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GABAergic neuroactive steroids: a new frontier in bipolar disorders?


Neurosteroids are synthesized in the brain and modulate brain excitability. There is increasing evidence of their sedative, anesthetic and antiseizure properties, as well as their influence on mood. Currently neurosteroids are classified as pregnane neurosteroids (allopregnanolone and allotetrahydrodeoxycorticosterone), androstane neurosteroids (androstanediol and etiocholanone) or sulfated neurosteroids (pregnenolone sulfate and dehydroepiandrosterone sulfate). Both preclinical and clinical findings indicate that progesterone derivative neurosteroids such as allopregnanolone and allotetrahydrodeoxycorticosterone play a role in mood disorders. Clozapine and olanzapine, which were shown to be effective in stabilizing bipolar disorder, elevate pregnenolone levels in rat hippocampus, cerebral cortex, and serum. In lithium-treated mice, the blood levels of allopregnanolone and pregnenolone were elevated compared to control levels. Women diagnosed with bipolar disorder typically show symptomatic exacerbation in relation to the menstrual cycle, and show vulnerability to the onset or recurrence of mood disorders immediately after giving birth, when the levels of neurosteroid derivatives of progesterone drop. Whereas in women who had recovered from bipolar disorder, the plasma concentration of allopregnanolone was elevated compared to either healthy controls or women with major depressive disorder during the premenstrual period. During depressive episodes, blood level of allopregnanolone is low. Treatment with fluoxetine tends to stabilize the levels of neurosteroids in depression. These findings converge to suggest that these steroids have significant mood-stabilizing effect. This hypothesis is consistent with the observation that a number of anticonvulsants are effective therapies for bipolar disorder, a finding also consistent with the antiseizure properties of neurosteroids. Further exploration of action of neuroactive steroids is likely to open new frontiers in the investigation of the etiology and treatment of mood disorders, particularly bipolar disorders.


Pharmacotherapy of severe mental disorders has not changed significantly since the introduction of antipsychotic compounds in the 1950s. The current classes of drugs available to treat schizophrenia, bipolar disorder and major depression involve essentially the same mechanisms of action and the same neurobiological target [1]. Arguably the most important advance in the pharmacotherapy of severe mental disorders in the last fifty years was the substitution of barbiturates with the clinically safer benzodiazepines and the introduction of the theory-driven selective serotonin reuptake inhibitors for the treatment of depression. Nevertheless, the effectiveness of currently available drugs is poor, both because only selected subgroups of patients were found to be good responders to the prescribed drugs [2, 3] and because compliance to treatment is generally low because of side effects and poor insight on the necessity of a severe mental disorder needing long-term therapy [4, 5].

The development of new therapeutic targets in the treatment of severe mental disorders is hampered by the lack of external, biological markers of the nosographic phenotypes [6, 7], the scarce knowledge of the neurobiological and genetic substrates of the categorically defined disorders [8] and the difficulties in devising valid and reliable animal models, which often lack predictive validity in the prediction of drug actions in humans [9]. Therefore, serendipity is as likely to guide discovery now as it was in the past. However, it is always possible to help serendipity-assisted drug discovery by looking at the crossroads of epidemiology with laboratory and clinical research.

Gender issues in the epidemiology of severe mental disorders

There is robust epidemiological evidence that patients diagnosed with schizophrenia and mood disorders show gender differences in the onset, course and outcome of their disorders. Since the German ABC study (Age, Beginning, Course) on schizophrenia, it is well known that females have two peaks in the onset of schizophrenia, contrary to males [10, 11]. Recent systematic reviews and meta-analyses confirmed that males are over-represented in the samples of patients diagnosed with first-episode schizophrenia. They are generally younger at first contact, and tend to have a poorer outcome compared to females [1215]. To account for these findings, it was suggested that estrogens may have modulated dopaminergic hyperactivity in females, thus leading to a gradual progression of the course of the disorder and a later onset of frank psychosis [11, 16, 17]. This hypothesis was compatible with the two incidence peaks in female psychosis onset; one in the early 20s, also common among males, albeit slightly later, and another after 40 years, possibly related to menopause [10, 18].

Mood disorders show a different picture, with women having an increased risk for developing major depression compared to males [19]. The risk of hypomania, rapid cycling and mixed episodes is also higher among women than men [20]. However, men and women suffer the same incidence of bipolar disorder and essentially with the same outcome [19, 20]. If steroids have a role in schizophrenia related psychoses, this role is reversed in affective psychoses. The discovery that the brain can synthesize neuroactive steroids and that their action is widespread on neuronal cells opened up an entirely new area in the investigation on rge effects of steroids on behavior [21, 22].

Sex steroids and the brain

Peripherally, steroids are produced mainly by the adrenal cortex and the gonads and are regulated by the hypothalamic-pituitary-adrenal axis and the hypothalamic pituitary-adrenal gonadal axis through negative feedback. The ovarian steroids regulate neuroendocrine, endocrine and behavioral functions through a number of cellular mechanisms. Typically, both estrogen and progesterone induce a relatively long-term action on neurons by activating a number of intracellular receptors that modulate the transcription and protein synthesis.

The steroid hormones play an important role in both the central and peripheral nervous systems; they act during development, growth, maturation and cellular differentiation. The progesterone receptor and the nuclear hormone family of intracellular estrogen receptors, alpha and beta (encoded by two separate genes), are dimeric molecules that regulate transcription of target genes in the nuclei [23, 24]. These receptors have a C-terminal and an N-terminal zinc-finger domains that mediate binding of the receptors to target DNA sequences. In the absence of the binding hormone, the C-terminal of the receptors inhibits transcription. The binding of the hormone induces a change in the dimeric structure of the receptors, and this removes the inhibitory action. Estrogens also bind to a G-protein coupled receptor, which as a transmembrane G-protein mediates estrogen-dependent kinase activation [25].

Both estradiol and progesterone receptors are found in the Central Nervous System (CNS) [26]. Progesterone is rapidly absorbed and metabolized in the cerebral cortex [27]. Because of their lipophilic nature, the steroids produced by the endocrine glands pass freely through the blood–brain barrier. The concentration of estradiol and progesterone in the brain closely follows peripheral concentrations. The brain is one of the targets of steroid hormones [28, 29]. In general, estradiol induces excitatory actions while progesterone induces inhibitory actions on the CNS. The ovarian steroids modulate many functions of the CNS, such as memory and learning [30], movement [31], and the perception of pain [32]. The ovarian steroids regulate neuroendocrine, endocrine and behavioral functions through a number of cellular mechanisms.

