Access the full text.
Sign up today, get DeepDyve free for 14 days.
Loading next page...
/lp/springer-journals/gabaergic-neuroactive-steroids-a-new-frontier-in-bipolar-disorders-My0AdoH2lU
- Publisher
- Springer Journals
- Copyright
- Copyright © 2012 by Carta et al.; licensee BioMed Central Ltd.
- Subject
- Biomedicine; Neurosciences; Neurology; Behavioral Therapy; Psychiatry
- eISSN
- 1744-9081
- DOI
- 10.1186/1744-9081-8-61
- pmid
- 23253178
- Publisher site
- See Article on Publisher Site
Abstract
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. Introduction effectiveness of currently available drugs is poor, both Pharmacotherapy of severe mental disorders has not because only selected subgroups of patients were found changed significantly since the introduction of anti- to be good responders to the prescribed drugs [2,3] and psychotic compounds in the 1950s. The current classes because compliance to treatment is generally low be- of drugs available to treat schizophrenia, bipolar disorder cause of side effects and poor insight on the necessity of and major depression involve essentially the same a severe mental disorder needing long-term therapy mechanisms of action and the same neurobiological tar- [4,5]. get [1]. Arguably the most important advance in the The development of new therapeutic targets in the pharmacotherapy of severe mental disorders in the last treatment of severe mental disorders is hampered by the fifty years was the substitution of barbiturates with the lack of external, biological markers of the nosographic clinically safer benzodiazepines and the introduction of phenotypes [6,7], the scarce knowledge of the neurobio- the theory-driven selective serotonin reuptake inhibitors logical and genetic substrates of the categorically defined for the treatment of depression. Nevertheless, the disorders [8] and the difficulties in devising valid and re- liable animal models, which often lack predictive validity in the prediction of drug actions in humans [9]. There- * Correspondence: mgcarta@tiscali.it Department of Public Health, Clinical and Molecular Medicine, University of fore, serendipity is as likely to guide discovery now as it Cagliari and Center for Consultation-Liaison Psychiatry and Psychosomatics was in the past. However, it is always possible to help University Hospital of Cagliari, Cagliari, Italy serendipity-assisted drug discovery by looking at the Full list of author information is available at the end of the article © 2012 Carta et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Carta et al. Behavioral and Brain Functions 2012, 8:61 Page 2 of 8 http://www.behavioralandbrainfunctions.com/content/8/1/61 crossroads of epidemiology with laboratory and clinical hormone family of intracellular estrogen receptors, alpha research. and beta (encoded by two separate genes), are dimeric molecules that regulate transcription of target genes in Gender issues in the epidemiology of severe mental the nuclei [23,24]. These receptors have a C-terminal disorders and an N-terminal zinc-finger domains that mediate There is robust epidemiological evidence that patients binding of the receptors to target DNA sequences. In diagnosed with schizophrenia and mood disorders show the absence of the binding hormone, the C-terminal of gender differences in the onset, course and outcome of the receptors inhibits transcription. The binding of the their disorders. Since the German ABC study (Age, Be- hormone induces a change in the dimeric structure of ginning, Course) on schizophrenia, it is well known that the receptors, and this removes the inhibitory action. females have two peaks in the onset of schizophrenia, Estrogens also bind to a G-protein coupled receptor, contrary to males [10,11]. Recent systematic reviews and which as a transmembrane G-protein mediates estrogen- meta-analyses confirmed that males are over-represented dependent kinase activation [25]. in the samples of patients diagnosed with first-episode Both estradiol and progesterone receptors are found in schizophrenia. They are generally younger at first con- the Central Nervous System (CNS) [26]. Progesterone is tact, and tend to have a poorer outcome compared to rapidly absorbed and metabolized in the cerebral cortex females [12-15]. To account for these findings, it was [27]. Because of their lipophilic nature, the steroids pro- suggested that estrogens may have modulated dopami- duced by the endocrine glands pass freely through the nergic hyperactivity in females, thus leading to a gradual blood–brain barrier. The concentration of estradiol and progression of the course of the disorder and a later progesterone in the brain closely follows peripheral con- onset of frank psychosis [11,16,17]. This hypothesis was centrations. The brain is one of the targets of steroid compatible with the two incidence peaks in female psych- hormones [28,29]. In general, estradiol induces excita- osis onset; one in the early 20s, also common among tory actions while progesterone induces inhibitory males, albeit slightly later, and another after 40 years, actions on the CNS. The ovarian steroids modulate possibly related to menopause [10,18]. many functions of the CNS, such as memory and learn- Mood disorders show a different picture, with women ing [30], movement [31], and the perception of pain having an increased risk for developing major depression [32]. The ovarian steroids regulate neuroendocrine, compared to males [19]. The risk of hypomania, rapid endocrine and behavioral functions through a number of cycling and mixed episodes is also higher among women cellular mechanisms. than men [20]. However, men and women suffer the same incidence of bipolar disorder and essentially with Neurosteroids and their role in the brain the same outcome [19,20]. If steroids have a role in Baulieu and co-workers were the first to observe that schizophrenia related psychoses, this role is reversed in the brain concentrations of dehydroepiandrosterone sul- affective psychoses. The discovery that the brain can fate were partially independent from adrenal and gonad synthesize