Proof-of-concept trial with the neurosteroid pregnenolone targeting cognitive and negative symptoms in schizophrenia

Abstract

The neurosteroid pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n=9/group). Pregnenolone was well tolerated. Patients receiving pregnenolone demonstrated significantly greater improvements in SANS scores (mean change=10.38) compared with patients receiving placebo (mean change=2.33), p=0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to pregnenolone compared with placebo. However, serum pregnenolone increases predicted BACS composite scores at 8 weeks in the pregnenolone group (r(s)=0.81, p=0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (r(s)=0.74, p=0.046). In addition, baseline pregnenolone (r(s)=-0.76, p=0.037), pregnenolone sulfate (r(s)=-0.83, p=0.015), and allopregnanolone levels (r(s)=-0.83, p=0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (r(s)=0.74, p<0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.

Conflict of interest statement

DISCLOSURE OF COMPENSATION OVER THE LAST 3 YEARS/CONFLICT OF INTEREST

Dr Marx has no compensation to disclose over the last 3 years. Dr Marx is a co-applicant on a pending US patent application on the use of neurosteroids for the treatment of central nervous system disorders. She is an unpaid scientific advisor and board member of NeuroScience Pharmaceuticals. Dr Keefe has received compensation from the following sources: Astra-Zeneca, Cyberonics, Gabriel Pharmaceuticals, Organon Pharmaceuticals, Otsuka, Pfizer, Saegis, Abbott, Acadia, BiolineRx, Bristol-Myers Squibb, Cephalo, Cortex, Dainippon Sumitomo Pharmaceutical, Eli Lilly, Johnson & Johnson, Lundbeck, Memory Pharmaceuticals, Merck, Orexigen, Sanofi/Aventis, Shering-Plough, Wyeth, and Xenoport. Dr Keefe is a contributor to a pending US patent application on the use of neurosteroids for the treatment of central nervous system disorders. Dr Keefe receives royalties for two of the cognitive test batteries used in this study, the BACS and the MATRICS Consensus Cognitive Battery. Dr Buchanan has received compensation from the following sources: Astra-Zeneca, GlaxoSmithKline, Janssen, Merck, Natixis Bleichroeder, Organon, Ortho-McNeil, Pfizer, Sanofi-Aventis, Solvay Pharmaceuticals, and Wyeth. Dr Hamer has received compensation from the following sources: Acadia, Allergan, Alpharma, Astra-Zeneca, Cenerx, Corcept, EnabledMD, Epix, Johnson & Johnson, Pfizer, Schwartz, Solvay Pharmaceuticals, Sanofi-Aventis, Takeda, and Wyeth. Dr Kilts, Dr Bradford, Dr Strauss, Dr Naylor, Dr Payne, Ms Leimone, Dr Dunn, Dr Porcu, Dr Morrow, and Mr Shampine have no compensation to disclose over the last 3 years. Dr Lieberman has received compensation from the following sources: Astra-Zeneca, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Pfizer, Wyeth, Solvay Pharmaceuticals, Bristol-Myers Squibb, Janssen, and Repligen. Dr Savitz has received compensation from the following sources: Astra-Zeneca, Sanofi-Aventis, Janssen, and Pfizer.

Figures

Figure 1

(a) Increases in serum pregnenolone following treatment with this neurosteroid are correlated with improvements in cognitive performance, as assessed by composite BACS z-scores. (b) Increases in serum allopregnanolone following treatment with pregnenolone are correlated with cognitive improvement, as assessed by composite BACS z-scores. (c) Baseline pregnenolone sulfate levels are inversely associated with cognitive improvement, as assessed by composite MCCB t-scores.