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Xenia Gonda Semmelweis University, Department of Psychiatry and Psychotherapy

Not all stressors are created equal : the divergent genetic background of distinct stressors in depression. Xenia Gonda Semmelweis University, Department of Psychiatry and Psychotherapy MTA-SE Neurochemistry and Neuropsychopharmacology Research Group

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Xenia Gonda Semmelweis University, Department of Psychiatry and Psychotherapy

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  1. Not all stressors are created equal:the divergent genetic background of distinct stressors in depression Xenia Gonda Semmelweis University, Department of Psychiatry and Psychotherapy MTA-SE Neurochemistry and Neuropsychopharmacology Research Group NAP-2-SE New Antidepressant Target Research Group

  2. Nature vs/or/and Nurture? • Ancient question, still no answer • More inclusive approach instead of dichotomy: from genes vs environment to genes AND environment • Genetic effects and environmental influences both impact the development of psychiatric disorders • The relative weight of the two factors differs by • Disorder (eg. UD, SCH) • Disorder subtypes (reactive vs endogenous UD) • Genes and stressors GENES ENVIRONMENT

  3. Relationship between genes and environment • Additive • Gene-environment correlation • Genes influence likelihood of exposure to life events (Rutter et al.,2006) • Passive rGE: parents pass on genes+ provide early effects • Active rGE: choice of risk environment resulting from own behaviour • Evocative rGE: behaviour influences reaction from others • Gene x environment interactions • Diathesis-stress model (Monroe and Simmons, 1996): vulnerability towards environmental triggers is a function of biological background – puffers/exacerbates effect of environmental stress • Differential susceptibility model (BelskyandPluess, 2009): biological context modulates susceptibility towards positive and negative environmental stimuli –not vulnerable but plastic GENE ENVIRONMENT GENE ENVIRONMENT GENE ENVIRONMENT

  4. Genetic research in depression • Depression: poli -> multi-> omnigenic + multifactorial • Complex genetic architecture: multiple loci, small effects • Heritability: 37-42%generalpopulation; 48-75%in hospital samples (Sullivan et al., 2000, 2012; Uher, 2014) • Few reproducible effects • Environmental interactions are often ignored • Early childhood traumas • Recent stressful life events • Immediate/direct and delayed effects • Timing, duration, severity, type • Life events + genetic effects contribute to a higher increase in depression risk than combination of individual effects Gonda et al., Pharm & Ther 2018 Environment Personality and cognitivetraits, temperament Gene set1 ? ? Gene set2 DEPRESSION ? Gene set3

  5. Genetic factors in the background of depression • Genetic risk for depression approx. 40-70% • Increased risk in first degree relatives of MDD patients: OR 2.84 • Unlike other common disorders, no consistently proven and replicated variants in MDD • Candidate gene studies: • More than 1500 papers • Nearly 200 genes but contradictory results • Metaanalysis for only 26 genes • Significant only for 7 genes: 5HTTLPR, HTR1A, DRD4, SLC3A, APOE, GNB3, MTHFR • 393 investigated polymorphisms, only 21 in at least three studies, only 5-HTTLPR, BDNF and MTHFR replicable • Few replicable studies considered the effect of environmental interaction: 5-HTTLPR, BDNF, DRD2, COMT, CRHR1, FKBP5, NRC31, GALR2 • GWAS: no genome wide replicable results • We do not take into consideration the environmental effects • Flint & Kendler2014; Domschke & Reif, 2012

  6. The role of life events in the development of depression • Heritability of depression is 37-42% (Sullivan et al., 2000) ↔ effect of environmental influence is 63% (Rutter and Silberg 2002) • Etiologically relevant distal and proximal stressors are common: 1/ 3-4 years • Depression develops only in 1/5 in those exposed to acute stress (Belsky and Pluess, 2009) • Individual differences in sensitivity to environmental exposure, partially based on genetic influences: genes do not directly contribute to depression but by increasing vulnerability towards depressogenic life events (Uher 2014) Depression Environment Genetics Depression Environment Genetics

  7. Can genetic effects be detected without environmental exposure? RELEVANCE SERT BDNF CB1 GAL2R 5-HT1AR 5-HT2AR P2X7R Gonda et alSciRep 2018

  8. Prototype of gene x environment interactions in Psychiatry: 5-HTTLPR • First major molecular genetic study on GxE interactions: effect of 5-HTTLPR and life events on the development of depression (Caspi et al., 2003) • Contradictory results (Karg et al., 2011, Risch et al., 2009, Culverhouse et al., 2017) • In most studies NO main effect (including original study): • The effect of this variant can only be detected if environmental effects are taken into consideration • But in some cases cannot be detected even if environmental interaction is considered

