what science can teach us about the prevention, diagnosis ...€¦ · reward monoamines da, 5-ht,...

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What Science Can Teach us about the Prevention, Diagnosis, and Treatment of

Alcohol Use Disorders

George F. Koob, Ph.D.Director

National Institute on Alcohol Abuse and Alcoholism

2018 Update: Science Policy and TreatmentUniversity of Utah

June 7, 2018

“Deaths of Despair”

Source: Case, A and Deaton, A (2015) Rising morbidity and mortality in midlife among white non-Hispanic Americans in the 21st century. PNAS 112: 15078-15083.

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Cost and Scope of Alcohol-Related Problems in US

• In 2016, 6% (14.6 million) of people 18+ reached criteria for alcohol use disorder (AUD)

• ~ 88,000 people die annually from alcohol-related causes

• ~ 50% of all liver disease deaths attributable to alcohol misuse

• Increase in the intensity of binge drinking, ED visits and hospitalizations in last 10 years

• <10% of people with AUD get any treatment and fewer than 4% receive pharmacotherapy

Sources: Prevalence – NSDUH (2016) ages 18+ using DSM-IV criteria, NCI (2014), CDC (2016); Cost – CDC (2015), National Drug Intelligence Center - National Drug Threat Assessment (2011), 2014 Surgeon General’s Report, NHLBI (2012), Hutchinson et al, 2006, Hingson et al, 2017

1.2

14.5

28.6

6.6

14.6

0 20 40

HIV/AIDS

Cancer

Tobacco

Illicit drugs

Alcohol

Millions in the US

Prevalence of disorder/disease

36

217

295

193

249

0 200 400

HIV/AIDS

Cancer

Tobacco

Illicit drugs

Alcohol

Billions of dollars

Cost to society

National Institute on Alcohol Abuse and Alcoholism

• NIAAA is the largest funder of alcohol research in the world

• Mission: Generate and disseminate fundamental knowledge about the effects of alcohol on health and well-being, and apply that knowledge to improve the diagnosis, prevention, and treatment of alcohol-related problems, including alcohol use disorder (AUD) across the lifespan

• 2017-2021 Research Priorities:Ø Identify mechanisms of alcohol action,

alcohol-related pathology, and recoveryØ Improve diagnosis and tracking of

alcohol misuse, AUD, and alcohol-related consequencesØ Prevent and treat alcohol misuse, AUD,

co-occurring conditions, and alcohol-related consequences

Ø Enhance the public health impact of NIAAA-supported research

Alcohol

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Flow of Talk1. The Science: Neurocircuitry Overview of Alcohol Use Disorder (AUD)

2. Prevention: Neuroprevention- NCANDA, ABCD, Adolescent Drinking and Fetal Alcohol Spectrum Disorder

3. Diagnosis: Alcohol Biosensor, FASD, Addiction Neuroclinical Assessment

4. Treatment: Novel Treatments for AUD and ALD

5. Emerging Challenges for AUD: Extreme Binge Drinking, Drinking in Women and Aged (Prevention), AUD and Comorbidity (Diagnosis), and Medical Education- Treatment Navigator (Treatment)






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Addiction

Addiction — Defined as a chronically relapsing disorder that is characterized by a compulsion to seek and take drug or stimulus, loss of control in limiting intake, and emergence of a negative emotional state (e.g. dysphoria, anxiety, irritability) when access to the drug or stimulus is prevented (here, defined as the �dark side� of addiction)

Conceptual Framework for Neurobiological Bases Driving Substance Use Disorders

From:

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Neurocircuitry/ Neurochemistry of the Binge/Intoxication Stage

Adapted from: Koob, GF 2008 Neuron 59:11-34 and George O, Koob GF. Proc Natl Acad Sci USA, 2013, 110:4165-4166.

