Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder.

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.

Acute stress effects on GABA and glutamate levels in the prefrontal cortex: A 7T 1H magnetic resonance spectroscopy study.

There is ample evidence that the inhibitory GABA and the excitatory glutamate system are essential for an adequate response to stress. Both GABAergic and glutamatergic brain circuits modulate hypothalamus-pituitary-adrenal (HPA)-axis activity, and stress in turn affects glutamate and GABA levels in the rodent brain. However, studies examining stress-induced GABA and glutamate levels in the human brain are scarce. Therefore, we investigated the influence of acute psychosocial stress (using the Trier Social Stress Test) on glutamate and GABA levels in the medial prefrontal cortex of 29 healthy male individuals using 7 Tesla proton magnetic resonance spectroscopy. In vivo GABA and glutamate levels were measured before and 30 min after exposure to either the stress or the control condition. We found no associations between psychosocial stress or cortisol stress reactivity and changes over time in medial prefrontal glutamate and GABA levels. GABA and glutamate levels over time were significantly correlated in the control condition but not in the stress condition, suggesting that very subtle differential effects of stress on GABA and glutamate across individuals may occur. However, overall, acute psychosocial stress does not appear to affect in vivo medial prefrontal GABA and glutamate levels, at least this is not detectable with current practice 1H-MRS.

Educational achievement in psychiatric patients and their siblings: a register-based study in 30 000 individuals in The Netherlands.

BACKGROUND: Poor educational achievement is associated with a range of psychiatric disorders. Several studies suggest that this underperformance is due to cognitive deficits that commence before disease onset and reflect a genetic risk for this disorder. However, the specificity and the familial contribution of this cognitive deficit are not clear. We analysed lifetime educational achievement of psychiatric patients diagnosed with schizophrenia, bipolar or depressive disorder and their unaffected siblings. METHOD: In a register-based case-control study, 1561 patients with schizophrenia, 813 patients with bipolar disorder, 8112 patients with depression, and their siblings were each matched with eight population controls. Patients, siblings and controls were compared on the highest educational stream they completed. RESULTS: Lower educational achievement was present in schizophrenia patients from primary school onwards [completing primary school: odds ratio (OR) 0.69; completing secondary school: OR 0.69; completing academic education: OR 0.46], compared to patients with bipolar disorder or depression. Siblings of schizophrenia, bipolar or depressed patients showed no underachievement at primary or secondary school, but siblings of schizophrenia patients as well as siblings of depressed patients were less successful in their educational achievement after secondary school (completing academic education, schizophrenia siblings: OR 0.90; depressive disorder siblings: OR 0.91). CONCLUSIONS: Educational underachievement from primary school onwards is specifically related to schizophrenia and not to bipolar disorder or depression. Moreover, it appears to be a harbinger of the illness, since it is not found in their siblings. These results add to evidence that early cognitive deficits are a distinct feature of the schizophrenia phenotype.

High educational performance is a distinctive feature of bipolar disorder: a study on cognition in bipolar disorder, schizophrenia patients, relatives and controls.

BACKGROUND: Schizophrenia is associated with lower intelligence and poor educational performance relative to the general population. This is, to a lesser degree, also found in first-degree relatives of schizophrenia patients. It is unclear whether bipolar disorder I (BD-I) patients and their relatives have similar lower intellectual and educational performance as that observed in schizophrenia. METHOD: This cross-sectional study investigated intelligence and educational performance in two outpatient samples [494 BD-I patients, 952 schizophrenia spectrum (SCZ) patients], 2231 relatives of BD-I and SCZ patients, 1104 healthy controls and 100 control siblings. Mixed-effects and regression models were used to compare groups on intelligence and educational performance. RESULTS: BD-I patients were more likely to have completed the highest level of education (odds ratio 1.88, 95% confidence interval 1.66-2.70) despite having a lower IQ compared to controls (ß = -9.09, S.E. = 1.27, p < 0.001). In contrast, SCZ patients showed both a lower IQ (ß = -15.31, S.E. = 0.86, p < 0.001) and lower educational levels compared to controls. Siblings of both patient groups had significantly lower IQ than control siblings, but did not differ on educational performance. IQ scores did not differ between BD-I parents and SCZ parents, but BD-I parents had completed higher educational levels. CONCLUSIONS: Although BD-I patients had a lower IQ than controls, they were more likely to have completed the highest level of education. This contrasts with SCZ patients, who showed both intellectual and educational deficits compared to healthy controls. Since relatives of BD-I patients did not demonstrate superior educational performance, our data suggest that high educational performance may be a distinctive feature of bipolar disorder patients.

