The fact that risk genes for schizophrenia are salient for brain development or that fetal brain insults mimic the cortical and behavioral pathology of schizophrenia has led to a certain degree of pessimism that these deficits could be ameliorated in the mature brain. Animal models of disorders like schizophrenia that are manifest primarily by cognitive symptoms such as disorganized thinking and hallucinations are based on rather tenuous behavioral inferences such as hyperactivity and stereotypic behavior and are equivalent to psychosis because it is reduced by antipsychotic drugs. Although it has long been known that schizophrenia is associated with loss of cortical volume and increased size of the lateral ventricles, the pathology of the mood disorders was thought to be primarily functional. Biogenic amine neurotransmitters were the major focus of translational research, given their role in mediating the therapeutic effects of antipsychotic and antidepressant medications.

Clozapine is an atypical antipsychotic drug with unique clinical features, particularly in treatment resistant schizophrenia. This chapter concentrates on the genetics of response to the antipsychotic drug clozapine, focusing mainly on pharmacodynamic factors related to clozapine's receptor binding. It is important to note, however, that a pharmacogenetic effect is dependent on functional genetic variation; for some genes, there may be no genetic variation that affects clozapine's action. The use of neuropsychology to assess treatment response in schizophrenia is a new area of investigation. Genetic variation in clozapine's receptor targets is a potential source of pharmacodynamic influence on drug response, by altering drug action. Clozapine therapy has been used as a model system for pharmacogenetic research into antipsychotic drugs. This is largely for the historical reasons that it has high affinity for the dopamine D4 receptor, which shows extensive genetic variability, but also because its pharmacology is well understood.

This chapter discusses the evidence for a heritable component to psychotropic drug response. It reviews basic methodological issues in pharmacogenetic studies of psychotropic drug response, and highlights future directions for pharmacogenetics research in psychiatry. The majority of heritability data on psychotropic drugs is from studies of antidepressant drug response. Antipsychotic drugs are potent dopamine receptor antagonists. Many of the single nucleotide polymorphisms (SNPs) that are being identified may be useful in pharmacogenetic studies. The considerable advantages of the case-control approach for pharmacogenetic studies, coupled with the genomic control methods, suggest that it should be feasible to conduct large-scale pharmacogenetic studies with increased power and with decreased potential for undetected ethnic stratification. The first generation of pharmacogenetic studies that utilized SNPs in relatively limited numbers of candidate genes will be replaced by pharmacogenomic studies in which the complete genome is assessed.

Brain imaging techniques combined with genetics contribute to developing an understanding of the pathophysiological mechanism of disease and treatment response. Psychiatric genetics identifies associations between allelic variation in genes and the risk for the development of psychiatric illness. Although the genetic association of apoE4 with the development of Alzheimer's disease is well established, there is a need to devise strategies that can fill in the missing links between apoE gene variation and the pathophysiological mechanism of Alzheimer's disease. Brain imaging addresses and bridges this gap. The combination of imaging, allelic characterization, and clinical response synergistically contributes to understanding the role apoE4 plays in the development of Alzheimer's disease and its response to treatment. An analogous argument is made for combining brain imaging with allelic subtyping to understand clinical antipsychotic response in schizophrenia. This chapter establishes the efficacy of new pharmacological treatments for groups of patients with schizophrenia and Alzheimer's disease.