Last week, the FDA approved gepirone hydrochloride ER for the treatment of major depressive disorder. This not-so-new antidepressant is in the same family as buspirone (BuSpar), which is FDA-approved as a treatment for generalized anxiety disorder. Like many other antidepressants, gepirone modulates serotonergic neurotransmission; however, rather than simply blocking reuptake, gepirone acts as a partial agonist at the serontonin 1A receptor and as an antagonist at the serotonin 2A receptor. Because it works differently than more commonly used serotonin reuptake inhibitors, it may offer a slightly different side effect profile. Specifically, it may have less impact on sexual functioning and weight.
Common side effects (5% or more) occurring in those treated with gepirone versus placebo included dizziness (49% vs 10%, respectively), nausea (35% vs 13%), insomnia (15% vs 5%), abdominal pain (7% vs 3%), and dyspepsia (6% vs 2%).
Gepirone will be marketed as Exxua by Fabre-Kramer Pharmaceuticals. It is expected to hit the market in January 2024.
Why Did It Take So Long for FDA Approval?
Back in 2004, Jonathan Alpert, MD PhD, Maurizio Fava, MD, and colleagues from the Depression Clinical and Research Program at Mass General evaluated the efficacy and tolerability of gepirone extended-release (ER) in patients with major depressive disorder (MDD) and high levels of anxiety (anxious depression). In this subgroup analysis derived from an 8-week randomized controlled trial, gepirone ER-treated patients with anxious depression (N = 58) experienced a statistically significant reduction in mean Hamilton Rating Scale for Depression (HAM-D-17) scores at weeks 3, 6, and 8 compared with patients receiving placebo (N = 75).
While two studies supported the efficacy of gepirone ER for the treatment of MDD, meeting the FDA requirement of positive results from two adequate, well-designed randomized controlled trials, other studies were negative or failed/non-informative. Thus, gepirone ER was not granted FDA approval; however, this rejection sparked a series of important debates, and an internal review. How much evidence from negative or failed studies is needed to override data from positive trials? What if gepirone works better for certain subtypes of depression than others? Can a post-hoc analysis of the data help to clarify the findings? the gepirone saga underscores the complexity and difficulty of designing and interpreting antidepressant clinical trials. Researchers face many challenges in conducting trials with a clinically heterogeneous patient population, high placebo response rates, and subjective measures of outcomes.
Antidepressant development has been plagued by failed trials. While negative and positive trials are informative, failed trials — studies that either by design or circumstance were unable to detect a treatment difference between drug and placebo — are uninformative. Our concern is that these methodologic issues may hinder the discovery and approval of potentially effective antidepressant medications.
Read More
Alpert JE, Franznick DA, Hollander SB, Fava M. Gepirone extended-release treatment of anxious depression: evidence from a retrospective subgroup analysis in patients with major depressive disorder. J Clin Psychiatry. 2004 Aug;65(8):1069-75.
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Maurizio Fava, MD is the Chair of the Department of Psychiatry/Psychiatrist-In-Chief at Mass General; Executive Director of the Clinical Trials Network & Institute; Associate Dean for Clinical & Translational Research, and Slater Family Professor of Psychiatry at Harvard Medical School. He was the co-principal investigator of the STAR*D trial with Dr. A. John Rush, the largest clinical trial ever conducted in depression. In addition to his numerous clinical trials and studies in treatment-resistant depression, Dr. Fava has contributed significantly to the field of psychiatric research in a number of other areas. He has edited eight books and authored or co-authored more than 900 original articles published in medical journals with international circulation, articles which have been cited more than 100,000 times in the literature and with an h index greater than 150 on Google Scholar.