Genome-wide association study of NMDA receptor coagonists in human cerebrospinal fluid and plasma.

The N-methyl-D-aspartate receptor (NMDAR) coagonists glycine, D-serine and L-proline play crucial roles in NMDAR-dependent neurotransmission and are associated with a range of neuropsychiatric disorders. We conducted the first genome-wide association study of concentrations of these coagonists and their enantiomers in plasma and cerebrospinal fluid (CSF) of human subjects from the general population (N=414). Genetic variants at chromosome 22q11.2, located in and near PRODH (proline dehydrogenase), were associated with L-proline in plasma (ß=0.29; P=6.38 × 10(-10)). The missense variant rs17279437 in the proline transporter SLC6A20 was associated with L-proline in CSF (ß=0.28; P=9.68 × 10(-9)). Suggestive evidence of association was found for the D-serine plasma-CSF ratio at the D-amino-acid oxidase (DAO) gene (ß=-0.28; P=9.08 × 10(-8)), whereas a variant in SRR (that encodes serine racemase and is associated with schizophrenia) constituted the most strongly associated locus for the L-serine to D-serine ratio in CSF. All these genes are highly expressed in rodent meninges and choroid plexus, anatomical regions relevant to CSF physiology. The enzymes and transporters they encode may be targeted to further construe the nature of NMDAR coagonist involvement in NMDAR gating. Furthermore, the highlighted genetic variants may be followed up in clinical populations, for example, schizophrenia and 22q11 deletion syndrome. Overall, this targeted metabolomics approach furthers the understanding of NMDAR coagonist concentration variability and sets the stage for non-targeted CSF metabolomics projects.

Antipsychotic use is associated with a blunted cortisol stress response: a study in euthymic bipolar disorder patients and their unaffected siblings.

There is ample evidence that the acute stress response is altered in schizophrenia and bipolar disorder. However, it is not clear whether such changes are related to the illness, a genetic vulnerability, or is the result of medication that is used in the majority of these patients. Therefore, we investigated determinants of the acute endocrine and autonomic stress response in healthy controls (n=48), euthymic BD1 patients (n=49) and unaffected siblings of BD1 patients (n=27). All participants completed a validated psychosocial stress task, the Trier Social Stress Test for Groups (TSST-G). Saliva levels of alpha-amylase and cortisol were measured before, during, and after exposure to stress. Compared to controls, we found a significantly blunted cortisol stress response in BD1 patients. Conversely, BD1 patients displayed exaggerated alpha-amylase levels in response to stress. Antipsychotic use was a significant contributing factor to the blunted cortisol stress response in BD1 patients. Unaffected BD1 siblings displayed similar stress-induced cortisol and alpha-amylase levels as controls, suggesting that familial risk for BD1 did not have a large effect on the functionality of the stress system. In conclusion, this study shows that euthymic BD1 patients have a substantially blunted endocrine stress response but an exaggerated autonomic stress response and that the endocrine stress response differences can be largely contributed to antipsychotic use rather than constitute a specific BD1 phenotype or vulnerability.

Change in cannabis use in the general population: a longitudinal study on the impact on psychotic experiences.

OBJECTIVE: To prospectively assess the relationship between cannabis use and psychotic experiences over time. METHOD: In a longitudinal design, young adults aged 18-27years (N=705) gave online information on cannabis use and completed the Community Assessment of Psychic Experiences (CAPE). These measures were repeated after an interval ranging from six months to five years. RESULTS: A decrease in cannabis use was associated with a decrease in total psychotic experiences (ß=-0.096, p=0.01) after adjustment for a range of potential confounders. An increase in cannabis use was associated with increased positive symptoms at follow-up (ß=0.07, p=0.02), but was not significantly associated with increases in Negative and Depression symptom scores, nor with the total number of psychotic experiences. CONCLUSION: In the first study to the association of change in cannabis use and psychotic experiences over time in the general population, we found an association between changes in cannabis use and changes in the frequency of psychotic experiences. While this does not prove a causal relationship between cannabis use and psychosis, our findings are consistent with studies suggesting that cessation of cannabis use may be beneficial in terms of reducing psychotic experiences.

Cannabis use is a better indicator of poor mental health in women than in men: a cross-sectional study in young adults from the general population.

