While multiple lines of evidence implicate the 5-HT1A receptor in the pathophysiology of anxiety and depression as well as in the mechanism of action of anxiolytics/antidepressants, its relevance to the therapeutic effectiveness of these drugs has been a matter of considerable debate (for review see Griebel, 1995; Hensler, 2003; Hjorth et al., 2000; Lesch et al., 2003). In the current issue of the International Journal of Neuropsychopharmacology, however, both Serretti et al. (2004) and Lemonde et al. (2004) make a strong argument for contribution of a functional 5-HT1A receptor gene variant in the pharmacogenetics of antidepressant treatment with prototypic tricyclics and selective serotonin reuptake inhibitors (SSRIs). Furthermore, the third study in this series by Huang and associates (2004) reveals an association of allelic variation of 5-HT1A receptor expression in a wide spectrum of psychopathology including schizophrenia, substance abuse, and panic disorder. Not unexpectedly, the failure to detect a consistent effect of this gene variation on 5-HT1A receptor functionality in the mature brain as indicated by both receptor binding in post-mortem brain and in-vivo receptor responsivity further supports a critical role of the 5-HT1A receptor in engineering neurodevelopmental processes which may have the potential to set the stage for the brain's permissiveness for psychopathology in later life. The availability of an increasing number of functional gene variants within the serotonergic pathway together with integration of emerging concepts of developmental genetics of complex traits will provide the groundwork for the molecular dissection of syndromal dimensions and treatment response.
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