Childhood trauma and its impact on emotional brain circuits, mood disorder and treatment outcomes

Transcription

1 Childhood trauma and its impact on emotional brain circuits, mood disorder and treatment outcomes Leanne (Lea) Williams, PhD med.stanford.edu/williamslab

2 Learning objectives a) Understand the prevalence of early life trauma in the population and its role in risk for depression and anxiety b) Understand the impact of trauma on the emotional circuits of the human brain c) Learn about new findings showing a combination of early life trauma, genetic variation and emotional brain circuit function predict response to depression treatments med.stanford.edu/williamslab

3 Brain Dynamics Center, Sydney PanLab, Stanford med.stanford.edu/williamslab

4 Acknowledgements Stanford Andrea Goldstein-Piekarski, PhD Chuck Debattista, MD Sydney Justine Gatt, PhD, Denise Chu, PhD Mayuresh Korgaonkar, PhD Brown and St Louis Missouri Rob Paul, PhD, Ron Cohen, PhD Funding NIMH: MH Australian Research Council: DP Sponsor of ispot-d: Brain Resource

5 Personalized neuroscience for mental health Williams. Lancet Psychiatry, 2016 (in press)

6 Personalized neuroscience for mental health Genetic risk Temperament Brain circuits Physiology Behavior Life experience Brain circuits and physiology as the most proximal measures of the disease state. Behavior = performance correlates Life experience, incl. early life stress = distal moderators Williams. Lancet Psychiatry, 2016 (in press)

7 Topics I will cover today. How does childhood trauma a) disrupt the normal maturation of emotional brain circuits during adolescence? b) interact with genotype to impact emotional brain circuits and confer risk for depression and anxiety? c) moderate treatment response outcomes in depression? med.stanford.edu/williamslab

8 How does childhood trauma a) disrupt the normal maturation of emotional brain circuits during adolescence? med.stanford.edu/williamslab

9 How do we define stress that has an adverse affect: bad stress? med.stanford.edu/williamslab

10 Bad stress Intense and prolonged Can include the childhood events we are focusing on here: physical or emotional abuse, neglect, family illness, family violence. Can impact brain maturation and increase risk for maladaptive stress reactions in adulthood

11 Mild and brief Good Stress Acts to increase resilience/adaption. Facilitated by support In between we have tolerable stress

12 Prevalence? Learning objective # c3 data sharing site med.stanford.edu/williamslab

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15 med.stanford.edu/williamslab

16 Prevalence: Learning objective 1. Type of trauma % Divorce 22.2 Severe Family conflict 20.3 Bullied 17.4 Separated from family 16.1 Premature birth 15.6 Major illness in family 14.9 Emotional Abuse 12.3 Domestic violence 11.8 Death in family 11.3 Hospitalization/Surgery 9.4 Natural Disaster 7.6 Major illness (self) 7.4 Physical abuse 5.2 Sexual abuse 4.6 War 4.1 Poverty/Neglect 3.7 Fire Destroyed Home 1.5 Adoption 1.2 ~ 50% females Sexual/emotional abuse > in females Bullying > in males. Cohen et al. Biol. Psychiatry, 2006 n=1045 from community sample Chu et al. J Psychiatric Research, 2013 n=1209 from community sample

17 Prevalence: Learning objective 1. Total number of traumatic events % or more 2.0 Cohen et al. Biol. Psychiatry, 2006 n=1045 from community sample

18 The odds for risk of depression increase with total number of traumatic events in childhood 5 4 Odds Ratio Adverse traumatic childhood events Source: Chapman et al, J. Affective Disorders, 2004

19 Risk factors for depression: Learning objective 1. Childhood trauma specifically predicts higher depression and anxiety in adulthood Chu et al. J Psychiatric Research, 2013 n=1209 from community sample

20 a) Childhood trauma and the normal maturation of emotional brain circuits during adolescence med.stanford.edu/williamslab

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24 Anterior Cingulate Amygdala Caudate Striatum

25 Anterior cingulate and Caudate are reduced in volume in adults who had >=2 childhood traumatic events BRAINnet data. Cohen et al. Biol. Psychiatry, 2006

26 Do we see this earlier? Anterior cingulate and amygdala Caudate are reduced in adolescents years who had >2 traumatic events

27 b) Childhood trauma interacts with genotype to impact emotional brain circuits and confer risk for depression and anxiety med.stanford.edu/williamslab

28 Serotonin Transporter, 5-HTT-LPR People with the Short allele have a higher risk for depression, especially when coupled with stress Caspi et al. Science, 2003

29 Depression Risk S = short allele L = long allele SS SL.30 LL No Abuse Moderate Abuse Severe Abuse Early Childhood Experience Source: Caspi (2003)

30 Is the Short allele contribution to risk due to intermediate effects on emotional brain circuits? Nonconscious, masked Conscious A Facial emotion task to activate emotional brain circuits

31 Williams et al. Neuroimage, 2009

32 5-HTT-LPR Short allele * Early Life Trauma è Higher self-reported negativity bias Williams et al. Neuroimage, 2009

33 BDNF; Met vs Val allele BDNF is involved in brain plasticity. It has a direct effect on plasticity of amygdala and on fronto-hippocampal circuits Urani et al., Neurosci Biobehv Rev, 2005

34 Dorsal lateral prefrontal cortex (DLPFC)

35 Gatt et al., Molecular Psychiatry, 2009

36 Gatt et al., Molecular Psychiatry, 2009

37 Gatt et al., Molecular Psychiatry, 2009

38 c) How does childhood trauma moderate treatment response outcomes in depression? med.stanford.edu/williamslab

