Task 5 Flashcards
resilience =
= “bouncing back” from difficult experience (stress, trauma, tragedy)
o its indicated by adaptive stress responses, rapid stress recovery, high coping self-efficacy, strong cognitive re-appraisal and emotion regulation and self-confidence
o lack of resilience increases the risk for developing stress-related psychiatric disorders
heritability of resiliance (an overview)
o twin studies?
- correlations?
- resilience is influenced by genetic factors –> heritable component
o show in twin studies, but proportion of genetic impact between studies varied a lot - genetic correlation between emotion-oriented coping and resilience -> indicates a common genetic background
- shared heritability between resilience and some psychiatric disorders (anxiety disorder, depression, PTSD - negative association)
candidate genes of the stress response system - serotonin/ 5-HT
(- the serotonergic system influences the HPA axis)
- gene SLC6A4 encodes serotonin transporters which carry serotonin away from the synapse after signal transmission for later reuse
- within the promoter region of SLC6A4, there is the polymorphism 5-HTTLPR (=serotonin-transporter-linked polymorphic region) –> influences the ability to encode transporter proteins
o 5-HTTLPR can have short or long alleles –> 3 possible genotypes: ss, ll, sl
o Short allele –> reduced expression of serotonin transporters (reduced serotonin uptake)
–> associated with lower resilience :(
o Long allele –> increased number of serotonin transporters (SERT)
- studies suggest a gene x environment interaction - risk for stress-related disorders:
o S-carriers are more likely to develop a disorder following environmental stress
candidate genes of the stress response system - DA and NE
- VNTR
- Rs1800497
which gene is affected? what does it do?
- COMT
- differences in striatal dopamine transporter (DAT) density in PTSD patients compared to healthy –> suggests influence of the dopaminergic system on vulnerable phenotypes + resilience
- 2 genetic variants in genes of the dopaminergic system with increased susceptibility to PTSD and depression were detected: o VNTR (=variable number tandem repeat) is a genetic polymorphism in the promoter region of the DAT gene (SCL6A3) o Rs1800497 polymorphism in the dopamine receptor D2 gene (DRD2) --> regulates synaptic modification in response to stress
- one enzyme affecting both systems -> COMT (breaks down DA + NE)
o Met allele –> decreased COMT enzyme activity –> higher NE and dopamine levels
–> greater risk for development of PTSD/depression after trauma or adversity –> lower resilience :(
candidate genes of the stress response system - HPA axis
- why is it interessting?
- CRHR1
- FKBP5
- The HPA axis = most important physiological stress response system -> genetic variants in this system likely influencing resilience + contribute to psychiatric disorders (in vulnerable phenotypes)
- some polymorphisms of the CRHR1 (=corticotropin-releasing hormone receptor 1) - associated with reduced! risk of depression after exposure to life stress
- elevated levels of FKBP5 (protein role in immunregulation) -> decreased negative feedback regulation of the HPA axis
(and glucocorticoid receptor resistance)
-> probably responsible for a dysfunctional stress response –> interacts with environmental trauma to predict PTSD
candidate genes of the stress response system - Neuropeptide Y
- what is it?
- resilience ass.?
