The anti-epileptic drug Valproic Acid (VPA) inhibits steroidogenesis in bovine theca and granulosa cells in vitro

Valproic acid (VPA) is used widely to treat epilepsy and bipolar disorder. Women undergoing VPA treatment reportedly have an increased incidence of polycystic ovarian syndrome (PCOS)-like symptoms including hyperandrogenism and oligo- or amenorrhoea. To investigate potential direct effects of VPA on ovarian steroidogenesis we used primary bovine theca (TC) and granulosa (GC) cells maintained under conditions that preserve their 'follicular' phenotype. Effects of VPA (7.8-500 µg/ml) on TC were tested with/without LH. Effects of VPA on GC were tested with/without FSH or IGF analogue. VPA reduced (P<0.0001) both basal (70% suppression; IC(50) 67±10 µg/ml) and LH-induced (93% suppression; IC(50) 58±10 µg/ml) androstenedione secretion by TC. VPA reduced CYP17A1 mRNA abundance (>99% decrease; P<0.0001) with lesser effects on LHR, STAR, CYP11A1 and HSD3B1 mRNA (<90% decrease; P<0.05). VPA only reduced TC progesterone secretion induced by the highest (luteinizing) LH dose tested; TC number was unaffected by VPA. At higher concentrations (125-500 µg/ml) VPA inhibited basal, FSH- and IGF-stimulated estradiol secretion (P<0.0001) by GC without affecting progesterone secretion or cell number. VPA reversed FSH-induced upregulation of CYP19A1 and HSD17B1 mRNA abundance (P<0.001). The potent histone deacetylase (HDAC) inhibitors trichostatin A and scriptaid also suppressed TC androstenedione secretion and granulosal cell oestrogen secretion suggesting that the action of VPA reflects its HDAC inhibitory properties. In conclusion, these findings refute the hypothesis that VPA has a direct stimulatory action on TC androgen output. On the contrary, VPA inhibits both LH-dependent androgen production and FSH/IGF-dependent estradiol production in this in vitro bovine model, likely by inhibition of HDAC.

Cognitive emotion regulation as a mediator between posttraumatic stress symptoms and hypomanic personality within a non-clinical population

Background: There is a high prevalence of traumatic life events within individuals diagnosed with bipolar disorder. However, currently there is limited theoretical understanding of this relationship. Aims: To explore whether non-clinical symptoms of posttraumatic stress have a direct effect on the non-clinical symptoms of bipolar disorder, or whether this relationship is mediated by cognitive emotion regulation strategies. Method: A cross-sectional design within non-clinical participants completing an online survey including the Impact of Events Scale, Cognitive Emotion Regulation Questionnaire and the Hypomanic Personality Scale. Results: Posttraumatic stress symptoms were associated with hypomanic personality. Intrusive memories contributed a small but significant proportion of the variance between these two measures. Rumination of negative emotions mediated the relationship between posttraumatic stress and hypomanic personality. Conclusions: The relationship between traumatic events and an increased prevalence of bipolar disorder remains poorly understood. Further research should explore rumination as a potential target for treatment within those suffering from both posttraumatic stress and bipolar disorder.

Female-specific intergenerational transmission patterns of the human corticolimbic circuitry

Parents have large genetic and environmental influences on offspring’s cognition, behavior, and brain. These intergenerational effects are observed in mood disorders, with particularly robust association in depression between mothers and daughters. No studies have thus far examined the neural bases of these intergenerational effects in humans. Corticolimbic circuitry is known to be highly relevant in a wide range of processes including mood regulation and depression. These findings suggest that corticolimbic circuitry may also show matrilineal transmission patterns. We therefore examined human parent-offspring association in this neurocircuitry, and investigated the degree of association in gray matter volume between parent and offspring. We used voxel-wise correlation analysis in a total of 35 healthy families, consisting of parents and their biological offspring. We found positive associations of regional grey matter volume in the corticolimbic circuit including the amygdala, hippocampus, anterior cingulate cortex, and ventromedial prefrontal cortex between biological mothers and daughters. This association was significantly greater than mother-son, father-daughter, and father-son associations. The current study suggests that the corticolimbic circuitry, which has been implicated in mood regulation, shows a matrilineal specific transmission patterns. Our preliminary findings are consistent with what has been found behaviorally in depression, and may have clinical implications for disorders known to have dysfunction in mood regulation such as depression. Studies such as ours will likely bridge animal work examining gene expression in the brains and clinical symptom-based observations, and provide promising ways to investigate intergenerational transmission patterns in the human brain.

