Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration

Summary & key facts

Researchers pooled the full clinical trial data that drug makers sent to the US Food and Drug Administration for four newer antidepressants. They checked how people’s starting depression level affected how much they improved on the drug compared with a placebo sugar pill. They found that pills were only a little better than placebo, and that benefit grew with worse starting depression but stayed small. The bigger drug-versus-placebo gap in very severe cases happened because very sick patients got less better on placebo, not because they got much more help from the drugs.

Key facts:

• The study used all the clinical trial data submitted to the US Food and Drug Administration for four newer antidepressant drugs.
• Researchers compared how much people improved on the drug versus a placebo sugar pill, and how that difference changed with how severe people’s depression was at the start.
• For people with moderate depression, there was almost no difference between drug and placebo.
• As starting depression became more severe, the drug-versus-placebo difference grew, but the extra benefit remained relatively small.
• The drug-versus-placebo gap reached common rules for being clinically meaningful only for people at the very highest levels of severity.
• The growing gap with severity was mainly because very severely depressed people responded less to placebo, not because they responded much more to the actual drugs.
• These results describe short-term trial outcomes for four specific newer drugs and do not by themselves tell people what treatment to choose or how well drugs work long term.

Abstract

BACKGROUND: Meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance. Yet, the efficacy of the antidepressants may also depend on the severity of initial depression scores. The purpose of this analysis is to establish the relation of baseline severity and antidepressant efficacy using a relevant dataset of published and unpublished clinical trials. METHODS AND FINDINGS: We obtained data on all clinical trials submitted to the US Food and Drug Administration (FDA) for the licensing of the four new-generation antidepressants for which full datasets were available. We then used meta-analytic techniques to assess linear and quadratic effects of initial severity on improvement scores for drug and placebo groups and on drug-placebo difference scores. Drug-placebo differences increased as a function of initial severity, rising from virtually no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression, reaching conventional criteria for clinical significance only for patients at the upper end of the very severely depressed category. Meta-regression analyses indicated that the relation of baseline severity and improvement was curvilinear in drug groups and showed a strong, negative linear component in placebo groups. CONCLUSIONS: Drug-placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.

Topics

Meta-analysis and systematic reviews Pain Management and Placebo Effect Treatment of Major Depression

Categories

Health Sciences Medicine Pharmacology

Tags

Alternative medicine Antidepressant Clinical trial Depression (economics) Drug Economics Hippocampus Internal medicine Macroeconomics Medicine Meta-analysis Pathology Placebo Psychiatry

Substances

Other

Conditions & symptoms

Depression Lack of energy or motivation Poor sleep Sadness or low mood