et al 2002). Of note, mineralocorticoid receptor (MR) gene expression is also affected by chronic antidepressant treatment in rats (Brady et al 1991), and MR function has also been linked to the pathophysiology of depression (Young et al 2003). Brain-derived neurotrophic factor and neurogenesis SSRIs can increase neurogenesis in the hippocampus (Malberg et al 2000; Santarelli et al 2003), and hippocampal neurogenesis has been implicated as a requirement for the behavioral effects of antidepressants (Santarelli et al 2003). Increased BDNF, a neurotropin, may mediate this antidepressant effect of SSRIs (Nibuya et al 1995; Duman et al 1997; Altar 1999; Duman et al 1999; Shirayama et al 2002). BDNF may also, in turn, regulate the expression of SERT, an affect that can be modulated by the 5-HTTLPR (Mossner et al 2000). A polymorphism in BDNF has been preliminarily associated with bipolar disorder (Neves- Pereira et al 2002), although this was not found in a Chinese population of subjects with mood disorders (Hong et al 2003). The receptor for BDNF is trkB (troponin/receptor kinase B), which is affected by antidepressant treatment, including SSRIs, and appears to be necessary for antidepressant effects (Rumajogee et al 2002; Saarelainen et al 2003). Moreover, antidepressants not only increase the expression of BDNF and trkB, but also neurotrophin-3, (Nibuya et al 1995; Smith et al 1995; Nibuya et al 1996; Duman et al 1997). Of note, transcription for each of these three is increased by CREB (Duman et al 1997). The cAMP/PKA/CREB mediated effects may therefore be ultimately mediated by BDNF acting at the trkB receptor (Galter and Unsicker 2000). Several intracellular kinases transduce BDNF effects. For example, there are mitogen-activated protein (MAP) kinase cascades, which also involve extracellular signal- regulated protein kinase (ERK) (Gould and Manji 2002; Manji and Chen 2002). BDNF infusion increases ERK phosphorylation and immediate early genes (Shirayama et al 2002). Inhibition of mitogen and extracellular signal- regulated protein kinase (MEK), which mediates the BNDF-induced phosphorylation of ERK, prevents the anti- depressant effects of BDNF in animal models (Shirayama et al 2002). Both MAP kinase and ERK have been implicated in mediating the 5-HT1A effect of inhibiting caspase-3 and apoptosis (Adayev et al 2003). Abnormalities in ERK1 and ERK2 have been noted in animal models of depression (Feng Neuropsychiatric Disease and Treatment 2005:1(1) Candidate genes for SSRI response et al 2003), and decreased neuronal ERK expression is seen in victims of suicide (Dwivedi et al 2001). Other potential downstream effector molecules for BDNF that may enhance neuronal survival, augment neuroplasticity, or decrease apoptosis include Bcl-2 and glycogen synthase kinase 3 (Manji et al 2001; Gould and Manji 2002; Manji and Chen 2002). Additional neurotransmitters There are multiple neurotransmitter systems that interact in complex ways. Further, many of these neurotransmitter systems share the same intracellular transduction pathways. The cholinergic, noradrenergic, and dopaminergic systems may all be dysregulated in depression (Leonard 1996; Chau et al 1999; Iversen 2000; Schatzberg et al 2002; Shytle et al 2002; Shaffery et al 2003). In fact, various polymorphisms in the norepinephrine and dopamine systems have been associated with mood disorders (Jonsson et al 1998; Mason et al 1999; Mitchell et al 2000; Suzuki et al 2001; Massat et al 2002; Ni et al 2002; Ranade et al 2002; Rosmond et al 2002; Urwin et al 2002; Jonsson et al 2003; Ueno 2003). A polymorphism in the muscarinic-2 receptor has also been associated with depression (Comings et al 2002). Preliminary studies do not support roles for select polymorphisms in D2 and D4 dopamine receptors in affecting treatment response (Serretti et al 2001b). However, polymorphisms in other monaminergic and cholinergic receptors may interact with SSRI efficacy. For example, catachol-O-methyltransferase primarily metabolizes dopamine and norepinephrine and has a polymorphism that has been associated with poor response to SSRIs (Catalano 2001). There are abnormalities in the glutamatergic system in depression (Skolnick 2002; Sanacora et al 2003). Moreover, enhancement of α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor activity and decreased NMDA receptor activity may potentiate the antidepressant effect of SSRIs (Rogoz et al 2002; Li et al 2003). Of the 5 genes coding for NMDA receptor subunits (NR1 and NR2A- NR2D) and 4 for AMPA receptors (GluR1-GluR4), a polymorphism in the NR1 gene has preliminarily been associated with mood disorders (Mundo et al 2003). The nitric oxide system also interacts with 5-HT in moderating behavior (McLeod et al 2001; Chiavegatto and Nelson 2003). Interestingly, a polymorphism for neuronal nitric oxide synthetase (C29T) has been preliminarily associated with depression and response to SSRIs (Yu, Chen, 25