Ascending Spirals from Nucleus Accumbens Shell to Core to Dorsal Striatum Mediates Compulsive-like Pathological Habits in Drug Seeking

Haber SN, Fudge JL, McFarland NR.J Neurosci, 2000, 20:2369-2382

goal-directed drug seeking & takingpavlovian conditioning

drug seeking & taking habits

compulsive drug seeking

vulnerability

abstinence/relapse

Everitt BJ, Robbins TW.Nat Neurosci, 2005, 8:1481-1489

Similar organization in rat brain:Ikemoto S. Brain Res Rev, 2007, 56:27-78.

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Neural Circuits of the Withdrawal/Negative Affect Stage

Adapted from: George O, Koob GF. Proc Natl Acad Sci USA, 2013, 110:4165-4166.

Key Neurochemical SystemsLoss:• DopamineGain:• CRF• dynorphin• norepinephrine• vasopressin• hypocretin (orexin)• neuroimmune

Neurocircuitry/ Neurochemistry of the Withdrawal Negative Affect Stage


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Neurocircuitry/ Neurochemistry of the Preoccupation/Anticipation “Craving” Stage


Gray Matter Volume Deficits Predict Time to Relapse in Alcohol-Dependent Patients

From: Rando K, Hong K-I, Bhagwagar Z, Li C-S R, Bergquist K, Guarnaccia J, Sinha R. Am J Psychiatry 168:2, February 2011

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Etiology of Addiction

Progression of the Addictive Process

Indi

vidu

al fa

ctor

s: G

enet

ics,

Life

Stre

ss

Escalating/Compulsive Use

Dependence/Withdrawal

Rewardpositive

reinforcement

Reliefnegative

reinforcementProtractedAbstinence

Relapse

RewardMonoamines

DA, 5-HT, NEAmino Acids

GABA, GLUOpioid PeptidesGlucocorticoids

DependenceDysregulation of reward NTsStress Systems

CRF, Dynorphin, Substance PNPY, Nociceptin (OrphFQ)

Glucocorticoids

RelapseGlutamateDopamineCRF

CB1 ReceptorsCB1 Receptors

CB1 Receptors






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The Science: Frontal Lobe Changes During Adolescence

From: Ball W et al with the Brain Development Cooperative Group (2012). Total and regional brain volumes in a population-based normative sample from 4 to 18 years: the NIH MRI Study of Normal Brain Development. Cerebral Cortex, 22(1):1-12.

• Planning, decision-making, impulse control, memory, language, processing social cues

• Gray matter goes down, white matter goes up, overall size stays about the same

Neuroprevention: National Consortium on Alcohol and Neurodevelopment in Adolescence (N-CANDA)

• Ongoing multisite longitudinal study of more than 800 youth ages 12-21 using advanced brain images and other tools

• Objectives:– To elucidate the short- and long-term effects of alcohol exposure

on the developing brain– To identify brain structural and functional anomalies that result

from alcohol exposure as well as predict onset of AUD and otherpsychopathology

• N-CANDA has already generated a number of important research findings including evidence that youth who drink heavily show structural abnormalities in the frontal cortex of the brain

• N-CANDA’s success demonstrated the much larger Alcohol Brain Cognitive Development (ABCD) Study could be done successfully

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Brain regions where heavy drinking adolescents have steeper reductions in gray matter volume than no/low drinking adolescents

Neuroprevention: Research Update – NCANDA National Consortium on Alcohol and Neurodevelopment in Adolescence

Source: Pfefferbaum et al. Am J Psychiatry 2017

Time

More than 9,500 children enrolled to date

Neuroprevention: Adolescent Brain Cognitive Development (ABCD) Study

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Prevention: Screening and Brief Intervention

• Research indicates adolescent alcohol screening and brief intervention can be effective

• 6 studies are evaluating NIAAA’s Alcohol Screening and Brief Interventions for Youth: A Practitioners Guide in:

– primary care– emergency departments– with children with a chronic medical illness– schools– juvenile justice settings

• School-based universal SBI grounded in the NIAAA youth screening guide, as well as a community-based intervention, both reduced overall alcohol use among American Indian and other youth in rural areas. Komro et. al. Am J Public Health, 2017

Opportunity– Encourage health care providers to screen for youth alcohol misuse in their practices.

