Candidate genes for SSRI response Administered SSRI Pharmacokinetics and Adherence Peripheral Concentration Phospholipase A2 COMT Norepinephrine Dopamine NET DAT MAOA, TPH Brain SSRI SERT 5-HT Inhibitory G-protein Stimulatory G-protein Phosphodiesterase 4 Adenylyl cyclase cAMP CREB Protein kinase A Protein Kinase C Protein Phosphatases DARPP-32 BDNF, trkB, CRH, CRHR2, glucocorticoid receptor, NOS, ion channels Phospholipase C G-protein Ion Channel Inositol triphosphate Calcium Calmodulin kinase II Dopamine and Norepinephrine Receptors 5-HT1A/B 5-HT 6,7 5-HT 2A/C 5-HT3 Antidepressant response Figure 1 Potential cascade of events mediating and moderating SSRI effects.The multiple inter-regulatory and feedback pathways are absent from this figure. Abbreviations: BDNF, brain-derived neurotrophic factor; COMT, catecholamine-O-methyl-transferase; CRH, corticotropin-releasing hormone; CRH2, CRH receptor2; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element binding protein; DARPP-32, dopamine and cAMP regulated phosphoprotein; DAT, dopamine transporter; MAOA, monoamine oxidase A; NOS, nitric oxide synthase; NET, norepinephrine transporter; 5-HT, serotonin; SERT, serotonin transporter; SSRI, selective serotonin reuptake inhibitor;TPH, tryptophan hydroxylase. and focused approach for selecting multiple candidate genes for association analyses is essential. Several strategies exist for selecting candidate genes for study (see Table 1). One is to focus on mechanisms of action. For example, it is now well established that SSRIs inhibit the serotonin transporter (SERT), acutely increasing serotonin (5-HT) within the synapse. 5-HT then binds to several receptors, triggering subsequent intracellular signaling events through G-proteins (Shelton 2000). Genetic differences influencing any of these initial and intracellular signaling events may alter the efficacy of SSRI treatment (Figure 1). A related strategy focuses on putative downstream effects of SSRIs, such as alterations in growth factors and synaptic remodeling, and the effects on synaptic transmission, other transmitter systems, and/or gluco- corticoids and corticotropin-releasing hormone (CRH). Another strategy is to identify genes potentially involved in the pathophysiology of major depression and related mood disorders such as bipolar depression (Table 2). Although the genes affecting treatment response are not necessarily the same as those increasing vulnerability to various types of depression, they are biologically plausible targets for investigation. Genetic studies using rodent models of depression are capable of identifying novel candidate genes. For example, the linkage of antidepressant response to various chromo- somal regions can be examined in selectively bred and recombinant inbred lines of mice. Candidate genes may be selected from these chromosomal regions; a strategy that is being employed for genes affecting sensitivity to drugs of abuse (Buck 1995; Phillips 1997; Fehr et al 2002). Similarly, pharmacogenomic and pharmacoproteomic studies in which Neuropsychiatric Disease and Treatment 2005:1(1) 19