neuroactive steroids and that their action is secretion [33]. Subsequently, the demonstration of de widespread on neuronal cells opened up an entirely new novo synthesis of active steroids in the brain leads to the area in the investigation on rge effects of steroids on be- conceptualization of these brain-acting steroids as neu- havior [21,22]. rosteroids [21]; neurosteroids are synthesized from cir- culating steroid hormones, which serve as precursors of Sex steroids and the brain active neurosteroids. Currently, neurosteroids are Peripherally, steroids are produced mainly by the adrenal defined as those that are synthesized in the brain. Neu- cortex and the gonads and are regulated by the roactive steroids refer to steroids that, independent of hypothalamic-pituitary-adrenal axis and the hypothal- their origin, are capable of modifying neural activities. amic pituitary-adrenal gonadal axis through negative Currently neuroactive steroids are classified as preg- feedback. The ovarian steroids regulate neuroendocrine, nane neurosteroids (allopregnanolone and allotetrahydro- endocrine and behavioral functions through a number of deoxycorticosterone or THDOC), androstane neurosteroids cellular mechanisms. Typically, both estrogen and pro- (androstanediol and etiocholanone) or sulfated neuroster- gesterone induce a relatively long-term action on neu- oids (pregnenolone sulfate or PS and dehydroepiandroster- rons by activating a number of intracellular receptors one sulfate or DHEAS). that modulate the transcription and protein synthesis. Several enzymes are involved in the synthesis of neu- The steroid hormones play an important role in both roactive steroids: neuroactive steroids such as allopreg- the central and peripheral nervous systems; they act dur- nanolone, THDOC, and androstanediol are produced by ing development, growth, maturation and cellular differ- 5α-reductase and 3α-hydroxysteroid oxidoreductase entiation. The progesterone receptor and the nuclear (3α-HSOR), which act by reducing the parent steroid in Carta et al. Behavioral and Brain Functions 2012, 8:61 Page 3 of 8 http://www.behavioralandbrainfunctions.com/content/8/1/61 peripheral tissues, such as liver and skin [34]. Both the determine differences in the functioning of the channel 5α-reductase and the 3α-HSOR were identified in both and differences in the response to the drugs acting on neural and glial cells [35,36] and found in neocortex and the receptor [46]. subcortical white matter and in hippocampal tissues Site-specific binding of the GABA receptor, in sub- [37,38]. In particular, a cytochrome P450 cholesterol unit beta, determines the opening of the ion channel side-chain cleavage enzyme (CYP450scc) was identified, and chloride influx. The increase in negative charge and was proven to have the ability to convert choles- leads to a hyperpolarization of the membrane, making it terol to pregnenolone, which is a precursor for the syn- less susceptible to excitation [46]. The activation of thesis of neurosteroids [39]. Another enzyme necessary GABA receptors prevents a potential short circuit in for the conversion of pregnenolone to progesterone, 3β- the depolarization induced by excitatory neurotransmit- hykdroxysteroid dehydrogenase, was found in the brain ters. The activity of these receptors is also modulated by [40]; further details on the synthesis of neuroactive ster- a number of agents including benzodiazepines, barbitu- oids in [41]. rates, some anesthetics and ethanol [47]. In the brain de novo synthesis of neurosteroids occurs The neurosteroids allopregnanolone and THDOC are in the cortex, the hippocampus and the amygdala, strong positive allosteric modulators of the GABA mainly in glutamatergic neurons [27]. Regulatory receptors [48], but at a different site than the site bound mechanisms involved in this de novo synthesis are still by the barbiturates and the benzodiazepines [48]. The unclear [42]. neuroactive steroids increase the flow of chloride ions from GABA receptors, by increasing both the fre- Non-genomic actions of neurosteroids quency and duration of the opening of the ion channel There is evidence that neurosteroids do not produce [49]. Due to the increased probability of opening of the most of their effects through an interaction with the chloride channel of the GABA receptor, neuroactive steroid hormone receptors that regulate gene transcrip- steroids increase a massive influx of the ion and potenti- tion. But, neurosteroids can regulate gene expression via ate inhibitory GABAergic transmission [49]. the progesterone receptor. But this occurs only after In vivo, the basal plasma concentration of neuroactive conversion of the neurosteroids to typical steroids. The steroids seems sufficient to significantly potentiate the induction of DNA binding and transcriptional activation function of the GABA receptor [50]. Neuroactive ster- of the progesterone receptor requires intracellular oxida- oids can also modulate recombination of various subu- tion of the neuroactive steroids into progesterone recep- nits of the GABA receptor [51]. This recombination tor active 5 alpha-pregnane steroids [43]. Most effects of can change the action of substances such as alcohol and neurosteroids occur by interaction with neuronal mem- drugs on the GABA receptor: the action of these sub- brane receptors and ion channels [44]. The post-synaptic stances on the GABA receptor depends on receptor as- GABA receptor is the most important site where neu- sembly [52]. roactive steroids act as positive or negative regulators The steroid sulfates are non-competitive antagonists [19], which is consistent with their chemical structure. of the GABA receptors, acting on different sites from those bound by allopregnanolone and THDOC Neurosteroids involvement in the regulation of [53]. The negative modulatory action of neuroactive GABAergic transmission steroids is produced through a reduction in channel The GABA receptor is the main target of action of opening, but the precise mechanism of this blocking neuroactive steroids. GABA receptors are heteropenta- is still