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Pregnenolone-Progesterone-Allopregnanolone Pathway and Schizophrenia

 

Neurosteroids have the ability to rapidly alter neuronal excitability through interactions with ligand-gated ion channels and cell surface receptors.  Among these neurosteroids, pregnenolone, progesterone, allopregnanolone, cortisol, and dehydroepiandrosterone are known to be involved in biological functions that have been implicated in the pathophysiology of various psychiatric disorders. Previous studies have identified possible links between low levels of serum pregnenolone and schizophrenia, as well as correlations between the severity of negative symptoms in male patients with schizophrenia and elevated levels of cortisol. A recent paper by Cai et al. sought to determine the role that pregnenolone pathway neurosteroids play in the development and treatment of schizophrenia. Hypothesizing that treatment for schizophrenia has it’s own effects on neurosteroid levels, the authors chose to limit entry to their study to patients experiencing their first schizophrenic episode who had not yet received any treatment with antipsychotic drugs. These patients were followed for 12 months after antipsychotic treatment was initiated, and compared to healthy age and sex matched controls.

Plasma samples were assayed for key neurosteroids prior to the start of treatment, and then again at 1 month, 6 months and 12 months after treatment began. They found that prior to treatment with antipsychotic drugs, the patients with schizophrenia had significantly lower levels of allopregnanolone (Allopregnanolone EIA Kit, Monoclonal Antibody Based, K061-H) and higher levels of its precursor pregnenolone as compared to healthy controls. Levels of progesterone, cortisol, dehydroepiandrosterone and DHEAS were found to be essentially unchanged between the patients diagnosed with schizophrenia and healthy controls. 1 month after the start of appropriate drug treatment, patients reported reduction in symptoms and severity, and a second round of plasma testing showed raising allopregnanolone levels and corresponding lower levels of pregnenolone and progesterone. Suggesting that relative neurosteroid rations were returning to normal along with the easing of symptoms. However over the next 11 months of continued treatment normalization of allopregnanolone waned. This may reflect reduced efficacy for the antipsychotic drugs on neurosteroid pathways, or it may be caused by some other compensating changes within the larger metabolome. For example; it is well known that several common antipsychotic drugs including haloperidol and risperidone cause elevation of serum prolactin. Prolactin inhibits 5a-reductase, the enzyme that catalyzes the conversion of progesterone to allopregnanolone, suggesting one feedback loop that could be responsible for the loss of allopregnanolone normalization as treatment progresses. Other feedback loops involving GABAergic signaling and dopamine regulation have also been proposed although much more study is needed to truly understand how allopregnanolone’s influence on these different pathways ultimately comes together with symptoms and treatment schizophrenia and other neurological disorders.

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