Sleep plays a pivotal role in normal biological functions. Sleep loss results in higher stress vulnerability and is often found in mental disorders. There is evidence that brain-derived neurotrophic factor (BDNF) could be a central player in this relationship. Recently, we could demonstrate that subjects suffering from current symptoms of insomnia exhibited significantly decreased serum BDNF levels compared with sleep-healthy controls. In accordance with the paradigm indicating a link between sleep and BDNF, we aimed to investigate if the stress system influences the association between sleep and BDNF.
Participants with current symptoms of insomnia plus a former diagnosis of Restless Legs Syndrome (RLS) and/or Periodic Limb Movement (PLM) and sleep healthy controls were included in the study. They completed questionnaires on sleep (ISI, Insomnia Severity Index) and stress (PSS, Perceived Stress Scale) and provided a blood sample for determination of serum BDNF. We found a significant interaction between stress and insomnia with an impact on serum BDNF levels. Moreover, insomnia severity groups and score on the PSS each revealed a significant main effect on serum BDNF levels. Insomnia severity was associated with increased stress experience affecting serum BDNF levels. Of note, the association between stress and BDNF was only observed in subjects without insomnia. Using a mediation model, sleep was revealed as a mediator of the association between stress experience and serum BDNF levels.
This is the first study to show that the interplay between stress and sleep impacts BDNF levels, suggesting an important role of this relationship in the pathogenesis of stress-associated mental disorders. Hence, we suggest sleep as a key mediator at the connection between stress and BDNF. Whether sleep is maintained or disturbed might explain why some individuals are able to handle a certain stress load while others develop a mental disorder.
A series of 1-hydroxy-1H-benzo[d]imidazol-2(3H)-ones were synthesized and evaluated for their ability to inhibit human and porcine forms of D-amino acid oxidase (DAAO). Inhibitory potency is largely dependent on the size and position of substituents on the benzene ring with IC50 values of the compounds ranging from 70 nM to greater than 100 µM. Structure-activity relationships of this new class of DAAO inhibitors will be presented in detail along with comparisons to previously published SAR data from other classes of DAAO inhibitors. Some of these compounds were given to mice orally together with D-serine to assess their effects on plasma D-serine pharmacokinetics.
D-amino acid oxidase (DAAO); D-serine; NMDA receptors; Glucuronidation
Second generation antipsychotics (SGAs) are currently the most prescribed drugs in the treatment of schizophrenia. Despite their advantages, which include greater improvement in negative symptoms, cognitive function, prevention of deterioration, quality of life, and fewer extrapyramidal symptoms, the concern regarding metabolic abnormalities which might cause cardiovascular diseases during treatment with SGAs have been rising. Paraoxonase 1 (PON1) is an enzyme mostly located on high-density lipoprotein particles, and has been shown to protect or inhibit lipoprotein oxidation. Growing evidence suggests that PON1 plays a key role in the pathophysiology of atherosclerosis.
In the present study, we measured serum PON1 activity and serum levels of total cholesterol (TC), triglyceride, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in patients with schizophrenia, who had been treated with either olanzapine or quetiapine, and in healthy controls. Thirty five patients who had been treated with olanzapine, 29 patients who had been treated with quetiapine, and 32 age, sex, and smoking status-matched healthy control (HC) participants were enrolled. Serum PON1 activity and serum levels of TC, triglyceride, HDL-C, and LDL-C were measured.
Serum PON1 activity in the olanzapine group was significantly lower than that of HC and quetiapine groups. Furthermore, serum levels of TC and LDL-C in the olanzapine group were significantly higher than those of quetiapine and HC groups. Interestingly, there was a positive correlation between PON1 activity and HDL-C levels in the olanzapine group.
These findings suggest that serum PON1 activity in patients treated with olanzapine was lower than that of HC and quetiapine groups, and that PON1 may play a role in the metabolic side effects associated with olanzapine treatment. A further study to examine the relationship between serum PON1 activity and cardiovascular and metabolic side effects during treatment with SGAs will be of great interest.