not well understood [54]. The neuroactive ste- meric GABA-gated chloride channels: they are involved roid sulfates also modulate GABAergic transmission in fast inhibitory neurotransmission. The GABA recep- through a poorly known presynaptic mechanism tor, distributed in large quantity throughout the CNS, is [55]. Given the abundance of pregnenolone sulfate (PS) a macromolecular complex consisting of five subunits, and dehydroepiandrosterone-3-sulfate (DHEAS) in the of which many homologs have been identified (alpha1-6, brain, it seems likely that they can act as endogenous beta1-3, gamma1-3, delta, epsilon, theta, pi and rho1-3). neuromodulators [56]; this in conjunction with neuro- In each receptor, these five subunits are assembled steroids such as allopregnanolone and THDOC, which from among 19 different subunit isoforms [45]. Compos- are strong positive allosteric modulators of the GABA ition of the five subunits determines the functional receptors. and pharmacological properties of GABA receptors. Studies carried out in amphibians showed that GABA, The best-known and most widely distributed form in through its GABA receptors, is involved in the control the CNS consists of two alphas, two betas, and a third of neurosteroidogenesis, with GABA inhibiting it [56]. subunit, which together constitute the chloride ion Therefore, a short, regulatory loop linking neuroactive channel. Different assemblages of the five subunits steroids’ effects to GABA actions might exist. Carta et al. Behavioral and Brain Functions 2012, 8:61 Page 4 of 8 http://www.behavioralandbrainfunctions.com/content/8/1/61 The study of progesterone derivatives in epilepsy and attack anxiety disorder is highly comorbid with type II mood disorders bipolar disorder, and it has been suggested that the clin- The role of allopregnanolone and THDOC has been ical manifestations of the panic attack is an expression studied in a number of pathologies including epilepsy of hyperthymia, specifically the “anxious hyperthymia”; [57], premenstrual syndrome [57], anxiety [58] and mood this is a possible personality pre-morbid trait in panic disorders [59,60]. disorder [71]. Both major depression and panic disorder These steroids show a protective action in epilepsy are strongly bound to bipolar disorder, in terms of and elevate the threshold of convulsive crisis, particu- comorbidity [72], familiarity [73] and in a purported syn- larly in so-called catamenial epilepsy, in which the crises dromic continuum with major depressive disturbance worsen during the premenstrual phase. Indeed, clinical [74,75]. studies have demonstrated the potential therapeutic util- Irritable mood is another component of mood eleva- ity of synthetic analogs of allopregnanolone in the treat- tion in bipolar disorder. Anabolic/androgenic steroids ment of catamenial epilepsy [57]. The reduction in the increase sex drive and mental acuity. If abused, such concentration of progesterone derivatives in the luteinizing steroids can cause irritability and impulsive aggression phase of the menstrual cycle impacts on the clinical [76]. Social isolation in male mice and long-term treat- manifestations of premenstrual syndrome and premen- ment with anabolic steroids in female mice induces strual dysphoric disorder (PMDD) [61], and it is consist- strong aggressive behavior towards intruders. In both ent with these findings. PMDD is associated with mood sexes, a decrease of brain allopregnanolone is associated disorders [62], and during depressive episodes, the level with such induced aggressive behavior [77]. Conversely, of allopregnanolone is low [63]. Conversely, the plasma progesterone and its metabolite allopregnanolone have concentration of allopregnanolone is elevated in patients been implicated in suppressing irritability. Johannson with panic disorder [64], or following a panic attack et al. [78] conducted a study to determine whether or [65]. not a history of manic/hypomanic irritability is asso- The treatment with fluoxetine stabilizes the level of ciated with low serum progesterone levels; they further neurosteroids in depression and panic, and it has been tested whether single nucleotide polymorphisms (SNPs) hypothesized that at least part of the therapeutic effect in genes coding for steroidogenetic enzymes were of selective serotonin re-uptake inhibitors (SSRIs) could coupled to previous manic irritability and/or with serum be through their influence on neurosteroids [66,67]. Re- progesterone concentrations. They found that in males cent findings indicate that neurosteroids such as dehy- with bipolar disorders, progesterone concentrations were droepiandrosterone, pregnenolone and their sulfate lower in those who had shown manic/hypomanic irrit- esters (progesterone and allopregnanolone) affect neur- ability compared with nonirritable patients. Specific onal survival, neurite outgrowth and neurogenesis [68]. SNPs were associated with manic/hypomanic irritability. Re-establishment of neuronal plasticity (dendritic re- Thus low progesterone levels and a cystine to serine modeling and synaptic contacts) in the hippocampus change at position 145 in AKR1C4 gene were associated may be important for the pathogenesis and amelioration with manic/hypomanic irritability in males. Given that of depressive symptoms [69]. Neurosteroids might have the enzyme AKR1C4 has both dehydrogenating and re- a role in resetting neurogenesis in some areas of the ductive activities in the steroidogenetic pathway, a mis- brain, and specifically in the hippocampus during recov- sense variation in the gene may predispose to manic/ ery from depressive episodes. hypomanic irritability by altering the relationship be- tween progesterone and allopregnanolone. A role for progesterone-derived neurosteroids in More recently, the same group [79] found that in bi- bipolar disorders? polar women, SNPs in AKR1C4 reduced the likelihood In women with bipolar disorders during euthymia, of exhibiting paranoid ideation during manic episodes by plasma concentration of the progesterone derivative allo- about 60%. Hence, gene variants in the