  9. 5-HTTLPR: what is the reason behind the lack of effect? Stress is not uniform • 4 validated category of stressors • 5-HTTLPR interacts only with financialstressors in development of depression • Gender effect: • In males interaction only with financial-economic stressors • In females no interaction with any type of recent stress • Age effect • In those older than 30 yrs interaction only with economic stressors • In those younger than thirty interaction only with stressors related to social networks Gonda et al., TranslPsychiatry 2016; Gonda et al, EurNeuropsychopharm 2016, 2018

  10. Risk and protective effect of 5-HTTLPR on depression in interaction with different stress types > AGE 30 * ≤ AGE 30 * Gonda et al., 2016, 2018

  11. Positive and negative effects of 5-HTTLPR Increased positive/negative emotionality Increased (social) cognition Decision making capacity Cognitive flexibility Response inhibition Performance monitoring and feedback integration Passive avoidance Risk aversion Motivational behaviours Attention set-shifting Reverselearning Delayed matching-to-sample Probability discounting Delay discounting • Psychosocial stressors • Fear conditioning • Startle reaction • Sad/happy faces • Attention bias for anxiety expressing words • Vegetative reactivity • Increased HPA axis reactivity • Increased inflammatory cytokine levels • Smoking, drinking, gambling • Internet overuse • Social blushing • Social aggression • Creative dancing • Social support Homberg and Lesch, 2011

  12. Positive and negative effects of 5-HTTLPR • Increased emotional reactivity and hypervigilance • Unstable environment + possibility to avoid unfavourable situation/ possibility for decision making • s allele carriers simultaneously avoid risk and exploit best opportunities • Stable environment / no possibility to avoid or change stressor • Depression, anxiety • 5-HTTLPR s allele: Increased adaptive capacity for (social) environmental changes • Threat + cannot influence life events (severe financial stress) – risk effect • Life events impacting social network – protective effects • If effects of 5-HTTLPR • manifested only in interaction with environment • manifested only in case of certain environmental effects • different in case of different environmental effects (risk/protective) • To understand the full spectrum of effects associated with a given genetic variants we most consider the full spectrum of environmental influences The detected outcome may be 0 Homberg and Lesch, 2011

  13. Beyondmonoamines GABA Endocannabinoidsystem Retrograde neurotransmitter Rimonabant: depression, anxiety and suicide (Christensen et al., 2008) CNR1 variation and stressreactivity rs7766029 may lead to decreased mRNA stability and reduced expression T allele associated with neuroticism: negative perception of life events and less adaptive coping (Juhasz et al., 2009) Significant interaction between CNR1 and stress on depressive symptoms (Juhasz et al. 2009) suggested to play a role in depression by impacting the experience of negative life events • Interacts with stressors in brain-level stress control • Exposure to stress has short- and long-term effects on GABA • availability, composition, neurosteroid sensitivity of GABA-A • altered response to subsequent or ongoing stressors • GABRA6 variation and stress reactivity • rs3219151 in regulatory regions that post-transcriptionally influence gene expression, altering micro-RNA binding site and regulation and when stimulated • T allele plays a role in stress-induced psychopathology Gonda et al. SciRep 2018

  14. Interaction of GABRA6 and CNR1 with recent stress Gonda et al., FrontiersCellularNeurosci 2019

  15. Interaction of CNR1andGABRA6with different types of recent stress Gonda et al., Front CellularNeurosci 2019

  16. Diversity of gene x environment interactions • Severity • GABRA6, 5-HTTLPR mediates severe stress exposure • CNR1 moderate stress exposure • Type • 5-HTTLPR, GABRA6 and CNR1 mediate the effect of only certain types of stressors • Outcome phenotype • 5-HTTLPR has opposite effects in case of different stressors • GABRA6 manifests with different symptoms in case of different stressors

  17. Stress is a heterogenuous phenomenon • Stress • Timing • Duration • Severity • Type • Different type and severity stressors act via distinct pathways? • Different genetic variants mediate onlygiven stressors? • Different stressor–different gene • Different stressor–same gene– different phenotype

  18. Varioustypes of GxE interactions Fan interaction Crossover interactions • Risk allele • Does not increase risk in baseline condition • In case of environmental risk factors, probability of illness significantly increases • Effect of „risk” and „wild” variant depends on context • Risk allele: protective in low risk environment, probability of illness increases with environmental exposition • Wild allele: probability of illness is increased with low environmental exposure, but decreases with increasing environmental exposure Dick, 2011; Sharma et al., 2016

  19. Diverse effects of gene x environment interactions • Genetic variants have diverging effects depending on environmental context • To understand genetic effects we need to consider • Full spectrum of possible environmental influences including both positive and negative • Full spectrum of outcomes including both negative and positive • Bias in present research • Focus on negative influences • Ask biological questions related to illness and negative outcomes • Variantspredisposing to illness in interaction with stress canbe adaptive and decrease probability of illness in certaincontexts Envrionment Outcome Envrionment Outcome

