Initial Treatment Approaches for Patients With Major Depressive Disorder

George I. Papakostas, MD

Department of Psychiatry, Harvard Medical School and Massachusetts General Hospital, Boston

Approaches to MDD Treatment

Three common approaches to treating MDD include: (1) antidepressant monotherapy, (2) psychotherapy as monotherapy, and (3) a combination of psychotherapy and antidepressants. Antidepressant monotherapy is the most widespread approach, although the combination of psychotherapy and antidepressants has been demonstrated to be superior to either pharmacotherapy or psychotherapy alone when depression is severe or recurrent.1 In addition, psychotherapy may be used as an adjunct to pharmacotherapy (as a first-line treatment), particularly when treating MDD with comorbid Axis I disorders found to respond to treatment with various psychotherapeutic treatment modalities (ie, anxiety or eating disorders), especially if the antidepressant selected has not been proven to be effective in the comorbid disorder.

A new approach that is not widely practiced combines 2 medications from the onset of therapy. Preliminary studies suggest that combining 2 antidepressant agents or an antidepressant with a nonantidepressant agent from the onset of treatment may result in a greater resolution of depressive symptoms than antidepressant monotherapy.2 For instance, adding sleep-promoting or wakefulness-promoting agents to an antidepressant may help target specific depressive symptoms, such as sleep disturbances.3,4

Combining medications may also be effective for treating comorbid Axis I disorders, especially if the patient’s current antidepressant is not proven to be effective in the comorbid disorder. For example, in contrast to the NDRI bupropion, SSRIs/SNRIs have not been proven to be effective in ADHD. In cases of patients with MDD and comorbid ADHD treated with an SSRI or SNRI, adjunctive therapy with a psychostimulant, atomoxetine, or bupropion may be indicated. In contrast, unlike the SSRIs/SNRIs, bupropion has not been proven to be effective in the treatment of anxiety disorders. In cases of patients with MDD and comorbid anxiety disorders treated with bupropion, adjunctive therapy with a benzodiazepine, buspirone, or an anticonvulsant (ie, pregabalin) may be indicated.

Efficacy of Antidepressants

Overall efficacy. The immediate mechanism of action of antidepressants involves either inhibiting the reuptake of monoamines, blocking monoaminergic receptors, or inhibiting the monoamine oxidase enzyme. Regardless of their mechanism of action, antidepressants appear to have, overall, comparable efficacy in treating MDD. For instance, a meta-analysis5 of randomized, double-blind, placebo-controlled trials reported a 53.8% response rate with antidepressants in adults with MDD versus a 37.3% response rate with placebo (NNT of approximately 1 in 6). Similarly, the results of the STAR*D study6 suggest that only about 50% of patients with MDD achieve clinical response, and only about one third achieve remission of their depressive episode following a single course of an antidepressant. Thus, few patients respond and fewer remit after an initial course of antidepressants; those who do not will require subsequent treatments in order to achieve remission and, ultimately, recovery from MDD.

Time course of improvement. The time course for symptom improvement with antidepressants is typically delayed, such that the majority of patients do not experience a full resolution of symptoms within the first 2 weeks of treatment.6,7 As a result, prematurely discontinuing treatment (ie, ≤ 4 weeks) due to lack of efficacy may deprive some patients of potentially effective therapy (AV 1AV 1).6 However, waiting too long (ie, ≥ 8 weeks) in the face of partial or nonresponse may unnecessarily increase a patient’s exposure to an ineffective therapy and, ultimately, delay recovery.7 In general, assessing whether or not a change in treatment regimen is indicated for MDD nonremitters is based upon (1) the trajectory of improvement (or lack thereof), (2) the duration of time since the most recent change in treatment regimen, and (3) the tolerability of the treatment regimen.

Residual symptoms. Residual symptoms, such as sleep disturbance, fatigue, poor concentration, anxiety, apathy, and anhedonia, are common among patients who have met criteria for remission (AV 2AV 2).8 Failure to achieve and sustain full symptomatic remission of MDD is associated with an increased risk of relapse and recurrence of symptoms, more chronic depressive episodes, shorter durations between episodes, continued functional impairment, and increased risk of medical comorbidity.9 Therefore, it is important for clinicians to assess and, if present, to target residual symptoms of depression among MDD-remitters.

Relative efficacy. In the medical literature, equivalent efficacy among antidepressants has been the norm, not the exception. However, it is unclear to what degree this finding is truly accurate or an artifact of poorly powered or underpowered studies. In order to further clarify whether differences in the overall efficacy of antidepressants exist and circumvent the limited statistical power of individual studies, a number of meta-analyses and pooled analyses have been conducted. These analyses10-17 often employ the SSRIs as the “benchmark” for comparison since, of all antidepressant classes, they are most often involved in “head-to-head” antidepressant comparator studies.