Cannabis use is a known risk factor for a range of mental health problems, but less is known on the association with general mental health. We aim to explore the relationship between cannabis use and general mental health. We did a cross-sectional online survey of 1,929 young adults aged 18-30 years. Participants reported socio-demographic data, substance use and the Symptom Checklist-90 (SCL-90). Monthly cannabis use was associated with a higher total score on the SCL-90, both in a crude (OR 1.94, 95% CI 1.57-2.38) and fully adjusted model (OR 1.48, 95% CI 1.07-2.03). The association between cannabis and mental health was stronger in women and weekly users, and was independent of age at first use of cannabis. We conclude that moderate cannabis use is associated with general mental health problems in young adulthood. This relationship is independent of age at first use and of other risk factors, and is strongest in women.

Cannabidiol as a potential treatment for psychosis.

Although cannabis use is associated with an increased risk of developing psychosis, the cannabis constituent cannabidiol (CBD) may have antipsychotic properties. This review concisely describes the role of the endocannabinoid system in the development of psychosis and provides an overview of currently available animal, human experimental, imaging, epidemiological and clinical studies that investigated the antipsychotic properties of CBD. In this targeted literature review we performed a search for English articles using Medline and EMBASE. Studies were selected if they described experiments with psychosis models, psychotic symptoms or psychotic disorders as outcome measure and involved the use of CBD as intervention. Evidence from several research domains suggests that CBD shows potential for antipsychotic treatment.

Seasonal variation of serotonin turnover in human cerebrospinal fluid, depressive symptoms and the role of the 5-HTTLPR.

Studying monoaminergic seasonality is likely to improve our understanding of neurobiological mechanisms underlying season-associated physiological and pathophysiological behavior. Studies of monoaminergic seasonality and the influence of the serotonin-transporter-linked polymorphic region (5-HTTLPR) on serotonin seasonality have yielded conflicting results, possibly due to lack of power and absence of multi-year analyses. We aimed to assess the extent of seasonal monoamine turnover and examined the possible involvement of the 5-HTTLPR. To determine the influence of seasonality on monoamine turnover, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured in the cerebrospinal fluid of 479 human subjects collected during a 3-year period. Cosine and non-parametric seasonal modeling were applied to both metabolites. We computed serotonin (5-HT) seasonality values and performed an association analysis with the s/l alleles of the 5-HTTLPR. Depressive symptomatology was assessed using the Beck Depression Inventory-II. Circannual variation in 5-HIAA fitted a spring-peak cosine model that was significantly associated with sampling month (P=0.0074). Season of sampling explained 5.4% (P=1.57 × 10(-7)) of the variance in 5-HIAA concentrations. The 5-HTTLPR s-allele was associated with increased 5-HIAA seasonality (standardized regression coefficient=0.12, P=0.020, N=393). 5-HIAA seasonality correlated with depressive symptoms (Spearman's rho=0.13, P=0.018, N=345). In conclusion, we highlight a dose-dependent association of the 5-HTTLPR with 5-HIAA seasonality and a positive correlation between 5-HIAA seasonality and depressive symptomatology. The presented data set the stage for follow-up in clinical populations with a role for seasonality, such as affective disorders.

Cigarette smoking and cannabis use are equally strongly associated with psychotic-like experiences: a cross-sectional study in 1929 young adults.

BACKGROUND: Cannabis use is associated with increased risk for psychotic-like experiences (PLEs) and psychotic disorders. It remains unclear whether this relationship is causal or due to confounding. METHOD: A total of 1929 young adults aged 18-30 years participated in a nationwide internet-based survey in The Netherlands and gave information on demographics, substance use and parental psychiatric illness and completed the Community Assessment of Psychic Experiences (CAPE). RESULTS: Cigarette smoking and cannabis use were equally strongly associated with the frequency of PLEs in a fully adjusted model (ß = 0.098 and 0.079 respectively, p < 0.05). Cannabis use was associated with distress from PLEs in a model adjusted for an elaborate set of confounders excluding smoking (ß = 0.082, p < 0.05). However, when cigarette smoking was included in the model, cannabis use was not a significant predictor of distress from PLEs. Cigarette smoking remained associated with distress from PLEs in a fully adjusted model (ß = 0.107, p < 0.001). CONCLUSIONS: Smoking is an equally strong independent predictor of frequency of PLEs as monthly cannabis use. Our results suggest that the association between moderate cannabis use and PLEs is confounded by cigarette smoking.

Cannabis use as an indicator of risk for mental health problems in adolescents: a population-based study at secondary schools.

