S18: Patterns of Exclusion: Antidepressant Clinical Trial Comorbidities
University of Southern California United States
To assess the degree of generalizability of clinical trials of commonly prescribed antidepressants approved by the United States Food and Drug Administration (FDA) for patients with Major Depressive Disorder (MDD), particularly those among vulnerable populations and with comorbid disease states.
Seven antidepressants were searched on clinicaltrials.gov under MDD. Studies utilizing an assessment scale to determine treatment efficacy were assessed. Exclusion criteria included the presence of various other medical conditions besides depression. Data was analyzed for similarities and trends.
Clinical trials of the seven most prescribed antidepressants conducted between 1994 and 2021 were examined (n=126). Of these studies, 104 (82.5%) used FDA-accepted primary endpoints to assess trial efficacy. 72 (69.2%) of the studies used the Hamilton Depression Rating Scale (HAM-D). Of these 72 trials, 72.2% used the 17-item version of the HAM-D, 18.1% used the 24-item version, and the remaining used other variations of the scale. A lesser number (27.8%) of studies used the Montgomery Asberg Depression Rating Scale (MADRS), 9.5% used the Children’s Depression Rating Scale, and 17.5% of studies did not use an FDA-accepted scale. Additionally, within the 126 studies, most (71.4%) excluded depressed patients with unstable medical conditions from participating, 69.8% excluded those at risk of suicide, and 61.1% excluded pregnant women. Because the majority (85.7%) of the clinical trials assessed were conducted prior to the removal of the multiaxial diagnosis of mental disorders by the Diagnostic and Statistical Manual of Mental Disorders in May 2013, data was collected still using this categorization. A total of 119 (94.4%) trials prohibited individuals with any Axis I comorbid mental disorder, the most common being bipolar disorder (59.7%), substance abuse disorder (58.8%), and schizophrenia (45.3%). Of the 50 trials that excluded participants with Axis II disorders, the most frequent comorbid conditions were mental retardation (38.0%), schizoaffective personality disorder (20.0%), and mania (24.0%).
Despite FDA draft guidance for the development of drugs for MDD released in 2018, regulations for the evaluation of antidepressants have not been formally revised since September 1977. This examination of clinical trials for the seven most commonly prescribed antidepressants demonstrated that, as a result of the lack of updates, these trials may not accurately nor adequately represent the clinically depressed population. Regardless of the use of FDA-accepted screening instruments to assess treatment efficacy in the majority of the trials, variation remains in regard to the assessment and version employed to determine primary and/or secondary outcomes. Of persons with MDD, 60-65% have at least one comorbid mental disorder, and those with chronic diseases are nearly three times as likely to get depressed. Thus, since MDD is rarely diagnosed in isolation, it is important to understand MDD in conjunction with comorbid disease states and/or other medical conditions. Pre-existing comorbid conditions are likely to affect individuals’ scores on these scales. However, the presence of many of these diseases excluded individuals from participating in the studies. The inclusion of these individuals is necessary to better understand the safety and efficacy of antidepressants in a context that mimics real world conditions. Furthermore, because the primary endpoints do not consider other diseases that can occur concurrently with depression, this places MDD individuals within special and vulnerable populations at an even greater disadvantage. A more accurate representation of the clinically depressed population, as well as standardization of study designs are necessary steps towards a better understanding of the safety and efficacy of antidepressants currently being by used by the general public.