Endophenotypes in schizophrenia research is a contemporary approach to studying this heterogeneous mental illness, and several candidate neurophysiological markers (e.g. P50 sensory gating) and neuropsychological tests (e.g. Continuous Performance Test (CPT) and Wisconsin Card Sorting Test (WCST)) have been proposed. However, the clinical utility of a single marker appears to be limited. In the present study, we aimed to construct a diagnostic model incorporating P50 sensory gating with other neuropsychological tests in order to improve the clinical utility.
We recruited clinically stable outpatients meeting DSM-IV criteria of schizophrenia and age- and gender-matched healthy controls. Participants underwent P50 sensory gating experimental sessions and batteries of neuropsychological tests, including CPT, WCST and Wechsler Adult Intelligence Scale Third Edition (WAIS-III).
A total of 106 schizophrenia patients and 74 healthy controls were enrolled. Compared with healthy controls, the patient group had significantly a larger S2 amplitude, and thus poorer P50 gating ratio (gating ratio = S2/S1). In addition, schizophrenia patients had a poorer performance on neuropsychological tests. We then developed a diagnostic model by using multivariable logistic regression analysis to differentiate patients from healthy controls. The final model included the following covariates: abnormal P50 gating (defined as P50 gating ratio >0.4), three subscales derived from the WAIS-III (Arithmetic, Block Design, and Performance IQ), sensitivity index from CPT and smoking status. This model had an adequate accuracy (concordant percentage = 90.4%; c-statistic = 0.904; Hosmer-Lemeshow Goodness-of-Fit Test, p = 0.64>0.05).
To the best of our knowledge, this is the largest study to date using P50 sensory gating in subjects of Chinese ethnicity and the first to use P50 sensory gating along with other neuropsychological tests to develop a diagnostic model for schizophrenia. Further research to validate the predictive accuracy of this model by applying it on other samples is warranted.
Psychiatry has been consistently shown to be a profession characterised by ‘high-burnout’; however, no nationwide surveys on this topic have been conducted in Japan.
The objective of this study was to estimate the prevalence of burnout and to ascertain the relationship between work environment satisfaction, work-life balance satisfaction and burnout among psychiatrists working in medical schools in Japan.
We mailed anonymous questionnaires to all 80 psychiatry departments in medical schools throughout Japan. Work-life satisfaction, work-environment satisfaction and social support assessments, as well as the Maslach Burnout Inventory (MBI), were used.
Sixty psychiatric departments (75.0%) responded, and 704 psychiatrists provided answers to the assessments and MBI. Half of the respondents (n = 311, 46.0%) experienced difficulty with their work-life balance. Based on the responses to the MBI, 21.0% of the respondents had a high level of emotional exhaustion, 12.0% had a high level of depersonalisation, and 72.0% had a low level of personal accomplishment. Receiving little support, experiencing difficulty with work-life balance, and having less work-environment satisfaction were significantly associated with higher emotional exhaustion. A higher number of nights worked per month was significantly associated with higher depersonalisation.
A low level of personal accomplishment was quite prevalent among Japanese psychiatrists compared with the results of previous studies. Poor work-life balance was related to burnout, and social support was noted to mitigate the impact of burnout.
Bipolar disorder is a severe mental illness characterized by recurrent manic and depressive episodes. In bipolar disorder, family and twin studies suggest contributions from genetic and environmental factors; however, the detailed molecular pathogenesis is yet unknown. Thus, identification of biomarkers may contribute to the clinical diagnosis of bipolar disorder. Monozygotic twins discordant for bipolar disorder are relatively rare but have been reported. Here we performed a comparative proteomic analysis of whole cell lysate derived from lymphoblastoid cells of monozygotic twins discordant for bipolar disorder by using two-dimensional differential in-gel electrophoresis (2D-DIGE). We found approximately 200 protein spots to be significantly differentially expressed between the patient and the co-twin (t test, p<0.05). Some of the proteins were subsequently identified by liquid chromatography tandem mass spectrometry and included proteins involved in cell death and glycolysis. To examine whether these proteins could serve as biomarkers of bipolar disorder, we performed Western blot analysis using case–control samples. Expression of phosphoglycerate mutase 1 (PGAM1), which is involved in glycolysis, was significantly up-regulated in patients with bipolar disorder (t test, p<0.05). Although PGAM1 cannot be regarded as a qualified biomarker of bipolar disorder from this preliminary finding, it could be one of the candidates for further study to identify biomarkers of bipolar disorder.
