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Antidepressants Work Better than Placebo for Severe Depression

An analysis of randomized trials comparing antidepressants with placebo suggests antidepressants provide the most value when used for severe depression.

Researchers discovered antidepressants may provide little benefit for patients with mild or moderate depression, but appear to provide substantial benefit for patients with very severe depression.

Antidepressant medications, combined with psychotherapy, are the current standard of treatment for major depressive disorder. But there is little evidence that they have a specific pharmacological effect relative to placebo for patients with less severe depression. Psychotherapy was not examined for this research, so no conclusion could be drawn about psychotherapy’s effectiveness compared to antidepressants.

Jay C. Fournier, M.A., of the University of Pennsylvania, Philadelphia, and colleagues conducted a meta-analysis to estimate the benefit of antidepressants vs. placebo across a wide range of initial symptom severity in patients diagnosed with depression.

The researchers combined data from 6 large-scale, placebo-controlled randomized trials. The studies included 718 adult outpatients.

The authors found that the efficacy of antidepressants for depression varied considerably, depending on symptom severity.

“True drug effects (an advantage of antidepressants over placebo) were nonexistent to negligible among depressed patients with mild, moderate, and even severe baseline symptoms, whereas they were large for patients with very severe symptoms.”

“What makes our findings surprising is the high level of depression symptom severity that appears to be required for clinically meaningful drug/placebo differences to emerge, particularly given the evidence that the majority of patients receiving antidepressants in clinical practice present with scores [measures of depression] below these levels.”

“Prescribers, policy makers, and consumers may not be aware that the efficacy of medications largely has been established on the basis of studies that have included only those individuals with more severe forms of depression.

“This important feature of the evidence base is not reflected in the implicit messages present in the marketing of these medications to clinicians and the public. There is little mention of the fact that efficacy data often come from studies that exclude precisely those major depressive disorder patients who derive little specific pharmacological benefit from taking medications.

“Pending findings contrary to those reported here and those obtained [in previous studies] by Kirsch et al and Khan et al, efforts should be made to clarify to clinicians and prospective patients that whereas antidepressants can have a substantial effect with more severe depressions, there is little evidence to suggest that they produce specific pharmacological benefit for the majority of patients with less severe acute depressions,” the authors conclude.

The report is found in the current Journal of the American Medical Association (JAMA).

Source: JAMA and Archives Journals

Antidepressants Work Better than Placebo for Severe Depression

Rick Nauert PhD

Rick Nauert, PhDDr. Rick Nauert has over 25 years experience in clinical, administrative and academic healthcare. He is currently an associate professor for Rocky Mountain University of Health Professionals doctoral program in health promotion and wellness. Dr. Nauert began his career as a clinical physical therapist and served as a regional manager for a publicly traded multidisciplinary rehabilitation agency for 12 years. He has masters degrees in health-fitness management and healthcare administration and a doctoral degree from The University of Texas at Austin focused on health care informatics, health administration, health education and health policy. His research efforts included the area of telehealth with a specialty in disease management.

APA Reference
Nauert PhD, R. (2018). Antidepressants Work Better than Placebo for Severe Depression. Psych Central. Retrieved on November 29, 2020, from
Scientifically Reviewed
Last updated: 8 Aug 2018 (Originally: 6 Jan 2010)
Last reviewed: By a member of our scientific advisory board on 8 Aug 2018
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