BACKGROUND: Although the association between cannabis use and a wide range of psychiatric symptoms is fairly well established, it is not clear whether cannabis use is also a risk factor for general mental health problems at secondary school. Method A total of 10 324 secondary school children aged 11-16 years, participating in an ongoing Public Health Service School Survey, gave information on demographics, substance use, school factors and stressful life events and completed the Strengths and Difficulties Questionnaire (SDQ). RESULTS: Cannabis use in the past month was associated with a clinically relevant score on the SDQ [unadjusted odds ratio (OR) 4.46, 95% confidence interval (CI) 3.46-5.76]. Other risk factors associated with poor psychosocial functioning were: a low level of education, alcohol use, cigarette smoking, hard drug use, frequent truancy, an unfavourable school evaluation, feeling unsafe at school, being victimized, frequent absence due to illness, a mentally ill parent, molestation by a parent, financial problems and feeling distressed by an adverse event. In a full model adjusting for these risk factors, cannabis was not significantly associated with mental health problems, although an association at trend level was apparent. Of these risk factors, regular alcohol use, cigarette smoking, hard drug use, frequent truancy, an unfavourable school evaluation and frequent absence due to illness were also associated with cannabis use. CONCLUSIONS: The association between cannabis use and poor psychosocial functioning in adolescence is due, at least in part, to confounding by other risk factors. Thus, cannabis use can best be viewed as an indicator of risk for mental health problems in adolescence.

Region and state specific glutamate downregulation in major depressive disorder: a meta-analysis of (1)H-MRS findings.

For major depressive disorder (MDD), magnetic resonance spectroscopy ((1)H-MRS) studies of glutamate, glutamine and Glx (the composite measure of mainly glutamate and glutamine) have yielded inconclusive or seemingly inconsistent results. We therefore systematically reviewed whether in vivo concentrations of glutamate, glutamine and Glx measured with (1)H-MRS differ between MDD patients and controls. Meta-analysis including meta-regression, sensitivity, statistical heterogeneity, and publication bias analyses were conducted. Glutamate and Glx concentrations were found to be lower in the anterior cingulate cortex (ACC) in patients compared to controls (standardized mean difference (SMD) for glutamate with 95% CIs: -0.86, -1.55 to -0.17; and for Glx: -1.15, -1.86 to -0.44). In addition, Glx was decreased in all brain regions together in current episode patients (SMD: -0.62, -1.17 to -0.07). We conclude that in MDD, glutamate and possibly glutamine are downregulated primarily in the ACC and during depressive states. These results fit the central role of the ACC in depressive symptomatology and suggest that in MDD changes in glutamatergic neurotransmission are state-dependent.

Association between cannabis and psychiatric hospitalization.

OBJECTIVE: To investigate the relationship between cannabis use and mental health. METHOD: A cross-sectional analysis in a sample of 17 698 individuals with a mean age of 22 years (SD: 4.2). Participants provided information on the amount and initial age of cannabis use and history of psychiatric hospitalizations through a web-based questionnaire. To quantify Δ(9) -tetrahydrocannabinol exposure, we operationalized cannabis use as the amount of money spent on cannabis per week over the last month. The odds ratio of having a history of psychiatric hospitalizations was the primary outcome measure. RESULTS: We found a dose-response relationship between the amount of cannabis use and the odds for psychiatric hospitalization. Adjusted odds ratios for hospitalization increased with the amount of cannabis consumed from 1.6 (95% CI: 1.1-2.3) in incidental users to 6.2 (95% CI: 4.3-8.9) in heavy users (>€25/week). Our data suggested that concomitant drug use was an intermediate factor. Exposure to cannabis before the age of 12 years was found to carry a 4.8 (95% CI: 2.9-7.8) times increased odds for past psychiatric hospitalizations. CONCLUSION: We conclude that early and heavy uses of cannabis are each and independently associated with poor mental health in its users.

Cannabis use at a young age is associated with psychotic experiences.

BACKGROUND: Cannabis use is associated with psychosis and a range of subclinical psychiatric symptoms. The strength of this association depends on dosage and age at first use. The current study investigates whether level of cannabis exposure and starting age are associated with specific profiles of subclinical symptoms. METHOD: We collected cross-sectional data from a young adult population sample by administering an online version of the Community Assessment of Psychic Experiences (CAPE). Cannabis exposure was quantified as the amount of Euros spent on cannabis per week and the age of initial cannabis use. The primary outcome measure was the odds ratio (OR) to belong to the highest 10% of scores on the total CAPE and the positive-, negative- and depressive symptom dimensions. RESULTS: In 17 698 adolescents (mean age 21.6, s.d.=4.2 years), cannabis use at age 12 years or younger was strongly associated with a top 10% score on psychotic experiences [OR 3.1, 95% confidence interval (CI) 2.1-4.3] and to a lesser degree with negative symptoms (OR 1.7, 95% CI 1.1-2.5). The OR of heavy users (>€25/week) for negative symptoms was 3.4 (95% CI 2.9-4.1), for psychotic experiences 3.0 (95% CI 2.4-3.6), and for depressive symptoms 2.8 (95% CI 2.3-3.3). CONCLUSIONS: Early start of cannabis use is strongly associated with subclinical psychotic symptoms and to a lesser degree with negative symptoms, while smoking high amounts of cannabis is associated with increased levels of all three symptom dimensions: psychotic, negative and depressive. These results support the hypothesis that the impact of cannabis use is age specific.