Clinical studies demonstrate that the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine, induces rapid antidepressant effects in patients with refractive major depressive disorder and bipolar depression. This rapid onset of action makes ketamine a highly attractive drug for patients, particularly those who do not typically respond to therapy. A recent study suggested that glycogen synthase kinase (GSK)-3 may underlie the rapid antidepressant action of ketamine, although the precise mechanisms are unclear. In this study, we examined the effects of ketamine and GSK-3 inhibitor SB216763 in the unpredictable, chronic mild stress (CMS) mouse model of mice.
Adult C57/B6 male mice were divided into 2 groups, a non-stressed control group and the unpredictable CMS (35 days) group. Then, either vehicle, ketamine (10 mg/kg), or the established GSK-3 inhibitor, SB216763 (10 mg/kg), were administered into mice in the CMS group, while vehicle was administered to controls. In the open field test, there was no difference between the four groups (control+vehicle, CMS+vehicle, CMS+ketamine, CMS+SB216763). In the sucrose intake test, a 1% sucrose intake drop, seen in CMS mice, was significantly attenuated after a single dose of ketamine, but not SB216763. In the tail suspension test (TST) and forced swimming test (FST), the increased immobility time seen in CMS mice was significantly attenuated by a single dose of ketamine, but not SB216763. Interestingly, the ketamine-induced increase in the sucrose intake test persisted for 8 days after a single dose of ketamine. Furthermore, a single administration of ketamine, but not SB216763, significantly attenuated the immobility time of the TST and FST in the control (non-stressed) mice.
These findings suggest that a single administration of ketamine, but not GSK-3 inhibitor SB216763, produces a long-lasting antidepressant action in CMS model mice.
Prenatal exposure to high levels of alcohol is strongly associated with poor cognitive outcomes particularly in relation to learning and memory. It is also becoming more evident that anxiety disorders and anxiety-like behaviour can be associated with prenatal alcohol exposure. This study used a rat model to determine if prenatal exposure to a relatively small amount of alcohol would result in anxiety-like behaviour and to determine if this was associated with morphological changes in the basolateral amygdala. Pregnant Sprague Dawley rats were fed a liquid diet containing either no alcohol (Control) or 6% (vol/vol) ethanol (EtOH) throughout gestation. Male and Female offspring underwent behavioural testing at 8 months (Adult) or 15 months (Aged) of age. Rats were perfusion fixed and brains were collected at the end of behavioural testing for morphological analysis of pyramidal neuron number and dendritic morphology within the basolateral amygdala. EtOH exposed offspring displayed anxiety-like behaviour in the elevated plus maze, holeboard and emergence tests. Although sexually dimorphic behaviour was apparent, sex did not impact anxiety-like behaviour induced by prenatal alcohol exposure. This increase in anxiety – like behaviour could not be attributed to a change in pyramidal cell number within the BLA but rather was associated with an increase in dendritic spines along the apical dendrite which is indicative of an increase in synaptic connectivity and activity within these neurons. This study is the first to link increases in anxiety like behaviour to structural changes within the basolateral amygdala in a model of prenatal ethanol exposure. In addition, this study has shown that exposure to even a relatively small amount of alcohol during development leads to long term alterations in anxiety-like behaviour.
Preclinical and clinical studies suggest that supplementation with omega-3 fatty acids after trauma might reduce subsequent posttraumatic stress disorder (PTSD). To date, we have shown in an open trial that PTSD symptoms in critically injured patients can be reduced by taking omega-3 fatty acids, hypothesized to stimulate hippocampal neurogenesis. The primary aim of the present randomized controlled trial is to examine the efficacy of omega-3 fatty acid supplementation in the secondary prevention of PTSD following accidental injury, as compared with placebo. This paper describes the rationale and protocol of this trial.
The Tachikawa Project for Prevention of Posttraumatic Stress Disorder with Polyunsaturated Fatty Acid (TPOP) is a double-blinded, parallel group, randomized controlled trial to assess whether omega-3 fatty acid supplementation can prevent PTSD symptoms among accident-injured patients consecutively admitted to an intensive care unit. We plan to recruit accident-injured patients and follow them prospectively for 12 weeks. Enrolled patients will be randomized to either the omega-3 fatty acid supplement group (1,470 mg docosahexaenoic acid and 147 mg eicosapentaenoic acid daily) or placebo group. Primary outcome is score on the Clinician-Administered PTSD Scale (CAPS). We will need to randomize 140 injured patients to have 90% power to detect a 10-point difference in mean CAPS scores with omega-3 fatty acid supplementation compared with placebo. Secondary measures are diagnosis of PTSD and major depressive disorder, depressive symptoms, physiologic response in the experiment using script-driven imagery and acoustic stimulation, serum brain-derived neurotrophic factor, health-related quality of life, resilience, and aggression. Analyses will be by intent to treat. The trial was initiated on December 13 2008, with 104 subjects randomized by November 30 2012.
