re$conceptualizing!the!e1ology!! …...dev psychopathol. exploring genetic moderators and epigenetic...
TRANSCRIPT
Re-‐conceptualizing the e1ology of substance use disorders:
gene1c and epigene1c mechanisms
Gilberto Gerra Chief
Drug Preven4on and Health Branch
A New Approach Based on Science, Compassion and Social Cohesion We recognize drug dependence as a complex, mul4factorial health disorder characterized by chronic and relapsing nature with social causes and consequences that can be prevented and treated… (General Assembly Resolu4on 19-‐04-‐2016, page 6, i)
Not a moral failure Not a criminal aJtude Not a social trend Not a free choice Not recrea4onal
SCIENCE BASED APPROACH RECOGNIZED AS ESSENTIAL Effec4ve scien4fic evidence based preven4on programs Effec4ve scien4fic evidence based drug treatment, care, and rehabilita4on programs Civil society, as well as the scien4fic community and academia, plays an important role in addressing the world drug problem.
General Assembly, 2016 Two CND resolu4ons (58th-‐59th Sess.) A con4nuous dialogue with the scien4fic community. The UNODC-‐WHO interna4onal informal scien4fic network
Am J Addict. Hintz and Mann, 2006
Many prac11oners con4nue to hold nega4ve opinions about drug dependent pa4ents:
"Substance Use disorders pa4ents are only weak-‐minded“
Subst Abus. AMtudes, prac1ces, and preparedness to care for pa1ents with substance use disorder: Results from a survey of general internists. Wakeman 2016 22% felt prepared to screen SUD 7% to discuss behavioural treatments 9% to discuss medica4on treatments 31% felt that SUD is different from other chronic diseases because using substances is a choice 14% felt treatment with opioid agonists was replacing one addic4on with another 12% of hospitalists believe that someone who uses drugs is commiJng a crime and deserves punishment
Health care workers aMtude:
Nega4ve aJtudes toward their drug users clients: -‐ they believe that drug use is within the control of the individual affected -‐ liZle or no educa4on or training in the care and treatment of drug users -‐ they would like to prevent contact with drug users -‐ they would reject the offer of educa1on and training in this area -‐ detec4ng drug use disorders in emergency room 25-‐50%
Kelleher et al, 2007; Brener et al., 2010; McLaughlin et al., 2006
Drug ini1a1on as a result of many co-‐occurring risk factors
Prolonged exposure to drugs does not necessarily induce drug use disorders
Sugar and salt do not necessarily induce diabetes and hypertension.
Diabetes ?
Hypertension ?
Addic4on Are there gene1c influences on addic1on: evidence from family, adop1on and twin studies. Agrawal and Lynskey, 2008
gene4c influences on addic4on with es4mates ranging from 0.30 to 0.70
Gene4c factors contribute to more than 50% of the varia4on in the vulnerability to alcohol dependence
Behav Pharmacol. From gene1c studies to precision medicine in alcohol dependence. Sun et al., 2015
What genes are able to influence?
Variants in genes coding for drugs/alcohol metabolic enzymes: -‐ Alcohol de-‐hydrogenasis, FAAH, MAO, COMT
Variants in genes coding for drugs/ alcohol effects on the brain: -‐ DRD2 -‐ DAT -‐ GABA receptor genes -‐ CHRNB3 nico4nic receptor genes -‐ OPR1 Variants in genes coding for personality traits: -‐ impulsivity (5-‐HTT) -‐ sensa4on seeking (DA) -‐ depressive/anxious trait
Pinto and Ansseau, 2009 Iyer-‐Eimerbrink and Nurnberger , 2014
Neuropsychopharmacology Several behavioral traits relevant for alcoholism are controlled by ɣ2 subunit containing GABAA receptors on dopamine neurons in mice. Stojakovic et al., 2018
-‐ Impulsive behaviour -‐ Less sensi4ve to the seda4ve effects -‐ More dopamine firing / more reward Gene4c varia4on in GABAA receptor subunits, including the ɣ2 subunit (Gabrg2), affects the risk for developing alcoholism.
Alcohol Alcohol. Influence of Dopaminergic System Gene1c Varia1on and Lifestyle Factors on Excessive Alcohol Consump1on. Celorrio et al., 2015
56 gene4c variants in 7 genes associated with the dopaminergic reward pathway and excessive alcohol consump4on.
