Differences in blood pregnenolone and dehydroepiandrosterone levels between schizophrenia patients and healthy subjects

Sha'ar Menashe Mental Health Center, Mobile Post Hefer 38814, Israel.
European Neuropsychopharmacology (Impact Factor: 4.37). 05/2007; 17(5):358-65. DOI: 10.1016/j.euroneuro.2006.10.001
Source: PubMed


Contradictory and confusing reports on serum dehydroepiandrosterone (DHEA) levels in schizophrenia led us to compare the serum concentration of its precursor, pregnenolone (PREG), between medicated schizophrenia patients and healthy subjects. The neurosteroid levels were monitored for two months and the relationship of these neurosteroids with schizophrenic symptomatology, emotional distress, and anxiety was examined.
We determined blood levels of PREG, and DHEA in 15 schizophrenia patients and 12 healthy controls at four time points: at the start of the study, after 2, 4 and 8 weeks. Analysis of covariance and canonical correlations across four time points were applied.
Controlling for age, serum concentrations of PREG were lower, while the DHEA level and the molar ratio values of DHEA/PREG were higher in schizophrenia patients compared to healthy controls. Both levels of PREG and DHEA and their molar ratio did not change significantly during the study's period either among schizophrenia patients or healthy controls. The blood levels of PREG appear to be associated with trait-anxiety scores in the schizophrenia patients, while associations of clinical symptoms with two neurosteroids did not reach a significant level when the confounding effect of emotional distress, and anxiety scores was controlled.
Low serum pregnenolone concentrations in schizophrenia appear to be associated with trait-anxiety scores independent of symptoms. Further research into the role of pregnenolone in schizophrenia is warranted.

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Available from: Michael S. Ritsner, Oct 13, 2015
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    • "In a recent study, serum pregnenolone levels were significantly reduced in first-episode antipsychotic-naïve participants with schizophrenia in both males and females (Bicikova et al. 2013). A prior study also reported lower serum pregnenolone levels in participants with schizophrenia (Ritsner et al. 2007). In contrast, pregnenolone levels in postmortem brain tissue samples (posterior cingulate and parietal cortex) were higher in schizophrenia (Marx et al. 2006c), potentially reflecting medication-induced pregnenolone elevations . "
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    ABSTRACT: 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.
    Psychopharmacology 07/2014; 231(17). DOI:10.1007/s00213-014-3673-4 · 3.88 Impact Factor
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    • "Beneficial effects of DHEA and DHEA-S supplementation as antidepressant treatment for anxiety and mood disorders, and EDs, were previously mentioned. In addition, low circulatory DHEA levels have been associated with high susceptibility to anxiety and mood disturbance in humans (Le Melledo and Baker 2004) and in animal models (Ritsner et al. 2007). Taken together, the fact that H1 is the predominant variant in various human populations, including the African population, and the notion that H1 corresponds to lower CYP17 activity, may suggest that lower DHEA and higher anxiety is evolutionarily advantageous. "
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    ABSTRACT: Dehydroepiandrosterone (DHEA), the main brain neurosteroid, has been implicated in various psychiatric disorders especially those including gender differences. We studied genetic variability in the DHEA-producing enzyme CYP17A1 in relation to anorexia nervosa (AN) susceptibility and AN-related co-morbidities. We performed analysis of 100 Israeli AN family trios accounting for CYP17A1 haplotypes characteristic of populations of European origin and studied genotype-phenotype relationships using correlation analyses and transmission disequilibrium test. Although our analysis revealed no evidence of association between CYP17A1 and AN per se, it revealed an association between specific CYP17A1 haplotypes and AN co-morbidity, specifically anxiety. We found that a common CYP17A1 haplotype (H1) was associated with higher anxiety in AN patients (Clinical Global Impression; CGI-anxiety ≥4). Moreover, H1 homozygotes were at higher risk for expressing high CGI-anxiety levels (OR = 3.7), and H1 was preferentially transmitted to AN patients with high CGI-anxiety levels (P = 0. 037). We suggest that CYP17A1 H1 haplotype may contribute to genetic predisposition to higher CGI-anxiety levels in AN patients and that this predisposition may be mediated by reduced CYP17A1 enzymatic activity and corresponding lower DHEA production.
    Archives of Women s Mental Health 06/2013; 16(5). DOI:10.1007/s00737-013-0363-x · 2.16 Impact Factor
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    • "Dysregulation of brain pregnenolone level has been implicated in a number of brain diseases, such as schizophrenia [18], [61], Alzheimer’s disease [10], [62], [63], bipolar disorder [18], [64] and depression [65], [66], suggesting that changes in neurosteroid levels may play a role in the neurobiology of these disorders. Furthermore, an atypical antipsychotic, clozapine, which is often used in patients whom do not respond to other medications, has been shown to increase pregnenolone levels in the rat hippocampus [11]. "
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    ABSTRACT: Pregnenolone belongs to a class of endogenous neurosteroids in the central nervous system (CNS), which has been suggested to enhance cognitive functions through GABA(A) receptor signaling by its metabolites. It has been shown that the level of pregnenolone is altered in certain brain areas of schizophrenic patients, and clozapine enhances pregnenolone in the CNS in rats, suggesting that pregnenolone could be used to treat certain symptoms of schizophrenia. In addition, early phase proof-of-concept clinical trials have indicated that pregnenolone is effective in reducing the negative symptoms and cognitive deficits of schizophrenia patients. Here, we evaluate the actions of pregnenolone on a mouse model for schizophrenia, the dopamine transporter knockout mouse (DAT KO). DAT KO mice mirror certain symptoms evident in patients with schizophrenia, such as the psychomotor agitation, stereotypy, deficits of prepulse inhibition and cognitive impairments. Following acute treatment, pregnenolone was found to reduce the hyperlocomotion, stereotypic bouts and pre-pulse inhibition (PPI) deficits in DAT KO mice in a dose-dependent manner. At 60 mg/kg of pregnenolone, there were no significant differences in locomotor activities and stereotypy between wild-type and DAT KO mice. Similarly, acute treatment of 60 mg/kg of pregnenolone fully rescued PPI deficits of DAT KO mice. Following chronic treatment with pregnenolone at 60 mg/kg, the cognitive deficits of DAT KO mice were rescued in the paradigms of novel object recognition test and social transmission of food preference test. Pregnenolone thus holds promise as a therapeutic candidate in schizophrenia.
    PLoS ONE 12/2012; 7(12):e51455. DOI:10.1371/journal.pone.0051455 · 3.23 Impact Factor
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