Peripheral serotonin levels as a predictor of antidepressant treatment response: A systematic review.

There are currently no reliable biomarkers to predict clinical response to pharmacological treatments of depressive disorders. Peripheral blood 5-hydroxytryptamine (5-HT; serotonin) has been suggested as a biomarker of antidepressant treatment response, but there has not been an attempt to systematically summarize and evaluate the scientific evidence of this hypothesis. In this systematic review we searched MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials. Twenty-six relevant studies investigating peripheral 5-HT as an antidepressant biomarker were identified. In all, we did not find robust support for an association between baseline 5-HT and treatment response. Several larger studies with lower risk of bias, however, showed that higher baseline 5-HT was associated with a greater antidepressant response to SSRIs, prompting future studies to investigate this hypothesis. Our results also confirm previous reports that SSRI treatment is associated with a decrease in peripheral 5-HT levels; however, we were not able to confirm that larger decreases of 5-HT are associated with better treatment outcome as results were inconclusive.

CYP2D6 Genotyping and Inhibition as Predictors of Adverse Drug Reactions in Depressive Disorders.

Objective: The primary aim of this study was to examine the association between the different predicted phenotypes of the polymorphic CYP2D6 gene and the prevalence of adverse drug reactions in patients suffering from depressive disorders. The secondary aim was to investigate if comedication with CYP2D6 inhibitors resulted in more adverse drug reactions due to phenoconversion.Methods: Between January 2012 and December 2021, 415 patients with a depressive disorder and insufficient treatment response in secondary psychiatric care were included in the naturalistic observational study Genes, Depression, and Suicidality (GEN-DS). The patients were subjected to a semistructured interview and diagnosed according to DSM-IV. Patients were also required to complete the self-rating version of the UKU Side Effect Rating Scale. All patients were genotyped for CYP2D6 and assigned a corresponding predicted CYP2D6 phenotype.Results: Out of the 415 patients, 147 patients with available genotyping and UKU scale results were also prescribed 1 or more drugs metabolized by CYP2D6. We did not find any evidence of an effect of the predicted CYP2D6 phenotype on the total burden of adverse drug reactions or in any of the specific symptom domains as measured with the UKU scale among these patients. We also investigated if comedication with 1 or more substances that inhibited the effect of the CYP2D6 enzyme resulted in more reported adverse drug reactions due to phenoconversion. Even though the rate of phenotypic PMs increased from 13 to 38 patients, we did not find any support for increased adverse drug reactions in this group.Conclusions: We did not find that CYP2D6 phenotype could predict the occurrence of adverse drug reactions in patients with depressive disorders in this naturalistic setting. However, information about CYP2D6 genotype may still be important in antidepressant treatment for the selection of appropriate drugs, for dosing recommendations of certain medications, or when the patient is suffering from severe adverse reactions.

Plasma circulating cell-free mitochondrial DNA in depressive disorders.

BACKGROUND: Plasma circulating cell-free mitochondrial DNA (ccf-mtDNA) is an immunogenic molecule and a novel biomarker of psychiatric disorders. Some previous studies reported increased levels of ccf-mtDNA in unmedicated depression and recent suicide attempters, while other studies found unchanged or decreased ccf-mtDNA levels in depression. Inconsistent findings across studies may be explained by small sample sizes and between-study variations in somatic and psychiatric co-morbidity or medication status. METHODS: We measured plasma ccf-mtDNA in a cohort of 281 patients with depressive disorders and 49 healthy controls. Ninety-three percent of all patients were treated with one or several psychotropic medications. Thirty-six percent had a personality disorder, 13% bipolar disorder. All analyses involving ccf-mtDNA were a priori adjusted for age and sex. RESULTS: Mean levels in ccf-mtDNA were significantly different between patients with a current depressive episode (n = 236), remitted depressive episode (n = 45) and healthy controls (n = 49) (f = 8.3, p<0.001). Post-hoc tests revealed that both patients with current (p<0.001) and remitted (p = 0.002) depression had lower ccf-mtDNA compared to controls. Within the depressed group there was a positive correlation between ccf-mtDNA and "inflammatory depression symptoms" (r = 0.15, p = 0.02). We also found that treatment with mood stabilizers lamotrigine, valproic acid or lithium was associated with lower ccf-mtDNA (f = 8.1, p = 0.005). DISCUSSION: Decreased plasma ccf-mtDNA in difficult-to-treat depression may be partly explained by concurrent psychotropic medications and co-morbidity. Our findings suggest that ccf-mtDNA may be differentially regulated in different subtypes of depression, and this hypothesis should be pursued in future studies.

Plasma serotonin levels are associated with antidepressant response to SSRIs.

BACKGROUND: Less than half of patients with major depressive disorder (MDD) respond to their first antidepressant trial. Our understanding of the underlying mechanisms of selective serotonin reuptake inhibitors (SSRIs) remains poor, and there is no reliable method of predicting treatment response. METHODS: Thirty-seven MDD subjects and 41 healthy controls, somatically healthy and medication-free for at least six weeks, were recruited, and plasma serotonin (5-HT) levels were assessed at baseline. Twenty-six of the MDD subjects were then treated in an open-label manner with clinically appropriate doses of sertraline for 8 weeks, after which plasma 5-HT levels were again assessed. Response to treatment was defined as an improvement of 50% or more on the Hamilton Depression Rating Scale. RESULTS: Non-responders to sertraline treatment had significantly lower pre-treatment 5-HT levels compared to both healthy controls and responders (F = 4.4, p = 0.004 and p = 0.036, respectively). There was a significant decrease in 5-HT levels over treatment in all MDD subjects (t = 6.2, p = 0.000003). The decrease was significantly more prominent in responders compared to non-responders (t = 2.1, p = 0.047). There was no significant difference in post-treatment 5-HT levels between responders and non-responders. LIMITATIONS: The study had a modest sample size. 5-HT levels in plasma may not reflect 5-HT levels in the brain. CONCLUSIONS: The results indicate that SSRI response may be facilitated by adequate baseline plasma 5-HT content and that successful SSRI treatment is associated with greater decreases in circulating 5-HT. Plasma 5-HT content may be a predictor of SSRI treatment outcome. Potential underlying mechanisms are discussed.