This study promises to be the first trial to provide a novel prevention strategy for PTSD among traumatized people.
ClinicalTrials.gov Identifier NCT00671099
Fish oil; Omega-3 fatty acid; Docosahexaenoic acid; Eicosapentaenoic acid; Posttraumatic stress disorder; Accidental injury; Prevention
Considering that epidemiological studies show that suicide rates in many countries are highest in the spring when vitamin D status is lowest, and that low vitamin D status can affect brain function, we sought to evaluate if a low level of 25-hydroxyvitamin D [25(OH)D] could be a predisposing factor for suicide.
We conducted a prospective, nested, case-control study using serum samples stored in the Department of Defense Serum Repository. Participants were previously deployed active duty US military personnel (2002–2008) who had a recent archived serum sample available for analysis. Vitamin D status was estimated by measuring 25(OH) D levels in serum samples drawn within 24 months of the suicide. Each verified suicide case (n = 495) was matched to a control (n = 495) by rank, age and sex. We calculated odds ratio of suicide associated with categorical levels (octiles) of 25(OH) D, adjusted by season of serum collection.
More than 30% of all subjects had 25(OH)D values below 20 ng/mL. Although mean serum 25(OH)D concentrations did not differ between suicide cases and controls, risk estimates indicated that subjects in the lowest octile of season-adjusted 25(OH)D (<15.5 ng/mL) had the highest risk of suicide, with subjects in the subsequent higher octiles showing approximately the same level of decreased risk (combined odds ratio compared to lowest octile = 0.49; 95% C.I.: 0.315–0.768).
Low vitamin D status is common in active duty service members. The lowest 25(OH)D levels are associated with an increased risk for suicide. Future studies could determine if additional sunlight exposure and vitamin D supplementation might reduce suicide by increasing 25(OH) D levels.
Murine and human iPSC-NS/PCs (induced pluripotent stem cell-derived neural stem/progenitor cells) promote functional recovery following transplantation into the injured spinal cord in rodents. However, for clinical applicability, it is critical to obtain proof of the concept regarding the efficacy of grafted human iPSC-NS/PCs (hiPSC-NS/PCs) for the repair of spinal cord injury (SCI) in a non-human primate model. This study used a pre-evaluated “safe” hiPSC-NS/PC clone and an adult common marmoset (Callithrix jacchus) model of contusive SCI. SCI was induced at the fifth cervical level (C5), followed by transplantation of hiPSC-NS/PCs at 9 days after injury. Behavioral analyses were performed from the time of the initial injury until 12 weeks after SCI. Grafted hiPSC-NS/PCs survived and differentiated into all three neural lineages. Furthermore, transplantation of hiPSC-NS/PCs enhanced axonal sparing/regrowth and angiogenesis, and prevented the demyelination after SCI compared with that in vehicle control animals. Notably, no tumor formation occurred for at least 12 weeks after transplantation. Quantitative RT-PCR showed that mRNA expression levels of human neurotrophic factors were significantly higher in cultured hiPSC-NS/PCs than in human dermal fibroblasts (hDFs). Finally, behavioral tests showed that hiPSC-NS/PCs promoted functional recovery after SCI in the common marmoset. Taken together, these results indicate that pre-evaluated safe hiPSC-NS/PCs are a potential source of cells for the treatment of SCI in the clinic.
The present study aimed at investigating whether neuromotor development, from birth to 14 months of age, shows seasonal, cyclic patterns in association with months of birth. Study participants were 742 infants enrolled in the Hamamatsu Birth Cohort (HBC) Study and followed-up from birth to the 14th month of age. Gross motor skills were assessed at the ages of 6, 10, and 14 months, using Mullen Scales of Early Learning. The score at each assessment was regressed onto a trigonometric function of months of birth, with an adjustment for potential confounders. Gross motor scores at the 6th and 10th months showed significant 1-year-cycle variations, peaking among March- and April-born infants, and among February-born infants, respectively. Changes in gross motor scores between the 10th and 14th months also showed a cyclic variation, peaking among July- and August-born infants. Due to this complementary effect, gross motor scores at the 14th month did not show seasonality. Neuromotor development showed cyclic seasonality during the first year of life. The effects brought about by month of birth disappeared around 1 year of age, and warmer months seemed to accelerate the neuromotor development.
