Pharmacogenetic Treatment With Anti-Glutaminergic Agents for Comorbid PTSD & AUD

Purpose

The primary study objective is to determine the efficacy of pregabalin administered orally for a period of 12 weeks in reducing risky drinking and symptoms of posttraumatic stress disorder who have selected genotypes at the gamma-amino butyric acid transporter and receptor genes. The secondary objective is to assess the safety and tolerability of pregabalin in participants with alcohol use disorder and co-occurring posttraumatic stress disorder who have selected genotypes at the gamma-amino butyric acid transporter and receptor genes. The investigators will utilize a large and diverse sample of African-Americans that includes both genders and individuals with different types of trauma. All participants will receive standardized bi-weekly Brief Behavioral Compliance Enhancement Treatment (BBCET).

Conditions

  • PTSD
  • Alcohol Use Disorder

Eligibility

Eligible Ages
Between 18 Years and 65 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  1. African American males and females who have given written informed consent
  2. Age 18 to 65 years and weighing within 30% of their ideal body weight (Metropolitan Life Tables). Also, subjects must weigh at least 40 kg and no more than 155 kg.
  3. Good physical health as determined by a complete physical examination, an EKG within normal limits, and laboratory screening tests within acceptable parameters (see

Exclusion Criteria

)

4. Current Diagnostic and Statistical Manual of Mental Disorders Version 5 (DSM-5) diagnosis of posttraumatic stress disorder (PTSD)

5. Current DSM-5 diagnosis of alcohol use disorder (AUD) of moderate or greater severity (i.e., 4 or more AUD criteria endorsed) in the last 3 months

6. Currently drinking ≥21 alcohol units/week for women and ≥28 alcohol units/week for men in the last 30 days and have met these criteria 7 days prior to randomization.

7. Provide evidence of stable residence in the last month prior to enrollment in the study, and have no plans to move in the next 9 months

8. The pregnancy test for females at intake must be negative. Additionally, women of childbearing potential must be using an acceptable form of contraception. These include: oral contraceptives, hormonal (levonorgestrel) or surgical implants, or barrier plus spermicide.

9. Literate in English and able to read, understand, and complete the rating scales and questionnaires accurately, follow instructions, and make use of the behavioral treatments

10. Express a wish to stop drinking

11. Willing to participate in behavioral treatments for PTSD and AUD

Exclusion Criteria:

1. Any current DSM 5 psychiatric disorder other than PTSD, AUD, or Tobacco Use Disorder that warrants treatment or would preclude safe participation in the protocol

2. Elevation of liver enzymes (SGOT), serum glutamic pyruvic transaminase (SGPT), blood urea nitrogen (BUN), or lactate dehydrogenase (LDH) greater than four times the upper limit of the normal range, or elevated bilirubin

3. Severe alcohol withdrawal symptoms that, in the physician's opinion, require inpatient treatment

4. Serious medical comorbidity requiring medical intervention or close supervision, or any condition that can interfere with the receipt of topiramate

5. Severe or life-threatening adverse reactions to medications in the past or during this clinical trial

6. Female subjects who are pregnant, lactating, or not adhering to an acceptable form of contraception at any time during the study

7. Received inpatient or outpatient treatment for alcohol dependence within the last 30 days

8. Compelled to participate in an alcohol treatment program to maintain their liberty

9. Members of the same household

10. Active tuberculosis

11. Concurrent treatment with any medications having a potential effect on alcohol consumption and related behaviors, or mood. These include: opioid antagonists (e.g., naltrexone), glutamate antagonists (e.g., topiramate or acamprosate), serotonin reuptake inhibitors (e.g., fluoxetine), serotonin antagonists (e.g., ritanserin or buspirone), other antidepressants (e.g., tricyclic antidepressants or monoamine oxidase inhibitors), dopamine antagonists (e.g., haloperidol), calcium channel antagonists (e.g., isradipine), or compounds with actions similar to disulfiram (Antabuse®) or nicotine.

12. Before double-blind randomization, urine positive for opiates, cocaine, amphetamines, barbiturates, benzodiazepines, or prescription or non-prescription drugs

Study Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Factorial Assignment
Primary Purpose
Treatment
Masking
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Pregabalin + BBCET - NI/I/II type
This group will be comprised of subjects with the NI/I/II type who receive study medication (Pregabalin) and Brief Behavioral Compliance Enhancement Treatment (BBCET).
  • Drug: Pregabalin plus BBCET
    Medication; BBCET = Brief Behavioral Compliance Enhancement Treatment
    Other names:
    • Lyrica
Experimental
Pregabalin + BBCET - NI/NI type
This group will be comprised of subjects with the NI/NI type who receive study medication (Pregabalin) and Brief Behavioral Compliance Enhancement Treatment (BBCET).
  • Drug: Pregabalin plus BBCET
    Medication; BBCET = Brief Behavioral Compliance Enhancement Treatment
    Other names:
    • Lyrica
Placebo Comparator
Placebo + BBCET - NI/I/II type
This group will be comprised of subjects with the NI/I/II type who receive placebo and Brief Behavioral Compliance Enhancement Treatment (BBCET).
  • Other: Placebo plus BBCET
    Placebo; BBCET = Brief Behavioral Compliance Enhancement Treatment
Placebo Comparator
Placebo + BBCET - NI/NI type
This group will be comprised of subjects with the NI/NI type who receive placebo and Brief Behavioral Compliance Enhancement Treatment (BBCET).
  • Other: Placebo plus BBCET
    Placebo; BBCET = Brief Behavioral Compliance Enhancement Treatment

