Back to top Open menu arrow
Download Reprints
Sections
METHODS RESULTS DISCUSSION Clinical Points
The Journal of Clinical Psychiatry The Journal of Clinical Psychiatry

The Journal of
Clinical Psychiatry
Access icon

Original Research March 8, 2023

A Double-Blind Randomized Controlled Trial of Doxazosin for Co-Occurring PTSD and Alcohol Use Disorder in Veterans

Sudie E. Back, PhD; Julianne C. Flanagan, PhD; Jim Mintz, PhD; Kathleen T. Brady, MD, PhD; Jennifer Jones, MD; Amber M. Jarnecke, PhD; Jane E. Joseph, PhD; David W. Shirley, PharmD; Robert J. Malcolm, MD; Mark Hamner, MD; Brett T. Litz, PhD; Barbara L. Niles, PhD; Stacey Young-McCaughan, RN, PhD; Terence M. Keane, PhD; Alan L. Peterson, PhD

J Clin Psychiatry 2023;84(2):21m14367

ABSTRACT

Objective: The aim of this study was to determine the efficacy of doxazosin, an α1-adrenergic antagonist, for the treatment of co-occurring posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD).

Methods: This 12-week, double-blind, randomized controlled trial of doxazosin (16 mg/d) was conducted between June 2016 and December 2019 at the Ralph H. Johnson VA Medical Center in Charleston, South Carolina. Participants were military veterans (N = 141) who met DSM-5 criteria for current PTSD and AUD and were randomly assigned to receive doxazosin (n = 70) or placebo (n = 71). Primary outcome measures were the Clinician Administered PTSD Scale (CAPS-5), the PTSD Checklist for DSM-5 (PCL-5), and the Timeline Follow-Back (TLFB).

Results: Findings from the intent-to-treat analyses revealed that participants in both groups demonstrated statistically significant reductions in CAPS-5 and PCL-5 scores (P < .0001), but, contrary to hypotheses, no significant differences were observed between groups. Percent drinking days and percent heavy drinking days also decreased significantly during treatment, but there were no differences between groups (P < .0001). Abstinence during treatment was significantly higher in the doxazosin versus the placebo group (22% vs 7%, P = .017); however, participants in the doxazosin group consumed a greater number of drinks on drinking days (6.15 vs 4.56, P = .0096). A total of 74.5% of the sample completed the treatment phase, and there were no group differences in retention or adverse events.

Conclusions: Doxazosin was safe and tolerable but was not more effective than placebo in reducing PTSD or AUD severity in this dually diagnosed sample. Clinical considerations such as heterogeneity of PTSD and AUD presentation and potential moderators are discussed in the context of future research directions.

Trial Registration: ClinicalTrials.gov Identifier: NCT02500602

Continue Reading...

Did you know members enjoy unlimited free PDF downloads as part of their subscription? Subscribe today for instant access to this article and our entire library in your preferred format. Alternatively, you can purchase the PDF of this article individually.

