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Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia

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Abstract

Rationale

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.

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Acknowledgments

We thank Larry Shampine and Gillian Parke for their excellent laboratory contributions.  This work was supported by the Translational and Clinical Research (TCR) Flagship Programme, Singapore National Medical Research Council (PI Chong), a VA Career Development Transition Award (Marx), and the Singapore Ministry of Health's National Medical Research Council under its Transition Award (Lee).This work was supported by a VA Career Development Transition Award (Marx), the Translational and Clinical Research (TCR) Flagship Programme, Singapore (PI Chong), and the Singapore Ministry of Health's National Medical Research Council under its Transition Award (Grant No.: NMRC/TA/002/20012, Lee).

Conflicts of interest

Dr. Marx is an applicant or co-applicant on pending patent applications for the use of neurosteroids and derivatives in CNS disorders and for lowering cholesterol; no patents issued; no licensing in place (CEM). Dr Jimmy Lee has served as a consultant and received an honorarium from Roche. Dr. Keefe currently or in the past 3 years has received investigator-initiated research funding support from the Feinstein Institute for Medical Research, GlaxoSmithKline, National Institute of Mental Health, Novartis, Psychogenics, Research Foundation for Mental Hygiene, Inc., and the Singapore National Medical Research Council. He currently or in the past 3 years has received honoraria, served as a consultant, or advisory board member for Abbvie, Akebia, Amgen, Astellas, Asubio, AviNeuro/ChemRar, BiolineRx, Biomarin, Boehringer-Ingelheim, Eli Lilly, EnVivo, GW Pharmaceuticals, Helicon, Lundbeck, Merck, Mitsubishi, Novartis, Otsuka, Pfizer, Roche, Shire, Sunovion, Takeda, and Targacept. Dr. Keefe receives royalties from the BACS testing battery and the MATRICS Battery (BACSSymbol Coding). He is also a shareholder in NeuroCog Trials, Inc. and Sengenix.

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Authors and Affiliations

  1. Psychiatry & Behavioral Sciences, Duke University Medical Center, Durham, NC, USA

    Christine E. Marx, Jason D. Kilts & Richard S. E. Keefe

  2. VA Mid-Atlantic MIRECC and Durham VA Medical Center, 508 Fulton Street, Durham, NC, USA

    Christine E. Marx & Jason D. Kilts

  3. Institute of Mental Health, Singapore, Singapore

    Jimmy Lee, Mythily Subramaniam, Attilio Rapisarda, Eu Pui Wai, Swapna Verma, Kang Sim, Jayaraman Hariram, Rajesh Jacob & Siow Ann Chong

  4. Duke-NUS Graduate Medical School, Singapore, Singapore

    Dianne C. T. Bautista, Edwin Chan, Richard S. E. Keefe & Siow Ann Chong

  5. Singapore Clinical Research Institute, Singapore, Singapore

    Dianne C. T. Bautista & Edwin Chan

  6. Maryland Psychiatric Research Center and the University of Maryland, College Park, MD, USA

    Robert W. Buchanan

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  1. Christine E. Marx
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Correspondence to Christine E. Marx.

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Christine E. Marx and Jimmy Lee contributed equally to this manuscript.

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Marx, C.E., Lee, J., Subramaniam, M. et al. Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia. Psychopharmacology 231, 3647–3662 (2014). https://doi.org/10.1007/s00213-014-3673-4

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  • DOI: https://doi.org/10.1007/s00213-014-3673-4

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