second generation antipsychotics; SGA; atherosclerosis; metabolic; dyslipidemia; LDL-C
In a recent positron emission tomography (PET) study, we demonstrated the ability to measure amphetamine-induced dopamine (DA) release in the human cortex with the relatively high affinity dopamine D2/3 radioligand [11C]FLB 457. Herein we report on reproducibility and reliability of [11C]FLB 457 binding potential relative to non-displaceable uptake (BPND) following an acute amphetamine challenge. Ten healthy human subjects were studied twice with [11C]FLB 457 following an acute amphetamine (oral, 0.5 mg kg-1 dose) challenge on two-separate days approximately one week apart. D2/3 receptor binding parameters were estimated using a two-tissue compartment kinetic analysis in the cortical regions of interest and cerebellum (reference region). The test-retest variability and intraclass correlation coefficient were assessed for distribution volume (VT), binding potential relative to plasma concentration (BPP), and BPND of [11C]FLB 457. The test-retest variability of [11C]FLB 457 VT, BPP and BPND were ≤ 17%, 22% and 11% respectively. These results, which are consistent with the published test-retest variability for this ligand measured under baseline conditions demonstrate that the post-amphetamine [11C]FLB 457 BPND is reproducible. These data further support the use [11C]FLB 457 and amphetamine to characterize cortical dopamine transmission in neuropsychiatric disorders.
Biases in attention processes are thought to play a crucial role in the aetiology and maintenance of Social Anxiety Disorder (SAD). The goal of the present study was to examine the efficacy of a programme intended to train attention towards positive cues and a programme intended to train attention towards negative cues. In a randomised, controlled, double-blind design, the impact of these two training conditions on both selective attention and social anxiety were compared to that of a control training condition. A modified dot probe task was used, and delivered via the internet. A total of 129 individuals, diagnosed with SAD, were randomly assigned to one of these three conditions and took part in a 14-day programme with daily training/control sessions. Participants in all three groups did not on average display an attentional bias prior to the training. Critically, results on change in attention bias implied that significantly differential change in selective attention to threat was not detected in the three conditions. However, symptoms of social anxiety reduced significantly from pre- to follow-up-assessment in all three conditions (dwithin = 0.63–1.24), with the procedure intended to train attention towards threat cues producing, relative to the control condition, a significantly greater reduction of social fears. There were no significant differences in social anxiety outcome between the training condition intended to induce attentional bias towards positive cues and the control condition. To our knowledge, this is the first RCT where a condition intended to induce attention bias to negative cues yielded greater emotional benefits than a control condition. Intriguingly, changes in symptoms are unlikely to be by the mechanism of change in attention processes since there was no change detected in bias per se. Implications of this finding for future research on attention bias modification in social anxiety are discussed.
Clinical diagnosis and severity of autism spectrum disorders (ASD) are determined by trained clinicians based on clinical evaluations of observed behaviors. As such, this approach is inevitably dependent on the expertise and subjective assessment of those administering the clinical evaluations. There is a need to identify objective biological markers associated with diagnosis or clinical severity of the disorder. To identify novel candidate metabolites as potential biomarkers for ASD, the current study applied capillary electrophoresis time-of-flight mass spectroscopy (CE-TOFMS) for high-throughput profiling of metabolite levels in the plasma of 25 psychotropic-naïve adult males with high-functioning ASD and 28 age-matched typically-developed control subjects. Ten ASD participants and ten age-matched controls were assigned in the first exploration set, while 15 ASD participants and 18 controls were included in the second replication set. By CE-TOFMS analysis, a total of 143 metabolites were detected in the plasma of the first set. Of these, 17 metabolites showed significantly different relative areas between the ASD participants and the controls (p<0.05). Of the 17 metabolites, we consistently found that the ASD participants had significantly high plasma levels of arginine (p = 0.024) and taurine (p = 0.018), and significantly low levels of 5-oxoproline (p<0.001) and lactic acid (p = 0.031) compared with the controls in the second sample set. Further confirmatory analysis using quantification of absolute metabolite concentrations supported the robustness of high arginine (p = 0.001) and low lactic acid (p = 0.003) in the combined sample (n = 53). The present study identified deviated plasma metabolite levels associated with oxidative stress and mitochondrial dysfunction in individuals with ASD.
With ageing populations, it becomes increasingly important to understand the determinants of cognitive ability among the elderly. We apply survey data of 17,070 respondents from ten countries to examine several domains of cognitive functioning at ages 60+, and we link them to the macro-economic deviations in the year of birth. We find that economic conditions at birth significantly influence cognitive functioning late in life in various domains. Recessions negatively influence numeracy, verbal fluency, recall abilities, as well as the score on the omnibus cognitive indicator. The results are robust; controlling for current characteristics does not change effect sizes and significance. We discuss possible causal social and biological pathways.
