ICCAM platform. Introduction. David Nutt November 2011

Transcription

1 ICCAM platform Introduction David Nutt November 2011

2 The ICCAM Platform New Drugs to Treat Addiction: Can a Knowledge of Brain Mechanisms Help? An MRC addiction cluster Imperial College London: David Nutt (PI), Anne Lingford-Hughes and Laurence John Reed Cambridge University: Trevor Robbins, Barry Everitt, Ed Bullmore, Karen Ersche, Jeff Dalley and Franklin Aigbirhio Manchester University: Bill Deakin and Rebecca Elliott. GSK: Ilan Rabiner and John Beaver

3 Why ICCAM? And what are we doing?

4 Addiction is a major health problem 27 EU countries + iceland switzerland and norway First time all brain diseases counted

5 Disorders of the brain- numbers affected Diagnostic group Brain tumor Neuromuscular disorders Multiple sclerosis Parkinsons disease Eating disorders Epilepsy Traumatic brain injury (TBI) estimated number of subjects Mental retardation Personality disorders Psychotic disorders Child/Adolescent disorders Dementias Stroke 8.2 Addiction 15.5 Somatoform disorder 20.3 Mood disorders 33.3 Sleep disorders 44.7 Anxiety disorders 69.2 Headache Estimated and adjusted number of persons in million

6 2011 Disability (DALY) estimates: + Gender comparison PTSD Multiple Sclerosis Panic Disorder Obessive--comp. Dis. Epilepsy Migraine Insomnia Parkinsons Disease Schizophrenia Bipolar disorders Drug use disorders Dementias Stroke Unipolar depression Alcohol use disorders Females Males Males: Total neuropsychiatric: 23.4% Other disease groups Females: Total neuropsychiatric: 30.1% 6.43 Other disease groups Mental dis. Neurological Mental dis other Neurological other DALY Rate per persons

7 Alcohol main cause of global disability in yr olds Males Females

8 Substance misuse deaths compared with other psychiatric disorders Mental Disorder and Life Expectancy Premature deaths from addiction Figure 1. Annual mortality risk (%) by age groups and diagnoses of mental illness, compared to England and Wales population in doi: /journal.pone g001

9 The many elements of addiction Loss of control Pleasure Reduce suffering Memory Meaning Wanting impulsivity Compulsion Habit Use/exposure Withdrawal Perpetuation/addiction

10 Effective treatments exist Substitution therapy (and withdrawal) Methadone, buprenorphine for heroin Acamprosate, oxybate, baclofen for alcohol Varenicline for tobacco Blockers Antagonists - naltrexone for heroin (low compliance) (Dopamine reuptake blockers failed for cocaine worked for nicotine = bupropion)? Vaccines nicotine, cocaine (under study) Anti-relapse drugs Opioid antagonists for alcohol nalmefene, naltrexone? Prevent loss of control New areas anti-stress, anti-impulsivity

11 many drug targets Dopamine Pleasure Reduce suffering GABA/gluta mate Memory Meaning Wanting Loss of control impulsivity Compulsion Noradrenaline Dopamine Endorphins SubP Habit Endorphins 5HT? Dopamine Withdrawal Multiple drug related

12 Relapse to Addiction The Core Problem Mechanisms of Relapse Reward? Opioid Impulsivity? Dopamine Stress? SubP fmri to identify the brain networks involved Survival analysis of the relapse during the 180-day period (Kaplan Meier). Neto D et al. Alcohol and Alcoholism 2007;42: Copyright The Author Published by Oxford University Press on behalf of the Medical Council on Alcohol.

13 In preclinical studies many drugs release dopamine coc > others (DiChiara) And stimulants in humans too The dopamine theory And in humans Dopamine-rich areas esp n accumbens respond to stimulant drugs and to drug cues dopamine promoting drugs eg agonists and L-DOPA in Parkinson s pts can lead to addictive-like behaviours

14 In preclinical studies many drugs release dopamine The dopamine theory coc > others (DiChiara) 5 sorts of dopamine receptors 2 families - D1 and D5 And in humans - D Dopamine-rich areas esp n accumbens D2 respond blockers to stimulant = antipsychotics drugs and in humans to drug little impact on drug use cues D3 dopamine blockers promoting stop relapse drugs to eg stimulant agonists use in rats and L-DOPA in Parkinson s pts can lead to addictive-like behaviours

15 Endorphins and opioid receptors Dopamine GABA/gluta mate Loss of control Noradrenaline Dopamine Endorphins Pleasure Reduce suffering Memory impulsivity Meaning Wanting Compulsion Habit Endorphins 5HT? Dopamine Withdrawal Multiple drug related

16 Human Mu receptors - [ 11 C]Carfentanil analgesia 5 1

17 Altered opioid receptors may be a major aspect of addiction Evidence for increase in brain receptors in humans (and rats) during Cocaine withdrawal Opiate withdrawal Alcohol withdrawal May reflect more receptors Or less endorphins? Endorphin release relapse

18 Amfetamine releases endorphins putamen Colasanti et al C- Carfentanyl PET - reductions after amfetamine

19 Amfetamine releases endorphins in 3 brain regions 11C- Carfentanyl PET Mu-selective? Endorphins increase drug seeking Note opioid receptor antagonist stopped cocaine seeking in rats Guiliano and Everitt this meeting Colasanti et al 2011

20 Substance P A peptide in the tachykinin family NK 1,2,3 receptors subp = NK1 Rodent studies released in stress and in craving for drugs Humans SubP antagonists reduce vomiting (Aprepitant - licensed) stress and alcohol craving (research)

21 Stress Relapse and Vofopitant Sinha model of stress dysregulation in Addiction Cerebral Distribution of Vofopitant (Neurokinin 1 or Substance P Antagonist)

22 The ICCAM Platform New Drugs to Treat Addiction: 3 addictions cocaine alcohol - heroin 3 drug candidates antagonists of DRD3 An - MRC subp addiction - mu opioid cluster receptors 3 tasks to probe drug relapse in fmri Imperial College London: David Nutt (PI), Anne Lingford-Hughes and Laurence John Reed stress reward - inhibitory control Can a Knowledge of Brain Mechanisms Help? Cambridge University: Trevor Robbins, Barry Everitt, Ed Bullmore, Karen Ersche, Jeff Dalley and Franklin Aigbirhio Manchester University: Bill Deakin and Rebecca Elliott. GSK: Ilan Rabiner and John Beaver

23 3x3x3 fmri matrix Candidate Target Assessment Antagonist Naltrexone Dopamine D3 Antagonist Neurokinin 1 Antagonist Placebo Reward Induced Stress/Cue Induced Inhibition Resting Network (fmri) In three addictions cocaine heroin and alcohol