Clinical trial NCT02884908: Pharmacogenetic Treatment With Anti-Glutaminergic Agents for Comorbid PTSD & AUD
Official title: Pharmacogenetic Treatment With Anti-Glutaminergic Agents for Comorbid PTSD & AUD
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: PTSD
Alcohol Use Disorder
Lead sponsor: University of Maryland, Baltimore
Sponsor class: OTHER
Collaborators: name: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
First posted: 2016-08-31
Enrollment: 57
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: 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 sample of African-Americans that includes both genders and individuals with different types of trauma.

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 neurotransmitter 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 the efficacy of pregabalin in reducing both alcohol consumption and PTSD symptoms in 2 treatment groups of medication (pregabalin 450 mg/day and placebo) x 2 genetic variants (NI/I/II vs. NI/NI) in a double- blind, placebo-controlled 14-week clinical trial (screening, 12 weeks of study medication, follow-up call). After a one-week screening period, pregabalin dose (and placebo) will be titrated to the target dose from baseline to week 3 using a double-dummy procedure to ensure equivalence of capsules received. The investigators will utilize a sample of African-American participants with co-occurring AUD and PTSD that includes both genders and individuals with different types of trauma. Participants will receive standardized discussions to enhance compliance with study medication at all visits. The specific aims are:

Specific Aim 1: Independent of race, to test the hypothesis that AUD/PTSD participants treated with pregabalin will demonstrate a greater reduction in heavy drinking than placebo treated participants.

Specific Aim 2: Independent of race, to test the hypothesis that AUD/PTSD participants treated with pregabalin will demonstrate a greater reduction in PTSD cluster B or E symptoms (or both) than placebo-treated participants.

Specific Aim 3: To test the hypothesis that race will moderate the effects of pregabalin examined in Aims 1 and 2.

Specific Aim 4: To test the hypothesis that the treatment responses to pregabalin specified in Aims 1 and 2 are modulated by genetic variations within SLC6A1 gene in AUD/PTSD in both African American and European American populations.

Eligibility criteria: Inclusion Criteria:

1. Males and females of self-reported European or African American ancestry 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

Primary outcomes:
measure: Heavy Drinking Days as Measured by the Time Line Follow Back (TLFB)
timeFrame: 12 weeks
measure: PTSD Cluster B Symptoms as Measured by the PTSD Checklist (PCL)
timeFrame: 12 weeks
measure: PTSD Cluster E Symptoms as Measured by the PCL
timeFrame: 12 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: University of Maryland School of Medicine
state: Maryland
Study officials:
References:
citation: Baldwin DS, Anderson IM, Nutt DJ, Allgulander C, Bandelow B, den Boer JA, Christmas DM, Davies S, Fineberg N, Lidbetter N, Malizia A, McCrone P, Nabarro D, O'Neill C, Scott J, van der Wee N, Wittchen HU. Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol. 2014 May;28(5):403-39. doi: 10.1177/0269881114525674. Epub 2014 Apr 8.
citation: Baniasadi M, Hosseini G, Fayyazi Bordbar MR, Rezaei Ardani A, Mostafavi Toroghi H. Effect of pregabalin augmentation in treatment of patients with combat-related chronic posttraumatic stress disorder: a randomized controlled trial. J Psychiatr Pract. 2014 Nov;20(6):419-27. doi: 10.1097/01.pra.0000456590.12998.41.
citation: Fowler M, Garza TH, Slater TM, Maani CV, McGhee LL. The relationship between gabapentin and pregabalin and posttraumatic stress disorder in burned servicemembers. J Burn Care Res. 2012 Sep-Oct;33(5):612-8. doi: 10.1097/BCR.0b013e31823dc710.
citation: Guglielmo R, Martinotti G, Clerici M, Janiri L. Pregabalin for alcohol dependence: a critical review of the literature. Adv Ther. 2012 Nov;29(11):947-57. doi: 10.1007/s12325-012-0061-5. Epub 2012 Nov 5.
citation: Johannessen Landmark C. Antiepileptic drugs in non-epilepsy disorders: relations between mechanisms of action and clinical efficacy. CNS Drugs. 2008;22(1):27-47. doi: 10.2165/00023210-200822010-00003.
citation: Martinotti G. Pregabalin in clinical psychiatry and addiction: pros and cons. Expert Opin Investig Drugs. 2012 Sep;21(9):1243-5. doi: 10.1517/13543784.2012.703179. Epub 2012 Jun 24.
citation: Martinotti G, Lupi M, Sarchione F, Santacroce R, Salone A, De Berardis D, Serroni N, Cavuto M, Signorelli M, Aguglia E, Valchera A, Iasevoli F, Di Giannantonio M. The potential of pregabalin in neurology, psychiatry and addiction: a qualitative overview. Curr Pharm Des. 2013;19(35):6367-74. doi: 10.2174/13816128113199990425.
citation: Martinotti G, Di Nicola M, Tedeschi D, Andreoli S, Reina D, Pomponi M, Mazza M, Romanelli R, Moroni N, De Filippis R, Di Giannantonio M, Pozzi G, Bria P, Janiri L. Pregabalin versus naltrexone in alcohol dependence: a randomised, double-blind, comparison trial. J Psychopharmacol. 2010 Sep;24(9):1367-74. doi: 10.1177/0269881109102623. Epub 2009 Apr 3.
citation: Mirijello A, Caputo F, Vassallo G, Rolland B, Tarli C, Gasbarrini A, Addolorato G. GABAB Agonists for the Treatment of Alcohol Use Disorder. Curr Pharm Des. 2015;21(23):3367-72. doi: 10.2174/1381612821666150619091858.
citation: Oulis P, Konstantakopoulos G. Efficacy and safety of pregabalin in the treatment of alcohol and benzodiazepine dependence. Expert Opin Investig Drugs. 2012 Jul;21(7):1019-29. doi: 10.1517/13543784.2012.685651. Epub 2012 May 9.
citation: Oulis P, Konstantakopoulos G. Pregabalin in the treatment of alcohol and benzodiazepines dependence. CNS Neurosci Ther. 2010 Spring;16(1):45-50. doi: 10.1111/j.1755-5949.2009.00120.x.
citation: Pae CU, Marks DM, Han C, Masand PS, Patkar AA. Pregabalin augmentation of antidepressants in patients with accident-related posttraumatic stress disorder: an open label pilot study. Int Clin Psychopharmacol. 2009 Jan;24(1):29-33. doi: 10.1097/YIC.0b013e32831feea9.
citation: Shorter D, Hsieh J, Kosten TR. Pharmacologic management of comorbid post-traumatic stress disorder and addictions. Am J Addict. 2015 Dec;24(8):705-12. doi: 10.1111/ajad.12306. Epub 2015 Nov 20.
citation: Strawn JR, Dowling BP, Geracioti TD Jr. Pregabalin treatment of posttraumatic stress disorder. J Clin Psychopharmacol. 2008 Oct;28(5):596-7. doi: 10.1097/JCP.0b013e318184c8f2. No abstract available.
citation: Marks RM, Bennett ME, Williams JBW, DuMez EL, Roche DJO. SIGH, what's in a name? An examination of the factor structure and criterion validity of the (Structured Interview Guide for the) Hamilton Anxiety scale (SIGH-A) in a sample of African American adults with co-occurring trauma experience and heavy alcohol use. Exp Clin Psychopharmacol. 2022 Dec;30(6):841-852. doi: 10.1037/pha0000508. Epub 2021 Jul 22.