Browsing by Subject "MAJOR DEPRESSION"

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  • Puurunen, Jenni; Sulkama, Sini; Tiira, Katriina; Araujo, Cesar; Lehtonen, Marko; Hanhineva, Kati; Lohi, Hannes (2016)
    Background: Attention deficit hyperactivity disorder (ADHD) is a prevalent and multifactorial neuropsychiatric disorder in the human population worldwide. Complex etiology and clinical heterogeneity have challenged the research, diagnostics and treatment of the disease. Hyperactive and impulsive behaviour has also been observed in dogs, and they could offer a physiologically relevant model for human ADHD. As a part of our ongoing study to understand the molecular etiology of canine anxiety traits, this study was aimed to pilot an approach to identify metabolic biomarkers in canine ADHD-like behaviours for research, diagnostics and treatment purposes. Methods: We collected fresh plasma samples from 22 German Shepherds with varying ADHD-like behaviours. All dogs were on the same controlled diet for 2 weeks prior to sampling. A liquid chromatography combined with mass spectrometry (LC-MS)-based non-targeted metabolite profiling was performed to identify plasma metabolites correlating with the ADHD-like behaviour of the dogs. Results: 649 molecular features correlated with ADHD-like behavioural scores (p(raw) <0.05), and three of them [sn-1 LysoPC(18: 3), PC(18: 3/18: 2) and sn-1 LysoPE(18: 2)] had significant correlations also after FDR correction (pFDR <0.05). Phospholipids were found to negatively correlate with ADHD-like behavioural scores, whereas tryptophan metabolites 3-indolepropionic acid (IPA) and kynurenic acid (KYNA) had negative and positive correlations with ADHD-like behavioural scores, respectively. Conclusions: Our study identified associations between canine ADHD-like behaviours and metabolites that are involved in lipid and tryptophan metabolisms. The identified metabolites share similarity with earlier findings in human and rodent ADHD models. However, a larger replication study is warranted to validate the discoveries prior to further studies to understand the biological role of the identified metabolites in canine ADHD-like behaviours.
  • Rosenstrom, Tom; Fawcett, Tim W.; Higginson, Andrew D.; Metsa-Simola, Niina; Hagen, Edward H.; Houston, Alasdair I.; Martikainen, Pekka (2017)
    Divorce is associated with an increased probability of a depressive episode, but the causation of events remains unclear. Adaptive models of depression propose that depression is a social strategy in part, whereas non-adaptive models tend to propose a diathesis-stress mechanism. We compare an adaptive evolutionary model of depression to three alternative non-adaptive models with respect to their ability to explain the temporal pattern of depression around the time of divorce. Register-based data (304,112 individuals drawn from a random sample of 11% of Finnish people) on antidepressant purchases is used as a proxy for depression. This proxy affords an unprecedented temporal resolution (a 3-monthly prevalence estimates over 10 years) without any bias from non-compliance, and it can be linked with underlying episodes via a statistical model. The evolutionary-adaptation model (all time periods with risk of divorce are depressogenic) was the best quantitative description of the data. The non-adaptive stress-relief model (period before divorce is depressogenic and period afterwards is not) provided the second best quantitative description of the data. The peak-stress model (periods before and after divorce can be depressogenic) fit the data less well, and the stress-induction model (period following divorce is depressogenic and the preceding period is not) did not fit the data at all. The evolutionary model was the most detailed mechanistic description of the divorce-depression link among the models, and the best fit in terms of predicted curvature; thus, it offers most rigorous hypotheses for further study. The stress-relief model also fit very well and was the best model in a sensitivity analysis, encouraging development of more mechanistic models for that hypothesis.