Behav Brain Res. Associa1on between DRD2, 5-‐HTTLPR, and ALDH2 genes and specific personality traits in alcohol-‐ and opiate-‐dependent pa1ents. Wang et al., 2013
Short allele: low-‐func4onal
LL
SL
SS
Abstinent
37,73%*
50,54%
11,83%
χ=7.13 p<0.005
Experimenters
23,19%
50,72%
26,09% *
LL
SL
SS
NOVELTY SEEKING
15,72
19,41
21,75*
BDHI DIRECT AGGRESSION
51,03
55,70
59,58*
J. Neural Transmission Gerra and Donnini, 2005
Serotonin transporter Gene variant SS associated with temperament among adolescents
Addic4on The gene1c epidemiology of cannabis use, abuse and dependence. Agrawal and Lynskey, 2006
The substan4al evidence for the heritability of … -‐ cannabis use -‐ abuse -‐ dependence Gene1c basis to each stage of cannabis involvement
Drug Alcohol Depend. Polygenic risk for alcohol consump1on and its associa1on with alcohol-‐related phenotypes: Do stress and life sa1sfac1on moderate these rela1onships? Mies et al., 2018
quan4ty of alcohol consump4on
polygenic risk for alcohol consump1on
alcohol-‐related problems
stress and life sa1sfac1on
Inherited vulnerability
Genotypes and alleles at risk Affec4ng neurotransmission Modula4ng temperament/ behavioural aJtude Egervari et al., 2017
Externalizing behaviour reward sensi4vity/deficit, novelty seeking, impulsivity/inhibitory control Internalizing behaviour depressive anxious aJtude
EPIGENETICS
Neurotox Res. Unravelling the Link Between Prenatal Stress, Dopamine and Substance Use Disorder. Pastor et al., 2017
The development of meso-‐cor4colimbic dopaminergic system is disrupted by prenatal stress
Prenatal stress as a candidate to explain SUD vulnerability
Dev Psychopathol. Prenatal influences on temperament development: The role of environmental epigene1cs. Gartstein and Skinner, 2017.
environmental inputs altera1ons to gene expression physiology behaviour Molecular mechanism of how environmental factors impact development and subsequent health and disease, including early brain and temperament development.
Genes are influencing: -‐ Temperaments (sensa4on seeking, harm avoidance) -‐ Mo4va4onal/reward system tone -‐ Inhibitory control mechanism(prefrontal cortex) -‐ Psychobiological response to emo4ons -‐ Ability to cope with stress -‐ Sociability and emo4onal stability
Direct vulnerability for substance use
Parent-‐child aZachment/ rela4onships
Planalp and Braungart-‐Rieker, 2013
Psychiatr Enfant. The development of attachment according to the temperament of the newborn Balleyguier, 1991 Infant Behav Dev. Infant and parent factors associated with early maternal sensi1vity: a caregiver-‐a`achment systems approach. Mills-‐Koonce et al., 2007 - irritable babies develop an anxious attachment - avoidant children reduce maternal sensitivity temperament at birth influences mother's attitude
Brain Behav. Maternal separa1on affects expression of stress response genes and increases vulnerability to ethanol consump1on. de Almeida Magalhães et al., 2017
Lancet Psychiatry. Early life adversity, genomic plas1city, and psychopathology. Turecki et al., 2014
Adverse Childhood Experiences (ACEs) affect the brain …
Physical/sexual abuse Physical neglect Emo4onal abuse Emo4onal neglect Household dysfunc4on
through epigene1c changes
Clin Epigene4cs Epigene1c altera1ons following early postnatal stress: a review on novel ae1ological mechanisms of common psychiatric disorders. Jawahar et al., 2015
suscep1bility to adult psychiatric disorders
early postnatal stress: changes in gene expression
regula4on of HPA axis: glucocor4coid receptor gene
brain-‐derived neurotrophic factor (BDNF) gene
serotonin transporter gene
Mol Neurobiol. Epigene1cs of Stress, Addic1on, and Resilience: Therapeu1c Implica1ons. Cadet, 2016 Molecular Neuropsychiatry Research Branch, NIH/NIDA Intramural Research Program, Na4onal Ins4tutes of Health early and adult stressful life events are risks factors for the development of addic4on and serve as cues that trigger relapses
stress
Neuron Paradise Lost: The Neurobiological and Clinical Consequences of Child Abuse and Neglect. Nemeroff, 2016
child abuse and neglect is associated with a marked increase in risk for major psychiatric, substance use disorders and medical disorders persistent biological altera4ons associated with childhood maltreatment epigene1c mechanisms thought to transduce environmental stressors into disease vulnerability
Addic4on. The risk for persistent adult alcohol and nico1ne dependence: the role of childhood maltreatment. EllioZ et al., 2014; EllioZ et al., 2015
A history of childhood maltreatment predicts persistent adult alcohol and nico4ne dependence.
