Antidepressant Response Not Linked to Serotonin Transporter Gene
SSRIs theoretically work by inhibiting the reuptake of serotonin, presumably by blocking the serotonin transporter pump whose job is to clean up excess serotonin in the synapses between neurons. Therefore, it makes intuitive sense that variations in the gene that produces the serotonin transporter protein might affect response to SSRIs. In support of this theory, a 1998 study found that people with two short alleles (SS) of this serotonin transporter gene (5-HTTLPR) were less likely to respond to fluvoxamine than patients with either one or two long alleles (Smeraldi E et al, Mol Psychiatry 1998;3:508–511). Several years later, a meta-analysis of 15 other genetic studies appeared to reinforce this finding, reporting that patients with either one or two short alleles of 5-HTTLPR had poorer treatment outcomes than those with normal long alleles (Seretti A et al, Mol Psychiatry 2007;12:247–257).
Research interest in this topic continues to grow. A new meta-analysis of 28 studies updates our understanding on the topic—with quite different results. Across 23 trials, there was no relationship between 5-HTTLPR genotype and antidepressant response. In 15 trials, there was a significantly lower chance of remission for participants with two short alleles (35.6%) compared to those with one or two long alleles (46.4%). However, the effects observed in the remission studies suggested publication bias; after controlling for this bias, there was no effect of 5-HTTLPR genotype on remission (Taylor MJ et al, Biol Psychiatry 2010;68:536–543).
They examined for publication bias by looking at a plot of the various studies’ effects; they noted that small trials tended to yield disproportionately large effects compared to larger studies. Under the likely accurate assumption that small studies without significant effects are unlikely to be published, the researchers plotted the assumed results of unpublished negative studies, which rendered the overall remission results nonsignificant (Risch N et al, JAMA 2009;301:2462–2471). While analysis of publication bias may seem a bit magical, it is explained well at the following link: http://bit.ly/dALmRH.
TCPR’s Take: Genetic research in psychiatry is still at an early stage. It appears that while variations in the serotonin transporter gene has great intuitive appeal as a possible predictor of antidepressant response, we will have to look elsewhere in the genome to find a valid biomarker.