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The Genetics of Treatment-Resistant Depression: A Critical Review and Future Perspectives.

ABSTRACT: Background:One-third of depressed patients develop treatment-resistant depression with the related sequelae in terms of poor functionality and worse prognosis. Solid evidence suggests that genetic variants are potentially valid predictors of antidepressant efficacy and could be used to provide personalized treatments. Methods:The present review summarizes genetic findings of treatment-resistant depression including results from candidate gene studies and genome-wide association studies. The limitations of these approaches are discussed, and suggestions to improve the design of future studies are provided. Results:Most studies used the candidate gene approach, and few genes showed replicated associations with treatment-resistant depression and/or evidence obtained through complementary approaches (e.g., gene expression studies). These genes included GRIK4, BDNF, SLC6A4, and KCNK2, but confirmatory evidence in large cohorts was often lacking. Genome-wide association studies did not identify any genome-wide significant association at variant level, but pathways including genes modulating actin cytoskeleton, neural plasticity, and neurogenesis may be associated with treatment-resistant depression, in line with results obtained by genome-wide association studies of antidepressant response. The improvement of aggregated tests (e.g., polygenic risk scores), possibly using variant/gene prioritization criteria, the increase in the covering of genetic variants, and the incorporation of clinical-demographic predictors of treatment-resistant depression are proposed as possible strategies to improve future pharmacogenomic studies. Conclusions:Genetic biomarkers to identify patients with higher risk of treatment-resistant depression or to guide treatment in these patients are not available yet. Methodological improvements of future studies could lead to the identification of genetic biomarkers with clinical validity.

SUBMITTER: Fabbri C

PROVIDER: S-EPMC6368368 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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The Genetics of Treatment-Resistant Depression: A Critical Review and Future Perspectives.

Fabbri Chiara C Corponi Filippo F Souery Daniel D Kasper Siegfried S Montgomery Stuart S Zohar Joseph J Rujescu Dan D Mendlewicz Julien J Serretti Alessandro A

The international journal of neuropsychopharmacology 20190201 2

<h4>Background</h4>One-third of depressed patients develop treatment-resistant depression with the related sequelae in terms of poor functionality and worse prognosis. Solid evidence suggests that genetic variants are potentially valid predictors of antidepressant efficacy and could be used to provide personalized treatments.<h4>Methods</h4>The present review summarizes genetic findings of treatment-resistant depression including results from candidate gene studies and genome-wide association st ...[more]

PMID: 29688548

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Project description:The Brown-Vialetto-Van Laere syndrome is a rare neurological disorder which may present at all ages with sensorineural deafness, bulbar palsy and respiratory compromise. Fazio-Londe syndrome is considered to be the same disease entity. Recently it was demonstrated that in some patients the disease is caused by mutations in the SLC52A3 gene which encodes the intestinal (hRFT2) riboflavin transporter. In these patients riboflavin deficiency is the cause of the BVVL/FL syndrome and supplementation of riboflavin proved a life saving treatment. Mutations in the SLC52A2 gene and the SLC52A1 (GPR172B) gene, coding for human riboflavin transporters hRFT3 and hRFT1 have been associated with the BVVL syndrome as well. We performed a review of the literature, with emphasis on the natural history and the effects of treatment in these patients. A total of 35 publications were traced reporting on the clinical presentation of 74 patients who presented before age 18. The most prevalent symptoms were bulbar palsy, hearing loss, facial weakness and respiratory compromise. Death was reported in 28 of the 61 untreated patients, with a very low survival in patients presenting before age 4. All 13 patients who were treated with riboflavin survived, with a strong clinical improvement after days to months of treatment in eight patients. Three patients demonstrated a stable clinical course and treatment was stopped early in two patients. Abnormalities in plasma flavin levels and/or plasma acylcarnitine profiles were observed in some but not in all patients, and also patients with normal plasma flavin levels and acylcarnitine profiles demonstrated a striking clinical improvement on riboflavin supplementation. It is now clear that proper diagnosis requires mutation analysis of all three transporter genes and treatment should be started immediately without first awaiting results of molecular analysis. Clinical improvement may be rapid or gradual over a period of more than 12 months.

Dataset Information

The Genetics of Treatment-Resistant Depression: A Critical Review and Future Perspectives.

Publications

The Genetics of Treatment-Resistant Depression: A Critical Review and Future Perspectives.

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