that the half-life of SERT is about 3 to 4 days (Vicentic et al 1999), a new steady-state in SERT levels would take about 2 weeks. Serotonin receptors At least 14 genes coding for 5-HT receptors are known, although post-transcriptional processing can result in over 30 5-HT receptor subtypes (Raymond et al 2001). Genetic differences in receptor number (Bmax), binding (Kd), kinetics (Vmax and Km), and desensitization rates for some of these receptors may potentially affect SSRI action. To date, there are data suggesting the plausible involvement of at least seven specific 5-HT receptors in mediating SSRI effects. One class of 5-HT receptors (including 5-HT1a and 5- HT1b) interacts primarily with inhibitory G-proteins to decrease adenylyl cyclase (AC) activity. The 5-HT1a receptor has been implicated in many SSRI effects (Dhaenen 2001; Bourin et al 2002; Blier and Ward 2003; Monaca et al 2003). For example, blockade of 5-HT1a with antagonists or the use of 5-HT1a knockout mice prevents the effect of SSRIs on paradoxical sleep (Monaca et al 2003). Blockade of this receptor also can augment antidepressant response to SSRIs (Artigas et al 2001). Moreover, a 5-HT1a polymorphism (C-1019G) has recently been associated with vulnerability to major depression (Lemonde et al 2003). The 5-HT1b receptor has also been associated with irritability, aggression, impulsivity, and possibly mood disorders (Sanders et al 2002). In knockout mice lacking 5-HT1b, some effects of SSRIs are abolished (Monaca et al 2003), and 5-HT1b antagonists can also attenuate some SSRI effects (Millan et al 2003). Polymorphisms in the gene for 5-HT1b, including a common A(-161)T SNP in the promoter region, have been preliminarily associated with several psychiatric phenotypes, including suicide (Hawi et al 2002; Sanders et al 2002). A second class of receptors includes 5-HT6 and 7. Each of these receptors primarily interacts with stimulatory G- proteins to increase adenylyl cyclase activity. Their function has been less studied to date. The 5-HT6 receptor is involved in neuronal serotonergic transmission and may have effects on anxiety and mood (Yoshioka et al 1998). Further, a 5- HT6 polymorphism (C267T) has been associated with Parkinson’s disease (Messina et al 2002). Although an initial study with 34 patients did not find an effect of a single 5- HT6 polymorphism on treatment response (Wu et al 2001), a more definitive study may be required to determine its Candidate genes for SSRI response potential involvement in SSRI efficacy. The 5-HT7 receptor is involved in hippocampal function (Gill et al 2002), and has been implicated in the regulation of the glucocorticoid receptor (Laplante et al 2002). 5-HT2a and 5-HT2c receptors primarily act at G-proteins associated with phospholipase C (PLC). The 5-HT2a receptor may play a role in SSRI response (Bonhomme and Esposito 1998). In fact, antagonism at 5-HT2a can augment the efficacy of SSRIs (Marek et al 2003), and response to SSRI treatment has been associated with normalization of 5-HT2a receptor binding (Messa et al 2003). Consistent with these findings, polymorphisms in the 5-HT2a gene (eg, G- 1438A and C102T) may be associated with vulnerability to depression and suicide (Enoch et al 1999; Du et al 2000; Arias et al 2001; Du et al 2001; Holmes et al 2003), although this association has not been replicated in all studies (Bondy et al 2000; Minov et al 2001). Further, a 5-HT2a poly- morphism (G-1438A) may be associated with the response to SSRIs in several populations (Cusin et al 2002; Sato et al 2002; Sugie et al 2003). A recent study in elderly depressed subjects suggested that a 5-HT2a polymorphism (C102T) may also be associated with sensitivity to the adverse effects of mirtazapine, but was without influence on SSRI adverse effects (Murphy GM et al 2003b). SSRIs also affect the function of the 5-HT2c receptor (Bristow et al 2000), with some adverse effects potentially mediated by 5-HT2c. For example, the acute increases in anxiety reported with SSRIs may be attenuated with 5-HT2c antagonists, as assessed in animal models (Dekeyne et al 2000; Bagdy et al 2001). The 5-HT3 receptor, which is an ionophore, may also be involved in mood disorders (Niesler et al 2001) and sensitivity to some SSRI effects (Redrobe and Bourin 1997). For example, 5-HT3 antagonists can decrease SSRI-induced nausea (Wilde and Markham 1996). G-proteins Other than for the 5-HT3 receptor, most of the downstream effects of 5-HT are mediated by G-proteins (Raymond et al 2001). There are 16 genes for G-protein α subunits, 5 for β, and 12 for γ (Downes and Gautam 1999). In general, the αs family activates adenylyl cyclases, the αi family inhibits adenylyl cyclases, and the αq family activates phospholipase C isozymes. The βγ complex modulates the activity of the G protein α subunit. Many of these subunits are expressed within the brain (Downes and Gautam 1999). The αs subunit, which mediates many of the effects of 5-HT6 and 5-HT7 receptors, has a polymorphism in exon 5 Neuropsychiatric Disease and Treatment 2005:1(1) 21