Progress to date, however, in the pharmacogenetics of depression has been limited. Several factors may be responsible. First, depression is an extremely heterogeneous disorder (or group of disorders), in which multiple genetic and environmental factors may interact in as yet unknown ways to contribute to the development of the full syndrome. Among the major psychiatric disorders, this can be observed by examination of heritability estimates for axis I adult psychiatric disorders. For schizophrenia and bipolar disorder, heritability estimates approximate 80%, but for depression, the considerably lower estimates of less than 40% (2) suggest that the underpinnings of this disorder may be even more complex. A second challenge is the difficulty in assuring that the assessment of the pharmacogenetic phenotype is sufficiently accurate to allow for detection of presumably subtle genetic effects. In clinical trials of depression, adherence rates may be as low as 50% (3). This may be permissible to some degree in clinical trials utilizing effectiveness models but will result in underestimation of the true effect sizes between genotypes and phenotypes in studies intended to assess a drug's effect on biological systems. Similarly, variable treatment with concomitant medications may further obscure genotype-phenotype relationships. Finally, placebo response rates are relatively high in depression, and "true" antidepressant drug responders may be grouped with a substantial number of placebo responders, thereby confounding pharmacogenetic analyses intended to identify specific gene-drug interactions.