Maternal weaning modulates emotional behavior and regulates the gut-brain axis

Evidence shows that nutritional and environmental stress stimuli during postnatal period influence brain development and interactions between gut and brain. In this study we show that in rats, prevention of weaning from maternal milk results in depressive-like behavior, which is accompanied by changes in the gut bacteria and host metabolism. Depressive-like behavior was studied using the forced-swim test on postnatal day (PND) 25 in rats either weaned on PND 21, or left with their mother until PND 25 (non-weaned). Non-weaned rats showed an increased immobility time consistent with a depressive phenotype. Fluorescence in situ hybridization showed non-weaned rats to harbor significantly lowered Clostridium histolyticum bacterial groups but exhibit marked stress-induced increases. Metabonomic analysis of urine from these animals revealed significant differences in the metabolic profiles, with biochemical phenotypes indicative of depression in the non-weaned animals. In addition, non-weaned rats showed resistance to stress-induced modulation of oxytocin receptors in amygdala nuclei, which is indicative of passive stress-coping mechanism. We conclude that delaying weaning results in alterations to the gut microbiota and global metabolic profiles which may contribute to a depressive phenotype and raise the issue that mood disorders at early developmental ages may reflect interplay between mammalian host and resident bacteria.

Thyroid hormones regulate anxiety in the male mouse

Thyroid hormone levels are implicated in mood disorders in the adult human but the mechanisms remain unclear partly because, in rodent models, more attention has been paid to the consequences of perinatal hypo and hyperthyroidism. Thyroid hormones act via the thyroid hormone receptor (TR) alpha and beta isoforms, both of which are expressed in the limbic system. TR's modulate gene expression via both unliganded and liganded actions. Though the thyroid hormone receptor (TR) knockouts and a transgenic TRalpha1 knock-in mouse have provided us valuable insight into behavioral phenotypes such as anxiety and depression, it is not clear if this is because of the loss of unliganded actions or liganded actions of the receptor or due to locomotor deficits. We used a hypothyroid mouse model and supplementation with tri-iodothyronine (T3) or thyroxine (T4) to investigate the consequences of dysthyroid hormone levels on behaviors that denote anxiety. Our data from the open field and the light-dark transition tests suggest that adult onset hypothyroidism in male mice produces a mild anxiogenic effect that is possibly due to unliganded receptor actions. T3 or T4 supplementation reverses this phenotype and euthyroid animals show anxiety that is intermediate between the hypothyroid and thyroid hormone supplemented groups. In addition, T3 but not T4 supplemented animals have lower spine density in the CA1 region of the hippocampus and in the central amygdala suggesting that T3-mediated rescue of the hypothyroid state might be due to lower neuronal excitability in the limbic circuit.

6-Sulfatoxymelatonin as a predictor of clinical outcome in depressive patients

Objectives This study established the value of the 6-sulfatoxymelatonin (aMT6s) urine concentration as a predictor of the therapeutic response to noradrenaline reuptake inhibitors in depressive patients. Methods Twenty-two women aged 18-60 years were selected. Depressive symptoms were assessed by using the Hamilton Depression Scale. Urine samples were collected at 0600-1200 h, 1200-1800 h, 1800-2400 h, and 2400-0600 h intervals, 1 day before and 1 day after starting on the nortriptyline treatment. Urine aMT6s concentration was analyzed by a one-way analysis of variance/Bonferroni test. Spearman`s rank correlation coefficient was used to analyze the correlation between depressive symptoms after 2 weeks of antidepressant treatment and the increase in aMT6s urine concentration. Results Higher and lower size effect groups were compared by independent Student`s t-tests. At baseline, the 2400- to 0600-h interval differed from all other intervals presenting a significantly higher aMT6s urine concentration. A significant difference in aMT6s urine concentrations was found 1 day after treatment in all four intervals. Higher size effect group had lower levels of depressive symptoms 2 weeks after the treatment. A positive correlation between depressive symptoms and the delta of aMT6s in the 2400-0600h interval was observed. Conclusion Our results reinforce the hypothesis that aMT6s excretion is a predictor of clinical outcome in depression, especially in regard to noradrenaline reuptake inhibitors. Copyright (C) 2011 John Wiley & Sons, Ltd.

Proteomic analysis of dorsolateral prefrontal cortex indicates the involvement of cytoskeleton, oligodendrocyte, energy metabolism and new potential markers in schizophrenia

Schizophrenia is likely to be a consequence of serial alterations in a number of genes that, together with environmental factors, will lead to the establishment of the illness. The dorsolateral prefrontal cortex (Brodmann`s Area 46) is implicated in schizophrenia and executes high functions such as working memory, differentiation of conflicting thoughts, determination of right and wrong concepts, correct social behavior and personality expression. We performed a comparative proteome analysis using two-dimensional gel electrophoresis of pools from 9 schizophrenia and 7 healthy control patients` dorsolateral prefrontal cortex aiming to identify, by mass spectrometry, alterations in protein expression that could be related to the disease. In schizophrenia-derived samples, our analysis revealed 10 downregulated and 14 upregulated proteins. These included alterations previously implicated in schizophrenia, such as oligodendrocyte-related proteins (myelin basic protein and transferrin), as well as malate dehydrogenase, aconitase, ATP synthase subunits and cytoskeleton-related proteins. Also, six new putative disease markers were identified, including energy metabolism, cytoskeleton and cell signaling proteins. Our data not only reinforces the involvement of proteins previously implicated in schizophrenia, but also suggests new markers, providing further information to foster the comprehension of this important disease. (C) 2008 Elsevier Ltd. All rights reserved.