Schizophrenia is a debilitating psychotic disorder that affects up to 1.5% of the population worldwide. Two recent studies in humans identified genome-wide significant associations between schizophrenia and single-nucleotide polymorphisms (SNPs) in an intron of CSMD1. The effect of deleting CSMD1 on mouse behavior is unknown. The present study utilized mice with a mutant Csmd1 allele in which the first exon had been ablated (KO mice). All Csmd1 transcripts that included the first exon were absent in the brains of KO mice, but there was persistent expression of at least one other transcript that does not include the first exon. Wild type (WT), heterozygous (HET), and KO mice were assessed using several well-established behavioral paradigms that model aspects of schizophrenia. Csmd1 KO mice did not differ from wild-type littermates for sensorimotor gating (measured as prepulse inhibition), social interaction, anhedonia (measured by sucrose preference), or sensitivity to the locomotor stimulant effects of the dopaminergic agent d-amphetamine. These data demonstrate that loss of Csmd1 transcripts that include the first exon does not alter multiple well-established behaviors that model aspects of schizophrenia. The SNP most strongly associated with schizophrenia in humans is between exons 3 and 4; therefore, ablation of exon 1 appeared to be a logical animal model. Nevertheless, future studies should consider alternative mouse models including gain-of-function mutations, and loss-of-function mutations that target alternative transcripts of Csmd1.
Pregnenolone belongs to a class of endogenous neurosteroids in the central nervous system (CNS), which has been suggested to enhance cognitive functions through GABAA receptor signaling by its metabolites. It has been shown that the level of pregnenolone is altered in certain brain areas of schizophrenic patients, and clozapine enhances pregnenolone in the CNS in rats, suggesting that pregnenolone could be used to treat certain symptoms of schizophrenia. In addition, early phase proof-of-concept clinical trials have indicated that pregnenolone is effective in reducing the negative symptoms and cognitive deficits of schizophrenia patients. Here, we evaluate the actions of pregnenolone on a mouse model for schizophrenia, the dopamine transporter knockout mouse (DAT KO). DAT KO mice mirror certain symptoms evident in patients with schizophrenia, such as the psychomotor agitation, stereotypy, deficits of prepulse inhibition and cognitive impairments. Following acute treatment, pregnenolone was found to reduce the hyperlocomotion, stereotypic bouts and pre-pulse inhibition (PPI) deficits in DAT KO mice in a dose-dependent manner. At 60 mg/kg of pregnenolone, there were no significant differences in locomotor activities and stereotypy between wild-type and DAT KO mice. Similarly, acute treatment of 60 mg/kg of pregnenolone fully rescued PPI deficits of DAT KO mice. Following chronic treatment with pregnenolone at 60 mg/kg, the cognitive deficits of DAT KO mice were rescued in the paradigms of novel object recognition test and social transmission of food preference test. Pregnenolone thus holds promise as a therapeutic candidate in schizophrenia.
Recently, multiple neurotrophic/growth factors have been proposed to play an important role in the therapeutic action of antidepressants. In this study, we prepared astrocyte- and neuron-enriched cultures from the neonatal rat cortex, and examined the changes in neurotrophic/growth factor expression by antidepressant treatment using real-time PCR. Treatment with amitriptyline (a tricyclic antidepressant) significantly increased the expression of fibroblast growth factor-2 (FGF-2), brain-derived neurotrophic factor, vascular endothelial growth factor and glial cell line-derived neurotrophic factor mRNA with a different time course in astrocyte cultures, but not in neuron-enriched cultures. Only the expression of FGF-2 was higher in astrocyte cultures than in neuron-enriched cultures. We focused on the FGF-2 production in astrocytes. Several different classes of antidepressants, but not non-antidepressants, also induced FGF-2 mRNA expression. Noradrenaline (NA) is known to induce FGF-2 expression in astrocyte cultures, as with antidepressants. Therefore, we also assessed the mechanism of NA-induced FGF-2 expression, in comparison to amitriptyline. NA increased the FGF-2 mRNA expression via α1 and β-adrenergic receptors; however, the amitriptyline-induced FGF-2 mRNA expression was not mediated via these adrenergic receptors. Furthermore, the amitriptyline-induced FGF-2 mRNA expression was completely blocked by cycloheximide (an inhibitor of protein synthesis), while the NA-induced FGF-2 mRNA was not. These data suggest that the regulation of FGF-2 mRNA expression by amitriptyline was distinct from that by NA. Taken together, antidepressant-stimulated astrocytes may therefore be important mediators that produce several neurotrophic/growth factors, especially FGF-2, through a monoamine-independent and a de novo protein synthesis-dependent mechanism.
