Dávid Kovacs

Variability in the Effect of 5-HTTLPR on Depression in a Large European Population: The Role of Age, Symptom Profile, Type and Intensity of Life Stressors

Background Although 5-HTTLPR has been shown to influence the risk of life stress-induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity. Methods In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject. Besides traditional statistical analysis we calculated Bayesian effect strength and relevance of 5-HTTLPR genotypes in specified models. Results The short (s) low expressing allele showed association with increased risk of depression related phenotypes, but all nominally significant effects would turn to non-significant after correction for multiple testing in the traditional analysis. Bayesian effect strength and relevance analysis, however, confirmed the role of 5-HTTLPR. Regarding current (BSI) and lifetime depression 5-HTTLPR-by-RLE interactions were confirmed. Main effect, with other words direct association, was supported with BSI anxiety. With more frequent RLE the prevalence or symptoms of depression increased in ss carriers. Although CHA failed to show an interaction with 5-HTTLPR, in young subjects CHA sensitized towards the depression promoting effect of even mild RLE. Furthermore, the direct association of anxiety with the s allele was driven by young (≤30) individuals. Limitations Our study is cross-sectional and applies self-report questionnaires. Conclusions Albeit 5-HTTLPR has only weak/moderate effects, the s allele is directly associated with anxiety and modulates development of depression in homogeneous subgroups.

Psychological side effects of immune therapies: symptoms and pathomechanism

Immunotherapies revolutionised the treatment of several disorders but show specific side-effect profiles which frequently involve psychological symptoms. Long term interferon-alpha (IFN-alpha) therapy can cause wide-ranging psychiatric side-effects from fatigue, insomnia, anxiety to full-blown depression. This treatment-emergent depression shares several symptoms with major depressive disorder (MDD) with a predominance of somatic/neurovegetative symptoms, and can be treated with antidepressants. However, this experience directed research to inflammatory mechanisms in MDD. MDD has been confirmed as a heterogeneous disorder with a subgroup of patients suffering from low-grade chronic inflammation and frequently resistant to traditional antidepressant treatment. Thus future research should develop strategies to identify those MDD patients who could benefit from drugs acting through inflammatory pathways.

Effects of IL1B single nucleotide polymorphisms on depressive and anxiety symptoms are determined by severity and type of life stress

Interleukin-1β is one of the main mediators in the cross-talk between the immune system and the central nervous system. Higher interleukin-1β levels are found in mood spectrum disorders, and the stress-induced expression rate of the interleukin-1β gene (IL1B) is altered by polymorphisms in the region. Therefore we examined the effects of rs16944 and rs1143643 single nucleotide polymorphisms (SNPs) within the IL1B gene on depressive and anxiety symptoms, as measured by the Brief Symptom Inventory, in a Hungarian population sample of 1053 persons. Distal and proximal environmental stress factors were also included in our analysis, namely childhood adversity and recent negative life-events. We found that rs16944 minor (A) allele specifically interacted with childhood adversity increasing depressive and anxiety symptoms, while rs1143643s minor (A) allele showed protective effect against depressive symptoms after recent life stress. The genetic main effects of the two SNPs were not significant in the main analysis, but the interaction effects remained significant after correction for multiple testing. In addition, the effect of rs16944 A allele was reversed in a subsample with low-exposure to life stress, suggesting a protective effect against depressive symptoms, in the post hoc analysis. In summary, both of the two IL1B SNPs showed specific environmental stressor-dependent effects on mood disorder symptoms. We also demonstrated that the presence of exposure to childhood adversity changed the direction of the rs16944 effect on depression phenotype. Therefore our results suggest that it is advisable to include environmental factors in genetic association studies when examining the effect of the IL1B gene.

Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: a potential risk mechanism for depression.

Alterations in the folate pathway have been related to both major depression and cognitive inflexibility; however, they have not been investigated in the genetic background of ruminative response style, which is a form of perseverative cognition and a risk factor for depression. In the present study, we explored the association of rumination (measured by the Ruminative Responses Scale) with polymorphisms of two distinct folate pathway genes, MTHFR rs1801133 (C677T) and MTHFD1L rs11754661, in a combined European white sample from Budapest, Hungary (n=895) and Manchester, United Kingdom (n=1309). Post hoc analysis investigated whether the association could be replicated in each of the two samples, and the relationship between folate pathway genes, rumination, lifetime depression and Brief Symptom Inventory depression score. Despite its functional effect on folate metabolism, the MTHFR rs1801133 showed no effect on rumination. However, the A allele of MTHFD1L rs11754661 was significantly associated with greater rumination, and this effect was replicated in both the Budapest and Manchester samples. In addition, rumination completely mediated the effects of MTHFD1L rs11754661 on depression phenotypes. These findings suggest that the MTHFD1L gene, and thus the C1-THF synthase enzyme of the folate pathway localized in mitochondria, has an important effect on the pathophysiology of depression through rumination, and maybe via this cognitive intermediate phenotype on other mental and physical disorders. Further research should unravel whether the reversible metabolic effect of MTHFD1L is responsible for increased rumination or other long-term effects on brain development.