Recently, we reported that low reward dependence, and to a lesser extent, low cooperativeness in the Temperature and Character Inventory (TCI) may be risk factors for treatment-resistant depression. Here, we analyzed additional psychological traits in these patients.
We administered Costa and McCrae's five-factor model personality inventory, NEO Personality Inventory-Revised (NEO-PI-R), to antidepressant-treatment resistant depressed patients (n = 35), remitted depressed patients (n = 27), and healthy controls (n = 66). We also evaluated the relationships between scores on NEO and TCI, using the same cohort of patients with treatment-resistant depression, as our previous study.
Patients with treatment-resistant depression showed high scores for neuroticism, low scores for extraversion, openness and conscientiousness, without changes in agreeableness, on the NEO. However, patients in remitted depression showed no significant scores on NEO. Patients with treatment-resistant depression and low openness on NEO showed positive relationships with reward dependence and cooperativeness on the TCI.
Many studies have reported that depressed patients show high neuroticism, low extraversion and low conscientiousness on the NEO. Our study highlights low openness on the NEO, as a risk mediator in treatment-resistant depression. This newly identified trait should be included as a risk factor in treatment-resistant depression.
Cognitive impairment in patients with schizophrenia is a core symptom of this disease. The computerized CogState Battery (CSB) has been used to detect seven of the most common cognitive domains in schizophrenia. The aim of this study was to examine the reliability and validity of the Chinese version of the CSB (CSB-C), in Chinese patients with schizophrenia.
Sixty Chinese patients with schizophrenia and 58 age, sex, and education matched healthy controls were enrolled. All subjects completed the CSB-C and the Repeated Battery for the Assessment of Neuropsychological Status (RBANS). To examine the test-retest reliability of CSB-C, we tested 33 healthy controls twice, at a one month interval. The Cronbach α value of CSB-C in patients was 0.81. The test-retest correlation coefficients of the Two Back Task, Gronton Maze Learning Task, Social Emotional Cognition Task, and Continuous Paired Association Learning Task were between 0.39 and 0.62 (p<0.01) in healthy controls. The composite scores and all subscores for the CSB-C in patients were significantly (p<0.01) lower than those of healthy controls. Furthermore, composite scores for patients on the RBANS were also significantly lower than those of healthy controls. Interestingly, there was a positive correlation (r = 0.544, p<0.001) between the composite scores on CSB-C and RBANS for patients. Additionally, in the attention and memory cognitive domains, corresponding subsets from the two batteries correlated significantly (p<0.05). Moreover, factor analysis showed a two-factor model, consisting of speed, memory and reasoning.
The CSB-C shows good reliability and validity in measuring the broad cognitive domains of schizophrenia in affected Chinese patients. Therefore, the CSB-C can be used as a cognitive battery, to assess the therapeutic effects of potential cognitive-enhancing agents in this cohort.
To investigate the temporal ordering of cognitive and functional declines separately in older adults with or without Alzheimer’s disease (AD).
Design and Setting
A community-based longitudinal study of aging and dementia in Northern Manhattan (Washington Heights/Hamilton Heights Inwood Columbia Aging Project) and a multicenter, clinic-based longitudinal study of prevalent AD at Columbia University Medical Center, Johns Hopkins School of Medicine, Massachusetts General Hospital, and the Hôpital de la Salpêtrière in Paris, France (the Predictors Study).
3,443 initially non-demented older adults (612 with eventual incident dementia) and 517 patients with AD.
Main Outcome Measures
Cognitive measures included the modified Mini-Mental State Exam and composite scores of memory and language derived from a standardized neuropsychological battery. Function was measured with the Blessed Dementia Rating Scale, completed by the participant (in the sample of non-demented older adults) or an informant (in the sample of prevalent AD patients). Data were analyzed with autoregressive cross-lagged panel analysis.
Cognitive scores more consistently predicted subsequent functional abilities than vice versa in non-demented older adults, participants with eventual incident dementia, and patients with prevalent AD.
Cognitive declines appear to precede and cause functional declines prior to and following dementia diagnosis. Standardized neuropsychological tests are valid predictors of later functional changes in both non-demented and demented older adults.