Lithium reduces Gsk3b mRNA levels: implications for Alzheimer Disease

There is evidence of increased systemic expression of active GSK3B in Alzheimer`s disease patients, which apparently is associated with the formation of senile plaques and neurofibrillary tangles. Due to its central role in the pathogenesis of AD, GSK3B is currently a promising target of the pharmaceutical industry. Whilst trials with specific GSK inhibitors in AD are under way, major attention has been focused on the neuroprotective effects of lithium. Whereas the direct and indirect inhibitory effects of lithium over GSK3 activity have been documented by several groups, its effects over Gsk3 transcription have not yet been addressed. We used quantitative PCR to evaluate the transcriptional regulation of Gsk3a and Gsk3b in lithium-treated primary cultures of rat cortical and hippocampal neurons. We found a significant and dose-dependent reduction in the expression of Gsk3b, which was specific to hippocampal cells. This same effect was further confirmed in vivo by measuring Gsk3 expression in different brain regions and in peripheral leukocytes of adult rats treated with lithium. Our studies show that LiCl can modulate Gsk3b transcription in vitro and in vivo. This observation suggest new regulatory effects of lithium over Gsk3b, contributing to the better understanding of its mechanisms of action, offering a new and complementary explanation for Gsk3b modulation and reinforcing its potential for the inhibition of key pathological pathways in Alzheimer`s disease.

Polymorphisms in genes involved in neurodevelopment may be associated with altered brain morphology in schizophrenia: Preliminary evidence

An abnormality in neurodevelopment is one of the most robust etiologic hypotheses in schizophrenia (SZ). There is also strong evidence that genetic factors may influence abnormal neurodevelopment in the disease. The present study evaluated in SZ patients, whose brain structural data had been obtained with magnetic resonance imaging (MRI), the possible association between structural brain measures, and 32 DNA polymorphisms,located in 30 genes related to neurogenesis and brain development. DNA was extracted from peripheral blood cells of 25 patients with schizophrenia, genotyping was performed using diverse procedures, and putative associations were evaluated by standard statistical methods (using the software Statistical Package for Social Sciences - SPSS) with a modified Bonferroni adjustment. For reelin (RELN), a protease that guides neurons in the developing brain and underlies neurotransmission and synaptic plasticity in adults, an association was found for a non-synonymous polymorphism (Va1997Leu) with left and right ventricular enlargement. A putative association was also found between protocadherin 12 (PCDH12), a cell adhesion molecule involved in axonal guidance and synaptic specificity, and cortical folding (asymmetry coefficient of gyrification index). Although our results are preliminary, due to the small number of individuals analyzed, such an approach could reveal new candidate genes implicated in anomalous neurodevelopment in schizophrenia. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

Kvinnors och mäns återhämtning från psykisk ohälsa

The overall aim with this thesis is to describe and analyze women’s and men’s recovery processes. More specifically, the aim is to determine what women and men with experience of mental illness describe as contributing to the personal recovery process. The point of departure for the studies was 30 in-depth interviews conducted with 15 men and 15 women. The selection of interview subjects was limited to individuals who had been treated in 24-hour psychiatric care and diagnosed as having schizophrenia, psychosis, a personality disorder, or a bipolar disorder.   Four studies have been carried.  Study 1 was a baseline article that examined what people in recovery from mental illness outline as facilitating factors to their recovery. The results that emerged from that study indicated areas for further analysis to condense the understanding of the recovery process. In study 2 the similarities and the differences in recovery described by women and men were examined. In Study 3 women’s and men’s meaning-making with reference to severe mental illness facilitate the recovery process were studied. The forth study explored how peer-support contribute to women’s and men’s recovery from mental illness.   The results emphasize recovery from mental illness as a social process in which relationships play a key role in creating new identities beside the mental illness. For a majority of the participants meeting peers facilitated the recovery process. The participants described how peer support meant an end to isolation and became an arena for identification, connection, and being important to others. Throughout these recovery processes the impact of gender has been emphasized. The results from this thesis provide new insight into gender as an important factor in understanding the recovery processes. The results from the four studies emphasize the mental patient, the psychiatric interventions and the individual recovery strategies as being influenced by gender constructions.

