Multicentric Assessment of a Multimorbidity-Adjusted Disability Score to Stratify Depression-Related Risks Using Temporal Disease Maps: Instrument Validation Study.

BACKGROUND: Comprehensive management of multimorbidity can significantly benefit from advanced health risk assessment tools that facilitate value-based interventions, allowing for the assessment and prediction of disease progression. Our study proposes a novel methodology, the Multimorbidity-Adjusted Disability Score (MADS), which integrates disease trajectory methodologies with advanced techniques for assessing interdependencies among concurrent diseases. This approach is designed to better assess the clinical burden of clusters of interrelated diseases and enhance our ability to anticipate disease progression, thereby potentially informing targeted preventive care interventions. OBJECTIVE: This study aims to evaluate the effectiveness of the MADS in stratifying patients into clinically relevant risk groups based on their multimorbidity profiles, which accurately reflect their clinical complexity and the probabilities of developing new associated disease conditions. METHODS: In a retrospective multicentric cohort study, we developed the MADS by analyzing disease trajectories and applying Bayesian statistics to determine disease-disease probabilities combined with well-established disability weights. We used major depressive disorder (MDD) as a primary case study for this evaluation. We stratified patients into different risk levels corresponding to different percentiles of MADS distribution. We statistically assessed the association of MADS risk strata with mortality, health care resource use, and disease progression across 1 million individuals from Spain, the United Kingdom, and Finland. RESULTS: The results revealed significantly different distributions of the assessed outcomes across the MADS risk tiers, including mortality rates; primary care visits; specialized care outpatient consultations; visits in mental health specialized centers; emergency room visits; hospitalizations; pharmacological and nonpharmacological expenditures; and dispensation of antipsychotics, anxiolytics, sedatives, and antidepressants (P<.001 in all cases). Moreover, the results of the pairwise comparisons between adjacent risk tiers illustrate a substantial and gradual pattern of increased mortality rate, heightened health care use, increased health care expenditures, and a raised pharmacological burden as individuals progress from lower MADS risk tiers to higher-risk tiers. The analysis also revealed an augmented risk of multimorbidity progression within the high-risk groups, aligned with a higher incidence of new onsets of MDD-related diseases. CONCLUSIONS: The MADS seems to be a promising approach for predicting health risks associated with multimorbidity. It might complement current risk assessment state-of-the-art tools by providing valuable insights for tailored epidemiological impact analyses of clusters of interrelated diseases and by accurately assessing multimorbidity progression risks. This study paves the way for innovative digital developments to support advanced health risk assessment strategies. Further validation is required to generalize its use beyond the initial case study of MDD.

Embers of the Past: Early Childhood Traumas Interact with Variation in P2RX7 Gene Implicated in Neuroinflammation on Markers of Current Suicide Risk.

Both early childhood traumatic experiences and current stress increase the risk of suicidal behaviour, in which immune activation might play a role. Previous research suggests an association between mood disorders and P2RX7 gene encoding P2X7 receptors, which stimulate neuroinflammation. We investigated the effect of P2RX7 variation in interaction with early childhood adversities and traumas and recent stressors on lifetime suicide attempts and current suicide risk markers. Overall, 1644 participants completed questionnaires assessing childhood adversities, recent negative life events, and provided information about previous suicide attempts and current suicide risk-related markers, including thoughts of ending their life, death, and hopelessness. Subjects were genotyped for 681 SNPs in the P2RX7 gene, 335 of which passed quality control and were entered into logistic and linear regression models, followed by a clumping procedure to identify clumps of SNPs with a significant main and interaction effect. We identified two significant clumps with a main effect on current suicidal ideation with top SNPs rs641940 and rs1653613. In interaction with childhood trauma, we identified a clump with top SNP psy_rs11615992 and another clump on hopelessness containing rs78473339 as index SNP. Our results suggest that P2RX7 variation may mediate the effect of early childhood adversities and traumas on later emergence of suicide risk.

Inflammation and Blood-Brain Barrier in Depression: Interaction of CLDN5 and IL6 Gene Variants in Stress-Induced Depression.