The objective of this study was to examine, first, the relationship of having a rural vs. urban background with suicidal ideation in Chinese college students, and second, whether a potential relationship was mediated by depression.
A survey was conducted among 1,145 undergraduate students at a university in China. Suicidal ideation and depressive symptoms were measured by the revised Hopkins’ Symptom checklist (SCL-90-R). Associations between rural vs. urban background, depression and suicidal ideation were estimated by multivariable linear regression-based β coefficients, logistic regression-based odds ratios (ORs), and corresponding 95% confidence intervals (CIs). The magnitude of indirect effect and bias-corrected 95% CIs were obtained through bootstrap techniques.
Rural background was positively associated with depression, which was in turn associated with suicidal ideation. The OR for rural status and suicidal ideation equaled 2.15 (95% CI = 1.36–3.41). This OR was slightly, though significantly (p<0.05) attenuated by additional adjustment for depressive symptoms (OR = 1.99, 95% CI = 1.15–3.44).
Having a rural background is a determinant of suicidal ideation in Chinese college students. Depression may only marginally mediate this association.
Vitamin D deficiency is common in the adult population, and this has been linked to depression and cognitive outcomes in clinical populations. The aim of this study was to investigate the effects of adult vitamin D (AVD) deficiency on behavioural tasks of relevance to neuropsychiatric disorders in male Sprague-Dawley rats.
Ten-week old male Sprague-Dawley rats were fed a control or vitamin D deficient diet for 6 weeks prior to, and during behavioural testing. We first examined a range of behavioural domains including locomotion, exploration, anxiety, social behaviour, learned helplessness, sensorimotor gating, and nociception. We then assessed locomotor response to the psychomimetic drugs, amphetamine and MK-801. Attention and vigilance were assessed using the 5 choice serial reaction time task (5C-SRT) and the 5 choice continuous performance task (5C-CPT) and, in a separate cohort, working memory was assessed using the delay match to sample (DMTS) task. We also examined excitatory and inhibitory neurotransmitters in prefrontal cortex and striatum.
AVD-deficient rats were deficient in vitamin D3 (<10 nM) and had normal calcium and phosphate levels after 8–10 weeks on the diet. Overall, AVD deficiency was not associated with an altered phenotype across the range of behavioural domains tested. On the 5C-SRT AVD-deficient rats made more premature responses and more head entries during longer inter-trial intervals (ITI) than control rats. On the 5C-CPT AVD-deficient rats took longer to make false alarm (FA) responses than control rats. AVD-deficient rats had increases in baseline GABA levels and the ratio of DOPAC/HVA within the striatum.
AVD-deficient rats exhibited no major impairments in any of the behavioural domains tested. Impairments in premature responses in AVD-deficient rats may indicate that these animals have specific alterations in striatal systems governing compulsive or reward-seeking behaviour.
The post-synaptic density (PSD) of glutamatergic synapses harbors a multitude of proteins critical for maintaining synaptic dynamics. Alteration of protein expression levels in this matrix is a marked phenomenon of neuropsychiatric disorders including schizophrenia, where cognitive functions are impaired. To investigate the genetic relationship of genes expressed in the PSD with schizophrenia, a family-based association analysis of genetic variants in PSD genes such as DLG4, DLG1, PICK1 and MDM2, was performed, using Japanese samples (124 pedigrees, n = 376 subjects). Results showed a significant association of the rs17203281 variant from the DLG4 gene, with preferential transmission of the C allele (p = 0.02), although significance disappeared after correction for multiple testing. Replication analysis of this variant, found no association in a Chinese schizophrenia cohort (293 pedigrees, n = 1163 subjects) or in a Japanese case-control sample (n = 4182 subjects). The DLG4 expression levels between postmortem brain samples from schizophrenia patients showed no significant changes from controls. Interestingly, a five marker haplotype in DLG4, involving rs2242449, rs17203281, rs390200, rs222853 and rs222837, was enriched in a population specific manner, where the sequences A-C-C-C-A and G-C-C-C-A accumulated in Japanese (p = 0.0009) and Chinese (p = 0.0007) schizophrenia pedigree samples, respectively. However, this could not be replicated in case-control samples. None of the variants in other examined candidate genes showed any significant association in these samples. The current study highlights a putative role for DLG4 in schizophrenia pathogenesis, evidenced by haplotype association, and warrants further dense screening for variants within these haplotypes.
