To our knowledge, this is the first study attempting to estimate the proportion of adults with MDD plus a lifetime history of subthreshold hypomania (D(m)) that would have been included in clinical trials with traditional eligibility criteria for MDD. We found that the proportion of individuals with D(m) might range from 7.98% to 22.59% in the full sample, and from 9.56% to 21.61% in the treatment-seeking subsample, in typical clinical trials for MDD.
Consistent with prior research 
, including a recent study examining generalizability of clinical trial results for current major depressive episode using the same database 
, findings indicate that clinical trials tend to exclude, by design, a majority of individuals with current pure MDD. In a typical efficacy trial for MDD, more than 7 out of ten respondents with pure MDD in both the full sample and the treatment-seeking subsample would have been excluded by at least one exclusion criterion. This result supports that clinical trials suffer from impaired external validity since their results may not be readily generalizable to community settings.
Restrictive eligibility criteria used by RCTs at the cost of diminished external validity are justified to reach high internal validity 
. However, beyond impaired external validity, we found that a substantial proportion of participants that would have been eligible in RCTs for MDD with classical eligibility criteria reported a lifetime history of subthreshold hypomania. In line with prior research supporting the validity of distinguishing depressed individuals with a lifetime history of subthreshold hypomania from those with pure MDD 
, we found that the pattern of exclusion rates (including significant risk of suicide, past-year comorbid anxiety disorders, and overall exclusion rate) in participants with a current diagnosis of MDD plus at least 4 lifetime concomitant hypomanic probes significantly differs from those with pure MDD, whereas it was similar to that in individuals with bipolar 2 disorder, except for the criterion “significant risk of suicide”, which was significantly higher in participants with D(m) when using the more stringent subthreshold bipolar-specifier. Lifetime subthreshold hypomania history among NESARC respondents selectively impacts eligibility on the basis of some exclusion criteria. In the full sample and in the treatment-seeking subsample, a lifetime history of subthreshold hypomania significantly increases at any level of stringency the likelihood of meeting exclusion criterion “significant risk for suicide”, whereas it impacts exclusion for any comorbid anxiety disorder diagnosis only in those endorsing 3 or 4 lifetime concomitant hypomanic probes in the treatment-seeking subsample. In contrast, exclusion rates based on other traditional exclusion criteria appear to be unaffected by D(m) status.
Overall exclusion rate of participants with MDD plus at least 2 hypomanic probes was not significantly different from that of participants with bipolar 2 disorder both in the full sample and in the subsample of participants seeking treatment for depression. With that in mind, including a substantial proportion of individuals with a lifetime history of subthreshold hypomania might be responsible of a selection bias affecting internal validity of trials for MDD. In fact, our results reinforce the possibility that a substantial proportion of individuals with D(m) share similarities with those with bipolar 2 disorder. It was previously suggested that individuals with D(m) have poor response to antidepressants 
, resembling those with bipolar depression 
. Such a potential bias selection might therefore lead to an underestimation of antidepressants’ efficacy in placebo-controlled trials and may impact on antidepressants head-to-head trials’ results. As such, despite of the use of restrictive eligibility criteria at the cost of important diminished external validity 
, a substantial proportion of participants with a lifetime history of subthreshold hypomania are nonetheless included, potentially resulting in impaired internal validity.