The common marmoset (Callithrix jacchus) is a small New World primate that has been used as a non-human primate model for various biomedical studies. We previously demonstrated that transplantation of neural stem/progenitor cells (NS/PCs) derived from mouse and human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) promote functional locomotor recovery of mouse spinal cord injury models. However, for the clinical application of such a therapeutic approach, we need to evaluate the efficacy and safety of pluripotent stem cell-derived NS/PCs not only by xenotransplantation, but also allotransplantation using non-human primate models to assess immunological rejection and tumorigenicity. In the present study, we established a culture method to efficiently derive NS/PCs as neurospheres from common marmoset ESCs. Marmoset ESC-derived neurospheres could be passaged repeatedly and showed sequential generation of neurons and astrocytes, similar to that of mouse ESC-derived NS/PCs, and gave rise to functional neurons as indicated by calcium imaging. Although marmoset ESC-derived NS/PCs could not differentiate into oligodendrocytes under default culture conditions, these cells could abundantly generate oligodendrocytes by incorporating additional signals that recapitulate in vivo neural development. Moreover, principal component analysis of microarray data demonstrated that marmoset ESC-derived NS/PCs acquired similar gene expression profiles to those of fetal brain-derived NS/PCs by repeated passaging. Therefore, marmoset ESC-derived NS/PCs may be useful not only for accurate evaluation by allotransplantation of NS/PCs into non-human primate models, but are also applicable to analysis of iPSCs established from transgenic disease model marmosets.
Earlier findings show seasonality in processes and behaviors such as brain plasticity and depression that in part are regulated by Brain-Derived Neurotrophic Factor (BDNF). Based on this we investigated seasonal variation in serum BDNF concentrations in 2,851 persons who took part in the Netherlands Study of Depression and Anxiety (NESDA). Analyses by month of sampling (monthly n’s >196) showed pronounced seasonal variation in serum BDNF concentrations (P<.0001) with increasing concentrations in the spring-summer period (standardized regression weight (ß) = 0.19, P<.0001) and decreasing concentrations in the autumn-winter period (ß = −0.17, P<.0001). Effect sizes [Cohen’s d] ranged from 0.27 to 0.66 for monthly significant differences. We found similar seasonal variation for both sexes and for persons with a DSM-IV depression diagnosis and healthy control subjects. In explorative analyses we found that the number of sunshine hours (a major trigger to entrain seasonality) in the week of blood withdrawal and the 10 weeks prior to this event positively correlated with serum BDNF concentrations (Pearson’s correlation coefficients ranged: 0.05 – 0.18) and this could partly explain the observed monthly variation. These results provide strong evidence that serum BDNF concentrations systematically vary over the year. This finding is important for our understanding of those factors that regulate BDNF expression and may provide novel avenues to understand seasonal dependent changes in behavior and illness such as depression. Finally, the findings reported here should be taken into account when designing and interpreting studies on BDNF.
We have recently shown that a molecular biomarker signature comprised of inflammatory, hormonal and growth factors occurs in the blood serum from first onset schizophrenia patients. Here, we use the same platform to investigate post mortem brain tissue (Brodmann area 10) from schizophrenia patients who were mainly chronically ill and drug treated. Twenty-one analytes are differentially expressed in post-mortem brain tissue. Comparison with our previous mRNA profiling studies of the same patient samples in another frontal cortical area showed that 9 of these molecules were also altered at the transcriptional level. Furthermore, 9 of the molecules were also altered in serum from living first onset schizophrenia patients compared to controls. We propose a model in which the brain and periphery are coordinated through hormones and other regulatory molecules released into the blood via the diffuse neuroendocrine system. These findings provide further evidence for the systemic nature of schizophrenia and give added validity to the concept that schizophrenia can be investigated through studies of blood-based biomarkers.
