Review Paper

Neuroactive Steroids in Schizophrenia

Yanina Shulman, BSc¹, Philip G Tibbo, MD, FRCPC²

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) Click here for author affiliations.  Click here for information on funding and support.  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 schizophrenia patients. Studies examining the effects of antipsychotic medication on NAS levels in humans are lacking. Key Words: schizophrenia, neuroactive steroids, NMDA receptors, GABAA receptors, DHEA, antipsychotics Résumé : Les stéroïdes neuroactifs dans la schizophrénie

Schizophrenia 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 Steroids

Classical 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 heterodimers to their respective response elements (DNA sequences in the promotor region of a gene). Binding by the receptor activates or represses expression of the gene controlled by that promoter. Thus, when bound to their receptor, classical steroid hormones act like transcription factors. As a result of the above mechanism of action, steroid hormones require from hours to days to exert their effects, because they are limited by the rate of protein synthesis (2).

Figure 1 Genomic and nongenomic (neuroactive) steroidal effects. NASs alter neuronal excitability at the cell membrane by interacting with cell surface receptors, in this case, a GABA_A receptor. Steroid hormones diffuse though the cells membrane, bind to intracellular receptors, enter the nucleus, and control gene transcription and, in turn, protein synthesis. NASs exert their effects in seconds to minutes, whereas the effects of steroid hormones are limited by the rate of protein synthesis and are not apparent for hours to days.

In the 1940s, Selye discovered that some PROG metabolites exhibit fast, central effects. In particular, he found that these metabolites had potent sedative and anesthetic effects in rodents and that these effects were too rapid to be accounted by genomic mechanisms of action (3,4), indicating that some steroids also affect neuronal function via nongenomic mechanisms. The term “neuroactive steroids” was later coined to describe those steroids that exhibit rapid, nongenomic effects on neuronal excitability by interacting with, and modulating the activity of, cell surface ligand-gated ion channel receptors, including GABA_A and NMDA receptors (5,6) (Figure 1). NASs can be synthesized in the brain and in the periphery from cholesterol (Figure 2). NAS synthetic enzymes are present in peripheral endocrine glands and in glia and nerve cells in the brain. All reactions, with the exception of those catalyzed by 3a-hydroxysteroid oxidoreductase, are irreversible (7–9).

Figure 2 Biosynthesis of NASs. Solid arrows represent single step reactions. Dashed arrows represent multistep reactions. Enzyme names (italicized), steroid names, and intermediates are shown.

Brain NASs are derived from both endocrine and centrally derived sources. Because of their lipophilic nature, NASs are likely able to cross the BBB. O’Dell and colleagues showed that brain and plasma NASs increase in parallel after acute ethanol administrations in rats and that adrenalectomy or gonadectomy prevents this increase (10). These findings implicate peripheral endocrine glands, rather than the brain, as the source of some NASs following ethanol administration, indicating that peripheral NASs can penetrate the BBB.

Owing to their inability to bind to intracellular steroid receptors, NASs were initially thought not to possess genomic effects. However, a study conducted by Rupprecht and colleagues revealed that some NASs do indeed affect transcription (11). The authors found that the 3a-hydroxy ring A-reduced pregnane steroids 3a, 5a-THP and 3a, 5a-THDOC can regulate gene expression via intracellular PROG receptors after being oxidized into PROG receptor active 5a-pregnane steroids. Thus these NASs regulate neuronal function through both genomic and nongenomic mechanisms. Through their fast modulating effects at ligand-gated ion channels, and possibly through their genomic effects, NASs have been found to exhibit neuropsychopharmacological properties. For example, PREG and DHEA may be memory enhancing, and 3a-hydroxy ring A-reduced pregnane steroids exhibit sedative, hypnotic, anesthetic, and anxiolytic properties (12,13).

