Meta-analysis of CYP2C19 and CYP2D6 metabolic activity on antidepressant response from 13 clinical studies using genotype imputation.

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. The association of CYP2C19 and CYP2D6 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 and CYP2D6, 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. CYP2D6 structural variants cannot be imputed from genotype data, limiting inference of pharmacogenetic effects. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes.

Identifying the Common Genetic Basis of Antidepressant Response.

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 schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.

Methodology for clinical genotyping of CYP2D6 and CYP2C19.

Many antidepressants, atomoxetine, and several antipsychotics are metabolized by the cytochrome P450 enzymes CYP2D6 and CYP2C19, and guidelines for prescribers based on genetic variants exist. Although some laboratories offer such testing, there is no consensus regarding validated methodology for clinical genotyping of CYP2D6 and CYP2C19. The aim of this paper was to cross-validate multiple technologies for genotyping CYP2D6 and CYP2C19 against each other, and to contribute to feasibility for clinical implementation by providing an enhanced range of assay options, customizable automated translation of data into haplotypes, and a workflow algorithm. AmpliChip CYP450 and some TaqMan single nucleotide variant (SNV) and copy number variant (CNV) data in the Genome-based therapeutic drugs for depression (GENDEP) study were used to select 95 samples (out of 853) to represent as broad a range of CYP2D6 and CYP2C19 genotypes as possible. These 95 included a larger range of CYP2D6 hybrid configurations than have previously been reported using inter-technology data. Genotyping techniques employed were: further TaqMan CNV and SNV assays, xTAGv3 Luminex CYP2D6 and CYP2C19, PharmacoScan, the Ion AmpliSeq Pharmacogenomics Panel, and, for samples with CYP2D6 hybrid configurations, long-range polymerase chain reactions (L-PCRs) with Sanger sequencing and Luminex. Agena MassARRAY was also used for CYP2C19. This study has led to the development of a broader range of TaqMan SNV assays, haplotype phasing methodology with TaqMan adaptable for other technologies, a multiplex genotyping method for efficient identification of some hybrid haplotypes, a customizable automated translation of SNV and CNV data into haplotypes, and a clinical workflow algorithm.

Genes associated with anhedonia: a new analysis in a large clinical trial (GENDEP).

A key feature of major depressive disorder (MDD) is anhedonia, which is a predictor of response to antidepressant treatment. In order to shed light on its genetic underpinnings, we conducted a genome-wide association study (GWAS) followed by investigation of biological pathway enrichment using an anhedonia dimension for 759 patients with MDD in the GENDEP study. The GWAS identified 18 SNPs associated at genome-wide significance with the top one being an intronic SNP (rs9392549) in PRPF4B (pre-mRNA processing factor 4B) located on chromosome 6 (P = 2.07 × 10-9) while gene-set enrichment analysis returned one gene ontology term, axon cargo transport (GO: 0008088) with a nominally significant P value (1.15 × 10-5). Furthermore, our exploratory analysis yielded some interesting, albeit not statistically significant genetic correlation with Parkinson's Disease and nucleus accumbens gray matter. In addition, polygenic risk scores (PRSs) generated from our association analysis were found to be able to predict treatment efficacy of the antidepressants in this study. In conclusion, we found some markers significantly associated with anhedonia, and some suggestive findings of related pathways and biological functions, which could be further investigated in other studies.

Genetic predictors of antidepressant side effects: a grouped candidate gene approach in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study.

BACKGROUND: The unwanted side effects associated with antidepressants are key determinants of treatment adherence in depression; propensity to experience these adverse drug reactions (ADRs) may be influenced by genetic variation. However, previous work attempting to ascertain the genetic variants involved has had limited success, in part due to the range of ADRs reported with antidepressants. METHOD: ADRs reported with antidepressant treatment were categorised using their likely pharmacological basis; adrenergic, cholinergic, serotonergic and histaminergic. To identify genetic predictors of susceptibility to each group of ADRs, a candidate gene analysis was performed with data from 431 depressed patients (from a total sample size of 811 patients) enrolled in the Genome-Based Therapeutic Drugs for Depression (GENDEP) project, who were randomly allocated to receive treatment with escitalopram or nortriptyline. Data from 474 patients treated with citalopram or reboxetine in the GenPod project (total sample of 601 patients) were used for replication of significant findings. RESULTS: We found no significant predictors of presumed adrenergic, cholinergic and histaminergic ADRs. Putative serotonergic ADRs were significantly associated with variation in the gene encoding the serotonin 2C receptor (HTR2C, rs6644093, odds ratio (OR)=1.72, 95% confidence interval (CI)=1.31-2.25, p=7.43×10(-5)) in GENDEP. However, this finding was not replicated in GenPod. CONCLUSIONS: The association between serotonergic side effects and variation in the HTR2C gene in the GENDEP sample supports the hypothesis that serotonin receptor-mediated mechanisms underlie these adverse reactions, however this finding was not replicated in GenPod.

