Peripheral Serotonin and CYP2D6: Candidate Biomarkers of Antidepressant Treatment Response

Background and aimMany patients with depressive disorders do not improve with first-line treatment with selective serotonin inhibitors (SSRIs). Adverse drug reactions (ADRs) are common. However, there are no reliable methods to predict treatment response.The general aim of this thesis was to investigate the role of peripheral serotonin and the polymorphic CYP2D6 gene as potential biomarkers of treatment response, including ADRs and suicidality, in depressive disorders. MethodsThe thesis includes material from two clinical cohorts and one systematic review. In the first cohort (paper I) plasma serotonin was analysed at baseline and at week 8 in 26 participants with major depressive disorder that were treated with SSRIs. Paper II is a systematic review that examines the association between peripheral serotonin levels and treatment response to antidepressants. Papers III and IV are based on the Genes, Depression and Suicidality (GEN-DS) cohort, a cross-sectional observational study where 415 patients with depressive disorders were subjected to rigorous diagnostic and anamnestic interviewing and genotyped for CYP2D6. ResultsPaper I: Higher baseline serotonin was associated with SSRI treatment response. Treatment was associated with a decrease of serotonin.Paper II: Several studies reported that higher baseline serotonin was associated with better response to SSRIs, but no studies showed an association between serotonin levels and response to non-SSRIs. Paper III: Patients with CYP2D6 phenotypes with lower metabolizing effect did not report significantly more ADRs. This result remained unchanged when phenoconversion due to CYP2D6-inhibiting comedication was considered.Paper IV: A history of suicide attempts was not overrepresented among CYP2D6 ultra-rapid metabolizers.ConclusionPeripheral serotonin levels may be associated with treatment response specifically to SSRI treatment in depressive disorders, but more studies are needed. The CYP2D6 polymorphism did not predict the occurrence of ADRs in a naturalistic setting. CYP2D6 UM phenotype was not associated with suicide attempts, and further studies of single-gene associations with suicidal behaviours are likely not warranted.