Neuroactive steroids as modulators of depression and anxiety

Department of Psychiatry, Ludwig-Maximilian-University, Munich, Germany.
Neuroscience (Impact Factor: 3.36). 02/2006; 138(3):1041-8. DOI: 10.1016/j.neuroscience.2005.07.007
Source: PubMed


Certain neuroactive steroids modulate ligand-gated ion channels via non-genomic mechanisms. Especially 3alpha-reduced pregnane steroids are potent positive allosteric modulators of the GABA type A-receptor. During major depression there is a dysequilibrium of 3alpha-reduced neuroactive steroids, which is corrected by clinically effective pharmacological treatment. To investigate whether these alterations are a general principle of successful antidepressant treatment we studied the impact of non-pharmacological treatment options on neuroactive steroid concentrations during major depression. Neither partial sleep deprivation, transcranial magnetic stimulation nor electroconvulsive therapy affected neuroactive steroid levels irrespectively of the response to these treatments. These studies suggest that the changes in neuroactive steroids observed after antidepressant pharmacotherapy more likely reflect distinct pharmacological properties of antidepressants rather than the clinical response. In patients with panic disorder changes in neuroactive steroid composition have been observed opposite of those seen in depression. These changes may represent counterregulatory mechanisms against the occurrence of spontaneous panic attacks. However, during experimental panic induction with either cholecystokinin-tetrapeptide or sodium lactate there was a pronounced decline in the concentrations of 3alpha-reduced neuroactive steroids in patients with panic disorder, which might result in a decreased GABAergic tone. In contrast, no changes in neuroactive steroid concentrations could be observed in healthy controls with the exception of 3alpha, 5alpha-tetrahydrodeoxycorticosterone, allotetrahydrodeoxycorticosterone. The modulation of GABA type A-receptors by neuroactive steroids might contribute to the pathophysiology of depression and anxiety disorders and might offer new targets for the development of novel anxiolytic compounds.