  • Direk, Nese; Williams, Stephanie; Smith, Jennifer A.; Ripke, Stephan; Air, Tracy; Amare, Azmeraw T.; Amin, Najaf; Baune, Bernhard T.; Bennett, David A.; Blackwood, Douglas H. R.; Boomsma, Dorret; Breen, Gerome; Buttenschon, Henriette N.; Byrne, Enda M.; Borglum, Anders D.; Castelao, Enrique; Cichon, Sven; Clarke, Toni-Kim; Cornelis, Marilyn C.; Dannlowski, Udo; De Jager, Philip L.; Demirkan, Ayse; Domenici, Enrico; van Duijn, Cornelia M.; Dunn, Erin C.; Eriksson, Johan G.; Esko, Tonu; Faul, Jessica D.; Ferrucci, Luigi; Fornage, Myriam; de Geus, Eco; Gill, Michael; Gordon, Scott D.; Grabe, Hans Joergen; van Grootheest, Gerard; Hamilton, Steven P.; Hartman, Catharina A.; Heath, Andrew C.; Hek, Karin; Hofman, Albert; Homuth, Georg; Horn, Carsten; Hottenga, Jouke Jan; Kardia, Sharon L. R.; Kloiber, Stefan; Koenen, Karestan; Kutalik, Zoltan; Ladwig, Karl-Heinz; Lahti, Jari; Levinson, Douglas F.; Lewis, Cathryn M.; Lewis, Glyn; Li, Qingqin S.; Llewellyn, David J.; Lucae, Susanne; Lunetta, Kathryn L.; MacIntyre, Donald J.; Madden, Pamela; Martin, Nicholas G.; McIntosh, Andrew M.; Metspalu, Andres; Milaneschi, Yuri; Montgomery, Grant W.; Mors, Ole; Mosley, Thomas H.; Murabito, Joanne M.; Mueller-Myhsok, Bertram; Nothen, Markus M.; Nyholt, Dale R.; O'Donovan, Michael C.; Penninx, Brenda W.; Pergadia, Michele L.; Perlis, Roy; Potash, James B.; Preisig, Martin; Purcell, Shaun M.; Quiroz, Jorge A.; Raikkonen, Katri; Rice, John P.; Rietschel, Marcella; Rivera, Margarita; Schulze, Thomas G.; Shi, Jianxin; Shyn, Stanley; Sinnamon, Grant C.; Smit, Johannes H.; Smoller, Jordan W.; Snieder, Harold; Tanaka, Toshiko; Tansey, Katherine E.; Teumer, Alexander; Uher, Rudolf; Umbricht, Daniel; Van der Auwera, Sandra; Ware, Erin B.; Weir, David R.; Weissman, Myrna M.; Willemsen, Gonneke; Yang, Jingyun; Zhao, Wei; Tiemeier, Henning; Sullivan, Patrick F. (2017)
    BACKGROUND: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder. METHODS: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures. RESULTS: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 x 10(-9)) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 x 10(-9)). CONCLUSIONS: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.
  • Seppala, Jussi; Koponen, Hannu; Kautiainen, Hannu; Eriksson, Johan G.; Kampman, Olli; Leiviska, Jaana; Mannisto, Satu; Mantyselka, Pekka; Oksa, Heikki; Ovaskainen, Yrj; Viikki, Merja; Vanhala, Mauno; Seppala, Jussi (2013)
  • Laine, Mikaela A.; Sokolowska, Ewa; Dudek, Mateusz; Callan, Saija-Anita; Hyytia, Petri; Hovatta, Iiris (2017)
    Chronic psychosocial stress is a well-established risk factor for neuropsychiatric diseases. Abnormalities in brain activity have been demonstrated in patients with stress-related disorders. Global brain activation patterns during chronic stress exposure are less well understood but may have strong modifying effects on specific brain circuits and thereby influence development of stress-related pathologies. We determined neural activation induced by chronic social defeat stress, a mouse model of psychosocial stress. To assess chronic activation with an unbiased brain-wide focus we used manganese-enhanced magnetic resonance imaging (MEMRI) and immunohistochemical staining of Delta FOSB, a transcription factor induced by repeated neural activity. One week after 10-day social defeat we observed significantly more activation in several brain regions known to regulate depressive and anxiety-like behaviour, including the prefrontal cortex, bed nucleus of stria terminalis, ventral hippocampus and periaqueductal grey in stressed compared to control mice. We further established that the correlation of Delta FOSB positive cells between specific brain regions was altered following chronic social defeat. Chronic activation of these neural circuits may relate to persistent brain activity changes occurring during chronic psychosocial stress exposure, with potential relevance for the development of anxiety and depression in humans.
