ORIGINAL INVESTIGATION Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia Christine E. Marx & Jimmy Lee & Mythily Subramaniam & Attilio Rapisarda & Dianne C. T. Bautista & Edwin Chan & Jason D. Kilts & Robert W. Buchanan & Eu Pui Wai & Swapna Verma & Kang Sim & Jayaraman Hariram & Rajesh Jacob & Richard S. E. Keefe & Siow Ann Chong Received: 15 January 2014 /Accepted: 22 June 2014 # Springer-Verlag Berlin Heidelberg (outside the USA) 2014 Abstract Rationale Preclinical and clinical data suggest that pregneno- lone may be a promising therapeutic in schizophrenia. Pregnenolone is neuroprotective and enhances learning and memory, myelination, and microtubule polymerization. Treatment with pregnenolone elevates allopregnanolone (a neurosteroid that enhances GABA A receptor responses) and pregnenolone sulfate (a positive NMDA receptor modulator). Pregnenolone could thus potentially mitigate GABA dysreg- ulation and/or NMDA receptor hypofunction in schizophrenia via metabolism to other neurosteroids. Objective The objective of this study is to conduct a random- ized controlled trial of adjunctive pregnenolone in schizophrenia. Methods Following a placebo lead-in, 120 participants were randomized to pregnenolone or placebo for 8 weeks (Institute for Mental Health, Singapore). Primary endpoints were changes in MATRICS Consensus Cognitive Battery (MCCB) composite scores (cognitive symptoms), UCSD Performance-based Skills Assessment—Brief (UPSA-B) composite scores (functional capacity), and Scale for Assessment of Negative Symptoms (SANS) total scores (neg- ative symptoms). A modified intent-to-treat analysis approach was utilized. Results No significant changes compared to placebo were demonstrated in composite MCCB scores. In con- trast, participants randomized to pregnenolone (n =56) demonstrated greater improvements in functional capac- ity (UPSA-B composite changes) compared to placebo (n =55), p =0.03. Pregnenolone was also superior to placebo in the communication subscale of the UPSA-B (p <0.001). Serum pregnenolone changes post-treatment were correlated with UPSA-B composite score changes in females (r s =0.497, p <0.042, n =17) but not in males. Mean total SANS scores were very low at baseline and did not improve further post-treatment. Pregnenolone was well-tolerated. Conclusions Pregnenolone improved functional capacity in participants with schizophrenia, but did not improve cognitive symptoms over an 8-week treatment period. Neurosteroid changes correlated with functional improve- ments in female participants. Neurosteroid interventions may exhibit promise as new therapeutic leads for schizophrenia. Keywords Schizophrenia . Pregnenolone . Neurosteroid . Allopregnanolone . Function . UPSA . Cognition . MCCB . Treatment . Therapeutic . RCT Christine E. Marx and Jimmy Lee contributed equally to this manuscript. C. E. Marx : J. D. Kilts : R. S. E. Keefe Psychiatry & Behavioral Sciences, Duke University Medical Center, Durham, NC, USA C. E. Marx (*) : J. D. Kilts VA Mid-Atlantic MIRECC and Durham VA Medical Center, 508 Fulton Street, Durham, NC, USA e-mail: christine.marx@duke.edu J. Lee : M. Subramaniam : A. Rapisarda : E. P. Wai : S. Verma : K. Sim : J. Hariram : R. Jacob : S. A. Chong Institute of Mental Health, Singapore, Singapore D. C. T. Bautista : E. Chan : R. S. E. Keefe : S. A. Chong Duke-NUS Graduate Medical School, Singapore, Singapore D. C. T. Bautista : E. Chan Singapore Clinical Research Institute, Singapore, Singapore R. W. Buchanan Maryland Psychiatric Research Center and the University of Maryland, College Park, MD, USA Psychopharmacology DOI 10.1007/s00213-014-3673-4