Graph analysis of dream reports is especially informative about psychosis

Early psychiatry investigated dreams to understand psychopathologies. Contemporary psychiatry, which neglects dreams, has been criticized for lack of objectivity. In search of quantitative insight into the structure of psychotic speech, we investigated speech graph attributes (SGA) in patients with schizophrenia, bipolar disorder type I, and non-psychotic controls as they reported waking and dream contents. Schizophrenic subjects spoke with reduced connectivity, in tight correlation with negative and cognitive symptoms measured by standard psychometric scales. Bipolar and control subjects were undistinguishable by waking reports, but in dream reports bipolar subjects showed significantly less connectivity. Dream-related SGA outperformed psychometric scores or waking-related data for group sorting. Altogether, the results indicate that online and offline processing, the two most fundamental modes of brain operation, produce nearly opposite effects on recollections: While dreaming exposes differences in the mnemonic records across individuals, waking dampens distinctions. The results also demonstrate the feasibility of the differential diagnosis of psychosis based on the analysis of dream graphs, pointing to a fast, low-cost and language-invariant tool for psychiatric diagnosis and the objective search for biomarkers. The Freudian notion that ‘‘dreams are the royal road to the unconscious’’ is clinically useful, after all.

Graph analysis of dream reports is especially informative about psychosis

Early psychiatry investigated dreams to understand psychopathologies. Contemporary psychiatry, which neglects dreams, has been criticized for lack of objectivity. In search of quantitative insight into the structure of psychotic speech, we investigated speech graph attributes (SGA) in patients with schizophrenia, bipolar disorder type I, and non-psychotic controls as they reported waking and dream contents. Schizophrenic subjects spoke with reduced connectivity, in tight correlation with negative and cognitive symptoms measured by standard psychometric scales. Bipolar and control subjects were undistinguishable by waking reports, but in dream reports bipolar subjects showed significantly less connectivity. Dream-related SGA outperformed psychometric scores or waking-related data for group sorting. Altogether, the results indicate that online and offline processing, the two most fundamental modes of brain operation, produce nearly opposite effects on recollections: While dreaming exposes differences in the mnemonic records across individuals, waking dampens distinctions. The results also demonstrate the feasibility of the differential diagnosis of psychosis based on the analysis of dream graphs, pointing to a fast, low-cost and language-invariant tool for psychiatric diagnosis and the objective search for biomarkers. The Freudian notion that ‘‘dreams are the royal road to the unconscious’’ is clinically useful, after all

Graph analysis of dream reports is especially informative about psychosis

Early psychiatry investigated dreams to understand psychopathologies. Contemporary psychiatry, which neglects dreams, has been criticized for lack of objectivity. In search of quantitative insight into the structure of psychotic speech, we investigated speech graph attributes (SGA) in patients with schizophrenia, bipolar disorder type I, and non-psychotic controls as they reported waking and dream contents. Schizophrenic subjects spoke with reduced connectivity, in tight correlation with negative and cognitive symptoms measured by standard psychometric scales. Bipolar and control subjects were undistinguishable by waking reports, but in dream reports bipolar subjects showed significantly less connectivity. Dream-related SGA outperformed psychometric scores or waking-related data for group sorting. Altogether, the results indicate that online and offline processing, the two most fundamental modes of brain operation, produce nearly opposite effects on recollections: While dreaming exposes differences in the mnemonic records across individuals, waking dampens distinctions. The results also demonstrate the feasibility of the differential diagnosis of psychosis based on the analysis of dream graphs, pointing to a fast, low-cost and language-invariant tool for psychiatric diagnosis and the objective search for biomarkers. The Freudian notion that ‘‘dreams are the royal road to the unconscious’’ is clinically useful, after all

Graph analysis of dream reports is especially informative about psychosis

Early psychiatry investigated dreams to understand psychopathologies. Contemporary psychiatry, which neglects dreams, has been criticized for lack of objectivity. In search of quantitative insight into the structure of psychotic speech, we investigated speech graph attributes (SGA) in patients with schizophrenia, bipolar disorder type I, and non-psychotic controls as they reported waking and dream contents. Schizophrenic subjects spoke with reduced connectivity, in tight correlation with negative and cognitive symptoms measured by standard psychometric scales. Bipolar and control subjects were undistinguishable by waking reports, but in dream reports bipolar subjects showed significantly less connectivity. Dream-related SGA outperformed psychometric scores or waking-related data for group sorting. Altogether, the results indicate that online and offline processing, the two most fundamental modes of brain operation, produce nearly opposite effects on recollections: While dreaming exposes differences in the mnemonic records across individuals, waking dampens distinctions. The results also demonstrate the feasibility of the differential diagnosis of psychosis based on the analysis of dream graphs, pointing to a fast, low-cost and language-invariant tool for psychiatric diagnosis and the objective search for biomarkers. The Freudian notion that ‘‘dreams are the royal road to the unconscious’’ is clinically useful, after all.