R E V I E W Candidate genes for antidepressant response to selective serotonin reuptake inhibitors Francis E Lotrich Bruce G Pollock University of Pittsburgh Medical Center, Western Psychiatric Institute and Clinic, Department of Psychiatry, Pittsburgh, PA, USA Correspondence: Francis Lotrich WPIC, 3811 Ohara Street Pittsburgh, PA 15213, USA Tel +1 412 246 6267 Fax +1 412 246 6260 Email lotrichfe@upmc.edu Abstract: Selective serotonin reuptake inhibitors (SSRIs) can safely and successfully treat major depression, although a substantial number of patients benefit only partially or not at all from treatment. Genetic polymorphisms may play a major role in determining the response to SSRI treatment. Nonetheless, it is likely that efficacy is determined by multiple genes, with individual genetic polymorphisms having a limited effect size. Initial studies have identified the promoter polymorphism in the gene coding for the serotonin reuptake transporter as moderating efficacy for several SSRIs. The goal of this review is to suggest additional plausible polymorphisms that may be involved in antidepressant efficacy. These include genes affecting intracellular transductional cascades; neuronal growth factors; stress-related hormones, such as corticotropin-releasing hormone and glucocorticoid receptors; ion channels and synaptic efficacy; and adaptations of monoaminergic pathways. Association analyses to examine these candidate genes may facilitate identification of patients for targeted alternative therapies. Determining which genes are involved may also assist in identifying future, novel treatments. Keywords: pharmacogenetic, pharmacogenomic, depression, SSRI Introduction Major depressive disorder (MDD) is a complex disorder associated with various monoaminergic disturbances, abnormalities of endocrine regulation, alterations in sleep physiology, neuroanatomic abnormalities, and neurophysiologic changes (Drevets 1998; Thase 1998; Manji et al 2001; Ordway et al 2002; Moretti et al 2003; Sheline 2003; Buysse 2004). Selective serotonin reuptake inhibitors (SSRIs) are frequently used to treat MDD; however, it is now clear that a large percentage of patients suffering from MDD may not benefit from SSRI treatment (Thase 2003). Evidence from family studies indicates that response to specific antidepressant treatments can be affected by genetic differences (Pare and Mack 1971; O’Reilly et al 1994; Serretti et al 1998). Pharmacogenetics holds the potential to genetically predict who will and will not benefit from SSRIs (Catalano 1999; Pickar and Rubinow 2001; Serretti et al 2002). Moreover, delineating the genes that are associated with poor response to an SSRI may be valuable in identifying alternative patient-specific treatments, such as novel treatments or currently known and available therapies. Until recently, the focus of pharmacogenetics has been on functional gene variants that may contribute to variable antidepressant exposure (ie, pharmacokinetics). Extensive information is now available regarding genetic variation in many important metabolic enzymes (for reviews see Brosen 1993; Cohen and De Vane 1996; Steimer et al 2001; Daly 2003; Evans and McLeod 2003; Mancama and Kerwin 2003). This review will primarily focus on the putative central mechanisms of SSRI activity and what is known about genetic variants that moderate those pathways. It will also discuss the selection of candidate genes based on these pathways. An extensive critique of Neuropsychiatric Disease and Treatment 2005:1(1) 17–35 © 2005 Dove Medical Press Limited. All rights reserved 17