steroidogenetic pregnanolone is elevated in the premenstrual period pathway and steroids concentration differences may be compared to healthy controls and women with major involved in the susceptibility to paranoia during mood depressive disorder [70]. This finding is independent elevation. Hardoy et al. [59] attempted to verify if differ- from pharmacological therapy status and not related to ences in neurohormonal blood levels may be directly linked to some syndromal lifetime clusters (dimensions) anxiety or eating disorders. It was speculated that these neurosteroids would act as endogenous mood stabilizers. using the Structural Clinical Interview for Mood Indeed, during episodes of depression levels of allopreg- Spectrum-Self Reported (SCI-MOODS-SR) [80] ques- tionnaire of the mood spectrum independent of diagno- nanolone were reported to be low [63], while the plasma concentration is elevated in patients with panic disorder sis in females with a lifetime diagnosis of major mood [64], or after the induction of a panic attack [65]. Panic disorder (Bipolar Disorder, Major Depressive Disorder). Carta et al. Behavioral and Brain Functions 2012, 8:61 Page 5 of 8 http://www.behavioralandbrainfunctions.com/content/8/1/61 This was done by investigating the patients during the Even the two atypical antipsychotics clozapine and luteal phase of their menstrual cycle and in a condition olanzapine, effective against the manic phase of bipolar of clinical well-being. The analysis of the main compo- disorder [85,86], were proven to modify the levels of nents of the syndromal cluster evidenced the presence neurosteroids in animal studies. Clozapine markedly ele- of 3 components identified by analysis of main compo- vates pregnenolone in rat hippocampus, cerebral cortex, nents with Varimax rotation and Kaiser's normalization: and serum; hippocampal levels were strongly correlated 1) mania, 2) depression with mixed symptoms of agita- with serum levels. Olanzapine elevates pregnenolone tion 3) irritable/elated cognition and suicidal ideas. levels, too, but to a lesser extent than clozapine [87,88]. Levels of allopregnanolone and progesterone were not Olanzapine, fluoxetine or their combination increased associated with the mixed-depressive or purely manic hippocampal pregnenolone and serum deoxycorticoster- syndromes, but rather with the symptom dimension one in both higher- and lower-dose experiments, and characterized by irritable/elated cognition associated elevated hippocampal allopregnanolone in higher-doses with suicidal thoughts. These results indicated that [89]. Since olanzapine and fluoxetine combination have patients in euthymic, stabilized condition but with a his- clinical utility particularly in bipolar depression [90,91], tory of irritable/elated symptoms mixed with suicide and decrease of pregnenolone levels have been linked to ideation had, at the evaluation time, higher blood depression, it is possible that olanzapine- and fluoxetine- levels of progesterone and derivates. These results are induced pregnenolone elevations may contribute to the in apparent contradiction with the above discussed antidepressant actions of these agents in bipolar Johansson et al. [78] findings of low progesterone blood depression. levels in bipolar patients of mixed states. However, Effects of neurosteroids on mood fluctuation might ex- taking into account the possibility that the steroids tend across the bipolar disorder spectrum. Women of would act as endogenous mood stabilizers, this data can reproductive age with mental disorders may experience also be interpreted as patients with more severe mixed a fluctuating course of illness over the menstrual cycle. states need higher steroid levels to reach recovery com- Some data suggest that for a subset of women there is a pared to patients without past mixed symptoms. On the relationship between phases of the menstrual cycle and other hand, the hypothesis that steroids may be an en- increased vulnerability for an exacerbation of ongoing dogenous mood stabilizer is supported by the evidence mood disorders [22] (the so-called “catamenial mood from case reports of recovery from post partum refrac- disorder” [70]). A critical period is the one immediately tory mania [81]. Thus, progesterone and derivates may following the birth of a child, when the level of proges- be particularly relevant on mixed – aggressive compo- terone neurosteroid derivatives drop; the post-natal nent of bipolar symtomathology. period is linked to an increased vulnerability to the onset It can also be hypothesized that a dysregulated system or recurrence of mood disorders [92]. in patients with bipolar disorder would cause low levels of neuroactive steroids during depression and mixed states. Neuroactive steroids and GABAergic drugs in bipolar Thus, drugs able to correct the malfunctioning of systems disorders based on neurosteroids could improve clinical status in Recent research data from some GABAergic com- patients with bipolar disorder spectrum conditions. pounds, including gabapentin [93,94], tiagabine [95], Fluoxetine, which is effective in panic attack and topiramate [96], have produced disappointing and con- major depression, also affect the levels of neurosteroids flicting results as far as their effectiveness in bipolar dis- [66,67]. A role for neurosteroids in bipolar disorder is order is concerned. Preliminary evidence of their also consistent with the observation that a number of effectiveness in patients diagnosed with bipolar disorder anticonvulsants (including valproate, lamotrigine and was not confirmed by subsequent randomized, placebo- carbamazepine) are effective in bipolar disorder [82,83], controlled studies [97-99]. an effect that could be partially due to action on neu- Most antiepileptic compounds exert a direct or indir- rosteroids. Therefore endogenous neuroactive steroids ect GABA-mediated inhibitory action [100]. However, with anticonvulsant properties may play a role in the the impact of the neuroactive steroids on the structure pathogenesis of bipolar disorders. Lithium is another of the GABA