Severity of Depression and Response to Antidepressants and Placebo: An Analysis of the Food and Drug Administration Database

Abstract

Some studies suggest that more severely ill patients with depression respond well to antidepressants and poorly to placebo, whereas those who are mildly ill respond equally well to antidepressants and placebo. This notion has implications for the design of clinical trials. To further assess and substantiate these putative predictors of antidepressant and placebo response, we assessed the Food and Drug Administration database of 45 phase II and III antidepressant clinical trials. The frequency of statistically significant differences between antidepressants and placebo was higher in the trials that included patients with more severe depression. In the antidepressant-treated groups, the magnitude of symptom reduction was significantly related to mean initial Hamilton Rating Scale for Depression (HAM-D) score; the higher the mean initial HAM-D score, the larger the change. With placebo treatment, however, the higher the mean initial HAM-D score, the smaller the change. Early discontinuation was more frequent among patients whose mean initial HAM-D scores were higher. These data may help inform the design of future antidepressant clinical trials.

Enhancing the Technology of Clinical Trials and the Trials Model to Evaluate Newly Developed, Targeted Antidepressants

“…Depressed outpatients have milder depressive symptomatology than the predominantly inpatient samples used to test the first established drugs. Patients with milder severity provide a narrower range of possible change, and produce a greater number of placebo responders (Fisher et al 1965;Bowden et al 2000;Khan et al 2002).…”

“…Major reasons for failure of some recent trials are the inclusion of patients as subjects who are "symptomatic volunteers", patients who barely meet the minimal level of qualification, or those who are admitted because of a tendency on the part of clinicians, consciously or unconsciously, to lower their threshold for perceiving symptoms. Patients or symptomatic volunteers in whom the condition of depression is mild to "marginal" tend to have a high placebo response rate (Khan et al 2002) in part because they are more responsive than more severely ill patients to non-specific psychosocial supports associated with clinical studies. Therefore, their presence could seriously undermine the ability to show efficacy.…”

“…Depressed outpatients have milder depressive symptomatology than the predominantly inpatient samples used to test the first established drugs. Patients with milder severity provide a narrower range of possible change, and produce a greater number of placebo responders (Fisher et al 1965;Bowden et al 2000;Khan et al 2002).As a consequence of the smaller difference between active treatment and placebo treatment, larger patient samples and/or more sensitive clinical methods are needed to detect differences between drug and placebo. The most commonly utilized scales, the Hamilton Depression Rating Scale (HDRS) (Hamilton 1960) and the Clinical Global Impression Scale (CGI) (Guy 1976), were designed to measure changes in overall severity of the disorder.…”

A Preliminary Analysis of the Effects of Coaching Feedback on Teacher Implementation Fidelity of First Step to Success

“…A drug company is required to produce only two studies that show a drug to perform better than placebo, notwithstanding the number of studies to the contrary, in order to obtain FDA approval. The Eli Lilly company had to conduct five studies of Prozac in order that two would produce positive results (Khan, Leventhal, Khan, & Brown, 2002).…”

Subjective Effects of Antidepressants

“…Whatever the cause, there can be no argument against the claim, "The impact of major depression on our society cannot be overemphasized" (Jain and Jain, 2002, p 65). These factors and others have contributed to the dramatic rise in antidepressant use, even though recent analyses suggest that the efficacy of SSRIs for depression may be significantly less than formerly believed (Khan et al, 2002;Kirsch and Antonuccio, 2002;Thase, 2002).…”