Clozapine decreases rat brain dehydroepiandrosterone and dehydroepiandrosterone sulfate levels

Nechmad, Allon; Maayan, Rachel; Ramadan, Edward; Morad, Oren; Poyurovsky, Michael; Weizman, Abraham

doi:10.1016/s0924-977x(02)00077-9

Cited by 32 publications

(15 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As mentioned earlier, clozapine decreases cortical DHEA and DHEAS in rats (39). While a reduction in DHEA or DHEAS may result in increased GABAergic tone, it may also result in decreased NMDA receptor function.…”

Section: The Antipsychotic Potential Of Nassmentioning

confidence: 56%

Neuroactive Steroids in Schizophrenia

Shulman

Tibbo

2005

Can J Psychiatry

View full text Add to dashboard Cite

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...

show abstract

Section: The Antipsychotic Potential Of Nassmentioning

confidence: 56%

Neuroactive Steroids in Schizophrenia

Shulman

Tibbo

2005

Can J Psychiatry

View full text Add to dashboard Cite

show abstract

“…Several preclinical studies have shown that haloperidol failed to alter the brain concentrations of neurosteroids (Barbaccia et al, 2001;Nechmad et al, 2003), whereas clozapine administered for 8 days reduced the brain concentrations of DHEA and DHEAS (Nechmad et al, 2003).…”

Section: Commentmentioning

confidence: 99%

Cortisol/Dehydroepiandrosterone Ratio and Responses to Antipsychotic Treatment in Schizophrenia

Ritsner

Gibel

Maayan

et al. 2005

Neuropsychopharmacol

Self Cite

View full text Add to dashboard Cite

Dehydroepiandrosterone (DHEA) or their sulfate conjugate (DHEAS) (together abbreviated DHEA(S)) exert multiple effects in the central nervous system, and may be involved in the pathophysiological processes in schizophrenia. This prospective study aimed to investigate whether serum cortisol/DHEA(S) molar ratios are associated with response to antipsychotic treatment during the exacerbation of schizophrenia. Serum DHEA(S) and cortisol were determined at baseline, and 2 and 4 weeks later for 43 medicated schizophrenia inpatients with acute exacerbation. The patients were treated with stable doses of antipsychotic agents up to 2 weeks prior to entering the study and for the 4-week duration of the study after which they were classified as either responders or nonresponders to treatment. Findings suggest that responders had significantly higher serum cortisol levels and cortisol/DHEA(S) ratios compared with nonresponders. These differences remained significant at three time points controlling for gender, age, severity of symptoms and emotional distress, benzodiazepines, type or dosage of antipsychotic agents, and background variables. The logistic regression model shows advantages of both cortisol/DHEA(S) molar ratios vs serum cortisol and DHEA(S) concentrations for prediction of responsivity to antipsychotic treatment. No significant canonical correlations were observed between changes from baseline through end-of-study in hormonal values and severity of symptoms and emotional distress among responders and nonresponders. Thus, these data provide evidence that elevated serum cortisol and cortisol/DHEA(S) ratios may serve as markers of biological mechanisms that are involved in responsivity of schizophrenia patients to antipsychotic treatment.

show abstract

“…Earlier reports have demonstrated an increase in DHEAS level, a putative stimulator of dopamine release (Murray and Gillies, 1997), also in schizophrenia (Oades and Schepker, 1994). Recently, it has been reported that treatment with the atypical antipsychotic clozapine, but not haloperidol, decreases the levels of DHEAS in rat cortex (Nechmad et al, 2003), thereby increasing GABAergic tone and leading to improvement of psychotic symptoms (Purdon et al, 2001). Indeed, monitoring of the DHEA/ DHEAS levels following olanzapine treatment may help to determine their relevance in antipsychotic mode of action.…”

Section: Discussionmentioning

confidence: 99%

Role of Neuroactive Steroid Allopregnanolone in Antipsychotic-like Action of Olanzapine in Rodents

Ugale

Hirani

Morelli

et al. 2004

Neuropsychopharmacol

View full text Add to dashboard Cite

Olanzapine increases brain allopregnanolone (ALLO) levels sufficiently to modulate neuronal activity by allosterically regulating GABA A receptors. Recently, we reported the antipsychotic-like profile of ALLO in rodents. The present study examined the hypothesis that olanzapine-induced elevation of endogenous neurosteroid ALLO is vital for its neuroleptic-like action. The conditioned avoidance response (CAR) and apomorphine-induced climbing behavioral paradigms were used in rodents. Administration of ALLO (1 mg, intracerebroventricular (i.c.v.)) or neurosteroidogenic agents such as the mitochondrial diazepam binding inhibitor receptor agonist, FGIN 1-27 (0.5 mg, i.c.v.) or the ALLO precursor, progesterone (10 mg/kg, i.p.) significantly potentiated olanzapine-induced blockade of CAR and apomorphine-induced climbing. In contrast, these agents failed to alter the antipsychotic-like effect of risperidone and haloperidol. On the other hand, inhibition of the endogenous biosynthesis of neurosteroids by the 3b-hydroxysteroid dehydrogenase inhibitor, trilostane (30 mg/kg, i.p.), the 3a-hydroxysteroid oxidoreductase inhibitor, indomethacin (5 mg/kg, i.p.), or the GABA A receptor antagonist bicuculline (1 mg/kg, i.p.) and dehydroepiandrosterone sulfate (DHEAS) (1 mg/kg, i.p.) blocked the effect of olanzapine, but not of risperidone and haloperidol. Socially isolated animals, known to exhibit decreased brain ALLO and GABA A receptor functions, displayed a shortening in the muscimol-induced loss of righting reflex and an increased susceptibility to apomorphine-induced climbing. Administration of olanzapine, but not of haloperidol and risperidone, normalized the duration of muscimol-elicited loss of righting reflex. Although all three antipsychotics proved capable of antagonizing the apomorphine-induced climbing, a dose almost five times higher of olanzapine was required in socially isolated animals. The data obtained suggest that enhancement of the GABAergic tone plays a key role in the antipsychotic-like effect exerted by olanzapine in rodents, likely as a consequence of augmented levels of neuroactive steroids, in particular ALLO, in the brain. The present findings provide the first specific behavioral evidence in support of the hypothesis that neuroactive steroid ALLO-mediated GABAergic modulation is essential for the antipsychotic-like action of olanzapine.

show abstract

Clozapine decreases rat brain dehydroepiandrosterone and dehydroepiandrosterone sulfate levels

Cited by 32 publications

References 16 publications

Neuroactive Steroids in Schizophrenia

Neuroactive Steroids in Schizophrenia

Cortisol/Dehydroepiandrosterone Ratio and Responses to Antipsychotic Treatment in Schizophrenia

Role of Neuroactive Steroid Allopregnanolone in Antipsychotic-like Action of Olanzapine in Rodents

Contact Info

Product

Resources

About