New insights on role of placebo in depression

A randomized controlled trial published in one of the last issue of Psychotherapy and Psychosomatics unravels new insights on the role of placebo in depression.

In randomized controlled trials (RCTs), major depressive disorder (MDD) patients treated with double-blind placebos often show substantial improvement. This study investigates this intriguing question for MDD. The investigators conducted a pilot RCT of open-label placebo in adult outpatients with a primary diagnosis of nonpsychotic MDD as diagnosed by the Structured Clinical Interview for DSM-IV. For the first two weeks, patients were randomized to either open-label placebo or waitlist control. After 2 weeks, participants originally randomized to open-label placebo continued for an additional 2 weeks on open-label placebo, and participants originally assigned to the waitlist control were switched to open-label placebo for an additional 4 weeks, so long as they continued to meet the eligibility requirements after 2 weeks on the waitlist. Patients were instructed to take two placebo pills, twice daily. The placebos were blue capsules containing microcrystalline cellulose. Blinded clinicians assessed patients at baseline and every 2 weeks thereafter. The primary outcome was the clinician-rated 17-item Hamilton Scale for Depression (HAM-D-17).

Secondary, self-report outcomess were the Quick Inventory of Depressive Symptoms (QIDS) and the Symptoms of Depression Questionnaire(SDQ). The primary test of efficacy was at 2 weeks. The entire sample was used to examine pre-post improvement after 4 weeks of open-label placebo treatment. Following an earlier model [4] , the rationale included four points: (a) in RCTs placebos are roughly 80% as effective as antidepressants; (b) classical conditioning is a possible mechanism for automatic self-healing; (c) placebo-treated pa tients who are more compliant have better outcomes, and therefore the placebos should be taken faithfully, and (d) positive expectations increase placebo effects, but it is OK to have doubts. Althoughthe rationale was scripted, treating psychiatrists were encouraged to deliver the rationale in a natural and supportive manner that allowed for questions and answers. All participants provided written informed consent. Patients were paid USD 20 for each completed assessment, and all patients were offered 3 months of free psychiatric treatment after the trial. The principal goal was to examine the feasibility of conducting trials of open-label placebo for MDD. At the two-week endpoint, there were no statistically significant differences between open-label placebo and waitlist, and the observed symptom improvement was relatively small compared with typical MDD RCTs. On the other hand, the effect size for the main outcome measure (HAM-D-17) was medium (d = 0.54), which is larger than typical effect sizes for the drug placebo difference in MDD RCTs and above the criterion for a clinically significant improvement set by the National Institute for Clinical Excellence (NICE) in the UK. In addition, there were statistically significant pre-post improvements on all three outcome measures after 4 weeks of open-label placebo treatment, with moderate to large effect sizes. However, improvement on the HAM-D-17 was relatively small as compared to the improvement typically seen in MDD RCTs. Despite the fact that investigators observed a medium-sized effect for the main outcome measure, these findings do not support the hypothesis that open-label placebo is effective for MDD. However, the results were in the predicted direction, and this pilot study was limited by the small sample size, low statistical power, and short duration.