Donepezil + Cognitive Training for Alcoholism

Overseen By Gihyun Yoon, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: VA Connecticut Healthcare System

Must not be taking: Opioids, Benzodiazepines

Disqualifiers: Psychotic disorder, Unstable cardiovascular, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 13 weeks

160 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing if a combination of a medication called donepezil and mental training exercises can help people who drink heavily due to alcohol use disorder. The goal is to see if this combination works better.

Will I have to stop taking my current medications?

The trial requires that you do not currently take opioids or benzodiazepines, as these may affect new learning. Other medications are not specifically mentioned, so it's best to discuss your current medications with the study team.

What data supports the effectiveness of the treatment Donepezil + Cognitive Training for Alcoholism?

Research shows that combining donepezil, a drug used for dementia, with cognitive remediation therapy (CRT) significantly improved memory and executive function in older veterans with alcohol-related mild cognitive impairment. This combination was more effective than historical controls, suggesting potential benefits for alcohol use disorder recovery. ^{1 2 3 4 5}

Is the combination of Donepezil and Cognitive Training safe for humans?

Donepezil, also known as Aricept, has been used safely in humans for conditions like Alzheimer's disease, showing beneficial effects without significant adverse effects. Cognitive Remediation Therapy (CRT) has been used in various conditions, including substance use disorders, with reports of good adherence and no major safety concerns. ^{3 4 6 7 8}

How is the treatment of Donepezil combined with Cognitive Remediation Therapy unique for alcoholism?

This treatment is unique because it combines Donepezil, a drug typically used for Alzheimer's disease, with Cognitive Remediation Therapy (CRT) to specifically target neurocognitive deficits in alcohol use disorder, which is not a common approach in existing treatments. ^{3 4 6 7 8}

Research Team

Gihyun Yoon, MD

Principal Investigator

Yale University, VA Connecticut Healthcare System

Eligibility Criteria

This trial is for adults aged 18-80 with alcohol use disorder who can read English at a 6th grade level or higher. Participants must have had heavy drinking days recently and be willing to attend follow-ups and undergo Breathalyzer and urine tests. Exclusions include those with certain mental health conditions, current opioid/benzodiazepine treatment, significant cognitive impairments, sensory issues affecting training, legal/incarceration risks, unstable housing or medical conditions, low IQ estimates, pregnancy/nursing women, or donepezil allergies.

Inclusion Criteria

Last alcohol use and at least one heavy drinking day within the past 30 days

I can fluently speak and read English at a 6th grade level or higher.

Willingness to submit to Urine Toxicology screenings

Exclusion Criteria

Pre-morbid intelligence quotient (IQ) estimate below 70

Unstable cardiovascular disease or unstable medical condition-clinically determined by a physician

Residential plans that would interfere with participation

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive donepezil and cognitive remediation therapy or placebo for 13 weeks

13 weeks

Weekly visits for Time Line Follow Back (TLFB) assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Cognitive Remediation Therapy (CRT)
• Donepezil

Trial Overview The study is testing if donepezil combined with cognitive remediation therapy (CRT) helps reduce heavy drinking in people with alcohol use disorder more effectively than placebo treatments. It's a double-blind trial where participants are randomly assigned to receive either the drug plus CRT, the drug plus placebo CRT, placebo medication plus CRT or both placebos.

Participant Groups

Group I: Placebo medication + Placebo CRT Experimental Treatment 1 Intervention

Subjects in this arm will receive (1) placebo medication and (2) placebo CRT. Subjects will take placebo oral medication in the evening for the first 4 weeks, then placebo oral medication in the evening until week 13.

Group II: Placebo medication + Cognitive remediation therapy (CRT) Experimental Treatment 1 Intervention

Subjects in this arm will receive (1) placebo medication and (2) cognitive remediation therapy (CRT). Subjects will take placebo oral medication in the evening for the first 4 weeks, then placebo oral medication in the evening until week 13.

Group III: Donepezil + Placebo CRT Experimental Treatment 1 Intervention

Subjects in this arm will receive (1) donepezil and (2) placebo CRT. Subjects will take 5 mg/day of oral donepezil in the evening for the first 4 weeks, then 10 mg/day of oral donepezil in the evening until week 13.

Group IV: Donepezil + Cognitive remediation therapy (CRT) Experimental Treatment 1 Intervention

Subjects in this arm will receive (1) donepezil and (2) cognitive remediation therapy (CRT). Subjects will take 5 mg/day of oral donepezil in the evening for the first 4 weeks, then 10 mg/day of oral donepezil in the evening until week 13.

Cognitive Remediation Therapy (CRT) is already approved in United States, European Union for the following indications:

Approved in United States as Cognitive Remediation Therapy for:

• Alcohol Use Disorder
• Schizophrenia
• Attention Deficit Disorders
• Brain Injury
• Mood Disorders

Approved in European Union as Cognitive Remediation Therapy for:

• Schizophrenia
• Attention Deficit Disorders
• Brain Injury
• Mood Disorders

Who Is Running the Clinical Trial?

VA Connecticut Healthcare System

Lead Sponsor

Trials

86

Recruited

8,800+

Yale University

Collaborator

Trials

1,963

Recruited

3,046,000+

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Collaborator

Trials

865

Recruited

1,091,000+

Findings from Research

In a study involving 509 alcohol-dependent patients, those who received Cognitive Bias Modification (CBM) training showed significantly lower relapse rates one year after treatment compared to those who only received standard treatment.