BACKGROUND: Evidence from rodents indicated that after recent stress, reduced expression of tight junction protein claudin-5 may weaken the blood-brain barrier and allow interleukin-6 to induce depressive symptoms. Our aims were to prove this pathomechanism in humans. METHODS: We used a large population genetic database (UK Biobank, n = 277 501) to test whether variation in the CLDN5 gene could modulate effects of the IL6 gene variant in stress-induced depression. Three-way interaction of functional polymorphisms, rs885985 of CLDN5, and rs1800795 of IL6 with recent stressful life events were tested on current depressive symptoms. Analyses were performed in male and female populations as well. RESULTS: The 3-way interaction including recent stress yielded highly significant results on current depressive symptoms in the UK Biobank sample, which was more pronounced in men and could be replicated on trend level in an independent cohort (NewMood, n = 1638). None of any other associations or interactions, including, for example, childhood stressors and lifetime depression as an outcome, yielded significance. CONCLUSIONS: These findings provide genetic evidence in humans for the interaction among interleukin-6, claudin-5, and recent stress, suggesting that inflammation is involved in the development of depression and that stress-connected brain entry of inflammatory molecules is a key factor in this pathomechanism. These genetic polymorphisms may help to identify people at higher risk for recent stress-induced depression.

Microstructural differences in migraine: A diffusion-tensor imaging study.

BACKGROUND: Diffusion-tensor imaging can be applied to describe the microstructural integrity of the whole brain. As findings about microstructural alterations in migraine are inconsistent, we aimed to replicate the most frequent results and assess a relationship between migraine parameters and changes in microstructure. METHODS: Diffusion-weighted MRI data of 37 migraine patients and 40 controls were collected. Two indices of diffusion of water molecules, fractional anisotropy and mean diffusivity were used in a voxel-wise analysis. Group comparisons were carried out in SPM12 using age and sex as covariates. Statistically significant results survived family-wise error correction (pFWE < 0.05). Migraine intensity, frequency, and duration were self-reported and correlated with mean fractional anisotropy and mean diffusivity values across clusters. RESULTS: Migraine patients showed significantly lower fractional anisotropy in occipital regions, and significantly higher fractional anisotropy in thirteen clusters across the brain. Mean diffusivity of migraine patients was significantly decreased in the cerebellum and pons, but it was not increased in any area. Correlation between migraine duration and fractional anisotropy was significantly positive in the frontal cortex and significantly negative in the superior parietal lobule. CONCLUSION: We suggest that microstructural integrity of the migraine brain is impaired in visual areas and shows duration-related alterations in regions of the default mode network.

A sound mind in a sound body: a novel concept unravelling heterogeneity of depression.

Depression is a highly prevalent and debilitating condition, yet we still lack both in-depth knowledge concerning its etiopathology and sufficiently efficacious treatment options. With approximately one third of patients resistant to currently available antidepressants there is a pressing need for a better understanding of depression, identifying subgroups within the highly heterogeneous illness category and to understand the divergent underlying biology of such subtypes, to help develop and personalise treatments. The TRAJECTOME project aims to address such challenges by (1) identifying depression-related multimorbidity subgroups and shared molecular pathways based on temporal disease profiles from healthcare systems and biobank data using machine learning approaches, and by (2) characterising these subgroups from multiple aspects including genetic variants, metabolic processes, lifestyle and environmental factors. Following the identification of multimorbidity trajectories, a disease burden score related to depression and adjusted for multimorbidity was established summarising the current state of the patient to weigh the molecular mechanisms associated with depression. In addition, the role of genetic and environmental factors, and also their interactions were identified for all subgroups. The project also attempted to identify potential metabolomic markers for the early diagnostics of these multimorbidity conditions. Finally, we prioritized molecular drug candidates matching the multimorbidity pathways indicated for the individual subgroups which would potentially offer personalised treatment simultaneously for the observable multimorbid conditions yet minimising polypharmacy and related side effects. The present paper overviews the TRAJECTOME project including its aims, tasks, procedures and accomplishments. (Neuropsychopharmacol Hung 2023; 25(4): 183-193)

Towards personalised antidepressive medicine based on "big data": an up-to-date review on robust factors affecting treatment response.

