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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.

SUBMITTER: Marx CE

PROVIDER: S-EPMC3427920 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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

Marx Christine E CE Keefe Richard S E RS Buchanan Robert W RW Hamer Robert M RM Kilts Jason D JD Bradford Daniel W DW Strauss Jennifer L JL Naylor Jennifer C JC Payne Victoria M VM Lieberman Jeffrey A JA Savitz Adam J AJ Leimone Linda A LA Dunn Lawrence L Porcu Patrizia P Morrow A Leslie AL Shampine Lawrence J LJ

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20090401 8

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 dis ...[more]

PMID: 19339966

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Project description:Few psychosocial approaches address the negative symptoms of schizophrenia, which shares common features with depression and anxiety. Behavioral activation (BA) is effective for addressing depression and anxiety in adults with various mental disorders. Motivational interviewing (MI) has been successfully applied to address ambivalence or lack of motivation toward treatment. Motivational and behavioral activation (mBA) has been developed by incorporating the core principles from BA and MI with recent findings on the negative symptoms of schizophrenia. In this study, we aimed to examine the feasibility and preliminary efficacy of mBA in a non-randomized controlled pilot study that included individuals with schizophrenia with mild to moderate negative symptoms receiving psychiatric rehabilitation. A total of 73 individuals with schizophrenia were recruited. Forty-seven of the participants who met the study inclusion and exclusion criteria were assigned to either an mBA + usual psychiatric rehabilitation group (mBA) or a usual psychiatric rehabilitation only group (treatment as usual, TAU). Administering mBA to individuals with schizophrenia with mild to moderate negative symptoms was feasible in a community mental health setting. Relative to TAU, mBA was associated with large effects in reducing negative symptoms measured using the Positive and Negative Syndrome Scale (PANSS) and the Brief Negative Symptom Scale (BNSS). However, after considering PANSS cognitive deficits and marital status as covariates due to significant differences in their baseline levels, the treatment effects on the BNSS were partially observed. In addition, participants in the mBA group showed improved verbal learning and memory compared with those in the TAU group. In individuals with schizophrenia receiving the usual forms of psychiatric rehabilitation in a community mental health setting, mBA appears to offer a promising adjunctive approach for addressing mild to moderate negative symptoms. Further investigations are needed to replicate the current findings in a randomized controlled trial.

Dataset Information

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

Publications

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

Similar Datasets

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