How to Utilize Clinical and Genetic Information for Personalized Treatment of Major Depressive Disorder: Step by Step Strategic Approach

Abstract

Depression is the single largest contributor to non-fatal health loss and affects 322 million people globally. The clinical heterogeneity of this disorder shows biological correlates and it makes the personalization of antidepressant prescription an important pillar of treatment. There is increasing evidence of genetic overlap between depression, other psychiatric and non-psychiatric disorders, which varies across depression subtypes. Therefore, the first step of clinical evaluation should include a careful assessment of psychopathology and physical health, not limited to previously diagnosed disorders. In part of the patients indeed the pathogenesis of depression may be strictly linked to inflammatory and metabolic abnormalities, and the treatment should target these as much as the depressive symptoms themselves. When the evaluation of the symptom and drug tolerability profile, the concomitant biochemical abnormalities and physical conditions is not enough and at least one pharmacotherapy failed, the genotyping of variants in CYP2D6 / CYP2C19 (cytochromes responsible for antidepressant metabolism) should be considered. Individuals with altered metabolism through one of these enzymes may benefit from some antidepressants rather than others or need dose adjustments. Finally, if available, the polygenic predisposition towards cardio-metabolic disorders can be integrated with non-genetic risk factors to tune the identification of patients who should avoid medications associated with this type of side effects. A sufficient knowledge of the polygenic risk of complex medical and psychiatric conditions is becoming relevant as this information can be obtained through direct-to-consumer genetic tests and in the future it may provided by national health care systems.

Genophenotypic Factors and Pharmacogenomics in Adverse Drug Reactions

“…PMs show higher improved symptomatology symptom improvement and higher remission rates compared to NMs. Gastro-intestinal, neurological and sexual ADRs are also more frequent in PMs than in NMs [175,176]. Compared to CYP2C19*1/*1 NMs, the exposure to citalopram increases by 95% in PMs (CYP2C19*2, *3/*2, *3), by 30% in NM/PM (CYP2C19*1/*2, *3), and by 25 % in UM/PM (CYP2C19*17/*2, *3).…”

“…Antidepressants reduce the symptom burden in Major Depressive Disorder (MDD) in over 50% of the cases, but ADRs and treatment resistance still present major challenges in over 30% of the cases [19,172]. Some studies did not identify significant predictive effect of PGx in depressive patients [173,174], whereas others found that over 40% of depressive patients receive inappropriate medication, and that with the aid of PGx testing it is possible to reverse inefficacy and unwanted effects after treatment rectification [19,169,175,176]. Polygenic Risk Scores (PRS) may allow MDD patients to be stratified for antidepressant response with modest reliability [177].…”

Rapid Onset of Intranasal Esketamine in Patients with Treatment Resistant Depression and Major Depression with Suicide Ideation: A Meta-Analysis

“…Multiple antidepressants are available, but approximately one-third of patients with MDD fail to achieve adequate response or remission and become treatment-resistant depression (TRD) [ 3 ]. Besides low remission and response rate, delayed onset of efficacy is another important limitation of conventional antidepressants [ 4 , 5 ]. Moreover, around 10−20% of patients with MDD attempt suicide over their lifetimee, and 3.4% of patients with MDD actually commit or complete suicide [ 6 , 7 ].…”

Pharmacogenetic‐Guided Treatment of Depression: Real‐World Clinical Applications, Challenges, and Perspectives

“…PRSs provide an estimate of the genetic predisposition toward a certain phenotype by calculating a weighted sum of common variants associated with it, independently from the gene or intergenic region they lay in. PRSs may provide information useful for the stratification of patients with MDD, for example, they support shared genetic mechanisms between MDD with atypical neurovegetative symptoms and metabolic diseases, with potential implications for treatment choice 25 . Another interesting finding is that the PRS of schizophrenia may predict poorer response to antidepressants, and suggest the need of considering potentiated therapeutic regimens in those with a high schizophrenia PRS 25 .…”

“…PRSs may provide information useful for the stratification of patients with MDD, for example, they support shared genetic mechanisms between MDD with atypical neurovegetative symptoms and metabolic diseases, with potential implications for treatment choice 25 . Another interesting finding is that the PRS of schizophrenia may predict poorer response to antidepressants, and suggest the need of considering potentiated therapeutic regimens in those with a high schizophrenia PRS 25 . However, these findings are still preliminary, PRSs explain only small fractions in the variance of antidepressant efficacy (~ 1.5%), and they may provide guidance only in some groups of patients (e.g., those with PRS in very high percentiles of the population).…”