Open-Label Placebo for Major Depressive Disorder: A Pilot Randomized Controlled Trial

In randomized controlled trials (RCTs), major depressive disorder (MDD) patients treated with double-blind placebos often show substantial improvement. Indeed, two meta-analyses have estimated that the double-blind placebo response is 80% as large as the double-blind antidepressant response [1,2]. This strong placebo response combined with the absence of side effects has prompted suggestions to use open-label placebo as a first-line treatment for depression [3]. In addition, a recent report on irritable bowel syndrome reported positive findings with open-label placebo [4]. Here we report a pilot study investigating this intriguing question for MDD.We 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 [5]. 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) [6]. Secondary, self-report outcomess were the Quick Inventory of Depressive Symptoms (QIDS) [7] and the Symptoms of Depression Questionnaire (SDQ) [8]. 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.Prior to randomization, the treating psychiatrists provided all participants with a rationale explaining why open-label placebos might be effective. 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 patients 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. Although the 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.Our principal goal was to examine the feasibility of conducting trials of open-label placebo for MDD. Recruitment for this study was the fastest of the ten most recently conducted MDD studies in the Depression Clinic at Massachusetts General Hospital. The mean number of patients screened per month was 4.13 as compared to only 2.55 for the other nine trials. In addition, 75% of patients completed the trial. We recruited a total of 20 patients, primarily women (70%) of middle age (38.8 ± 12.6 years) with moderately severe depression at baseline (mean HAM-D-17 = 18.0 ± 4.9). There were no significant differences between the open-label placebo (n = 11) and waitlist control (n = 9) groups on demographics or baseline severity.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 (table 1a). 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 [1] and above the criterion for a clinically significant improvement set by the National Institute for Clinical Excellence (NICE) in the UK [9]. 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 (table 1b). However, improvement on the HAM-D-17 was relatively small as compared to the improvement typically seen in MDD RCTs.To our knowledge, this is the first RCT to test the efficacy of open-label placebo for MDD. Despite the fact that we observed a medium-sized effect for the main outcome measure, our 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.An important question that might be raised is whether this study tests open-label placebo or the power of suggestion of the rationale. Critics might contend that a true test of open-label placebo should provide no rationale for effectiveness. However, this eliminates positive expectancy, which is as important to the placebo effect as the placebo pill itself. Moreover, in clinical practice, treatment is always accompanied by a rationale for effectiveness. If placebo antidepressants were to be used in clinical practice, they too would need to be delivered with a rationale for effectiveness.Another possible criticism of this study is that it only generalizes to patients willing to try open-label placebo for MDD. We agree that this limits generalizability, but the same limit applies to any treatment (e.g. antidepressant trials only generalize to patients willing to take antidepressants). Moreover, the only population to which we would seek to generalize is patients who are willing to try open-label placebo as a first-line treatment for depression.In summary, this pilot study demonstrated that trials of open-label placebo for depression are feasible. Patients were readily recruited, and 75% completed a 4-week trial. However, our results are insufficient to support the hypothesis that open-label placebo is an effective treatment for depression. We did, however, see a small but