Prescribing antidepressant medication is currently the most effective way of treating major depression, but only very few patients achieve permanent improvement. Therefore, it is important to identify objectively measurable markers for effective, personalized therapy. The aim of this review article is to collect all the markers that are robustly predictive of the outcome of therapy. We searched for systematic review articles that have simultaneously investigated the effects of as many different markers as possible on the response to antidepressant therapy in major depressive patients. From these we extracted markers that have been found to be significant by at least two independent review studies and that have proven replicable also within each of these reviews. A separate search was performed for meta-analyses of pharmacogenetic genome-wide association studies. Based on our results, onset time, symptom severity, presence of anhedonia, early treatment response, comorbid anxiety, alcohol consumption, frontal EEG theta activity, hippocampal volume, activity of anterior cingulate cortex, as well as a peripheral marker, serum BDNF levels have proven replicable predictors of antidepressant response. Pharmacogenomic studies to date have not yielded replicable results. Predictors identified as robust by our study may provide a starting point for future machine learning models within a 'big data' database of major depressive patients. (Neuropsychopharmacol Hung 2022; 24(1): 17-28).

A cross-sectional study on the quality of life in migraine and medication overuse headache in a Hungarian sample: understanding the effect of headache characteristics.

Background and purpose: Previous studies using generic and disease specific instruments showed that both migraine and medication overuse headache are associated with lower health-related quality of life (HRQoL). The aim of our study was to assess HRQoL differences in migraineurs and in patients with MOH and to examine how headache characteristics such as years with headache, aura symptoms, triptan use, headache pain severity and headache frequency are related to HRQoL. Methods: In this cross-sectional study 334 participants were examined (248 were recruited from a tertiary headache centre and 86 via advertisements). The Comp-rehensive Headache-related Quality of life Questionnaire (CHQQ) was used to measure the participants' HRQoL. Data showed normal distribution, therefore beside Chi-squared test parametric tests (e.g. independent samples t-test) were used with a two-tailed p<0.05 threshold. Linear regression models were used to determine the independent effects of sex, age, recruitment method, headache type (migraine vs. MOH) and headache characteristics (presence of aura symptoms, years with headache, headache pain severity, headache frequency and triptan use) separately for each domain and for the total score of CHQQ. Significance threshold was adopted to p0.0125 (0.05/4) to correct for multiple testing and avoid Type I error. Results: Independent samples t-tests showed that patients with MOH had significantly lower scores on all CHQQ domains than migraineurs, except on the social subscale. Results of a series of regression analyses showed that triptan use was inversely related to all the domains of HRQoL after correction for multiple testing (p<0.0125). In addition, headache pain severity was associated with lower physical (p=0.001) and total scores (p=0.002) on CHQQ subscales. Conclusion: Based on the results, different headache characteristics (but not the headache type, namely migraine or MOH) were associated with lower levels of HRQoL in patients with headache. Determining which factors play significant role in the deterioration of HRQoL is important to adequately manage different patient populations and to guide public health policies regarding health service utilization and health-care costs.

Complex mediating effects of rumination facets between personality traits and depressive symptoms.

This study investigates whether facets of rumination statistically mediate the relationships between Big Five personality traits and depressive symptoms. Self-reported personality traits and rumination were investigated as predictors of depressive symptoms in a cross-sectional sample of 3043 participants aged 18-60 years (68.8% female). Multiple regression analysis investigated which personality traits and rumination facets best explained variance in depressive symptoms. Structural equation modelling was used to determine whether facets of rumination mediated the relationships between personality traits and depressive symptoms. Multiple regression analysis found that variance in depressive symptoms was best explained by the personality traits neuroticism, extroversion, conscientiousness; and both facets of rumination, brooding and reflection. Structural equation modelling added that the effects of neuroticism, extroversion, conscientiousness and openness on depressive symptoms were statistically mediated by brooding; the effects of neuroticism, extroversion and openness to depressive symptoms were statistically mediated by reflection. Rumination facets statistically mediated the effects of various personality traits on depressive symptoms. These results provide insights into which individuals may be best suited to treatments for depression targeting rumination.