Subscribe Now

Already a member? Login

Purchase PDF for $40

Members enjoy free PDF downloads on all articles. Join today

  1. Smith NDL, Cottler LB. The epidemiology of post-traumatic stress disorder and alcohol use disorder. Alcohol Res. 2018;39(2):113–120. PubMed
  2. Vujanovic AA, Back SE. Posttraumatic Stress and Substance Use Disorders: A Comprehensive Clinical Handbook. 1st ed. Routledge; 2019.
  3. Khantzian EJ. The self-medication hypothesis of addictive disorders: focus on heroin and cocaine dependence. Am J Psychiatry. 1985;142(11):1259–1264. PubMed CrossRef
  4. Hawn SE, Cusack SE, Amstadter AB. A systematic review of the self-medication hypothesis in the context of posttraumatic stress disorder and comorbid problematic alcohol use. J Trauma Stress. 2020;33(5):699–708. PubMed CrossRef
  5. Kehle SM, Reddy MK, Ferrier-Auerbach AG, et al. Psychiatric diagnoses, comorbidity, and functioning in National Guard troops deployed to Iraq. J Psychiatr Res. 2011;45(1):126–132. PubMed CrossRef
  6. Fulton JJ, Calhoun PS, Wagner HR, et al. The prevalence of posttraumatic stress disorder in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans: a meta-analysis. J Anxiety Disord. 2015;31:98–107. PubMed CrossRef
  7. Petrakis IL, Rosenheck R, Desai R. Substance use comorbidity among veterans with posttraumatic stress disorder and other psychiatric illness. Am J Addict. 2011;20(3):185–189. PubMed CrossRef
  8. Blanco C, Xu Y, Brady K, et al. Comorbidity of posttraumatic stress disorder with alcohol dependence among US adults: results from National Epidemiological Survey on Alcohol and Related Conditions. Drug Alcohol Depend. 2013;132(3):630–638. PubMed CrossRef
  9. Marx BP, Brailey K, Proctor SP, et al. Association of time since deployment, combat intensity, and posttraumatic stress symptoms with neuropsychological outcomes following Iraq war deployment. Arch Gen Psychiatry. 2009;66(9):996–1004. PubMed CrossRef
  10. Monson CM, Taft CT, Fredman SJ. Military-related PTSD and intimate relationships: from description to theory-driven research and intervention development. Clin Psychol Rev. 2009;29(8):707–714. PubMed CrossRef
  11. Ouimette P, Moos RH, Finney JW. PTSD treatment and 5-year remission among patients with substance use and posttraumatic stress disorders. J Consult Clin Psychol. 2003;71(2):410–414. PubMed CrossRef
  12. Pietrzak RH, Goldstein RB, Southwick SM, et al. Prevalence and Axis I comorbidity of full and partial posttraumatic stress disorder in the United States: results from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions. J Anxiety Disord. 2011;25(3):456–465. PubMed CrossRef
  13. Pietrzak RH, Goldstein MB, Malley JC, et al. Subsyndromal posttraumatic stress disorder is associated with health and psychosocial difficulties in veterans of Operations Enduring Freedom and Iraqi Freedom. Depress Anxiety. 2009;26(8):739–744. PubMed CrossRef
  14. Batki SL, Pennington DL, Lasher B, et al. Topiramate treatment of alcohol use disorder in Veterans with PTSD: a randomized controlled pilot trial. Alcohol Clin Exp Res. 2014;38(8):2169–2177. PubMed CrossRef
  15. Brady KT, Sonne S, Anton RF, et al. Sertraline in the treatment of co-occurring alcohol dependence and posttraumatic stress disorder. Alcohol Clin Exp Res. 2005;29(3):395–401. PubMed CrossRef
  16. Foa EB, Yusko DA, McLean CP, et al. Concurrent naltrexone and prolonged exposure therapy for patients with comorbid alcohol dependence and PTSD: a randomized clinical trial. JAMA. 2013;310(5):488–495. PubMed CrossRef
  17. Petrakis IL, Simpson TL. Posttraumatic stress disorder and alcohol use disorder: a critical review of pharmacologic treatments. Alcohol Clin Exp Res. 2017;41(2):226–237. PubMed CrossRef
  18. Sofuoglu M, Rosenheck R, Petrakis I. Pharmacological treatment of comorbid PTSD and substance use disorder: recent progress. Addict Behav. 2014;39(2):428–433. PubMed CrossRef
