Lotrich and Pollock genotyping procedures (Schulze et al 2003) that require consideration. Many studies reviewed above have insufficient sample sizes to meaningfully interpret “negative” findings. Future studies carefully attending to these issues will likely yield a useful picture regarding the genetic variation affecting SSRI response. Candidate genes for these association analyses, selected from known and putative pathways of SSRI action, include polymorphisms affecting the serotonin transporter, serotonin receptors, intracellular transduction, the HPA axis, BDNF and neurogenesis, and other neurotransmitter systems. A complete picture of genetic variation will involve determining the relative role of multiple polymorphisms, their effect sizes, their interactions, their interactions with pharmacokinetic differences, and their relationship with environmental factors that influence treatment outcome. As noted above, there are many methodological issues that require close consideration. There is wide variation among studies in attention to these issues (eg, careful definition of the study population in terms of ethnicity, demographics, environment, diagnoses, and comorbidities; careful definition of types of response; controlling for genetic variability in placebo response; controlling for differences in medication exposure; appropriate statistical analyses and attention to population substructure; and appropriate selection of a set of polymorphisms across the candidate gene). This is a nascent, but quickly maturing field. To date, studies that have carefully attended to these concerns are very limited. Nonetheless, it is reasonable to predict that the goal of genetically determining which individual patients will benefit from SSRIs and which should be targeted for alternative therapies may be attainable in the near future. Acknowledgments Supported by NIMH grants MH65416, MH30915, MH52247, and MH16804. Abbreviations AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid; AKAP79/150, A-kinase anchoring protein 79/150; AC, adenylyl cyclase; ApoE, apolipoprotein E; BCL-2, B-cell leukemia-2; GluR1-GluR4, AMPA receptor subunits; BDNF, brain-derived neurotrophic factor; CAMKII, calcium/calmodulin-dependent protein kinase II; CRH, corticotropin- releasing hormone; cAMP, cyclic adenosine monophosphate; CRE, cAMP response element; CREB, cAMP response element-binding protein; DARPP-32, dopamine and cAMP regulated phosphoprotein; ERK, extracellular signal-regulated protein kinase; GIRK, G-protein-gated inwardly rectifying potassium channel; Kir, GIRK subunit; GR, glucocorticoid receptor; HPA, hypothalamic-pituitary-adrenal; MDD, major depressive disorder; MTHFR, methylenetetrahydrofolate reductase; MAP2, microtubule associated protein 2; MR, mineralocorticoid receptor; MAP, mitogen-activated protein; MEK, mitogen and extracellular signal- regulated protein kinase; MAOA, monoamine oxidase A; MAOB, monoamine oxidase B; MARCKS, myrisoylated alanine-rich C-kinase substrate; NMDA, N-methyl-D-aspartate; NR, NMDA receptor subunit; PDE, phosphodiesterase; PLC, phospholipase C; Pyk2, proline-rich tyrosine kinase 2; PKA, protein kinase A; PKA RIIb, PKA regulatory subunit IIb; PKC, protein kinase C; PP, protein phosphatase; RACK, receptor for activated PKC; RGS, regulator of G-protein signaling; SSRI, selective serotonin reuptake inhibitor; 5-HT, serotonin; SERT, serotonin transporter; SLC6A4, SERT gene; 5-HTTLPR, serotonin transporter linked polymorphic region; SNP, single nucleotide polymorphism; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor; trkB, troponin/receptor kinase B; TPH, tryptophan hydroxylase. 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