Lotrich and Pollock the expression levels of genes (either measuring mRNA or the protein itself) are evaluated following SSRI treatment, may be useful in identifying novel genes that are important in mediating SSRI effects (Yamada et al 2000; Landgrebe et al 2002). This review will highlight candidate genes that are selected based on known or prominently postulated mechanisms of SSRI action, including the initial effects on synaptic serotonin, intracellular events, and the downstream effects on growth factors and other neurotransmitter systems (Figure 1). Supplementary evidence for the involvement of genes or polymorphisms (Table 2) in depression and related mood disorders will also be noted. 5-HT transporter and 5-HT availability Several proteins and the genes that encode them affect the initial pathways of SSRI action. A polymorphism in the upstream regulatory site for the SERT gene (SLC6A4) has been widely studied. This SERT polymorphism (serotonin transporter linked polymorphic region; 5-HTTLPR) involves the presence or absence of a 44 base-pair segment, which produces a long (L) or short (S) allele; a difference that can influence transcriptional activity (Heils et al 1997; Lesch 1998). 5-HTTLPR has been associated with susceptibility to depression (Caspi et al 2003), although there is considerable heterogeneity between studies (Lotrich et al 2001; Lotrich and Pollock 2004). The S allele has also been associated with diminished response to several SSRIs as compared with the L allele in multiple studies (Arias et al 2000; Pollock et al 2000; Zanardi et al 2000; Rausch, Johnson, et al 2002; Yu et al 2002; Arias et al 2003), with two exceptions in Asian populations (Kim et al 2000; Yoshida, Iko, et al 2002). The S allele may also increase vulnerability to SSRI side effects (Mundo et al 2001; Murphy GM et al 2003b). While the general finding of worse outcome in SSRI-treated patients with the S allele has been well replicated, discrepant reporting in several of these studies makes it difficult to determine the effect size of this polymorphism. Among issues to be further clarified is the effect of 5-HTTLPR in different ethnic populations; linkage disequilibrium with other polymorphisms in different ethnic populations; the effect size in different age groups and at different doses of SSRIs; delineating which depressive symptoms and side effects are influenced; and determining how this polymorphism interacts with other polymorphisms. Moreover, the role of other SLC6A4 polymorphisms remains comparatively unexamined (Lesch 1998; Battersby et al 1999; Michaelovsky et al 1999; Nakamura et al 2000; Ito et al 2002). In addition to SERT, monoamine oxidase A (MAOA), although not typically expressed in 5-HT neurons, also affects 5-HT levels (Saura et al 1996; Richards et al 1998). A functional polymorphism in the upstream regulatory region for MAOA (Sabol et al 1998) can influence response to SSRIs (Yoshida, Naito et al 2002; Yoshida et al 2003). As with 5-HTTLPR, the frequency and effect size may differ among ethnic groups (Yoshida, Naito et al 2002). Monoamine oxidase B (MAOB) is present in 5-HT neurons but is less effective in metabolizing 5-HT than MAOA (Saura et al 1996; Richards et al 1998). MAOB polymorphisms (Balciuniene et al 2002) have been examined for associations with Parkinson’s disease, but we are unaware of any published studies examining a role in affecting SSRI response. Tryptophan hydroxylase (TPH) is the rate-limited enzyme in 5-HT synthesis. A single nucleotide polymorph- ism (SNP), A218C, may be part of a GATA transcription factor binding site, and has been associated with suicidal behavior in Caucasians (Rujescu et al 2003). Initial reports associated this polymorphism with the rate of response to SSRIs (Serretti et al 2001a; Serretti, Zanardi, Rossini, et al 2001), although this was not replicated in a smaller study with Japanese subjects (Yoshida, Naito, et al 2002). A second gene coding for tryptophan hydroxylase has been identified; however, whether it is expressed in the human brain remains controversial (Patel et al 2004). An additional enzyme, methylenetetrahydrofolate reductase (MTHFR), is involved in monoamine synthesis, and an MTHFR polymorphism (C677T) has been associated with major depression (Bjelland et al 2003). There are also a number of pathways indirectly regulating synaptic 5-HT by influencing SERT. For example, protein kinase C (PKC) activation can decrease SERT activity (Qian et al 1997; Ramamoorthy et al 1998). Conversely, SERT co-exists in a complex with protein phosphatase 2A (PP2A), and dephosphorylation by PP2A can increase transporter activity at the cell surface (Bauman et al 2000). Phosphorylation by calcium/calmodulin- dependent protein kinase II (CAMKII) may also enhance SERT activity (Yura et al 1996), as can various tyrosine kinases (Helmeste and Tang 1995). Moreover, transcription of the SERT gene may be affected by both PKC and protein kinase A (PKA) (Mossner et al 2000). Interestingly, given 20 Neuropsychiatric Disease and Treatment 2005:1(1)