  19. Haass-Koffler CL, Swift RM, Leggio L. Noradrenergic targets for the treatment of alcohol use disorder. Psychopharmacology (Berl). 2018;235(6):1625–1634. PubMed CrossRef
  20. Kalk NJ, Nutt DJ, Lingford-Hughes AR. The role of central noradrenergic dysregulation in anxiety disorders: evidence from clinical studies. J Psychopharmacol. 2011;25(1):3–16. PubMed CrossRef
  21. Lanteri C, Salomon L, Torrens Y, et al. Drugs of abuse specifically sensitize noradrenergic and serotonergic neurons via a non-dopaminergic mechanism. Neuropsychopharmacology. 2008;33(7):1724–1734. PubMed CrossRef
  22. Sinha R, Fox HC, Hong KA, et al. Enhanced negative emotion and alcohol craving, and altered physiological responses following stress and cue exposure in alcohol dependent individuals. Neuropsychopharmacology. 2009;34(5):1198–1208. PubMed CrossRef
  23. Giustino TF, Maren S. Noradrenergic modulation of fear conditioning and extinction. Front Behav Neurosci. 2018;12:43. PubMed CrossRef
  24. Aston-Jones G, Cohen JD. Adaptive gain and the role of the locus coeruleus-norepinephrine system in optimal performance. J Comp Neurol. 2005;493(1):99–110. PubMed CrossRef
  25. Southwick SM, Bremner JD, Rasmusson A, et al. Role of norepinephrine in the pathophysiology and treatment of posttraumatic stress disorder. Biol Psychiatry. 1999;46(9):1192–1204. PubMed CrossRef
  26. Bremner JD, Innis RB, Ng CK, et al. Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder. Arch Gen Psychiatry. 1997;54(3):246–254. PubMed CrossRef
  27. Erb S, Hitchcott PK, Rajabi H, et al. Alpha-2 adrenergic receptor agonists block stress-induced reinstatement of cocaine seeking. Neuropsychopharmacology. 2000;23(2):138–150. PubMed CrossRef
  28. Verplaetse TL, McKee SA, Petrakis IL. Pharmacotherapy for co-occurring alcohol use disorder and post-traumatic stress disorder: Targeting the opioidergic, noradrenergic, serotonergic, and gabaergic/glutamatergic systems. Alcohol Res. 2018;39(2):193–205. PubMed
  29. Burnette EM, Nieto SJ, Grodin EN, et al. Novel agents for the pharmacological treatment of alcohol use disorder. Drugs. 2022;82(3):251–274. PubMed CrossRef
  30. Germain A, Richardson R, Moul DE, et al. Placebo-controlled comparison of prazosin and cognitive-behavioral treatments for sleep disturbances in US Military Veterans. J Psychosom Res. 2012;72(2):89–96. PubMed CrossRef
  31. Raskind MA, Peskind ER, Hoff DJ, et al. A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder. Biol Psychiatry. 2007;61(8):928–934. PubMed CrossRef
  32. Raskind MA, Peskind ER, Kanter ED, et al. Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo-controlled study. Am J Psychiatry. 2003;160(2):371–373. PubMed CrossRef
  33. Singh B, Hughes AJ, Mehta G, et al. Efficacy of prazosin in posttraumatic stress disorder: a systematic review and meta-analysis. Prim Care Companion CNS Disord. 2016;18(4)PCC.16r01943. PubMed CrossRef
  34. Fox HC, Anderson GM, Tuit K, et al. Prazosin effects on stress- and cue-induced craving and stress response in alcohol-dependent individuals: preliminary findings. Alcohol Clin Exp Res. 2012;36(2):351–360. PubMed CrossRef
  35. Simpson TL, Malte CA, Dietel B, et al. A pilot trial of prazosin, an alpha-1 adrenergic antagonist, for comorbid alcohol dependence and posttraumatic stress disorder. Alcohol Clin Exp Res. 2015;39(5):808–817. PubMed CrossRef
  36. Simpson TL, Saxon AJ, Meredith CW, et al. A pilot trial of the alpha-1 adrenergic antagonist, prazosin, for alcohol dependence. Alcohol Clin Exp Res. 2009;33(2):255–263. PubMed CrossRef
  37. Petrakis IL, Desai N, Gueorguieva R, et al. Prazosin for Veterans with posttraumatic stress disorder and comorbid alcohol dependence: a clinical trial. Alcohol Clin Exp Res. 2016;40(1):178–186. PubMed CrossRef
  38. Raskind MA, Peskind ER, Chow B, et al. Trial of prazosin for post-traumatic stress disorder in Military Veterans. N Engl J Med. 2018;378(6):507–517. PubMed
