Nora D. Volkow, M.D. Director National Institute on Drug Abuse

1. How Does COMORBIDITY with DRUG ABUSE Inform Us On the Neurobiology of Mental Illnesses? Nora D. Volkow, M.D. Director National Institute on Drug Abuse

2. 100 80 60 40 20 0 Prevalence of Drug Disorders (other than nicotine) Prevalence of Nicotine Addiction 40 35 30 Percent 25 Percent 20 15 10 5 0 Mania Depression Social Phobia General public Any Mood Disorder Depression Generalized Anxiety Any Anxiety Disorder Panic w/ Agoraphobia Schizophrenia Panic w/out Agoraphobia General public Conway et al., J Clin Psychiatry, February 2006.

3. Why we can not afford to further ignore substance abuse in patients with mental illness • Overlapping developmental, environmental and genetic vulnerabilities • Drugs can trigger mental disorders in those that are vulnerable and can exacerbate their course • Patients with mental illness are at greater risk for substance abuse • Drugs contribute significantly to the morbidity and mortality of patients with mental illness

4. Age of Onset of Brain Disorders Drug Abuse and Addiction 10 – 13 Years Obsessive-Compulsive Disorders Percent of Initiates Developed from Time Magazine, January 20, 2003, p. 82 Age at Which Marijuana Use Is First Initiated 80 70 60 50 40 30 20 10 0 Drug Abuse Child <12 Teen 12-17 Young Adult 18-25 Adult >25 Source: Gfroerer, JC et al., SMA 02-3711, OA, SAMHSA – Data from National Survey of Drug Use and Health.

5. The brain undergoes major changes from childhood through adulthood

6. Amygdalar Innervation of Prefrontal Cortex ` Preweanling (P16) (childhood) Postweanling (P25) (adolescence) Postweanling (P65) (adult) Cunningham, M.G. et al,J Comparative Neurology, 453:116-130, 2002. adolescent adult Prefrontal Amygdala When Reading Emotion Adults Rely More on the Frontal CortexWhile Teens Rely More on the Amygdala Deborah Yurgelon-Todd 2000.

7. What Do We Know About the Genetics of Drug Abuse and Mental Illness? Twin studies consistently show that there is a heritablecomponent to these disorders Now we are able to examine genetic variants, or single nucleotide polymorphisms (SNP) that contribute to addiction vulnerability

8. presynaptic { Dendritic Spines { postsynaptic De Camilli et al, 2001 Many of these Genes Participate in Neuroplasticity CELL ADHESION NEURO- TRANSMISSION SIGNAL TRANSDUCTION TRANSCRIPTION FACTORS Dean and Dresbach, TINS, 2006

9. NRG1 BDNF Neuroplasticity Owen, M. J. et al. Schizophr Bull 2007 0:sbm053v1-1; doi:10.1093/schbul/sbm053

10. Low MAOA Activity , n=163 1 0.75 0.5 0.25 0 -0.25 -0.5 High MAOA Activity , n=279 Composite Index of Antisocial Behavior (z scores) None Probable Severe Childhood Maltreatment Source: Caspi, A. et al., Science 297, 2 August 2002. Antisocial Behavior as a Function of MAOA Activity and a Childhood History of Maltreatment

11. Ever Addicted 35 10 30 25 8 Odds ratio 20 6 15 4 10 5 2 0 0 1 2 3 4 0 Adverse Childhood Experiences 0 1 2 3 4 5 Stressful Events Increase the Risks for some of the Mental Illnesses and for Drug Disorders Individuals with the short allele of the 5HT gene % s Depression Stressful events Caspi et al., Science 301: 386-389 2003. PEDIATRICS 111: 564-572, 2003 (n=8603)

12. Effects of Social Stressors on Illicit and Licit Drug Use Facilitate Initiation Increase Risk of Addiction 3. Trigger Relapse