- Neuropeptide Y acts as neuromodulator in the brain –> it counteracts effects of the corticotrophin-releasing hormone -> necessary for the compensation of stress reaction
- some polymorphisms in the NPY gene are associated with lower NPY expression –> lower resilience to stress risk for several disorders in case of early life stress
candidate genes of the stress response system - neural and synaptic placticity
- Neurotrophic hypothesis of MDD
- Brain-derived neurotrophic factor
- depression associated with impaired structural plasticity and cellular resilience
- the neurotrophin BDNF is involved in the regulation of synaptic plasticity, neurogenesis, neuronal survival and differentiation
> BDNF levels are affected by stress in PTSD and depression - alternations in BDNF might contribute to a variety of psychiatric disorders (PTSD, anxiety, depression)
GWAS
- gwas on resilience
- gwas on ptsd and deperession
- Genome-wide association studies - new way for scientists to identify genes involved in human disease
= method: searches the genome for small variations, called single nucleotide polymorphisms (SNPs) occuring more frequently in people with a particular disease
–> hypothesis-free detection of genetic variants associated with specific phenotypes - GWAS recently performed on resilience:
o SNP-based heritability estimated 16%
o some genome-wide significant hits were obtained (although sample was small)
o DCLK2 (=a member of the doublecortin family of kinases) –> promotes survival and regeneration of neurons –> also possible that alters brain structure or cognitive function and thus resilience
o NR3C2
–> there are potential gene candidates for resiliece - Since so little studies on resilience, it makes sense to look at psychiatric disorders that result of a lack of resilience (eg. PTSD or depression) –> indirect imlpications
o several risk factors for PTSD: retinoid-related orphan receptor alpha (RORA), LINCO1090, etc.
o upregulation of BICC1 might be involved in depression (antidepressants that improve symptoms reduce the expression of BICC1)
GENE-ENVIRONMENT INTERACTIONS BETWEEN STRESS AND 5-HTTLPR IN DEPRESSION: A META-ANALYTIC UPDATE (BLEYS) - Method
What will be tested?
- meta-analysis investigated total effect size and publication bias
- stratified meta-analyses investigated the potential moderating influence of different methodological approaches on heterogeneity in study findings
o dimensional vs. categorical assessment
o self-report vs. interview-based assessment
o timing of stress (childhood vs. adulthood)
- stratified meta-analyses investigated the potential moderating influence of different methodological approaches on heterogeneity in study findings
- meta-regression investigated combined influence of methodological approaches on overall effect size
GENE-ENVIRONMENT INTERACTIONS BETWEEN STRESS AND 5-HTTLPR IN DEPRESSION: A META-ANALYTIC UPDATE (BLEYS) - Results
- Meta-analysis
- Stratified meta-analysis
- Meta-regression
–>
- Meta-analysis
- no evidence of publication bias
- small but significant effect of 5-HTTLPR in interaction with stress –> predicting depression
- moderate to high heterogeneity between studies - Stratified meta-analysis
- heterogeneity of effect sizes = result of outliers - not due to different methodological approaches towards assessment of stress and depression
o none of the examined moderators (assessment type or timing of stress) had a significant influence on the heterogeneity of effect sizes of the GxE effect
o excluding outliers reduces heterogeneity - Meta-regression
- combined set of predictors explained 42% of heterogeneity
- some evidence that studies adopting a categorical and interview approach to the assessment of stress report higher GxE effects (further replication needed)
–> meta-analysis provides new evidence for the robustness of the interaction between stress and 5-HTTLPR in depression!!!
GENE-ENVIRONMENT INTERACTIONS BETWEEN STRESS AND 5-HTTLPR IN DEPRESSION: A META-ANALYTIC UPDATE (BLEYS) - Limitaitons
- large amount of heterogeneity (46%) was not explained
- meta-analysis did not control for other possible moderators (gender, ethnicity, personality traits etc.)
- low response rate of invited studies (only 48% of the eligible studies could be included)
Heritabiltity of depression
- how much?
- genes involved?
- why difficulties in robustly identifying genetic cotributors?
o
- genetic component to depression (heritability estimates vary from 37-70%)
- genetic association studies have identified some candidate genes: 5HTTLPR, APOE, DRD4, GNB3, HTR1A, MTHER and SLC6A3
o heterogeneity (in diagnostics) o might be multiple tiny genetic effects (need larger samples) o complex interplay between genes and environmental factors
- but, strong association between stress and depression!
methodological issues regarding stress assessment
o interview vs. self-report
o direction of causality?
o research confirmed that semi-structured interviews are more accurate and effective than simple questionnaires
o Does mental state influence the event or does the event evoke depression? –> acute life events consistently predict the onset of a depressive episode, but childhood stress has been shown to increase risk of depression in adulthood
How to define life events? (considerations)
- heritability of life events?