For the most part, these meta-analyses10-17 have confirmed that major differences in efficacy do not exist when comparing the SSRIs with other antidepressants for patients with MDD. However, in an analysis comparing various SSRIs with the SNRI venlafaxine,16 remission rates were higher in patients with MDD who were treated with venlafaxine compared with those treated with SSRIs. This finding has sparked a debate regarding whether or not antidepressants that possess a noradrenergic and serotonergic mechanism of action are more effective than SSRIs in treating MDD. On one hand, this assertion has been supported by a number of meta-analyses, the largest of which confirmed a statistically significant (P = .003) but modest in magnitude (NNT of approximately 1 in 24) superiority in response rates for serotonergic-noradrenergic agents versus SSRIs.17

However, another meta-analysis18 found comparable efficacy results for venlafaxine XR and the SSRI escitalopram in MDD. The debate about whether agents that function on more neurotransmitters possess greater efficacy than agents that work on fewer neurotransmitters is still ongoing.

Parallel to this line of investigation examining whether differences in overall efficacy exist, a number of published reports have focused on examining whether contemporary antidepressants may differ in their efficacy profile with regards to the treatment of specific subpopulations of MDD patients or in the resolution of specific depressive symptoms or symptom clusters (AV 3AV 3).18-24


Tolerability of Antidepressants

Tolerability is one of the main considerations, along with efficacy and indication, for clinicians when selecting an initial MDD treatment approach.25 Antidepressant side effects may add to patient suffering and distress, contribute to a delay or failure to attain an effective or optimal antidepressant dose, and also contribute to poor or intermittent compliance or noncompliance altogether. It has recently been estimated that as many as 50% of patients who were prescribed an antidepressant discontinued their treatment within a 6-month period.26 Patients who had concerns about side effects were 3.3 times more likely to discontinue their antidepressant treatment than patients who did not have tolerability concerns.26

Antidepressant side effects most often rated by patients as bothersome include sexual dysfunction, drowsiness, weight gain, insomnia, and nausea.27 Compared with differences in efficacy, differences in the tolerability profile of modern antidepressants are more pronounced. The relative likelihood of developing these side effects (with the exception of weight gain) during treatment with SSRI versus non-SSRI agents is shown in AV 4AV 4.28

Data for weight gain with antidepressants are limited, but tentative comparisons can be made.28 The SSRIs vary in their weight gain profiles. Fluoxetine and escitalopram appear to result in long-term weight changes, which are more or less comparable to placebo, while long-term treatment with paroxetine appears to result in more weight gain than placebo, as well as the SSRIs fluoxetine and sertraline. TCAs and mirtazapine are also associated with a higher risk of weight gain than placebo, while bupropion and nefazodone appear to have weight gain profiles similar to that of placebo. Duloxetine dosed at 60mg/d does not appear to result in greater weight gain versus placebo during long-term treatment. However, higher doses of duloxetine (80 mg/d or 120 mg/d) appear to be more likely to result in weight gain than placebo. Presently, there is insufficient data to help determine the risk of weight gain during long-term treatment with venlafaxine, trazodone, and the MAOIs.

Safety of Antidepressants

Initial treatment approaches for patients with MDD must include considering antidepressant safety. MAOIs and TCAs have an inferior safety profile to SSRIs and other newer agents because of their risks of hypertensive crisis, hypotensive crisis, and serotonin syndrome and of seizure and arrhythmogenesis, respectively. However, because serious adverse events among marketed drugs are, by definition, rare compared to nonserious adverse events (otherwise they would have been detected during the process of drug development leading to the termination of the clinical development of that agent), identifying these rare events requires the accumulation of data involving large sample sizes and extensive follow-up periods.

Relatively well-quantified safety risks with modern antidepressants include an increased risk of suicidal ideation and/or suicide gestures (but not suicide mortality) during the treatment of children, adolescents, and young adults (early 20’s),29 and an increased risk of seizure associated with bupropion at daily doses greater than 300 mg.30 Other examples of rare but serious adverse events are numerous,31 although not as thoroughly studied as the emergence/worsening of suicidal ideation (AV 5AV 5). Clearly, more needs to be done to better assess the safety profile of contemporary antidepressants. A practicing clinician must, nonetheless, be informed of potential serious adverse events associated with antidepressant use in order to be able to disclose the relative risks and benefits of antidepressant agents when treating patients with MDD, as well as monitor for the emergence of such adverse events following the initiation of pharmacotherapy.


The mainstays of initial MDD treatment have been antidepressant monotherapy or the combination of psychotherapy and antidepressants. Combining 2 antidepressants or an antidepressant with a nonantidepressant drug as a first-line treatment strategy is an emerging area of research that is not yet widely practiced. Factors in choosing an antidepressant include indication, efficacy, tolerability, and safety. Patient preference and treatment history are other considerations when deciding which initial treatment approach is appropriate.

Drug Names

bupropion (Aplenzin, Wellbutrin, and others), buspirone (Buspar and others), citalopram (Celexa and others), duloxetine (Cymbalta), escitalopram (Lexapro and others), fluoxetine (Prozac and others), mirtazapine (Remeron and others), nefazodone (Serzone and others), paroxetine (Paxil and others), pregabalin (Lyrica), sertraline (Zoloft and others), trazodone (Desyrel), venlafaxine (Effexor and others)


ADHD = attention-deficit/hyperactivity disorder, MAOI = monoamine oxidase reuptake inhibitor, MDD = major depressive disorder, NDRI = norepinephrine and dopamine reuptake inhibitor, NNT = number needed to treat, SNRI = serotonin norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor, STAR*D = Sequenced Treatment Alternatives to Relieve Depression, TCA = tricyclic antidepressant

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