Profiling of childhood adversity-associated DNA methylation changes
in alcoholic patients and healthy controls.
Childhood adversities could induce
methylation alterations in the promoter regions of specific genes and
changes in gene transcription with increased
risk for substance use disorders
(Zhang et al.2013)
Epigenetic mechanisms in vulnerability
Transl Psychiatry. Methyla1on of the leukocyte glucocor1coid receptor gene promoter in adults: associa1ons with early adversity and depressive, anxiety and substance-‐use disorders. Tyrka et al., 2005
Dev Psychopathol. Exploring genetic moderators and epigenetic mediators of contextual and family effects: From Gene × Environment to epigenetics. Beach et al., 2016
the association between family context and mental and physical health outcomes early environments may influence epigenetic motifs that potentially serve as mediators of long-term effects of early family and community environments genotype may sometimes influence epigenetic outcomes
Epigene4c mechanisms, affec4ng the expression of genes implicated in stress responses. Social adversity (parent-‐offspring interac4ons) alters the expression of a wide range of genes regula4ng hypothalamic-‐pituitary-‐adrenal func4on.
Dialogues Clin Neurosci. Early life adversity and the epigene1c programming of hypothalamic-‐pituitary-‐adrenal func1on. Anacker et al., 2014
Childhood neglect Altered response to emotions HPA axis dysfunction Addiction Severity
Gerra et al., 2013
Bellis et al., 2014
Na4onal household survey of adverse childhood experiences and their rela4onship with resilience to health-‐harming behaviours in England
58.7 % of heroin / crack cocaine use could be aZributed to ACEs
ACEs and health-‐harming behaviours both associated to social depriva4on/poverty
9.0% 4 or more ACEs in the general popula4on 4.3% 4 or more ACEs among the most affluent 12.7% 4 or more ACEs among the most deprived
Individuals living in socially deprived regions were found to carry more alcohol dependence risk alleles which may contribute to the increased prevalence of problem drinking.
Addict Biol. Polygenic risk for alcohol dependence associates with alcohol consump1on, cogni1ve func1on and social depriva1on in a popula1on-‐based cohort. Clarke et al., 2015
Blair, C. (2010), Stress and the Development of Self-‐Regula4on. Child Development Perspec4ves
“early stress in the context of poverty affects the func4oning of neural networks that underlie execu4ve func4ons and self-‐regula4on”
-‐ hyperac4ve amygdala (emo4ons store) -‐ hypoac4ve prefrontal cortex (emo4ons regula4on)
Luan Phan et al., 2013
Poverty and stress during childhood:
Is non-‐medical use of controlled drugs ‘recrea1onal’?
Recrea1onal for whom?
gene4c factors, environmental, social factors contribute to the determina4on of a person’s unique suscep4bility to using drugs ini1ally, sustaining drug use, undergoing the progressive changes in the brain that characterize addic4on Volkow et al., 2016
Schizophr Bull. Gene-‐environment interplay between cannabis and psychosis. Henquet et al., 2008
Pharmacogene4c factors and individual history (epigene4cs)
Individual vulnerability underlying drug ini4a4on and alcohol abuse Pregnancy:
mother stress
Gene variants, problema4c temperament
Early childhood adversity, stress neglect abuse trauma social exclusion
Parent child insecure aZachment
Early onset mental health disorders/SUD
Lack of bonding to family and school Drug availability
peer pressure
Pregnancy: mother wellbeing
Gene variants, posi4ve temperament
Parent child secure aZachment
Early childhood wellbeing, care social inclusion
Bonding to family and school
No drug availability Low peer pressure
No mental health disorders/SUD
Psychol Med. The rearing environment and risk for drug abuse: a Swedish na1onal high-‐risk adopted and not adopted co-‐sibling control study. Kendler et al., 2016 Although drug abuse is strongly familial, with gene4c influences, we need to know more about the role of rearing environment.