Findings on song perception and song production have increasingly suggested that common but partially distinct neural networks exist for processing lyrics and melody. However, the neural substrates of song recognition remain to be investigated. The purpose of this study was to examine the neural substrates involved in the accessing “song lexicon” as corresponding to a representational system that might provide links between the musical and phonological lexicons using positron emission tomography (PET). We exposed participants to auditory stimuli consisting of familiar and unfamiliar songs presented in three ways: sung lyrics (song), sung lyrics on a single pitch (lyrics), and the sung syllable ‘la’ on original pitches (melody). The auditory stimuli were designed to have equivalent familiarity to participants, and they were recorded at exactly the same tempo. Eleven right-handed nonmusicians participated in four conditions: three familiarity decision tasks using song, lyrics, and melody and a sound type decision task (control) that was designed to engage perceptual and prelexical processing but not lexical processing. The contrasts (familiarity decision tasks versus control) showed no common areas of activation between lyrics and melody. This result indicates that essentially separate neural networks exist in semantic memory for the verbal and melodic processing of familiar songs. Verbal lexical processing recruited the left fusiform gyrus and the left inferior occipital gyrus, whereas melodic lexical processing engaged the right middle temporal sulcus and the bilateral temporo-occipital cortices. Moreover, we found that song specifically activated the left posterior inferior temporal cortex, which may serve as an interface between verbal and musical representations in order to facilitate song recognition.
Dopamine D2 receptor partial agonist antipsychotic drugs can modulate dopaminergic neurotransmission as functional agonists or functional antagonists. The effects of antipsychotics on presynaptic dopaminergic functions, such as dopamine synthesis capacity, might also be related to their therapeutic efficacy. Positron emission tomography (PET) was used to examine the effects of the partial agonist antipsychotic drug aripiprazole on presynaptic dopamine synthesis in relation to dopamine D2 receptor occupancy and the resulting changes in dopamine synthesis capacity in healthy men. On separate days, PET studies with [11C]raclopride and L-[β-11C]DOPA were performed under resting condition and with single doses of aripiprazole given orally. Occupancy of dopamine D2 receptors corresponded to the doses of aripiprazole, but the changes in dopamine synthesis capacity were not significant, nor was the relation between dopamine D2 receptor occupancy and these changes. A significant negative correlation was observed between baseline dopamine synthesis capacity and changes in dopamine synthesis capacity by aripiprazole, indicating that this antipsychotic appears to stabilize dopamine synthesis capacity. The therapeutic effects of aripiprazole in schizophrenia might be related to such stabilizing effects on dopaminergic neurotransmission responsivity.
Npas4 is a transcription factor, which is highly expressed in the brain and regulates the formation and maintenance of inhibitory synapses in response to excitatory synaptic activity. A deregulation of the inhibitory-excitatory balance has been associated with a variety of human developmental disorders such as schizophrenia and autism. However, not much is known about the role played by inhibitory synapses and inhibitory pathways in the development of nervous system disorders. We hypothesized that alterations in the inhibitory pathways induced by the absence of Npas4 play a major role in the expression of the symptoms observed in psychiatric disorders. To test this hypothesis we tested mice lacking the transcription factor (Npas4 knock-out mice (Npas4-KO)) in a battery of behavioral assays focusing on general activity, social behaviors, and cognitive functions. Npas4-KO mice are hyperactive in a novel environment, spend less time exploring an unfamiliar ovariectomized female, spend more time avoiding an unfamiliar male during a first encounter, show higher social dominance than their WT littermates, and display pre-pulse inhibition, working memory, long-term memory, and cognitive flexibility deficits. These behavioral deficits may replicate schizophrenia-related symptomatology such as social anxiety, hyperactivity, and cognitive and sensorimotor gating deficits. Immunohistochemistry analyses revealed that Npas4 expression is induced in the hippocampus after a social encounter and that Npas4 regulates the expression of c-Fos in the CA1 and CA3 regions of the hippocampus after a cognitive task. Our results suggest that Npas4 may play a major role in the regulation of cognitive and social functions in the brain with possible implications for developmental disorders such as schizophrenia and autism.
Chromatin remodeling through histone modifications has emerged as a key mechanism in the pathophysiology of psychiatric disorders. Valproate (VPA), a first-line medication for bipolar disorder, is known to have histone deacetylase (HDAC) inhibitor activity, but the relationship between its efficacy as a mood stabilizer and HDAC inhibitory activity is unclear. Here we provide evidence that prostate apoptosis response-4 (Par-4), an intracellular binding partner of dopamine D2 receptors (DRD2), plays a role in mediating the effectiveness of VPA. We found that chronic VPA treatment enhanced the expression of Par-4 in cultured neurons and adult mouse brains. This Par-4 induction phenomenon occurred at the transcriptional level and was correlated with an increase in histone H3 and H4 acetylation of the Par-4 promoter regions. Furthermore, chronic VPA treatment potentiated the suppression of the cAMP signaling cascade upon dopamine stimulation, which was blocked by sulpiride treatment. These results indicate that VPA potentiates DRD2 activity by enhancing Par-4 expression via a chromatin remodeling mechanism.
