Abstract
<jats:p>After completing this activity, participants should be able to: Differentiate gepirone's selective 5-HT1A receptor agonism from the SERT-blocking mechanism of SSRIs/SNRIs and from buspirone's partial agonism; explaining how full agonism at presynaptic somatodendritic autoreceptors desensitizes them over 2–4 weeks to disinhibit serotonergic firing, how the absence of clinically significant SERT/NET/DAT binding accounts for its weight neutrality, lack of sedation, and minimal sexual dysfunction, and how the active metabolites 3'-OH-gepirone (5-HT1A agonist) and 1-PP (α2-adrenergic antagonist) contribute to efficacy and to noradrenergic adverse effects such as jitteriness and palpitations. Implement gepirone's QTc-safe initiation and titration protocol — obtaining a baseline ECG and electrolytes and not starting if QTc >450 ms, titrating 18.2 mg → 36.3 mg (day 4) → 54.5 mg (day 7) → 72.6 mg (day 14) taken with food at the same time daily, and repeating the ECG with each escalation — while managing CYP3A4 interactions: contraindicating strong inhibitors (≈5× exposure) and strong inducers. Evaluate where gepirone fits in the MDD treatment algorithm by stratifying candidacy — selecting it as a second-line option after SSRI/SNRI failure or intolerance, particularly for treatment-emergent sexual dysfunction or weight concerns when bupropion is unsuitable, or for prominent anxious features while weighing its modest efficacy signal, and screening out poor candidates (baseline QTc >450 ms, congenital long QT, concurrent QT-prolonging or strong CYP3A4 drugs, Child-Pugh C, or unreliable food intake).</jats:p>