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*D) 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*D cohort. GAP43 molecular pathway was associated with both response and remission in the STAR*D, 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.

PPP3CC gene: a putative modulator of antidepressant response through the B-cell receptor signaling pathway.

Antidepressant pharmacogenetics represents a stimulating, but often discouraging field. The present study proposes a combination of several methodologies across three independent samples. Genes belonging to monoamine, neuroplasticity, circadian rhythm and transcription factor pathways were investigated in two samples (n=369 and 88) with diagnosis of major depression who were treated with antidepressants. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the STAR*D (Sequenced Treatment Alternatives to Relieve Depression) genome-wide study (n=1861). Top genes were further studied through a pathway analysis. In both original samples, markers associated with outcomes were concentrated in the PPP3CC gene. Other interesting findings were particularly in the HTR2A gene in one original sample and the STAR*D. The B-cell receptor signaling pathway proved to be the putative mediator of PPP3CC's effect on antidepressant response (P=0.03). Among innovative candidates, PPP3CC, involved in the regulation of immune system and synaptic plasticity, seems promising for further investigation.

Association between lifetime headache and history of suicide attempts in the elderly.

BACKGROUND: Pain-related conditions have been reported to play a key role among risk factors for suicide. Headache in particular has been repeatedly associated with suicidal thoughts and behaviors. The aims of this study were: 1) to assess the association between lifetime headache (both non-migrainous headache and migraine) and lifetime suicide attempts (SA); 2) to differentiate, within subjects with lifetime SA, patients with and without lifetime headache in terms of socio-demographic and clinical features. METHODS: We studied 1965 subjects from a cohort of community-dwelling persons aged 65 years and over without dementia (the ESPRIT study), divided in two groups: those with (n=75), and those without a lifetime SA (n=1890). Logistic regression analyses were used to compare these groups according to lifetime headache status. RESULTS: After adjusting for gender, living alone, tobacco and alcohol consumption, and depressive, manic/hypomanic and anxiety disorders, lifetime headache frequency was significantly higher in subjects with a lifetime SA compared with controls (OR=1.92 [1.17-3.15]). Additionally, different factors were identified as being associated with lifetime SA in participants with lifetime headache (female gender, a lower level of high-density lipoprotein cholesterol, insomnia, lifetime major depression) versus participants without headache (glycemia and lifetime major depression). CONCLUSIONS: Lifetime headache was associated with lifetime SA. Subjects who are women and report the co-occurrence of headache and insomnia as well as lifetime major depression require higher attention and a careful screening for suicidal thoughts and behaviors.

5-HTTLPR and gender differences in affective disorders: A systematic review.

BACKGROUND: Serotonin transporter-linked polymorphic region (5-HTTLPR) variants have been extensively studied in psychiatric disorders. Although gender effects have been reported, they have not been comprehensively reviewed. The aim of our study was to summarize literature findings on 5-HTTLPR and gender differences in affective disorders. METHODS: A systematic search of PubMed, ISI Web of Knowledge, and PsycINFO databases was performed for dates until January 2015. The included articles (n=78) analyzed the association between 5-HTTLPR and affective spectrum disorders, taking into account gender. The quality of each study was assessed through STROBE and CONSORT. RESULTS: 5-HTTLPR modulation of affective disorders varied by gender. The S allele (or SS genotype) seemed to be differently associated with an increased risk of depression, depressive symptoms, anxiety traits and symptoms, and symptoms of internalizing behavior among women and an increased risk of aggressiveness, conduct disorder and symptom counts of externalizing behavior among men. Moreover, the presence of stressful life events reinforced the association. Interestingly, these differences seemed to begin with adolescence and were not consistent among the elderly, suggesting a plausible role of hormonal fluctuations. LIMITATIONS: The review is limited by the small number of included papers, due to the paucity of information in the literature regarding 5-HTTLPR and gender. CONCLUSIONS: 5-HTTLPR variants may exert a differential modulation on a number of features depending on gender. Further studies are needed to more deeply investigate the effect of 5-HTTLPR×gender on the modulation of affective disorders.

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 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.

Association between the estrogen receptor TA polymorphism and Harm avoidance.

In the last decade a large number of studies focused on the recognition of gene variants modulating temperamental traits. The gene coding for the estrogen receptor alpha (ESR1) appears to be an interesting candidate and it has been found to be linked to Harm avoidance (HA). The aim of the present study was to investigate whether the ESR1 TA dinucleotide repeat polymorphism is associated with HA temperamental trait in a sample of Caucasian University students. One hundred ninety healthy subjects were genotyped for ESR1 TA dinucleotide repeat polymorphism and were administered the Temperament and Character Inventory (TCI). ESR1 TA repeat lengths were dichotomized into short and long categories. ANOVA was used to examine the influence of ESR1 variants (short/long) on the means of the TCI HA scores. HA was significantly associated with age and gender in our sample, being higher in older and female subjects. In the global sample as well as in men and women separately, individuals carrying the S/S variant showed significantly higher HA scores. Further analysis on the HA subscales revealed that specific differences could exist between men and women. Our results further suggest a possible role of ESR1 variants on HA. Further research is needed to replicate our findings as well as to better explore the neuro-biological mechanisms of the modulation of ESR1 on HA.