  20. Gene x environment interactions: From vulnerability to plasticity • Biological context modulates sensitivity to different environmental effects • Outcome of genetic variation may be positive or negative depending on the context • genetic variants make individuals not vulnerable but plastic (Bousman et al., 2016) • Risk alleles better be called phenotype plasticity alleles • Do not necessarily carry risk • Depending on the negative or positive nature of the environmental influence may predict better or worse outcomes (Bousman et al., 2016)

  21. Multigene, multistress, multiphenotype? • Depression is heterogeneous • Different endophenotypes – different genetic background • Different endophenotype constellations in the background of different depression phenotypes • Stress is heterogeneous • Distant-proximal • Acute or chronic • Severity • Type • Given variant in interaction with stress impacts given depression endophenotype Different stressor – different gene • Different stressor – same gene – different phenotype • Endophenotypes of distinct subtypesof depression determined by gene variants interacting with different types and severity of stressors –possible new targets for more individualised treatment

  22. Gene x environment interactions: implications for pharmacotherapy • Efficacy of pharmacotherapy for major depression is far from desirable (Rush et al., 2003, Warden et al., 2007) • Depression is a heterogeneous phenomenon, underlied by multiple neurological systems • Different mechanisms need to be targeted during treatment • Based on the clinical presentation and etiological factors • If the genetic factors in the development of depression interact with the environment, then GxE interactions influence treatment as well (Keers and Uher, 2012)

  23. Genetic effects underlying antidepressant efficacy • 5-HTTLPR(Kato and Serretti, 2010) • BDNF(Zou et al., 2010; Chi et al., 2010) • FKBP5(Lekman et al., 2008; Kirchheiner et al., 2008) • CRHR1(Keers et al., 2010; Kato and Serretti, 2010) • NR3C1(Kato and Serretti, 2010) • Effects can’t be replicated in metaanalyses or STAR*D

  24. Effect of the environment on response to pharmacotherapy • Depression following exposure to stress (”reactive depression”) responds better to psychotherapy or placebo (Keers and Uher, 2012) • Depression developing independently of environmental exposure (”endogenous depression”) • Responds better to antidepressive pharmacotherapy or ECT • Responds better to TCA-s than to SSRI-s (Anderson et al., 1990) • GENDEP: effect of stressful life event on antidepressant efficacy depends on the medications used • In case of recent stressors better response to escitalopram • No effect on nortryptilin response (Keers and Uher, 2010)

  25. GxE interactions in antidepressive pharmacotherapy • Based on family studies, few clinical studies • 5-HTTLPR: worse response to SSRIs only in depression following stress exposure • 5-HTTLPR x adverse life events: fluoxetine (Mandelli et al., 2009) • 5-HTTLPR x stress: escitalopram (Keers et al., 2011) • No effect in case of nortryptiline (Keers et al., 2011) • SLC6A2 x childhood abuse: antidepressant response (Xu et al., 2011) • 5HTR1B x negative life events, TPH2 x childhood trauma (Xu et al., 2011) • Stin4 x stress: SSRI response (Keers et al., 2010) • CRHR1, FKBP5: significant GxE interaction in therapeutic efficacy (Keers & Uher, 2012) • Interaction with stress during DEVELOPMENT of depression, not during TREATMENT

  26. Effects of antidepressants are influenced by genetic and environmental factors • Antidepressant response is polygenic and multifactorial • Response to antidepressant treatment is influenced by environmental effects on multiple levels: • Environmental exposure in the etiology of the depressive episode • Environmental exposure during antidepressive treatment • Environmental effects may mask genetic effects: depending on environmental influences during pharmacotherapy certain variants may positively or negatively influence therapeutic response • GxE is rarely investigated in pharmacotherapeutic effect • Effects of environmental stress should be considered in clinical pharmacotherapy studies Kovács et al., 2014

  27. Concl/Fusion • Complex interaction between genetic variants in different neurobiological systems and different type and severity of stress in depression and treatment efficacy • In the absence of exposure, the effect of several genetic variants cant be detected • Effect of distinct types and severity of exposures is different • May be positive or negative • May be different in different age or gender groups • Effects of different severity, duration, timing, type of stress mediated by different genes lead to distinct phenotypes • Stress exposure during development of depression or during pharmacotherapy may influence treatment efficacy • Insight to these may help in • Understanding depression • Identifying novel pharmacotherapy targets • Evaluation of antidepressants • Subtyping the heterogeneous depression category and studying possible treatment by subtypes • PREVENTION SCREENING DIAGNOSIS INTERVENTION

  28. Acknowledgements ÚNKP-18-4-SE-33 New National Excellence Program of theMinistry of Human Capacities Bolyai Janos Research Fellowship of theHungarianAcademy of Sciences MTA-SE Neuropsychopharmacology and Neurochemistry Research Group NAP-2-SE New AntidepressantTarget Research Group EU LSHM-CT-2004-503474 National Institute for Health Research Manchester Biomedical Research Centre EU LSHM-CT-2004-503474 TAMOP-4.2.1.B-09/1/KMR-2010-0001

  29. Thankyouforyourattention! gonda.xenia@med.semmelweis-univ.hu

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