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The standard of care for a moderate to severe MDE (not an MDE occurring in the context of BPD or ongoing substance abuse) combines antidepressant medication with patient education, psychotherapy, or other nondrug treatments. Because a mild MDE often is self-limited, the best approach in any given patient may be to withhold treatment and monitor. This should not be viewed as permission to ignore or overlook mild depression. Instead, the clinician should put depression—whatever its intensity—on the problem list and recommend treatment if symptoms persist and cause significant distress or dysfunction.
The workup of a patient with depressive symptoms must include an assessment of suicide risk. Most patients with mood disorders do not make suicide attempts or commit suicide. However, at least 50% of suicides are committed by patients with a mood disorder. If the patient does not spontaneously mention or allude to suicidal thoughts or thoughts of death, the clinician must ask. Contrary to the beliefs of some, asking does not sow the seed of suicidal thinking. Although patients are typically reluctant to talk about such issues, they generally experience relief when given the opportunity to do so.
The patient who has risk factors for suicide (e.g., personal or family history of attempts or completions, alcoholism, drug abuse, severe anxiety, violence, or impulsivity) and asserts intent or plan should be referred for urgent or emergent evaluation. Clinician skill, judgment, and experience, as well as resource availability, influence disposition and whether a referral should be routine (within 2 weeks), urgent (within 24-48 hours), or emergent (within 12 hours on site or at another site—emergency department or psychiatrist’s office—to which the patient’s transport is assured).
Patients are often relieved when a diagnosis has been identified that accounts for their symptoms. The stigma of a diagnosis of MDD can be dispelled with information about its medical underpinnings and the availability of effective treatments. Educating the patient helps foster a strong therapeutic alliance and adherence to treatment.
In addition to medication, a variety of treatments are indicated for MDD and include psychotherapy, exercise, light therapy, and a growing number of neuromodulation techniques, the most established of which is electroconvulsive therapy (ECT).
The pharmacologic treatment of MDD is generally divided into three phases: acute, continuation, and maintenance. The indications, goals, duration, and strategies of treatment during these phases are presented in Table 2 and can also be reviewed by consulting the Agency for Healthcare Research and Quality (formerly the Association for Health Care Policy and Research).15
Phase of Treatment |
Typical Duration |
Indication(s) |
Goals |
Strategy |
| Acute | 4-12 wk | Single or recurrent episode of major depression | Remission of index episode |
|
Continuation |
4-6 mo |
Goal of acute phase treatment achieved |
Continued remission Prevent relapse (return of the index episode) |
Continue same dose required to achieve remission during acute phase Monitor for relapse If relapse occurs, increase dose, initiate augmentation strategy, or switch to new agent |
Maintenance |
>9-12 mo Optimal duration is uncertain |
Three prior episodes of depression or Two prior episodes plus
|
Prevent recurrence of depression |
|
*Adapted from Agency for Health Care Policy and Research: Clinical Practice Guideline: Depression in Primary Care, vols. I and II. Washington, DC, U.S. Government Printing Office, 1993. |
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Antidepressant medication should be considered for moderate to severe MDD.16 A large variety of antidepressants is available (see Table 2). There is no single best agent, and selection depends on the patient’s antidepressant treatment history, potential drug interactions, and desired side-effect profile (Tables 2, 3, and 4).