Regulatory risk communications are an important method for disseminating drug safety information, but their impact varies. Two significant UK risk communications about antipsychotic use in older people with dementia were issued in 2004 and 2009. These varied considerably in their content and dissemination, allowing examination of their differential impact.
Segmented regression time-series analysis 2001–2011 for people aged ≥65 years with dementia in 87 Scottish general practices, examining the impact of two pre-specified risk communications in 2004 and 2009 on antipsychotic and other psychotropic prescribing.
The percentage of people with dementia prescribed an antipsychotic was 15.9% in quarter 1 2001 and was rising by an estimated 0.6%/quarter before the 2004 risk communication. The 2004 risk communication was sent directly to all prescribers, and specifically recommended review of all patients prescribed relevant drugs. It was associated with an immediate absolute reduction in antipsychotic prescribing of 5.9% (95% CI −6.6 to −5.2) and a change to a stable level of prescribing subsequently. The 2009 risk communication was disseminated in a limited circulation bulletin, and only specifically recommended avoiding initiation if possible. There was no immediate associated impact, but it was associated with a significant decline in prescribing subsequently which appeared driven by a decline in initiation, with the percentage prescribed an antipsychotic falling from 18.4% in Q1 2009 to 13.5% in Q1 2011. There was no widespread substitution of antipsychotics with other psychotropic drugs.
The two risk communications were associated with reductions in antipsychotic use, in ways which were compatible with marked differences in their content and dissemination. Further research is needed to ensure that the content and dissemination of regulatory risk communications is optimal, and to track their impact on intended and unintended outcomes. Although rates are falling, antipsychotic prescribing in dementia in Scotland remains unacceptably high.
We have shown the involvement of mitochondrial uncoupling protein-2 (UCP2) in the cytotoxicity by N-methyl-D-aspartate receptor (NMDAR) through a mechanism relevant to the increased mitochondrial Ca2+ levels in HEK293 cells with acquired NMDAR channels. Here, we evaluated pharmacological profiles of ethanol on the NMDA-induced increase in mitochondrial Ca2+ levels in cultured murine neocortical neurons.
In neurons exposed to glutamate or NMDA, a significant increase was seen in mitochondrial Ca2+ levels determined by Rhod-2 at concentrations of 0.1 to 100 µM. Further addition of 250 mM ethanol significantly inhibited the increase by glutamate and NMDA in Rhod-2 fluorescence, while similarly potent inhibition of the NMDA-induced increase was seen after exposure to ethanol at 50 to 250 mM in cultured neurons. Lentiviral overexpression of UCP2 significantly accelerated the increase by NMDA in Rhod-2 fluorescence in neurons, without affecting Fluo-3 fluorescence for intracellular Ca2+ levels. In neurons overexpressing UCP2, exposure to ethanol resulted in significantly more effective inhibition of the NMDA-induced increase in mitochondrial free Ca2+ levels than in those without UCP2 overexpression, despite a similarly efficient increase in intracellular Ca2+ levels irrespective of UCP2 overexpression. Overexpression of UCP2 significantly increased the number of dead cells in a manner prevented by ethanol in neurons exposed to glutamate. In HEK293 cells with NMDAR containing GluN2B subunit, more efficient inhibition was similarly induced by ethanol at 50 and 250 mM on the NMDA-induced increase in mitochondrial Ca2+ levels than in those with GluN2A subunit. Decreased protein levels of GluN2B, but not GluN2A, subunit were seen in immunoprecipitates with UCP2 from neurons with brief exposure to ethanol at concentrations over 50 mM.
Ethanol could inhibit the interaction between UCP2 and NMDAR channels to prevent the mitochondrial Ca2+ incorporation and cell death after NMDAR activation in neurons.
The psychotomimetic effects of N-methyl-D-aspartate (NMDA) receptor antagonists in healthy humans and their tendency to aggravate psychotic symptoms in schizophrenic patients have promoted the notion of altered glutamatergic neurotransmission in the pathogenesis of schizophrenia.
The NMDA-receptor antagonist MK-801 was chronically administered to rats (0.02 mg/kg intraperitoneally for 14 days). In one subgroup the antipsychotic haloperidol (1 mg/kg) was employed as a rescue therapy. Glutamate distribution and 3-NT (3-nitrotyrosine) as a marker of oxidative stress were assessed by immunohistochemistry in tissue sections. In parallel, the effects of MK-801 and haloperidol were investigated in primary embryonal hippocampal cell cultures from rats.
