Identifying genetic basis for suicide prevention by clozapine: the EGF-MAPK-ERK signaling pathway

There is now unequivocal evidence that clozapine is superior to any other antipsychotic drug (APD) to reduce the risk for suicide in schizophrenia. Twin and family studies suggested that there is a significant heritability of 30 to 50% for suicidal behavior. Identifying genetic markers for the risk for suicide, and prediction of the ability of clozapine to reduce the risk would be expected to significantly increase its utilization for suicide risk reduction by reducing the risk to benefit ratio Genetic markers might also facilitate the identification of novel drug targets for other, easier to use, perhaps even more effective, anti-suicide drugs. Neurobiological and genetic studies suggest that complex interaction of networks of genes and environmental factors contribute to suicide. GWAS has identified subgroups of suicide attempters consistent with the 5-HT hypothesis of suicide risk. We and others have shown that action of clozapine on a variety of 5-HT receptors, specifically, 5-HT2A, 5-HT1A, 5-HT2C, 5-HT6 and 5-HT7 receptors, as well as dopamine (DA) D1 and D2 receptors, are of great importance for some of its special clinical advantages, including treatment resistant positive symptoms, low extrapyramidal side effects, weight gain, and cognition. No other atypical or typical APD has exactly this receptor profile, which leaves open the possibility that this combination of neurotransmitter effects could be relevant to its most unique feature, reducing the risk for suicide, especially since 5-HT receptors are key regulators of dopamine, glutamate, GABA, and cholinergic neurons. It is unlikely, however, that serotonergic or dopaminergic mechanisms alone, are sufficient to explain the unique effects of clozapine on suicide or to be the sole basis for the necessary polygenic approach. There is evidence for the involvement of genes involving intracellular signaling as risk factors for suicide and for a differential effect of clozapine compared to other APDs on these crucial complex pathways that are tightly coupled to the actions of GPCRs. In this study, we will conduct a case-control study to identify genetic variants associated with suicide using GWAS and genotyping of candidate genes. We will also verify any genes associated with suicide from a longitudinal study from InterSePT. The proposed work is expected to identify risk genes for suicide attempt in schizophrenia patients based upon a GWAS with the special feature of a focus on intracellular signaling mechanism which are activated by clozapine in a unique manner and for which there is evidence that this activation is relevant to its ability to diminish suicide risk.