Second-generation antipsychotics (SGAs), such as risperidone, clozapine and olanzapine, are the most common drug treatments for schizophrenia. SGAs presented an advantage over first-generation antipsychotics (FGAs), particularly regarding avoidance of extrapyramidal symptoms. However, most SGAs, and to a lesser degree FGAs, are linked to substantial weight gain. This substantial weight gain is a leading factor in patient non-compliance and poses significant risk of diabetes, lipid abnormalities (that is, metabolic syndrome) and cardiovascular events including sudden death. The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic-induced weight gain (AIWG). We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases. There has been considerable progress reaffirming previous findings and discovery of novel genetic factors. The HTR2C and leptin genes are among the most promising, and new evidence suggests that the DRD2, TNF, SNAP-25 and MC4R genes are also prominent risk factors. Further promising findings have been reported in novel susceptibility genes, such as CNR1, MDR1, ADRA1A and INSIG2. More research is required before genetically informed, personalized medicine can be applied to antipsychotic treatment; nevertheless, inroads have been made towards assessing genetic liability and plausible clinical application.

Context Second-generation antipsychotics (SGAs) are increasingly used in the treatment of many psychotic and non-psychotic disorders. Unfortunately, SGAs are often associated with substantial weight gain, with no means to predict which patients are at greatest risk. Objective To detect alleles of single nucleotide polymorphisms (SNPs) associated with antipsychotic drug-induced weight gain. Design Pharmacogenetic association study Setting Discovery cohort was collected at a U.S. general psychiatric hospital. Three additional cohorts were collected from psychiatric hospitals in the U.S. and Germany, and from a European antipsychotic drug trial. Participants The discovery cohort was comprised of 139 pediatric patients undergoing first exposure to SGA treatment. An additional three cohorts were comprised of 73, 40 and 92 subjects. Intervention Patients in the discovery cohort were treated with SGAs for twelve weeks. Additional cohorts were treated for six and twelve weeks. Main outcome measure We conducted a genome-wide association study (GWAS) assessing weight gain associated with twelve weeks of SGA treatment in patients undergoing first exposure to antipsychotic treatment. We next genotyped three independent cohorts of subjects assessed for antipsychotic drug-induced weight gain. Results GWAS yielded twenty SNPs at a single locus exceeding a statistical threshold of p < 10−5. This locus, near the melanocortin 4 receptor (MC4R) gene, overlaps a region previously identified by large-scale GWAS of obesity in the general population. Effects were recessive, with minor allele homozygotes gaining extreme amounts of weight over the 12-week trial. These results were replicated in three additional cohorts with SNP rs489693 demonstrating consistent recessive effects; meta analysis revealed a genome-wide significant effect (p=5.59×10−12). Moreover, we observed consistent effects on related metabolic indices, including triglycerides, leptin, insulin, and HOMA-IR in our discovery cohort. Conclusion These data implicate the MC4R locus in extreme SGA-induced weight gain and related metabolic disturbances. A priori identification of high-risk subjects could lead to alternative treatment strategies in this population.

Suicide is a prominent public health problem. Its aetiology is complex, and the brain-derived neurotrophic factor (BDNF) has been implicated. We performed the first meta-analysis of the functional BDNF marker Val⁶⁶Met (rs6265, 196G>A) in suicidal behaviour using data from 11 previously published samples plus our present sample (total n=3352 subjects, 1202 with history of suicidal behaviour. The meta-analysis including all 12 studies showed a trend for the Met-carrying genotypes and Met allele conferring risk for suicide (random-effects model p=0.096; ORMet-carrier=1.13, 95% CI 0.98-1.30, and random-effects model p=0.032; ORMet=1.16, 95% CI 1.01-1.32, respectively). Furthermore, we found the Met allele and the Met allele-carrying genotypes to be associated with history of suicide attempt (eight studies; allelic meta-analysis--random-effects model: p=0.013; fixed-effects model: p=0.006; genotypic meta-analysis--random-effects model: p=0.017; fixed-effects model: p=0.008). Taken together, the results from our study suggest that BDNF Val⁶⁶Met is involved in suicidality. Further studies are required to elucidate its role in suicidal behaviour.

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Antipsychotic medication has been enormously helpful in the treatment of psychotic symptoms during the past several decades. Unfortunately, several important side effects that can cause significant morbidity and mortality. The two most common are abnormal involuntary movements (tardive dyskinesia) and weight gain progressing through diabetes to metabolic syndrome. A more rare and life-threatening adverse effect is clozapine-induced agranulocytosis (CIA), which has been linked to clozapine use. Clozapine itself has a unique position among antipsychotic medications, representing the treatment of choice in refractory schizophrenia. Unfortunately, the potential risk of agranulocytosis, albeit small, prevents the widespread use of clozapine. Very few genetic determinants have been clearly associated with CIA due to small sample sizes and lack of replication in subsequent studies. The HLA system has been the main hypothesized region of interest in the study of CIA, and several gene variants in this region have been implicated, particularly variants of the HLA-DQB1 locus. A preliminary genome-wide association study has been conducted on a small sample for CIA, and a signal from the HLA region was noted. However, efforts to identify key gene mechanisms that will be useful in predicting antipsychotic side effects in the clinical setting have not been fully successful, and further studies with larger sample sizes are required.