Neurosteroids and their role in the brain

Baulieu and co-workers were the first to observe that the brain concentrations of dehydroepiandrosterone sulfate were partially independent from adrenal and gonad secretion [33]. Subsequently, the demonstration of de novo synthesis of active steroids in the brain leads to the conceptualization of these brain-acting steroids as neurosteroids [21]; neurosteroids are synthesized from circulating steroid hormones, which serve as precursors of active neurosteroids. Currently, neurosteroids are defined as those that are synthesized in the brain. Neuroactive steroids refer to steroids that, independent of their origin, are capable of modifying neural activities.

Currently neuroactive steroids are classified as pregnane neurosteroids (allopregnanolone and allotetrahydrodeoxycorticosterone or THDOC), androstane neurosteroids (androstanediol and etiocholanone) or sulfated neurosteroids (pregnenolone sulfate or PS and dehydroepiandrosterone sulfate or DHEAS).

Several enzymes are involved in the synthesis of neuroactive steroids: neuroactive steroids such as allopregnanolone, THDOC, and androstanediol are produced by 5α-reductase and 3α-hydroxysteroid oxidoreductase (3α-HSOR), which act by reducing the parent steroid in peripheral tissues, such as liver and skin [34]. Both the 5α-reductase and the 3α-HSOR were identified in both neural and glial cells [35, 36] and found in neocortex and subcortical white matter and in hippocampal tissues [37, 38]. In particular, a cytochrome P450 cholesterol side-chain cleavage enzyme (CYP450scc) was identified, and was proven to have the ability to convert cholesterol to pregnenolone, which is a precursor for the synthesis of neurosteroids [39]. Another enzyme necessary for the conversion of pregnenolone to progesterone, 3β-hykdroxysteroid dehydrogenase, was found in the brain [40]; further details on the synthesis of neuroactive steroids in [41].

In the brain de novo synthesis of neurosteroids occurs in the cortex, the hippocampus and the amygdala, mainly in glutamatergic neurons [27]. Regulatory mechanisms involved in this de novo synthesis are still unclear [42].

Non-genomic actions of neurosteroids

There is evidence that neurosteroids do not produce most of their effects through an interaction with the steroid hormone receptors that regulate gene transcription. But, neurosteroids can regulate gene expression via the progesterone receptor. But this occurs only after conversion of the neurosteroids to typical steroids. The induction of DNA binding and transcriptional activation of the progesterone receptor requires intracellular oxidation of the neuroactive steroids into progesterone receptor active 5 alpha-pregnane steroids [43]. Most effects of neurosteroids occur by interaction with neuronal membrane receptors and ion channels [44]. The post-synaptic GABAA receptor is the most important site where neuroactive steroids act as positive or negative regulators [19], which is consistent with their chemical structure.

Neurosteroids involvement in the regulation of GABAergic transmission

The GABAA receptor is the main target of action of neuroactive steroids. GABAA receptors are heteropentameric GABA-gated chloride channels: they are involved in fast inhibitory neurotransmission. The GABAA receptor, distributed in large quantity throughout the CNS, is a macromolecular complex consisting of five subunits, of which many homologs have been identified (alpha1-6, beta1-3, gamma1-3, delta, epsilon, theta, pi and rho1-3). In each receptor, these five subunits are assembled from among 19 different subunit isoforms [45]. Composition of the five subunits determines the functional and pharmacological properties of GABAA receptors. The best-known and most widely distributed form in the CNS consists of two alphas, two betas, and a third subunit, which together constitute the chloride ion channel. Different assemblages of the five subunits determine differences in the functioning of the channel and differences in the response to the drugs acting on the receptor [46].

Site-specific binding of the GABAA receptor, in subunit beta, determines the opening of the ion channel and chloride influx. The increase in negative charge leads to a hyperpolarization of the membrane, making it less susceptible to excitation [46]. The activation of GABAA receptors prevents a potential short circuit in the depolarization induced by excitatory neurotransmitters. The activity of these receptors is also modulated by a number of agents including benzodiazepines, barbiturates, some anesthetics and ethanol [47].

The neurosteroids allopregnanolone and THDOC are strong positive allosteric modulators of the GABAA receptors [48], but at a different site than the site bound by the barbiturates and the benzodiazepines [48]. The neuroactive steroids increase the flow of chloride ions from GABAA receptors, by increasing both the frequency and duration of the opening of the ion channel [49]. Due to the increased probability of opening of the chloride channel of the GABAA receptor, neuroactive steroids increase a massive influx of the ion and potentiate inhibitory GABAergic transmission [49].

In vivo, the basal plasma concentration of neuroactive steroids seems sufficient to significantly potentiate the function of the GABAA receptor [50]. Neuroactive steroids can also modulate recombination of various subunits of the GABAA receptor [51]. This recombination can change the action of substances such as alcohol and drugs on the GABAA receptor: the action of these substances on the GABAA receptor depends on receptor assembly [52].

The steroid sulfates are non-competitive antagonists of the GABAA receptors, acting on different sites from those bound by allopregnanolone and THDOC [53]. The negative modulatory action of neuroactive steroids is produced through a reduction in channel opening, but the precise mechanism of this blocking is still not well understood [54]. The neuroactive steroid sulfates also modulate GABAergic transmission through a poorly known presynaptic mechanism [55]. Given the abundance of pregnenolone sulfate (PS) and dehydroepiandrosterone-3-sulfate (DHEAS) in the brain, it seems likely that they can act as endogenous neuromodulators [56]; this in conjunction with neurosteroids such as allopregnanolone and THDOC, which are strong positive allosteric modulators of the GABAA receptors.

Studies carried out in amphibians showed that GABA, through its GABAA receptors, is involved in the control of neurosteroidogenesis, with GABA inhibiting it [56]. Therefore, a short, regulatory loop linking neuroactive steroids’ effects to GABA actions might exist.

The study of progesterone derivatives in epilepsy and mood disorders

The role of allopregnanolone and THDOC has been studied in a number of pathologies including epilepsy [57], premenstrual syndrome [57], anxiety [58] and mood disorders [59, 60].

These steroids show a protective action in epilepsy and elevate the threshold of convulsive crisis, particularly in so-called catamenial epilepsy, in which the crises worsen during the premenstrual phase. Indeed, clinical studies have demonstrated the potential therapeutic utility of synthetic analogs of allopregnanolone in the treatment of catamenial epilepsy [57]. The reduction in the concentration of progesterone derivatives in the luteinizing phase of the menstrual cycle impacts on the clinical manifestations of premenstrual syndrome and premenstrual dysphoric disorder (PMDD) [61], and it is consistent with these findings. PMDD is associated with mood disorders [62], and during depressive episodes, the level of allopregnanolone is low [63]. Conversely, the plasma concentration of allopregnanolone is elevated in patients with panic disorder [64], or following a panic attack [65].