  • Castren, Eero; Monteggia, Lisa M. (2021)
    Neurotrophic factors, particularly BDNF (brain-derived neurotrophic factor), have been associated with depression and antidepressant drug action. A variety of preclinical and clinical studies have implicated impaired BDNF signaling through its receptor TrkB (neurotrophic receptor tyrosine kinase 2) in the pathophysiology of mood disorders, but many of the initial findings have not been fully supported by more recent meta-analyses, and more both basic and clinical research is needed. In contrast, increased expression and signaling of BDNF has been repeatedly implicated in the mechanisms of both typical and rapid-acting antidepressant drugs, and recent findings have started to elucidate the mechanisms through which antidepressants regulate BDNF signaling. BDNF is a critical regulator of various types of neuronal plasticities in the brain, and plasticity has increasingly been connected with antidepressant action. Although some equivocal data exist, the hypothesis of a connection between neurotrophic factors and neuronal plasticity with mood disorders and antidepressant action has recently been further strengthened by converging evidence from a variety of more recent data reviewed here.
  • Yang, Lei; Hu, Yaoyue; Silventoinen, Karri; Martikainen, Pekka (2020)
    Objectives: A number of studies have established the link between childhood adversity (CA) and depression across the life span. This association can be culturally specific, and it remains unclear whether and how different aspects of CA affect depressive symptoms in later life in non-Western societies. Method: Data were from the China Health and Retirement Longitudinal Study in 2011, 2013, 2014 (Life Event History survey) and 2015 (N = 13,710). Depressive symptoms were measured repeatedly in 2011, 2013, and 2015 using the ten-item Centre for Epidemiologic Studies Depression Scale (CES-D-10). CA was assessed in 2014 by parental physical abuse, maternal emotional neglect, early parental death, parental mental health problems, poor quality of parental relationship, and childhood socioeconomic disadvantage. Multilevel linear models were used to analyse the data. Results: Parental physical abuse was associated with 0.51 (95% confidence interval [CI]: 0.28, 0.74) and 0.59 (95% CI: 0.31, 0.88) higher CES-D-10 scores compared to those without such abuse experience for men and women, respectively. Emotional neglect predicted 0.30 (95% CI: 0.07, 0.51) and 0.33 (95% CI: 0.08, 0.58) higher CES-D-10 scores for men and women. Elevated CES-D-10 scores were also found among men and women whose parents had poor mental health and poor relationship, and those who experienced food inadequacy (men: 0.78, 95% CI: 0.54, 1.01; women: 1.15, 95% CI: 0.90, 1.41). Early parental death nevertheless was not associated with CES-D-10 scores. Conclusion: CA exerts long-term detrimental effects on mental health in mid- and late-life among Chinese adults. The findings are consistent with those from Western societies, except for early parental death.
  • Jokela, Markus; García-Velázquez, Regina; Airaksinen, Jaakko; Gluschkoff, Kia; Kivimäki, Mika; Rosenström, Tom (2019)
    Background: Depression is a heterogeneous mental disorder with multiple symptoms, but only few studies have examined whether associations of risk factors with depression are symptom-specific. We examined whether chronic diseases and social risk factors (poverty, divorce, and perceived lack of emotional support) are differently associated with somatic and cognitive/affective symptoms of depression. Methods: Cross-sectional analyses were based on individual-level data from the 31,191 participants of six cross-sectional U.S. National Health and Nutrition Examination Surveys (NHANES) carried out between 2005 and 2016. Depressive symptoms were assessed using the 9-item Patient Health Questionnaire. Information on chronic diseases and social risk factors was self-reported by participants. Results: After adjustment for sex, age, race/ethnicity, and all the of other symptoms besides the outcome symptom, higher number of chronic diseases was independently related to fatigue, psychomotor retardation/agitation, and sleep problems in a dose-response pattern (range of odds ratios: 1.21 to 2.59). Except for concentration problems, social risk factors were associated with almost all of the cognitive/affective symptoms (range of odds ratios: 1.02 to 2.09) but only sporadically with somatic symptoms. Limitations: All measures were self-reported by the participants, which may have introduced bias to the associations. Cross-sectional data did not allow us to study temporal dynamics. Conclusions: Specific symptoms of depression may be useful in characterizing the heterogeneous etiology of depression with respect to somatic versus social risk factors.
