Late-life depression (LLD), defined as depression in adults over the age 60, may be a biologically-distinct disorder compared to depression in younger adults. LLD is challenging to treat due to the changes that occurs with aging, therefore we are trying to understand how genetic variation affects response to antidepressants in late life.

We reviewed the scientific literature to provide a summary of the literature exploring genetic associations with antidepressant treatment outcomes in late-life. We conducted a systematic search of three integrated electronic databases. We identified 29 articles investigating genetic associations with antidepressant treatment outcomes, pharmacokinetic parameters, and adverse drug reactions in older adults. Given the small number of investigations conducted in older adults, it is difficult to conclude the presence or absence of genetic associations with the outcomes of interest.

Our Conclusion:
The most substantial amount of evidence exists for the CYP2D6 metabolizer status, SLC6A4 5-HTTLPR, and BDNF rs6265.

These findings are consistent in the literature when not restricting to older adults, suggesting that similar treatment recommendations may be provided for older adults regarding genetic variation, such as those outlined for CYP2D6 by the Clinical Pharmacogenetics Implementation Consortium. Nonetheless, further studies are required in well-characterized samples, including genome-wide data, to validate if similar treatment adjustments are appropriate in older adults, given that there appear to be significant effects of genetic variation on antidepressant treatment factors.

A Candidate-Gene Approach

The primary objective of this study was to investigate five putatively functional variants of the norepinephrine transporter (SLC6A2, NET) and serotonin transporter (SLC6A4, SERT) genes and remission in depressed older adults treated with venlafaxine. A secondary objectivewas to analyze 17 other variants in serotonergic system genes (HTR1A, HTR2A, HTR1B, HTR2C, TPH1, TPH2) potentially involved in the mechanism of action of venlafaxine.

The sample included 350 adults age 60 or older with DSM-IV-defined major depressive disorder and a score of at least 15 on the Montgomery-Åsberg Depression Rating Scale (MADRS). Participants received protocolized treatment with open-label venlafaxine, up to 300 mg/day for approximately 12 weeks, as part of a three-site clinical trial. Each individual was genotyped for 22 polymorphisms in eight genes, which were tested for association with venlafaxine remission (a MADRS score less than 10) and changes in MADRS score during treatment.

A Genome-Wide Approach

Antidepressant outcomes in older adults with depression are poor, possibly because of comorbidities such as cerebrovascular disease. Therefore, we leveraged multiple genome-wide approaches to understand the genetic architecture of antidepressant response. We conducted a standard genome-wide association study (GWAS) for post-treatment remission status, followed by in silico biological characterization of associated genes, as well as polygenic risk scoring for depression, neurodegenerative, and cerebrovascular disease.

The top-associated variants for remission status and percentage symptom improvement were located in the PIEZO1 gene and an intergenic locus on chromosome 6. Pathway analysis revealed significant contributions from genes involved in the ubiquitin-proteasome system, which regulates intracellular protein degradation with has implications for inflammation, as well as atherosclerotic cardiovascular disease. Although our findings did not reach genome-wide significance, they point to previously-implicated mechanisms and provide support for the roles of vascular and inflammatory pathways in LLD. Overall, significant enrichment of genes involved in protein degradation pathways that may be impaired, as well as the predictive capacity of risk for cardioembolic stroke, support a link between late-life depression remission and risk for vascular dysfunction.

Given the polygenicity of complex outcomes such as antidepressant response, we also explored 11 polygenic risk scores associated with risk for Alzheimer's disease and stroke. Of the 11 scores, risk for cardioembolic stroke was the second-best predictor of non-remission, after being male (Accuracy=0.70 [0.59, 0.79], Sensitivity=0.72, Specificity=0.67; p<0.05).