Anticipation and violated expectation of pain are influenced by trait rumination: An fMRI study.

Rumination - as a stable tendency to focus repetitively on feelings related to distress - represents a transdiagnostic risk factor. Theories suggest altered emotional information processing as the key mechanism of rumination. However, studies on the anticipation processes in relation to rumination are scarce, even though expectation in this process is demonstrated to influence the processing of emotional stimuli. In addition, no published study has investigated violated expectation in relation to rumination yet. In the present study we examined the neural correlates of pain anticipation and perception using a fear conditioning paradigm with pain as the unconditioned stimulus in healthy subjects (N = 30). Rumination was assessed with the 10-item Ruminative Response Scale (RRS). Widespread brain activation - extending to temporal, parietal, and occipital lobes along with activation in the cingulate cortex, insula, and putamen - showed a positive correlation with rumination, supporting our hypothesis that trait rumination influences anticipatory processes. Interestingly, with violated expectation (when an unexpected, non-painful stimulus follows a pain cue compared to when an expected, painful stimulus follows the same pain cue) a negative association between rumination and activation was found in the posterior cingulate cortex, which is responsible for change detection in the environment and subsequent behavioral modification. Our results suggest that rumination is associated with increased neural response to pain perception and pain anticipation, and may deteriorate the identification of an unexpected omission of aversive stimuli. Therefore, targeting rumination in cognitive behavioral therapy of chronic pain could have a beneficial effect.

Increased activation of the pregenual anterior cingulate cortex to citalopram challenge in migraine: an fMRI study.

BACKGROUND: The anterior cingulate cortex (ACC) is a key structure of the pain processing network. Several structural and functional alterations of this brain area have been found in migraine. In addition, altered serotonergic neurotransmission has been repeatedly implicated in the pathophysiology of migraine, although the exact mechanism is not known. Thus, our aim was to investigate the relationship between acute increase of brain serotonin (5-HT) level and the activation changes of the ACC using pharmacological challenge MRI (phMRI) in migraine patients and healthy controls. METHODS: Twenty-seven pain-free healthy controls and six migraine without aura patients participated in the study. All participant attended to two phMRI sessions during which intravenous citalopram, a selective serotonin reuptake inhibitor (SSRI), or placebo (normal saline) was administered. We used region of interest analysis of ACC to compere the citalopram evoked activation changes of this area between patients and healthy participants. RESULTS: Significant difference in ACC activation was found between control and patient groups in the right pregenual ACC (pgACC) during and after citalopram infusion compared to placebo. The extracted time-series showed that pgACC activation increased in migraine patients compared to controls, especially in the first 8-10 min of citalopram infusion. CONCLUSIONS: Our results demonstrate that a small increase in 5-HT levels can lead to increased phMRI signal in the pregenual part of the ACC that is involved in processing emotional aspects of pain. This increased sensitivity of the pgACC to increased 5-HT in migraine may contribute to recurring headache attacks and increased stress-sensitivity in migraine.

Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide.