NASs synthesized in the brain and the periphery are among the most selective, potent, and efficacious allosteric modulators of the GABA_A receptor complex (14). At nM concentrations, 3a-reduced NASs, including the PROG metabolites 3a, 5a-THP and 3a, 5b-THP and the deoxycorticosterone metabolite 3a, 5a-THDOC, are positive allosteric modulators of GABA_A receptors (15) and act by increasing both the probability and the frequency of chloride channel opening (16,17). At higher concentrations (mM range), 3a-reduced NASs also activate GABA_A receptors in the absence of GABA; however, this is not relevant physiologically because endogenous NAS levels are not present at such high concentrations (14,18). 3b-reduced neuroactive PROG metabolites, including 3b,5a-THP and 3b,5b-THP, may act as functional antagonists of GABA_A-agonistic steroids, since they do not modulate GABA_A receptors directly but competitively inhibit the effects of 3a-reduced NASs (19–21).

Other NASs such as DHEA, PREG, and their sulfated metabolites, DHEAS and PREGS, are negative GABA_A receptor or positive NMDA receptor modulators (6,17,22). At low mM concentrations, PREGS and DHEAS (23) are negative GABA_A receptor modulators (24). PREGS acts as a mixed GABA_A receptor agonist–antagonist, and DHEAS behaves solely as an antagonist. DHEA is also antagonistic at GABA_A receptors; however, it is less potent than DHEAS (23–25). PREGS is a potent positive allosteric modulator at NMDA receptors. DHEA and DHEAS also display NMDA agonistic properties (16), although these effects are not as potent as those seen with PREGS (25).

Neuroactive steroids also modulate other neurotransmitter receptors, including nicotinic acetylcholine, AMPA, kainite, oxytocin, sigma, glycine, and serotonin receptors (13). This review focuses only on NAS modulation of GABA_A and NMDA receptors and discusses how NASs that modulate these receptors are implicated in the pathophysiology of schizophrenia.

NASs in Schizophrenia

Currently, there is limited investigation of NASs in schizophrenia in the literature. However, altered circulating DHEA, DHEAS, testosterone, cortisol, PROG, and estrogen levels have been reported in some patients with schizophrenia (Table 1). Early work by Tourney and Erb reported low DHEA levels first thing in the morning in chronically ill, unmedicated patients with schizophrenia, compared with healthy control subjects (27). However, in a recent study, Marx and others reported elevated DHEA plasma levels (28), and interestingly, DHEA levels inversely correlated with negative symptom severity in drug-free men with first-episode psychosis. Oades and Schepker also reported elevated plasma DHEAS levels in medicated young men with psychosis, as well as low estradiol and high testosterone but no difference in DHEAS plasma levels in medicated young women with psychosis, when compared with healthy control subjects (29). The authors suggested that low estradiol levels in women may increase their vulnerability to psychosis, whereas testosterone changes in women and DHEAS changes in men may be a consequence of the illness. Shirayama and colleagues studied DHEAS, testosterone, and cortisol plasma levels in chronically ill, medicated men with schizophrenia and found no difference in DHEAS concentration between patients and control subjects (30). They did, however, find high cortisol and low testosterone levels in patients with a moderate but not low negative symptom severity, when compared with control subjects. Also, cortisol levels were directly correlated and testosterone levels were inversely correlated with negative symptom severity in patients with schizophrenia. Ritsner and colleagues also measured DHEA, DHEAS, and cortisol levels in patients with schizophrenia and found no difference between patients and control subjects when these steroids were measured separately (31). However, the cortisol-to-DHEA and cortisol-to-DHEAS ratios in patients with schizophrenia (8.9 and 0.05, respectively) were significantly higher than those in healthy control subjects. Although the ratios did not correlate with schizophrenia symptom severity assessed by the PANSS, cortisol-to-DHEA ratios correlated with depression, anxiety, anger, and hostility levels in schizophrenia patients. The authors suggested that elevated cortisol-to-DHEA and cortisol-to-DHEAS ratios may be markers of abnormal stress processing in schizophrenia. Thus low, high, and normal DHEA and DHEAS levels have been reported in patients with schizophrenia, and these NASs correlate, to varying degrees, with symptom severity. We discuss the possible beneficial and detrimental effects of DHEA and DHEAS in later sections.