13. 1100 AMPHETAMINE 1000 900 800 700 600 % of Basal Release 500 400 300 200 100 0 0 1 2 3 4 5 hr frontal cortex Time After Amphetamine FOOD 200 nucleus accumbens VTA/SN 150 % of Basal Release 100 Empty 50 Box Feeding 0 0 60 120 180 Time (min) Di Chiara et al. Dopamine Neurotransmission

14. 10 8 6 4 2 m e t h y l p h e n i d a t e 0 -2 -10 0 10 20 30 40 DA and Drug Reinforcement “High” T Y R O S I N E T Y R O S I N E Self-Reports (0-10) D O P A D O P A D A D A DA D A DA D A D A D A D A D A raclopride D A D A Change in Dopamine D A D A raclopride D A R D A D A R R D A Bmax/kd (Placebo - MP) R R R DA initiates and maintains responses to salient stimuli such as drugs Volkow et al., JPET 291(1):409-415, 1999.

15. DA Release In Ventral Striatum In Response To Psychological Stress In Subjects with High and Low Parental Care Maternal Care 4.0 3.5 3.0 2.5 2.0 1.5 0 Low High BP (ventral striatum) F[1,8]=7.78 p=.02 Control Stress Control Stress Condition Pruessner et al J Neurosci. 2004 Mar 17;24(11):2825-31.

16. Why we can not afford to further ignore substance abuse in patients with mental illness • Overlapping developmental, environmental and genetic vulnerabilities • Drugs can trigger mental disorders in those that are vulnerable and can exacerbate their course • Patients with mental illness are at greater risk for substance abuse • Drugs contribute significantly to the morbidity and mortality of patients with mental illness

17. Molecular Targets for Drugs of AbuseAppear Early in Gestation and Are Involved in Fetal Brain Development CANNABINOID RECEPTORS NICOTINIC RECEPTORS Postnatal 7 Postnatal 7 ADULT ADULT GENSAT Drug Stimulation of these Receptors is Likely to Affect Development

18. Adolescent Cannabis Use Effects Adult Psychosis in Individuals with Variations in the COMT Gene 20 no adolescent cannabis use adolescent cannabis use 15 % with schizophreniform disorder at age 26 10 5 0 Met/Met Val/Met Val/Val COMT genotype Source: Caspi, A. et al. Biol. Psychiatry, 57: 1117-1127; 2005.

19. Adolescent Exposure to Cannabinoids Alters the Response of VTA Dopamine Neurons to Drugs of Abuse 125 100 75 50 125 100 75 50 vehicle pretreated CB adolescent Percent baseline firing rate Percent baseline firing rate vehicle pretreated CB adolescent .1 1 .1 1 10 Amphetamine (mg/kg) Cocaine (mg/kg) Source: Pistis, M. et al., Biol Psychiatry, 56: 86-94, 2004. Early exposure to cannabinoids renders DA cells more reactive which could trigger a psychotic episode in a vulnerable individual

20. Why we can not afford to further ignore substance abuse in patients with mental illness • Overlapping developmental, environmental and genetic vulnerabilities • Drugs can trigger mental disorders in those that are vulnerable and can exacerbate their course • Patients with mental illness are at greater risk for substance abuse • Drugs contribute significantly to the morbidity and mortality of patients with mental illness

21. Depression

22. Depression Ratings for Baseline & Weeks 1 & 2 of A Quit Attempt in Depressed and Non-Depressed Women Smokers 1.5 1.0 0.5 0.0 Non-Depressed Depressed Mean Depression Rating baseline week 2 week 1 WEEK Source: Pomerleau, CS et al., Journal of Addictive Diseases, 20(10, pp. 73-80, 2001.

