Carta MG, Bhat KM, Preti A. GABAergic neuroactive steroids: a new frontier in bipolar disorders? Behav Brain Funct 8: 61

Behavioral and Brain Functions (Impact Factor: 1.97). 12/2012; 8(1):61. DOI: 10.1186/1744-9081-8-61
Source: PubMed


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.

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    • "From these considerations, the literature reports a relationship between biological rhythm disturbances and treatment and the onset, maintenance and remission of bipolar episodes [3]. There is also evidence about the relevance of dys-regulation of hormones and neurotransmitters that command biological rhythms in bipolar disorders [4] [5] [6] [7] [8]. Physiological and behavioral timekeeping processes are frequently found abnormal in bipolar disorders, thus a vulnerability to alterations in biological rhythms may play a certain role in the course of the disease [9]. "
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    ABSTRACT: Introduction: Abnormalities in biological rhythms (BR) may have a role in the pathophysiology of Bipolar Disorders (BD). The objective of this study is to validate the Italian version of the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN), a useful tool in studying BR, and measure its accuracy in discriminating BD. Methods: 44 outpatients with DSM-IV-TR diagnosis of BD and 38 controls balanced for sex and age were consecutively recruited. The discriminant validity of BRIAN for the screening of BD and its test re-test reliability in two evaluations were assessed. Results: BD patients scored 22.22±11.19 in BRIAN against 7.13±5.6 of the control group (P<0.0001). BRIAN showed a good accuracy to screen between BD non-BD at cutoff 16, a sensitivity was 68.2 and specificity was 92.5. The test-retest stability measured using Pearson’s coefficient found very high r values for each section and the total score, thus indicating a correlation at the two times of statistical significance in all measures. Cohen’s Kappa varied from 0.47 in the sociality section to 0.80 in the sleep section, with a total K mean of 0.65. Conclusion: The results show that the Italian version of BRIAN has good discriminant validity in detecting BD from healthy controls and shows good test-retest reliability. The study suggests the possibility of developing mixed screening tools by introducing items on dysregulation of biological rhythms to the usual measures of mood.
    Clinical Practice and Epidemiology in Mental Health 06/2014; 10:48-52. DOI:10.2174/1745017901410010048
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    • "It has been hypothesized that neurosteroids deriving from progesterone may play a role as endo-mood stabilizers [8], and high levels of 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THPROG) and 3alpha,21-dihydroxy-5alpha-pregnan-20-one have been found in women with bipolar disorder, clinically compensated for and in symptomatic remission [20]. Not much is known about how cortisol might influence the level of neuroactive steroid hormones deriving from progesterone, or rather their analogues sulfates, or testosterone, which apparently have a different effect on mood [21]. Indeed, a recent study found that in the elderly, the perception of Quality of Life was not affected by testosterone levels [22]. "
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    ABSTRACT: Introduction: Cortisol plays a central role in the stress response; while high stress can determine physical and psychological impairment, moderate stress, with a mild increase in cortisol level, may have a positive effect on coping and physical performance. This trial attempted to determine whether cortisol levels were associated with Quality of Life (QoL) in a sample of elderly subjects undertaking an exercise program. Methods: 42 subjects aged ≥65 years were randomlyassigned in a 1:1 fashion either to a vigorous physical activity (VAG: N=21) or to a postural gimnastic group (PGG: N=21). Differences between the two groups in QoL (on SF-12), and blood cortisol levels were assessed by ANOVA at different times. Results: In both the VAG and PGG, cortisol levels rose at the end of the trial, with statistically significant differences as compared to the baseline. QoL at the end of the trial was higher than in the national normative sample. Cortisol and QoL in both groups decreased slightly 12 weeks after the end of the trial (T2); however, only in the VAG did the difference from the initial level remain statistically significant. At T1 and T2, subjects with higher SF-12 scores were found in subsamples in both groups with cortisol levels moderately increased (between 200 and 300 mg/ml). Conclusion: In a sample of elderly subjects undergoing two different kinds of exercise, a better perception of Quality of Life was associated with a moderate, non-pathological increase in cortisol. The results need to be confirmed by trials on larger samples.
    Clinical Practice and Epidemiology in Mental Health 06/2014; 10(1):67-72. DOI:10.2174/1745017901410010067
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    • "Whilst synthesis and control of neurosteroids differs from peripheral steroids, the rate-limiting step in both is TSPO-mediated movement of cholesterol across the OMM. Hence, an altered cholesterol transport regulation may potentially affect the biosynthesis of neurosteroids, which have been directly implicated in the pathophysiology of BD (Carta et al., 2012). Interestingly, an association between rs6971 and alteration in peripheral pregnenolone production has been reported (Costa et al., 2009a). "
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    ABSTRACT: TSPO mediated transport of cholesterol into the mitochondrion is a necessary step in steroid synthesis. The rs6971 polymorphism in the TSPO gene causes an amino acid substitution (Ala147Thr) within the transmembrane domain where the cholesterol-binding pocket is located, and has been shown to affect the steroidogenic pathway. We report a nominal association between this TSPO polymorphism and the diagnosis of Bipolar Disorder in both the genome-wide dataset of the Wellcome Trust Case-Control Consortium and the Psychiatric Genome-Wide Association Study Consortium Bipolar Disorder group (OR=1.11, p=0.007; OR=1.10, p=0.011, respectively). We propose that the amino acid substitution affects hypothalamic-pituitary-adrenal (HPA) regulation, and hence may predispose to Bipolar Disorder. This supports the hypothesis that HPA dysregulation has a causal role in Bipolar Disorder, and is not just a consequence of the disease.
    Psychoneuroendocrinology 08/2013; 38(11). DOI:10.1016/j.psyneuen.2013.07.007 · 4.94 Impact Factor
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