A Review of the Nature and Impact of Exclusion Criteria in Depression Treatment Outcome Research

Special Article - Depression Disorders & Treatment

Ann Depress Anxiety. 2015; 2(5): 1058.

A Review of the Nature and Impact of Exclusion Criteria in Depression Treatment Outcome Research

Halvorson MA¹* and Humphreys K²

¹Department of Veterans Affairs Palo Alto Health Care System, Center for Innovation to Implementation, USA

²Department of Psychiatry & Behavioral Sciences, Stanford University, USA

*Corresponding author: Max A. Halvorson, VA Palo Alto Health Care System, Center for Innovation to Implementation (152-MPD), 795 Willow Rd, Menlo Park, CA 94025, USA

Received: February 26, 2015; Accepted: August 05, 2015;Published: August 14, 2015


Background: Depression treatment outcome research is typically designed to maximize internal validity. However, many studies utilize extensive exclusion criteria that reduce the extent to which study samples resemble clinical populations. A better understanding of exclusion criteria and their use in depression treatment outcome research is necessary to generalize accurately from studies. This review identifies the most commonly-used exclusion criteria, the proportion of potential participants excluded, and differences between participant patient samples and patient samples excluded from studies.

Methods: Eighteen studies of exclusion in depression treatment research were identified through PubMed and reviewed by both authors.

Results: A typical study of depression utilizes approximately 8-11 exclusion criteria and excludes between 75% and 85% of depressed individuals. Insufficient depression severity and comorbid Axis I disorders excluded the most potential participants. Excluded individuals tended to be younger and male, and to have poorer mental health status in the form of longer depressive episodes and more psychiatric comorbidities. Treatment response and remission were generally worse for excluded patients than enrolled subjects. Conclusion: Most depressed individuals would be excluded from a typical clinical trial of depression. These excluded individuals differ significantly in baseline characteristics and outcomes from study participants. More inclusive samples and more thorough reporting of exclusion criteria are needed to safely generalize from depression treatment outcome studies.

Keywords: Depression; Clinical trials; Treatment; Antidepressants; CBT/ cognitive behavior therapy


Methodologically sound clinical trials of pharmacotherapy and psychotherapy for depression can inform evidence-based care for this prevalent and disabling disorder [e.g., 1,2]. In such trials, depression treatment researchers typically strive to maximize sample homogeneity by excluding patients with particular characteristics (e.g., suicidal impulses, alcohol dependence).The use of exclusion criteria can protect the safety of potential participants and can also sometimes increase ability to detect significant differences in treatment outcome with in small samples, but may have the unintended consequence of lowering generalizability [3,4]. For example, about 4 in 5 patients with schizophrenia are excluded from schizophrenia treatment research [5] and an even higher proportion of patients with cardiovascular disease are excluded from treatment research focused on their disorder [6]. When such large proportions of individuals are not studied in a clinical research area, it becomes less plausible that the results of treatment research can be generalized to front-line healthcare.

To our knowledge, no systematic review has been conducted in the depression field regarding whether exclusion criteria create treatment research samples that differ significantly from real-world patient samples in their clinical characteristics and outcomes. Accordingly, this review summarizes the evidence base on the use and impact of exclusion criteria in clinical research on depression. We first present the prevalence of specific exclusion criteria employed in the literature, followed by a summary of reported rates of overall exclusion. Next, we present percentages of participants excluded by each individual criterion. Finally, we summarize evidence linking exclusions to sample characteristics and outcomes.


The Cross-Disease Review of Exclusion Across Medicine (CREAM) project is a structured literature review of studies of exclusion criteria and their impact across a range of disciplines (e.g., oncology, cardiology, psychiatry). Methods are described in detail elsewhere [5], but to summarize: literature was identified by conducting English-language searches in PubMed on the following terms: “Eligibility criteria and generalizability” (anywhere in paper), “exclusion criteria and generalizability” (anywhere in paper), “exclusion criteria” (in title of paper) and “eligibility criteria” (in title of paper). To be considered relevant, studies had to analyze data on [1] The prevalence and nature of exclusion criteria in a particular field, and/or [2] The impact of exclusion criteria on sample representatives or study results. Reference lists of all studies identified in the search were themselves scanned for more potential studies.


Our search terms yielded three reviews of the prevalence of specific exclusion criteria in clinical trials of depression treatment and 15 empirical examinations of study exclusion in depression treatment research. Three of the studies focused on exclusion criteria in psychotherapy efficacy trials and the remaining 12 studies focused on exclusion in antidepressant efficacy trials.

Prevalence of exclusion criteria in depression treatment trials

Exclusion criteria are utilized in virtually all clinical trials; however, the number of criteria used varies greatly across studies. For example, in the five retrospective studies which included information on specific exclusion criteria used in the original trial, between 3 and 21 criteria were reported [7-11]. In a study of 20 psychotherapy efficacy trials by van der Lem [12], the authors identified 38 unique exclusion criteria which they categorized into 15 groups. Eight of these criteria appeared in 50% or more of the studies and the average study used eight of these 15 criteria.

We identified three reviews of the depression literature which sought to describe the prevalence of common exclusion criteria in depression treatment studies (Table 1). Posternak, Zimmerman [13] characterized rates of exclusion criteria use in all 31 antidepressant efficacy trials published between 1994 and 1998 in 5 major psychiatry journals. The authors excluded studies which focused on a specific subgroup of patients. Zimmerman, Chelminski [14] reported rates of exclusion in all 39 antidepressant efficacy trials in 5 major psychiatry journals published from 1994 to 2000. It should be noted that the sample of studies in (Posternak, Zimmerman [13]) is a subset of the sample of studies in Zimmerman, Chelminski [14]. However, as the two reviews reported rates of use for different criteria, each provides unique data. A third study by van der Lem, de Wever [12] presented rates of exclusion criteria for 20 trials of psychotherapy in adults found in a literature search of PubMed and PsycInfo.