Moderators of Antidepressant Response in Major Depression

Richard C. Shelton, MD (Chair)

Department of Psychiatry, Vanderbilt School of Medicine, Nashville, Tennessee

Madhukar H. Trivedi, MD

Mood Disorders Research Program and Clinic, University of Texas Southwestern Medical Center, Dallas

What makes a clinician a great clinician? We propose that a truly great clinician uses measurement-based care and optimizes each treatment step before moving to the next step. Great clinicians also pay attention to putative moderators of treatment response, because improved understanding of moderators can lead to improved patient outcomes.

What Are Moderators?

Moderators are baseline variables that predict response to treatment. Because depression encompasses a variety of conditions and has a greater range of treatments than many other disorders, moderators should be considered in depression treatment. None of the therapies available is effective for all people, so the key concept is to match the treatment to the patient, not the patient to the treatment. The ability to recognize moderators of antidepressant response can help clinicians predict an individual’s response to treatment, select particular treatments over time, and quickly adjust treatment when response is inadequate. Moderators can be prognostic or prescriptive.

Prognostic Moderators of Depression Treatment Response

Prognostic moderators predict relative response regardless of the type of treatment. For example, patients with anxious depression have been shown to have significantly lower remission rates than those without anxiety (AV 1AV 1).1,2 Other prognostic moderators that have a less robust response include depression chronicity, low intelligence, and older age (>40 years).3 Having limited education,4 living alone/being unmarried,5 being unemployed,6 and having psychiatric comorbidities such as drug and alcohol abuse,4,7 vascular depression,8 cluster A personality disorders,6 or PTSD4,6 are also established prognostic moderators of response. Prognostic moderators associated with treatment-resistance can be useful in alerting clinicians to provide more intensive treatment from the outset or to move patients more rapidly through treatment stages.

Prescriptive Moderators of Depression Treatment Response

Prescriptive moderators predict differential response to particular treatments. Knowing these moderators can be useful in selecting treatment to optimize outcomes for individual patients.

Demographic variables. Gender, age, and menopausal status can predict response to specific antidepressant treatments. In a study by Kornstein and colleagues,9 premenopausal women showed greater response to the SSRI sertraline than to the TCA imipramine (57% vs 46%, P = .02), while men showed greater response to the TCA than to the SSRI (62% vs 45%, P = .04). Postmenopausal women responded similarly to the 2 medications. However, subsequent data10 indicate that the response of postmenopausal women may be moderated by hormone replacement status.

Thase et al10 compared antidepressant efficacy of SSRIs and an SNRI by patient age (< 50 years vs ≥ 50 years), gender, and HRT status. With SSRIs, remission rates were similar (about 36%) among men of both age groups and women less than 50 years of age, but older women had lower remission rates (28%). With the SNRI, remission rates were lower for older men (41%), similar for younger men and women (about 45%), and highest for older women (48%). When remission rates among older women were analyzed by HRT status, women not taking HRT had higher remission rates with the SNRI than with SSRIs, whereas women taking HRT showed less difference in remission rates between the 2 treatments (AV 2AV 2). Thus, an older woman who is not taking HRT should typically be treated with an SNRI, not an SSRI.

Illness features. Illness features, such as subtype, age at onset, chronicity, and severity, may moderate differential response to antidepressants. For example, a classic prescriptive moderator is melancholic versus atypical depression.

Patients with melancholic features of depression are more likely to respond to TCAs than to MAOIs or SSRIs. Several studies found greater remission rates with TCAs than with SSRIs in patients with melancholic depression (AV 3AV 3).11 SSRIs should not be used in patients with melancholic depression unless a compelling reason exists. However, SNRIs can be tried briefly before switching to a TCA.

Patients with atypical features of depression may have a better response to MAOIs than to TCAs. For example, in a study of patients with atypical depression, Quitkin et al12 found response rates of 83% for those treated with the MAOI phenelzine versus 50% for those treated with the TCA imipramine.


