Neurosteroid Perturbation and Neuropsychiatric Symptoms in Schizophrenia: From the Mechanisms to the Treatment

Schizophrenia is a psychiatric disorder with a complex pathophysiol- ogy, involving many biochemical abnormalities (Dopaminergic, GABAergic, Glutamatergic) and neurodevelopmental alterations resulting in a disconnectivity in the brain. Since neurosteroids modulate neurotransmitter systems as well as growth factor expression implicated in schizophrenia, recent research has focused on examining the role that neurosteroids play in the illness phenomenology. Beginning with clinical evidence of variation in symptom severity over the men- strual cycle of schizophrenics, it has been shown that Progesterone and its reduced metabolite tetrahydroprogesterone (THP) affect dopamine-mediated behaviour, sug- gesting their antipsychotic-like profile. Indeed, THP, the most potent endogenous positive modulator of GABA A receptors, is able to regulate the Dopaminergic release, via GABA. Interestingly, low cerebral levels of THP were found in a post-mortem study of schizophrenics. Moreover, a positive correlation between THP levels and aggressiveness/hostility, and a negative correlation between negative symptoms and testosterone levels have been evidenced in schizophrenics. Also, low estradiol levels in schizophrenic women have been related with a major vulnerability to psychosis. Finally, progesterone and dihydroprogesterone, acting on the genome, may modulate growth factor expression (i.e., BDNF), and regulate the expression of D5 receptors, suggesting their likely neuroprotective and neuroplastic role. This chapter summarizes the current understanding of these neurosteroids in schizophrenia, their potential antipsychotic role, and discusses new avenues for this area of schizophrenia research.