Major depressive disorder (MDD) is a substantial burden to patients, families, and society, but many patients cannot be treated adequately. Rodent experiments suggest that the neuropeptide galanin (GAL) and its three G protein-coupled receptors, GAL1-3, are involved in mood regulation. To explore the translational potential of these results, we assessed the transcript levels (by quantitative PCR), DNA methylation status (by bisulfite pyrosequencing), and GAL peptide by RIA of the GAL system in postmortem brains from depressed persons who had committed suicide and controls. Transcripts for all four members were detected and showed marked regional variations, GAL and galanin receptor 1 (GALR1) being most abundant. Striking increases in GAL and GALR3 mRNA levels, especially in the noradrenergic locus coeruleus and the dorsal raphe nucleus, in parallel with decreased DNA methylation, were found in both male and female suicide subjects as compared with controls. In contrast, GAL and GALR3 transcript levels were decreased, GALR1 was increased, and DNA methylation was increased in the dorsolateral prefrontal cortex of male suicide subjects, however, there were no changes in the anterior cingulate cortex. Thus, GAL and its receptor GALR3 are differentially methylated and expressed in brains of MDD subjects in a region- and sex-specific manner. Such an epigenetic modification in GALR3, a hyperpolarizing receptor, might contribute to the dysregulation of noradrenergic and serotonergic neurons implicated in the pathogenesis of MDD. Thus, one may speculate that a GAL3 antagonist could have antidepressant properties by disinhibiting the firing of these neurons, resulting in increased release of noradrenaline and serotonin in forebrain areas involved in mood regulation.

[Significance of the endocannabinoid system in migraine]. / Az endokannabinoid rendszer jelentosége a migrénben.

Based on the traditional pain-relieving effect of Cannabis species an endogenous cannabinoidlike system was discovered in the human body. Endocannabinoids have important role in the homeostasis of the body, such as stress response and mood control, feeding behaviour, energy balance and metabolism, immunological processes, and also play important role in controlling pain processing. Previous studies suggested that an endokannabinoid dysfunction, namely endokannabinoid deficit, might contribute to the development of migraine and its chronification. Although, the exact nature of the relationship between migraine and endokannabinoid system is not fully understood yet, in this brief review we summarise research results suggesting that the endokannabinoid system may be a potential drug target in the migraine therapy.

[Anxiety and depression - the role of blood-brain barrier integrity]. / Szorongás és depresszió ­ a vér-agy gát integritásának szerepe.

Among mental illnesses, anxiety disorders represent the second most frequent disorder. According to WHO Survey 2017, 264 million people suffer from their different types globally. The emergence of anxiety disorders can often increase the likelihood of developing other psychiatric illnesses such as depression, which is the most common mental illness with 300 million people affected worldwide. Although the two diseases mentioned above are widespread throughout the world, the exact physiological causes of their development and the way they are connected are not well understood. However, in order to be able to use right treatment it would be important to know the physiological background in their development. The use of anxiolytics and antidepressants is not always effective and safe, which may be due to the subtypes of these mental disorders with different etiologies. Identifying the right therapeutic strategies could be also challenging because of the phenotypic overlap between anxiety disorders and depression. Their comorbidity has been confirmed by many studies, but their exact physiological relationship is still unclear. Previous studies suggested that blood-brain barrier proteins play an important role in the development of depression and anxiety disorders and might partially explain their comorbidities. In our summary we review the current literature related to this topic.

Transcriptomic changes following chronic administration of selective serotonin reuptake inhibitors: a review of animal studies.

The review focuses on transcriptomic changes following treatment with serotonin reuptake inhibitor (SSRI) antidepressants. We aimed to overview results of the most established methods for the investigation of the gene expression alterations including northern blotting, in situ hybridization, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), microarray and RNAseq in various brain regions and after chronic treatment protocols. In spite of some measurable changes in serotonin system mRNA expression, serotonin transporter levels remained mostly unaltered following various treatment protocols. In contrast, tryptophan hydroxylase 2 appeared to be downregulated in serotonergic nuclei, and upregulated in the midbrain regions. Alterations in serotonin receptors lack clear conclusions and changes probably reflect animal strain/substance related- and brain region dependent effects. Brain derived neurotrophic factor was upregulated following many, but not all chronic treatment regimens. GABA and glutamate genes also showed heterogeneous changes, with a surprising NMDA receptor downregulation in areas including the striatum and amygdala, known to be involved in depressive states and stress reactions. The review of the above studies suggests alterations in multiple processes, reflecting the heterogeneity of the action depending on brain area and type of SSRI, and raises the possibility of a novel grouping of antidepressant medications based on their chronic molecular profile rather than on their initial actions.