The treatment with fluoxetine stabilizes the level of neurosteroids in depression and panic, and it has been hypothesized that at least part of the therapeutic effect of selective serotonin re-uptake inhibitors (SSRIs) could be through their influence on neurosteroids [66, 67]. Recent findings indicate that neurosteroids such as dehydroepiandrosterone, pregnenolone and their sulfate esters (progesterone and allopregnanolone) affect neuronal survival, neurite outgrowth and neurogenesis [68]. Re-establishment of neuronal plasticity (dendritic remodeling and synaptic contacts) in the hippocampus may be important for the pathogenesis and amelioration of depressive symptoms [69]. Neurosteroids might have a role in resetting neurogenesis in some areas of the brain, and specifically in the hippocampus during recovery from depressive episodes.

A role for progesterone-derived neurosteroids in bipolar disorders?

In women with bipolar disorders during euthymia, plasma concentration of the progesterone derivative allopregnanolone is elevated in the premenstrual period compared to healthy controls and women with major depressive disorder [70]. This finding is independent from pharmacological therapy status and not related to anxiety or eating disorders. It was speculated that these neurosteroids would act as endogenous mood stabilizers. Indeed, during episodes of depression levels of allopregnanolone were reported to be low [63], while the plasma concentration is elevated in patients with panic disorder [64], or after the induction of a panic attack [65]. Panic attack anxiety disorder is highly comorbid with type II bipolar disorder, and it has been suggested that the clinical manifestations of the panic attack is an expression of hyperthymia, specifically the “anxious hyperthymia”; this is a possible personality pre-morbid trait in panic disorder [71]. Both major depression and panic disorder are strongly bound to bipolar disorder, in terms of comorbidity [72], familiarity [73] and in a purported syndromic continuum with major depressive disturbance [74, 75].

Irritable mood is another component of mood elevation in bipolar disorder. Anabolic/androgenic steroids increase sex drive and mental acuity. If abused, such steroids can cause irritability and impulsive aggression [76]. Social isolation in male mice and long-term treatment with anabolic steroids in female mice induces strong aggressive behavior towards intruders. In both sexes, a decrease of brain allopregnanolone is associated with such induced aggressive behavior [77]. Conversely, progesterone and its metabolite allopregnanolone have been implicated in suppressing irritability. Johannson et al. [78] conducted a study to determine whether or not a history of manic/hypomanic irritability is associated with low serum progesterone levels; they further tested whether single nucleotide polymorphisms (SNPs) in genes coding for steroidogenetic enzymes were coupled to previous manic irritability and/or with serum progesterone concentrations. They found that in males with bipolar disorders, progesterone concentrations were lower in those who had shown manic/hypomanic irritability compared with nonirritable patients. Specific SNPs were associated with manic/hypomanic irritability. Thus low progesterone levels and a cystine to serine change at position 145 in AKR1C4 gene were associated with manic/hypomanic irritability in males. Given that the enzyme AKR1C4 has both dehydrogenating and reductive activities in the steroidogenetic pathway, a missense variation in the gene may predispose to manic/hypomanic irritability by altering the relationship between progesterone and allopregnanolone.

More recently, the same group [79] found that in bipolar women, SNPs in AKR1C4 reduced the likelihood of exhibiting paranoid ideation during manic episodes by about 60%. Hence, gene variants in the steroidogenetic pathway and steroids concentration differences may be involved in the susceptibility to paranoia during mood elevation. Hardoy et al. [59] attempted to verify if differences in neurohormonal blood levels may be directly linked to some syndromal lifetime clusters (dimensions) using the Structural Clinical Interview for Mood Spectrum-Self Reported (SCI-MOODS-SR) [80] questionnaire of the mood spectrum independent of diagnosis in females with a lifetime diagnosis of major mood disorder (Bipolar Disorder, Major Depressive Disorder). This was done by investigating the patients during the luteal phase of their menstrual cycle and in a condition of clinical well-being. The analysis of the main components of the syndromal cluster evidenced the presence of 3 components identified by analysis of main components with Varimax rotation and Kaiser's normalization: 1) mania, 2) depression with mixed symptoms of agitation 3) irritable/elated cognition and suicidal ideas. Levels of allopregnanolone and progesterone were not associated with the mixed-depressive or purely manic syndromes, but rather with the symptom dimension characterized by irritable/elated cognition associated with suicidal thoughts. These results indicated that patients in euthymic, stabilized condition but with a history of irritable/elated symptoms mixed with suicide ideation had, at the evaluation time, higher blood levels of progesterone and derivates. These results are in apparent contradiction with the above discussed Johansson et al. [78] findings of low progesterone blood levels in bipolar patients of mixed states. However, taking into account the possibility that the steroids would act as endogenous mood stabilizers, this data can also be interpreted as patients with more severe mixed states need higher steroid levels to reach recovery compared to patients without past mixed symptoms. On the other hand, the hypothesis that steroids may be an endogenous mood stabilizer is supported by the evidence from case reports of recovery from post partum refractory mania [81]. Thus, progesterone and derivates may be particularly relevant on mixed – aggressive component of bipolar symtomathology.

It can also be hypothesized that a dysregulated system in patients with bipolar disorder would cause low levels of neuroactive steroids during depression and mixed states. Thus, drugs able to correct the malfunctioning of systems based on neurosteroids could improve clinical status in patients with bipolar disorder spectrum conditions.

Fluoxetine, which is effective in panic attack and major depression, also affect the levels of neurosteroids [66, 67]. A role for neurosteroids in bipolar disorder is also consistent with the observation that a number of anticonvulsants (including valproate, lamotrigine and carbamazepine) are effective in bipolar disorder [82, 83], an effect that could be partially due to action on neurosteroids. Therefore endogenous neuroactive steroids with anticonvulsant properties may play a role in the pathogenesis of bipolar disorders. Lithium is another effective therapeutic agent in bipolar disorder. Preclinical evidence suggests that lithium might induce its action via an effect on neurosteroids. The levels of allopregnanolone and pregnenolone were found significantly elevated in lithium-treated mice. Pregnenolone levels also tend to be higher following lithium treatment in humans [84].

Even the two atypical antipsychotics clozapine and olanzapine, effective against the manic phase of bipolar disorder [85, 86], were proven to modify the levels of neurosteroids in animal studies. Clozapine markedly elevates pregnenolone in rat hippocampus, cerebral cortex, and serum; hippocampal levels were strongly correlated with serum levels. Olanzapine elevates pregnenolone levels, too, but to a lesser extent than clozapine [87, 88]. Olanzapine, fluoxetine or their combination increased hippocampal pregnenolone and serum deoxycorticosterone in both higher- and lower-dose experiments, and elevated hippocampal allopregnanolone in higher-doses [89]. Since olanzapine and fluoxetine combination have clinical utility particularly in bipolar depression [90, 91], and decrease of pregnenolone levels have been linked to depression, it is possible that olanzapine- and fluoxetine-induced pregnenolone elevations may contribute to the antidepressant actions of these agents in bipolar depression.

