Neuroactive Steroids are Altered in Schizophrenia and Bipolar Disorder: Relevance to Pathophysiology and Therapeutics

Abstract

Evidence suggests that neuroactive steroids may be candidate modulators of schizophrenia pathophysiology and therapeutics. We therefore investigated neuroactive steroid levels in post-mortem brain tissue from subjects with schizophrenia, bipolar disorder, nonpsychotic depression, and control subjects to determine if neuroactive steroids are altered in these disorders. Posterior cingulate and parietal cortex tissue from the Stanley Foundation Neuropathology Consortium collection was analyzed for neuroactive steroids by negative ion chemical ionization gas chromatography/mass spectrometry preceded by high-performance liquid chromatography. Subjects with schizophrenia, bipolar disorder, nonpsychotic depression, and control subjects were group matched for age, sex, ethnicity, brain pH, and post-mortem interval (n ¼ 14-15 per group, 59-60 subjects total). Statistical analyses were performed by ANOVA with post-hoc Dunnett tests on log transformed neuroactive steroid levels. Pregnenolone and allopregnanolone were present in human post-mortem brain tissue at considerably higher concentrations than typically observed in serum or plasma. Pregnenolone and dehydroepiandrosterone levels were higher in subjects with schizophrenia and bipolar disorder compared to control subjects in both posterior cingulate and parietal cortex. Allopregnanolone levels tended to be decreased in parietal cortex in subjects with schizophrenia compared to control subjects. Neuroactive steroids are present in human post-mortem brain tissue at physiologically relevant concentrations and altered in subjects with schizophrenia and bipolar disorder. A number of neuroactive steroids act at inhibitory GABA A and excitatory NMDA receptors and demonstrate neuroprotective and neurotrophic effects. Neuroactive steroids may therefore be candidate modulators of the pathophysiology of schizophrenia and bipolar disorder, and relevant to the treatment of these disorders.

Altered levels of sex and stress steroid hormones assessed daily over a 28-day cycle in early abstinent cocaine-dependent females

“…Notably, allopregnanolone has been shown to reduce alcohol withdrawal symptoms in voluntary and chronic alcohol-drinking rats (Martin-García et al 2007) as well as reduce prenatal stress (Zimmerberg and Blaskey 1998) and cocaine-induced kindling in mice (Leskiewicz et al 2003). In humans, high levels of both progesterone and allopregnanolone have been observed in schizophrenia (Marx et al 2006) anxiety and panic disorders (Brambilla et al 2003(Brambilla et al , 2005 as well as after laboratory manipulated panic (Eser et al 2005). It may be the case then, that increased levels of progesterone in early abstinent CD females potentially represent a compensatory adaptation to an enhanced distressed state, characterized in the current sample, by increased levels of cortisol and enhanced negative mood.…”

Ethanol Alters Local Cellular Levels of (3α,5α)-3-Hydroxypregnan-20-one (3α,5α-THP) Independent of the Adrenals in Subcortical Brain Regions

“…Both 3a,5a-THP and 3a,5a-THDOC enhance neuronal inhibition at binding sites on GABA A receptors (Hosie et al, 2006) and produce behavioral effects similar to those of ethanol. These GABAergic steroids are potent positive modulators of GABA A receptors, producing pharmacological effects in nanomolar concentrations (Morrow et al, 1987), and studies suggest that modulating GABAergic steroid levels may have therapeutic value for treating multiple psychiatric disorders (Marx et al, 2006;Morrow, 2007;Rasmusson et al, 2006;Strohle et al, 2002;Uzunova et al, 1998).…”

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].…”