Recruiting Locations

University of Maryland School of Medicine
Baltimore, Maryland 21228
Contact:
Brian Brandler, MS
410-402-6425
bbrandler@som.umaryland.edu

More Details

NCT ID
NCT02884908
Status
Recruiting
Sponsor
University of Maryland, Baltimore

Study Contact

Melanie Bennett, PhD
4107060892
mbennett@psych.umaryland.edu

Detailed Description

Nearly 60% of individuals with posttraumatic stress disorder (PTSD) have a comorbid alcohol use disorder (AUD). This comorbidity is associated with more severe PTSD symptoms, higher rates of psychosocial and medical problems, higher relapse rates, and poorer treatment outcome. Pre-clinical studies have indicated that PTSD and AUD share common molecular underpinnings. Particularly, the adaptations in the brain neuro- transmitter systems to chronic excessive drinking that are evident during alcohol withdrawal share similarities with PTSD cluster B and E symptoms (characterized by symptoms of re-experiencing and hyper-arousal), which initiate a cycle of relapse into excessive drinking and worsening of PTSD symptoms. Excessive glutamate and reduced gamma-amino butyric acid (GABA) neurotransmitter concentrations were found in various brain regions in individuals with co-morbid PTSD/AUD. The anticonvulsant pregabalin (with high affinity for the alpha-2-delta auxiliary site of voltage gated calcium channels) that modulates the effects of the GABA transporter (GAT-1) and increases its density of GABA, has shown preliminary efficacy in reducing drinking in AUD with comorbid generalized anxiety disorder, and improves outcomes from PTSD. Large scale studies with ample statistical power in VA settings and community populations, with diverse combat and non-combat related trauma, are now warranted to evaluate the promising preliminary evidence that pregabalin can improve outcomes for those with AUD and PTSD. An important personalized medicine approach to optimize pregabalin efficacy would be to select individuals with AUD and PTSD with genetic variation at the GAT-1 transporter so as to match its potential therapeutic effects with specific types of individual. In African-Americans, variants at the SLC6A1 gene promoter region insertion (i.e., non-insertion/insertion or insertion/insertion (NI/I or I/I) compared with those of Non-insertion/Non-insertion (NI/NI) type have significantly higher levels of GAT-1promoter activity. The investigators will, therefore, segregate our target sample by genetic variation at the GAT-1 transporter. Because of the low allelic frequency of individuals with the double copy insertion, the investigators will combine these into one group with those with the single copy (i.e., NI/I/II).

This study will test pregabalin efficacy in reducing both AUD and PTSD Clusters B or E in 2 treatment groups of medication (pregabalin, placebo) x 2 genetic variants (NI/I/II vs. NI/NI) in a double- blind, placebo-controlled 12-week clinical trial with a set target quit-date (TQD) for drinking. The investigators will utilize a large and diverse sample of African-Americans that includes both genders and individuals with different types of trauma. Pregabalin dose and placebo will be titrated to the maximum dose from baseline to week 6 using a double-dummy procedure to ensure equivalence of capsules received. The TQD will be set at week 6. The split design (post-TQD vs. pre-TQD) will allow the study to separately examine both whether pregabalin's therapeutic effects reduce drinking and prevent relapse post cessation and whether the cessation of drinking results in improved PTSD cluster B or E symptoms in carriers of specific GAT-1 transporter genotypes. All participants will receive standardized bi-weekly Brief Behavioral Compliance Enhancement Treatment (BBCET) and follow-up post treatment and 3 month assessments. The specific aims are as follows:

Specific Aim 1: To test the hypothesis that AUD patients treated with pregabalin and having the non-insertion/insertion or insertion/insertion (NI/I or I/I) variant of the SLC6A1 gene for GABA transporter (GAT-1) will be more predictive of the ability not drink heavily than pregabalin-treated patients with the NI/NI genetic variant and placebo-treated patients.

Specific Aim 2: To test the hypothesis that AUD patients treated with pregabalin and having the non-insertion/insertion or insertion/insertion (NI/I or I/I) variant of the SLC6A1 gene for GABA transporter (GAT-1) will be more efficacious in reducing PTSD cluster B or E symptoms (or both) than pregabalin-treated patients with the NI/NI genetic variant and placebo-treated patients.