Gepirone is a newly approved antidepressant with a novel mechanism as a selective 5-HT1A receptor agonist, distinguishing it from first-line SSRIs and SNRIs. While its overall antidepressant effect size is considered modest, gepirone's key advantages lie in its favorable tolerability profile, notably a reduced risk of sexual dysfunction and emotional blunting compared to common antidepressants. This positions it as a potential alternative for patients who are intolerant of, or do not respond to, first-line therapies, particularly those with anxious depression. In comparison to the related azapirone buspirone, which is primarily used for anxiety, gepirone is specifically developed and approved for Major Depressive Disorder (MDD) in an extended-release formulation, and it is expected to hold greater clinical relevance for this condition. Although its commercial journey has been interrupted (approved in 2023, withdrawn in 2024, with a planned relaunch in 2025), gepirone offers a distinct therapeutic option for MDD, especially for patients prioritizing tolerability. [1, 2]
Based on the 2019 APA guidelines for treating depression in adults, the panel recommends that clinicians offer either psychotherapy or second-generation antidepressants as initial treatment, using a shared decision-making approach with patients. For psychotherapy, comparative effectiveness studies showed similar results across different models, so the panel does not recommend one specific type over others among behavioral therapy, cognitive therapy, cognitive-behavioral therapy, interpersonal psychotherapy, psychodynamic therapy, and supportive therapy. If combined treatment is being considered, the panel specifically recommends cognitive-behavioral therapy or interpersonal psychotherapy paired with a second-generation antidepressant. For patients who are partial or non-responders to initial antidepressant treatment, the panel recommends switching from medication alone to cognitive therapy alone or switching to a different antidepressant medication. Regarding relapse prevention, the panel conditionally suggests offering psychotherapy rather than antidepressant medication or treatment as usual. The guidelines emphasize that most patients prefer psychotherapy over medication (about 75%), though an important minority (25%) prefer pharmacotherapy. While combined treatments may be more effective than either treatment alone in some populations, they also involve greater costs, side effects, and patient demands, with some research suggesting they may interfere with psychotherapy's enduring effects. For patients with chronic and treatment-resistant depression, combined treatment is typically recommended. The panel notes that psychotherapies generally demonstrate longer-term effects lasting 6-12 months after treatment ends, while antidepressants have very high relapse rates after discontinuation, making psychotherapy potentially superior for long-term outcomes. [3]
The 2022 Department of Veterans Affairs (VA)/Department of Defense (DoD) clinical guidelines on the management of major depressive disorder (MDD) provide recommendations regarding the use of pharmacologic and non-pharmacologic interventions in adult patients. The guideline emphasizes an evidence-based approach, combining both pharmacotherapy and psychotherapy based on patient preference and specific clinical scenarios. It advocates for treatment in either primary care settings using collaborative care models or within specialty mental health care with a focus on patient-centered practices and shared decision-making. In patients with uncomplicated MDD, psychotherapy or pharmacotherapy monotherapy is recommended based on patient preference, with consideration of treatment modalities based upon individual factors such as the severity, chronicity, prior treatment response, and patient characteristics. Psychotherapy options include behavioral therapy, cognitive behavioral therapy, and psychodynamic therapy, among others; no ranking of psychotherapy type is provided. For the treatment of uncomplicated MDD in patients who are initiating pharmacotherapy treatment or previously responded well to pharmacotherapy, the following are recommended: bupropion, mirtazapine, a serotonin-norepinephrine reuptake inhibitor, trazodone, vilazodone, vortioxetine, or a selective serotonin reuptake inhibitor. A combination of pharmacotherapy and psychotherapy is recommended for patients with severe, persistent (>2 years), or recurrent (≥2 episodes) MDD. The guideline also delineates strategies for managing cases with partial or no response to initial treatments, highlighting the potential role of pharmacologic augmentation with second-generation antipsychotics, switching to another antidepressant drug class, or alternatives such as repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT). The guidelines underscore the importance of ongoing monitoring and the use of measurement-based care to track treatment progress and outcomes. In high-risk populations, such as those with persistent depressive disorder, the guidelines suggest extending treatment duration to prevent relapses. Overall, the guideline provides a comprehensive, systematic framework for aligning depression treatment with the latest evidence and clinical practice, ensuring a patient-centric approach to managing MDD in both veteran and active military populations. [4]