Affective dysregulation is a core feature of bipolar disorder (BD), and inter-episodic affect lability is associated with more severe outcomes including comorbidity. Rates of daily tobacco smoking and substance use disorders in BD are high. Knowledge regarding relationships between affective lability and abuse of the most commonly used substances such as tobacco, alcohol and cannabis in BD is limited.
We investigated whether dimensions of inter-episodic affective lability as measured with the Affective Lability Scale - short form (ALS-SF) were associated with lifetime daily tobacco use or alcohol (AUD) or cannabis use disorders (CUD) in a sample of 372 French and Norwegian patients with BD I and II.
ALS-SF total score and all sub-dimensions (anxiety-depression, depression-elation and anger) were significantly associated with AUD, while only the depression-elation sub-dimension was associated with CUD, after controlling for possible confounders such as gender, age at interview, age at illness onset, BD subtype, duration of illness and other substance use disorders. Daily tobacco smoking was not significantly associated with affective lability.
Data for recent substance use or psychiatric comorbidities such as personality or hyperkinetic disorders were not available, and could have mediated the relationships.
AUD is associated with several dimensions of inter-episodic affective lability in BD, while CUD is associated with increased oscillations between depression and elation only. Increased affective lability may partly explain the increased illness severity of patients with BD and AUD or CUD. Affective lability should be treated in order to prevent these comorbidities.
Genetic variants in ankyrin 3 (ANK3) have recently been shown to be associated with bipolar disorder (BD). We genotyped three ANK3 SNPs previously found to be associated with BD (rs10994336, rs1938526, and rs9804190) in a Scandinavian BD case-control sample (N = 854/2,614). Due to evidence of genetic overlap between BD and schizophrenia (SZ), we also genotyped these three SNPs in a Scandinavian SZ case-control sample (N = 1,073/2,919). Combining our Scandinavian samples with an Icelandic sample (N = 435 BD cases, 651 SZ cases, and 11,491 healthy controls), we found rs10994336 and rs9804190 to be nominally significantly associated with BD in this combined Nordic BD sample (N = 1,289/14,105). Nominal P was 0.015/0.018 (fixed/random effect) for rs10994336 (Bonferroni corrected P = 0.044/0.053) and 0.023 for rs9804190 (Bonferroni corrected P = 0.069). None of the SNPs were significantly associated with SZ in the combined Nordic SZ case-control sample (N = 1,724/14,410). These results further support that ANK3 is a susceptibility gene specific to BD and that more than one risk locus is involved.
Several lines of evidence support the theory of schizophrenia (SZ) being a neurodevelopmental disorder. The structural, cytoarchitectural and functional brain abnormalities reported in patients with SZ, might be due to aberrant neuronal migration, since the final position of neurons affects neuronal function, morphology, and formation of synaptic connections. We have investigated the putative association between SZ and gene variants engaged in the neuronal migration process, by performing an association study on 839 cases and 1,473 controls of Scandinavian origin. Using a gene-wide approach, tagSNPs in 18 candidate genes have been genotyped, with gene products involved in the neuron-to-glial cell adhesion, interactions with the DISC1 protein and/or rearrangements of the cytoskeleton. Of the 289 markers tested, 19 markers located in genes MDGA1, RELN, ITGA3, DLX1, SPARCL1, and ASTN1, attained nominal significant P-values (P
A recent hypothesis is that suicidality in schizophrenia may be linked to the patients' altered basic self-awareness or sense of self, termed self-disorders (SDs).
The aim of the study was to investigate whether SDs in first-episode schizophrenia spectrum disorders are related to suicidality and whether this relationship is independent of or mediated by depression or other standard clinical measures.
Self-disorders were assessed in 49 patients with first-episode schizophrenia by means of the Examination of Anomalous Self-Experience (EASE) instrument. Symptoms severity and functioning were assessed using the Structured Clinical Interview for the Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia, and Global Assessment of Functioning-Split Version. Suicidality was measured by the Calgary Depression Scale for Schizophrenia item 8.
Analyses detected a significant association between current suicidality, current depression, and SDs as measured by the EASE. The effect of SDs on suicidal ideation appeared to be mediated by depression.
The interaction between anomalous self-experiences and depression could be a rational clinical target for the prevention of suicidality in the early phases of schizophrenia and supports the rationale for including assessment of SDs in early intervention efforts.
The MCTP2 gene is involved in intercellular signal transduction and synapse function. We genotyped 37 tagging SNPs across the MCTP2 gene to study a possible association with schizophrenia in three independent Scandinavian samples. We report, for the first time, a possible involvement of MCTP2 as a potential novel susceptibility gene for schizophrenia.