Psychometric properties of the Slovenian version of temperament evaluation of Memphis, Pisa, Paris, and San Diego-Autoquestionnaire (TEMPS-A): temperament profiles in Slovenian university students.

BACKGROUND: TEMPS-A (Temperament Evaluation of Memphis, Pisa, Paris and San Diego-Autoquestionnaire) is a self-rated instrument that measures five affective temperaments: depressive, cyclothymic, hyperthymic, irritable, and anxious. The aim of our study was to examine the psychometric characteristics of the Slovenian TEMPS-A and to ascertain if temperament profile is related to the professions chosen by Slovenian students. METHODS: 892 Slovenian university students in six different professional fields (economics, geography, engineering, law, sports pedagogy and nursing) were included in our study. RESULTS: Cronbach's reliability coefficients denoted acceptable internal consistency of the subscales. Principal component analysis revealed relatively good internal structure of the instrument. Nursing and geography students scored the highest on depressive temperament. Sports pedagogues as well as engineers demonstrated the most firm personality structure with distinctive hyperthymic temperament. Law students revealed the most irritable temperament, while nursing and law students scored the highest on anxious temperament. LIMITATIONS: Sample of Slovenian students is not representative for general population. The structure of the sample was crucial as well, as it comprised mainly of younger students who just started their study. CONCLUSIONS: The Slovenian version of the TEMPS-A proved to have relatively good internal consistency and internal structure. The questionnaire verified as a reliable and valid instrument and generally in line with previous studies. This study strengthens the perspective that professional areas could be associated with distinct affective temperament profile that could influence career decisions. The findings in students of economics, geography, and sport pedagogy are new as they have not been previously investigated by TEMPS researchers. The results open new possibilities for future research.

Quality of life and clinical outcome comparison of semitendinosus and gracilis tendon versus patellar tendon autografts for anterior cruciate ligament reconstruction: an 11-year follow-up of a randomized controlled trial.

BACKGROUND: There are still controversies about graft selection for primary anterior cruciate ligament reconstruction. Prospective, randomized long-term studies are needed to determine the differences between the graft materials. HYPOTHESIS: Eleven years after anterior cruciate ligament reconstruction there is no difference in functional outcome and quality of life between patients with patellar tendon or hamstring tendon autografts; however, the patients with patellar tendon autograft would have a higher prevalence of osteoarthritis. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: From June 1999 to March 2000, 64 patients were included in this prospective study. A single surgeon performed primary arthroscopically assisted anterior cruciate ligament reconstruction in an alternating sequence. In 32 patients, anterior cruciate ligament reconstruction was performed with hamstring tendon autograft (semitendinosus and gracilis [STG] group) while in the other 32 patients the reconstruction was performed with patellar tendon autograft (PT group). RESULTS: At the 11-year follow-up, no statistically significant differences were seen with respect to the Lysholm score and Short Form-36, KT-1000 arthrometer laxity testing, anterior knee pain, single-legged hop test, or International Knee Documentation Committee (IKDC) classification results. Positive pivot-shift test (1+) was significantly more frequent in the PT group (P = .036). Twenty-two patients (81%) in the STG group and 18 patients (72%) in the PT group were still at their preinjury level of activity. Graft rupture occurred in 2 patients from the STG group (6%) and in 4 patients from the PT (12%). Grade B and C abnormal radiographic findings were seen in 84% (21 of 25) of patients in the PT group and in 63% (17 of 27) of patients in the STG group (P = .008). CONCLUSION: Both hamstring and patellar tendon autografts provided good subjective outcomes and objective stability at 11 years. Positive pivot-shift test (1+) was significantly more frequent in the PT group. No significant differences in the rate of graft failure were identified. Patients with patellar tendon graft had a greater prevalence of osteoarthritis at 11 years after surgery.