receptor is a factor that has not been effective therapeutic agent in bipolar disorder. Precli- adequately examined in the investigation of the phar- nical evidence suggests that lithium might induce its macological action of putatively GABAergic drugs. action via an effect on neurosteroids. The levels of Indeed, patients with bipolar disorder often abuse allopregnanolone and pregnenolone were found signifi- alcohol or drugs such as benzodiazepines [101], which cantly elevated in lithium-treated mice. Pregnenolone can induce changes in the heteropentameric structure levels also tend to be higher following lithium treatment of the GABA receptor, changes that may alter the in humans [84]. subsequent action of drugs targeting the GABA A Carta et al. Behavioral and Brain Functions 2012, 8:61 Page 6 of 8 http://www.behavioralandbrainfunctions.com/content/8/1/61 receptor. In addition, benzodiazepines such as diazepam drug discovery for schizophrenia. Ann N Y Acad Sci 2011, 1236:30–43. doi:10.1111/j.1749-6632.2011.06216. or midazolam were found to promote neurosteroid syn- 2. Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria A, Moore TJ, Johnson BT: thesis [102-104]. Moreover, if neurosteroids really are Initial severity and antidepressant benefits: a meta-analysis of data involved in the etiology of bipolar disorder and their submitted to the Food And Drug Administration. PLoS Med 2008, 5(2):e45. levels fluctuate during the different phases of the dis- 3. Turner EH, Knoepflmacher D, Shapley L: Publication bias in antipsychotic order, the influence of neurosteroids on the GABA trials: an analysis of efficacy comparing the published literature to the receptors also will fluctuate. This will further modify the US Food and Drug Administration database. PLoS Med 2012, 9(3):e1001189. Epub 2012 Mar 20. responsiveness to GABAergic compounds. Effectiveness 4. Goff DC, Hill M, Freudenreich O: Treatment adherence in schizophrenia of potentially antimanic GABAergic drugs would depend and schizoaffective disorder. J Clin Psychiatry 2011, 72:e13. of the status of the GABA receptors on which they A 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 exert their action, and on levels of neurosteroids acting perspectives in the assessment of antipsychotic medication adherence. on the GABA receptors. Overall, the chance of finding Psychopathology 2009, 42(5):311–7. a therapeutic effectiveness of GABAergic compounds 6. George I: Papakostas, maurizio fava predictors, moderators, and mediators (correlates) of treatment outcome in major depressive will be a function of: a) inter-individual differences in disorderDialogues. Clin Neurosci 2008, 10(4):439–451. neurosteroids synthesis, secretion and action at the tar- 7. Carta MG, Angst J: Epidemiological and clinical aspects of bipolar get receptor; b) the conformation of the GABA recep- A disorders: controversies or a common need to redefine the aims and methodological aspects of surveys. Clin Pract Epidemol Ment Health tor as a function of alcohol and/or preceding treatment 2005, 1(1):4. with drugs acting on it; the phase of the disorder, 8. Sullivan PF: The Psychiatric GWAS Consortium: big science comes to whether depressive or excitatory. Gender differences in psychiatry. Neuron 2010, 68:182–186. 9. Nestler EJ, Hyman SE: Animal models of neuropsychiatric disorders. neurosteroids functioning also would have an impact on Nature Neurosci. 2010, 13:1161–1169. the effectiveness of GABAergic compounds in bipolar 10. Häfner H, an der Heiden W, Behrens S, et al: Causes and consequences of disorder, and should be accounted for. the gender difference in age at onset of schizophrenia. Schizophr Bull 1998, 242:6–12. 11. Häfner H: Gender differences in schizophrenia. Psychoneuroendocrinology Conclusions 2003, 28:17–54. Literature on the role of neuroactive steroids in mental 12. Leung A, Chue P: Sex differences in schizophrenia: a review of the literature. Acta Psychiatr Scand 2000. Suppl 2000, 401:3–38. disorders is sparse. Nonetheless we have made an at- 13. Cascio MT, Cella M, Preti A, Meneghelli A, Cocchi A: Gender and duration tempt to present a narrative review of existing studies of untreated psychosis: a systematic review and meta-analysis. Early on neurosteroids acting on the GABAergic receptors. Interv Psychiatry 2012, 6(2):115–27. Current evidence suggests that the investigation of neu- 14. Grossman LS, Harrow M, Rosen C, Faull R, Strauss GP: Sex differences in schizophrenia and other psychotic disorders: a 20-year longitudinal roactive steroids on mental disorders might open new study of psychosis and recovery. Compr Psychiatry 2008, 49:523–529. frontiers in the investigation of the etiology and treat- 15. Haro JM, Novick D, Bertsch J, Karagianis J, Dossenbach M, Jones PB: ment of mood disorders, particularly bipolar disorder. Cross-national clinical and functional remission rates: worldwide schizophrenia outpatient health outcomes (W-SOHO) study. Neurosteroids might be an endogenous mood stabilizer Br J Psychiatry 2011, 199:194–201. and the alteration of their functioning on a genetic or 16. Reicher-Rossler A, Hafner H, Dutsch-Strobel A, et al: Further evidence for a biochemical level might be responsible for the display of specific role of estradiol in schizophrenia? Biol Psychiatry 1994, 36:492–494. symptoms in individuals vulnerable to bipolar disorder. 17. Seeman M, Lang M: The role of estrogens in schizophrenia gender differences. Schizophr Bull 1990, 16:185–194. Competing interests 18. Thorup A, Petersen L, Jeppesen P, et al: Gender differences in young The authors’ declare that they have no competing interest. adults with first-episode schizophrenia spectrum disorders at baseline in the Danish OPUS study. J Nerv Ment Dis 2007, 195:396–405. Authors’ contributions 19. Waraich P, Goldner EM, Somers JM, Hsu L: Prevalence and incidence MGC conceived the idea of the paper and drafted the manuscript after studies of mood disorders: a systematic review of the literature. discussion with KMB and AP. KMB and AP contributed to the molecular Can J Psychiatry 2004, 49(2):124–38. (particularly KMB) and clinical (AP) aspects of the paper. All authors read and 20. Diflorio A, Jones I: Is sex important? Gender differences in bipolar approved the final manuscript. disorder. Int Rev Psychiatry 2010, 22(5):437–52. 