Leslie Foldager

CACNA1C (rs1006737) is associated with schizophrenia

molecules are not altered in all neuropsychiatric disorders. Taken together, these findings show that hyperinsulinemia may have a role in the onset of schizophrenia. This has important implications, as elevated insulin levels can have deleterious effects on brain function. In addition, this suggests the possibility that drugs that improve insulin signaling may represent a novel treatment strategy. In this regard, the insulin-related molecules identified here, and potentially other co-secreted insulin-secretory granule proteins, may have utility as biomarkers for patient stratification and for monitoring the responses to existing and novel therapeutic treatment strategies.

Testing the self-medication hypothesis of depression and aggression in cannabis-dependent subjects

BACKGROUND: A self-medication hypothesis has been proposed to explain the association between cannabis use and psychiatric and behavioral problems. However, little is known about the reasons for use and reactions while intoxicated in cannabis users who suffer from depression or problems controlling violent behavior. METHOD: We assessed 119 cannabis-dependent subjects using the Schedules of Clinical Assessment in Neuropsychiatry (SCAN), parts of the Addiction Severity Index (ASI), and questionnaires on reasons for cannabis use and reactions to cannabis use while intoxicated. Participants with lifetime depression and problems controlling violent behavior were compared to subjects without such problems. Validity of the groupings was corroborated by use of a psychiatric treatment register, previous use of psychotropic medication and convictions for violence. RESULTS: Subjects with lifetime depression used cannabis for the same reasons as others. While under the influence of cannabis, they more often experienced depression, sadness, anxiety and paranoia, and they were less likely to report happiness or euphoria. Participants reporting problems controlling violent behavior more often used cannabis to decrease aggression, decrease suspiciousness, and for relaxation; while intoxicated they more often reacted with aggression. CONCLUSIONS: Subjects with prior depression do not use cannabis as a mean of self-medication. They are more likely to experience specific increases of adverse symptoms while under the influence of cannabis, and are less likely to experience specific symptom relief. There is some evidence that cannabis is used as a means of self-medication for problems controlling aggression. Language: en

10-Year trends in the treatment and outcomes of patients with first-episode schizophrenia

Nielsen J, le Quach P, Emborg C, Foldager L, Correll CU. 10‐Year trends in the treatment and outcomes of patients with first‐episode schizophrenia.

Evidence implicating BRD1 with brain development and susceptibility to both schizophrenia and bipolar affective disorder

Linkage studies suggest that chromosome 22q12–13 may contain one or more shared susceptibility genes for schizophrenia (SZ) and bipolar affective disorder (BPD). In a Faeroese sample, we previously reported association between microsatellite markers located at 22q13.31-qtel and both disorders. The present study reports an association analysis across five genes (including 14 single nucleotide and two microsatellite polymorphisms) in this interval using a case–control sample of 162 BPD, 103 SZ patients and 200 controls. The bromodomain-containing 1 gene (BRD1), which encodes a putative regulator of transcription showed association with both disorders with minimal P-values of 0.0046 and 0.00001 for single marker and overall haplotype analysis, respectively. A specific BRD1 2-marker ‘risk’ haplotype showed a frequency of ∼10% in the combined case group versus ∼1% in controls (P-value 2.8 × 10−7). Expression analysis of BRD1 mRNA revealed widespread expression in mammalian brain tissue, which was substantiated by immunohistochemical detection of BRD1 protein in the nucleus, perikaryal cytosol and proximal dendrites of the neurons in the adult rat, rabbit and human CNS. Quantitative mRNA analysis in developing fetal pig brain revealed spatiotemporal differences with high expression at early embryonic stages, with intense nuclear and cytosolar immunohistochemical staining of the neuroepithelial layer and early neuroblasts, whilst more mature neurons at later embryonic stages had less nuclear staining. The results implicate BRD1 with SZ and BPD susceptibility and provide evidence that suggests a role for BRD1 in neurodevelopment.

Mutational screening and association study of glutamate decarboxylase 1 as a candidate susceptibility gene for bipolar affective disorder and schizophrenia

Recent evidence from postmortem studies suggests that GAD1 encoding the gamma‐aminobutyric acid (GABA) synthetic enzyme GAD67 is a functional candidate susceptibility gene for both bipolar affective disorder (BPAD) and schizophrenia. Previous studies suggest linkage between D2S326 near GAD1 and BPAD. We systematically screened GAD1 exons, flanking intronic sequences, and the promoter sequence for polymorphisms in 16 BPAD patients and five controls from Denmark. We identified eight single nucleotide polymorphisms (SNPs) including two in the promoter sequence. An association study of SNPs covering GAD1 was performed in a Danish sample of 82 BPAD subjects and 120 controls and in a Scottish sample of 197 individuals with schizophrenia, 200 BPAD subjects and 199 controls. Linkage disequilibrium (LD) and haplotype frequencies were estimated from genotype data from eight SNPs. Strong pairwise LD was observed among all pairs of neighboring markers. In the Danish sample, we found weak association between BPAD and two promoter SNPs spaced 1 kb apart. Furthermore, one, two, and three loci haplotype analysis showed weak association with BPAD in the Danish sample. The results from the association studies indicate that promoter variants are of importance for the Danish BPAD cases and we cannot reject the hypothesis of GAD1 as a functional candidate gene for BPAD. No association was observed between BPAD or schizophrenia and any of the investigated SNPs in the Scottish sample set. Thus the results obtained from the Scottish sample suggest that the GAD1 gene variants do not play a major role in the predisposition to schizophrenia.

