Neuroactive Steroids in Schizophrenia

Abstract

S chizophrenia is a severe psychiatric disorder that significantly impairs a person's ability to think clearly, manage emotions, make decisions, and relate to others. Many biochemical theories attempt to explain the primary pathophysiological changes in schizophrenia. The DA hypothesis, which postulates hyperdopaminergia in the mesolimbic dopamine system and hypodopaminergia in the mesocortical dopamine system (1), is one of the most popular biochemical theories but is limited by its inability to account for all aspects of the illness. Other neurotransmitter systems that have been implicated and that are being examined for their role in schizophrenia include glutamate, serotonin, and GABA. NASs play a modulatory role in the central nervous system and affect many of these neurotransmitter systems. NASs have not been extensively studied in schizophrenia, yet growing evidence suggests that they may play an important role in the pathophysiology of the illness. This paper reviews NAS effects on neuronal excitability and discusses the evidence implicating NASs in schizophrenia. Future directions for NAS research in schizophrenia are also discussed. Neuroactive SteroidsClassical steroid hormones (for example, cortisol, dihydrotestosterone, and aldosterone) exert their effects via genomic mechanisms (Figure 1). Because of their lipophilic nature, steroid hormones diffuse through the cell membrane into the cytosol, where they bind to their intracellular receptors, which subsequently change conformation and dissociate from associated chaperone molecules. These bound complexes then translocate to the nucleus and bind as homo-or Schizophrenia is a psychiatric disorder with a complicated pathophysiology, involving many biochemical abnormalities in the brain. Because neuroactive steroids (NASs) modulate neurotransmitter systems that are implicated in the pathology of schizophrenia, recent research has focused on examining the role that NASs play in the illness. Although research in this area is relatively new, it appears that NASs may potentially be implicated in the pathophysiology of the illness. This paper reviews the current understanding of NASs, the research literature on NASs in schizophrenia and in animal models of the illness (including the effects of antipsychotic medication on NASs) and on the potential antipsychotic role of NASs themselves and, finally, discusses future directions for this area of schizophrenia research.(Can J Psychiatry 2005;50:695-702)Information on funding and support and author affiliations appears at the end of the article. Clinical Implications· NASs are altered in individuals with schizophrenia. · Antipsychotic-induced alteration of NAS levels may contribute to their therapeutic effects. · Some NASs may possess intrinsic antipsychotic properties. Limitations· There is limited investigation of NASs and the role they play in schizophrenia, making it difficult to establish the precise changes in NAS levels in the illness. · There are some contradictory findings regarding NAS levels in schizoph...

Evidence for a Role of Progesterone in Menstrual Cycle-Related Variability in Prepulse Inhibition in Healthy Young Women

“…This effect can be attributed to a drop in progesterone level (Shulman and Tibbo, 2005). Studies have also reported high progesterone levels in unmedicated chronic patients in response to metabolic stress (Breier and Buchanan, 1992) but normal progesterone levels in medicated early psychosis (Oades and Schepker, 1994) as well medicated chronic schizophrenia patients (Taherianfard and Shariaty, 2004).…”

“…Studies have also reported high progesterone levels in unmedicated chronic patients in response to metabolic stress (Breier and Buchanan, 1992) but normal progesterone levels in medicated early psychosis (Oades and Schepker, 1994) as well medicated chronic schizophrenia patients (Taherianfard and Shariaty, 2004). Progesterone has been suggested to act as an endogenous antipsychotic and serve to restore normal functions during the times of stress (Shulman and Tibbo, 2005). Further support for this notion comes from the reports that progesterone metabolite 3a, 5a-THP produces a behavioral profile similar to that of dopamine receptor antagonists by increasing GABAergic tone in rodents (Motzo et al, 1996;Khisti et al, 1998Khisti et al, , 2002.…”

Serum Cortisol and DHEA-S Levels in Schizophrenic Patients with Different Response to Antipsychotic Therapy: Association with Psychopathology / Серумски Концентрации На Кортизол И DHEA-S Кал Пациенти Со Шизофренша Со Различен Одговор На Антипсихотичната Терапша Асоци.1Аци.1А Со Психопатологшата

“…Previous studies have suggested that alterations in cortisol and DHEA-S levels may play a role in the pathophysiology of schizophrenia [3,16,[20][21][22][23]. Serum cortisol and DHEA-S levels may be used as a biological marker for the diagnosis of schizophrenia; however, further studies with larger sample sizes are warranted to support this finding [3].…”

Neuroprotection and Pain Management

“…In addition to the classic effect of steroids on gene transcription via binding to intracellular steroid receptors, neuroactive steroids can alter neuronal excitability via nongenomic effects by acting at inhibitory Gama Amino Butiric Acid A (GABA A ) receptors and/or excitatory NMDA receptors, among others (Shulman and Tibbo 2005), (Marx et al 2006). There is also evidence for a potential role of these neurosteroids in controlling GABA and glutamate release.…”