Addiction as a multi-factorial disease: early evidence-based prevention Gilberto Gerra GLOBAL CHALLENGES SECTION Human Security Branch Division for Operations

does not need evidence-based interventions no serious evaluation can be done uncoordinated initiatives are acceptable A social problem? A moral problem? An educational problem? A cultural problem? SUBSTANCE ABUSE

'addiction treatments' as rhetoric masquerading as medicine... … to place responsibility for excessive drug-taking where it is usually absent in public discourse: on the individual drug-user (2000)

On marginalized children?

On abused children?

On emotionally neglected children?

On socially deprived adolescents?

WHO, 2004 Substance dependence is as much a disorder of the brain as any other psychiatric illness

Substance-induced (predictable after chronic exposure) mRNA level peptides proteomics neurochemistry behaviors Genetic (25-70%) DNA SNPs Other polymorphisms Environmental (very high) Prenatal Postnatal Contemporary Cues Kreek et al., 2004, NeuroMolecular Medicine

prolonged alcohol ingestion leads to neuronal loss Ruela et al., 1994

Abstinent cocaine addicts The effects of verbal cues: words related with cocaine Venneri and Gardini, 2007

Abstinent heroin addicts The effects of verbal cues: words related with heroin Venneri and Gardini, 2007

Healthy control subjects who never used illicit drugs The effects of verbal cues: words related with cocaine and heroin Venneri and Gardini, 2007

MEASURES TO PREVENT DRUG USE DISORDERS - DISSEMINATING INFORMATION - INCREASING RISK PERCEPTION - RAISING AWARENESS - STRENGTHENING PEER PRESSURE RESISTENCE - REDUCING SUPPLY

Gene variants influencing temperament and personality traits

Difficult temperament Impaired parents attachment Reduced bonding to family Reduced engagement in school Problematic behavior

LLSLSS Abstinent 37,73%* 50,54% 11,83%  =7.13 p<0.005 Experimenters 23,19% 50,72% 26,09% *

LLSLSS NOVELTY SEEKING15,7219,4121,75* BDHI DIRECT AGGRESSION51,0355,7059,58*

LLSL SS smokers26.53%50.00% 23.47% never- smoking subjects 37.63%52.69% 9.68% * * chi2=7.33, p<0.05

gene variants that alter levels of DAT expression provide the best current candidate mechanism for reported associations between DAT gene markers, ADHD and other more tentatively associated neuropsychiatric disorders Vandenbergh et al., 2000

American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 141B:1–7 (2007) _____________________________________________________________________________ Perceived Parenting Behavior in the Childhood of Cocaine Users: Relationship With Genotype and Personality Traits G. Gerra,1* A. Zaimovic,1 L. Garofano,2 F. Ciusa,1 G. Moi,1 P. Avanzini,3 E. Talarico,3 F. Gardini,4 F. Brambilla,1 M. Manfredini,5 and C. Donnini5 1Centro Studi Farmaco-tossicodipendenze, Ser.T., AUSL, Parma, Italy 2Reparto Investigazioni Scientifiche (RIS), Carabinieri di Parma, Parma, Italy 3Servizio Immuno-trasfusionale, Azienda Universita`-Ospedale di Parma, Italy 4Dipartimento di Medicina Interna, Azienda Universita`-Ospedale di Parma, Italy 5Dipartimento di Genetica Antropologia Evoluzione, Universita` degli Studi di Parma, Parma, Italy

PBI Paternal care PBI Maternal care BDHI Direct aggression abstinent subjects 25,49  0,42 27,59  0,  2.9 cocaine users LL-SL 5-HTT genotypes 22,56    2.9 cocaine users SS 5-HTT genotypes    2.5 Perceived parenting behaviour in the childhood of cocaine users: relationship with genotype and personality traits (Gerra et al., 2007

adolescents with the S allele of the 5-HTT gene and with family relations being "neutral" or "bad" had a 12- to 14-fold increased risk for high alcohol intoxication frequency Nilsson et al., 2005

aggressive behavioural under-control novelty- sensation seeking harm avoidant behavioural control submissive