Prevention: Underage DrinkingAny successful approach must consider many factors, including:

• Genetics• Personality• Rate of maturation and

development

• Level of risk• Social factors• Environmental factors

Evidence-based approaches can prevent and reduce youth alcohol misuse:

• Environmental interventions • Limit access to alcohol, e.g. enforcing the minimum drinking age of 21• Zero-tolerance laws - outlaw driving after any amount of drinking for

youth

• Individual-level interventions - change the way young people think about alcohol, so they are better able to resist pressures to drink

• School-based interventions - provide students with the knowledge, skills, motivation, and opportunities they need to remain alcohol free

• Family-based interventions - empower parents to set and enforce clear rules against drinking, as well as improve communication between children and parents about alcohol

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Progress: Reducing Underage and College Drinking

• Underage and young adult harmful drinking is a major focus at NIAAA

• Underage drinking prevention = 27 grants ($8 million) in FY 17

• College-age drinking prevention = 47 grants ($15 million) in FY 17

• Alcohol Screening and Brief Intervention for Youth: A Practitioner’s Guide

• CollegeAIM — Resource for helping colleges address harmful and underage student drinking

• National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) – Examines impact of alcohol on teen brain development in 831 subjects

• Adolescent Brain Cognitive Development (ABCD) study – Tracks brain development of roughly 10,000 kids aged 9-10 for 10 years

Source:MonitoringtheFuture,2017

0

5

10

15

20

25

30

35

% o

f 8th

, 10t

h an

d 12

th g

rade

rs

Alcohol use past 30 days

Percentage of teens who drink decreased by one-third in the past decade

Note: Active grants include all grants except no cost extensions and supplements. In addition there were 58 grants ($39 million) in FY 17 for research on alcohol and the adolescent brain

Prevention: The Case for Screening and Brief Intervention

• 2012: U.S. Preventive Services Task Force recommends alcohol screening and brief intervention for adults in primary care

• Alcohol screening and brief intervention recognized as one of the highest ranking preventive services among 28 effective services.

• Similar score as screening for:- cervical cancer- colorectal cancer

• NIAAA provides a Clinician’s Guide to facilitate alcohol screening in adults.

Maciosek et al., Annuals of Family Medicine, 2017

Opportunity– Encourage health care providers to screen for adult alcohol misuse in their practices.

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Progress: Alcohol Policy Research

• NIAAA’s Policy Portfolio:

Ø12 active grants ($7.4 million) in FY 2014 and 18 active grants ($9.5 million) in FY 2017

ØPolicy grants = 10% of the budget in Division of Epidemiology and Prevention Research in 2014 and 10% in 2017

• Program Announcement “Public Policy Effects of Alcohol, Marijuana, and Other Substance Related Behaviors and Outcomes” (Issued in 2017; NIDA and NCI also participate) to encourage more applications on policy research

• NIAAA maintains the Alcohol Policy Information System (APIS), a large searchable database of alcohol-related federal and state policies:

Ø In 2018 the contract supporting APIS was renewed for 5 years

Ø Marijuana policies recently added






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• Winning prototype submitted by BACtrack, a company known for designing and selling portable breath alcohol testers for consumer use

• Their entry, the BACtrack Skyn:– Worn on the wrist– Detects alcohol using a fuel cell technology

similar to that used in roadside testing devices– Offers continuous, non-invasive BAC monitoring– Stores data to a smartphone via Bluetooth

• Opportunity to spread the word - NIAAA will issue additional challenges to stimulate inventors to create and adapt different technologies that measure alcohol directly in blood or interstitial fluid for real time quantification in a wearable device.

