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 500âmg/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 (rs=0.81, p=0.022). Increases in allopregnanolone, a GABAergic pregnenolone metabolite, also predicted BACS composite scores (rs=0.74, p=0.046). In addition, baseline pregnenolone (rs=â0.76, p=0.037), pregnenolone sulfate (rs=â0.83, p=0.015), and allopregnanolone levels (rs=â0.83, 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 (rs=0.74, p<0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.
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Acknowledgements
This work was supported by the following sources: The VA Mid-Atlantic Mental Illness, Research, Education, and Clinical Center, VA Advanced Research Career Development Award (CEM), K23 MH65080 (CEM), National Alliance for Research on Schizophrenia and Affective Disorders (CEM), Durham VA REAP (PI Roger D. Madison, PhD), R37AA10564 (ALM), VA Career Development Award (JLS). We thank Gillian Parke for her excellent assistance with this project.
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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.
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Marx, C., Keefe, R., Buchanan, R. et al. Proof-of-Concept Trial with the Neurosteroid Pregnenolone Targeting Cognitive and Negative Symptoms in Schizophrenia. Neuropsychopharmacol 34, 1885â1903 (2009). https://doi.org/10.1038/npp.2009.26
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DOI: https://doi.org/10.1038/npp.2009.26
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