Chronic NMDA-R antagonism led to a marked increase of intracellular glutamate in the hippocampus (126.1 +/− 10.4% S.E.M of control; p = 0.037), while 3-NT staining intensity remained unaltered. No differences were observed in extrahippocampal brain regions. Essentially these findings could be reproduced in vitro.
The combined in vivo and in vitro strategy allowed us to assess the implications of disturbed glutamate metabolism for the occurrence of oxidative stress and to investigate the effects of antipsychotics. Our data suggest that oxidative stress plays a minor role in this model than previously suggested. The same applies to apoptosis. Moreover, the effect of haloperidol seems to be mediated through yet unidentified mechanisms, unrelated to D2-antagonism. These convergent lines of evidence indicate that further research should be focused on the glutamatergic system and that our animal model may provide a tool to explore the biology of schizophrenia.
Recent experimental evidence suggests that stressed males find heavier women more attractive than non-stressed males. The aim of this study is to examine whether these results also appear in actual mating patterns of adults from a national sample.
Regression analysis linking partner weight measures to own measures of childhood stress, as measured by mistreatment. Cross-sectional data from the National Longitudinal Study of Adolescent Health, Romantic Partners Sample is used to measure partner weight, childhood stressful events, and socio-demographic characteristics. Childhood experiences of adult mistreatment are retrospectively collected.
Men who experienced childhood mistreatment are more likely to have obese female partners during young adulthood. The results are strongest for interactions with social services, adult neglect and physical abuse. We also present novel evidence of the opposite association in similarly stressed women whose male partners are more likely to be thin.
These results suggest that preferences for partner characteristics are sensitive to histories of stress and that previously hypothesized patterns occur outside the experimental setting.
Cognitive impairment occurs in both schizophrenia and diabetes. There is currently limited understanding whether schizophrenia with diabetes has more serious cognitive deficits than schizophrenia without diabetes or diabetes only. This study assessed cognitive performance in 190 healthy controls, 106 diabetes only, 127 schizophrenia without diabetes and 55 schizophrenia with diabetes. This study was conducted from January 2008 to December 2010. Compared to healthy controls, all patient groups had significantly decreased total and five index RBANS scores (all p<0.01–p<0.001), except for the visuospatial/constructional index. Schizophrenia with diabetes performed worse than schizophrenia without diabetes in immediate memory (p<0.01) and total RBANS scores (<0.05), and showed a trend for decreased attention (p = 0.052) and visuospatial/constructional capacity (p = 0.063). Schizophrenia with diabetes performed worse than diabetes only in immediate memory (p<0.001) and attention (p<0.05), and showed a trend for decreased total RBANS scores (p = 0.069). Regression analysis showed that the RBANS had modest correlations with schizophrenia’ PANSS scores, their duration of current antipsychotic treatment, and diagnosis of diabetes. Schizophrenia with co-morbid diabetes showed more cognitive impairment than schizophrenia without diabetes and diabetes only, especially in immediate memory and attention.
Disturbances of brain derived neurotrophic factor (BDNF) signalling have been implicated in the evolution of depression, which likely arises, in part, as a result of diminished synaptic plasticity. Predictably, given stressor involvement in depression, BDNF is affected by recent stressors as well as stressors such as neglect experienced in early life. The effects of early life maltreatment in altering BDNF signalling may be particularly apparent among those individuals with specific BDNF polymorphisms. We examined whether polymorphisms of the Val66Met genotype might be influential in moderating how early-life events play out with respect to later coping styles, cognitive flexibility and depressive features. Among male and female undergraduate students (N = 124), childhood neglect was highly related to subsequent depressive symptoms. This outcome was moderated by the BDNF polymorphism in the sense that depressive symptoms appeared higher in Met carriers who reported low levels of neglect than in those with the Val/Val allele. However, under conditions of high neglect depressive symptoms only increased in the Val/Val individuals. In effect, the Met polymorphism was associated with depressive features, but did not interact with early life neglect in predicting later depressive features. It was further observed that among the Val/Val individuals, the relationship between neglect and depression was mediated by emotion-focused styles and diminished perceived control, whereas this mediation was not apparent in Met carriers. In contrast to the more typical view regarding this polymorphism, the data are consistent with the perspective that in the presence of synaptic plasticity presumably associated with the Val/Val genotype, neglect allows for the emergence of specific appraisal and coping styles, which are tied to depression. In the case of the reduced degree of neuroplasticity expected in the Met carriers, early life adverse experiences are not tied to coping styles, and hence less likely to be translated into depressive states.