Comorbidities in the diseasome are more apparent than real: What Bayesian filtering reveals about the comorbidities of depression.

Comorbidity patterns have become a major source of information to explore shared mechanisms of pathogenesis between disorders. In hypothesis-free exploration of comorbid conditions, disease-disease networks are usually identified by pairwise methods. However, interpretation of the results is hindered by several confounders. In particular a very large number of pairwise associations can arise indirectly through other comorbidity associations and they increase exponentially with the increasing breadth of the investigated diseases. To investigate and filter this effect, we computed and compared pairwise approaches with a systems-based method, which constructs a sparse Bayesian direct multimorbidity map (BDMM) by systematically eliminating disease-mediated comorbidity relations. Additionally, focusing on depression-related parts of the BDMM, we evaluated correspondence with results from logistic regression, text-mining and molecular-level measures for comorbidities such as genetic overlap and the interactome-based association score. We used a subset of the UK Biobank Resource, a cross-sectional dataset including 247 diseases and 117,392 participants who filled out a detailed questionnaire about mental health. The sparse comorbidity map confirmed that depressed patients frequently suffer from both psychiatric and somatic comorbid disorders. Notably, anxiety and obesity show strong and direct relationships with depression. The BDMM identified further directly co-morbid somatic disorders, e.g. irritable bowel syndrome, fibromyalgia, or migraine. Using the subnetwork of depression and metabolic disorders for functional analysis, the interactome-based system-level score showed the best agreement with the sparse disease network. This indicates that these epidemiologically strong disease-disease relations have improved correspondence with expected molecular-level mechanisms. The substantially fewer number of comorbidity relations in the BDMM compared to pairwise methods implies that biologically meaningful comorbid relations may be less frequent than earlier pairwise methods suggested. The computed interactive comprehensive multimorbidity views over the diseasome are available on the web at Co=MorNet: bioinformatics.mit.bme.hu/UKBNetworks.

The validation of the Hungarian version of the ID-migraine questionnaire.

BACKGROUND: Despite its high prevalence, migraine remains underdiagnosed and undertreated. ID-Migraine is a short, self-administrated questionnaire, originally developed in English by Lipton et al. and later validated in several languages. Our goal was to validate the Hungarian version of the ID-Migraine Questionnaire. METHODS: Patients visiting two headache specialty services were enrolled. Diagnoses were made by headache specialists according to the ICHD-3beta diagnostic criteria. There were 309 clinically diagnosed migraineurs among the 380 patients. Among the 309 migraineurs, 190 patients had only migraine, and 119 patients had other headache beside migraine, namely: 111 patients had tension type headache, 3 patients had cluster headache, 4 patients had medication overuse headache and one patient had headache associated with sexual activity also. Among the 380 patients, 257 had only a single type headache whereas 123 patients had multiple types of headache. Test-retest reliability of the ID-Migraine Questionnaire was studied in 40 patients. RESULTS: The validity features of the Hungarian version of the ID-Migraine questionnaire were the following: sensitivity 0.95 (95% CI, 0.92-0.97), specificity 0.42 (95% CI, 0.31-0.55), positive predictive value 0.88 (95% CI, 0.84-0.91), negative predictive value 0.65 (95% CI, 0.5-0.78), missclassification error 0.15 (95% CI, 0.12-0.19). The kappa coefficient of the questionnaire was 0.77. CONCLUSION: The Hungarian version of the ID-Migraine Questionnaire had adequate sensitivity, positive predictive value and misclassification error, but a low specificity and somewhat low negative predictive value.

Phylogenetic analysis of a transfusion-transmitted hepatitis A outbreak.

A transfusion-associated hepatitis A outbreak was found in the first time in Hungary. The outbreak involved five cases. Parenteral transmission of hepatitis A is rare, but may occur during viraemia. Direct sequencing of nested PCR products was performed, and all the examined samples were identical in the VP1/2A region of the hepatitis A virus genome. HAV sequences found in recent years were compared and phylogenetic analysis showed that the strain which caused these cases is the same as that had spread in Hungary recently causing several hepatitis A outbreaks throughout the country.