  • Aaltonen, Kari; Naatanen, Petri; Heikkinen, Martti; Koivisto, Maaria; Baryshnikoy, Ilya; Karpov, Boris; Oksanen, Jorma; Melartin, Tarja; Suominen, Kirsi; Joffe, Grigori; Paunio, Tiina; Isometsa, Erkki (2016)
    Background: Substantial literature exists on risk factors for suicidal behaviour. However, their comparative strength, independence and specificity for either suicidal ideation or suicide attempt(s) remain unclear. Methods: The Helsinki University Psychiatric Consortium (HUPC) Study surveyed 287 psychiatric care patients with ICD-10-DCR depressive or bipolar disorders about lifetime suicidal behaviour, developmental history and attachment style, personality and psychological traits, current and lifetime symptom profiles, and life events. Psychiatric records were used to confirm diagnosis and complement information on suicide attempts. Multinomial regression models predicting lifetime suicidal ideation and single or repeated suicide attempts were generated. Results: Overall, 21.6% patients had no lifetime suicidal behaviour, 33.8% had lifetime suicide ideation without attempts, and 17.1% had a single and 27.5% repeated suicide attempts. In univariate analyses, lifetime suicidal behaviour was associated with numerous factors. In multivariate models, suicidal ideation was independently predicted by younger age, severe depressive disorder, bipolar disorder type II/nos, hopelessness, and childhood physical abuse. Repeated suicide attempts were independently predicted by younger age, female sex, severe depressive disorder with or without psychotic symptoms, bipolar disorder type II/nos, alcohol use disorder, borderline personality disorder traits, and childhood physical abuse. Limitations: Cross-sectional and retrospective study design, utilization of clinical diagnoses, and relatively low response rate. Conclusions: Risk factors for suicidal ideation and attempts may diverge both qualitatively and in terms of dose response. When effects of risk factors from multiple domains are concurrently examined, proximal clinical characteristics remain the most robust. All risk factors cluster into the group of repeated attempters. (C) 2015 Elsevier B.V. All rights reserved.
  • SUPER Researchers Listed Acknowle; Ahti, Johan; Kieseppä, Tuula; Suvisaari, Jaana; Suokas, Kimmo; Holm, Minna; Wegelius, Asko; Ahola-Olli, Ari; Hakkinen, Katja; Kampman, Olli; Lähteenvuo, Markku; Paunio, Tiina; Tiihonen, Jari; Tuulio-Henriksson, Annamari; Isometsä, Erkki (2022)
    Background: Psychotic disorders differ in their impact on psychosocial functioning. However, few studies have directly compared psychosocial functioning and its determinants between schizophrenia, schizoaffective disorder (SAD), bipolar disorder (BD), and major depressive disorder with psychotic features (psychotic MDD). Objective: We compared rates of independent living, employment, marriage, and having children between these diagnostic groups in a large national sample of participants with psychotic disorders in Finland. Methods: A cross-sectional substudy of participants (N = 9148) aged 18 to 65 years in the Finnish SUPER study, recruited nationwide from health-and social care settings and with advertisements. Psychosis diagnoses, age of onset, and hospitalizations were collected from healthcare registers. Participants were interviewed for psychosocial functioning. Associations of age of onset, hospitalizations, gender, and education with psychosocial functioning were analyzed using logistic regression models. Results: Of participants, 13.8% were employed or studying, 72.0% living independently and 32.5% had children. Overall, BD was associated with best, SAD and psychotic MDD with intermediate, and schizophrenia with worst level of psychosocial functioning. Greatest differences were found in independent living (OR 4.06 for BD vs. schizophrenia). In multivariate models, gender and number of hospitalizations predicted employment, marriage, and independent living in all diagnostic categories, and age of onset in some diagnostic categories. Conclusions: Level of functioning and psychosocial outcomes differed markedly between psychotic disorders, particularly in independent living. Outcomes were worst for schizophrenia and best for BD. Across all psychotic disorders, female gender and lifetime number of hospitalizations had strong independent associations with marriage, employment, and independent living.