It has been well established that schizophrenia patients display impaired NMDA receptor (NMDAR) functions as well as exacerbation of symptoms in response to NMDAR antagonists. Abnormal NMDAR signaling presumably contributes to cognitive deficits which substantially contribute to functional disability in schizophrenia. Establishing a mouse genetic model will help investigate molecular mechanisms of hypoglutmatergic neurotransmission in schizophrenia. Here, we examined the responses of Sp4 hypomorphic mice to NMDAR antagonists in electroencephalography and various behavioral paradigms. Sp4 hypomorphic mice, previously reported to have reduced NMDAR1 expression and LTP deficit in hippocampal CA1, displayed increased sensitivity and prolonged responses to NMDAR antagonists. Molecular studies demonstrated reduced expression of glutamic acid decarboxylase 67 (GAD67) in both cortex and hippocampus, consistent with abnormal gamma oscillations in Sp4 hypomorphic mice. On the other hand, human SP4 gene was reported to be deleted in schizophrenia. Several human genetic studies suggested the association of SP4 gene with schizophrenia and other psychiatric disorders. Therefore, elucidation of the Sp4 molecular pathway in Sp4 hypomorphic mice may provide novel insights to our understanding of abnormal NMDAR signaling in schizophrenia.
A wide body of evidence suggests that 5-HT7 receptors are implicated in a variety of central nervous system functions, including control of learning and memory processes. According to recent preclinical data, the selective blockade of these receptors may be a potential target for cognitive improvement in schizophrenia. The first aim of the present study was to evaluate the effects of the selective 5-HT7 receptor antagonist, SB-269970, and the antipsychotic drug with a high affinity for 5-HT7 receptors, amisulpride, on ketamine-induced deficits in attentional set-shifting and novel object recognition tasks in rats. Because the role of 5-HT7 receptor blockade in ameliorating positive and negative symptoms of schizophrenia remains equivocal, the second aim of these experiments was to examine the effectiveness of SB-269970 and amisulpride in reversing ketamine-induced deficits in prepulse inhibition of the startle reflex and in social interaction test in rats. The study revealed that acute administration of SB-269970 (1 mg/kg) or amisulpride (3 mg/kg) ameliorated ketamine-induced cognitive inflexibility and novel object recognition deficit in rats. Both compounds were also effective in attenuating ketamine-evoked disruption of social interactions. In contrast, neither SB-269970 nor amisulpride affected ketamine-disrupted prepulse inhibition or 50 kHz USVs accompanying social behaviour. In conclusion, antagonism of 5-HT7 receptors may represent a useful pharmacological approach in the treatment of cognitive deficits and some negative symptoms of schizophrenia.
Olanzapine (OLZ) is one of the most prescribed atypical antipsychotic drugs but its use is associated with unfavorable metabolic abnormalities. N-desmethyl-olanzapine (DMO), one of the OLZ metabolites by CYP1A2, has been reported to have a normalizing action on metabolic abnormalities, but this remains unclear. Our aim was to explore the correlation between the concentrations of OLZ or DMO with various metabolic parameters in schizophrenic patients.
The chromatographic analysis was carried out with a solvent delivery system coupled to a Coulochem III coulometric detector to determine OLZ and DMO simultaneously in OLZ-treated patients. The correlation between the concentration of OLZ or DMO and the metabolic parameters was analyzed by the Spearman rank order correlation method (rs).
The established analytical method met proper standards for accuracy and reliability and the lower limitation of quantification for each injection of DMO or OLZ was 0.02 ng. The method was successfully used for the analysis of samples from nonsmoking patients (n = 48) treated with OLZ in the dosage range of 5–20 mg per day. There was no correlation between OLZ concentrations and tested metabolic parameters. DMO concentrations were negatively correlated with glucose (rs = –0.45) and DMO concentrations normalized by doses were also negatively correlated with insulin levels (rs = –0.39); however, there was a marginally positive correlation between DMO and homocysteine levels (rs = +0.38).
The observed negative correlations between levels of DMO and glucose or insulin suggest a metabolic normalization role for DMO regardless of its positive correlation with a known cardiovascular risk factor, homocysteine. Additional studies of the mechanisms underlying DMO’s metabolic effects are warranted.