o - different findings in 5HTTPR –> why?
o study: relatives of depressed subjects not only have an increased risk of depression, but also appeared to have an elevated rate of threatening events
o Twin studies: suggest modest, but significant heritable component to self-reported life events
o BUT parental reports of life events for the same adolescents -> no evidence of heritability
- contradictory findings in studies investigating gene x environment interactions on the risk of depression (5HTTLPR x stressful life events) –>
inconsistency might be due to how life events were assessed/defined
o studies using subjective self-report reported no interaction - might also be that the s-allele of the 5HTTLPR polymorphism confers a differential sensitivity to the environment, which can be negative or beneficial
o children with s-allele were more vulnerable to depression at high stressful live event exposure, but showed reduced rates of depression at low stressful event exposure (benefit from better environment) - also, the GxE interactions could be mediated by epigenetic mechanisms (DNA methylation)
INTERACTION BETWEEN THE 5-HTTLRP GENOTYPE, IMPACT OF STRESSFUL LIFE EVENTS, AND TRAIT NEUROTICISM ON DEPRESSIVE SYMPTOMS IN HEALTHY VOLUNTEERS (MARKUS) - Method
- hypothesis
- sample
- measurement
- biallelic vs. triallelic
- Hypothesis: s-allele genotypes, compared to l-allele genotypes, are more susceptible to the effects of life events when they are high on trait neuroticism
- Sample: 771 healthy individuals (595 women and 176 men); aged 21.0±2.1 years
- Measurement: genotype for the 5-HHTLPR polymorphism, depressive symptoms, neuroticism, negative life events (self-report)
o Eg.: divorce of parents, suicide attempts in self/family/friend, victim of fire, financial problems, violence within family
o ratings of the events’ impact (“no impact” to “very negative”)
o outcome measure = sum of impact rating of all experienced events
- data were analysed and reported for: o biallelic: L/S classification --> without controlling for Lg and La differences o triallelic: L’/ S’ classification --> including Lg and La differences --> Lg = S’
INTERACTION BETWEEN THE 5-HTTLRP GENOTYPE, IMPACT OF STRESSFUL LIFE EVENTS, AND TRAIT NEUROTICISM ON DEPRESSIVE SYMPTOMS IN HEALTHY VOLUNTEERS (MARKUS) - Results
Effects of 5-HTTLPR, impact of life events and neuroticism on depression sores:
- main effects
- interaction effects
Effects of 5-HTTLPR & neuroticism on impact of life events:
- main effect
- interaction effect
Effects of 5-HTTLPR on neuroticism sores:
- main effect
- interaction effect
Effects of 5-HTTLPR, impact of life events and neuroticism on depression sores:
- Main effects of neuroticism & impact of life events –> both factors associated independently with higher depression scores
- No main effect of the 5-HTTLPR genotype on depressive symptomatology –> no differences in depression scores between S, La and Lg carriers
- Significant 3-way interaction: only S-carriers showed vulnerability to depression exclusively when exposure to high-impact events + showed high neuroticism
- -> results were similar for a biallelic and a triallelic approach
Effects of 5-HTTLPR & neuroticism on impact of life events:
- Main effect of neuroticism: S and LL carriers with high trait neuroticism experienced comparable variability of impact of life events
- No effect of genotype & no interaction of genotype and neuroticism
Effects of 5-HTTLPR on neuroticism sores:
- No main effect of genotype on neuroticism score
- No interaction between genotype x impact of life events on neuroticism score
INTERACTION BETWEEN THE 5-HTTLRP GENOTYPE, IMPACT OF STRESSFUL LIFE EVENTS, AND TRAIT NEUROTICISM ON DEPRESSIVE SYMPTOMS IN HEALTHY VOLUNTEERS (MARKUS) - Conclusion
- depression is unlikely to be directly linked to the mutual interaction of one gene and one environmental factor
- there are additional mediating factors in link between genes, environment and risk for depression
o personal psychological resilience
o cognitive vulnerability to attribute events as highly threatening = neuroticism
–> Findings suggests: 5-HTTLPR –> cognitive vulnerabilities (mediator) –> life event (genotype x environmetal interaction) –> depression
DOES PSYCHOLOGICAL RESILIENCE BUFFER AGAINST THE LINK BETWEEN 5-HTTLPR POLYMORPHISM AND DEPRESSION FOLLOWING STRESS? (SHARPLEY) - Whats it about?
