19. Randomized Controlled Trial of a Neurosteroid Intervention in Schizophrenia

Abstract

Background: Neurosteroids are endogenous molecules synthesized de novo in brain, adrenals, and other tissues. They demonstrate pleiotropic actions that are highly relevant to the neurobiology of schizophrenia. Clozapine markedly elevates neurosteroids in rodent hippocampus, potentially contributing to its superior therapeutic effcacy. Clinical evidence from a randomized controlled trial (RCT) conducted in Singapore suggests that pregnenolone signifcantly enhances functional capacity (as demonstrated by improvements in the UPSA Total Score and UPSA Communication Subscale Score) and that neurosteroid changes posttreatment predict therapeutic response (Marx et al 2014; Psychopharmacology). We thus conducted an RCT investigating adjunctive pregnenolone in schizophrenia. Method(s): After a 2-week placebo lead-in, 88 participants with schizophrenia were randomized to pregnenolone (n = 42) or placebo (n = 46) for 8 weeks. Neurosteroids were quantifed at baseline and posttreatment by mass spectrometry. Functional end points included the UPSA Total Score and UPSA Communication Subscale. Cognitive end points included the MCCB Composite Score and MCCB Subscales. Modifed intent-to-treat analyses were conducted. Result(s): Participants randomized to the pregnenolone group did not out-perform placebo on the UPSA Total Score or MCCB Composite Score. However, the pregnenolone group demonstrated signifcantly greater improvement in the UPSA Communication Subscale compared to participants randomized to placebo (P =.034), replicating prior RCT fndings from Singapore. Elevations in pregnenolone post-treatment also predicted improvements in UPSA Total Score (r =.373; P =.039), again replicating prior efforts. In addition, the pregnenolone group demonstrated sig-nifcantly greater improvement in the MCCB Verbal Learning Subscale compared to placebo (P =.023). Pregnenolone did not outperform placebo in the BACS Composite Score, SANS Total Score, or PANSS Total Score. Pregnenolone was well tolerated. Conclusion(s): Treatment with pregnenolone appears to improve functional capacity in a US population with schizophrenia, as assessed by the UPSA Communication Subscale and also supported by a signifcant positive correlation between pregnenolone changes and UPSA Total Score improve-ments-thus replicating fndings from a prior RCT conducted in Singapore. Pregnenolone may also improve verbal memory. Given the positive correlation between pregnenolone increases posttreatment and UPSA Total Score improvements, it is possible that higher doses of pregnenolone may be clinically effcacious, and that neurosteroid quantifcation has biomarker potential for the predication of therapeutic response. Additional dose-fnd-ing investigations will be required to test these hypotheses. A pregnenolone decanoate formulation is currently in preclinical development.