Generic |
Trade |
Drug Class |
Date of Approval (m/d/y) |
Starting Dose† (mg/d) |
Therapeutic Range‡ (mg/d) |
Half-Life§ (h) |
Schedule |
| Amitriptyline | Elavil | TCA | 4/7/1961 | 25 | 150-300 | 12-24 | qhs |
| Amoxapine¶ | Asendin | NSRI | 9/22/1980 | 100 | 200-300 | 8-30 | bid |
| Bupropion | Wellbutrin | NDRI | 12/30/1985 | 75 | 300-450 | 20 | tid |
| Wellbutrin SR | NDRI | 10/4/1996 | 100 | 300-450 | 20 | bid | |
| Wellbutrin XL | NDRI | 8/29/2003 | 150 | 300-450 | 20 | qd | |
| Citalopram | Celexa | SSRI | 7/17/1998 | 10 | 20-40 | 35 | qd |
| Desipramine | Norpramin | TCA | 11/20/1964 | 25 | 150-300 | 21-23 | qd |
| Doxepin | Sinequan | TCA | 9/23/1969 | 25 | 150-300 | 17-51 | qhs |
| Duloxetine | Cymbalta | NSRI | 8/3/2004 | 20 | 30-60 | 12 | bid |
| Escitalopram | Lexapro | SSRI | 8/14/2002 | 10 | 10-20 | 27-32 | qd |
| Fluoxetine | Prozac, Serafem | SSRI | 12/29/1987 | 10 | 20 | 4-16 d | qd |
| Imipramine | Tofranil | TCA | 4/16/1959 | 25 | 150-300 | 11-25 | qhs |
| Tofranil PM | TCA | 3/11/1973 | 75 | qhs | |||
| L-Deprenyl¶ | Emsam (Selegiline) | MAOI | 2/27/2006 | 6 | 12 | 10 | qd** |
| Maprotiline¶¶ | Ludiomil | NRI/TetraCA | 12/1/1980 | 25 | 150 | 43-90 | qhs |
| Mirtazapine | Remeron | Other | 6/14/1996 | 15 | 15-45 | 20-40 | qhs |
| Nefazodone‡‡ | Other | 9/16/2003 | 200 | 600 | 2-4 | bid-tid | |
| Nortriptyline | Pamelor | TCA | 8/1/1977 | 10 | 75-150 | 16-44 | qd |
| Paroxetine | Paxil | SSRI | 12/29/1992 | 10 | 20-40 | 24 | qd |
| Paxil-CR | SSRI | 2/16/1999 | 12.5 | 25-62.5 | 21 | qd | |
| Phenelzine | Nardil | MAOI | 6/9/1961 | 15 | 45-90 | 12 | bid-tid |
| Protriptyline | Vivactyl | TCA | 9/27/1967 | 5 | 15-30 | 60-90 | tid |
| Sertraline | Zoloft | SSRI | 12/30/1991 | 50 | 50-200 | 26 | qd |
| Tranylcypromine | Parnate | MAOI | 2/21/1961 | 10 | 20-60 | 4-8 | bid-tid |
| Trazodone†† | Desyrel | Other | 12/24/1981 | 100 | 300-600 | 3-9 | bid-tid |
| Trimipramine | Surmontil | TCA | 6/12/1979 | 25 | 11-23 | qhs | |
| Venlafaxine | Effexor | NSRI | 12/28/1993 | 25 | 225-375 | 5-11 | tid |
| Effexor XR | NSRI | 10/20/1997 | 37.5 | 225-375 | 5-11 | qd | |
FDA, United States Food and Drug Administration; MAOI, monoamine oxidase inhibitor; NDRI, norepinephrine-dopamine reuptake inhibitor; NRI/TetraCA, norepinephrine reuptake inhibitor/tetracyclic antidepressant; NSRI, norepinephrine-serotonin reuptake inhibitor; SSRI, serotonin selective reuptake inhibitor; TCA, tricyclic antidepressant. *Obtained from FDA website on January 1, 2007. †Elderly, debilitated, or anxious patients might need to start treatment at lower doses than these. ‡Increase dose until either therapeutic or adverse effects occur. §The wide ranges reported are a function of active metabolites or individual metabolic rates. ¶Still in production but have limited usefulness because of the adverse effect profiles. Therefore, use is relegated to severe, treatment-resistant depression. Amoxapine and maprotaline can cause severe extrapyramidal side effects and have low toxic-to-therapeutic ratios, leading to elevated risks of seizures and cardiac arrhythmias at high-normal doses. The U.S. manufacturer discontinued production of Serzone when a small number of reports of fatal hepatitis appeared in the literature. Several generic manufacturers, however, continue to produce it. ¶¶The levo-isomer and, therefore, a close chemical relative of citalopram, escitalopram has distinctive activity that distinguishes it clinically from citalopram. **Administered transdermally from a patch that must be changed daily. ††In low doses (50-150 mg) it is effective for promoting and maintaining sleep. ‡‡No longer manufactured. |
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Drug |
Anticholinergic Effects* |
Sedation |
Activation† |
Postural Hypotension |
Hypertension |
Sexual Dysfunction†† |
Seizures§ |
Weight Gain |
Comments |
| Amitriptyline | +++ | ++++ | + | +++ | ++ | ++ | ++++ | ||
| Amoxapine | +++ | +++ | ++ | ++++ | +++ | Loxapine, an antipsychotic, is an active metabolite that accounts for reports of amoxapine-associated extrapyramidal effects, including movement disorders, tardive dyskinesia, and neuroleptic malignant syndrome | |||
| Bupropion | +++ | +++ | Seizure risk is elevated at therapeutic doses, and the risk of seizures increases dramatically at doses >450 mg qd | ||||||
| Citalopram | +++ | + | + | ||||||
| Desipramine | +++ | + | ++ | ++ | ++ | ++ | ++ | Quinidine-like effects that can prolong the QTc and lead to heart block | |
| Doxepin | +++ | +++ | +++ | ++ | ++ | ++++ | Quinidine-like effects that can prolong the QTc and lead to heart block | ||