21. Baulieu EE, Robel P: Dehydroepiandrosterone and Author details dehydroepiandrosterone sulfate as neuroactive neurosteroids. Department of Public Health, Clinical and Molecular Medicine, University of J Endocrinol 1996, 150:S221–S239. Cagliari and Center for Consultation-Liaison Psychiatry and Psychosomatics 22. Agís-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A: University Hospital of Cagliari, Cagliari, Italy. Department of Neuroscience Characterization of brain neurons that express enzymes mediating and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA. neurosteroid biosynthesis. Proc Natl Acad Sci USA 2006, 103(39):14602–7. 23. Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Received: 8 August 2012 Accepted: 30 November 2012 Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA: International Published: 19 December 2012 union of pharmacology. LXIV. Estrogen receptors. Pharmacol Rev 2006, 58(4):773–781. References 1. Marder SR, Roth B, Sullivan PF, Scolnick EM, Nestler EJ, Geyer MA, 24. Scarpin KM, Graham JD, Mote PA, Clarke CL: Progesterone action in Welnberger DR, Karayiorgou M, Guidotti A, Gingrich J, Akbarian S, Buchanan human tissues: regulation by progesterone receptor (PR) isoform RW, Lieberman JA, Conn PJ, Haggarty SJ, Law AJ, Campbell B, Krystal JH, expression, nuclear positioning and coregulator expression. Nucl Recept Moghaddam B, Saw A, Caron MG, George SR, Allen JA, Solis M: Advancing Signal 2009, 7:e009. Carta et al. Behavioral and Brain Functions 2012, 8:61 Page 7 of 8 http://www.behavioralandbrainfunctions.com/content/8/1/61 25. Prossnitz ER, Arterburn JB, Smith HO, Oprea TI, Sklar LA, Hathaway HJ: 49. Kelley SP, Alan JK, O'Buckley TK, Mennerick S, Krishnan K, Covey DF, Leslie Estrogen signaling through the transmembrane G protein-coupled Morrow A: Antagonism of neurosteroid modulation of native gamma- receptor GPR30. Annu Rev Physiol 2008, 70:165–90. aminobutyric acid receptors by (3alpha,5alpha)-17-phenylandrost-16-en- 26. Woolley CS, McEwen BS: Estradiol regulates hippocampal dendritic spine 3-ol. Eur J Pharmacol 2007, 572(2–3):94–101. density via an N-methyl-D-aspartate receptor-dependent mechanism. 50. Harney SC, Frenguelli BG, Lambert JJ: Phosphorylation influences J Neurosci 1994, 14(12):7680–7. neurosteroid modulation of synaptic GABAA receptors in rat CA1 and 27. Appelgren LE: Sites of steroid hormone formation. Autoradiographic dentate gyrus neurones. Neuropharmacology 2003, 45:873–883. studies using labelled precursors. Acta Physiol Scand Suppl 1967, 51. Lambert JJ, Belelli D, Peden DR, Vardy AW, Peters JA: Neuroactive steroid 301:1–108. modulation of GABAA receptors. Prog Neurobiol 2003, 71:67–80. 28. Seyle H: The stress of life. New York: Mac Graw Hill; 1956. 52. Boehm SL 2nd, Ponomarev I, Blednov YA, Harris RA: From gene to behavior and back again: new perspectives on GABAA receptor subunit 29. Holzbauer M: Ovarian secretion of steroids with central depressant selectivity of alcohol actions. Adv Pharmacol 2006, 54:171–2037. actions. J Physiol 1971, 215(1):16P–17P. 30. Sherwin BB: Estrogen and cognitive functioning in women. Endocr Rev 53. Park-Chung M, Malayev A, Purdy RH, Gibbs TT, Farb DH: Sulfated and 2003, 24(2):133–151. unsulfated steroids modulate γ aminobutyric acidA receptor function 31. Kompoliti K: Estrogen and movement disorders. Clin Neuropharmacol through distinct sites. Brain Res 1999, 830:72–87. 1999, 22(6):318–326. 54. Akk G, Bracamontes J, Steinbach JH: Pregnenolone sulfate block of GABAA receptors: mechanism and involvement of a residue in the M2 region of 32. Craft RM, Ulibarri C, Leitl MD, Sumner JE: Dose- and time-dependent the α subunit. J Physiol (Lond) 2001, 532:673–684. estradiol modulation of morphine antinociception in adult female rats. 55. Mtchedlishvili Z, Kapur J: A presynaptic action of the neurosteroid Eur J Pain 2008, 12(4):472–9. pregnenolone sulfate on GABAergic synaptic transmission. 33. Corpechot C, Robel P, Axelson M, Sjovall J, Baulieu EE: Characterization and Mol Pharmacol 2003, 64:857–864. measurement of dehydroepiandrosterone sulfate in rat brain. Proc Natl Acad Sci USA 1981, 78:4704–4707. 56. Twede V, Tartaglia AL, Covey DF, Bamber BA: The neurosteroids 34. Do Rego JL, Seong JY, Burel D, Leprince J, Luu-The V, Tsutsui K, Tonon MC, dehydroepiandrosterone sulfate and pregnenolone sulfate inhibit the Pelletier G, Vaudry H: Neurosteroid biosynthesis: enzymatic pathways and UNC-49 GABA receptor through a common set of residues. neuroendocrine regulation by neurotransmitters and neuropeptides. Mol Pharmacol 2007, 72(5):1322–9. Front Neuroendocrinol 2009, 30(3):259–301. 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 35. Melcangi RC, Celotti F, Castano P, Martini L: Differential localization of the neurotransmitters and neuropeptides. Front Endocrinol (Lausanne) 2012, 5 alpha-reductase and the 3 alpha-hydroxysteroid dehydrogenase in 3:4. Epub 2012 Jan 24. neuronal and glial cultures. Endocrinology 1993, 132(3):1252–9. 58. Guille C, Spencer S, Cavus I, Epperson CN: The role of sex steroids in 36. Petratos S, Hirst JJ, Mendis S, Anikijenko P, Walker DW: Localization of catamenial epilepsy and premenstrual dysphoric disorder: implications p450scc and 5α-reductase type-2 in the cerebellum of fetal and for diagnosis and treatment. Epilepsy Behav 2008, 13(1):12–24. newborn sheep. Developmental Brain Research. 2000, 123:81–86. 37. Stoffel-Wagner B: Neurosteroid metabolism in the human brain. 59. Kita A, Furukawa K: Involvement of neurosteroids in the anxiolytic-like Eur J Endocrinol 2001, 145(6):669–79. effects of AC-5216 in mice. Pharmacol Biochem Behav 2008, 89(2):171–8. 