Age at onset and chronicity are also prescriptive moderators, particularly in patients with atypical depression. Stewart and colleagues13 showed that, although response rates to MAOIs did not differ from TCAs when patients with atypical depression had late onset (<21 years) or early onset (>21 years) or chronic or nonchronic depression, those with early-onset, chronic depression had much lower response rates with TCAs than those with late-onset, nonchronic depression.

A study14 in patients with or without atypical depression examined response to treatment with a TCA plus case management, placebo plus case management, or psychotherapy. While psychotherapy efficacy did not significantly differ between depressive subtypes, the TCA showed significantly greater response in patients without atypical features (65%) than in those with atypical features (24%, P = .01). In fact, patients with atypical features had greater response to placebo (46%) than to the TCA (24%).

Therefore, in treating patients with melancholic depression, the following steps can be taken in clinical practice, moving from one step to the next if the patient does not achieve remission:

  1. Start with an SNRI (venlafaxine or duloxetine)
  2. Move quickly to a TCA (eg, nortriptyline, plasma level = 120–150 ng/ml)
  3. Augment with lithium
  4. Switch to clomipramine (± lithium)


In patients with melancholic depression, CBT monotherapy would preferably not be used; however, CBT could be combined with medication.

In contrast, when treating patients with late-onset, nonchronic atypical depression, the following steps can be taken:

  1. Start with an SSRI or CBT monotherapy
  2. Combine an SSRI and CBT
  3. Switch to the selegiline transdermal patch (12 mg/d)
  4. Switch to an oral MAOI (eg, isocarboxazid 40–60 mg/d, phenelzine 45–90 mg/d, or tranylcypromine 30–60 mg/d in divided doses)


For early-onset, chronic atypical depression, prescribing the MAOI transdermal patch should be the first step.

Another illness feature that may moderate differential response to treatment is the severity of depression, which may determine whether medication or psychotherapy should be used. Some evidence suggests that antidepressants are more effective in severe depression than in mild depression.15 In patients with severe depression, APA guidelines16 recommend the use of antidepressants with psychotherapy rather than psychotherapy alone. However, in patients with moderate-to-severe depression, research17 suggests that cognitive therapy may be as efficacious as antidepressants, particularly when administered by therapists with a high level of expertise.

Moderators of treatment response were examined in patients with moderate-to-severe MDD treated with antidepressants, cognitive therapy, or placebo.3,6,17 Moderators favoring cognitive therapy over antidepressants included being unemployed, being married, and having multiple recent stressful life events.3 Among those taking antidepressants, moderators of poorer response were having Axis I comorbidity, having chronic depression, and being unemployed.17


Knowledge of prognostic and prescriptive moderators can help clinicians tailor and optimize treatment for individual patients and can help clinicians quickly move patients through treatment steps if remission is not achieved. As more moderators of treatment response are identified, computer-based algorithms and decision support systems can help clinicians deal with an expanding number of variables.

For Clinical Use

  • Use prognostic moderators to predict patient response to all antidepressants
  • Use prescriptive moderators to guide treatment choices for individual patients
  • When response is inadequate, move patients through the appropriate treatment steps

Drug Names

citalopram (Celexa and others), clomipramine (Anafranil and others), duloxetine (Cymbalta), escitalopram (Lexapro and others), imipramine (Tofranil and others), isocarboxazid (Marplan), lithium (Lithobid and others), nortriptyline (Pamelor, Aventyl, and others), phenelzine (Nardil and others), selegiline transdermal (Emsam), sertraline (Zoloft and others), tranylcypromine (Parnate and others), venlafaxine (Effexor and others)


APA=American Psychiatric Association, CBT=cognitive-behavioral therapy, DUAG=Danish University Antidepressant Group, HDRS=Hamilton Depression Rating Scale, HRT=hormone replacement therapy, IPT=interpersonal psychotherapy, MDD=major depressive disorder, MAOI=monoamine oxidase inhibitor, PTSD=posttraumatic stress disorder, SSRI=selective serotonin reuptake inhibitor, SNRI=serotonin-norepinephrine reuptake inhibitor, STAR*D=Sequenced Treatment Alternatives to Relieve Depression, TCA=tricyclic antidepressant

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