Choose an initial treatment.

  • Aim to induce remission of the major depressive episode and achieve a full return to the patient's baseline level of functioning. 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.

  • When selecting an initial treatment modality, consider the following:

    • Severity of symptoms

    • Presence of co-occurring disorders or psychosocial stressors

    • Biological, psychological, and environmental factors contributing to the current episode of depression

    • Patient preference

    • Prior treatment experiences

  • Integrate treatment with psychiatric management and any other treatments provided for other co-occurring psychiatric disorders and general medical conditions.


Recommended Modalities

  • Figure 1 describes recommended modalities according to the patient's severity of illness.

  • Clinical features that may suggest that medications are the preferred treatment include the following:

    • Prior positive response to an antidepressant

    • Moderate to severe symptomatology

    • Significant sleep or appetite disturbances or agitation

    • Anticipation of need for maintenance therapy

    • Patient preference

  • Clinical features that may suggest the use of a depression-focused psychotherapy include the following:

    • Availability of clinicians with appropriate training and expertise

    • Prior positive response to psychotherapy

    • Significant psychological factors, psychosocial stressors, or interpersonal difficulties

    • Co-occurring Axis II disorders

    • Mild to moderate severity of illness

    • Patient preference

  • In addition to the above, in women who are pregnant or wish to become pregnant or are breastfeeding, a depression-focused psychotherapy alone is recommended and, depending on the severity of symptoms, should be considered as an initial option.

  • In patients who prefer complementary and alternative therapies, S-adenosyl methionine (SAMe) or St. John's wort might be considered, although evidence for their efficacy is modest, and careful attention to drug-drug interactions is needed with St. John's wort.

  • Bright light therapy may be considered to treat seasonal affective disorder as well as nonseasonal depression.

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


  • The effectiveness of antidepressant medications is generally comparable between and within classes of medications, including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), bupropion, tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs). Therefore, choose a medication largely based on the following:

    • Patient preference

    • Nature of prior response to medication

    • Safety, tolerability, and anticipated side effects

    • Co-occurring psychiatric or general medical conditions

    • Pharmacological properties of the medication (e.g., half-life, actions on cytochrome P450 enzymes, other drug interactions; consult the full guideline or a current drug database)

    • Cost

  • For most patients, a SSRI, a SNRI, mirtazapine, or bupropion is optimal.

  • In general, the use of MAOIs should be restricted to patients who do not respond to other treatments.

  • Table 2 provides the starting and usual doses of medications that have been shown to be effective for treating major depressive disorder.

  • If side effects occur, lowering the dose or changing to a different antidepressant should be considered. If these approaches are not effective, other strategies can be considered, as shown in Table 3.

  • When the medication is being changed to or from an MAOI, a washout period is essential (Table 4) to prevent a potentially lethal interaction: the serotonin syndrome.

  • The initial dose should be raised incrementally as tolerated until a therapeutic dose is reached or the patient achieves remission. Titration generally can be accomplished over initial weeks, but more time may be needed depending on development of side effects, the patient's age, and the presence of co-occurring medical and psychiatric conditions.

  • Improvement may be observed as early as the first 1–2 weeks and continue for up to 12 weeks. Remind patients who achieve some improvement during initial weeks that full benefit at a given dose may not be achieved until 4–8 weeks.

  • Some antidepressants can be lethal in overdose (e.g., ingestion of a 10-day supply of a tricyclic agent administered at a dose of 200 mg/day). Early on in treatment, it is prudent to dispense only small quantities of such medications and to keep in mind the possibility of hoarding. In patients who are suicidal, it may be preferable to employ an agent that is safer in overdose, such as an SSRI.

Table Reference Number
Table 2. Dosing of Medications Shown to Be Effective in Treating Major Depressive Disordera
Table Reference Number
Table 3. Potential Treatments for Side Effects of Antidepressant Medications
Table Reference Number
Table 4. Required Washout Times between Antidepressant Trials

Electroconvulsive Therapy (ECT)

  • ECT has the highest rates of response and remission of any form of antidepressant treatment, with 70%–90% of patients treated showing improvement.

  • Evaluation for ECT should identify potential indications for caution or modifications in ECT technique or anesthesia, such as recent myocardial infarction, cardiac arrhythmias, or intracranial space-occupying lesions.

  • ECT may have cardiovascular side effects, which 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. 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.

  • Patients may experience cognitive effects after ECT. The most common of these effects is confusion that generally lasts 30–60 minutes after treatment. Retrograde amnesia may also occur but typically resolves.

  • Treatments are usually administered two or three times per week. An acute course of ECT typically consists of 6–12 treatments, until symptoms have remitted or clearly reached a plateau.