38. Stoffel-Wagner B, Watzka M, Steckelbroeck S, Ludwig M, Clusmann H, 60. Hardoy MC, Sardu C, Dell'osso L, Carta MG: The link between Bidlingmaier F, Casarosa E, Luisi S, Elger CE, Beyenburg S: Allopregnanolone neurosteroids and syndromic/syndromal components of the mood serum levels and expression of 5 alpha-reductase and 3 alpha- spectrum disorders in women during the premenstrual phase. Clin Pract hydroxysteroid dehydrogenase isoforms in hippocampal and temporal Epidemol Ment Health 2008, 4:3. cortex of patients with epilepsy. Epilepsy Res 2003, 54(1):11–9. 61. Eser D, Schüle C, Baghai TC, Romeo E, Rupprecht R: Neuroactive steroids in depression and anxiety disorders: clinical studies. Neuroendocrinology 39. Patte-Mensah C, Kappes V, Freund-Mercier MJ, Tsutsui K, Mensah-Nyagan 2006, 84(4):244–54. AG: Cellular distribution and bioactivity of the key steroidogenic enzyme, 62. Sundstrom Poromaa I, Smith S, Gulinello M: GABA receptors, progesterone cytochrome P450side chain cleavage, in sensory neural pathways. and premenstrual dysphoric disorder. Arch Women Ment Health 2003, J Neurochem 2003, 86(5):1233–46. 6(1):23–41. 40. Guennoun R, Fiddes RJ, Gouézou M, Lombès M, Baulieu EE: A key enzyme in the biosynthesis of neurosteroids, 3 beta-hydroxysteroid 63. Miller MN, Miller BE: Premenstrual exacerbations of mood disorders. dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD), is expressed in Psychopharmacol Bull 2001, 35(3):135–149. rat brain. Brain Res Mol Brain Res 1995, 30(2):287–300. 64. Pisu MG, Serra M: Neurosteroids and neuroactive drugs in mental 41. Nothdurfter C, Rammes G, Baghai TC, Schüle C, Schumacher M, disorders. Life Sci 2004, 74:3181–3197. Papadopoulos V, Rupprecht R: Translocator protein (18 kDa) as a target 65. Brambilla F, Biggio G, Pisu MG, Bellodi L, Perna GP, Bogdanovich-Djukic V, for novel anxiolytics with a favourable side-effect profile. Purdy RH, Serra M: Neurosteroid secretion in panic disorder. Psychiatry Res J Neuroendocrinol 2012, 24(1):82–92. 2003, 118:107–116. 42. Reddy DS: Neurosteroids: endogenous role in the human brain and 66. Strohle A, Romeo E, di Michele F, Pasini A, Hermann B, Gajewsky G, therapeutic potentials. Prog Brain Res 2010, 186:113–37. Holsboer F, Rupprecht R: Induced panic attacks shift γ-aminobutyric acid 43. Rupprecht R, Reul JM, Trapp T, van Steensel B, Wetzel C, Damm K, type A receptor modulatory neuroactive steroid composition in patients Zieglgänsberger W, Holsboer F: Progesterone receptor-mediated effects with panic disorder: preliminary results. Arch Gen Psychiatry 2003, of neuroactive steroids. Neuron 1993, 11(3):523–30. 60:161–168. 44. Reddy DS: Pharmacology of endogenous neuroactive steroids. Crit Rev 67. Uzunov DP, Cooper TB, Costa E, Guidotti A: Fluoxetine-elicited changes in Neurobiol 2003, 15:197–234. brain neurosteroid content measured by negative ion mass fragmentography. Proc Natl Acad Sci USA 1996, 93:12599–12604. 45. Olsen RW, Siegart W: International union of pharmacology. Subtypes of 68. Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, gamma aminobutyric acid a receptors: classification on the basis of Guidotti A: Increase in the cerebrospinal fluid content of neurosteroids in subunit composition, pharmacology and function. Pharmacol Rev 2008, patients with unipolar major depression who are receiving fluoxetine or 60:243–260. fluvoxamine. Proc Natl Acad Sci USA 1998, 95(6):3239–3244. 46. McKernan RM, Whiting PJ: Which GABAA receptor subtypes really occur in the brain? Trends Neurosci 1996, 19:139–143. 69. Charalampopoulos I, Remboutsika E, Margioris AN, Gravanis A: 47. Botta P, Radcliffe RA, Carta M, Mameli M, Daly E, Floyd KL, Deitrich RA, Neurosteroids as modulators of neurogenesis and neuronal survival. Valenzuela CF: Modulation of GABAA receptors in cerebellar granule Trends Endocrinol Metab 2008, 19(8):300–7. neurons by ethanol: a review of genetic and electrophysiological 70. Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA, Almeida OF, studies. Alcohol 2007, 41(3):187–99. Epub 2007 May 23. Sousa N: The mood-improving actions of antidepressants do not depend 48. Reddy DS: Pharmacology of endogenous neuroactive steroids. Crit Rev on neurogenesis but are associated with neuronal remodeling. Neurobiol 2003, 15(3–4):197–234. Mol Psychiatry 2009, 14(8):764–773. 739. Carta et al. Behavioral and Brain Functions 2012, 8:61 Page 8 of 8 http://www.behavioralandbrainfunctions.com/content/8/1/61 71. Hardoy MC, Serra M, Carta MG, Contu P, Pisu MG, Biggio G: Increased implications for therapeutic actions. Pharmacol Biochem Behav. 2006, neuroactive steroid concentrations in women with bipolar disorder or 84(4):609–17. major depressive disorder. J Clin Psychopharmacol 2006, 26(4):379–84. 91. Tohen M, Vieta E, Calabrese J, Ketter TA, Sachs G, Bowden C, Mitchell PB, 72. Féline A: Hyperthymic disorders. Encéphale 1993, 19(2):103–7. Centorrino F, Risser R, Baker RW, Evans AR, Beymer K, Dube S, Tollefson GD, 73. Carta MG, Tondo L, Balestrieri M, et al: Sub-threshold depression and Breier A: Efficacy of olanzapine and olanzapine-fluoxetine combination in antidepressants use in a community sample: searching anxiety and the treatment of bipolar I depression. Arch Gen Psychiatry. finding bipolar disorder. BMC Psychiatry 2011, 11:164. 2003;60(11):1079–88. Erratum in. Arch Gen Psychiatry. 2004, 61(2):176. doi:10.1186/1471-244X-11-164. 92. Brown E, Dunner DL, McElroy SL, Keck PE, Adams DH, Degenhardt E, Tohen 74. Frank E, Cyranowski JM, Rucci P, Shear MK, Fagiolini A, Thase ME, Cassano M, Houston JP: Olanzapine/fluoxetine combination vs. lamotrigine in the GB, Grochocinski VJ, Kostelnik B, Kupfer DJ: Clinical significance of lifetime 6-month treatment of bipolar I depression. Int J Neuropsychopharmacol. panic spectrum symptoms in the treatment of patients with bipolar I 2008, 11:1–10. disorder. Arch Gen Psychiatry 2002, 59(10):905–911. 93. Arnold LM: Gender differences in bipolar disorder. Psychiatr Clin North Am. 2003, 26(3):595–620. 75. Cassano GB, Rucci P, Frank E, Fagiolini A, Dell'Osso L, Shear MK, Kupfer DJ: 94. Cabras PL, Hardoy MJ, Hardoy MC, Carta MG: Clinical Experience with The mood spectrum in unipolar and bipolar disorder: arguments for a gabapentin in patients with Bipolar or Scizoaffective Disorder. unitary approach. Am J Psychiatry 2004, 161(7):1264–1269. J Clin Psychiatry 1999, 60(4):245–248. 