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1
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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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+
Figure 1. Recommended Modalities for Acute Phase Treatment of Major Depressive Disorder
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2. Pharmacotherapy

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.

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Table Reference Number
Table 3. Factors to Consider in Choosing an Antidepressant Medication
+
Table Reference Number
Table 4. Cytochrome P450 Enzyme Metabolism of Antidepressive Agentsa
+
Table Reference Number
Table 5. Cytochrome P450 Enzyme Inhibition by Antidepressive Agentsa
+
Table Reference Number
Table 6. Dosing of Medications Shown To Be Effective in Treating Major Depressive Disordera

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
+ 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 (8488), even when anxiety symptoms are considered (85, 8790).

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, 9295). 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).

+ 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.

+ 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).

+ 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).

+ 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.

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Table Reference Number
Table 7. Potential Treatments for Side Effects of Antidepressant Medications

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.

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Table Reference Number
Table 8. Required Washout Times Between Antidepressant Trials

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.

+ 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.

+ a. Gastrointestinal

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.

+ b. Activation/insomnia

SSRIs sometimes precipitate or exacerbate restlessness, agitation, and sleep disturbances—side 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.

+ c. Sexual side effects

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).

+ 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.

+ e. Falls

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).

+ f. Effects on weight

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).

+ g. Serotonin syndrome

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).

+ h. Drug interactions

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).

+ 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).

+ 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.

+ 3. Other antidepressant medications
+ a. Bupropion

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.

+ b. Mirtazapine

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).

+ c. Trazodone

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).

+ d. Nefazodone

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).

+ c. Sedation

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.

+ d. Weight gain

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 TCA—especially 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).

+ f. Falls

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 crises

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.

+ b. Serotonin syndrome

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.

+ d. Weight gain

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).

+ e. Sexual side effects

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.

+

4. Psychotherapy

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).

+ 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.

+ 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.

+ 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).

+ 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).

+ 6. Group therapy

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.

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b. Implementation

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.

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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.

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a. St. John's wort

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.

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c. Omega-3 fatty acids

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.

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d. Folate

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.

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e. Light therapy

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.

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f. Acupuncture

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.

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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.

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Table Reference Number
Table 9. Potential Reasons for Treatment Nonresponse

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.

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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.

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Figure 2. Assessment of Treatment Tolerability and Adequacy of Response

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).

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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.

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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, 270272) 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).

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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 medication—such 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.

Figure 1. Recommended Modalities for Acute Phase Treatment of Major Depressive Disorder

Figure 2. Assessment of Treatment Tolerability and Adequacy of Response
Table Reference Number
Table 3. Factors to Consider in Choosing an Antidepressant Medication
Table Reference Number
Table 4. Cytochrome P450 Enzyme Metabolism of Antidepressive Agentsa
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Table 5. Cytochrome P450 Enzyme Inhibition by Antidepressive Agentsa
Table Reference Number
Table 6. Dosing of Medications Shown To Be Effective in Treating Major Depressive Disordera
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Table 7. Potential Treatments for Side Effects of Antidepressant Medications
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Table 8. Required Washout Times Between Antidepressant Trials
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Table 9. Potential Reasons for Treatment Nonresponse

References

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