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Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. CYP2D6 structural variants cannot be imputed from genotype data, limiting the determination of metabolic phenotypes, and precluding testing for association with response. The association of CYP2C19 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR = 1.46, 95% CI [1.03, 2.06], p = 0.033, heterogeneity I2 = 0%, subgroup difference p = 0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression me

BACKGROUND: Antidepressants are a first-line treatment for depression. However, only a third of individuals experience remission after the first treatment. Common genetic variation, in part, likely regulates antidepressant response, yet the success of previous genome-wide association studies has been limited by sample size. This study performs the largest genetic analysis of prospectively assessed antidepressant response in major depressive disorder to gain insight into the underlying biology and enable out-of-sample prediction. METHODS: Genome-wide analysis of remission (n remit = 1852, n nonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism-based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA. RESULTS: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism-based heritability was significantly different from zero for remission (h 2 = 0.132, SE = 0.056) but not for percentage improvement (h 2 = -0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response. CONCLUSIONS: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap sc

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder often persisting in adulthood. Genetic studies of ADHD mainly focused on the Dopamine Transporter (DAT1) and the Dopamine Receptor 4 (DRD4) genes. Nevertheless, polymorphisms of these genes explain only a small fraction of the assigned risk, suggesting that intermediate dimensions and environmental factors should also be considered. We investigated in 77 adult ADHD subjects compared to 474 controls, how polymorphisms within the genes coding for DAT1 (40-bp VNTR in 3′UTR), the Dopamine Receptor 2 (DRD2) (rs1799732) and DRD4 (48-bp VNTR in exon 3), may modulate the expression of the disorder. By genotyping DAT1, we detected a new 9.5R allele showing a deletion of 40bp and also an insertion of 19bp compared to the 10R allele. This novel allele was found to be significantly protective for ADHD (p<0.0001). Another significant difference was found in the distribution of DRD4 48-bp VNTR 6R allele when comparing patients and controls (p=0.0007). In addition significant results were also found for DAT1 9.5R allele, which was associated with impulsiveness (p=1.98×10−4) and trait anger scores (p=7.66×10−4). Moreover, impulsiveness scores were partly modulated by an interaction between the DRD4 48-bp VNTR 6R allele and childhood maltreatment (p=0.01), however, this result did not resist correction for multiple comparisons. Altogether, our results show the putative involvement of DAT1 and DRD4 genes in the aetiology of ADHD with a main role in modulation of key dimensions of the disorder.

© 2018 Baggio, Fructuoso, Guimaraes, Fois, Golay, Heller, Perroud, Aubry, Young, Delessert, Gétaz, Tran and Wolff. Background: Previous studies have reported a high prevalence of attention deficit hyperactivity disorder (ADHD) among people living in detention (PLD) corresponding to a five- to ten-fold increase compared to the general population. Our main study objective was to provide an updated ADHD prevalence rate for PLD, including PLD in psychiatric units. Sub-objectives included (i) comparing different ways of assessing ADHD, including DSM-5 criteria and (ii) identifying which types of PLD are more likely to have ADHD. Methods: We conducted a systematic review and meta-analysis following the PRISMA guidelines and the MOOSE checklist. PubMed/Medline, PsycINFO, and Web of Sciences were searched combining "ADHD" and "prison" keywords and synonyms for articles published between January 1, 1966 and January 2, 2018. Potential sources of variation to the meta-analytic ADHD prevalence rate were investigated using meta-regressions and subgroups analyses. Results: The meta-analysis pooled 102 original studies including 69,997 participants. The adult ADHD prevalence rate was 26.2% (95% confidence interval: 22.7-29.6). Retrospective assessments of ADHD in childhood were associated with an increased prevalence estimate (41.1, 95% confidence interval: 34.9-47.2, p < 0.001). There was no significant difference in the prevalence estimate between screenings and clinical interviews in adulthood. Only three studies used the DSM-5 definition of ADHD and results were non-significantly different with other DSM versions. We found no difference according to participants' characteristics. Conclusion: Our results confirmed the high prevalence rate of ADHD among PLD, corresponding to a five-fold increase compared to the general population. In light of such high ADHD prevalence, our results reinforce the importance of addressing this critical public health issue by (i) systematically offe