Physical co-morbidity among treatment resistant vs. treatment responsive patients with major depressive disorder

Co-morbid physical illness has been suggested to play an important role among the factors contributing to treatment resistance in patients with major depressive disorder. In the current study we compared the rate of physical co-morbidity, defined by ICD-10, among a large multicenter sample of 702 patients with major depressive disorder. A total of 356 of the participants were defined as treatment resistant depression (TRD) patients-having failed two or more adequate antidepressant trials. No significant difference was found between TRD and non-TRD participants in the prevalence of any ICD-10 category. This finding suggests that although physical conditions such as diabetes, thyroid dysfunction, hypertension, ischemic heart disease, and peptic diseases are often accompanied by co-morbid MDD, they do not necessarily have an impact on the course of MDD or the likelihood to respond to treatment. Marginally higher rates of co-morbid breast cancer, migraine and glaucoma were found among TRD participants. Possible explanations for these findings and their possible relation to TRD are discussed

The impact of Cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes on suicide attempt and suicide risk-a European multicentre study on treatment-resistant major depressive disorder.

Recently published data have reported associations between cytochrome P450 metabolizer status and suicidality. The aim of our study was to investigate the role of genetic polymorphisms of the cytochrome P450 genes on suicide risk and/or a personal history of suicide attempts. Two hundred forty-three major depressive disorder patients were collected in the context of a European multicentre resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using the Mini International Neuropsychiatric Interview and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D ≤ 17 and remission as HAM-D ≤ 7 after 4 weeks of treatment with antidepressants at adequate dose. Genotyping was performed for all relevant variations of the CYP1A2 gene (*1A, *1F, *1C, *1 J, *1 K), the CYP2C9 gene (*2, *3), the CYP2C19 gene (*2, *17) and the CYP2D6 gene (*3, *4, *5, *6, *9, *19, *XN). No association between both suicide risk and personal history of suicide attempts, and the above mentioned metabolic profiles were found after multiple testing corrections. In conclusion, the investigated cytochrome gene polymorphisms do not seem to be associated with suicide risk and/or a personal history of suicide attempts, though methodological and sample size limitations do not allow definitive conclusions

The serotonin transporter and the activity regulated cytoskeleton-associated protein genes in antidepressant response and resistance: 5-HTTLPR and other variants

Objective: Previous evidence suggested the involvement of serotonin transporter (SLC6A4) and activity regulated cytoskeleton-associated protein (ARC) in antidepressant action. This study investigated their role in antidepressant efficacy and treatment-resistant depression (TRD). Methods: Three samples (n total = 648) were investigated to test the association between treatment outcomes (response, remission, symptom improvement, and TRD) and 11 polymorphisms within SLC6A4 and ARC genes. The possible modulating effect of age and gender was considered. Response and remission were also investigated using a fixed-effects meta-analysis of the three samples. Results: SLC6A4 5-HTTLPR/rs25531 effects on symptom improvement were modulated by age (better improvement in L/LA carriers in older subjects) and gender (better improvement in L/LA female carriers). SLC6A4 STin2 long alleles were associated with remission and lower risk of TRD. Preliminary evidence of association between ARC rs11167152/rs10110456 and different outcomes was found. Conclusions: 5-HTTLPR/rs25531 effect on antidepressant efficacy was modulated by age, in line with previous literature data. STin2 effect on antidepressant efficacy was in line with previous meta-analyses. A new possible effect of ARC variants on antidepressant efficacy was observed; however, further studies in larger samples are needed to confirm their role

The impact of COMT gene polymorphisms on suicidality in treatment resistant major depressive disorder--a European multicenter study.

Many association studies have reported associations between the catechol-O-methyltransferase (COMT) gene and psychiatric disorders including major depression (MDD). The COMT gene has further been associated with suicidal behaviour, as well as with treatment response, although with conflicting results. In the present study, we further elucidate the impact of COMT in treatment response in MDD patients with suicide risk and/or a personal history of suicide attempts. Two hundred fifty MDD patients were collected in the context of a European multicentre resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using Mini International Neuropsychiatric Interview (MINI) and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D ≤ 17 and remission as HAM-D ≤ 7 after 4 weeks of treatment with antidepressants at adequate dose. Genotyping was performed for seven SNPs (rs4680, rs2075507, rs737865, rs6269, rs4633, rs4818 and rs165599) within the COMT gene. With regard to suicide risk and personal history of suicide attempts, neither single marker nor haplotypic association was found with any SNP after multiple testing correction. In non-responders, we found significant single marker and haplotypic association with suicide risk, but not in responders. The same holds true for both remitters and non-remitters, and when testing for association with a personal history of suicide attempts and treatment response phenotypes. In conclusion, we found significant association of COMT SNPs with suicide risk in MDD patients not responding to antidepressant treatment. Larger well-defined cohorts will be required to dissect this further.Controlled Clinical TrialJournal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Comorbidity in obsessive-compulsive disorder (OCD): a report from the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS)