23. Brain MAO B & Smoking Status 0.3 0.2 MAO B (basal ganglia) 0.1 0 non- smokers smokers former L-deprenyl smokers Brain MAO Is Reduced by 30-40% in Smokers MAO MAO A MAO B non-smoker smoker Fowler, J.S., Volkow, N.D., Wang, G-J., Pappas, N. et al., Nature 379, pp. 733-736, February 2, 1996. Fowler, J.S., Volkow, N.D., Wang, G-J., Pappas, N. et al., PNAS 93, pp. 14065-14069, November 1996.

24. Attention Deficit Hyperactivity Disorder The co-occurrence of Substance Abuse Disorder and ADHD in addiction treatment settings has been estimated to range from 15-50% In some instances individuals may be abusing drugs to automedicate themselves

25. 10 8 6 4 2 m e t h y l p h e n i d a t e 0 -2 -10 0 10 20 30 40 DA and Drug Reinforcement “High” T Y R O S I N E T Y R O S I N E Self-Reports (0-10) D O P A D O P A D A D A DA D A DA D A D A D A D A D A raclopride D A D A Change in Dopamine D A D A raclopride D A R D A D A R R D A Bmax/kd (Placebo - MP) R R R DA initiates and maintains responses to salient stimuli such as drugs Volkow et al., JPET 291(1):409-415, 1999.

26. Methylphenidate-induced Increases in Striatal DA in Controls and in Cocaine Abusers 35 Placebo MP 30 25 20 15 10 5 0 Normal Control Cocaine Abuser P< 0.003 % Change Bmax/Kd 21% 9% Controls (n = 20) Abusers (n = 20) Cocaine abusers showed decreased DA increases and reduced reinforcing responses to MP Volkow et al., Nature 386:830-833, 1997.

27. Control ADHD 35 5 30 25 20 15 Placebo Placebo 10 5 0 Caudate Putamen 0 Ratio Methylphenidate Methylphenidate Changes in Dopamine After Methylphenidate Measured with PET and [11C]racloproide B Controls ADHD * Percent Change (Bmax/Kd) ADHD Ss had decreased DA release as assessed by blunted MP-induced decrease in [11C]raclopride binding Source: Volkow, ND et al., Archives of General Psychiatry, 2007

28. 28 28 26 26 24 24 22 22 20 20 18 18 16 16 14 14 10 15 20 25 30 35 -10 -5 0 5 10 15 20 25 30 Relationship Between Changes in DA and Inattention(Scores CAARS) E In ADHD Subjects CAARS E Caudate Putamen % Change Bmax/Kd % Change Bmax/Kd Subjects with lower DA release had higher scores in inattention Source: Volkow, ND et al., Archives of General Psychiatry, 2007.

29. Schizophrenia

30. 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 α7/β-actin Controls Medicated Non-medicated Comorbidity with Mental Illness i.e > 80% Schizophrenics Smoke Schizophrenics have Fewer 7 AChR in Hippocampus mRNA Levels of 7 AChR are Lower in Schizophrenics control subjects schizophrenic patients Perl, O et al., FASEB J, 17, pp. 1948-1950, 2003. nicotine normalizes a sensory gating abnormality defect, found in most schizophrenics Freedman et al, Biol Psychiat 38, 22-33, 1995

31. # of Cigarettes Smoked at Age 18 and Risk for Schizophrenia During 4–16-Year Follow-Up in 14,248 Males • Smokers were at greater risk • to develop schizophrenia; • relative risk 1.94 • Numbers of cigarettes • smoked was significantly • associated with schizophrenia • Compared with non • smokers the increased risk • for schizophrenia on those • who smoked > 10 cigarettes • was 2.28 greater Weiser et al., Am J Psychiatry 161:1219-1223 2004.

32. Why we can not afford to further ignore substance abuse in patients with mental illness • Overlapping developmental, environmental and genetic vulnerabilities • Drugs can trigger mental disorders in those that are vulnerable and can exacerbate their course • Patients with mental illness are at greater risk for substance abuse • Drugs contribute significantly to the morbidity and mortality of patients with mental illness

33. Lichtermann et al Arch Gen Psychiatry 2001