High-‐quality rearing environments can substan4vely reduce risk for substance abuse in those at high gene4c risk
J Consult Clin Psychol. 77(1):1-11. Parenting moderates a genetic vulnerability factor in longitudinal increases in youths' substance use. Brody et al., 2009
5-HTTLPR status SS linked with increases in substance use over time the association was greatly reduced by involved-supportive parenting
- Am. J. Med Genet Part B Perceived Parenting Behaviour in the Childhood of Cocaine Users: Relationship With Genotype and Personality Traits. Gerra et al., 2007 - Am J Med Genet Part B Relevance of perceived childhood neglect, 5-HTT gene variants and hypothalamus-pituitary-adrenal axis dysregulation to substance abuse susceptibility. Gerra et al., 2010
Substance ini1a1on
Mother Father Neglect CECA-‐Q
HPA Axis dysfunc1on
Serotonin Transporter
Gene S-‐ allele
Proc Natl Acad Sci U S A. Maternal support in early childhood predicts larger hippocampal volumes at school age. Luby et al., 2012
Maternal support has been shown to promote specific gene expression and neurogenesis
Animal studies have revealed dozens of enduring changes in gene expression following prolonged exposure to cocaine
Neuropsychopharmacology. Environmental, gene1c and epigene1c contribu1ons to cocaine addic1on. Pierce et al., 2018
DNMTs, DNA methyltransferases HATs, histone acetyltransferases HDACs, histone deacetylases HDMs, histone demethylases
Allostasis – Place preference
Epigene4c changes induced by exposure to drugs
Epigene4c changes induced by adverse childhood experiences
Unexplored territory
Alcohol. Drinking beyond a life1me: New and emerging insights into paternal alcohol exposure on subsequent genera1ons. Finegersh et al., 2015 transmission of epigene4c variants in the development of behavioural phenotypes, including drug preference and substance-‐induced behaviour
paternal transmission of epigene4c variants
Alcohol. Alcohol effects on the epigenome in the germline: Role in the inheritance of alcohol-‐related pathology. Chastain and Sarkar, 2017
Alcohol exposure has been shown to induce changes in the epigenome of sperm of exposed male animals, and these epimuta4ons are inherited in the offspring.
Nihon Eiseigaku Zasshi. Epigene1c Effect of Environmental Factors on Neurodevelopmental Disorders. Kubota, 2016
one advantage of epigene1c changes is their reversibility
Sci Rep. DNA methyla1on signatures of chronic alcohol dependence in purified CD3+ T-‐cells of pa1ents undergoing alcohol treatment. Brückmann et al., 2017
The mean global DNA methyla4on was significantly lower in pa4ents prior to treatment compared to controls, but reverted back to levels similar to controls auer treatment.
Biol Aujourdhui. Epigene1c mechanisms and alcohol use disorders: a poten1al therapeu1c target. Legastelois et al., 2017
Histone deacetylases (HDAC) inhibitors are able to counter ethanol-‐induced behaviors and the ethanol-‐induced changes in the levels of HDAC and/or levels of acetylated HDAC. Trichosta4n A treatment caused the reversal of ethanol-‐induced tolerance, anxiety, and ethanol drinking by inhibi4ng HDAC ac4vity, thereby increasing histone acetyla4on in the amygdala of rats.
Front Psychiatry. Epigene1c Biomarkers as Predictors and Correlates of Symptom Improvement Following Psychotherapy in Combat Veterans with PTSD. Yehuda et al., 2013
Responders to psychotherapy showing higher gene expression at post-‐treatment than non-‐responders. Psychotherapy may alter epigene1c state?
Programs for children social protec4on
Programs to reduce school drop out
The large framework of health, welfare and wellbeing
-‐ Children social protec4on -‐ Improving parental skills -‐ School connectedness
reduce uptake or experimenta4on with smoking 32%. authorita1ve paren1ng: -‐ strong interest in children -‐ care for the children -‐ rule seJng -‐ supervision different from -‐ authoritarian paren4ng (do as I say) -‐ neglecwul paren4ng -‐ unsupervised paren4ng
Cochrane Database Syst Rev. Family-‐based programmes for preven1ng smoking by children and adolescents. Thomas et al., 2015
32%
Pre-‐school interven4on
Skills training programmes for students and parents
7,2 4,3
69,1
3,6 2,3
75,8
0
10
20
30
40
50
60
70
80
General popula4on Priviledged Unpriviledged 2000-‐2001 2010-‐2011
-‐ Parents unemployed -‐ Parents low level of educa4on -‐ Adolescents depression
4 2,1
22,4
2,2 1,4
41,7
0
5
10
15
20
25
30
35
40
45
General popula4on Priviledged Unpriviledged 2000-‐2001 2010-‐2011
-‐ Parents unemployed -‐ Parents low level of educa4on -‐ Adolescents depression
The complexity of drug use disorders
Gene variants Temperament
Impaired parent-‐child aZachment
Early stress, trauma, neglect, abuse
Epigene1c changes
Pharmacogene4cs
Abnormal associa1ve learning, condi1oned drug seeking behaviour
Mo4va4onal system, inhibitory control derangement
Neurobiological changes Mental health disorders
Health and social consequences
Drugs ini1a1on
Con1nuous drug use
Poor social environment
