Therapeutic implications of the serotonin transporter gene in depression

Background: A natural variant of the serotonin transporter gene has been studied in mood disorders and its treatment with serotonin transporter inhibitors. It is now available on gene testing profiles to help guide treatment. But the actual interpretation of the data regarding clinical actionable items is controversial. Methods: A review is undertaken to understand the role of the short form in the biology of the brain and its effect on depression and response to serotoninergic antidepressants. Results: There are naturally occurring variants of the serotonin reuptake transporter (SERT) gene that express approximately 50 % fewer SERT units in the synapse. People with these low-expressing variants (frequently referred to as the ‘short form’) are more likely to: 1) develop depression in the setting of adversity; 2) attempt or re-attempt suicide; 3) respond inadequately to an antidepressant; 4) develop side effects when taking an antidepressant; or 5) develop rapid cycling if they have bipolar illness. Emerging data suggest that due to the similarity between these natural variants and the mechanism of action of most antidepressants, chronic use of antidepressants may significantly worsen these consequences in patients with the low-expressing variants or induce similar outcomes in people that do not have the short form variants. Conclusions: Greater caution is required regarding exposure to serotonin reuptake inhibitors (or serotonin/norepinephrine reuptake inhibitors) for people that have the low expressing short form variants of SERT.