Mul$ple  Pathways  to  Addic$ons  

Bob  Pihl  McGill  University  

Why  the  need  to  determine  differen$al  pathways?  

The  Epidemiology  and  Consequences  of  Alcohol  Abuse  

 •   Life$me  Prevalence  10.3  –  23%    Male=13.8,  female=  7.1  Na$ve  American=  18.4  

•   Peak  age    late  teens  early  twen$es    

•  Highly  co  morbid    mood,  anxiety  and  personality  disorders  

 

 •  3rd  most  prevalent  health  problem  

•   A  cause  in  1/3  of  general  hospital  admissions  

•  Primary  cause  of  emergency  room  admissions  

•   Involved  in  39%  of  traffic  accidents  ,  50%  of  violent  interac$ons.  

 

Treatment    &  Preven$on  

•   %  treated  in  ones  life$me.      

•   8%  Abuse  •   38%  Dependence  •   Deference  is  given  to  trea$ng  co  morbid  disorders.  

•   Relapse  is  the  rule.  

•   Generalized  preven$on  programs  can  increase  drug  use.  

•   More  than  40%  of  those  who  begin  drinking  before  age  15  become  dependent,  versus  10%  a_er21.  

7  

Advantages  of  High  Risk  Research  

•  Contemporaneous  recording  of  events  •  Allows  study  of  “escape”  from  risk  process  •  Allows  the  study  of  the  heterogeneity  of  abnormal  outcomes  •  Allows  for  subdivision  in  terms  of  age  of  onset  •  Allows  for  assessment  of  changes  over  $me  within  individuals  •  Can  some$mes  elucidate  feedback  mechanisms,  circular  

processes  and  chain  of  events  typically  important  in  causa$on  

Some  At  Risk  Groups  

•   Family  History  •   Par$cular  Personality  Traits.  

•   ADHD,  CD,  ASPD.  •   Anxiety/  Depressive  Disorders  

•  Early  Alcohol  Use  •  Biological  Varia$ons    

•   Certain  Occupa$ons  •   Premature  Adolescence  

•   School  Failure  •   Peer  Rela$onships  •   Family  Status  •   Bureaucra$c  Induced  Disorders  

Date of download: 3/21/2013" Copyright © 2012 American Medical Association. All rights reserved."

From: Mapping Common Psychiatric Disorders:  Structure and Predictive Validity in the National Epidemiologic Survey on Alcohol and Related Conditions"

JAMA Psychiatry. 2013;70(2):199-207. doi:10.1001/jamapsychiatry.2013.281"

Figure. Three-dimensional representation of the space among psychiatric disorders. Each disorder is represented in the color of the factor for which it has higher loadings. Although the factors are correlated (see Table 1 and the “Results” section), they are represented as orthogonal to facilitate visualization. 1 indicates alcohol abuse; 2, alcohol dependence; 3, drug abuse; 4, drug dependence; 5, nicotine dependence; 6, major depressive disorder; 7, bipolar disorder; 8, dysthymia; 9, panic disorder; 10, social anxiety disorder; 11, specific phobia; 12, generalized anxiety disorder; 13, pathological gambling; 14, avoidant personality disorder; 15, dependent personality disorder; 16, obsessive compulsive personality disorder; 17, paranoid personality disorder; 18, schizoid personality disorder; 19, histrionic personality disorder; 20, antisocial personality disorder."

Figure Legend:"

Moms  who  drink  a  lot  •  NLSCY  study  

– Over  Canadian  10000  families  

12  

13  

14  

15  

             Bureaucra(c        Induced      Disorders        

Immature  

Problems  

Labeled  

900,000  ADHD’s    misdiagnosed  and  treated  in  the  US.  (  Elder,  2010,    Journal  of  Health  Economics)  

Family Pedigree

19  

Assump$ons  &  Strategy  

•   There  are  mul$ple  and  o_en  discrete  e$ologies.  

•   A  high  risk  approach  is  required.  •   How  an  individual  responds  to  the  drug  should  differen$ate  suscep$bility.  Hence  procedurally  an  alcohol  challenge  is  preferable.  

21

Alcohol Challenge – Basic Design

Subject  Selec(on  

Pre-­‐tes(ng/  Control  

Manipula(on  

Alcohol/  Placebo  Challenge  

Post-­‐tes(ng  Manipula(o

n  

Dampening  

Drinking  to  Cope  &  Brain  Response  to  Emo$onal  Faces    

Amygdalar  Response  to  Dis(nct  Facial  Expressions  in  Anxiety-­‐Sensi(ve  Subjects  

M-­‐AS  VS  F-­‐AS  

AG HC Putamen Caudate NAc mFOG

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

BO

LD S

igna

l Int

ensi

ty (a

.u.)

Brain Region

Alcohol Placebo

AG HC Putamen Caudate NAc lOFG

-0.6

-0.4

-0.2

0.0

0.2

BO

LD S

igna

l Int

ensi

ty (a

.u.)