Brain galanin system genes interact with life stresses in depression-related phenotypes.

Galanin is a stress-inducible neuropeptide and cotransmitter in serotonin and norepinephrine neurons with a possible role in stress-related disorders. Here we report that variants in genes for galanin (GAL) and its receptors (GALR1, GALR2, GALR3), despite their disparate genomic loci, conferred increased risk of depression and anxiety in people who experienced childhood adversity or recent negative life events in a European white population cohort totaling 2,361 from Manchester, United Kingdom and Budapest, Hungary. Bayesian multivariate analysis revealed a greater relevance of galanin system genes in highly stressed subjects compared with subjects with moderate or low life stress. Using the same method, the effect of the galanin system genes was stronger than the effect of the well-studied 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4). Conventional multivariate analysis using general linear models demonstrated that interaction of galanin system genes with life stressors explained more variance (1.7%, P = 0.005) than the life stress-only model. This effect replicated in independent analysis of the Manchester and Budapest subpopulations, and in males and females. The results suggest that the galanin pathway plays an important role in the pathogenesis of depression in humans by increasing the vulnerability to early and recent psychosocial stress. Correcting abnormal galanin function in depression could prove to be a novel target for drug development. The findings further emphasize the importance of modeling environmental interaction in finding new genes for depression.

Why are migraineurs more depressed? A review of the factors contributing to the comorbidity of migraine and depression.

The comorbidity of migraine and depression is well-known. Patients with both conditions show stronger headache-related symptoms, a more severe clinical course and higher risk for migraine chronification. Therefore, it's important to identify factors underlying comorbid migraine and depression. The growing body of literature suggests complex, biopsychosocial mechanisms in the background, including shared genetic risk factors and abnormal brain mechanisms, and also different environmental (stress) and psychological variables (for example: rumination, neuroticism). In this short review we summarize the most important findings regarding the interacting factors in the pathomechanism of the co-existence of migraine and depression. Finally, we conclude some therapeutical considerations regarding treatment of patients with the migraine-depression phenotype.

[Genetic association analyses of the endocannabinoid system on anxious phenotype]. / Az endokannabinoid rendszer genetikai asszociációs vizsgálatai szorongással összefüggésben.

BACKGROUND: Accumulating data confirmed that the endocannabinoid system (ECS) is involved in the regulation of stress response and emotional processes, therefore ECS became an important pharmacological target as a potential anxiolytic. Although unequivocal data from animal studies confirmed the relevancy of the ECS in anxious phenotype, human genetic data are poorly available in the literature in this field. In the presented studies we tested possible associations between anxious phenotype and the cannabinoid receptor 1 and the fatty acid amide hydrolase gene polymorphisms. METHODS: Almost 900 subjects were involved in our study from the general population. Anxious phenotype was measured by the State-Trait Anxiety Inventory (STAI) and the anxious subscale of the Brief Symptom Inventory (BSI-ANX). Genetic polymorphisms were genotyped from buccal mucosa samples' DNA by MassArray Sequenom technic. General linear models and post hoc tests were performed for statistical analyses. RESULTS: Phenotypic variances were not dependent on single marker's effect. However, interaction analyses provided significant results. Carriers of GG genotype of the rs2180619 scored significantly higher on the STAI-T scale in presence of SS genotype of 5-HTTLPR compared to other allelic variants (p=0.0006). SS genotype together with GG genotype meant almost a 5-fold risk to be anxious (OR=4.64, 95% CI: 1.7-12.71). In case of the C385A polymorphism of FAAH gene, A allele was associated with high scores of the BSI-ANX and the STAI-T if there were multiple childhood traumas in the anamnesis compared to C allele (pinteract=0.00002; pinteract=0.0023; respectively). CONCLUSION: Our results confirmed earlier positive data on the association between ECS and anxious phenotype. According to our findings ECS plays a significant role in the pathomechanism of anxious disorders by a complex mechanism of genetic interaction with the serotonin transporter gene and childhood traumas.