Antidepressant treatment response is modulated by genetic and environmental factors and their interactions

Although there is a wide variety of antidepressants with different mechanisms of action available, the efficacy of treatment is not satisfactory. Genetic factors are presumed to play a role in differences in medication response; however, available evidence is controversial. Even genome-wide association studies failed to identify genes or regions which would consequently influence treatment response. We conducted a literature review in order to uncover possible mechanisms concealing the direct effects of genetic variants, focusing mainly on reports from large-scale studies including STAR*D or GENDEP. We observed that inclusion of environmental factors, gene-environment and gene-gene interactions in the model improves the probability of identifying genetic modulator effects of antidepressant response. It could be difficult to determine which allele of a polymorphism is the risk factor for poor treatment outcome because depending on the acting environmental factors different alleles could be advantageous to improve treatment response. Moreover, genetic variants tend to show better association with certain intermediate phenotypes linked to depression because these are more objective and detectable than traditional treatment outcomes. Thus, detailed modeling of environmental factors and their interactions with different genetic pathways could significantly improve our understanding of antidepressant efficacy. In addition, the complexity of depression itself demands a more comprehensive analysis of symptom trajectories if we are to extract useful information which could be used in the personalization of antidepressant treatment.

Financial difficulties but not other types of recent negative life events show strong interactions with 5-HTTLPR genotype in the development of depressive symptoms

Several studies indicate that 5-HTTLPR mediates the effect of childhood adversity in the development of depression, while results are contradictory for recent negative life events. For childhood adversity the interaction with genotype is strongest for sexual abuse, but not for other types of childhood maltreatment; however, possible interactions with specific recent life events have not been investigated separately. The aim of our study was to investigate the effect of four distinct types of recent life events in the development of depressive symptoms in a large community sample. Interaction between different types of recent life events measured by the List of Threatening Experiences and the 5-HTTLPR genotype on current depression measured by the depression subscale and additional items of the Brief Symptom Inventory was investigated in 2588 subjects in Manchester and Budapest. Only a nominal interaction was found between life events overall and 5-HTTLPR on depression, which failed to survive correction for multiple testing. However, subcategorising life events into four categories showed a robust interaction between financial difficulties and the 5-HTTLPR genotype, and a weaker interaction in the case of illness/injury. No interaction effect for the other two life event categories was present. We investigated a general non-representative sample in a cross-sectional approach. Depressive symptoms and life event evaluations were self-reported. The 5-HTTLPR polymorphism showed a differential interaction pattern with different types of recent life events, with the strongest interaction effects of financial difficulties on depressive symptoms. This specificity of interaction with only particular types of life events may help to explain previous contradictory findings.

Rumination in migraine: Mediating effects of brooding and reflection between migraine and psychological distress

Objective: The relationship between migraine and psychological distress has been consistently reported in cross-sectional and longitudinal studies. We hypothesised that a stable tendency to perseverative thoughts such as rumination would mediate the relationship between migraine and psychological distress. Design and Main Outcomes Measures: Self-report questionnaires measuring depressive rumination, current psychological distress and migraine symptoms in two independent European population cohorts, recruited from Budapest (N = 1139) and Manchester (N = 2004), were used. Structural regression analysis within structural equation modelling was applied to test the mediational role of brooding and reflection, the components of rumination, between migraine and psychological distress. Sex, age and lifetime depression were controlled for in the analysis. Results: Migraine predicted higher brooding and reflection scores, and brooding proved to be a mediator between migraine and psychological distress in both samples, while reflection mediated the relationship significantly only in the Budapest sample. Conclusions: Elevated psychological distress in migraine is partially attributed to ruminative response style. Further studies are needed to expand our findings to clinical samples and to examine how rumination links to the adjustment to migraine.

Distinct types of life events interact with 5-HTTLPR in the development of depressive symptoms in an age-dependent manner

Semmelweis University, Department of Psychiatry and Psychotherapy and MTA-SE Neuropsychopharmacology and Neurochemistry Research Group of the Hungarian Academy of Sciences, Budapest, Hungary Semmelweis University, Department of Pharmacodynamics and MTA-SE Neuropsychopharmacology and Neurochemistry Research Group of the Hungarian Academy of Sciences, Budapest, Hungary University of Manchester, Neuroscience and Psychiatry UnitInstitute of Brain Behaviour and Mental Health, Manchester, United Kingdom Semmelweis University, Department of Pharmacodynamics and MTA-SE-NAP B Genetic Brain Imaging Migraine Research Group of the Hungarian Academy of Sciences, Budapest, Hungary

The role of gender in the effect of folate pathway-related MTHFD1L gene on ruminative response style

Our previous results recently demonstrated that the rs11754661 polymorphism A allele, situated in the folate-related MTHFD1L gene, increases the risk of ruminative response style (depressive rumination, or shortly rumination) in a European white population, and this association completely explains the risk that the A allele confers to depression [1]. Although it has been shown that gender differences in rumination play a considerable part in explaining the gender differences in depressive symptoms [2], data on gender differences in the effect of the MTHFD1L gene on neuropsychiatric [3] or neural [4] outcomes are lacking. Our present aim was to explore the role of gender in the association between rs11754661 and rumination.

Interleukin-6 and interleukin-1B polymorphisms show different interaction patterns with stressors on trait anxiety

Neuroinᴀammatory mechanisms received more and more attention recently in neuroscience examining depression and anxiety. Disturbances in the genetic expression pro᐀�le of proinᴀammatory cytokines such as Interleukin-1B (IL-1B) and Interleukin-6 (IL-6) has been reported to inᴀuence these mood disorder pheontypes profoundly, however it has been also shown that different stressors are needed to exert such effect. That means that signi᐀�cant main effects of these genes on depression and anxiety are lacking, but highly signi᐀�cant interaction effects could be observed even after correcting for multiple testing [1,2]. The interactions carried by the large array of different environmental effects are far from clear at this moment.