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The Psychiatric Inclusion and Exclusion Criteria in Placebo-Controlled Monotherapy Trials of Bipolar Depression: An Analysis of Studies of the Past 20 Years



Concerns about the generalizability of pharmacotherapy efficacy trials to “real-world” patients have been raised for more than 40 years. Almost all of this literature has focused on treatment studies of major depressive disorder (MDD).


The aim of the study was to review the psychiatric inclusion and exclusion criteria used in placebo-controlled trials that assessed the efficacy of medications for bipolar depression (bipolar disorder efficacy trials [BDETs]) and compare the criteria used in BDETs with those used in efficacy trials of antidepressants to treat MDD (antidepressant efficacy trials [AETs]).


We searched the MEDLINE, Embase, and PsycINFO databases for articles published from January 1995 through December 2014. We identified 170 placebo-controlled AETs and 22 BDETs published during these 20 years. Two of the authors independently reviewed each article and completed a pre-specified information extraction form listing the psychiatric inclusion and exclusion criteria used in the study.


Six inclusion/exclusion criteria were used in at least half of the BDETs: minimum severity on a depression symptom severity scale, significant suicidal ideation, diagnosis of alcohol or drug use disorder, presence of a comorbid nondepressive, nonsubstance use Axis I disorder, current episode of depression being too long, and absence of current manic symptoms. BDETs were significantly less likely than AETs to exclude patients with a history of psychotic features/disorders, borderline personality disorder, and post-traumatic stress disorder and more likely to exclude individuals who scored too low on the first item of the Hamilton Depression Rating Scale. Nearly two-thirds of the BDETs placed an upper limit on the duration of the current depressive episode, three times higher than the rate in the AETs. There was no difference on other variables between the AETs and BDETs.


Similar to treatment studies of nonbipolar MDD, the treatment studies of bipolar depression frequently excluded patients with comorbid psychiatric and substance use disorders and insufficient severity of depressive symptoms as rated on standardized scales. These findings indicate that concerns about the generalizability of data from trials of recently approved medications for the treatment of bipolar depression are as relevant as the concerns that have been raised about studies of antidepressants for nonbipolar depression.

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Corresponding author

Correspondence to Mark Zimmerman.

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Funding source

No sources of funding were used to conduct this study or prepare this manuscript.

Conflicts of interest

M Zimmerman has participated on advisory boards for F. Hoffmann-La Roche, Genentech, and Lundbeck; received research support from Azevan and Eli Lilly; and prepared educational material for Otsuka. Ms. Holst, Ms. Clark, Mr. Multach, Ms. Walsh, Ms. Rosenstein, and Mr. Gazarian do not have any conflicts.

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Zimmerman, M., Holst, C.G., Clark, H.L. et al. The Psychiatric Inclusion and Exclusion Criteria in Placebo-Controlled Monotherapy Trials of Bipolar Depression: An Analysis of Studies of the Past 20 Years. CNS Drugs 30, 1209–1218 (2016).

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  • Major Depressive Disorder
  • Eating Disorder
  • Personality Disorder
  • Major Depressive Disorder
  • Efficacy Trial