title: Safety of research into severe and treatment-resistant mood disorders: analysis of outcome data from 12 years of clinical trials at the US National Institute of Mental Health.
abstract: BACKGROUND
  Placebo-controlled trials in drug-free patients have long been considered a key research component in the study of mood disorders and relevant treatment mechanisms. However, concerns have been raised about the ethics of such research, leading to an ongoing debate as to whether placebo controls are ethically acceptable. We aimed to assess the cumulative effects of research in individuals with mood disorders and to provide data to address ethical concerns regarding research in this population.
  
  
  METHODS
  We obtained empirical data for patients screened between between Dec 13, 2001, and Jan 31, 2014, with either major depressive disorder or bipolar disorder who were enrolled in one or more of 18 clinical trials at a US National Institute of Mental Health (NIMH) inpatient or outpatient behavioural health research clinic. We assessed the cumulative effects of research in our patient population, including the effects of drug taper, drug washout, and placebo administration on mood state. Two subgroups were examined: patients enrolled in trials explicitly requiring treatment resistance and patients with a current or past history of suicidal ideation or behaviour. We used the percentage change from screening as the primary outcome measure for statistical analysis of change in mood over study periods. This study is registered with ClinicalTrials.gov, number NCT00024635.
  
  
  RESULTS
  We obtained data for 540 patients; 360 (71%) patients were enrolled in trials requiring treatment resistance, 58 (12%) of 465 patients had suicidal ideation at screening, and 191 (60%) of 321 patients had a history of suicidal ideation. Mean mood severity at screening was in the moderate to severe range. Full participation in research, including drug tapers, drug-free periods, and placebo-controlled trials, had a low risk of symptom exacerbation. Patients undergoing drug taper had a mean increase in symptom severity of 4·2% (SD 19·56, tdegrees of freedom 96=1·85; p=0·036). We recorded modest increases in the subgroup who tapered to no medications (mean percentage change 5·1% [SD 18·10], t56=2·12; p=0·039), but increases were not significant in participants enrolled in trials requiring treatment resistance (4·3% [18·60], t72=1·96; p=0·054) and those with a current or past history of suicidal ideation or behaviour (1·8% [18·78], t51=0·68; p=0·50). Six serious adverse events were reported, including one suicide attempt that occurred during the standard treatment phase and not during the clinical trial.
  
  
  CONCLUSIONS
  In general, research participation at the NIMH was not detrimental to health and safety, and conferred benefit in many cases. This finding was true not only in our entire research population, but also in treatment-resistant subgroups and subgroups with a history of suicidality. Our study provides evidence to guide ethical analysis of issues in psychiatric research, and to support continued scientific investigation.
  
  
  BACKGROUND
  Intramural Research Program, NIMH, National Institutes of Health.
authors.affiliation: Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA. Electronic address: nugenta@mail.nih.gov.
authors.forename: Allison C
authors.initials: AC
authors.lastname: Nugent
authors.affiliation: The Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Nicolas D
authors.initials: ND
authors.lastname: Iadarola
authors.affiliation: Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Frank G
authors.initials: FG
authors.lastname: Miller
authors.affiliation: Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Luckenbaugh
authors.affiliation: Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Zarate
mesh_terms: D000328:Adult; D035843:Biomedical Research / Q000941:ethics; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019964:Mood Disorders / Q000628:therapy*; D009315:National Institute of Mental Health (U.S.); D061214:Patient Safety; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014481:United States