The phosphodiesterase 4B (PDE4B), which is involved in cognitive function in animal models, is a candidate susceptibility gene for schizophrenia (SZ) and bipolar disorder (BP). Variations in PDE4B have previously been associated with SZ, with a suggested gender-specific effect. We have genotyped and analyzed 40 and 72 tagging single nucleotide polymorphisms (tagSNPs) in SZ and BP multicenter samples, respectively, from the Scandinavian Collaboration on Psychiatric Etiology (SCOPE), involving 837 SZ cases and 1,473 controls plus 594 BP cases and 1,421 partly overlapping controls. Six and 16 tagSNPs were nominally associated (0.0005
Protein encoding genes have long been the major targets for research in schizophrenia genetics. However, with the identification of regulatory microRNAs (miRNAs) as important in brain development and function, miRNAs genes have emerged as candidates for schizophrenia-associated genetic factors. Indeed, the growing understanding of the regulatory properties and pleiotropic effects that miRNA have on molecular and cellular mechanisms, suggests that alterations in the interactions between miRNAs and their mRNA targets may contribute to phenotypic variation.
We have studied the association between schizophrenia and genetic variants of miRNA genes associated with brain-expression using a case-control study design on three Scandinavian samples. Eighteen known SNPs within or near brain-expressed miRNAs in three samples (Danish, Swedish and Norwegian: 420/163/257 schizophrenia patients and 1006/177/293 control subjects), were analyzed. Subsequently, joint analysis of the three samples was performed on SNPs showing marginal association. Two SNPs rs17578796 and rs1700 in hsa-mir-206 (mir-206) and hsa-mit-198 (mir-198) showed nominal significant allelic association to schizophrenia in the Danish and Norwegian sample respectively (P = 0.0021 & p = 0.038), of which only rs17578796 was significant in the joint sample. In-silico analysis revealed that 8 of the 15 genes predicted to be regulated by both mir-206 and mir-198, are transcriptional targets or interaction partners of the JUN, ATF2 and TAF1 connected in a tight network. JUN and two of the miRNA targets (CCND2 and PTPN1) in the network have previously been associated with schizophrenia.
We found nominal association between brain-expressed miRNAs and schizophrenia for rs17578796 and rs1700 located in mir-206 and mir-198 respectively. These two miRNAs have a surprising large number (15) of targets in common, eight of which are also connected by the same transcription factors.
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Evidence of associations between neurocognitive function and cannabis use in schizophrenia is inconclusive. However, direct measures of cannabis intake and premorbid function are rarely explored in this context. We investigated the relation between cannabis use, determined by its presence in urine, and neurocognitive functioning in schizophrenia controlling for the potential bias of premorbid functioning.
Naturalistic study of 364 patients with schizophrenia spectrum disorder from catchment areas in Oslo, Norway. Hierarchical multiple regression analyses were used to assess the relationship between cannabis in urine and measures of neurocognitive functioning, with adjustment for confounders, including premorbid functioning.
Cannabis was detected in the urine of 21 patients, who had significant dysfunction in several neurocognitive domains independent of a current diagnosis of cannabis abuse. However, level of premorbid functioning explained the associations for all measures.
Differences in premorbid functioning may explain apparent differences in neurocognitive function between schizophrenia spectrum patients using cannabis or not. The findings suggest that illness-related traits present early in life can affect both later cannabis use and neurocognition, probably by complex mechanisms.
Patients with schizophrenia spectrum disorders and substance use may have an earlier onset of illness compared to those without substance use. Most previous studies have, however, too small samples to control for confounding variables and the effect of specific types of substances. The present study aimed to examine the relationship between substance use and age at onset, in addition to the influence of possible confounders and specific substances, in a large and heterogeneous multisite sample of patients with schizophrenia spectrum disorders.
The patients (N=1119) were recruited from catchment areas in Oslo, Stavanger and Bergen, Norway, diagnosed according to DSM-IV and screened for substance use history. Linear regression analysis was used to examine the relationship between substance use and age at onset of illness.
Patients with substance use (n=627) had about 3years earlier age at onset (23.0years; SD 7.1) than the abstinent group (n=492; 25.9years; SD 9.7). Only cannabis use was statistically significantly related to earlier age at onset. Gender or family history of psychosis did not influence the results.
Cannabis use is associated with 3years earlier onset of psychosis.
The gene encoding Catechol O-methyltransferase (COMT), a dopamine catabolic enzyme, is an important candidate gene in several psychiatric disorders. Several studies have shown an association between the functional Val(158)Met polymorphism and cognitive performance. However, the results have been inconsistent and there are few studies addressing other COMT single nucleotide polymorphisms (SNPs).
We investigated SNPs across the whole COMT gene, including the Val(158)Met polymorphism, for a putative effect on working memory, executive function and IQ in 315 patients with schizophrenia or bipolar disorder and 340 healthy controls.
We replicated the association between the Val(158)Met variant and working memory performance, and found a significant interaction between this SNP and diagnosis, with patients with schizophrenia showing a specific, reduced performance on the 2-back test. Several other COMT SNPs were associated with different cognitive functions, but did not remain significant after controlling for multiple testing. We also found significant interaction effects between the SNP variants and gender.
The present study replicates earlier findings showing an association between the functional Val(158)Met polymorphism and working memory performance, with schizophrenia subjects particularly vulnerable. Furthermore, our findings suggest that other parts of the COMT gene seem to affect several related cognitive domains, which further support the notion that COMT is a modifier gene in prefrontal dopamine functioning.