MEASURES TO PREVENT DRUG USE DISORDERS Dealing with difficult temperaments and personality traits Training for parents Strengthening family program Training for teachers Personalized educational plans School/Family efforts integration Support to families

prenatal stress induces permanent alterations in dopaminergic activity and in cerebral asymmetry increase in reactivity to anxiety-provoking situations in pre-natally stressed offspring Fride and Weinstock, 1988

prenatal stress induces long-lasting changes in the dopamine sensitivity of the nucleus accumbens and in the capacity to develop amphetamine-induced sensitization in adulthood Henry et al., 1995

European Journal of Pharmacology, 2004 Prenatal stress affects 3,4-methylenedioxy methamphetamine pharmacokinetics and drug induced motor alterations in adolescents female rats Morley-Fletcher S., Puopolo M., Gentili S., Gerra G., Macchia T. and Laviola G Episodes of Inactivity Inactivity **

Psychopharmacology, Huot et al., 2001 Rat pups - normal animal facility rearing - 15 min of maternal separation (postnatal days 2-14) min of maternal separation (postnatal days 2-14) “180 min. rats”: - an elevation in ACTH and CORTISOL responses - less time in the open arms – elevated plus maze (anxiety) - drank less of a water-sucrose solution - drank more of an ethanol-sucrose solution

Monkeys who suffer maternal deprivation in childhood tend to be fearful, more aggressive, less exploratory, and subject to binge drinking on exposure to alcohol Ichise et al., 2006 Reduced serotonin transporter

VariablesCoeff.p-value Age Antipathy mother (ref. <28) Antipathy father (ref. <30) Neglect mother (ref. <25) Neglect father (ref. <26) R2R2.263 DOPAMINE SYSTEM AND NEGLECT

Physical/emotional abuse predicted poly-substance use and weight concerns, and these associations were mediated by impaired current attachment. Childhood adversity, poly-substance use, and disordered eating in adolescent Latinas: mediated and indirect paths in a community sample. Hodson et al., 2006

Stress (adverse childhood experiences) as a mediating factor in the association between the DRD2 TaqI polymorphism and alcoholism Madrid et al., 2001 DRD2 GENE, STRESS AND ALCOHOLISM

J Psychosoc Nurs Ment Health Serv. Social isolation and sexual abuse among women who smoke crack. Young et al., 2001 sexually abused women social isolation substance abuse

low childhood socio-economic status was associated with an increased risk of substance dependence (tobacco, alcohol, drugs) and poor physical health cardiovascular risk in adulthood Melchior et al., 2007

MEASURES TO PREVENT DRUG USE DISORDERS Protect children from adverse social experiences Laws and norms to protect pregnancy Laws and norms to protect early childhood Strengthening family program for families at risk Economic support to family Life skills programs in school Selected-indicated prevention Alleviate poverty and social exclusion Community empowerment

J Abnorm Child Psychol. Conduct problems, depressive symptomatology and their co-occurring presentation in childhood as predictors of adjustment in early adolescence - lower academic adjustment - lower social competence - risk for substance use disorders Ingoldsby et al., 2006

Arch Gen Psychiatry Prospective effects of attention-deficit/hyperactivity disorder, conduct disorder, and sex on adolescent substance use and abuse. Elkins et al., 2007 Hyperactivity/impulsivity predicts later substance problems, even after growth in later-emerging CD is considered Inattention alone poses less risk

Dev Psychopathol. Course and outcome of bipolar spectrum disorder in children and adolescents: a review of the existing literature. Birmaher and Axelson, 2006 Bipolar Disorder in children and adolescents is associated with high rates of: hospitalizations, psychosis, suicidal behaviors, substance abuse, family and legal problems, as well as poor psychosocial functioning

MEASURES TO PREVENT DRUG USE DISORDERS - The involvement of childhood neuropsychiatry not for children medicalization, but for support to parents and teachers - Early screening of sub-clinical disorders - Early family therapy and behavioural therapy

Taking into account: - Subgroups of individuals (special population) - Social-ethnical-environmental differences Standard evaluation per se may present very consistent limitations

The spectrum of substance use disorders Adolescent at risk Minimal experimenter Experimenter Chronic user Abuser Dependent Severely dependent Concomitant psychiatric disorders Policy-Program Evaluation

Prevention – National Responses

A benefit-cost ratio of $9.60 per $1 invested FAMILY BASED PREVENTION PROGRAMS SCHOOL BASED PREVENTION PROGRAMS A benefit-cost ratio of $4.25 per $1 invested