Recent efforts have linked neurosteroids to selective serotonin reuptake inhibitors. In a clinical study of 15 patients with major depression, cerebrospinal fluid (CSF) levels of the GABAergic neurosteroid allopregnanolone were decreased at baseline compared to control subject levels (Uzunova et al., 1998). Following treatment with fluoxetine(Drug information on fluoxetine) (Prozac) or fluvoxamine(Drug information on fluvoxamine) (Luvox), CSF allopregnanolone levels increased in subjects with depression and correlated strongly with improvements in depressive symptoms. The authors hypothesized that SSRI-induced increases in allopregnanolone may represent a novel mechanism contributing to SSRI efficacy.
Enzyme kinetic studies subsequently demonstrated that fluoxetine, paroxetine(Drug information on paroxetine) (Paxil) and sertraline(Drug information on sertraline) (Zoloft) increase the efficiency of the enzyme 3-HSD, which catalyzes allopregnanolone biosynthesis from its immediate precursor 5-dihydroprogesterone (Griffin and Mellon, 1999), resulting in dramatically enhanced allopregnanolone formation. In addition, allopregnanolone is known to exhibit marked anxiolytic effects in rodents (Crawley et al., 1986; Wieland et al., 1991), consistent with its GABAA receptor actions. These studies support the possibility that SSRI-induced allopregnanolone biosynthesis may be relevant to SSRI therapeutic actions in depression and anxiety.Antipsychotic Drug Action
Neurosteroids have also been linked to antipsychotic drug action in recent rodent investigations. For example, the antipsychotic olanzapine(Drug information on olanzapine) (Zyprexa) dose-dependently increases the potent GABAergic neurosteroid allopregnanolone in rat cerebral cortex (Marx et al., 2000a), and preliminary evidence indicates that clozapine (Clozaril) has similar effects (Marx et al., 2001). Since GABAergic neurotransmission appears to be altered in schizophrenia (Lewis, 2000), antipsychotic-induced elevations in allopregnanolone may be relevant to this component of schizophrenia pathophysiology. If olanzapine also induces elevation in allopregnanolone in humans, it is possible that allopregnanolone may contribute to the efficacy of this antipsychotic. Olanzapine also has anxiolytic-like effects in animals (Arnt and Skarsfeldt, 1998), and, therefore, olanzapine-induced elevations in the anxiolytic neurosteroid allopregnanolone may represent a mechanism contributing to these actions. Finally, olanzapine has marked effects on rodent serum progesterone(Drug information on progesterone) levels, a steroid that appears to have non-reproductive functions in addition to its well-established reproductive actions. For example, recent evidence suggests that progesterone plays an important role in myelination (Baulieu and Schumacher, 2000), a finding that may be relevant to schizophrenia, since recent evidence suggests a dysregulation in myelin-related genes in the disorder (Hakak et al., 2001). Future investigations will be required to determine the potential clinical significance of antipsychotic-induced neurosteroid alterations for schizophrenia pathophysiology and treatment.Neuroprotection
Many lines of investigation demonstrate that neurosteroids have neuroprotective properties. For example, the GABAergic neurosteroid allopregnanolone demonstrates anticonvulsant effects in a variety of animal seizure models (Belelli et al., 1989; Devaud et al., 1995). A synthetic homologue of the inhibitory neurosteroid pregnanolone sulfate inhibits NMDA-induced current and cell death in rat hippocampal neuronal cultures and significantly reduces cortical and subcortical infarct size in rats (Weaver et al., 1997). The neurosteroid DHEA and its sulfated derivative DHEAS protect rodent embryonic cerebral cortical neurons from anoxia (Marx et al., 2000b), a neurodevelopmental stressor associated with increased schizophrenia risk. DHEA also protects neurons against glutamate and amyloid ß-protein toxicity (Cardounel et al., 1999), glucocorticoid toxicity (Kimonides et al., 1999), and numerous other insults resulting in oxidative stress.
Interestingly, DHEA and DHEAS levels decrease markedly with age in humans, and levels in elderly populations are reduced to 20% to 30% of peak levels in young adulthood (Labrie et al., 1997; Orentreich et al., 1992), but the clinical relevance of this finding has not yet been established. Since DHEA has memory-enhancing effects in animals (Flood et al., 1992; Roberts et al., 1987), it has been hypothesized that DHEA has neuroprotective effects on cognition and that its age-related decline may be related to declining cognitive function with age in the elderly. Since a number of neurosteroids demonstrate prominent neuroprotective effects in a variety of rodent experimental systems, these molecules may function to modulate neuronal insults leading to psychiatric morbidity and merit further exploration in the clinical realm.The Role of Stress
Several neurosteroids, including allopregnanolone and THDOC, have pronounced effects on the HPA axis. Allopregnanolone decreases corticotropin-releasing factor release from the hypothalamus (Patchev et al., 1994) and also dampens adrenocorticotropin hormone (Patchev et al., 1996) and corticosterone release (Guo et al., 1995; Patchev et al., 1996) in rats. Allopregnanolone is known to increase with stress (Purdy et al., 1991), and, therefore, stress-induced elevations in this neurosteroid would ultimately suppress the HPA axis. It has been hypothesized that stress-induced allopregnanolone induction may therefore represent an endogenous autoregulatory mechanism to restore homeostasis following a stressful event (Morrow et al., 1995).
The GABAergic neurosteroid THDOC also appears to demonstrate HPA axis modulation. Specifically, THDOC appears to be protective against early adverse events in neonatal rats subjected to intermittent maternal deprivation (Patchev et al., 1997). Rats treated with THDOC and exposed to this stressor were protected against HPA axis dysregulation. Since many psychiatric disorders are stress-sensitive and illnesses such as depression demonstrate a dysregulation in stress hormones (including cortisol), neurosteroid modulation of the HPA axis may have important clinical ramifications.Pharmacological Intervention
Given accumulating evidence suggesting that neurosteroids may be important in psychiatric disorders and treatment strategies, the possibility that neurosteroids (or the enzymes leading to neurosteroid biosynthesis) may serve as targets for pharmacological intervention has received increasing attention. Limiting factors in drug development have included the rapid metabolism and poor water-solubility of neurosteroids, but efforts are currently underway to address these difficulties. For example, the synthetic neurosteroid ganaxolone is a 3ß-methylated analogue of allopregnanolone with more favorable pharmacokinetic properties (Gasior et al., 1999). Similar to allopregnanolone, it demonstrates anticonvulsant efficacy. At this time, it appears likely that neurosteroid drug development initiatives will yield a number of promising compounds to be utilized in the treatment of neuropsychiatric disorders in future years.Concluding Remarks
Neurosteroids are fascinating molecules with potential relevance to the pathophysiology and treatment of psychiatric disorders. Although future research will be required to characterize the precise roles of neurosteroids in psychiatric illness, current evidence is compelling and justifies further investigations into the actions of these unique compounds in the central nervous system.Acknowledgements
The author thanks A. Leslie Morrow, Ph.D., and Jeffrey A. Lieberman, M.D., at University of North Carolina for their generous assistance.