  • García Velázquez, Regina; Jokela, Markus; Rosenstrom, Tom Henrik (2020)
    Psychopathology could arise from direct interactions between symptoms. Evidence suggests that the mechanisms underlying somatic and cognitive-affective symptoms of depression are different. The aim of this study was to explore dynamic associations among cognitive-affective depression criteria. We used distribution-based direction of dependence models, which estimate whether the presence of symptom A is more likely to depend on the presence of symptom B than vice versa. We analyzed six large samples of adults from the United States (N = 34,963) and conducted a simulation study to test the performance of the algorithm with ordinal variables and a second simulation study focusing on Type I error. Our results were consistent with the literature: Depressed mood and anhedonia were reactive to changes in other symptoms, whereas suicidality may reinforce other symptoms or reflect factors doing so. We discuss the results in the context of other empirical findings and theories of depression, reflect on the potential of these methods in psychopathology, and consider some practical implications.
  • ADHD Working Grp Psychiat Genomics; Early Lifecourse Genetic; 23andMe Res Team; Daly, Mark J. (2019)
    Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
  • Flink, Niko; Honkalampi, Kirsi; Lehto, Soili M.; Viinamaki, Heimo; Koivumaa-Honkanen, Heli; Valkonen-Korhonen, Minna; Lindeman, Sari (2019)
    Background Schema therapy has been proposed as a potentially effective treatment for chronic depression. However, little is known about early maladaptive schemas (EMSs), a key concept in schema therapy, in relation to chronic depression or chronic depression with comorbid personality pathology. The aim of the present study was to compare EMSs between currently chronically depressed patients with comorbid cluster C personality disorder (CDCPD), currently chronically depressed patients (CD), and patients remitted from chronic depression (CDR). Methods Based on data from a naturalistic follow-up study on psychiatric outpatients with major depressive disorder, three groups were formed according to Diagnostic and Statistical Manual of Mental Disorders-IV: CDCPD (n = 15), CD (n = 23), and CDR (n = 13). Groups were compared in terms of background information and measurements for depression (Beck Depression Inventory) and EMSs (Young Schema Questionnaire). Results Patients with CDCPD and CD did not differ in terms of background variables or the severity of depressive symptoms, but patients with CDCPD were more maladaptive with respect to the majority of EMSs. Patients with CDR were less depressed than CDCPD or CD patients, but did not differ in terms of EMSs compared with CD patients. Conclusions Comorbid cluster C personality disorder appears to be associated with more severe EMS endorsement in chronically depressed patients. Remitted patients show similar cognitive vulnerability factors in terms of EMSs compared to those currently chronically depressed. The findings suggest that EMSs may contribute to vulnerability to chronic depression. Focusing on EMSs may be beneficial in the treatment of chronic depression.