| Duloxetine | +++ | ++ | +++ | + | ++ | Risk of medication-induced hypertension is dose relatedk | |||
| Escitalopram | ++ | + | + | ||||||
| Fluoxetine | +++ | +++ | + | + | |||||
| Imipramine | +++ | +++ | +++ | ++ | ++ | +++ | Quinidine-like effects that can prolong the QTc and lead to heart block | ||
| L-Deprenyl | ++ | Patients taking MAOIs must adhere to a low-tyramine diet and avoid medications that can result in life-threatening hypertensive crisis or serotonin syndrome Doses ≤9 mg are much less likely than other MAOI drugs to cause harmful interactions with tyramine and drugs |
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| Maprotiline | +++ | +++ | ++ | +++ | +++ | Quinidine-like effects that can prolong the QTc and lead to heart block | |||
| Mirtazapine | ++++ | +++ | ++++ | ||||||
| Nefazodone | ++++ | +++ | ++ | Risk of medication-induced hypertension is dose related | |||||
| Nortriptyline | ++ | + | ++ | + | +++ | ++ | ++ | Quinidine-like effects that can prolong the QTc and lead to heart block This is the TCA least likely to cause postural hypotension |
|
| Paroxetine | + | ++ | ++ | + | +++ | + | ++ | Minor withdrawal symptoms (flulike) can occur with sudden discontinuation | |
| Phenelzine | ++ | ++ | ++++ | ++ | ++++ | Risk of medication-induced hypertension is dose related | |||
| Protriptyline | ++++ | +++ | ++ | ++ | + | Quinidine-like effects that can prolong the QTc and lead to heart block | |||
| Sertraline | +++ | +++ | + | + | |||||
| Tranylcypromine | +++ | ++ | Patients taking MAOIs must adhere to a low-tyramine diet and avoid a wide variety of medications that can result in life-threatening hypertensive crisis or serotonin syndrome | ||||||
| Trazodone | ++++ | +++ | ++ | +++ | Associated with non–dose-related priapism | ||||
| Trimipramine | +++ | +++ | ++ | +++ | ++ | ++ | +++ | Quinidine-like effects that can prolong the QTc and lead to heart block | |
| Venlafaxine | +++ | +++ | +++ | + | + | Risk of medication-induced hypertension is dose related Minor withdrawal symptoms (flulike) can occur with sudden discontinuation |
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MAOI, monoamine oxidase inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. *Clinical manifestations include dry mouth, blurred vision, mydriasis, tachycardia, constipation, and confusion. †Headache, tremor, restlessness. ††Impotence, delayed ejaculation, anorgasmia. Bupropion, mirtazapine, and nefazodone are the antidepressants least likely to cause sexual side effects. §Nearly all antidepressants reduce seizure threshold. SSRIs, however, are unlikely to have a clinically significant effect on seizure threshold, even in overdose. |
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There is no test available that predicts individual response to antidepressant medication in general or to any single agent in particular. Empirical trial and error are necessary, with a favorable response in roughly one-half of patients and remission in nearly one-third of patients with a single therapeutic medication trial.17 If the first agent is ineffective, the diagnosis should be reviewed for accuracy and then, if depression is still present, another antidepressant should be tried. At least one within-class alternative should be tried before switching to an agent from a different class (see Table 2).17
Many patients who initially respond favorably still have residual symptoms. Increasing the antidepressant dosage, using augmentation strategies, or switching to another medication are treatment options for such patients. Referral to a psychiatrist should be considered for persistent depression that has not responded to one or, at most, two trials of antidepressant medication.
Familiarity with antidepressant classes and side-effect profiles helps inform treatment selection (see Tables 2 and 3). In an antidepressant-naïve patient, virtually any antidepressant qualifies as a first-line agent. Selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), and escitalopram (Lexapro), enjoy the widest prescription in the United States and are generally the first to be prescribed. Compared with SSRIs, bupropion (Wellbutrin), mirtazapine (Remeron), and the norepinephrine-serotonin reuptake inhibitors (NSRIs) such as venlafaxine (Effexor) and duloxetine (Cymbalta) have similar efficacy and favorable side-effect profiles. Many clinicians consider venlafaxine and duloxetine superior to SSRIs, but the database is insufficient to verify this impression.