Effects of neurosteroids on mood fluctuation might extend across the bipolar disorder spectrum. Women of reproductive age with mental disorders may experience a fluctuating course of illness over the menstrual cycle. Some data suggest that for a subset of women there is a relationship between phases of the menstrual cycle and increased vulnerability for an exacerbation of ongoing mood disorders [22] (the so-called “catamenial mood disorder” [70]). A critical period is the one immediately following the birth of a child, when the level of progesterone neurosteroid derivatives drop; the post-natal period is linked to an increased vulnerability to the onset or recurrence of mood disorders [92].

Neuroactive steroids and GABAergic drugs in bipolar disorders

Recent research data from some GABAergic compounds, including gabapentin [93, 94], tiagabine [95], topiramate [96], have produced disappointing and conflicting results as far as their effectiveness in bipolar disorder is concerned. Preliminary evidence of their effectiveness in patients diagnosed with bipolar disorder was not confirmed by subsequent randomized, placebo-controlled studies [9799].

Most antiepileptic compounds exert a direct or indirect GABA-mediated inhibitory action [100]. However, the impact of the neuroactive steroids on the structure of the GABAA receptor is a factor that has not been adequately examined in the investigation of the pharmacological action of putatively GABAergic drugs. Indeed, patients with bipolar disorder often abuse alcohol or drugs such as benzodiazepines [101], which can induce changes in the heteropentameric structure of the GABAA receptor, changes that may alter the subsequent action of drugs targeting the GABAA receptor. In addition, benzodiazepines such as diazepam or midazolam were found to promote neurosteroid synthesis [102104]. Moreover, if neurosteroids really are involved in the etiology of bipolar disorder and their levels fluctuate during the different phases of the disorder, the influence of neurosteroids on the GABAA receptors also will fluctuate. This will further modify the responsiveness to GABAergic compounds. Effectiveness of potentially antimanic GABAergic drugs would depend of the status of the GABAA receptors on which they exert their action, and on levels of neurosteroids acting on the GABAA receptors. Overall, the chance of finding a therapeutic effectiveness of GABAergic compounds will be a function of: a) inter-individual differences in neurosteroids synthesis, secretion and action at the target receptor; b) the conformation of the GABAA receptor as a function of alcohol and/or preceding treatment with drugs acting on it; the phase of the disorder, whether depressive or excitatory. Gender differences in neurosteroids functioning also would have an impact on the effectiveness of GABAergic compounds in bipolar disorder, and should be accounted for.


Literature on the role of neuroactive steroids in mental disorders is sparse. Nonetheless we have made an attempt to present a narrative review of existing studies on neurosteroids acting on the GABAergic receptors. Current evidence suggests that the investigation of neuroactive steroids on mental disorders might open new frontiers in the investigation of the etiology and treatment of mood disorders, particularly bipolar disorder. Neurosteroids might be an endogenous mood stabilizer and the alteration of their functioning on a genetic or biochemical level might be responsible for the display of symptoms in individuals vulnerable to bipolar disorder.


  1. 1.

    Marder SR, Roth B, Sullivan PF, Scolnick EM, Nestler EJ, Geyer MA, Welnberger DR, Karayiorgou M, Guidotti A, Gingrich J, Akbarian S, Buchanan RW, Lieberman JA, Conn PJ, Haggarty SJ, Law AJ, Campbell B, Krystal JH, Moghaddam B, Saw A, Caron MG, George SR, Allen JA, Solis M: Advancing drug discovery for schizophrenia. Ann N Y Acad Sci. 2011, 1236: 30-43. 10.1111/j.1749-6632.2011.06216.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  2. 2.

    Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT: Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food And Drug Administration. PLoS Med. 2008, 5 (2): e45-10.1371/journal.pmed.0050045.

    PubMed Central  PubMed  Article  Google Scholar 

  3. 3.

    Turner EH, Knoepflmacher D, Shapley L: Publication bias in antipsychotic trials: an analysis of efficacy comparing the published literature to the US Food and Drug Administration database. PLoS Med. 2012, 9 (3): e1001189-10.1371/journal.pmed.1001189. Epub 2012 Mar 20

    PubMed Central  PubMed  Article  Google Scholar 

  4. 4.

    Goff DC, Hill M, Freudenreich O: Treatment adherence in schizophrenia and schizoaffective disorder. J Clin Psychiatry. 2011, 72: e13-10.4088/JCP.9096tx6cc.

    PubMed  Article  Google Scholar 

  5. 5.

    Barbui C, Kikkert M, Mazzi MA, Becker T, Bindman J, Schene A, Nosè M, Helm H, Thornicroft G, Tansella M: Comparison of patient and clinician perspectives in the assessment of antipsychotic medication adherence. Psychopathology. 2009, 42 (5): 311-7. 10.1159/000232973.

    PubMed  Article  Google Scholar 

  6. 6.

    George I: Papakostas, maurizio fava predictors, moderators, and mediators (correlates) of treatment outcome in major depressive disorderDialogues. Clin Neurosci. 2008, 10 (4): 439-451.

    Google Scholar 

  7. 7.

    Carta MG, Angst J: Epidemiological and clinical aspects of bipolar disorders: controversies or a common need to redefine the aims and methodological aspects of surveys. Clin Pract Epidemol Ment Health. 2005, 1 (1): 4-10.1186/1745-0179-1-4.

    Article  Google Scholar 

  8. 8.

    Sullivan PF: The Psychiatric GWAS Consortium: big science comes to psychiatry. Neuron. 2010, 68: 182-186. 10.1016/j.neuron.2010.10.003.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  9. 9.

    Nestler EJ, Hyman SE: Animal models of neuropsychiatric disorders. Nature Neurosci. 2010, 13: 1161-1169. 10.1038/nn.2647.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  10. 10.

    Häfner H, an der Heiden W, Behrens S: Causes and consequences of the gender difference in age at onset of schizophrenia. Schizophr Bull. 1998, 242: 6-12.

    Google Scholar 

  11. 11.

    Häfner H: Gender differences in schizophrenia. Psychoneuroendocrinology. 2003, 28: 17-54.

    PubMed  Article  Google Scholar 

  12. 12.

    Leung A, Chue P: Sex differences in schizophrenia: a review of the literature. Acta Psychiatr Scand 2000. Suppl. 2000, 401: 3-38.

    CAS  Google Scholar 

  13. 13.

