads to improvements in function, with the best evidence
available for amitriptyline (959). Beneficial effects
are observed in those with or without co-occurring major depressive
disorder (960–962). Although evidence from controlled
trials is more limited for nonpharmacological approaches than for
antidepressant treatment, education, exercise, and CBT are generally
recommended for the treatment of fibromyalgia in combination with
antidepressant medication (963, 964).
In the context of rheumatoid arthritis, antidepressant medications
also appear to be effective in reducing pain as well as treating
depressive symptoms (965–967). Evidence for
psychosocial treatment is less consistent, with mindfulness meditation
and emotion regulation therapy being associated with reduced pain
and enhanced coping in individuals with rheumatoid arthritis and
depression (968), but CBT having mixed results (966, 968).
In individuals with co-occurring depression and osteoarthritis,
collaborative depression care has been associated with reduced pain
severity, improved function, and enhanced quality of life in those
with low pain scores at baseline but had no effect when compared
with usual treatment in those with severe arthritis pain (969, 970).
For individuals with chronic low back pain, there are conflicting
opinions about the utility of antidepressant medications in reducing
pain or improving function, even in the presence of co-occurring
depression (971, 972). Nevertheless, antidepressant
medications may still be indicated to treat depression on the basis
of individual circumstances.
Since depressed patients with concurrent pain are often treated
by primary care physicians and other medical specialists with a
variety of potent analgesic medications, including narcotics, psychiatrists
treating such patients are advised to be in contact with these other
physicians initially and on a regular ongoing basis as indicated.
The purposes of such contacts are to review the entire treatment
plan, to assure that all prescribing physicians are aware of the
full extent of pharmacological interventions, to coordinate specific
prescribing areas and responsibilities so that patients do not receive
prescriptions for the same medications or have their doses for given
medications adjusted by several different prescribing clinicians,
and to set up a mechanism and plan whereby all prescribing clinicians
consistently keep one another informed about changes in their treatment
plans and prescriptions.
+
11. Obstructive uropathy
Enlarged prostate size and other causes of bladder outlet
obstruction are relative contraindications to the use of antidepressant
medication compounds with antimuscarinic effects. For this reason,
tertiary amine TCAs are best avoided in these patients. Benzodiazepines,
trazodone, and MAOIs may also retard bladder emptying. The antidepressant
medications with the least propensity to do this are SSRIs, SNRIs,
and bupropion. If a TCA is chosen, the secondary amine desipramine
is the least likely to cause urinary hesitancy or retention.
Medications with anticholinergic
potency may precipitate acute narrow-angle glaucoma in susceptible
individuals (i.e., those with shallow anterior chambers) (973).
Patients with glaucoma receiving local miotic therapy may be treated
with antidepressant medications, including those possessing anticholinergic
properties, provided that their intraocular pressure is monitored
during antidepressant medication treatment. Prescription of agents
lacking anticholinergic activity avoids this risk. Other agents
sometimes used in psychiatry, e.g., topiramate and related sulfa-based
medications, may cause acute angle closure glaucoma by ciliary body edema,
a different mechanism (974).