Initial conditions of psychotropic drug response: Studies of serotonin transporter long promoter region (5-HTTLPR), serotonin transporter efficiency, cytokine and kinase gene expression relevant to depression and antidepressant outcome

The Hypothesis of Initial Conditions posits that differences in psychotropic drug response result from individual differences in receptor site kinetics, and differences in the sensitivity of downstream receptor-linked responses. This work examines data consistent with the hypothesis, specific to genetic and kinetic differences of the serotonin (5-HT) transporter (SERT), as they may be linked to divergent antidepressant response (ADR). The mechanisms for divergent ADR in association with different initial SERT function are considered within the context of SERT trafficking as sensitive to various different kinase and cytokine signals, some of which are dependent on the 5-HTTLPR polymorphism of the SERT gene. Pilot data suggest that human lymphocytes show kinase changes similar to those found in rat brain with ADT. These studies additionally suggest that ADT prompts a shift in cytokine gene expression toward a greater anti-inflammatory/inflammatory ratio. These latter findings are discussed within the context of a literature suggesting increased inflammatory cytokine levels in depression, and recent observations of increased temperature associated with depression. In sum, the data suggest the opportunity to identify response dependent protein (RDP) expression patterns that may differ with dichotomous ADR, and suggest new insights into understanding the mechanisms of psychotropic drug response through an understanding of initial differences in potential for psychotropic drug target regulation during therapy.