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Available from: Thomas C Baghai, Jul 02, 2014
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    • "Support for 3a-reduced neurosteroids in the pathogenesis of depressive disorders has derived from preclinical and clinical studies of the past two decades, which postulated a therapeutically relevant contribution by these endogenous modulators to the anxiolytic properties of some SSRIs (e.g. fluoxetine – (Guidotti and Costa, 1998; Eser et al., 2006; Uzunova et al., 2006; Schule et al., 2014). Thus, the plasma and CSF levels of 5a3a-THPROG are reduced in depressed patients (Romeo et al., 1998; Uzunova et al., 1998) and, similarly in animal models of depression, or post-traumatic stress disorder (PTSD) in a brain region specific manner (Serra et al., 2001, 2008; Pinna, 2010). "
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    ABSTRACT: Regulation of hypothalamic-pituitary-adrenocortical (HPA) axis activity by stress is a fundamental survival mechanism and HPA-dysfunction is implicated in psychiatric disorders. Adverse early life experiences, e.g. poor maternal care, negatively influence brain development and programs an abnormal stress response by encoding long-lasting molecular changes, which may extend to the next generation. How HPA-dysfunction leads to the development of affective disorders is complex, but may involve GABAA receptors (GABAARs), as they curtail stress-induced HPA axis activation. Of particular interest are endogenous neurosteroids that potently modulate the function of GABAARs and exhibit stress-protective properties. Importantly, neurosteroid levels rise rapidly during acute stress, are perturbed in chronic stress and are implicated in the behavioral changes associated with early-life adversity. We will appraise how GABAAR-active neurosteroids may impact on HPA axis development and the orchestration of the stress-evoked response. The significance of these actions will be discussed in the context of stress-associated mood disorders.
    Frontiers in Neuroendocrinology 06/2014; 36. DOI:10.1016/j.yfrne.2014.06.001 · 7.04 Impact Factor
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    • "In humans, both plasma and CSF ALLO concentrations are consistently decreased in patients with MDD (Eser et al. 2006; Nappi et al. 2001; Romeo et al. 1998; Strohle et al. 1999; Strohle et al. 2000; Uzunova et al. 1998; Uzunova et al. 2006), while basal cortisol levels are elevated (Young et al. 2004a; Young et al. 2004b; Young and Veldhuis 2006). In contrast, results from studies of DHEA and DHEA-S concentrations in individuals with depression, have shown them to be elevated (Hansen et al. 1982; Heuser et al. 1998; Takebayashi et al. 1998), decreased (Barrett-Connor et al. 1999; Michael et al. 2000; Morsink et al. 2007; Wong et al. 2011) or unchanged (Erdincler et al. 2004; Fabian et al. 2001), compared to controls. "
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    ABSTRACT: A robust epidemiological literature suggests an association between chronic stress and the development of affective disorders. However, the precise biological underpinnings of this relationship remain elusive. Central to the human response and adaptation to stress, activation and inhibition of the hypothalamic pituitary adrenal (HPA) axis involves a multi-level, multi-system, neurobiological stress response which is as comprehensive in its complexity as it is precarious. Dysregulation in this complex system has implications for human stress related illness. The pioneering research of Robert Purdy and colleagues has laid the groundwork for advancing our understanding of HPA axis regulation by stress-derived steroid hormones and their neuroactive metabolites (termed neurosteroids), which are potent allosteric modulators of GABAA receptor function in the central nervous system. This review will describe what is known about neurosteroid modulation of the HPA axis in response to both acute and chronic stress, particularly with respect to the current state of our knowledge of this process in humans. Implications of this research to the development of human stress-related illness are discussed in the context of two human stress-related psychiatric disorders - major depressive disorder and premenstrual dysphoric disorder. Neurosteroid-mediated HPA axis dysregulation is a potential pathophysiologic mechanism which may cross traditional psychiatric diagnostic classifications. Future research directions are identified.
    Psychopharmacology 04/2014; 231(17). DOI:10.1007/s00213-014-3572-8 · 3.88 Impact Factor
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    • "3α-reduced neuroactive steroids have anxiolytic and antidepressant-like effects in the preclinical studies (Eser et al., 2006). Even though PG meets this effect, it failed to improve immobility scores in the forced swim test. "
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    ABSTRACT: Unlabelled: A number of studies demonstrated a rapid onset of an antidepressant effect of non-competitive N-methyl-d-aspartic acid receptor (NMDAR) antagonists. Nonetheless, its therapeutic potential is rather limited, due to a high coincidence of negative side-effects. Therefore, the challenge seems to be in the development of NMDAR antagonists displaying antidepressant properties, and at the same time maintaining regular physiological function of the NMDAR. Previous results demonstrated that naturally occurring neurosteroid 3α5β-pregnanolone sulfate shows pronounced inhibitory action by a use-dependent mechanism on the tonically active NMDAR. The aim of the present experiments is to find out whether the treatment with pregnanolone 3αC derivatives affects behavioral response to chronic and acute stress in an animal model of depression. Adult male mice were used throughout the study. Repeated social defeat and forced swimming tests were used as animal models of depression. The effect of the drugs on the locomotor/exploratory activity in the open-field test was also tested together with an effect on anxiety in the elevated plus maze. Results showed that pregnanolone glutamate (PG) did not induce hyperlocomotion, whereas both dizocilpine and ketamine significantly increased spontaneous locomotor activity in the open field. In the elevated plus maze, PG displayed anxiolytic-like properties. In forced swimming, PG prolonged time to the first floating. Acute treatment of PG disinhibited suppressed locomotor activity in the repeatedly defeated group-housed mice. Aggressive behavior of isolated mice was reduced after the chronic 30-day administration of PG. PG showed antidepressant-like and anxiolytic-like properties in the used tests, with minimal side-effects. Since PG combines GABAA receptor potentiation and use-dependent NMDAR inhibition, synthetic derivatives of neuroactive steroids present a promising strategy for the treatment of mood disorders. Highlights: -3α5β-pregnanolone glutamate (PG) is a use-dependent antagonist of NMDA receptors.-We demonstrated that PG did not induce significant hyperlocomotion.-We showed that PG displayed anxiolytic-like and antidepressant-like properties.
    Frontiers in Behavioral Neuroscience 04/2014; 8:130. DOI:10.3389/fnbeh.2014.00130 · 3.27 Impact Factor
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