    Cascio MT, Cella M, Preti A, Meneghelli A, Cocchi A: Gender and duration of untreated psychosis: a systematic review and meta-analysis. Early Interv Psychiatry. 2012, 6 (2): 115-27. 10.1111/j.1751-7893.2012.00351.x.

    PubMed  Article  Google Scholar 

  14. 14.

    Grossman LS, Harrow M, Rosen C, Faull R, Strauss GP: Sex differences in schizophrenia and other psychotic disorders: a 20-year longitudinal study of psychosis and recovery. Compr Psychiatry. 2008, 49: 523-529. 10.1016/j.comppsych.2008.03.004.

    PubMed Central  PubMed  Article  Google Scholar 

  15. 15.

    Haro JM, Novick D, Bertsch J, Karagianis J, Dossenbach M, Jones PB: Cross-national clinical and functional remission rates: worldwide schizophrenia outpatient health outcomes (W-SOHO) study. Br J Psychiatry. 2011, 199: 194-201. 10.1192/bjp.bp.110.082065.

    PubMed  Article  Google Scholar 

  16. 16.

    Reicher-Rossler A, Hafner H, Dutsch-Strobel A: Further evidence for a specific role of estradiol in schizophrenia?. Biol Psychiatry. 1994, 36: 492-494. 10.1016/0006-3223(94)90649-1.

    Article  Google Scholar 

  17. 17.

    Seeman M, Lang M: The role of estrogens in schizophrenia gender differences. Schizophr Bull. 1990, 16: 185-194. 10.1093/schbul/16.2.185.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Thorup A, Petersen L, Jeppesen P: Gender differences in young adults with first-episode schizophrenia spectrum disorders at baseline in the Danish OPUS study. J Nerv Ment Dis. 2007, 195: 396-405.

    PubMed  Google Scholar 

  19. 19.

    Waraich P, Goldner EM, Somers JM, Hsu L: Prevalence and incidence studies of mood disorders: a systematic review of the literature. Can J Psychiatry. 2004, 49 (2): 124-38.

    PubMed  Google Scholar 

  20. 20.

    Diflorio A, Jones I: Is sex important? Gender differences in bipolar disorder. Int Rev Psychiatry. 2010, 22 (5): 437-52. 10.3109/09540261.2010.514601.

    PubMed  Article  Google Scholar 

  21. 21.

    Baulieu EE, Robel P: Dehydroepiandrosterone and dehydroepiandrosterone sulfate as neuroactive neurosteroids. J Endocrinol. 1996, 150: S221-S239.

    CAS  PubMed  Google Scholar 

  22. 22.

    Agís-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A: Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis. Proc Natl Acad Sci USA. 2006, 103 (39): 14602-7. 10.1073/pnas.0606544103.

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  23. 23.

    Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA: International union of pharmacology. LXIV. Estrogen receptors. Pharmacol Rev. 2006, 58 (4): 773-781. 10.1124/pr.58.4.8.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Scarpin KM, Graham JD, Mote PA, Clarke CL: Progesterone action in human tissues: regulation by progesterone receptor (PR) isoform expression, nuclear positioning and coregulator expression. Nucl Recept Signal. 2009, 7: e009-

    PubMed Central  PubMed  Google Scholar 

  25. 25.

    Prossnitz ER, Arterburn JB, Smith HO, Oprea TI, Sklar LA, Hathaway HJ: Estrogen signaling through the transmembrane G protein-coupled receptor GPR30. Annu Rev Physiol. 2008, 70: 165-90. 10.1146/annurev.physiol.70.113006.100518.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Woolley CS, McEwen BS: Estradiol regulates hippocampal dendritic spine density via an N-methyl-D-aspartate receptor-dependent mechanism. J Neurosci. 1994, 14 (12): 7680-7.

    CAS  PubMed  Google Scholar 

  27. 27.

    Appelgren LE: Sites of steroid hormone formation. Autoradiographic studies using labelled precursors. Acta Physiol Scand Suppl. 1967, 301: 1-108.

    CAS  PubMed  Google Scholar 

  28. 28.

    Seyle H: The stress of life. 1956, New York: Mac Graw Hill

    Google Scholar 

  29. 29.

    Holzbauer M: Ovarian secretion of steroids with central depressant actions. J Physiol. 1971, 215 (1): 16P-17P.

    CAS  PubMed  Google Scholar 

  30. 30.

    Sherwin BB: Estrogen and cognitive functioning in women. Endocr Rev. 2003, 24 (2): 133-151. 10.1210/er.2001-0016.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Kompoliti K: Estrogen and movement disorders. Clin Neuropharmacol. 1999, 22 (6): 318-326.

    CAS  PubMed  Google Scholar 

  32. 32.

    Craft RM, Ulibarri C, Leitl MD, Sumner JE: Dose- and time-dependent estradiol modulation of morphine antinociception in adult female rats. Eur J Pain. 2008, 12 (4): 472-9. 10.1016/j.ejpain.2007.07.014.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Corpechot C, Robel P, Axelson M, Sjovall J, Baulieu EE: Characterization and measurement of dehydroepiandrosterone sulfate in rat brain. Proc Natl Acad Sci USA. 1981, 78: 4704-4707. 10.1073/pnas.78.8.4704.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  34. 34.

    Do Rego JL, Seong JY, Burel D, Leprince J, Luu-The V, Tsutsui K, Tonon MC, Pelletier G, Vaudry H: Neurosteroid biosynthesis: enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides. Front Neuroendocrinol. 2009, 30 (3): 259-301. 10.1016/j.yfrne.2009.05.006.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Melcangi RC, Celotti F, Castano P, Martini L: Differential localization of the 5 alpha-reductase and the 3 alpha-hydroxysteroid dehydrogenase in neuronal and glial cultures. Endocrinology. 1993, 132 (3): 1252-9. 10.1210/en.132.3.1252.

    CAS  PubMed  Google Scholar 

  36. 36.