The diagnosis of schizoaffective disorder has long maintained an uncertain status in psychiatric nosology. Studies comparing clinical and biological features of patients with schizoaffective disorder to patients with related disorders [e.g., schizophrenia and bipolar disorder] can provide an evidence base for judging the validity of the diagnostic category. However, because most prior studies of schizoaffective disorder have only evaluated differences between groups at a static timepoint, it is unclear how these disorders may be related when the entire illness course is taken into consideration.
We ascertained a large cohort [N = 993] of psychiatric patients with a range of psychotic diagnoses including schizophrenia with no history of major affective episodes [SZ−; N = 371], schizophrenia with a superimposed mood syndrome [SZ+; N = 224], schizoaffective disorder [SAD; N = 129] and bipolar I disorder with psychotic features [BPD+; N = 269]. Using cross-sectional data we designed key clinical and neurocognitive dependent measures that allowed us to test longitudinal hypotheses about the differences between these diagnostic entities.
Large differences between diagnostic groups on several demographic and clinical variables were observed. Most notably, groups differed on a putative measure of cognitive decline. Specifically, the SAD group demonstrated significantly greater post-onset cognitive decline compared to the BP+ group, with the SZ− and SZ+ group both exhibiting levels of decline intermediate to BPD+ and SAD.
These results suggest that schizoaffective disorder may possess distinct features. Contrary to earlier formulations, schizoaffective disorder may be a more severe form of illness.
The clinical outcome of antidepressant treatment in patients with major depressive disorder (MDD) is thought to be associated with personality traits. A number of studies suggest that depressed patients show high harm avoidance, low self-directedness and cooperativeness, as measured on the Temperament and Character Inventory (TCI). However, the psychology of these patients is not well documented.
Psychological evaluation using Cloninger’s TCI, was performed on treatment-resistant MDD patients (n = 35), remission MDD patients (n = 31), and age- and gender-matched healthy controls (n = 174).
Treatment-resistant patients demonstrated high scores for harm avoidance, and low scores for reward dependence, self-directedness, and cooperativeness using the TCI, compared with healthy controls and remission patients. Interestingly, patients in remission continued to show significantly high scores for harm avoidance, but not other traits in the TCI compared with controls. Moreover, there was a significant negative correlation between reward dependence and harm avoidance in the treatment-resistant depression cohort, which was absent in the control and remitted depression groups.
This study suggests that low reward dependence and to a lesser extent, low cooperativeness in the TCI may be risk factors for treatment-resistant depression.
Depression is a serious and potentially life-threatening mental disorder with unknown etiology. Emerging evidence shows that brain-derived neurotrophic factor (BDNF) and microRNAs (miRNAs) play critical roles in the etiology of depression. Here this study was aimed to identify and characterize the roles of BDNF and its putative regulatory miRNAs in depression. First, we identified that miR-182 may be a putative miRNA that regulates BDNF levels by bioinformatic studies, and characterized the effects of miR-182 on the BDNF levels using cell-based studies, side by side with miR-132 (a known miRNA that regulates BDNF expression). We showed that treatment of miR-132 and miR-182 respectively decreased the BDNF protein levels in a human neuronal cell model, supporting the regulatory roles of miR-132 and miR-182 on the BDNF expression. Furthermore, we explored the roles of miR-132 and miR-182 on the BDNF levels in depression using human subjects by assessing their serum levels. Compared with the healthy controls, patients with depression showed lower serum BDNF levels (via the enzyme-linked immunosorbent assays) and higher serum miR-132 and miR-182 levels (via the real-time PCR). Finally, the Pearson’s (or Spearman’s) correlation coefficient was calculated to study whether there was a relationship among the Self-Rating Depression Scale score, the serum BDNF levels, and serum BDNF-related miRNA levels. Our results revealed that there was a significant negative correlation between the SDS scores and the serum BDNF levels, and a positive correlation between the SDS scores and miR-132 levels. In addition, we found a reverse relationship between the serum BDNF levels and the miR-132/miR-182 levels in depression. Collectively, we provided evidence supporting that miR-182 is a putative BDNF-regulatory miRNA, and suggested that the serum BDNF and its related miRNAs may be utilized as important biomarkers in the diagnosis or as therapeutic targets of depression.