Abnormal serum levels of PROG have also been reported in some patients with schizophrenia (Table 1). Although 2 studies showed no difference in PROG levels between schizophrenia patients and control subjects (29,30), 3 studies have reported PROG abnormalities. Brier and Buchanan reported abnormal elevation of PROG in response to metabolic stress in unmedicated, chronically ill men with schizophrenia (32), and Prior and others reported that newly diagnosed, unmedicated men with schizophrenia had elevated PROG serum levels that were positively associated with positive and negative symptom severity (33). It may be possible that PROG acts like an endogenous antipsychotic and anxiolytic and that an increases in PROG levels during the early phase of the illness and during times of stress serves to restore normal functioning.

Alternatively, Taherianfard and Shariaty reported low serum PROG levels in men with schizophrenia before and during treatment with antipsychotic agents (type unspecified) and benzodiazepines and after clinical remission, compared with control subjects (34). In this study, PROG levels significantly increased during treatment and remission stages, compared with pretreatment levels. They also found low serum estrogen levels in all 3 stages of the study, as well as low serum testosterone before and during treatment, but not after remission, in patients with schizophrenia, compared with control subjects.

Patients with schizophrenia often have comorbid anxiety disorders. Using DSM-IV criteria in individuals with schizophrenia, Tibbo and colleagues found that up to 27% of patients have a comorbid anxiety disorder (35). Comorbid patients scored higher on the PANSS than did those with schizophrenia alone, indicating that comorbid anxiety disorders further compromise function in schizophrenia patients. NASs are implicated in the pathology of anxiety disorders. For example, 3a-hydroxy ring A-reduced pregnane steroids exhibit anxiolytic properties in animal models of anxiety and may serve to prevent the occurrence of spontaneous panic attacks in humans (18,26). Also, NAS plasma levels are altered in patients with anxiety disorders (18). Since circulating NAS levels are altered in patients with anxiety disorders and in those with schizophrenia, and since NASs appear to be implicated in the pathology of both disorders, NASs may be a link between the 2 seemingly separate disorders. Thus research investigating NASs in patients with schizophrenia alone, in those with anxiety disorders, and in those comorbid for both disorders may explain the high comorbidity rates of the 2 disorders.

Our laboratory is currently expanding our above-described epidemiology study (35) by investigating NAS plasma levels following a pentagastrin-induced panic attack in individuals with schizophrenia alone and in those with a comorbid anxiety disorder. Because DHEA is a positive NMDA receptor and a negative GABA_A receptor modulator (15,25–27), it may be possible that higher DHEA levels in comorbid individuals render them more susceptible to anxiety than individuals with schizophrenia alone. Alternatively, elevated DHEA plasma levels have been reported in some patients with schizophrenia (29), which may render these individuals more vulnerable to anxiety than patients without elevated DHEA levels. We are currently increasing sample sizes and comparing results with those from individuals with panic disorder and from healthy volunteers to investigate the reason behind the high comorbidity rates of schizophrenia and anxiety disorders.

Results from studies described above, although at times contradictory, suggest potential dysregulation of NASs in schizophrenia. Because of the lack of studies investigating NASs in drug-naive individuals with schizophrenia, it is unclear at this point whether altered steroid plasma levels are due to the disease process or to comorbid symptoms or are the result of treatment itself. Following NASs over time and during treatment would help to establish the precise changes in steroid concentrations and their relation to symptom domains in schizophrenia.