- What is investigated?
- What is the aim?
- study investigates the associations between:
o 5-HTTLPR and depression
o 5-HTTLPR and psychological resilience
o psychological resilience and depression
- develop a model of these interactions –> informs clinical practice + help to explain the previous inconsistent findings regarding the 5-HTTPR – depression link
DOES PSYCHOLOGICAL RESILIENCE BUFFER AGAINST THE LINK BETWEEN 5-HTTLPR POLYMORPHISM AND DEPRESSION FOLLOWING STRESS? (SHARPLEY) - Methods
- hypotheses
- sample
- measures
- study tested the comparative strength of 5-HTTLPR polymorphism as predictor of depression after major stress vs. the protective effect of psychological resilience against depression after major stress –> 2 hypotheses
- PCa patients who are carriers of the ss-allele will have higher depression scores than carriers of the ll-allele
- PCa patients with higher PR will have lower depression scores than patients with lower PR scores
- Sample: homogeneous group of older men who had all received a diagnosis and treatment for prostate cancer
o naturally occurring, objective stressor (no self-report or interview)
o associated with elevated rates of depression
o homogeneous group to reduce possible confounding influence of age and gender - Depression -> PHQ9
- Psychological resilience -> CDRISC
(?) considering multiple levels to identify which level influences the 5-HTTLPR – depression link
o Scale level
o Factor level:
–> personal competence, high standards and tenacity
–> trust in one’s instincts, tolerance of negative affect
–> positive acceptance of change
–> control
–> spiritual influences
o Item level
DOES PSYCHOLOGICAL RESILIENCE BUFFER AGAINST THE LINK BETWEEN 5-HTTLPR POLYMORPHISM AND DEPRESSION FOLLOWING STRESS? (SHARPLEY) - Results
- hypothesis 1
- hypothesis 2
- no association between 5-HTTLPR and elevated depression after stress –> reject hypothesis 1
o no difference in depression scores of ss vs. ll carriers following a major stressor - association between psychological resilience and lower depression after stress
- -> support hypothesis 2
o Scale level: inverse correlation between total scores of CDRISC and PHQ9
o Factor level:
–> Regression analysis: only factor 1 (personal competence ect.) significant inverse contribution to depression score –> most “protective” aspect of PR
o Item level: only item 10 “to give my best effort, no matter what” was significantly associated with the 5-HTTLPR: L-carriers had significant inverse correlation between PR scores and depression scores
DOES PSYCHOLOGICAL RESILIENCE BUFFER AGAINST THE LINK BETWEEN 5-HTTLPR POLYMORPHISM AND DEPRESSION FOLLOWING STRESS? (SHARPLEY) - Discussion
Conclusion
DISCUSSION
- specific associations between depression and single aspects of PR –> possible that due to the heterogeneity of PR measures, previous studies have missed this association
- -> specific aspects of psychological resilience have a protective function against depression following major stressor
- further studies should focus on “key dimensions” underlying protective function of PR for application in therapeutic settings
CONCLUSIONS
- Data suggests that S-carrier of 5-HTTLPR may negate the protective effect of psychological resilience against depression in these men OR that psychological resilience may nullify the depression vulnerability in s-carriers of the 5-HTTLPR
- may explain some of the “null” findings regarding the link between the 5-HTTLPR and depression in the wider literature –> it might be due to an interaction between these two factors in the association between major stress and depression
- study does not contradict, but complement and extend the presence of contradictory findings
