https://www.cell.com/trends/neurosciences/pdf/S0166-2236(08)00132-X.pdf

White matter in learning, cognition and psychiatric disorders.

Risk assessment is a core skill in psychiatry. Risk prediction for suicide in schizophrenia is known to be complex. We undertook a systematic review of all original studies concerning suicide in schizophrenia published since 2004. We found 51 data-containing studies (from 1281 studies screened) that met our inclusion criteria, and ranked these by standardized quality criteria. Estimates of rates of suicide and risk factors associated with later suicide were identified, and the risk factors were grouped according to type and strength of association with suicide. Consensus on the lifetime risk of suicide was a rate of approximately 5%. Risk factors with a strong association with later suicide included being young, male, and with a high level of education. Illness-related risk factors were important predictors, with number of prior suicide attempts, depressive symptoms, active hallucinations and delusions, and the presence of insight all having a strong evidential basis. A family history of suicide, and comorbid substance misuse were also positively associated with later suicide. The only consistent protective factor for suicide was delivery of and adherence to effective treatment. Prevention of suicide in schizophrenia will rely on identifying those individuals at risk, and treating comorbid depression and substance misuse, as well as providing best available treatment for psychotic symptoms.

/pdf/suicide-and-schizophrenia-a-systematic-review-of-rates-and-emwem38nf2.pdf

Suicide and schizophrenia: a systematic review of rates and risk factors

https://www.cell.com/trends/pharmacological-sciences/pdf/S0165-6147(04)00171-3.pdf

Importance of P-glycoprotein at blood-tissue barriers.

Molecular genetic studies of personality began with two high impact papers in 1996 that showed provisional associations between the dopamine DRD4 exon III repeat region and Novelty Seeking/Extraversion. These first two reports were shortly followed by an investigation linking Neuroticism/Harm Avoidance with the serotonin transporter (SLC6A4) promoter region polymorphism (5-HTTLPR). In the ensuing decade, thousands of subjects have been studied for association between these genes and personality, assessed by using self-report questionnaires, with erratic success in replication of the first findings for Novelty Seeking (DRD4) and Harm Avoidance (5-HTTLPR). Small effect sizes characteristic of non-Mendelian traits, polygenic patterns of inheritance and true heterogeneity between studies confound attempts to reach a consensus regarding the role of common polymorphisms in contributing to personality domains. Nevertheless, the current state of personality genetics is far from being bleak. Several new paradigms especially functional neuroimaging or 'imaging genomics' have strengthened the connection between 5-HTTLPR and anxiety-related personality traits. The demonstrations that early environmental information can considerably strengthen and even uncover associations between genes and behavior (Caspi's seminal studies and more recently the demonstration that early environment impacts on DRD4 and Novelty Seeking) are notable and herald a new era of personality genetics. Finally, consideration of the broader phenotypic expression of common polymorphisms (e.g. the 'social brain', altruism, etc.) and the use of new experimental paradigms including neurophysiological, neuropsychological and computer games that go beyond the narrow self-report questionnaire design will enable a deeper understanding of how common genetic polymorphisms modulate human behavior. Human personality, defined by Webster as the quality or state of being a person or the complex of characteristics that distinguishes an individual, surely requires a more encompassing view towards understanding its complex molecular genetic architecture.

The molecular genetic architecture of human personality: beyond self-report questionnaires

Molecular and cellular mechanisms of altered GAD1/GAD67 expression in schizophrenia and related disorders

Most antipsychotic drugs act on the forebrain by blocking dopamine receptors. In rodents, the M5 muscarinic receptor (CHRM5) is important for prolonged dopamine release. We typed polymorphisms in CHRM5 and alpha7-nicotinic receptor (CHRNA7) genes on 15q13 in 82 Canadian families having at least 1 schizophrenic patient. Using the Family-Based Association Test, we performed haplotype analysis of the 2 loci and found biased transmission in schizophrenia (z = -2.651, p = 0.008). In the families tested, the 2 cholinergic genes interacted to affect schizophrenia in combination, while neither was sufficiently alone to confer susceptibility. Our present study provided the first line of direct evidence suggesting that the CHRM5 gene combined with the CHRNA7 gene may be linked to schizophrenia.

Linkage of M5 Muscarinic and α7-Nicotinic Receptor Genes on 15q13 to Schizophrenia

Cholinergic dysfunction is one of the hypotheses for the cognitive deficits of schizophrenia. Neurocognitive deficits, which are well-described clinical features of schizophrenia, may be remediated by nicotine; therefore investigations of nicotinic receptor subtypes is of considerable clinical interest. We typed polymorphisms in CHRNA4 and CHRNB2 genes controlling the expression of neuronal high-affinity nicotinic receptors in 117 Canadian families having at least one schizophrenic patient. Using a family-based association strategy, we performed allele, haplotype and interaction analysis of these two loci. In the families tested, the two cholinergic genes interact to affect schizophrenia in combination (P=0.010), while neither was sufficient alone to confer susceptibility. Our present study provided the first line of direct evidence suggesting that the CHRNA4 gene combined with CHRNB2 receptor gene may be linked to schizophrenia.

Genetic interaction between α4 and β2 subunits of high affinity nicotinic receptor: analysis in schizophrenia

Gene-gene interaction between MAOA and COMT in suicidal behavior: analysis in schizophrenia.

The involvement of the multi-drug-resistant 1 P-glycoprotein gene (MDR1 P-gp) in the transport of antidepressants across the blood-brain barrier makes it a good candidate for the prediction of antidepressant response and side effects. We investigated the role of the MDR1 P-gp gene in predicting the induction of mania in bipolar patients (BP) treated with proserotonergic drugs. Participants met the DSM-IV criteria for BP or BPII and had at least one depressive episode treated with proserotonergic antidepressants. The first group (n=26) included patients with at least one DSM-IV manic/hypomanic episode developed during antidepressant treatment; the second group (N=29) included patients with no antidepressant-induced switches. The common polymorphism of the MDR1 was genotyped for both groups and comparison was made with respect to the presence/absence of induced mania between the two groups. No association between antidepressant-induced mania and the MDR1 alleles or genotypes was found (chi2=1.85, 2 df, P=0.39; chi2=0.13, 1 df, P=0.72).

Greg W.H. Wong

Papers

Linkage of M5 Muscarinic and α7-Nicotinic Receptor Genes on 15q13 to Schizophrenia

Genetic interaction between α4 and β2 subunits of high affinity nicotinic receptor: analysis in schizophrenia

Gene-gene interaction between MAOA and COMT in suicidal behavior: analysis in schizophrenia.

Investigation of polymorphism in the MDR1 gene and antidepressant-induced mania.

Association study between the novel functional polymorphism of the serotonin transporter gene and suicidal behaviour in schizophrenia.