The pharmacogenomics of selective serotonin reuptake inhibitors

Abstract

The introduction of selective serotonin (5-HT) reuptake inhibitors (SSRIs) has significantly improved the pharmacological treatment of a range of psychiatric disorders. Nevertheless, despite the undoubted advantages of antidepressant treatment in terms of improved tolerability to therapy while maintaining a high level of efficacy, not all patients benefit from it; an appreciable proportion do not respond adequately, while others may show adverse reactions. The necessary change of the initial treatment choice often requires extended periods for the remission of symptomatology. Such difficulties could be avoided if it should be possible to determine more quickly the most suitable drug. Several factors have been thought to influence the outcome of antidepressant therapy. Among the factors influencing the interindividual variability in response to treatment with SSRI, differences in genetic features may play a significant role. Several genetic polymorphisms have been associated with therapeutic SSRI response, including genetic variants of the 5-HT transporter, 5-HT-2A-receptor, tryptophan hydroxylase, brain-derived neurotrophic factor, G-protein beta3 subunit, interleukin-1beta and angiotensin-converting enzyme, although with conflicting results; also cytochrome P450 drug-metabolising enzymes may bear a particular importance, although further corroboration of the findings is necessary, and further key participating genes remain to be identified. The hope is that the identification of these genetic components will eventually facilitate the development of a customised SSRI treatment. 1 These drugs show high efficacy, and relatively few adverse reactions compared with the previously used tricyclic antidepressants, even though their mechanism of action is not entirely understood yet. However, these drugs are effective in only about two-thirds of depressed patients.2 The necessary change of the initial treatment choice often requires extended periods for the remission of symptomatology. Such difficulties could be avoided if it would be possible to determine more quickly the most suitable drug for each subject. Several factors have been thought to influence the outcome of antidepressant therapy and efficient clinical predictors have not been yet identified, but there is some evidence suggesting that genetic factors play a substantial role.

Transgenic elimination of high-affinity antidepressant and cocaine sensitivity in the presynaptic serotonin transporter

“…Whereas the actions of 5-HT are mediated by more than a dozen different receptors, 5-HT inactivation is dictated largely by a single protein, the presynaptic 5-HT transporter (i.e., SERT, SLC6A4). Recognition of the mood regulating actions of 5-HT in the CNS and a desire to eliminate the side effects of first-generation antidepressants led to the development of selective 5-HT reuptake inhibitors (SSRIs), typified by fluoxetine (Prozac) (5). Subsequent drug development resulted in more selective SSRIs, including citalopram (Celexa), s-citalopram (Lexapro), paroxetine (Paxil), and sertraline (Zoloft), among others.…”

“…Indeed, despite their high affinity for SERT, SSRIs have been found to interact with many other proteins, including ion channels (7,8), receptors (9), signaling proteins (10)(11)(12)(13)(14), and transcription factors (15)(16)(17), conceivably accounting for dose-limiting side effects and/or therapeutic actions (18). Finally, many patients treated with SSRIs have a poor treatment course outcome or do not show a response and may abandon treatment, with potentially life-threatening consequences (5). Tools are needed that can clarify the role of SERT in the actions of SSRIs and psychostimulants (and thereby 5-HT) in vivo.…”

Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients

“…Hardy-Weinberg equilibrium was examined in studies where genotype frequencies were included. 9,[15][16][17][18][19][20][21][22][23][24][25] Given the lack of unequivocal data for 5-HTTLPR genotype pooling, we tested both dominant and recessive hypotheses: l/l versus l/s-s/s and l/l-l/s versus s/s. Outcome was defined with three phenotypes: remission rate, response rate, and response rate within 4 weeks.…”

Pharmacogenomic Evaluation of the Antidepressant Citalopram in the Mouse Tail Suspension Test

“…Using genetic information to identify patients that are most likely to respond to a particular antidepressant would allow for more rational drug treatment that could improve overall therapeutic efficacy by matching individual patients to the best treatments. Several polymorphisms have been associated with SSRI response in humans, including genetic variants of the 5-HT transporter, 5-HT 2A receptor, tryptophan hydroxylase, G-protein beta3 subunit, and interleukin-1beta (Serretti and Artioli, 2004).…”