Diagnosis: Wearable Alcohol Biosensor Challenges

1st Prize: $200,0002nd Prize: $100,000

The Science: Research Update –FASD Research Fetal alcohol spectrum disorders (FASD) – A broad range of health effects caused by prenatal alcohol exposure:

•Fetal alcohol syndrome (FAS)•Partial FAS •Alcohol-Related Neurodevelopmental Disorder•Alcohol-Related Birth Defects

Most profound effects are brain damage and the resulting impairments in behavioral and cognitive functioning.

A new NIAAA-supported study determined the prevalence of FASD ranged from 1.1 – 5% among four U.S. communities• > 6,600 first grade children examined using comprehensive criteria based

on facial features, growth, and neurodevelopmental performance• Communities in the Midwest, Rocky Mountain, Southeast and Pacific

Southwest selected to be more reflective of U.S. community populations• Further evidence that FASD is a significant public health problem and

strategies to expand screening, diagnosis, prevention, and treatment in communities are needed

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Diagnosis: Advances in FASD Research

NIAAA funded researchers developed 3-D photography and image analysis techniques to enhance detection of alcohol-induced facial features in children prenatally exposed to alcohol.

Facial signatures captured through this method can be visualized as heat maps as shown: Red indicates where facial features are contracted; blue where they are expanded, and green where they are similar in the individual with FAS compared to age-matched controls.

The new technique will help identify individuals within the FASD spectrum with facial features too subtle for detection by the human eye.

Fetal alcohol syndrome•Growth Deficiency•Microcephaly•Characteristic facial features•Cognitive and/or Behavioral Impairment

Insula

VTA

mPFC(AC)

Hippo

OFC

DS GP

Thal

VSVTA

VS

IncentiveSalience

Binge-Intoxication

Withdrawal-Negative affect

Preoccupation-Anticipation

NegativeEmotionality

ExecutiveFunction

Cue ReactivityTask

Facial EmotionMatching Task

Delay Discounting

Diagnosis- Addictions Neuroclinical Assessment Associations with Neurocircuits Provides a Framework for improved Diagnosis, Prevention and Treatment

Adapted from George Koob . Curr Top Behav Neurosci. 2011 Jul 10. Modified from: Kwako LE et al. Biological Psychiatry ,

August 2016

Dr. Laura Kwako

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Treatment: Developing Medications to Treat AUD

• NIAAA Division of Medications Development:

• SBIR/STTR program facilitates studies leading to FDA IND application

• Human laboratory screening studies bridge gap between preclinical and clinical trials

• NIAAA Clinical Investigations Group (NCIG) conducts “fast success/fast fail” phase II clinical trials with 18 month turn-around time

• Intramural program conducts clinical studies on novel compounds with AUD treatment potential

Molecular Targets

Animal Models

Human Laboratory Models

Clinical Trials

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Treatment: Novel AUD Targets by Stage of the Addiction Cycle

Dopamine receptors (DRD2)GABAA receptors (GABRA2)Opioid receptors (OPMR1)Acetylcholine receptors (CNRNA5)Glycine receptors (GLRA1)Serotonin receptors (HTR3A)Serine/Threonine Kinases (MTOR)Cannabinoid receptors (CNR1)GIRK channels (KCNJ6)

Norepinephrine receptor (ADRB2)Hypocretin (Orexin) receptor (HCRTR1)Neuropeptide Y receptor (NPY1R)CRF receptor (CRHR1)Kappa opioid receptor (OPRK1)Substance P receptor (TACR1)Nociceptin receptor (OPRL1)Oxytocin receptor (OXTR)Vasopressin receptor (AVPR1B)Glucocorticoid receptor (NR3C1)Neuroimmune factors (NFKB1)

Phosphodiesterases (PDE10A)Protein kinases (PRKCE)Transcription factors (CREB1, FOSB)NMDA & AMPA receptors (GRIN2B, GRIA1)Metabotropic glutamate receptors (GRM8)Actin cytoskeleton (ACTB) Matrix Metallopeptidase (MMP9)

Treatment: Mifepristone Reduces Alcohol-cued Craving and Drinking in Alcoholics While Improving Liver Function

From: Vendruscolo LF, Estey D, Goodell V, Macshane LG, Logrip ML, Schlosburg JE, McGinn MA, Zamora-Martinez ER, Belanoff JK, Hunt HJ, Sanna PP, George O, Koob GF, Edwards S, Mason BJ, Journal of Clinical Investigation 2015;125(8):3193–3197.