"Forward genetics" as a method to maximize power and cost-efficiency in studies of human complex traits.

There is increasing interest in methods to disentangle the relationship between genotype and (endo)phenotypes in human complex traits. We present a population-based method of increasing the power and cost-efficiency of studies by selecting random individuals with a particular genotype and then assessing the accompanying quantitative phenotypes. Using statistical derivations, power- and cost graphs we show that such a "forward genetics" approach can lead to a marked reduction in sample size and costs. This approach is particularly apt for implementing in epidemiological studies for which DNA is already available but the phenotyping costs are high.

The involvement of GSK3beta in bipolar disorder: integrating evidence from multiple types of genetic studies.

We aimed to get a comprehensive insight into the genetic evidence supporting the role of GSK3beta in bipolar disorder (BD). Using broad searches in NCBI's PubMed and the Genetic Association Database we looked for association, whole-genome linkage, genome-wide association, gene expression, pharmocogenomic, epigenetic, cytogenetic, and mouse model studies performed for BD until July 2009. Per gene, we rated the degree of converging evidence across these types of genetic studies. The genes most consistently associated with BD in the genetic studies we reviewed were GSK3beta , GRK3, 5-HTTLPR, GRIN3, COMT, and GLUR3. GSK3beta stood out as it was implicated in at least five types of genetic studies. Although our results are limited by design differences of included studies and possibly by publication bias, GSK3beta is a plausible candidate gene for BD from a pharmacological and a genetic perspective. Future studies investigating the effects of GSK3beta manipulation in BD seem warranted.

Treatment of unipolar psychotic depression: a randomized, double-blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine.

OBJECTIVE: It remains unclear whether unipolar psychotic depression should be treated with an antidepressant and an antipsychotic or with an antidepressant alone. METHOD: In a multi-center RCT, 122 patients (18-65 years) with DSM-IV-TR psychotic major depression and HAM-D-17 > or = 18 were randomized to 7 weeks imipramine (plasma-levels 200-300 microg/l), venlafaxine (375 mg/day) or venlafaxine-quetiapine (375 mg/day, 600 mg/day). Primary outcome was response on HAM-D-17. Secondary outcomes were response on CGI and remission (HAM-D-17). RESULTS: Venlafaxine-quetiapine was more effective than venlafaxine with no significant differences between venlafaxine-quetiapine and imipramine, or between imipramine and venlafaxine. Secondary outcomes followed the same pattern. CONCLUSION: That unipolar psychotic depression should be treated with a combination of an antidepressant and an antipsychotic and not with an antidepressant alone, can be considered evidence based with regard to venlafaxine-quetiapine vs. venlafaxine monotherapy. Whether this is also the case for imipramine monotherapy is likely, but cannot be concluded from the data.

The genetics of symptom dimensions of schizophrenia: review and meta-analysis.

BACKGROUND: The use of symptom dimensions of schizophrenia as quantitative phenotypes has been proposed as a mean to reduce the heterogeneity of schizophrenia and facilitate genetic research. However, the genetic background of symptom dimensions is not clear. AIM: We aim to investigate whether the symptom dimensions "reality distortion", "psychomotor poverty" and "disorganization" are heritable phenotypes. METHOD: We performed a Medline search including all papers from 1980 to August 2007. In addition to reviewing the articles, we performed meta-analyses on these studies where possible. RESULTS: We identified 18 relevant papers. Only the studies on affected sibling pairs were suitable for meta-analysis. Data from twin and affected sibling studies are consistent with a genetic contribution to the disorganization dimension. However these studies did not unequivocally support a large genetic contribution to neither the reality distortion symptom dimension nor to the psychomotor poverty symptom dimension. In contrast several molecular genetic studies did report associations of genes with psychomotor poverty. CONCLUSIONS: These data suggest that only the disorganization symptom dimension may provide an useful alternative phenotype for genetic research. More research is required to make any definitive conclusions.