statistically significant pre-post improvement at 4 weeks for the entire sample. Given the small sample size of this pilot study, larger trials of open-label placebo for MDD are warranted.T.J.K. and J.M.K. were partially funded by NIH-NCCAM grant No. K24 AT004095. We thank the editor, Dr. Giovanni Fava, and two anonymous reviewers for their helpful suggestions. M.F. reports the following potential conflicts of interest:Research support: Abbot Laboratories; Alkermes, Inc.; Aspect Medical Systems; AstraZeneca; BioResearch; BrainCells, Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Clinical Trials Solutions, LLC; Clintara, LLC; Covance; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; Ganeden Biotech, Inc.; GlaxoSmithKline; Icon Clinical Research; i3 Innovus/Ingenix; Johnson & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; National Alliance for Research on Schizophrenia and Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Novartis AG; Organon Pharmaceuticals; PamLab, LLC; Pfizer, Inc.; Pharmavite® LLC; Photothera; Roche Pharmaceuticals; RCT Logic, LLC; Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Synthelabo, and Wyeth-Ayerst Laboratories.Advisory/consulting: Abbott Laboratories; Affectis Pharmaceuticals AG; Alkermes, Inc.; Amarin Pharma, Inc.; Aspect Medical Systems; AstraZeneca; Auspex Pharmaceuticals; Bayer AG; Best Practice Project Management, Inc.; BioMarin Pharmaceuticals, Inc.; Biovail Corporation; BrainCells, Inc; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon, Inc.; Clinical Trials Solutions, LLC; CNS Response, Inc.; Compellis Pharmaceuticals; Cypress Pharmaceutical, Inc.; DiagnoSearch Life Sciences (P) Ltd.; Dinippon Sumitomo Pharma Co., Inc.; Dov Pharmaceuticals, Inc.; Edgemont Pharmaceuticals, Inc.; Eisai, Inc.; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; ePharmaSolutions; EPIX Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; GenOmind, LLC; GlaxoSmithKline; Grunenthal GmbH; i3 Innovus/Ingenis; Janssen Pharmaceutica; Jazz Pharmaceuticals, Inc.; Johnson & Johnson Pharmaceutical Research & Development, LLC; Knoll Pharmaceuticals Corp.; Labopharm, Inc.; Lorex Pharmaceuticals; Lundbeck, Inc.; MedAvante, Inc.; Merck & Co., Inc.; MSI Methylation Sciences, Inc.; Naurex, Inc.; Neuronetics, Inc.; NextWave Pharmaceuticals; Novartis AG; Nutrition 21; Orexigen Therapeutics, Inc.; Organon Pharmaceuticals; Otsuka Pharmaceuticals; PamLab, LLC.; Pfizer, Inc.; PharmaStar; Pharmavite® LLC.; PharmoRx Therapeutics; Precision Human Biolaboratory; Prexa Pharmaceuticals, Inc.; Puretech Ventures; PsychoGenics; Psylin Neurosciences, Inc.; Rexahn Pharmaceuticals, Inc.; Ridge Diagnostics, Inc.; Roche; RCT Logic, LLC; Sanofi-Aventis US LLC; Sepracor, Inc.; Servier Laboratories; Schering-Plough Corporation; Solvay Pharmaceuticals, Inc.; Somaxon Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; Sunovion Pharmaceuticals; Supernus Pharmaceuticals, Inc.; Synthelabo; Takeda Pharmaceutical Company Limited; Tal Medical, Inc.; Tetragenex Pharmaceuticals, Inc.; TransForm Pharmaceuticals, Inc.; Transcept Pharmaceuticals, Inc., and Vanda Pharmaceuticals, Inc.Speaking/publishing: Adamed, Co.; Advanced Meeting Partners; American Psychiatric Association; American Society of Clinical Psychopharmacology; AstraZeneca; Belvoir Media Group; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Cephalon, Inc.; CME Institute/Physicians Postgraduate Press, Inc.; Eli Lilly and Company; Forest Pharmaceuticals, Inc.; GlaxoSmithKline; Imedex, LLC; MGH Psychiatry Academy/Primedia; MGH Psychiatry Academy/Reed Elsevier; Novartis AG; Organon Pharmaceuticals; Pfizer, Inc.; PharmaStar; United BioSource, Corp., and Wyeth-Ayerst Laboratories. Equity holdings: Compellis.Royalty/patent, other income: patent for Sequential Parallel Comparison Design (SPCD) and patent application for a combination of azapirones and bupropion in MDD, copyright royalties for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), and SAFER. Patent for research and licensing of SPCD with RCT Logic; Lippincott, Williams & Wilkins; Wolkers Kluwer, and World Scientific Publishing Co. Pte. Ltd. None of the other authors report any potential conflicts of interest.