Brain Region

Alcohol Placebo

     S$mula$on  

-0.8

-0.6

-0.4

-0.2

0.0

0.2

0.4

0.6

0.8

* p < 0.03

* **

** p < 0.02

**

Low Heart Rate Respondersto Alcohol Intoxication

High Heart Rate Respondersto Alcohol IntoxicationZs

core

(Ave

rage

of 1

988

to 1

995

long

itudi

nal s

core

s)

Physical Aggression Destruction of Property Theft

-0.6

-0.4

-0.2

0.0

0.2

0.4

0.6

High HR RespondersLow HR Responders

Zsco

re (M

ean

Sho

ck S

elec

ted)

Sober Intoxicated

Aggressive  Behavior  and  the  High  Heart  Rate  Response  

age 10 to 17 delinquency scores TAP - Mean Shock Level Selected

A.  High  &  B.  Low  nega$ve  effects  of  alcohol    

a

t"

3.1"

5.7"

b

t"

-3.1"

-7.2"

   

Alcohol Self-Administration  

Barrett et al, 2005

-10

0

10

20

30

Etha

nol-I

nduc

ed ∆ H

eart

Rate

-1 -0.5 0 0.5 1 1.5∆ Alcohol Self-Administration

(log PR breakpoint)

r = 0.713, p ≤ 0.002

0

0.5

1

1.5

2

2.5

3

Prog

ress

ive

Ratio

Bre

akpo

int (

log)

High HR Low HR

APTD+DOPA

APTD

BAL

***

Subjects  with  a  High  Heart  rate  Response  to  Alcohol  Challenge  

•  Self-­‐rate  more  of  a  posi$ve  response  •  Drink  more  •  Remember  more  words  learned  before  drinking  

•   Increase  plasma  endorphin  levels  •   The  heart  rate  response  is  blocked  by  neltrexone  

•   It  can  be  reduced  via  condi$oning.  

-0.4-0.3-0.2-0.1

00.10.20.30.4

SP SR

Dimensions of the SPSRQ

Z s

co

res o

n t

he S

PS

RQ Low HR responders

High HR responders

Alcohol Induced Changes in BAES Stimulation

-­‐30

-­‐20

-­‐10

0

10

20

30

40

50

pre-­‐alcohol 30min 40min 60min 90min 120min 150min

HHR RLHR R

The  High  Heart  Rate  Response  and  the  Subjec$ve  High  

-0.4

-0.2

0.0

0.2

0.4

0.6

0.8

*

* p = 0.052

High Heart Rate Respondersto Alcohol Intoxication

Low Heart Rate Respondersto Alcohol Intoxication

Zsco

re (S

ubje

ctiv

e H

igh

Ass

essm

ent S

cale

) Subjective effects of alcohol "The worst that I have ever felt" "The best that I have ever felt"

Subjective High Assessment Scale Subjective High across the blood alcohol curve

34  

-0.4-0.3-0.2-0.1

00.10.20.30.4

SP SR

Dimensions of the SPSRQ

Z sc

ores

on

the

SPSR

Q Low HR respondersHigh HR responders

Alcohol-Induced HR Change as a Function of HR Group and Drinking Condition (Reward/Non-Reward)

02

46

810

1214

Low HRresponders

High HRresponders

HR response to alcohol intoxication groups

HR

in

cre

ase

in

BP

M

HR day 1HR day 2 n-rHR day 2 r

Design

•  N= 56 males

•  Day I

–  Alcohol challenge

–  Subjects divided (medium split) into High and Low HR response

•  Day II

–  While sober, participated in a task where auditory and visual cues were paired With reward or no reward

–  Subjects then randomly assigned and alcohol challenged and were exposed to conditioned cues.

-0.5-0.4-0.3-0.2-0.1

00.10.20.30.40.5

H/I AS IMP SS

Dimensions of the SURPS

Z sc

ores

on

the

SURP

S Low HR respondersHigh HR responders

38  

   

39  

0

10

20

30

40

50

60

EducationalFilm

MotivationMisMatched

MotivationMatched

Rat

e of

Rem

issi

on(%

of w

omen

no

long

er m

eetin

g cr

iteria

for s

ubst

ance

abu

se o

r dep

ende

nce)

Brief Intervention

Date of download: 3/21/2013" Copyright © 2012 American Medical Association. All rights reserved."

From: Effectiveness of a Selective, Personality-Targeted Prevention Program for Adolescent Alcohol Use and Misuse:  A Cluster Randomized Controlled Trial"

JAMA Psychiatry. 2013;70(3):334-342. doi:10.1001/jamapsychiatry.2013.651"

Figure 4. Estimated probability of reporting problem drinking symptoms × severity of problem drinking symptoms in high-risk (HR) and low-risk (LR) youth attending intervention and control schools. T2 indicates 6 months after intervention; T3,12 months after intervention; T4,18 months after intervention; and T5, 24 months after intervention."

Figure Legend:"

General  Ques$ons  

•   The  long  term  interven$on  effect  for  the  different  risk  groups.  

•   The  neuropsychological/cogni$ve  correlates  of  each  risk  group,  the  effect  of  substance  use  and  non/limited  use.  

•   The  brain  correlates  of  risk  for  each  group,  the    effect  of  the  interven$on  and  the  effect  of  substance  use  and  abuse.  

Inner   Peace ���   If you can start the day without caffeine, If you   can always be cheerful, ignoring aches and pains, If  you  can  resist  complaining  and    boring  people  with  your  troubles, If  you  can  eat  the  same  food  every    day    and  be  grateful  for  it, If  you  can  understand  when  your  loved    ones  are  too  busy  to  give  you  any  $me, If  you  can  take  cri$cism  and    blame  without  resentment, If  you  can  conquer  tension    without    medical  help, If  you  can  relax  without  alcohol,   If    you  can  sleep  without  the  aid  of  drugs,        

A  DOG