Cochrane Briefs

Effectiveness of Antidepressants Compared with Placebo for Depression in Primary Care


Am Fam Physician. 2010 Jul 1;82(1):42.

Clinical Question

What is the effectiveness of antidepressants compared with placebo for the treatment of depression in primary care settings?

Evidence-Based Answer

Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) are more effective than placebo for the treatment of depression in primary care settings. (Strength of Recommendation = A, based on consistent, good-quality patient-oriented evidence)

Practice Pointers

In patients with mild to moderate depression symptoms, there is little or no benefit of antidepressant medications compared with placebo. Medications are more beneficial in patients with severe depression.1 This Cochrane review compared the effectiveness of antidepressant medications with placebo for patients with depression who were recruited from primary care practices. It included 14 randomized controlled trials of patients 18 to 65 years of age. Most trials reported short-term outcomes at four to six weeks; four trials had follow-up for 12 to 24 weeks. Most studies were sponsored by pharmaceutical companies.

Compared with placebo, TCAs showed greater improvement in depression scores and a greater clinical response to remission (number needed to treat [NNT] = 9; 95% confidence interval [CI], 6 to 16), assessed by primary care physicians or psychiatrists. The number needed to harm (NNH) ranged from 4 to 30 in participants taking TCAs who discontinued treatment because of adverse effects.

SSRIs showed a clinical benefit for improvement in depression scores (NNT = 7; 95% CI, 7 to 8). More patients in the SSRI group withdrew from trials because of adverse effects (relative risk [RR] = 2.05; 95% CI, 1.11 to 3.75; NNH = 20 to 90) compared with placebo, but fewer patients in the SSRI group withdrew because of treatment failure (RR = 0.51; 95% CI, 0.34 to 0.78). Other reviews have shown higher drop-out rates related to tolerability in participants taking SSRIs.

The American College of Physicians recommends that when physicians choose pharmacologic therapy to treat patients with acute major depression, they select second-generation antidepressants on the basis of adverse effect profiles, cost, and patient preference.2 The Institute for Clinical Systems Improvement states that SSRIs—as well as venlafaxine (Effexor), duloxetine (Cymbalta), mirtazapine (Remeron), and bupropion (Wellbutrin)—are often chosen as first-line antidepressant treatment options because of the quality and quantity of published data for these medications; their relative tolerability of adverse effects compared with TCAs and monoamine oxidase inhibitors; and their overall relative safety.3


Author disclosure: Nothing to disclose.


Arroll B, Elley CR, Fishman T, et al. Antidepressants versus placebo for depression in primary care. Cochrane Database Syst Rev. 2009;(3):CD007954.


1. Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA. 2010;303(1):47–53.

2. Qaseem A, Snow V, Denberg TD, Forciea MA. Owens DK; Clinical Efficacy Subcommittee of American College of Physicians. Using second-generation antidepressants to treat depressive disorders: a clinical practice guideline from the American College of Physicians [published correction appears in Ann Intern Med. 2009;150(2):148]. Ann Intern Med. 2008;149(10):725–733.

3. Institute for Clinical Systems Improvement. Health care guideline: major depression in adults in primary care. 12th ed. May 2009. Accessed May 11, 2010.



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