Generalizability of Antidepressant Efficacy Trials: Differences Between Depressed Psychiatric Outpatients Who Would or Would Not Qualify for an Efficacy Trial

During the past few years there have been increasing concerns about the generalizability of the results of tightly controlled efficacy trials to real-world clinical practice (1). We recently applied typically used exclusion criteria to a large group of depressed outpatients and found that most depressed patients treated in routine clinical practice would not have qualified for an antidepressant efficacy trial (2). In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, we turn to the question of the comparability of the patients who would or would not qualify for an antidepressant efficacy trial. Central to the question of generalizability is whether there are important differences in characteristics that are not the basis for exclusion between patients who would or would not qualify for an antidepressant efficacy trial.

Method

The study group included 599 psychiatric outpatients 18 years old or older whose principal diagnosis was DSM-IV nonbipolar, nonpsychotic major depressive disorder. The majority were women (65.4% [N=392]); their mean age was 39.2 years (SD=12.4).

On presentation for outpatient treatment, all patients were interviewed by a trained diagnostic rater who administered the Structured Clinical Interview for DSM-IV supplemented with questions from the Schedule for Affective Disorders and Schizophrenia (SADS) (3) assessing the severity of symptoms during the week preceding the evaluation. An extracted 21-item Hamilton Depression Rating Scale score (4) was derived from the SADS ratings. The interview also included items from the SADS on best level of social functioning during the past 5 years, social functioning during adolescence, and the amount of time employed during the past 5 years. For patients with major depressive disorder we determined the number of episodes, duration of the current episode, age at onset, lifetime history of suicide attempts, and number of hospitalizations. Personality disorders were assessed in 391 of the patients with the Structured Interview for DSM-IV Personality (5). The Rhode Island Hospital Institutional Review Board approved the research protocol, and all patients provided informed consent. The training of the raters and the reliability of the diagnostic assessments in the MIDAS project have been described in detail elsewhere (6).

The present report is based on nonpsychotic patients because treatment recommendations differ for psychotic depression. The four criteria used to define the excluded group are those used in the majority of antidepressant efficacy trials (minimum severity on the Hamilton depression scale, substantial suicide risk, recent DSM-IV diagnosis of alcohol or drug abuse or dependence, and presence of a comorbid axis I disorder) (7). The comorbid disorders used as the basis for exclusion were current posttraumatic stress disorder (PTSD), panic disorder, generalized anxiety disorder, or obsessive-compulsive disorder (OCD).

We decided a priori to subdivide the excluded group into those who would be excluded because of low symptom severity and those who would be excluded because of comorbidity or suicidality, because these variables have different prognostic implications (8). We conducted two planned two-group comparisons of the included patients with each of the excluded groups. A comparison of the two excluded groups was not conducted because it was peripheral to our central question of whether patients who are included or excluded from an antidepressant efficacy trial differ.

Results

The mean extracted Hamilton depression scale score for all 599 patients was 20.3 (SD=5.9). Forty-eight percent of the patients (N=289) scored below 20, the most commonly used severity threshold for inclusion in an efficacy trial (9). Twelve percent of the patients (N=74) had evidence of a current drug or alcohol use disorder. Thirty-nine patients (6.5%) were rated 4 or higher on the SADS suicidal ideation item, indicating the presence of frequent suicidal thoughts with a plan. Forty-one percent (N=246) had current PTSD, generalized anxiety disorder, OCD, or panic disorder. Based on all four criteria, 79.5% (N=476) of the 599 patients would be excluded from an antidepressant efficacy trial.

We compared demographic, psychosocial, and clinical characteristics of the 123 patients who would qualify for an antidepressant efficacy trial with those of the 289 patients whose symptom severity was too mild to qualify for an antidepressant efficacy trial and the 187 patients who would be excluded because they were suicidal or had a comorbid anxiety or substance use disorder (Table 1). The only difference between the included patients and the group excluded for low symptom severity was on the Global Assessment of Functioning Scale (DSM-IV, p. 32), which was expected because symptom severity is one of the components of this scale.

Compared with the included patients, the patients who would be excluded because of comorbidity or suicidal ideation had more social impairment, more frequently missed work because of psychiatric reasons, were more likely to have an episode duration of greater than 2 years, experienced more previous episodes, made more suicide attempts, and were more likely to have a cluster B or cluster C personality disorder.

Discussion

When applying the exclusion criteria of recently published antidepressant efficacy trials (7) to our patients, we found that the majority would not qualify for most antidepressant efficacy trials. The 79% exclusion rate found in the present study is consistent with our previous findings. The present report extends our earlier results by demonstrating that the demographic, clinical, and psychosocial profile of patients who would be excluded from an antidepressant efficacy trial because of a comorbid anxiety or substance use disorder or substantial suicidal ideation differs from that of patients who would qualify for a trial. Specifically, we found that these excluded patients are a more chronically ill group, with more previous episodes, greater social and occupational impairment, and more personality pathology. In contrast, the psychosocial and clinical characteristics of patients who would be excluded because of insufficient symptom severity were virtually the same as the patients who would qualify for an antidepressant efficacy trial.

Antidepressant efficacy trials tend to exclude two groups of patients: those who are less likely to respond to treatment because they have substantial personality pathology and associated greater chronicity and poorer psychosocial functioning and those who are less likely to demonstrate differences in response between active medication and placebo by virtue of the milder severity of their symptoms. Although there are some studies demonstrating the efficacy of antidepressants in chronically and mildly depressed patients (8), these are relatively few. We are unaware of any large-scale placebo-controlled studies that have focused on the efficacy of treating depression in patients with personality disorders.

The results of the present study, added to the findings of studies demonstrating that a low percentage of applicants are accepted into antidepressant efficacy trials and that a low percentage of patients in clinical practice would qualify for an antidepressant efficacy trial, call for a discussion regarding how the results of antidepressant efficacy trials should be interpreted and promoted. Antidepressant efficacy trials are generally limited to patients with the greatest likelihood of demonstrating drug-placebo differences. Yet, antidepressant medications are approved and marketed without acknowledging the generalizability issue. It seems reasonable that antidepressants should be approved and marketed only for the narrow range of patients in whom they are proven effective. Approval for other groups of depressed patients should be dependent on demonstration of efficacy, analogous to requiring additional study to obtain an indication for pediatric depression or bipolar depression.

TABLE 1

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