The effectiveness of CBM was linked to changes in alcohol-approach bias, with older patients and those with a strong initial approach bias benefiting the most from the intervention, suggesting that CBM can effectively address maladaptive cognitive processes in alcoholism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approach bias modification in alcohol dependence: do clinical effects replicate and for whom does it work best? Eberl, C., Wiers, RW., Pawelczack, S., et al.[2022]

Cognitive remediation therapy was implemented successfully in a study of 16 abstinent alcohol-dependent patients over 6 months, showing significant improvements in cognitive performance as measured by the Mini-Mental State Examination (MMSE) and the Memory Alteration Test (M@T).

The therapy was well-received by participants, indicating high satisfaction and viability, suggesting that cognitive remediation can be an effective intervention for cognitive impairments in alcohol-dependent patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Remediation therapy in patients with alcohol use disorders and neurocognitive disorders: A Pilot Study. Frías-Torres, C., Moreno-España, J., Ortega, L., et al.[2019]

In an open-label trial involving 11 older male veterans with Alcohol Use Disorder and Mild Cognitive Impairment, the combination of donepezil and Cognitive Remediation Therapy led to significant improvements in neurocognitive functions, particularly in learning, memory, and executive function (p < .0001).

Participants also showed a high rate of clinical recovery, with 90.9% reporting improvement on the Clinical Global Impression scale, compared to 59.5% of historical controls, suggesting that this combined treatment approach may be beneficial for individuals with AUD-MCI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Donepezil and cognitive remediation therapy to augment treatment of alcohol use disorder related mild cognitive impairment (AUD-MCI): An open label pilot study with historical controls. Bell, MD., Pittman, B., Petrakis, I., et al.[2022]

Cognitive remediation therapy (CRT) significantly improved working memory and executive function in outpatient veterans with substance use disorders, compared to standard work therapy alone, based on a pilot study with 48 participants over 6 months.

Both treatment groups showed excellent substance use outcomes, with high rates of abstinence, indicating that while CRT enhanced cognitive functions, it did not significantly change overall substance use recovery rates compared to work therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized controlled trial of cognitive remediation and work therapy in the early phase of substance use disorder recovery for older veterans: Neurocognitive and substance use outcomes. Bell, MD., Laws, HB., Petrakis, IB.[2018]

Cognitive remediation (CR) therapy significantly improved cognitive functioning, particularly in attention and memory, in 41 alcohol-dependent inpatients who received 12 sessions of CR alongside conventional treatment.

Patients who underwent CR also experienced greater improvements in psychological well-being and reduced alcohol craving, suggesting that CR not only enhances cognitive abilities but also positively impacts overall treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cognitive remediation therapy during treatment for alcohol dependence. Rupp, CI., Kemmler, G., Kurz, M., et al.[2022]

A 30-week double-blind study in the US showed that Donepezil (5 or 10 mg) significantly improved cognitive and clinical assessments compared to placebo, indicating its efficacy in treating cognitive decline.

The use of Donepezil in the UK emphasizes the importance of addressing non-cognitive behaviors, which can greatly enhance quality of life, alongside cognitive improvements, without significant adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience with Donepezil (Aricept) in the UK. Wilkinson, D.[2019]

In a 12-week study involving 468 patients with mild to moderately severe Alzheimer disease, donepezil hydrochloride significantly improved cognitive function and clinical outcomes compared to placebo, with notable improvements in ADAS-cog and CIBIC plus scores.

Donepezil was well-tolerated, with a similar incidence of side effects compared to placebo, and did not show the hepatotoxic effects seen with other cholinesterase inhibitors, making it a safe option for treating Alzheimer's symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Rogers, SL., Doody, RS., Mohs, RC., et al.[2022]

In a 24-week study involving 30 adults with Down syndrome and mild to moderate Alzheimer's disease, donepezil was found to be generally safe and well-tolerated, with no life-threatening side effects reported.

While the results showed some potential efficacy, with 50% of donepezil patients improving in dementia scores compared to 31% on placebo, the small sample size limited the statistical significance of these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Down syndrome and Alzheimer's disease--pilot study. Prasher, VP., Huxley, A., Haque, MS.[2019]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Approach bias modification in alcohol dependence: do clinical effects replicate and for whom does it work best? [2022]

2. Spain pubmed.ncbi.nlm.nih.gov

Remediation therapy in patients with alcohol use disorders and neurocognitive disorders: A Pilot Study. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Donepezil and cognitive remediation therapy to augment treatment of alcohol use disorder related mild cognitive impairment (AUD-MCI): An open label pilot study with historical controls. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

A randomized controlled trial of cognitive remediation and work therapy in the early phase of substance use disorder recovery for older veterans: Neurocognitive and substance use outcomes. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Cognitive remediation therapy during treatment for alcohol dependence. [2022]

6. Austria pubmed.ncbi.nlm.nih.gov

Clinical experience with Donepezil (Aricept) in the UK. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. [2022]

8. England pubmed.ncbi.nlm.nih.gov

A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Down syndrome and Alzheimer's disease--pilot study. [2019]