Furthermore, we found that individuals with D(m) may have greater risk for suicide compared with those with bipolar 2 disorder, when using the more stringent subthreshold bipolar-specifier (Model 4) in the full sample as well as in the treatment-seeking subsample. One possible explanation is that these participants, considered by the current psychiatric classifications as having unipolar depressive disorder, are less likely to benefit from a mood stabilizer compared to those with bipolar 2 disorder, as previously suggested 
Some limitations should be considered in interpreting these findings. First, we followed a methodology described by Blanco and colleagues 
and applied eligibility criteria derived from the work of Zimmerman and colleagues 
to the NESARC sample. Other conventions might have yield different exclusion estimates. For example, we excluded all individuals with suicide attempt within the last 12 month, considering this question as closest available data to approximate the criterion “significant risk of suicide”. In addition, the 12-month timeframe used by the AUDADIS-IV when assessing the presence of “current” symptoms could have led to an overestimation of the exclusion rate and the proportion of individuals potentially eligible in RCTs for MDD. However, the percentage of excluded participants was high and consistent with those observed in earlier research 
, suggesting that commonly applied criteria are likely to exclude a majority of individuals with pure MDD. Nevertheless, development of procedures to operationalize eligibility criteria selection might help refine future generalizability estimates.
Second, in absence of consensus subthreshold bipolar-specifier diagnosis 
, we defined four models including different subthreshold bipolar-specifier diagnoses. We thus identified participants with MDD plus a lifetime history of subthreshold hypomania based on the lifetime presence during over one week of at least one, two, three or four concomitant hypomanic probes, screening criterion A or B for hypomania. These definitions were somewhat arbitrary and other conventions might have lead to different results. Furthermore, these narrow definitions, both in terms of the choice of hypomanic symptoms and their duration, could have led to underestimate the proportion of depressed participants with a lifetime subthreshold hypomania 
. At last, it has to be raised that the way models where compared in the present work implicitly accept the notion that with more subthreshold positive probes of hypomanic symptoms, the risk to reflect bipolar disorder is increasing. We would like to suggest that a consensus subthreshold bipolar-specifier diagnosis would be helpful to operationalize eligibility assessment of subthreshold hypomania in clinical trials for major depressive disorder 
Third, two exclusion criteria were not available in the NESARC and may theoretically have led to underestimate the proportion of participants excluded in clinical trials. For example, Zimmerman et al. 
have estimated that a score lower than 14 on HAM-D would exclude 32% to 47% of individuals with MDD. However, the percentage of excluded participants was high and consistent with those observed in earlier research 
, supporting that these two missing criteria may have little impact on the overall exclusion rate.
Fourth, as previously indicated by Blanco and colleagues 
, our approach focuses on the a priori
eligibility of participants and was based on national epidemiological data. It provides no information on individuals who actually enter those studies. In this way, we estimate an upper bound of the generalizability of clinical trials. Particularly, a substantial proportion of potential eligible individuals may be unwilling to participate 
. Furthermore, the likelihood of entering a trial may be influenced by several factors, including anxiety, extroversion, work satisfaction, and performance measures 
Fifth, although similar pattern of exclusion rates was observed in the treatment-seeking subsample compared to that of the full sample, no significant difference was found in overall exclusion rate between participants with D(m) and those with pure MDD. Although this result might be due to a lack of statistical power and a floor effect, it is possible that D(m) status may exert less impact on eligibility in individuals seeking treatment for depression.
At last, severity and clinical significance of each disorder are determined by the AUDADIS-IV at the syndromal rather than symptom level. In addition, AUDADIS-IV reliability for diagnoses of anxiety disorders is only fair 
Despite these limitations, this study suggests that the current design of clinical trials for MDD suffers from impaired external validity as well as potential impaired internal validity due to the inclusion of a substantial proportion of individuals with D(m), that may differ from those with pure MDD but not from those with bipolar 2 disorder. We want to emphasize the need of assessing lifetime hypomanic symptoms in eligibility assessment for RCTs for MDD. Individuals with at least 4 lifetime concomitant hypomanic probes might be more accurately excluded from RCTs for MDD and considered as having bipolar 2 disorder, and those with at least 2 hypomanic probes should be systematically subject to a sensitivity analysis to test the robustness of trials’ results. Future studies would benefit from evaluating the influence of individuals with a lifetime history of subthreshold hypomania on placebo-controlled and antidepressants head-to-head clinical trials’ results, as well as efficacy and adverse effects of antidepressants in these patients.