    Petratos S, Hirst JJ, Mendis S, Anikijenko P, Walker DW: Localization of p450scc and 5α-reductase type-2 in the cerebellum of fetal and newborn sheep. Developmental Brain Research. 2000, 123: 81-86. 10.1016/S0165-3806(00)00076-6.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Stoffel-Wagner B: Neurosteroid metabolism in the human brain. Eur J Endocrinol. 2001, 145 (6): 669-79. 10.1530/eje.0.1450669.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Stoffel-Wagner B, Watzka M, Steckelbroeck S, Ludwig M, Clusmann H, Bidlingmaier F, Casarosa E, Luisi S, Elger CE, Beyenburg S: Allopregnanolone serum levels and expression of 5 alpha-reductase and 3 alpha-hydroxysteroid dehydrogenase isoforms in hippocampal and temporal cortex of patients with epilepsy. Epilepsy Res. 2003, 54 (1): 11-9. 10.1016/S0920-1211(03)00036-6.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Patte-Mensah C, Kappes V, Freund-Mercier MJ, Tsutsui K, Mensah-Nyagan AG: Cellular distribution and bioactivity of the key steroidogenic enzyme, cytochrome P450side chain cleavage, in sensory neural pathways. J Neurochem. 2003, 86 (5): 1233-46. 10.1046/j.1471-4159.2003.01935.x.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Guennoun R, Fiddes RJ, Gouézou M, Lombès M, Baulieu EE: A key enzyme in the biosynthesis of neurosteroids, 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD), is expressed in rat brain. Brain Res Mol Brain Res. 1995, 30 (2): 287-300. 10.1016/0169-328X(95)00016-L.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Nothdurfter C, Rammes G, Baghai TC, Schüle C, Schumacher M, Papadopoulos V, Rupprecht R: Translocator protein (18 kDa) as a target for novel anxiolytics with a favourable side-effect profile. J Neuroendocrinol. 2012, 24 (1): 82-92. 10.1111/j.1365-2826.2011.02166.x.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Reddy DS: Neurosteroids: endogenous role in the human brain and therapeutic potentials. Prog Brain Res. 2010, 186: 113-37.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  43. 43.

    Rupprecht R, Reul JM, Trapp T, van Steensel B, Wetzel C, Damm K, Zieglgänsberger W, Holsboer F: Progesterone receptor-mediated effects of neuroactive steroids. Neuron. 1993, 11 (3): 523-30. 10.1016/0896-6273(93)90156-L.

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Reddy DS: Pharmacology of endogenous neuroactive steroids. Crit Rev Neurobiol. 2003, 15: 197-234.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Olsen RW, Siegart W: International union of pharmacology. Subtypes of gamma aminobutyric acid a receptors: classification on the basis of subunit composition, pharmacology and function. Pharmacol Rev. 2008, 60: 243-260. 10.1124/pr.108.00505.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  46. 46.

    McKernan RM, Whiting PJ: Which GABAA receptor subtypes really occur in the brain?. Trends Neurosci. 1996, 19: 139-143. 10.1016/S0166-2236(96)80023-3.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Botta P, Radcliffe RA, Carta M, Mameli M, Daly E, Floyd KL, Deitrich RA, Valenzuela CF: Modulation of GABAA receptors in cerebellar granule neurons by ethanol: a review of genetic and electrophysiological studies. Alcohol. 2007, 41 (3): 187-99. 10.1016/j.alcohol.2007.04.004. Epub 2007 May 23

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  48. 48.

    Reddy DS: Pharmacology of endogenous neuroactive steroids. Crit Rev Neurobiol. 2003, 15 (3–4): 197-234.

    CAS  PubMed  Google Scholar 

  49. 49.

    Kelley SP, Alan JK, O'Buckley TK, Mennerick S, Krishnan K, Covey DF, Leslie Morrow A: Antagonism of neurosteroid modulation of native gamma-aminobutyric acid receptors by (3alpha,5alpha)-17-phenylandrost-16-en-3-ol. Eur J Pharmacol. 2007, 572 (2–3): 94-101.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  50. 50.

    Harney SC, Frenguelli BG, Lambert JJ: Phosphorylation influences neurosteroid modulation of synaptic GABAA receptors in rat CA1 and dentate gyrus neurones. Neuropharmacology. 2003, 45: 873-883. 10.1016/S0028-3908(03)00251-X.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Lambert JJ, Belelli D, Peden DR, Vardy AW, Peters JA: Neuroactive steroid modulation of GABAA receptors. Prog Neurobiol. 2003, 71: 67-80. 10.1016/j.pneurobio.2003.09.001.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Boehm SL, Ponomarev I, Blednov YA, Harris RA: From gene to behavior and back again: new perspectives on GABAA receptor subunit selectivity of alcohol actions. Adv Pharmacol. 2006, 54: 171-2037.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Park-Chung M, Malayev A, Purdy RH, Gibbs TT, Farb DH: Sulfated and unsulfated steroids modulate γ aminobutyric acidA receptor function through distinct sites. Brain Res. 1999, 830: 72-87. 10.1016/S0006-8993(99)01381-5.

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Akk G, Bracamontes J, Steinbach JH: Pregnenolone sulfate block of GABAA receptors: mechanism and involvement of a residue in the M2 region of the α subunit. J Physiol (Lond). 2001, 532: 673-684. 10.1111/j.1469-7793.2001.0673e.x.

    CAS  Article  Google Scholar 

  55. 55.

    Mtchedlishvili Z, Kapur J: A presynaptic action of the neurosteroid pregnenolone sulfate on GABAergic synaptic transmission. Mol Pharmacol. 2003, 64: 857-864. 10.1124/mol.64.4.857.

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Twede V, Tartaglia AL, Covey DF, Bamber BA: The neurosteroids dehydroepiandrosterone sulfate and pregnenolone sulfate inhibit the UNC-49 GABA receptor through a common set of residues. Mol Pharmacol. 2007, 72 (5): 1322-9. 10.1124/mol.107.034058.

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Do Rego JL, Seong JY, Burel D, Leprince J, Vaudry D, Luu-The V, Tonon MC, Tsutsui K, Pelletier G, Vaudry H: Regulation of neurosteroid biosynthesis by neurotransmitters and neuropeptides. Front Endocrinol (Lausanne). 2012, 3: 4-Epub 2012 Jan 24

    CAS  Google Scholar 

  58. 58.

    Guille C, Spencer S, Cavus I, Epperson CN: The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: implications for diagnosis and treatment. Epilepsy Behav. 2008, 13 (1): 12-24. 10.1016/j.yebeh.2008.02.004.

    PubMed Central  PubMed  Article  Google Scholar 

  59. 59.

    Kita A, Furukawa K: Involvement of neurosteroids in the anxiolytic-like effects of AC-5216 in mice. Pharmacol Biochem Behav. 2008, 89 (2): 171-8. 10.1016/j.pbb.2007.12.006.

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Hardoy MC, Sardu C, Dell'osso L, Carta MG: The link between neurosteroids and syndromic/syndromal components of the mood spectrum disorders in women during the premenstrual phase. Clin Pract Epidemol Ment Health. 2008, 4: 3-10.1186/1745-0179-4-3.

    Article  Google Scholar 

  61. 61.

    Eser D, Schüle C, Baghai TC, Romeo E, Rupprecht R: Neuroactive steroids in depression and anxiety disorders: clinical studies. Neuroendocrinology. 2006, 84 (4): 244-54. 10.1159/000097879.