Cognitive impairment is an established phenomenon in HIV infected individuals and patients that have psychosis. However there is need to establish the severity of the impairment if patients are co morbid with both conditions.
To compare cognitive function among HIV positive individuals and HIV negative individuals with psychosis.
We recruited patients with psychosis at two national referral hospitals. A standardized demographics questionnaire and psychiatric, physical, and laboratory assessments were conducted. Types of psychosis were diagnosed using the Mini International Neuropsychiatric Inventory-PLUS while cognitive functioning was determined using the Mini mental state examination (MMSE) and a neuropsychological test battery. Follow-up assessments on cognitive function and severity of psychiatric illness were performed at 3 and 6 months. Pairwise comparison and multivariable logistic regression analysis were used to determine the differences between the HIV positive and HIV negative individuals.
There were 156 HIV positive and 322 HIV negative participants. The mean age was 33 years for the HIV positive group and 29 years for the HIV negative group (p<0.001). The HIV positive individuals were almost three times (OR = 2.62 CI 95% 1.69–4.06) more likely to be cognitively impaired on the MMSE as well as the following cognitive tests:- WHO-UCLA Auditory Verbal Learning Test (OR 1.79, 95% CI 1.09–2.92), Verbal Fluency (OR 3.42, 95% CI 2.24–5.24), Color Trails 1 (OR 2.03, 95% CI 1.29–3.02) and Color Trails 2 (OR 3.50 95% 2.00–6.10) all p = 0.01. There was improvement in cognitive function at follow up; however the impairment remained higher for the HIV positive group (p<0.001).
Cognitive impairment in psychosis was worsened by HIV infection. Care plans to minimize the effect of this impairment should be structured for the management of individuals with HIV and psychosis.
There is an urgent need for novel treatment strategies for stressor related disorders, particularly depression and anxiety disorders. Indeed, existing drug treatments are only clinically successful in a subset of patients and relapse is common. This likely stems from the fact that stressor disorders are heterogeneous with multiple biological pathways being affected. To this end, the present investigation sought to assess in mice the contribution of the c-Jun N terminal kinase (JNK) pathway to the behavioral, hormonal and neurochemical effects of an acute stressor. Indeed, although JNK has been shown to modulate glucocorticoid receptors in vitro, virtually nothing is known of the role for JNK in affecting stressor induced pathology. We presently found that the JNK antagonist, SP600125, (but not the p38 antagonist, SB203580) increased plasma corticosterone levels under resting conditions and in the context of an acute stressor (wet bedding + restraint). SP600125 also reduced exploration in an open field arena, but prevented the stressor induced increase in open arm exploration in an elevated plus maze. Finally, SP600125 affected noradrenergic activity in the central amygdala and locus coruleus under resting condition, but prevented the noradrenergic effects within the paraventricular nucleus of the hypothalamus that were induced by the acute stressor exposure. These data suggest inhibiting endogenous JNK can have stressor-like corticoid, behavioral and central monoamine effects under basal conditions, but can actually reverse some behavioral and neurochemical effects of an acute stressor. Thus, endogenous JNK appears to affect stress relevant processes in a context-dependent manner.
Oxytocin (OT) plays a key regulatory role in human social behaviour. While prior studies have examined the effects of OT on observable social behaviours, studies have seldom examined the effects of OT on psychophysiological markers such as heart rate variability (HRV), which provides an index of individual’s motivation for social behaviour. Furthermore, no studies have examined the impact of OT on HRV under resting conditions, which provides an index of maximal capacity for social engagement.
To examine the effects of OT on HRV measures in healthy male participants while at rest. OT was hypothesised to increase HRV, compared to placebo, and that the effects would be greatest for a non-linear measure of HRV (the detrended fluctuation scaling exponent).
Twenty-one male participants were recruited for this study. Participants were non-smokers, not on any medications and reported no history of psychiatric illness, neurological disorder, or any other serious medical condition (e.g. diabetes, cardiovascular disease). The study employed a randomised, placebo-controlled, within-subject, crossover, experimental design.
Main Outcome Measures
HRV was calculated from electrocardiography under a standardized, 10-minute, resting state condition.
As hypothesised, OT increased HRV and these effects were largest using the detrended fluctuation scaling exponent, a non-linear measure. These changes were observed in the absence of any change in state mood, as measured by the profile of mood states. Importantly, participants were unable to correctly guess which treatment they had been assigned at either of the two assessments.