The Effects of Antipsychotics on Neuroactive Steroid Levels

Interestingly, NAS concentrations may be affected by antipsychotic treatment. Atypical but not typical antipsychotics have been found to alter NAS brain levels. The atypical agents olanzapine (36–38) and clozapine (38) dose-dependently increased cortical 3a ,5a-THP and PROG concentrations, and clozapine increased cortical 3a, 5a-THDOC concentrations (36) following acute administration in rats. Clozapine also retained the ability to increase these NASs after chronic administration in these animals (36). Risperidone (37) and the typical antipsychotic haloperidol (36,37) had no effect on NAS levels in these studies. In another study, clozapine, but not haloperidol, decreased DHEA and DHEAS concentrations in the rat cerebral cortex (39).

Antipsychotic-induced NAS level alterations may contribute to the antipsychotic effects of these drugs. Reduced GABAergic neurotransmission may contribute to schizophrenia pathophysiology (40). Thus antipsychotic-induced increase of 3a, 5a-THP, a positive allosteric modulator of GABA_A receptors, and decrease of DHEA and DHEAS, both negative allosteric modulators of GABA_A receptors, may augment GABAergic tone in the cortex, resulting in symptom improvement. Consistent with this hypothesis, the PROG metabolite 3a, 5a-THP has been reported to suppress DA neurotransmission by increasing GABAergic tone in rodents (41,42) and to cause the same behavioural changes as haloperidol (43). Also, Ugale and colleagues used the CAR and apomorphine-induced climbing paradigms in rats to provide behavioural evidence showing that 3a, 5a-THP-mediated GABAergic modulation is essential for the antipsychotic-like action of olanzapine and that elevation of this NAS is an important mechanism of action of olanzapine and not simply a side effect of the drug (44). They found that drugs that interfere with 3a, 5a-THP synthesis block olanzapine’s inhibitory effect on CAR and apomorphine-induced climbing behaviour. Further, DHEAS, a negative GABA_A receptor modulator, blocked the effects of olanzapine in this study, indicating that antipsychotic-induced decreases of DHEA and DHEAS (39) may also be important for antipsychotic-like actions of atypical agents.

The Antipsychotic Potential of NASs

NASs, such as DHEA and DHEAS, may also possess intrinsic antipsychotic properties. DHEA and DHEAS are positive allosteric NMDA receptor modulators (26), and DHEAS has been reported to increase the number of NMDA receptors in the rat brain (45). Since NMDA receptor hypofunction is indicated in the illness (1,46), DHEA or DHEAS therapy may be beneficial for some patients. In addition to enhancing NMDA receptor function, DHEA can be converted into androsterone, a positive allosteric GABA_A receptor modulator (47), and can therefore augment GABAergic tone and possibly improve symptoms. DHEA and DHEAS can also enhance DA release in the frontal cortex. Hypodopaminergia in the mesocortical DA system is a pathological state in schizophrenia (46), and DHEA-and DHEAS-induced enhancement of DA release in the frontal cortex may also be a mechanism by which these NASs contribute to symptom improvement.

The hypothesis that DHEA is therapeutic in schizophrenia is supported by clinical studies examining the effects of DHEA and DHEAS. Harris and colleagues found that higher DHEA plasma levels were correlated with lower scores on the Brief Psychiatric Rating Scale and with better performance on some measures of memory in medicated, chronic patients with schizoaffective disorder and schizophrenia (48). Strauss and colleagues found that DHEA administration to patients with schizophrenia improves negative symptoms (49). More recently, in a double-blind, placebo-controlled study, Strous and others found significant improvements in negative, depressive, and anxiety symptoms in medicated patients with schizophrenia after 6 weeks of DHEA therapy (50).

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. Thus DHEA therapy may be beneficial for those with predominant glutamatergic pathology but detrimental to those with predominant GABAergic pathology.

