Genetic Analysis of Neurobiological Indicators of Antidepressant Drug Response

The genetic analysis of complex behavioural traits has taught us that the phenotype definition is most critical in establishing genotype-phenotype relationships. Global behavioural variables are not directly related to their molecular genetic determinants as many modifying factors are operating. However, neurobiological phenotypes are closer to the impacting molecular genetic variants, and genotype-phenotype relationships can be detected more easily and consistently.

Thus, defining the phenotype in pharmacogenetics by changes in psychopathologically based rating scales might produce inconsistent results with only small effect sizes. Using pharmacologically changes in brain functions as phenotypes might produce more robust results.

In a highly standardized pharmacological treatment protocol (fixed doses, monotherapy with citalopram) in 80 patients with unipolar depression and homogeneous background we selected a series of neurobiological indicators of clinical efficacy as targeted phenotypes. We report on two neurobiological indicators: Antidepressant-induced changes (a) in the regulation of the hypothalamus-pituitary axis (HPA) measured by the DEX-CRH test, and (b) in cognitive functions (memory). We focus on candidate genes which are a priori likely to influence these selected phenotypes (e.g., glucocorticoid- and mineralocorticoid-receptor genes). Haplotype analysis is used to increase the information content of markers. This more hypothesis-driven, standardized approach is able to produce meaningful genotype-phenotype relationships.