  • Korhonen, Tellervo; Sihvola, Elina; Latvala, Antti; Dick, Danielle M.; Pulkkinen, Lea; Nurnberger, John; Rose, Richard J.; Kaprio, Jaakko (2018)
    Background: Developmental relationships between tobacco use and suicide-related behaviors (SRB) remain unclear. Our objective was to investigate the longitudinal associations of tobacco use in adolescence and SRB in adulthood. Methods: Using a prospective design, we examined whether tobacco use in adolescence is associated with SRB (intentional self-injury, suicide ideation) in young adulthood in a population-based sample of 1330 twins (626 males, 704 females). The baseline and follow-up data were collected by professionally administered semi-structured poly-diagnostic interviews at ages 14 and 22, respectively. Results: After adjusting for multiple potential confounders, those who reported early-onset of regular tobacco use had a significantly increased risk for intentional self-injury, such as cutting or burning, at age 22 (adjusted odds ratio[AOR] 4.57, 95% CI 1.93-10.8) in comparison to those who had not at all initiated tobacco use. Also, daily cigarette smoking at baseline was associated with future intentional self-injury (AOR 4.45, 95% CI 2.04-9.70). Early-onset tobacco use was associated with suicidal ideation in females (AOR 3.69, 95% CI 1.56-8.72) but not in males. Considering any SRB, baseline daily smokers (AOR 2.13, 95% CI 1.12-4.07) and females with early onset of regular tobacco use (AOR 3.97, 95% CI 1.73-9.13) had an increased likelihood. Within-family analyses among twin pairs discordant for exposure and outcome controlling for familial confounds showed similar, albeit statistically non-significant, associations. Conclusion: Early-onset tobacco use in adolescence is longitudinally associated with SRB (intentional self-injury and/or suicide ideation) in young adulthood, particularly among females. Further investigation may reveal whether this association has implications for prevention of SRB in adolescence and young adulthood.
  • Diniz, C. R. A. F.; Becari, C.; Lesnikova, A.; Biojone, C.; Salgado, M. C. O.; Salgado, H. C.; Resstel, L. B. M.; Guimaraes, F. S.; Castren, E.; Casarotto, P. C.; Joca, S. R. L. (2018)
    Several pieces of evidence indicate that elastase-2 (ELA2; chymotrypsin-like ELA2) is an alternative pathway to the generation of angiotensin II (ANGII). Elastase-2 knockout mice (ELA2KO) exhibit alterations in the arterial blood pressure and heart rate. However, there is no data on the behavioral consequences of ELA2 deletion. In this study, we addressed this question, submitting ELA2KO and wild-type (WT) mice to several models sensitive to anxiety- and depression-like, memory, and repetitive behaviors. Our data indicates a higher incidence of barbering behavior in ELA2KO compared to WT, as well as an anxiogenic phenotype, evaluated in the elevated plus maze (EPM). While a decrease in locomotor activity was observed in ELA2KO in EPM, this feature was not the main source of variation in the other parameters analyzed. The marble-burying test (MBT) indicated increase in repetitive behavior, observed by a higher number of buried marbles. The actimeter test indicated a decrease in total activity and confirmed the increase in repetitive behavior. The spatial memory was tested by repeated exposure to the actimeter in a 24-h interval. Both ELA2KO and WT exhibited decreased activity compared to the first exposure, without any distinction between the genotypes. However, when submitted to the cued fear conditioning, ELA2KO displayed lower levels of freezing behavior in the extinction session when compared to WT, but no difference was observed during the conditioning phase. Increased levels of BDNF were found in the prefrontal cortex but not in the hippocampus of ELA2KO mice compared to WT. Finally, in silico analysis indicates that ELA2 is putatively able to cleave BDNF, and incubation of the purified enzyme with BDNF led to the degradation of the latter. Our data suggested an anxiogenic- and antidepressant-like phenotype of ELA2KO, possibly associated with increased levels of BDNF in the prefrontal cortex.