More research is needed that examines the effects of DHEA and DHEAS in schizophrenia. While some studies show that DHEA or DHEAS therapy improves some symptoms in schizophrenia (48–50), other studies reveal that low levels of these NASs may be beneficial for patients (44). Determining which symptoms improve and which get worse with DHEA and (or) DHEAS therapy and assessing each patient’s symptom profile and primary pathological changes in the brain will determine which patients would benefit from DHEA therapy. Further, DHEA can be metabolized in vivo to other pharmacologically active steroids with differential effects, making it difficult to assess whether the effects of DHEA therapy are caused by DHEA or by its metabolites. Thus the pharmacokinetic profile of DHEA and the variability of DHEA metabolism among individuals need to be considered when examining the effects of DHEA and deciding whether DHEA therapy is appropriate. Synthetic DHEA and DHEAS analogues with limited potential for metabolism are needed to conclusively determine the effects of DHEA in schizophrenia.

Other NASs, including PROG and its metabolites, may also possess antipsychotic properties. Symptoms in schizophrenia vary across the menstrual cycle (51), and women are more vulnerable to psychosis and the onset of schizophrenia both postpartum and after menopause (52), which is attributed to a drop in PROG levels. Rupprecht and others examined neuroleptic properties of PROG in rats by examining the effect of PROG on apomorphine-induced disruption of PPI (53). PPI is an animal model for measuring sensorimotor gating, which is disrupted in some individuals with schizophrenia. Apomorphine-induced disruption of PPI in rats is antagonized by both typical and atypical antipsychotics and is therefore considered to be an animal model for antipsychotic drug action. Rupprecht and colleagues found that PROG antagonizes apomorphine-induced disruption of PPI (53); this is an effect caused by PROG itself, rather than the PROG metabolite, 3a, 5a-THP, since 3a, 5a-THP did not restore PPI in this study. They also found that PROG dose-dependently decreases locomotion, an effect similar to that produced by both typical and atypical antipsychotics. In contrast to haloperidol, PROG did not induce catalepsy and did not antagonize amphetamine-induced stereotypy, indicating that PROG and its metabolites do not cause extrapyramidal symptoms and, as such, have a side effects profile similar to atypical antipsychotics (53).

These data are difficult to explain at this time and may appear contradictory to the finding that PROG plasma levels are elevated in newly diagnosed men with schizophrenia (33). A possible explanation may be that PROG acts like an endogenous antipsychotic and that an increase in PROG during early phases of the illness serves to restore normal functioning.

Conclusion

Research examining the effects of NASs in schizophrenia is a relatively new field with many unknowns and sometimes seemingly contradictory findings. Because NASs modulate many neurotransmitter systems that are implicated in schizophrenia, studies examining NAS effects in the central nervous system and the role they play in schizophrenia are essential for understanding the pathology of the illness.

Growing evidence implicates NASs in the pathology of schizophrenia. Recent studies reveal NAS plasma level and possibly brain level fluctuations in the illness. However, the precise NAS level abnormalities are not yet known and warrant further investigation. Further, NASs may improve some symptoms in schizophrenia but exacerbate others. It also appears that antipsychotic drugs, particularly atypical agents, exert their therapeutic effects partly by altering NAS plasma and brain levels. Although further investigation is needed, the ever-growing role of NASs in the pathophysiology of schizophrenia and in the antipsychotic activity of current antipsychotics represents an exciting path for the development of new medications for the treatment of schizophrenia.

Funding and Support

This study was supported in part by the Natural Sciences and Engineering Research Council of Canada and Alberta Heritage Foundation for Medical Research graduate student awards.

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Author(s)

Manuscript received September 2004, revised, and accepted February 2005.

1. PhD Student, Centre for Neuroscience, University of Alberta, Edmonton, Alberta.

2. Associate Professor, Co-Director Bebensee Schizophrenia Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Alberta.

Address for correspondence: Dr PG Tibbo, Department of Psychiatry, University of Alberta, 1E7 11 WMC, Edmonton, AB T6G 2B7

e-mail: ptibbo@ualberta.ca

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