Abstract
BackgroundGrowing evidence supports the validity of distinguishing major depressive disorder (MDD) plus a lifetime history of subthreshold hypomania (D(m)) from pure MDD in psychiatric classifications. The present study sought to estimate the proportion of individuals with D(m) that would have been included in RCTs for MDD using typical eligibility criteria, and examine the potential impact of including these participants on internal validity.MethodsData were derived from the 2001–2002 National Epidemiological Survey on Alcohol and Related Conditions (NESARC), a national representative sample of 43,093 adults of the United States population. We examined the proportion of participants with a current diagnosis of pure MDD and D(m) that would have been eligible in clinical trials for MDD with a traditional set of eligibility criteria, and compared it with that of participants with bipolar 2 disorder if the same set of eligibility criteria was applied. We considered 4 models including different definitions of subthreshold hypomania.ResultsWe found that more than 7 out of ten participants with pure MDD and with D(m) would have been excluded by at least one classical eligibility criterion. Prevalence rate of individuals with D(m) in RCTs for MDD with traditional eligibility criteria would have ranged from 7.98% to 22.59%. Overall exclusion rate of individuals with MDD plus at least 4 lifetime concomitant hypomanic probes significantly differ from those with pure MDD, whereas it was not significantly different in those with at least 2 lifetime concomitant hypomanic probes compared to those with bipolar 2 disorder.ConclusionsThe current design of clinical trials for MDD may suffer from impaired external validity and potential impaired internal validity, due to the inclusion of a substantial proportion of individuals with subthreshold hypomania presenting with similar pattern of exclusion rates to those with bipolar 2 disorder, possibly resulting in a selection bias.
Highlights
The practice of evidence-based medicine is generally understood as the application to clinical care of knowledge derived from double blind, randomized placebo-controlled trials (RCTs) [1,2]
We examined the proportion of all participants with a current diagnosis of D(m) and pure major depressive disorder (MDD) in the NESARC that would have been eligible if the traditional eligibility criteria were applied to these samples, and compared it with that of individuals with bipolar 2 disorder if they were applied the same set of eligibility criteria
The percentage of participants currently presenting with major depressive disorder that would have been excluded by at least 1 out of the 6 traditional and available criteria in clinical trials for MDD ranged respectively from 71.32% to 71.96% in participants with pure MDD, and from 73.41% to 80.16% in those with D(m), according to the model used (Table 1)
Summary
The practice of evidence-based medicine is generally understood as the application to clinical care of knowledge derived from double blind, randomized placebo-controlled trials (RCTs) [1,2]. Growing clinical and epidemiologic evidence indicates that at least part of the heterogeneity observed in MDD is due to the high prevalence of bipolar features, supporting the validity of distinguishing MDD plus a lifetime history of subthreshold hypomania (D(m)) from pure MDD (i.e., MDD without a lifetime history of subthreshold hypomania) in psychiatric classifications, recently acknowledged in the posted DSM-5 update [9,10]. Previous studies conducted in both clinical and general population [9,10,11,12,13,14,15] suggest that the prevalence of lifetime history of subthreshold hypomania in individuals with MDD ranges from 30% to 55%, supporting the existence of large overlaps between unipolar and bipolar disorders. Growing evidence supports the validity of distinguishing major depressive disorder (MDD) plus a lifetime history of subthreshold hypomania (D(m)) from pure MDD in psychiatric classifications. The present study sought to estimate the proportion of individuals with D(m) that would have been included in RCTs for MDD using typical eligibility criteria, and examine the potential impact of including these participants on internal validity
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