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Sundstrom Poromaa I, Smith S, Gulinello M: GABA receptors, progesterone and premenstrual dysphoric disorder. Arch Women Ment Health. 2003, 6 (1): 23-41. 10.1007/s00737-002-0147-1.

    CAS  Article  Google Scholar 

  63. 63.

    Miller MN, Miller BE: Premenstrual exacerbations of mood disorders. Psychopharmacol Bull. 2001, 35 (3): 135-149.

    CAS  PubMed  Google Scholar 

  64. 64.

    Pisu MG, Serra M: Neurosteroids and neuroactive drugs in mental disorders. Life Sci. 2004, 74: 3181-3197. 10.1016/j.lfs.2003.12.002.

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Brambilla F, Biggio G, Pisu MG, Bellodi L, Perna GP, Bogdanovich-Djukic V, Purdy RH, Serra M: Neurosteroid secretion in panic disorder. Psychiatry Res. 2003, 118: 107-116. 10.1016/S0165-1781(03)00077-5.

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Strohle A, Romeo E, di Michele F, Pasini A, Hermann B, Gajewsky G, Holsboer F, Rupprecht R: Induced panic attacks shift γ-aminobutyric acid type A receptor modulatory neuroactive steroid composition in patients with panic disorder: preliminary results. Arch Gen Psychiatry. 2003, 60: 161-168. 10.1001/archpsyc.60.2.161.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Uzunov DP, Cooper TB, Costa E, Guidotti A: Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography. Proc Natl Acad Sci USA. 1996, 93: 12599-12604. 10.1073/pnas.93.22.12599.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  68. 68.

    Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, Guidotti A: Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine. Proc Natl Acad Sci USA. 1998, 95 (6): 3239-3244. 10.1073/pnas.95.6.3239.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  69. 69.

    Charalampopoulos I, Remboutsika E, Margioris AN, Gravanis A: Neurosteroids as modulators of neurogenesis and neuronal survival. Trends Endocrinol Metab. 2008, 19 (8): 300-7. 10.1016/j.tem.2008.07.004.

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA, Almeida OF, Sousa N: The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry. 2009, 14 (8): 764-773. 10.1038/mp.2008.119. 739

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Hardoy MC, Serra M, Carta MG, Contu P, Pisu MG, Biggio G: Increased neuroactive steroid concentrations in women with bipolar disorder or major depressive disorder. J Clin Psychopharmacol. 2006, 26 (4): 379-84. 10.1097/

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Féline A: Hyperthymic disorders. Encéphale. 1993, 19 (2): 103-7.

    PubMed  Google Scholar 

  73. 73.

    Carta MG, Tondo L, Balestrieri M: Sub-threshold depression and antidepressants use in a community sample: searching anxiety and finding bipolar disorder. BMC Psychiatry. 2011, 11: 164-10.1186/1471-244X-11-164.

    PubMed Central  PubMed  Article  Google Scholar 

  74. 74.

    Frank E, Cyranowski JM, Rucci P, Shear MK, Fagiolini A, Thase ME, Cassano GB, Grochocinski VJ, Kostelnik B, Kupfer DJ: Clinical significance of lifetime panic spectrum symptoms in the treatment of patients with bipolar I disorder. Arch Gen Psychiatry. 2002, 59 (10): 905-911. 10.1001/archpsyc.59.10.905.

    PubMed  Article  Google Scholar 

  75. 75.

    Cassano GB, Rucci P, Frank E, Fagiolini A, Dell'Osso L, Shear MK, Kupfer DJ: The mood spectrum in unipolar and bipolar disorder: arguments for a unitary approach. Am J Psychiatry. 2004, 161 (7): 1264-1269. 10.1176/appi.ajp.161.7.1264.

    PubMed  Article  Google Scholar 

  76. 76.

    Carta MG, Hardoy MC, Garofalo A, Pisano E, Nonnoi V, Intilla G, Serra G, Balestrieri C, Chessa L, Cauli C, Lai ME, Farci P: Association of chronic hepatitis C with major depressive disorders: irrespective of interferon-alpha therapy. Clin Pract Epidemol Ment Health. 2007, 23 (3): 22-

    Article  Google Scholar 

  77. 77.

    Pearson H: Hormone therapy: a dangerous elixir?. Nature. 2004, 431: 500-501. 10.1038/431500a.

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Pinna G, Costa E, Guidotti A: Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior. Proc Natl Acad Sci U S A. 2005, 102 (6): 2135-40. 10.1073/pnas.0409643102. Epub 2005 Jan 27

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  79. 79.

    Johansson AG, Nikamo P, Schalling M, Landén M: AKR1C4 gene variant associated with low euthymic serum progesterone and a history of mood irritability in males with bipolar disorder. J Affect Disord. 2011, 133 (1–2): 346-51.

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Johansson AG, Nikamo P, Schalling M, Landén M: Polymorphisms in AKR1C4 and HSD3B2 and differences in serum DHEAS and progesterone are associated with paranoid ideation during mania or hypomania in bipolar disorder. Eur Neuropsychopharmacol. 2012, 22 (9): 632-640. 10.1016/j.euroneuro.2012.01.007.

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Fagiolini A, Dell’Osso L, Pini S, Armani A, Bouanani S, Rucci P, Cassano GB, Endicott J, Maser J, Shear MK, Grochocinski VJ, Frank E: Validity and reliability of a new instrument for assessing mood symptomatology: the Structured Clinical Interview for Mood Spectrum (SCI MOODS). Int J Meth Psych Res. 1999, 8: 71-81. 10.1002/mpr.58.

    Article  Google Scholar 

  82. 82.

    Huang MC, Wang YB, Chan CH: Estrogen-progesterone combination for treatment-refractory post-partum mania. Psychiatry Clin Neurosci. 2008, 62: 126-10.1111/j.1440-1819.2007.01782.x.

    PubMed  Article  Google Scholar 

  83. 83.

    Bowden CL: Anticonvulsants in bipolar disorders: current research and practice and future directions. Bipolar Disord. 2009, 11 (2): 20-33.

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Grunze HC: Anticonvulsants in bipolar disorder. J Ment Health. 2010, 19 (2): 127-41. 10.3109/09638230903469186.

    PubMed  Article  Google Scholar 

  85. 85.

    Marx CE, Yuan P, Kilts JD, Madison RD, Shampine LJ, Manji HK: Neuroactive steroids, mood stabilizers, and neuroplasticity: alterations following lithium and changes in Bcl-2 knockout mice. Int J Neuropsychopharmacol. 2008, 11 (4): 547-52.

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Chang JS, Ha KS, Young Lee K, Sik Kim Y, Min Ahn Y: The effects of long-term clozapine add-on therapy on the rehospitalization rate and the mood polarity patterns in bipolar disorders. J Clin Psychiatry. 2006, 67 (3): 461-7. 10.4088/JCP.v67n0318.

