SUN-303 Effects of Open-Label, Adjunctive Ganaxalone Treatment on Resistant Depression in Postmenopausal Women: A Pilot Study
Authors: Dichtel Laura E , Nyer Maren , Dording Christina , Fisher Lauren B , Cusin Christin , Shapero Benjamin G , Pedrelli Paola , Kimball Allison , Rao Elizabeth M , Mischoulon David , Fava Maurizio , Miller Karen Klahr 
Published: May 2020

Abstract
Resistance to selective serotonin reuptake inhibitor and serotonin norepinephrine reuptake inhibitor treatment occurs in about 50% to 70% of patients with major depressive disorder (MDD), a condition associated with significant morbidity that affects women at higher rates than men. Few well-tolerated, effective augmentation therapies are available for such patients, and new therapeutic strategies for resistant depression are needed. The neuroactive steroid metabolite of progesterone, allopregnanolone, is a positive allosteric modulator of GABAA receptors and a putative treatment for mood disorders. We performed a pilot study to determine whether an oral allopregnanolone analog (ganaxolone) may be effective adjunctive therapy for resistant depression in postmenopausal women. Ten postmenopausal women (age 62.8±6.3 years, range 53–69) with resistant depression [current DSM-IV major depressive episode per the Structured Clinical Interview for DSM-IV, Montgomery-Asberg Depression Rating Scale (MADRS) ≥16 despite treatment with an adequately dosed antidepressant for ≥6 weeks] were studied. Open-label ganaxolone (225 mg BID, increased to 450 mg BID if tolerated) was administered for 8 weeks, followed by a 2-week taper. Mean total MADRS depression score (primary endpoint) decreased by 8 weeks [24.4±1.6 (SEM) to 12.8±2.9, p=0.015] and persisted over the two-week taper (p=0.019); 44% of subjects experienced response (score decrease ≥50%) and remission (final score &lt;10), which persisted in 100% and 50% of subjects at 10 weeks, respectively. Secondary endpoints showed significant improvement, including the Inventory of Depressive Symptomatology-Self-Report (IDS-SR; p=0.003), MADRS Reduced Sleep subscale (p&lt;0.001), Symptoms of Depression Questionnaire (SDQ) total score (p=0.012), and SDQ subscales for disruptions in sleep quality (p=0.003) and changes in appetite and weight (p=0.009) over 8 weeks. No significant effects were observed on quality of life or sexual function. All subjects experienced sleepiness and fatigue; 60% experienced dizziness. In conclusion, adjunctive ganaxolone in this open label pilot study appeared to exert antidepressant effects in postmenopausal women with resistant depression but produces sedation with twice-daily dosing. The observed positive effects on sleep and the potential for sustained treatment effects merit further study, as ganaxolone may be particularly beneficial to patients with depression and insomnia. Randomized, placebo-controlled studies are necessary to rule out placebo effects. Given the sedation experienced by most participants, nighttime dosing only should be considered for future studies. Finally, should rigorous studies confirm an antidepressant effect, it will be important to identify subsets of women who respond (e.g. women with neuroactive steroid dysregulation) and mechanisms of action.