title: Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia.
abstract: BACKGROUND
  Preclinical and clinical data suggest that pregnenolone 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 GABAA receptor responses) and pregnenolone sulfate (a positive NMDA receptor modulator). Pregnenolone could thus potentially mitigate GABA dysregulation and/or NMDA receptor hypofunction in schizophrenia via metabolism to other neurosteroids.
  
  
  OBJECTIVE
  The objective of this study is to conduct a randomized 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 (negative symptoms). A modified intent-to-treat analysis approach was utilized.
  
  
  RESULTS
  No significant changes compared to placebo were demonstrated in composite MCCB scores. In contrast, participants randomized to pregnenolone (n = 56) demonstrated greater improvements in functional capacity (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 improvements in female participants. Neurosteroid interventions may exhibit promise as new therapeutic leads for schizophrenia.
authors.affiliation: Psychiatry & Behavioral Sciences, Duke University Medical Center, Durham, NC, USA, christine.marx@duke.edu.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Marx
authors.forename: Jimmy
authors.initials: J
authors.lastname: Lee
authors.forename: Mythily
authors.initials: M
authors.lastname: Subramaniam
authors.forename: Attilio
authors.initials: A
authors.lastname: Rapisarda
authors.forename: Dianne C T
authors.initials: DC
authors.lastname: Bautista
authors.forename: Edwin
authors.initials: E
authors.lastname: Chan
authors.forename: Jason D
authors.initials: JD
authors.lastname: Kilts
authors.forename: Robert W
authors.initials: RW
authors.lastname: Buchanan
authors.forename: Eu Pui
authors.initials: EP
authors.lastname: Wai
authors.forename: Swapna
authors.initials: S
authors.lastname: Verma
authors.forename: Kang
authors.initials: K
authors.lastname: Sim
authors.forename: Jayaraman
authors.initials: J
authors.lastname: Hariram
authors.forename: Rajesh
authors.initials: R
authors.lastname: Jacob
authors.forename: Richard S E
authors.initials: RS
authors.lastname: Keefe
authors.forename: Siow Ann
authors.initials: SA
authors.lastname: Chong
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D018377:Neurotransmitter Agents / Q000097:blood; D011284:Pregnenolone / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D012727:Sex Characteristics; D016896:Treatment Outcome
chemical_list: D014150:Antipsychotic Agents; D018377:Neurotransmitter Agents; D011284:Pregnenolone