Emerging preclinical and clinical evidence suggests that
pregnenolone may be a promising novel therapeutic candidate in
schizophrenia.
Pregnenolone is a
neurosteroid with pleiotropic actions in rodents that include the enhancement of learning and memory, neuritic outgrowth, and myelination. Further,
pregnenolone administration results in elevations in downstream
neurosteroids such as
allopregnanolone, a molecule with
neuroprotective effects that also increases neurogenesis, decreases apoptosis and
inflammation, modulates the hypothalamic-pituitary-adrenal axis, and markedly increases
GABA(A) receptor responses. In addition,
pregnenolone administration elevates
pregnenolone sulfate, a
neurosteroid that positively modulates
NMDA receptors. There are thus multiple mechanistic possibilities for
pregnenolone as a potential therapeutic agent in
schizophrenia, including the amelioration of
NMDA receptor hypofunction (via metabolism to
pregnenolone sulfate) and the mitigation of
GABA dysregulation (via metabolism to
allopregnanolone). Additional evidence consistent with a therapeutic role for
pregnenolone in
schizophrenia includes
neurosteroid changes following administration of certain
antipsychotics in rodent models. For example,
clozapine elevates
pregnenolone levels in rat hippocampus, and these increases may potentially contribute to its superior
antipsychotic efficacy [Marx et al. (2006a) Pharmacol Biochem Behav 84:598-608]. Further,
pregnenolone levels appear to be altered in postmortem brain tissue from patients with
schizophrenia compared to control subjects [Marx et al. (2006c) Neuropsychopharmacology 31:1249-1263], suggesting that
neurosteroid changes may play a role in the neurobiology of this disorder and/or its treatment. Although clinical trial data utilizing
pregnenolone as a therapeutic agent in
schizophrenia are currently limited, initial findings are encouraging. Treatment with adjunctive
pregnenolone significantly decreased negative symptoms in patients with
schizophrenia or
schizoaffective disorder in a pilot proof-of-concept randomized controlled trial, and elevations in
pregnenolone and
allopregnanolone post-treatment with this intervention were correlated with cognitive improvements [Marx et al. (2009) Neuropsychopharmacology 34:1885-1903]. Another pilot randomized controlled trial recently presented at a scientific meeting demonstrated significant improvements in negative symptoms, verbal memory, and attention following treatment with adjunctive
pregnenolone, in addition to enduring effects in a small subset of patients receiving
pregnenolone longer-term [Savitz (2010) Society of Biological Psychiatry Annual Meeting New Orleans, LA]. A third pilot clinical trial reported significantly decreased positive symptoms and extrapyramidal side effects following adjunctive
pregnenolone, in addition to increased attention and working memory performance [Ritsner et al. (2010) J Clin Psychiatry 71:1351-1362]. Future efforts in larger cohorts will be required to investigate
pregnenolone as a possible therapeutic candidate in
schizophrenia, but early efforts are promising and merit further investigation. This article is part of a Special Issue entitled:
Neuroactive Steroids: Focus on Human Brain.