Dr. Barbara Mason

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• Multisite clinical trial of ABT- 436, a novel V1b receptor antagonist

• ABT-436 significantly increased percentage of days abstinent

• Participants who reported high levels of stress responded better: decreased frequency of drinking and number of heavy drinking days

Treatment: Vasopressin Receptor Antagonist as Possible Treatment for AUD

Treatment: Potential AALD Targets and Drugs by Pathogenic Mechanism

IMPAIRED PROTECTIVE RESPONSES

STEATOSIS & HEPATOTOXICITY

INFLAMMATION & STEATOHEPATITIS

FIBROGENESIS & CARCINOGENESIS

FattyLiver

Steato-Hepatitis

Fibrosis and End-Stage Diseases

(6)

Autophagy inhibition

ER stress and apoptosis

Severity of steatosis,inflammation and fibrogenesis

Oxidative stress and JNK-MAPK activation

Fatty acid and bile acid metabolism

Hepatocellular death

Metabolic-, oxidative-, and inflammatory-related stress

Neutrophil infiltration

liver-gut crosstalk

Susceptibility of aged livers to ethanol-induced injury

Extracellular vesicles

Kupffer cell activation via TLR4

Up-regulation of type I collagen

Up-regulation of connective issue growth factor (CCN2)

(3)

(7)

(3)

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The Science: “Liver in the Brain”: Neuroimmune Interactions?

Modified From: Koob, G.F. 2008 Neuron 59:11-34; Szabo G. and Mandrekar P. 2009 Alcohol Clin Exp Res. . 33: 220–232

Progress: Advances in Alcohol Associated Liver Diseases

• Alcoholic Hepatitis Network: NIAAA is establishing a clinical and translational network to streamline the design, initiation, and conduct of clinical trials for alcoholic hepatitis, reduce administrative redundancy, and optimize the use of scientific innovations

• NIAAA, FDA, and the American Association for the Study of Liver Diseases hosted a 2-day workshop in March to develop recommendations for standardized definitions, variable sets, screening and assessment tools, and research and drug development procedures

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Final Plug: New Drug (IND)-enabling Development of Medications to Treat Alcohol Use Disorders (U44/UT2)

• Small business (SBIR) or Small business and academic partner (STTR) opportunity

• Purpose: Translating research discoveries into new treatments for AUD or alcohol related diseases by supporting efforts to achieve an IND.

• Mechanism: U44/UT2 – cooperative agreement –work closely with NIAAA Medication’s Development staff.

• Budget: Up to $1.0M total costs per year for Phase I and up to $1.5M total costs per year for Phase II may be requested.

https://grants.nih.gov/grants/guide/pa-files/PAR-15-153.html

https://grants.nih.gov/grants/guide/pa-files/PAR-15-154.html






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Emerging Issues – Increase in Alcohol-Related Emergency Department Visits

Source: White, A. et al 2018, Alcohol Clin Exp Res

The rate of ED visits involving alcohol in the U.S. population aged ≥12 increased 47% between 2006 and 2014, yet per capita consumption increased <2% during the same time period. The number of alcohol-related ED visits increased from 3,080,214 to 4,976,136. Increases were larger for women.