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Tohen M, Sutton VK, Calabrese JR, Sachs GS, Bowden CL: Maintenance of response following stabilization of mixed index episodes with olanzapine monotherapy in a randomized, double-blind, placebo-controlled study of bipolar 1 disorder. J Affect Disord. 2009, 116 (1-2): 43-50. 10.1016/j.jad.2008.11.003.

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Marx CE, Stevens RD, Shampine LJ, Uzunova V, Trost WT, Butterfield MI, Massing MW, Hamer RM, Morrow AL, Lieberman JA: Neuroactive steroids are altered in schizophrenia and bipolar disorder: relevance to pathophysiology and therapeutics. Neuropsychopharmacology. 2006, 31 (6): 1249-63.

    CAS  PubMed  Google Scholar 

  89. 89.

    Marx CE, Shampine LJ, Duncan GE, VanDoren MJ, Grobin AC, Massing MW, Madison RD, Bradford DW, Butterfield MI, Lieberman JA, Morrow AL: Clozapine markedly elevates pregnenolone in rat hippocampus, cerebral cortex, and serum: candidate mechanism for superior efficacy?. Pharmacol Biochem Behav. 2006, 84 (4): 598-608. 10.1016/j.pbb.2006.07.026.

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Marx CE, Shampine LJ, Khisti RT, Trost WT, Bradford DW, Grobin AC, Massing MW, Madison RD, Butterfield MI, Lieberman JA, Morrow AL: Olanzapine and fluoxetine administration and coadministration increase rat hippocampal pregnenolone, allopregnanolone and peripheral deoxycorticosterone: implications for therapeutic actions. Pharmacol Biochem Behav. 2006, 84 (4): 609-17. 10.1016/j.pbb.2006.07.032.

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Tohen M, Vieta E, Calabrese J, Ketter TA, Sachs G, Bowden C, Mitchell PB, Centorrino F, Risser R, Baker RW, Evans AR, Beymer K, Dube S, Tollefson GD, Breier A: Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60(11):1079–88. Erratum in. Arch Gen Psychiatry. 2004, 61 (2): 176-

    Article  Google Scholar 

  92. 92.

    Brown E, Dunner DL, McElroy SL, Keck PE, Adams DH, Degenhardt E, Tohen M, Houston JP: Olanzapine/fluoxetine combination vs. lamotrigine in the 6-month treatment of bipolar I depression. Int J Neuropsychopharmacol. 2008, 11: 1-10.

    Google Scholar 

  93. 93.

    Arnold LM: Gender differences in bipolar disorder. Psychiatr Clin North Am. 2003, 26 (3): 595-620. 10.1016/S0193-953X(03)00036-4.

    PubMed  Article  Google Scholar 

  94. 94.

    Cabras PL, Hardoy MJ, Hardoy MC, Carta MG: Clinical Experience with gabapentin in patients with Bipolar or Scizoaffective Disorder. J Clin Psychiatry. 1999, 60 (4): 245-248. 10.4088/JCP.v60n0408.

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Carta MG, Hardoy MC, Hardoy MJ, Grunze H, Carpiniello B: The clinical use of gabapentin in bipolar spectrum disorders. J Affect Disord. 2003, 75 (1): 83-91. 10.1016/S0165-0327(02)00046-0.

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Carta MG, Hardoy MC, Grunze H, Carpiniello B: The use of tiagabine in affective disorders. Pharmacopsychiatry. 2002, 35 (1): 33-4. 10.1055/s-2002-19836.

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Kushner SF, Khan A, Lane R, Olson WH: Topiramate monotherapy in the management of acute mania: results of four double-blind placebo-controlled trials. Bipolar Disord. 2006, 8 (1): 15-27. 10.1111/j.1399-5618.2006.00276.x.

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Pande AC, Crockatt JG, Janney CA, Werth JL, Tsaroucha G: Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Gabapentin bipolar disorder study group. Bipolar Disord. 2000, 2 (3 Pt 2): 249-55.

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Suppes T, Chisholm KA, Dhavale D, Frye MA, Altshuler LL, McElroy SL, Keck PE, Nolen WA, Kupka R, Denicoff KD, Leverich GS, Rush AJ, Post RM: Tiagabine in treatment refractory bipolar disorder: a clinical case series. Bipolar Disord. 2002, 4 (5): 283-9. 10.1034/j.1399-5618.2002.01201.x.

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Roy Chengappa KN, Schwarzman LK, Hulihan JF, Xiang J, Rosenthal NR: Clinical affairs product support study-168 investigators. Adjunctive topiramate therapy in patients receiving a mood stabilizer for bipolar I disorder: a randomized, placebo-controlled trial. J Clin Psychiatry. 2006, 67 (11): 1698-706. 10.4088/JCP.v67n1105.

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Elger CE, Schmidt D: Modern management of epilepsy: a practical approach. Epilepsy Behav. 2008, 12 (4): 501-39. 10.1016/j.yebeh.2008.01.003.

    PubMed  Article  Google Scholar 

  102. 102.

    Carta MG, Kovess V, Hardoy MC, Brugha T, Fryers T, Lehtinen V, Xavier M: Psychosocial wellbeing and psychiatric care in the European Communities: analysis of macro indicators. Social Psychiatry and Psychiatric Epidemiology. 2004, 39 (11): 883-92. 10.1007/s00127-004-0871-0.

    PubMed  Article  Google Scholar 

  103. 103.

    Rupprecht R, Papadopoulos V, Rammes G, Baghai TC, Fan J, Akula N, Groyer G, Adams D, Schumacher M: Translocator protein(18kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat. Rev. Drug Discov. 2010, 9: 971-9. 10.1038/nrd3295.

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Tokuda K, O’ Dell KA, Izumi Y, Zorumski CF: Midazolam inhibits hippocampal long-term potentiation and learning through dual central and peripheral benzodiazepine receptor activation and neurosteroidogenesis. J. Neurosci. 2010, 30: 16788-16795. 10.1523/JNEUROSCI.4101-10.2010.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

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Correspondence to Mauro Giovanni Carta.

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The authors’ declare that they have no competing interest.

Authors’ contributions

MGC conceived the idea of the paper and drafted the manuscript after discussion with KMB and AP. KMB and AP contributed to the molecular (particularly KMB) and clinical (AP) aspects of the paper. All authors read and approved the final manuscript.

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Carta, M.G., Bhat, K.M. & Preti, A. GABAergic neuroactive steroids: a new frontier in bipolar disorders?. Behav Brain Funct 8, 61 (2012).

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  • Bipolar Disorder
  • Clozapine
  • Olanzapine
  • Mood Disorder
  • GABAA Receptor