Together with the broader literature on OT and HRV, findings suggest that acute administration of OT may facilitate a fundamental psychophysiological feature of social behaviour, increasing capacity for social engagement. Findings also suggest that HRV changes may provide a novel biomarker of response to OT nasal spray that can be incorporated into research on response to treatment.
The antioxidant defense system, which is known to be dysregulated in schizophrenia, is closely linked to the dynamics of purine pathway. Thus, alterations in the homeostatic balance in the purine pathway may be involved in the pathophysiology of schizophrenia.
Breakdown products in purine pathway were measured using high-pressure liquid chromatography coupled with a coulometric multi-electrode array system for 25 first-episode neuroleptic-naïve patients with schizophrenia at baseline and at 4-weeks following initiation of treatment with antipsychotic medication. Associations between these metabolites and clinical and neurological symptoms were examined at both time points. The ratio of uric acid and guanine measured at baseline predicted clinical improvement following four weeks of treatment with antipsychotic medication. Baseline levels of purine metabolites also predicted clinical and neurological symtpoms recorded at baseline; level of guanosine was associated with degree of clinical thought disturbance, and the ratio of xanthosine to guanosine at baseline predicted degree of impairment in the repetition and sequencing of actions.
Findings suggest an association between optimal levels of purine byproducts and dynamics in clinical symptoms and adjustment, as well as in the integrity of sensory and motor processing. Taken together, alterations in purine catabolism may have clinical relevance in schizophrenia pathology.
DYT1 is caused by a partly penetrant dominant mutation in TOR1A that leads to a glutamic acid deletion (ΔE) in torsinA. Identifying environmental factors that modulate disease pathogenesis and penetrance could help design therapeutic strategies for dystonia. Several cell-based studies suggest that expression of torsinA(ΔE) increases the susceptibility of neuronal cells to challenges to their oxidative/energy metabolism. Based on those reports, we hypothesized that mice expressing torsinA(ΔE) would be more susceptible than control littermates to the effects of oxidative stress and ATP deficits caused by disruption of the mitochondrial respiratory chain in neurons. To test this hypothesis, we administered 20 or 50 mg/kg/day of the irreversible complex-II inhibitor 3-nitropropionic acid (3-NP) intraperitoneally for 15 consecutive days to young heterozygote DYT1 knock-in (KI) mice and wild type littermates. Repeated phenotypic assessments were performed at baseline, during and after the injections. Animals were then sacrificed and their brains processed for protein analysis. The administration of 20 mg/kg 3-NP led to increased levels of torsinA in the striatum, the main target of 3-NP, but did not cause motor dysfunction in DYT1 KI or control mice. The administration of 50 mg/kg/day of 3-NP caused the death of ∼40% of wild type animals. Interestingly, DYT1 KI animals showed significantly reduced mortality. Surviving animals exhibited abnormal motor behavior during and right after the injection period, but recovered by 4 weeks postinjection independent of genotype. In contrast to the findings reported in cultured cells, these studies suggest the DYT1 mutation does not sensitize central neurons against the toxic effects of oxidative stress and energy deficits.
Meta-analyses have identified serum levels of brain-derived neurotrophic factor (BDNF) as a potential biomarker for major depressive disorder (MDD). However, at the time, commercially available human ELISA kits are unable to distinguish between proBDNF (precursor of BDNF) and mature BDNF because of limited BDNF antibody specificity. In this study, we examined whether serum levels of proBDNF, mature BDNF, and matrix metalloproteinase-9 (MMP-9), which converts proBDNF to mature BDNF, are altered in patients with MDD.
Sixty-nine patients with MDD and 78 age- and gender-matched healthy subjects were enrolled. Patients were evaluated using 17 items on the Structured Interview Guide for the Hamilton Depression Rating Scale. Cognitive impairment was evaluated using the CogState battery. Serum levels of proBDNF, mature BDNF, and MMP-9 were measured using ELISA kits. Serum levels of mature BDNF in patients with MDD were significantly lower than those of normal controls. In contrast, there was no difference in the serum levels of proBDNF and MMP-9 between patients and normal controls. While neither proBDNF nor mature BDNF serum levels was associated with clinical variables, there were significant correlations between MMP-9 serum levels and the severity of depression, quality of life scores, and social function scores in patients.
These findings suggest that mature BDNF may serve as a biomarker for MDD, and that MMP-9 may play a role in the pathophysiology of MDD. Further studies using larger sample sizes will be needed to investigate these results.