Emerging Issues – Extreme Binge Drinking

Binge drinking – 4+ drinks for women, 5+ drinks for men, on an occasion

Extreme binge drinking – consuming 2 or more times these thresholds• Nearly 32 million adults engaged in extreme binge drinking

(Hingson, R. et. al. 2017, Am. J. Prev. Med.)

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• Gaps between women and men are narrowing for prevalence, frequency and intensity of drinking, early onset drinking, having AUD, drunk driving, and self-reported consequences (Slade et al., 2016; White et al, 2017)

• Women more likely to experience blackouts, liver inflammation, brain atrophy, cognitive deficits, certain cancers, and to experience negative affect during withdrawal and stress or anxiety-induced relapse (Becker and Koob, 2016)

• But we still know very little about why

• Out of 230 structural neuroimaging studies on substance use over 23 years only 26% evaluated sex differences (Lind et al., 2017)

Emerging Issues – Alcohol and Women’s Health

Sources – Lind K et al (2017) Drug Alc Dependence; Slade T et al (2016) BMJ Open; White A et al (2015) ACER

Emerging Issues – More People Aged 65+ Are Drinking and Binge Drinking

Source – Breslow R, et al (2017) Trends in Alcohol Consumption Among Older Americans: National Health Interview Surveys, 1997 to 2014. ACER, 41, 976-986

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Emerging Issues: Addressing AUD and Co-Occurring Conditions

• AUD frequently co-occurs with other SUDs and mental health conditions (e.g., depression, bipolar disorder, anxiety disorders, PTSD)

• AUD patients with co-occurring mental health conditions tend to have poorer prognosis

• NIAAA supports research to elucidate the relationship between AUD and co-occurring conditions and develop preventive and treatment interventions

• FOA: Alcohol-PTSD Co-morbidity: Preclinical Studies of Models and Mechanisms• Issued in collaboration with Cohen

Veterans Bioscience

• To develop, validate, or apply animal models for mechanistic studies of comorbid PTSD and AUD

Emerging Issues: Urgent Need to Grow the Addiction Medicine Workforce

• Many providers do not perform screening, are not aware of evidence-based treatments or where to refer people

• A study of 54 primary care clinics found 88% had no policies or requirements to ask patients about alcohol use, and those with policies had no consistent evidence-based methods for screening or referral (Mertens et al., 2015)

• Goals:

• Improve physician training in substance use prevention and treatment at all levels, from undergraduate and graduate medical educationthrough residency, fellowship, and beyond

• Integrate prevention, early intervention, and treatment into routine medical care

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• To assist people in finding AUD treatment, NIAAA has developed the NIAAA Alcohol Treatment Navigator℠

• One-of-a kind resource that:

ü Outlines the features of evidence-based AUDtreatment

ü Describes the varied routes to recovery

ü Provides a strategy for locating qualifiedtreatment specialists

• Launched October 3, 2017

Emerging Issues: Brand New – NIAAA Treatment Navigator

AlcoholTreatment.niaaa.nih.gov

• As the diversity of the US population increases, so should the participation of under-represented groups in NIAAA-sponsored clinical research.

• The availability of research measures in non-English languages is one way to help enhance participation by underserved populations.

• NIAAA has launched an effort to create a database of alcohol measures in Spanish and Asian languages to:

• Increase minority research participation

• Encourage investigators to include underserved populations

• Lower overall costs to engage linguistic minorities in clinical research

Emerging Issues: Increasing Participation of Under-Represented Minorities in Clinical Trials

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1. Identify mechanisms of alcohol action, pathology, and recovery

2. Improve diagnosis and tracking3. Develop & improve prevention

strategies4. Develop & improve treatments5. Enhance public health impact of

NIAAA research

https://www.niaaa.nih.gov/about-niaaa/our-work/strategic-plan

NIAAA Strategic Plan: 2017-2021

NIAAAYour source for credible,

evidence-based information about alcohol

and health.

www.niaaa.nih.gov

what science can teach us about the prevention, diagnosis ...€¦ · reward monoamines da, 5-ht,...

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