Addiction behavior, depression, and other behavioral barriers to successful

lifestyle intervention

F. Gerard Moeller, M.D.

Division Chair, Addiction Psychiatry

Director, C. Kenneth and Dianne Wright Center for Clinical and Translational Research and Institute for Drug and

Alcohol Studies

Virginia Commonwealth University, Richmond VA, USA

Disclosures

• Grant support from Indivior Pharmaceuticals and NektarTherapeutics

• Consultant for Nektar Therapeutics

• Medications discussed are not approved for Fatty Liver Disease and are not related to industry grant support or consulting listed above

Fatty Liver, Mood, and Opioids

• Survey of over 28 million patients across 21 health care organizations electronic health records across the United States using TriNetX

• 298,796 Patients with an ICD-10 diagnosis of Fatty (change of) Liver not elsewhere classified

298,796 Patients with Fatty Liver

Mean age 55 years54% Female

ICD-10 K76.0 Fatty change of liver, not elsewhere classified Pain and Opioids

58% with Abdominal and pelvic pain diagnosis

72% prescribed Opioid analgesics at some point (Fentanyl, Oxycodone, Hydrocodone, Hydromorphone)

Prior Research has Found Similar High Use of Opioids in Other Liver Disease

ICD-10 K76.0 Fatty change of liver, not elsewhere classified Pain and Opioids

• Risks of Opioids • Addiction

• Overdose

• CNS/GI Side Effects

ICD-10 K76.0 Fatty change of liver, not elsewhere classified Mood Disorders

39% of Patients treated with Antidepressants

35% have a diagnosis of an Anxiety Disorder

34% have a Mood Disorder diagnosis

• Compared with 976,131 patients with congestive heart failure as comparison chronic disease• 32% treated with Antidepressants• 24% with Anxiety Disorder • 25% with a Mood Disorder• 66% treated with Opioids

Fatty Liver and Opioids Prescribing compared to Congestive Heart Failure Opioid Prescribing

Higher Opioid Prescribing for Fatty Liver Across multiple Prescription Opioids

Same Relationship with Mood, Anxiety, and Opioids for NASH

• 73% treated with Opioid Analgesics

• 41% treated with Antidepressants

• 39% Diagnosed with Sleep disorders

• 35% Diagnosed with Mood disorders

• 34% Diagnosed with Anxiety disorders

ICD-10 K75.81 Nonalcoholic steatohepatitis (34,844 patients)

Risk Factors for Opioid Misuse

Depression and anxiety risk factors for opioid misuse

“Among participants with severe depression, rates of opioid misuse were 75.3% among those with severe anxiety and 50% among those with mild or moderate anxiety”

Post-mortem observation of fatty liver in opioid fatalities

• 1Post-mortem CT of cohort (n=55) who died from fatal opioid intoxication (Europe)

• Statistically significant finding of fatty liver in 36% of opioid OD patients vs. 18% in control patients

• 2Post-mortem autopsies from heroin/methadone OD (n=841) (Australia)

• 37% of patients had steatosis, more common in individuals > 44 years

1Winklhofer, S., Surer, E., Ampanozi, G. et al. Eur Radiol (2014) 24:

1276. https://doi.org/10.1007/s00330-014-3128-7

2Darke, Shane, Sharlene Kaye, and Johan Duflou. "Systemic disease

among cases of fatal opioid toxicity." Addiction 101.9 (2006): 1299-1305.

Opioids and Fatty Liver

• Opioid prescribing common in fatty liver in the US

• Opioid use for chronic pain increases risk of addiction/overdose

• High rate of depression/anxiety in fatty liver patients increase this risk

• Are there other factors linking fatty liver and risk for substance misuse?

Eating Disorders and Fatty Liver

• In our EHR analysis only 1% of patients with fatty liver have formal diagnosis of eating disorder

• Fatty liver patients 1.7X more likely to have eating disorder diagnosis than non-fatty liver disease patients

• Possible under-diagnosis of eating disorders?

Binge Eating Disorder and Risk factors for Fatty Liver Disease

Hudson et al., Am J Clin Nutr 2010;91:1568–73

• 5 year follow-up 134 patients with binge-eating disorder and 134 with no history of eating disorders

• Frequency-matched for age, sex, and baseline body mass index (BMI)

Binge Eating as an Impulse Control Disorder

Binge eating and impulsivity are related in clinical studies

“Based on the evidence for impaired inhibitory control in BED, affected patients might profit from interventions that address impulsive behavior…”

Binge Eating and Impulsivity: Preclinical Studies

Rats separated into Hi and LowImpulsive Groups based on PrematureResponses on 1-CSRT

Hi Impulsive Rats Show GreaterBinge High Fat Food Intake

Anastasio et al., Neuropsychopharmacology, 2019

Impulsivity is Closely Linked with Addictions

What is the Underlying Neurobiology of Impulsivity?

Translational brain research on impulsivity

Higher 5-HT2AR and Lower 5-HT2CR Expression in

PFC in Rodents is Related to Impulsivity

5-HT2CR Agonists and Antagonists Effects on Impulsivity

From Cunningham and Anastasio, 2014

5-HT2C Agonist Reduces Binge High Fat Food Intake

WAY163909 preferentially suppresses high fat food (HFF) binge intake over standard food (SF) non-

binge intake. (A) WAY163909 (1.0, 2.0 mg/kg) suppressed HFF binge intake in an intermittent access

binge intake paradigm (n=6). (B) WAY163909 did not alter SF non-binge intake (n=8). *p

5-HT2A antagonist and 5-HT2C Agonist Reduce Binge Eating in Rodents

Additive effect of 5-HT2A antagonist and 5-HT2C agonist on binge eating in rodents

Mood and Impulse Control Problems in Fatty Liver Disease

• High incidence of mood disorders (anxiety and depression) in patients with NAFLD and NASH

• Binge eating also linked to fatty liver disease and impulsivity

• Impulsivity and anxiety disorders are linked to addiction

• High rate of opioid treatment in fatty liver patients

Mood and Impulse Control Problems in Fatty Liver Disease

• Pain, depression, and anxiety factors that should be considered in patients with fatty liver

• Significant risk for addiction and overdose with opioids and fatty liver

• Impulsivity could be therapeutic target for at least some patients with fatty liver

Study Team Co Investigators: Arun Sanyal, MDAlbert Arias, MDLori Keyser-Marcus, PhDBrian Taylor, PhDJames Bjork, PhDLiangsuo Ma, PhDJoel Steinberg, MD

Research Staff:Mandy Adams, M.AAndrea Mendes, M.S.Grace HerrickAysha SamiEddie ZunigaErika LopezGray McDiarmidMaia McDanielsKatie Schifano, M.S.

UT Medical Branch Collaborators:

Noelle Anastasio, PhDKatheryn Cunningham, PhD Funded by NCATS UL1TR002649, NIDA U54DA038999 FGM,

NIDA R00DA033374, NCA, NIDA P50DA033935 KAC

VCU Wright Center for Clinical and Translational Research

Supported by NCATS UL1TR002649