Obsessive-compulsive disorder (OCD) is often associated with significant psychiatric comorbidity. Comorbid disorders include mood and anxiety disorders as well as obsessive-compulsive spectrum disorders (OCSDs). This paper aims to investigate comorbidity of DSM Axis I-disorders, including OCSDs, in patients with OCD from 10 centers affiliated with the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS). This is a cross-sectional study of comorbidity of Axis I disorders including OCSDs in 457 outpatients with primary OCD (37% male; 63% female), with ages ranging from 12 to 88years (mean: 39.8±13). Treating clinicians assessed Axis I disorders using the Mini International Neuropsychiatric Interview and assessed OCSDs using the Structured Clinical Interview for OCD related/spectrum disorders (SCID-OCSD). In terms of the OCSDs, highest comorbidity rates were found for tic disorder (12.5%), BDD (8.71%) and self-injurious behavior (7.43%). In terms of the other Axis I-disorders, major depressive disorder (MDD; 15%), social anxiety disorder (SAD; 14%), generalized anxiety disorder (GAD; 13%) and dysthymic disorder (13%) were most prevalent. High comorbidity of some OCSDs in OCD supports the formal recognition of these conditions in a separate chapter of the nosology. Rates of other Axis I disorders are high in both the general population and in OCSDs, indicating that these may often also need to be the focus of intervention in OC

Neuronal cell adhesion genes and antidepressant response in three independent samples

Drug-effect phenotypes in human lymphoblastoid cell lines recently allowed to identify CHL1 (cell adhesion molecule with homology to L1CAM), GAP43 (growth-Associated protein 43) and ITGB3 (integrin beta 3) as new candidates for involvement in the antidepressant effect. CHL1 and ITGB3 code for adhesion molecules, while GAP43 codes for a neuron-specific cytosolic protein expressed in neuronal growth cones; all the three gene products are involved in synaptic plasticity. Sixteen polymorphisms in these genes were genotyped in two samples (n=369 and 90) with diagnosis of major depressive episode who were treated with antidepressants in a naturalistic setting. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the Sequenced Treatment Alternatives to Relieve Depression (STAR 17D) genome-wide study (n=1861) as both individual genes and through a pathway analysis (Reactome and String databases). Gene-based analysis suggested CHL1 rs4003413, GAP43 rs283393 and rs9860828, ITGB3 rs3809865 as the top candidates due to their replication across the largest original sample and the STAR 17D cohort. GAP43 molecular pathway was associated with both response and remission in the STAR 17D, with ELAVL4 representing the gene with the highest percentage of single nucleotide polymorphisms (SNPs) associated with outcomes. Other promising genes emerging from the pathway analysis were ITGB1 and NRP1. The present study was the first to analyze cell adhesion genes and their molecular pathways in antidepressant response. Genes and biomarkers involved in neuronal adhesion should be considered by further studies aimed to identify predictors of antidepressant response

The impact of Cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes on suicide attempt and suicide risk—a European multicentre study on treatment-resistant major depressive disorder

Recently published data have reported associations between cytochrome P450 metabolizer status and suicidality. The aim of our study was to investigate the role of genetic polymorphisms of the cytochrome P450 genes on suicide risk and/or a personal history of suicide attempts. Two hundred forty-three major depressive disorder patients were collected in the context of a European multicentre resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using the Mini International Neuropsychiatric Interview and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D ≤ 17 and remission as HAM-D ≤ 7 after 4 weeks of treatment with antidepressants at adequate dose. Genotyping was performed for all relevant variations of the CYP1A2 gene (*1A, *1F, *1C, *1 J, *1 K), the CYP2C9 gene (*2, *3), the CYP2C19 gene (*2, *17) and the CYP2D6 gene (*3, *4, *5, *6, *9, *19, *XN). No association between both suicide risk and personal history of suicide attempts, and the above mentioned metabolic profiles were found after multiple testing corrections. In conclusion, the investigated cytochrome gene polymorphisms do not seem to be associated with suicide risk and/or a personal history of suicide attempts, though methodological and sample size limitations do not allow definitive conclusions.JOURNAL ARTICLESCOPUS: ar.jinfo:eu-repo/semantics/publishe