The growing number of reports on candidate genes an genomic regions of interest in bipolar disorder reveals a tremendously active field of study. As with other complex psychiatric syndromes, these early findings will require a great deal of effort to replicate and clarify. This review serves both as an update and an introduction to some of the issues confronting investigators. Potential strategies in study design, population selection, and molecular methods are explored as well.

Clozapine is a prototype atypical antipsychotic drug and displays efficacy in 30% to 60% of schizophrenia patients who do not respond to traditional antipsychotics. There is considerable evidence supporting a concentration-response relationship for clozapine. A plasma clozapine concentration >200 to 420 ng/mL increases the probability of antipsychotic effects. Approximately 70% to 80% of variability in clozapine plasma concentration can be attributed to variability in cytochrome P450 1A2 activity. Measurement of caffeine metabolites in plasma or urine can be used as an in vivo index of cytochrome P450 1A2 activity, since caffeine is primarily eliminated by oxidative metabolism through this cytochrome P450 enzyme. Caffeine-based tests may contribute to individualization of clozapine dosages and optimization of its antipsychotic effects in schizophrenia patieents There are several lines of evidence suggesting the potential involvement of the dopamine D4 receptor in pharmacodynamic effects of clozapine. Clozapine has a 10-fold higher affinity for the dopamine D4 receptor in comparison to the D2 and the D3 receptors. Moreover, the free plasma fluid concentration of clozapine is comparable to its binding affinity for the D4 receptor in vitro. Blockade of the D4 receptor in the mesocorticolimbic region, a brain area implicated in the pathogenesis of schizophrenia, may contribute to efficacy of clozapine in negative symptoms. Moreover, the dopamine D4 receptor gene (DRD4) displays an unusual degree of genetic variation (polymorphism). In a recent preliminary study, investigated the (G)n mononucleotide repeat polymorphism within the first intron of the D4 gene in 50 schizophrenia patients refractory to traditional antipsychotics. These patients were prospectively followed for antipsychotic response during clozapine treatment. Analysis of variance found significant differences in antipsychotic response as demonstrated by mean change in Brief Psychiatric Rating Scale scores among the genotype panels for this polymorphism F[3,49]=4.1 (P=0.01). Future studies investigating the mechanistic basis of variability in response to clozapine should focus on both pharmacokinetic and pharmacodynamic factors.

Twin and family studies of obsessive-compulsive disorder (OCD) have gleaned important data regarding the influence of genetic factors in the development of this disorder. These studies have shown that understanding the importance of genetic factors in OCD is largely dependent upon how the phenotype is classified. The last decade of research has found that substantial variability of symptomatology exists across individuals diagnosed with OCD. Considering this, a number of analyses have been conducted to determine if possible subtypes of OCD exist, including analysis of age of onset, cluster analysis, factor analysis, and segregation analysis. These methodologies, and possibly others, could aid in identifying the genes involved in the development of OCD.

Systematic studies on the genetics of panic disorder as a distinct nosologic entity separate from anxiety disorders date back to the 1980s. It is, therefore, a relatively new topic for psychiatric genetic investigation. For this reason, available data are not numerous, but findings ensuing from “classical” methods, such as family and twin studies, suggest the involvement of genetic mechanisms to a broad extent, confirmed by the most recent studies. The approaches of molecular genetics, particularly linkage analyses and association studies exploring candidate genes, have led to inconclusive results but have also provided interesting findings that need to be tested in future research.

This article presents a rationale for the hypothesis that an autoimmune mechanism might be involved in the pathogenesis of some forms of obsessive-compulsive aborder (OCO). Existing clinical studies suggesting that some individuals with OCD may have an autoimmune-mediated disorder are briefly summarized. A case example where intravenous immunoglobulin G has been successfully used to treat an adult with OCD spectrum disorder is presented. Preclinical data demonstrating that fragments from the group Αβ hemolytic streptococcus cell wall M proteins can generate antibodies that bind to rat and human tissue are also presented.

Twin, family, and adoption studies indicate that genetic factors play a major role in predisposition to schizophrenia. To date, molecular genetic studies have implicated many different chromosomal locations for the disorder. However, no one site replicates across the majority of investigations. This creates an impasse in the study of schizophrenia genetics, because of the large number of chromosomal sites that require further detailed research. It is difficult to plan to move ahead with expensive and labor-intensive research in an attempt to determine the etiologie genetic factor, when any given site proves to be only weakly positive. Therefore, the use of a hypothesis-driven approach may be cost effective, and may ultimately have more power to detect etiologie genes. Several lines of evidence suggest that a neurodevelopmental defect may play an important role in the etiology of this disorder. Neurodevelopment is a complex process in which genetic and nongenetic factors may interact to create the mature differentiated neuron, with its particular network of synaptic connections. A reasonable chance exists that polymorphisms of the genes that control normal development of the central nervous system (CNS) may produce a slightly altered trajectory of brain development, predisposing individuals to schizophrenia. This assumption has led geneticists to begin to study neurodevelopmental genes in schizophrenia subjects. This article reviews and discusses genetic studies of some developmental genes in schizophrenia. Genetic association and linkage studies of neurotrophic factors (brain-derived neurotrophic factor, or BDNF, and neurotrophin-3, or NT-3), neuronal cell adhesion molecule (NCAM), synapsin, and synaptosome-associated protein with a mass of 25 kd (SNAP-25) have proven to be of most interest.