  • Cattaneo, Annamaria; Cattane, Nadia; Malpighi, Chiara; Czamara, Darina; Suarez, Anna; Mariani, Nicole; Kajantie, Eero; Luoni, Alessia; Eriksson, Johan G.; Lahti, Jari; Mondelli, Valeria; Dazzan, Paola; Räikkönen, Katri; Binder, Elisabeth B.; Riva, Marco A.; Pariante, Carmine M. (2018)
    To date, gene-environment (GxE) interaction studies in depression have been limited to hypothesis-based candidate genes, since genome-wide (GWAS)-based GxE interaction studies would require enormous datasets with genetics, environmental, and clinical variables. We used a novel, cross-species and cross-tissues "omics" approach to identify genes predicting depression in response to stress in GxE interactions. We integrated the transcriptome and miRNome profiles from the hippocampus of adult rats exposed to prenatal stress (PNS) with transcriptome data obtained from blood mRNA of adult humans exposed to early life trauma, using a stringent statistical analyses pathway. Network analysis of the integrated gene lists identified the Forkhead box protein O1 (FoxO1), Alpha-2-Macroglobulin (A2M), and Transforming Growth Factor Beta 1 (TGF-beta 1) as candidates to be tested for GxE interactions, in two GWAS samples of adults either with a range of childhood traumatic experiences (Grady Study Project, Atlanta, USA) or with separation from parents in childhood only (Helsinki Birth Cohort Study, Finland). After correction for multiple testing, a meta-analysis across both samples confirmed six FoxO1 SNPs showing significant GxE interactions with early life emotional stress in predicting depressive symptoms. Moreover, in vitro experiments in a human hippocampal progenitor cell line confirmed a functional role of FoxO1 in stress responsivity. In secondary analyses, A2M and TGF-beta 1 showed significant GxE interactions with emotional, physical, and sexual abuse in the Grady Study. We therefore provide a successful 'hypothesis-free' approach for the identification and prioritization of candidate genes for GxE interaction studies that can be investigated in GWAS datasets.
  • Rietschel, Liz; Streit, Fabian; Zhu, Gu; McAloney, Kerrie; Frank, Josef; Couvy-Duchesne, Baptiste; Witt, Stephanie H.; Binz, Tina M.; McGrath, John; Hickie, Ian B.; Hansell, Narelle K.; Wright, Margaret J.; Gillespie, Nathan A.; Forstner, Andreas J.; Schulze, Thomas G.; Wust, Stefan; Nothen, Markus M.; Baumgartner, Markus R.; Walker, Brian R.; Crawford, Andrew A.; Colodro-Conde, Lucia; Medland, Sarah E.; Martin, Nicholas G.; Rietschel, Marcella; CORtisolNETwork CORNET Consortium; Major Depressive Disorder; Palotie, Aarno (2017)
    Hair cortisol concentration (HCC) is a promising measure of long-term hypothalamus-pituitary-adrenal (HPA) axis activity. Previous research has suggested an association between HCC and psychological variables, and initial studies of inter-individual variance in HCC have implicated genetic factors. However, whether HCC and psychological variables share genetic risk factors remains unclear. The aims of the present twin study were to: (i) assess the heritability of HCC; (ii) estimate the phenotypic and genetic correlation between HPA axis activity and the psychological variables perceived stress, depressive symptoms, and neuroticism; using formal genetic twin models and molecular genetic methods, i.e. polygenic risk scores (PRS). HCC was measured in 671 adolescents and young adults. These included 115 monozygotic and 183 dizygotic twin-pairs. For 432 subjects PRS scores for plasma cortisol, major depression, and neuroticism were calculated using data from large genome wide association studies. The twin model revealed a heritability for HCC of 72%. No significant phenotypic or genetic correlation was found between HCC and the three psychological variables of interest. PRS did not explain variance in HCC. The present data suggest that HCC is highly heritable. However, the data do not support a strong biological link between HCC and any of the investigated psychological variables.
  • Savilahti, Emma M.; Haravuori, Henna; Rytilä-Manninen, Minna; Lindberg, Nina; Kettunen, Kirsi; Marttunen, Mauri (2018)
    Beck Depression Inventory (BDI) is widely used in assessing adolescents' psychological wellbeing, but occasionally the result diverges from diagnostics. Our aim was to identify factors associated with discrepancies between BDI scores and diagnostic assessment in adolescent psychiatric patients and general population. The study comprised 206 inpatients (13-17 years old) and 203 age and gender matched non -referred adolescents. Study subjects filled self-reports on depression symptoms (BDI-21), alcohol use (AUDIT), defense styles (DSQ-40) and self-image (OSIQ-11), and on background information and adverse life events. Diagnostics was based on K-SADS-PL interview, and/or clinical interview and clinical records when available. We compared subjects who scored in BDI-21 either 0-15 points or 16-63 points firstly among subjects without current unipolar depression (n = 284), secondly among those with unipolar depression (n = 105). High BDI-21 scores in subjects without depression diagnosis (n = 48) were associated with female sex, adverse life events, parents' psychiatric problems, higher comorbidity, higher AUDIT scores, worse self-image and more immature defense styles. Low BDI-21 scores among subjects with depression diagnosis (n = 23) were associated with male sex, more positive self-image and less immature defense style. In conclusion, high BDI-21 scores in the absence of depression may reflect a broad range of challenges in an adolescent's psychological development.