Unlike the monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), all of these newer antidepressants have a lower risk of cardiovascular side effects and are comparatively safe in overdose. SSRIs and NSRIs can cause sexual dysfunction (delayed or inhibited sexual climax) in 25% to 40%, whereas bupropion, mirtazapine, and nefazodone are much less likely to do so. The risk of hypertension increases with daily doses of venlafaxine greater than 225 mg. Mirtazapine, like TCAs (e.g., amitriptyline, imipramine, doxepin), can cause unacceptable weight gain, and it also increases the risk of orthostatic hypotension. The U.S. manufacturer of Serzone (nefazodone) discontinued the product in 2004 because of reports of fatal liver toxicity. Generic nefazodone, however, continues to be manufactured. Like maprotaline and amoxapine (see Table 2), it should be reserved for treatment-resistant MDD when other agents have failed.
After remission has been achieved in the acute phase, the antidepressant dosage used to achieve remission should be continued for another 4 to 6 months.15 Thereafter, the decision to prescribe maintenance therapy depends on the number and severity of past MDEs.
Any decision to discontinue medication should be followed by gradually tapering medication. This involves reducing the total daily dosage by approximately 30% weekly, or more slowly if the patient develops withdrawal symptoms (e.g., tremulousness, excitability, vertigo, nausea, or other nonspecific discomfort). Attempts to discontinue antidepressant medication may be thwarted either by the patient’s intolerance of withdrawal or by recurrence of depressive symptoms. Distinguishing drug withdrawal from symptom recurrence can be difficult but is best accomplished by prolonging the taper.
Fundamental to all successful antidepressant therapy is a therapeutic trial of adequate dosage and adequate duration of treatment.15 There is substantial evidence that a majority of patients with MDD do not receive adequate treatment trials.4 The clinician must arrange for follow-up to ensure that the maximum recommended dosage of medication has been taken daily for at least 4 to 6 weeks. If some response is evident within the first 4 weeks, treatment should be continued for at least 6 weeks. No response to a therapeutic dose of medication by week 4, however, is an almost certain indication that another agent should be tried.15
Psychotherapy alone may be effective for mild to moderate MDD or as an adjunct to antidepressant medication for moderate to severe MDD.15 Most primary care physicians are unlikely to provide psychotherapy, but knowledge about this treatment modality should facilitate selection and referral of appropriate patients. Commonly used models of psychotherapy include cognitive-behavioral therapy (CBT), interpersonal therapy (IPT), and insight-oriented approaches such as psychodynamic and client-centered therapies. Formats in which psychotherapies are delivered include individual, group, marital (or couples), family, and intensive outpatient programs. The goal of psychotherapy is to relieve depressive symptoms by exploring for and resolving issues such as grief, cognitive distortions, role changes, interpersonal disputes, and impaired coping.
Exercise should be recommended to all depressed patients. Numerous studies substantiate its positive effect on mood. If nothing else, exercise provides a structured activity that, when performed regularly, can enhance the depressed patient’s sense of competence and self-esteem.
Light therapy has been used effectively to treat seasonal depression. SAD (or seasonal mood disorder) is a subtype of MDD that occurs annually, usually starting in fall or winter and ending in spring or early summer. It is more than just “winter blues” or “cabin fever.” Morning light therapy for at least 30 minutes every day is the most effective treatment. Improvement can occur within 2 to 4 days and reach full benefits within 2 to 4 weeks. An appliance that delivers at least 10,000 lux is recommended. Companies that manufacture lamps with the appropriate specifications include SunBox and Northern Light Technologies.
An unusual form of SAD that occurs during the summer months appears to be triggered by unusual heat sensitivity. Not surprisingly, the treatment involves minimizing heat exposure.
Electroconvulsive therapy (ECT) is perhaps the most effective antidepressant treatment available.15 It is typically used only as a last resort because of the need for hospital-level care and general anesthesia. A significant number of patients who are resistant to antidepressant medication, however, benefit from ECT. Maintenance ECT is indicated for those whose recurrent depressions do not respond to maintenance antidepressant medication.
Vagus nerve stimulation (VNS) received Food and Drug Administration approval in 2005 for treatment of refractory depression. Its special value may be in reducing the need for ECT and medication therapies in the maintenance phase of treatment.
Other novel neuromodulation techniques that are still under investigation include repetitive transcranial magnetic stimulation (rTMS) and deep brain stimulation (DBS). The efficacy of rTMS remains controversial, and the need for daily treatments administered by a technician presents logistic challenges. The use of DBS for treatment-refractory depression has produced some exciting results, but the scope of its application has yet to be determined.
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