Sexual dysfunction during treatment with serotonergic and noradrenergic antidepressants: clinical description and the role of the 5-HTTLPR.

OBJECTIVES: Sexual dysfunction (SD) is a frequently reported side-effect of antidepressant treatment, particularly of selective serotonin reuptake inhibitors (SSRIs). In the multicentre clinical and pharmacogenetic GENDEP study (Genome-based Therapeutic Drugs for Depression), the effect of the serotonin transporter gene promoter polymorphism 5-HTTLPR on sexual function was investigated during treatment with escitalopram (SSRI) and nortriptyline (tricyclic antidepressant). METHODS: A total of 494 subjects with an episode of DSM-IV major depression were randomly assigned to treatment with escitalopram or nortriptyline. Over 12 weeks, depressive symptoms and SD were measured weekly with the Montgomery-Asberg Depression Rating Scale, the Antidepressant Side-Effect Checklist, the UKU Side Effect Rating Scale, and the Sexual Functioning Questionnaire. RESULTS: The incidence of reported SD after 12 weeks of treatment was relatively low, and did not differ significantly between antidepressants (14.9% escitalopram, 19.7% nortriptyline). There was no significant interaction between the 5-HTTLPR and antidepressant on SD. Improvement in depressive symptoms and younger age were both associated with lower SD. The effect of age on SD may have been moderated by the 5-HTTLPR. CONCLUSIONS: In GENDEP, rates of reported SD during treatment were lower than those described in previous reports. There was no apparent effect of the 5-HTTLPR on the observed decline in SD.

The effect of graft choice on functional outcome in anterior cruciate ligament reconstruction.

A prospective, randomised, 5-year follow-up study was designed to compare the functional results between patellar tendon and hamstring tendon autografts after anterior cruciate ligament reconstruction. Primary reconstruction was performed in 32 patients using the central third of the patellar ligament and in 32 patients using double-looped semitendinosus and gracilis tendons. All reconstructions were performed by a single surgeon, with identical surgical technique and rehabilitation protocol. Of the total 64 patients in the study, 54 (85%) were available for the 5-year follow-up. No statistically significant differences were seen with respect to Lysholm score, International Knee Documentation Committee (IKDC) classification, clinical and KT-2000 arthrometer laxity testing, single-legged hop test and anterior knee pain. Graft rupture occurred in two patients (8%) in the patellar tendon group and in two patients (7%) in the hamstring tendon group; 23 patients (88%) in the patellar tendon group and 23 patients (82%) in the hamstring tendon group returned to their pre-injury activity level. Good subjective outcome and stability can be obtained by using either graft; no statistically significant differences were found in functional outcome between the grafts.

Attitudes towards suicide in Slovenia: a cross-sectional survey.

BACKGROUND: Slovenia has been experiencing a very high suicide rate (30 per 10,000 inhabitants per year or higher) and there are no data on public attitudes towards suicide in Slovenia. AIMS: To identify public attitudes towards suicide in order to expand the basis for prevention. METHODS: A Suicide Attitudes Questionnaire (SUIATT) was sent to a representative sample of adult Slovenian citizens. RESULTS: Some 5.2% of respondents had at least one previous suicidal attempt and 21.6% reported suicidal ideation (SI). More respondents with SI than respondents without SI reported: 1) the suicidal act as deliberated, 2) less importance attached to the mental illness in suicidal behaviour, 3) that a person has the right to commit suicide, and 4) the suicidal act as an act of cowardice. CONCLUSIONS: Results do not allow a general statement whether attitudes towards suicide are permissive or restrictive. However, in the subgroup of respondents with SI we found a tendency towards permissiveness regarding suicide.

Community rehabilitation service for patients with severe psychotic disorders: the Slovene experience.

BACKGROUND: Rehabilitation can be carried out at various sites. METHOD: Two groups of patients with severe mental disorders were compared: those included in community rehabilitation service and those only attending an outpatient clinic regarding their clinical status, social functioning, standard of living and quality of life. RESULTS: We found no significant global differences in group characteristics, social functioning and clinical status, but we did prove the lower social status of the group included in the rehabilitation service and their satisfaction with the services they use. CONCLUSIONS: The community rehabilitation services in Slovenia are coping with existential social needs of their users but this study failed to demonstrate their success in improving health or social functioning.