  • Parhiala, P.; Ranta, K.; Gergov, Vera; Kontunen, J.; Law, R.; La Greca, A. M.; Torppa, M.; Marttunen, M. (2020)
    In order to offer early and accessible treatment for adolescents with depression, brief and effective treatments in adolescents' everyday surroundings are needed. This randomized controlled trial studied the preliminary effectiveness, feasibility, and acceptability of interpersonal counseling (IPC) and brief psychosocial support (BPS) in school health and welfare services. The study was conducted in the 28 lower secondary schools of a large city in Southern Finland, randomized to provide either IPC or BPS. Help-seeking 12-16-year-old adolescents with mild-to-moderate depression, with and without comorbid anxiety, were included in the study. Fifty-five adolescents received either 6 weekly sessions of IPC or BPS and two follow-up sessions. Outcome measures included self- and clinician-rated measures of depression, global functioning, and psychological distress/well-being. To assess feasibility and acceptability of the treatments, adolescents' and counselors' treatment compliance and satisfaction with treatment were assessed. Both treatments were effective in reducing depressive disorders and improving adolescents' overall functioning and well-being. At post-treatment, in both groups, over 50% of adolescents achieved recovery based on self-report and over 70% based on observer report. Effect sizes for change were medium or large in both groups at post-treatment and increased at 6-month follow-up. A trend indicating greater baseline symptom severity among adolescents treated in the IPC-providing schools was observed. Adolescents and counselors in both groups were satisfied with the treatment, and 89% of the adolescents completed the treatments and follow-ups. This trial suggests that both IPC and BPS are feasible, acceptable, and effective treatments for mild-to-moderate depression in the school setting. In addition, IPC seems effective even if comorbid anxiety exists. Our study shows that brief, structured interventions, such as IPC and BPS, are beneficial in treating mild-to-moderate depression in school settings and can be administered by professionals working at school.
  • Taylor, Amy E.; Fluharty, Meg E.; Bjorngaard, Johan H.; Gabrielsen, Maiken Elvestad; Skorpen, Frank; Marioni, Riccardo E.; Campbell, Archie; Engmann, Jorgen; Mirza, Saira Saeed; Loukola, Anu; Laatikainen, Tiina; Partonen, Timo; Kaakinen, Marika; Ducci, Francesca; Cavadino, Alana; Husemoen, Lise Lotte N.; Ahluwalia, Tarunveer Singh; Jacobsen, Rikke Kart; Skaaby, Tea; Ebstrup, Jeanette Frost; Mortensen, Erik Lykke; Minica, Camelia C.; Vink, Jacqueline M.; Willemsen, Gonneke; Marques-Vidal, Pedro; Dale, Caroline E.; Amuzu, Antoinette; Lennon, Lucy T.; Lahti, Jari; Palotie, Aarno; Räikkönen, Katri; Wong, Andrew; Paternoster, Lavinia; Wong, Angelita Pui-Yee; Horwood, L. John; Murphy, Michael; Johnstone, Elaine C.; Kennedy, Martin A.; Pausova, Zdenka; Paus, Tomas; Ben-Shlomo, Yoav; Nohr, Ellen A.; Kuh, Diana; Kivimaki, Mika; Eriksson, Johan G.; Morris, Richard W.; Casas, Juan P.; Preisig, Martin; Boomsma, Dorret I.; Linneberg, Allan; Power, Chris; Hypponen, Elina; Veijola, Juha; Jarvelin, Marjo-Riitta; Korhonen, Tellervo; Tiemeier, Henning; Kumari, Meena; Porteous, David J.; Hayward, Caroline; Romundstad, Pal R.; Smith, George Davey; Munafo, Marcus R. (2014)