39 An illustration from the ispot-d biomarker trial of depression treatment outcomes

40 Primary phase of study Baseline Visit Week 0 A. Randomized Escitalopram to B. Sertraline Medication Usual C. Venlafaxine Care and Titration XR Telephone Monitoring Weeks 2, 4 and 6 Repeat Visit Week 8 Naturalistic follow-up Williams LM, et al. Trials, 2013

41 Category and Type of Trauma questions % Prevalence of Trauma Group Difference MDD Control χ 2 p-value N=1008 N=336 % % Abuse/interpersonal violation Were you physically abused? <.0001 Were you sexually abused? <.0001 Were you emotionally abused? <.0001 Did you experience extreme poverty or neglect? <.0001 Did you witness domestic violence within your family? <.0001 Did you experience sustained bullying or rejection by schoolmates? <.0001 Family breakup Did your parents divorce or separate? Were you separated for a long period from a parent, brother or sister? <.0001 Was there sustained conflict within your family? <.0001 Family health/death Did one of your parents, a brother or sister die? Did one of your parents, a brother or sister experience a lifethreatening illness? Personal Health Did you undergo major surgery or repeated hospitalization? Did you experience a life-threatening illness or injury? Disaster/war Did you witness first-hand a natural disaster such as earthquake, flood or fire? Did you witness warfare? Other traumatic events Were you born prematurely, or experience other birth complications? Were you adopted? Was your house destroyed by fire or other means? Williams et al. Translational Psychiatry, in revision

42 Category and Type of Trauma questions % Prevalence of Trauma Group Difference MDD Control χ 2 p-value N=1008 N=336 % % Abuse/interpersonal violation Were you physically abused? <.0001 Were you sexually abused? <.0001 Were you emotionally abused? <.0001 Did you experience extreme poverty or neglect? <.0001 Did you witness domestic violence within your family? <.0001 Did you experience sustained bullying or rejection by schoolmates? <.0001 Family breakup Did your parents divorce or separate? Were you separated for a long period from a parent, brother or sister? <.0001 Was there sustained conflict within your family? <.0001 Family health/death Did one of your parents, a brother or sister die? Did one of your parents, a brother or sister experience a lifethreatening illness? Personal Health Williams et al. Translational Psychiatry, in revision

43 A. B. Abuse at < 8 years has the greatest impact on antidepressant treatment outcomes Williams et al. Translational Psychiatry, in revision

44 Primary phase of study Baseline Visit Week 0 IMAGING A. Randomized Escitalopram to B. Sertraline Medication Usual C. Venlafaxine Care and Titration XR Telephone Monitoring Weeks 2, 4 and 6 Repeat Visit Week 8 IMAGING Naturalistic follow-up Williams LM, et al. Trials, 2013

45 Antidepressants are typically effective for <50 % of those with major depressive disorder (MDD) 1 Alterations in Amygdala Circuitry 2,3 Early Life Stress (ELS) 4, 5 6, 7 Depression Course & Treatment outcome Goldstein-Piekarski et al. in submission

46 80 Depressed unmedicated patients from ispot-d 8.9 ELS Questionnaire10 QIDS 11 HAM-D 12 SOFAS 13 Emotion: 16.7ms Happy Fear Mask: 143.3ms Blocks of 8 masked emotion faces (10 Sec) with the same emotion were repeated 5 times in pseudorandom order Patients randomized to Escitalopram, Sertraline or Venlafaxine-XR 8 Weeks Assessed by a composite measure of symptoms and function. Specifically, treatment response was defined as a score of <=7 on both the HAM-D & QIDS and >=10 point improvement on the SOFAS Participants Pre-treatment Assessment Treatment Outcome Goldstein-Piekarski et al. in preparation

47 Goldstein-Piekarski et al. in submission 0% 25% 50% 75% 100% 0% 25% 50% 75% 100% % Non Responders Classified as Responders % Responders Classified as Responders Regression Model Δχ 2 Δdf p AIC 5. Age + MDD Duration + Happy * ELS + Fear * ELS * Age + MDD Duration + Happy + Fear + ELS Age + MDD Duration + Happy + Fear * Age + MDD Duration + ELS Age + MDD Duration AIC: Akaike s Information Criterion Better Worse Worse Better Sensitivity 1 - Specificity Overall Accuracy Full Model 86.5% No Interaction 79.9% Amygdala Only 75.4% ELS Only 66.9% Base model (age + MDD Dur.) 58.9% ELS & Amygdala Reactivity Predicting Treatment Outcome Variable β Z-value p (Intercept) ** Happy ELS Fear * Age MDD Duration Happy * ELS *& Fear * ELS % Regression Model Performance Base Age + MDD Duration Better Model Performance ELS Only ELS x Full Model + x ELS ELS + No Interaction + ELS Amygdala Only + Worse Table 2: Logistic regression analysis of ELS, amygdala reactivity to fearful and happy faces, and their interactions predicting antidepressant treatment outcomes (Full Model) Table 1: Multivariate model fitting results +p < 0.10, *p < 0.05, **p < 0.01

48 Toward a personalized approach

49 Conclusions? Childhood trauma a) is prevalent, and confers risk for depressionanxiety med.stanford.edu/williamslab

50 b) disrupts the normal maturation of emotional brain circuits during adolescence; especially emotional brain circuits c) interacts with serotonin system genotypes to increase the effects on emotional brain circuits, and risk for depression-anxiety d) Is more prevalent with overt depression and interacts with emotional brain function to determine antidepressant response med.stanford.edu/williamslab

51 This knowledge can be used to improve mental health outcomes med.stanford.edu/williamslab

52 Thank you med.stanford.edu/williamslab