  • Depression-focused psychotherapies include cognitive-behavioral therapy (CBT), interpersonal psychotherapy, and problem-solving therapy. Psychodynamic psychotherapy is an alternative option.

  • Individual or group formats may be used.

  • Marital and family problems are common in the course of major depressive disorder and can be addressed by marital or family therapy.

  • Considerations in the choice of a specific type of psychotherapy include the following:

    • Goals of treatment (in addition to resolving major depressive symptoms)

    • Prior positive response to a specific type of psychotherapy

    • Patient preference

    • Availability of clinicians skilled in the specific psychotherapeutic approach


Evaluate response.

  • Ensure that the treatment has been administered for a sufficient duration and at a sufficient frequency or dose. Generally, 4–8 weeks are needed before it can be concluded that a patient is partially responsive or unresponsive to a specfic intervention.

  • No treatment should continue unmodified if there has been no symptomatic improvement after 1 month.

  • For full response, proceed to the continuation phase of treatment.

  • For less than moderate response, assess the following and modify the treatment plan as needed:

    • Diagnosis

    • Side effects

    • Complicating co-occurring conditions

    • Psychosocial factors

    • Quality of therapeutic alliance

    • Treatment adherence

    • For patients receiving psychotherapy, frequency of sessions and whether the specific approach to psychotherapy is adequately addressing the patient's needs

    • For patients receiving pharmacotherapy, medication dose adjustments to take into account pharmacokinetic or pharmacodynamic factors

  • After an additional 4–8 weeks, if the patient continues to show minimal or no improvement, conduct another thorough review and make additional changes. Consider consultation.


Address inadequate response.


Maximizing the Initial Treatment

Patients Treated With an Antidepressant

  • Optimizing (i.e., raising) the dose is a reasonable first step if side-effect burden is tolerable, especially if the upper dosage limit has not yet been reached.

  • Some patients may require doses higher than those approved by the Food and Drug Administration.

  • In patients who have shown a partial response, particularly those who have features of personality disorders and prominent psychosocial stressors, extending the antidepressant medication trial (e.g., by 4–8 weeks, but not indefinitely) can be considered.

Patients Treated With Psychotherapy

  • As for patients treated with an antidepressant, an initial strategy is to increase the intensity of treatment (i.e., increase the frequency of psychotherapy sessions).

  • The appropriateness of the type of psychotherapy used and the quality of the therapeutic alliance should be reviewed.


Changing to Other Treatments

  • For patients treated with psychotherapy, switching to an antidepressant medication can be considered. (Another option is to combine treatments, as described in the section that follows.)

  • For patients who do not show at least a partial response to an initial antidepressant, a common strategy is to change to a different non-MAOI antidepressant in the same class (e.g., from one SSRI to another SSRI) or in a different class (e.g., from a SSRI to a TCA).

  • For patients who can adhere to dietary and medication restrictions, a nonselective MAOI after sufficient washout period (Table 4) is an option.

  • Transdermal selegiline could be considered.

  • Recent evidence supports the efficacy of quetiapine monotherapy, but potential side effects need to be taken into consideration.


Augmenting and Combining Treatments

  • Pharmacotherapy combined with psychotherapy may offer advantages over either modality alone, particularly for patients with chronic, severe, or complex illness. For patients with less severe symptoms, advantages may be modest.

  • For patients treated with an antidepressant, augmentation strategies with a modest evidence base include the following:

    • Adding another non-MAOI antidepressant, generally from a different class

    • Adding lithium

    • Adding thyroid hormone

    • Adding a second-generation antipsychotic

  • Strategies with less supporting evidence include the following:

    • Adding an anticonvulsant

    • Adding omega-3 fatty acids

    • Adding folate

    • Adding a psychostimulant medication (e.g., modafinil)

    • If anxiety or insomnia is prominent, adding an anxiolytic or sedative-hypnotic medication, including buspirone, a benzodiazepine, or a selective gamma-aminobutyric acid (GABA) agonist hypnotic (e.g., zolpidem, eszopiclone)


Treatment-Resistant Depression

  • ECT is the most effective form of therapy for patients with treatment-resistant symptoms.

  • Another option to consider, with less supporting evidence, is transcranial magnetic stimulation.

  • Vagus nerve stimulation (VNS) may be an option for patients who have not responded to at least four adequate trials of antidepressant treatment, including ECT.

Figure 1–1. Recommended Modalities for Acute Phase Treatment of Major Depressive Disorder
Table Reference Number
Table 2. Dosing of Medications Shown to Be Effective in Treating Major Depressive Disordera
Table Reference Number
Table 3. Potential Treatments for Side Effects of Antidepressant Medications
Table Reference Number
Table 4. Required Washout Times between Antidepressant Trials


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