Pregnenolone-progesterone-allopregnanolone pathway as a potential therapeutic target in first-episode antipsychotic-naïve patients with schizophrenia

•Plasma pregnenolone pathways were assessed between controls (HC) and first–episode schizophrenia (SZ) before antipsychotic treatment (AT).•Levels of pregnenolone (PREG) were significantly higher and allopregnanolone (ALLO) were lower in first–episode patients with SZ than in HC.•In response to AT for one month (1 - m), ALLO levels in SZ patients were markedly elevated whereas PREG and progesterone (PROG) levels decreased.•SZ patients with lower levels of PROG at baseline may predict better therapeutic outcome after 1 - m antipsychotic treatment.•PREG–PROG–ALLO pathway was abnormal early in psychosis, and future study may inform alternative and innovative therapeutic targets for SZ. Neurosteroids are both endogenous and exogenous steroids that rapidly alter neuronal excitability through interactions with ligand-gated ion channels and other cell surface receptors. They are originated from cholesterol and have important implications for schizophrenia (SZ) pathophysiology and treatment strategies. Specifically, pregnenolone (PREG), progesterone (PROG) and allopregnanolone (ALLO) exhibit similar psychotropic properties. Using enzyme immunoassay, we compared the neurosteroids in PREG downstream pathways in plasma between healthy controls (HC, n = 43) and first-episode antipsychotic-naïve patients with SZ (FEAN-SZ, n = 53) before antipsychotic drug (APD) treatment. Comparisons were also made particularly along PREG-PROG-ALLO pathway in the same FEAN-SZ patients across multiple time points following initiation of treatment for 12 months (m). Firstly, at baseline, levels of PREG were significantly higher and those of ALLO were lower in FEAN-SZ than in HC, whereas PROG, cortisol, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) were not different. Consequently, the molar ratios of ALLO/PREG and ALLO/PROG in FEAN-SZ were significantly reduced. Secondly, in response to APD at 1 month, ALLO levels in FEAN-SZ were markedly elevated, whereas PREG and PROG levels decreased. Thirdly, among FEAN-SZ, lower levels of PROG (reflecting higher conversion to ALLO) at baseline may predict better therapeutic outcome after 1 month of APD treatment. These findings point to the perturbations of the PREG-PROG-ALLO pathway early in psychosis, and further study of this pathway may inform alternative and innovative therapeutic targets for SZ.