76. Carta MG, Hardoy MC, Garofalo A, Pisano E, Nonnoi V, Intilla G, Serra G, 95. Carta MG, Hardoy MC, Hardoy MJ, Grunze H, Carpiniello B: The clinical use Balestrieri C, Chessa L, Cauli C, Lai ME, Farci P: Association of chronic of gabapentin in bipolar spectrum disorders. J Affect Disord. 2003, hepatitis C with major depressive disorders: irrespective of interferon- 75(1):83–91. alpha therapy. Clin Pract Epidemol Ment Health 2007, 23(3):22. 96. Carta MG, Hardoy MC, Grunze H, Carpiniello B: The use of tiagabine in 77. Pearson H: Hormone therapy: a dangerous elixir? Nature. 2004, affective disorders. Pharmacopsychiatry 2002, 35(1):33–4. 431:500–501. 97. Kushner SF, Khan A, Lane R, Olson WH: Topiramate monotherapy in the 78. Pinna G, Costa E, Guidotti A: Changes in brain testosterone and management of acute mania: results of four double-blind allopregnanolone biosynthesis elicit aggressive behavior. Proc Natl Acad placebo-controlled trials. Bipolar Disord. 2006, 8(1):15–27. Sci U S A 2005, 102(6):2135–40. Epub 2005 Jan 27. 98. Pande AC, Crockatt JG, Janney CA, Werth JL, Tsaroucha G: Gabapentin in 79. Johansson AG, Nikamo P, Schalling M, Landén M: AKR1C4 gene variant bipolar disorder: a placebo-controlled trial of adjunctive therapy. associated with low euthymic serum progesterone and a history of Gabapentin bipolar disorder study group. Bipolar Disord. 2000, mood irritability in males with bipolar disorder. J Affect Disord 2011, 2(3 Pt 2):249–55. 133(1–2):346–51. 99. Suppes T, Chisholm KA, Dhavale D, Frye MA, Altshuler LL, McElroy SL, Keck 80. Johansson AG, Nikamo P, Schalling M, Landén M: Polymorphisms in PE, Nolen WA, Kupka R, Denicoff KD, Leverich GS, Rush AJ, Post RM: AKR1C4 and HSD3B2 and differences in serum DHEAS and progesterone Tiagabine in treatment refractory bipolar disorder: a clinical case series. are associated with paranoid ideation during mania or hypomania in Bipolar Disord. 2002, 4(5):283–9. bipolar disorder. Eur Neuropsychopharmacol 2012, 22(9):632–640. 100. Roy Chengappa KN, Schwarzman LK, Hulihan JF, Xiang J, Rosenthal NR: 81. Fagiolini A, Dell’Osso L, Pini S, Armani A, Bouanani S, Rucci P, Cassano GB, Clinical affairs product support study-168 investigators. Adjunctive Endicott J, Maser J, Shear MK, Grochocinski VJ, Frank E: Validity and topiramate therapy in patients receiving a mood stabilizer for bipolar I reliability of a new instrument for assessing mood symptomatology: the disorder: a randomized, placebo-controlled trial. J Clin Psychiatry 2006, Structured Clinical Interview for Mood Spectrum (SCI MOODS). Int J Meth 67(11):1698–706. Psych Res 1999, 8:71–81. 101. Elger CE, Schmidt D: Modern management of epilepsy: a practical 82. Huang MC, Wang YB, Chan CH: Estrogen-progesterone combination for approach. Epilepsy Behav. 2008, 12(4):501–39. treatment-refractory post-partum mania. Psychiatry Clin Neurosci. 2008, 102. Carta MG, Kovess V, Hardoy MC, Brugha T, Fryers T, Lehtinen V, Xavier M: 62:126. Psychosocial wellbeing and psychiatric care in the European 83. Bowden CL: Anticonvulsants in bipolar disorders: current research and Communities: analysis of macro indicators. Social Psychiatry and Psychiatric practice and future directions. Bipolar Disord 2009, 11(2):20–33. Epidemiology 2004, 39(11):883–92. 84. Grunze HC: Anticonvulsants in bipolar disorder. J Ment Health 2010, 103. Rupprecht R, Papadopoulos V, Rammes G, Baghai TC, Fan J, Akula N, Groyer 19(2):127–41. G, Adams D, Schumacher M: Translocator protein(18kDa) (TSPO) as a 85. Marx CE, Yuan P, Kilts JD, Madison RD, Shampine LJ, Manji HK: Neuroactive therapeutic target for neurological and psychiatric disorders. steroids, mood stabilizers, and neuroplasticity: alterations following Nat. Rev. Drug Discov. 2010, 9:971–9. lithium and changes in Bcl-2 knockout mice. Int J Neuropsychopharmacol. 104. Tokuda K, O’ Dell KA, Izumi Y, Zorumski CF: Midazolam inhibits 2008, 11(4):547–52. hippocampal long-term potentiation and learning through dual central 86. Chang JS, Ha KS, Young Lee K, Sik Kim Y, Min Ahn Y: The effects of and peripheral benzodiazepine receptor activation and long-term clozapine add-on therapy on the rehospitalization rate and neurosteroidogenesis. J. Neurosci 2010, 30:16788–16795. the mood polarity patterns in bipolar disorders. J Clin Psychiatry 2006, 67(3):461–7. doi:10.1186/1744-9081-8-61 87. Tohen M, Sutton VK, Calabrese JR, Sachs GS, Bowden CL: Maintenance of Cite this article as: Carta et al.: GABAergic neuroactive steroids: a new response following stabilization of mixed index episodes with frontier in bipolar disorders?. Behavioral and Brain Functions 2012 8:61. olanzapine monotherapy in a randomized, double-blind, placebo- controlled study of bipolar 1 disorder. J Affect Disord 2009, 116(1-2):43–50. 88. Marx CE, Stevens RD, Shampine LJ, Uzunova V, Trost WT, Butterfield MI, Massing MW, Hamer RM, Morrow AL, Lieberman JA: Neuroactive steroids Submit your next manuscript to BioMed Central are altered in schizophrenia and bipolar disorder: relevance to and take full advantage of: pathophysiology and therapeutics. Neuropsychopharmacology. 2006, 31(6):1249–63. • Convenient online submission 89. Marx CE, Shampine LJ, Duncan GE, VanDoren MJ, Grobin AC, Massing MW, • Thorough peer review Madison RD, Bradford DW, Butterfield MI, Lieberman JA, Morrow AL: Clozapine markedly elevates pregnenolone in rat hippocampus, cerebral • No space constraints or color figure charges cortex, and serum: candidate mechanism for superior efficacy? • Immediate publication on acceptance Pharmacol Biochem Behav. 2006, 84(4):598–608. 90. Marx CE, Shampine LJ, Khisti RT, Trost WT, Bradford DW, Grobin AC, Massing • Inclusion in PubMed, CAS, Scopus and Google Scholar MW, Madison RD, Butterfield MI, Lieberman JA, Morrow AL: Olanzapine and • Research which is freely available for redistribution fluoxetine administration and coadministration increase rat hippocampal pregnenolone, allopregnanolone and peripheral deoxycorticosterone: Submit your manuscript at www.biomedcentral.com/submit
Journal
Behavioral and Brain Functions – Springer Journals
Published: Dec 19, 2012