Depression, the Val66Met polymorphism, age, and gender influence the serum BDNF level

Brain-derived neurotrophic factor (BDNF) has been suggested as a candidate gene for depression and numerous studies have investigated the possible association between genetic variants within BDNF and depression. Clinical studies have investigated the serum BDNF levels in individuals with depression. However, few studies have combined genetic association studies with serum BDNF measurements. The purpose of the present study was therefore to perform an investigation of BDNF using 162 individuals with depression and 289 healthy individuals. All individuals returned a completed questionnaire and participated in a semi-structured diagnostic interview. The major contribution of the present study is the integration of clinical assessment of cases and control individuals, simultaneous analyses of several genetic variants, serum BDNF measurements, and information on socio-demographic variables, lifestyle, and health indicators in a statistical model. In the present study the serum BDNF levels were increased in the depressive subjects compared to control individuals. Additionally, six SNPs were successfully analyzed, but did not associate with depression. Multiple linear regression models were applied and age, depression, gender, the Val66Met polymorphism, and the interaction between Val66Met and gender were identified as significant determinants of the serum BDNF level. In conclusion, our data demonstrate that other factors than a diagnosis of depression influence the serum BDNF level and the importance of these factors should be emphasized comparing different studies.

Withdrawal Symptoms Do Not Predict Relapse among Subjects Treated for Cannabis Dependence

This is the first follow-up study on the association between cannabis withdrawal symptoms and risk of relapse to cannabis use. Withdrawal symptoms were assessed in 36 subjects seeking treatment for cannabis dependence. All were free of other substance use or alcohol abuse in the month before abstinence from cannabis. Follow-up was performed 26+/-4 months later, and at this point, the withdrawal symptoms were re-assessed. The following symptoms were significantly elevated after abstinence compared with follow-up: irritability, anger, depression, restlessness, craving, sleep problems, strange dreams, increased appetite, violent outbursts, sweating, hot flashes, chills, and shakiness. This offers further validation of a cannabis withdrawal syndrome. Average withdrawal scores at baseline did not differ with gender, age, treatment type, extent of cannabis use, or a lifetime history of anxiety or affective disorders. Withdrawal scores at baseline did not predict relapse during follow-up.

Increased use of antibiotics in patients treated with clozapine

Clozapine has the potential to cause agranulocytosis and an association to an increased risk of infections has been suggested. Patients with an ICD-10 F20.x were identified from the Danish Central Psychiatric Research Registry and were linked to the national prescription database to identify schizophrenia patients treated with clozapine from 1996 to 2005(N=3374). Binomial regression and Cox proportional hazards models were used. An increased use of antibiotics was found RR=1.43, CI: 1.26-1.61, P<0.0001 and HR 1.14, 95% CI: 1.05-1.24, P=0.0025 with binomial regression and Cox proportional hazard model, respectively. The exact mechanism for the increased risk remains unknown, but the increased risk might be due to aspiration pneumonia caused by hypersalivation and the sedating properties of clozapine. The findings reported here should alert clinicians to be mindful of infectious processes as yet another possible somatic manifestation of clozapine treatment.

Depression and BMI influences the serum vascular endothelial growth factor level.

Recent studies suggest that the angiogenic cytokine vascular endothelial growth factor (VEGF) is involved in the pathogenesis of depression. However, only a few studies have investigated serum VEGF levels in individuals with depression, or the possible association between genetic variants within the VEGF gene and depression. The purpose of the present study was to investigate differences between serum VEGF levels in individuals with depression vs. control individuals, and associations between genetic markers located within VEGF and depression. In addition, determinants of the serum VEGF levels were identified. One-hundred and fifty-five depressed subjects and 280 controls were included in the study. All individuals returned a questionnaire and participated in a semi-structured diagnostic interview. Eleven single nucleotide polymorphisms were successfully analysed. VEGF levels were measured in serum by immunoassay and independent determinants of the serum VEGF level were assessed by generalized linear models.The main findings were that depression, severity of depression, previous depressive episodes, age and body mass index (BMI) were associated with higher serum VEGF levels. The genetic marker rs10434 was significantly associated with depression after correction for multiple testing, but not with the serum VEGF level. Our final model included depression and BMI as predictors of serum VEGF levels. Our study suggests a role for circulating serum VEGF in depression. Furthermore, our data also demonstrate that other factors than a diagnosis of depression influence the serum VEGF level. The importance of these factors should be emphasized when studies are compared.

An association study of suicide and candidate genes in the serotonergic system.

INTRODUCTION Strong evidence demonstrates a genetic susceptibility to suicidal behaviour and a relationship between suicide and mental disorders. The aim of this study was to test for association between suicide and five selected genetic variants, which had shown association with suicide in other populations. METHOD We performed a nationwide case-control study on all suicide cases sent for autopsy in Denmark between the years 2000 and 2007. The study comprised 572 cases and 1049 controls and is one of the largest genetic studies in completed suicide to date. The analysed markers were located within the Serotonin Transporter (SLC6A4), Monoamine Oxidase-A (MAOA) and the Tryptophan Hydroxylase I and II (TPH1 and TPH2) genes. RESULTS None of the genetic markers within SLC6A4, MAOA, TPH1 and TPH2 were significantly associated with completed suicide or suicide method in the basic association tests. Exploratory interaction test showed that the minor allele of rs1800532 in TPH1 has a protective effect for males younger than 35 years and females older than 50 years, whereas for the oldest male subjects, it tended to be a risk factor. We also observed a significant interaction between age-group and the 5-HTTLPR genotype (with and without rs25531) in SLC6A4. The long allele or high expression allele tends to have a protective effect in the middle age-group. LIMITATION We only analysed a limited number of genetic variants. CONCLUSION None of the analysed variants are strong risk factors. To reveal a better understanding of the genes involved in suicide, we suggest future studies should include both genetic and non-genetic factors.