  39. Haass-Koffler CL, Goodyear K, Zywiak WH, et al. Higher pretreatment blood pressure is associated with greater alcohol drinking reduction in alcohol-dependent individuals treated with doxazosin. Drug Alcohol Depend. 2017;177:23–28. PubMed CrossRef
  40. Sinha R, Wemm S, Fogelman N, et al. Moderation of prazosin’s efficacy by alcohol withdrawal symptoms. Am J Psychiatry. 2021;178(5):447–458. PubMed CrossRef
  41. Simpson TL, Saxon AJ, Stappenbeck C, et al. Double-blind randomized clinical trial of prazosin for alcohol use disorder. Am J Psychiatry. 2018;175(12):1216–1224. PubMed CrossRef
  42. Kenna GA, Haass-Koffler CL, Zywiak WH, et al. Role of the α1 blocker doxazosin in alcoholism: a proof-of-concept randomized controlled trial. Addict Biol. 2016;21(4):904–914. PubMed CrossRef
  43. Weiss RD. Adherence to pharmacotherapy in patients with alcohol and opioid dependence. Addiction. 2004;99(11):1382–1392. PubMed CrossRef
  44. Fulton B, Wagstaff AJ, Sorkin EM. Doxazosin: an update of its clinical pharmacology and therapeutic applications in hypertension and benign prostatic hyperplasia. Drugs. 1995;49(2):295–320. PubMed CrossRef
  45. Kirby RS, Chapple CR, Sethia K, et al. Morning vs evening dosing with doxazosin in benign prostatic hyperplasia: efficacy and safety. Prostate Cancer Prostatic Dis. 1998;1(3):163–171. PubMed CrossRef
  46. O’Neil ML, Beckwith LE, Kincaid CL, et al. The α1-adrenergic receptor antagonist, doxazosin, reduces alcohol drinking in alcohol-preferring (P) Rats. Alcohol Clin Exp Res. 2013;37(2):202–212. PubMed CrossRef
  47. Lopez MF, Reasons SE, Carper BA, et al. Evaluation of the effect of doxasozin and zonisamide on voluntary ethanol intake in mice that experienced chronic intermittent ethanol exposure and stress. Alcohol. 2020;89:37–42. PubMed CrossRef
  48. De Jong J, Wauben P, Huijbrechts I, et al. Doxazosin treatment for posttraumatic stress disorder. J Clin Psychopharmacol. 2010;30(1):84–85. PubMed CrossRef
  49. Rodgman C, Verrico CD, Holst M, et al. Doxazosin XL reduces symptoms of posttraumatic stress disorder in veterans with PTSD: a pilot clinical trial. J Clin Psychiatry. 2016;77(5):e561–e565. PubMed CrossRef
  50. Richards A, Inslicht S, Ruoff LM, et al. An open-label study of doxazosin extended-release for ptsd: Findings and recommendations for future research on doxazosin. Focus Am Psychiatr Publ. 2018;16(1):67–73. PubMed CrossRef
  51. Weathers FW, Blake DD, Schnurr PP, et al. The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5). Instrument available from the National Center for PTSD at www.ptsd.va.gov; 2013. Accessed December 21, 2021.
  52. Weathers FW, Litz B, Keane TM, et al. The PTSD Checklist for DSM-5 (PCL-5). The National Center for PTSD. PTSD.VA.gov website. www.ptsd.va.gov; 2013. Accessed December 21, 2021.
  53. Sobell LC, Sobell MB. Timeline follow-back: a technique for assessing self-reported alcohol consumption. In: Measuring Alcohol Consumption: Psychosocial and Biochemical Methods. Totowa, NJ: Humana Press; 1992:41–72.
  54. Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59(suppl 20):22–33, quiz 34–57. PubMed
  55. Sullivan JT, Sykora K, Schneiderman J, et al. Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict. 1989;84(11):1353–1357. PubMed CrossRef
  56. Peterson AL, Young-McCaughan S, Roache JD, et al; STRONG STAR Consortium and the Consortium to Alleviate PTSD. STRONG STAR and the Consortium to Alleviate PTSD: shaping the future of combat PTSD and related conditions in military and veteran populations. Contemp Clin Trials. 2021;110:106583. PubMed CrossRef
  57. Back SE, Flanagan JC, Jones JL, et al; Consortium to Alleviate PTSD. Doxazosin for the treatment of co-occurring PTSD and alcohol use disorder: Design and methodology of a randomized controlled trial in military veterans. Contemp Clin Trials. 2018;73:8–15. PubMed CrossRef
  58. Babor TF, Robaina K. The Alcohol Use Disorders Identification Test (AUDIT): a review of graded severity algorithms and national adaptations. Int J Alcohol Drug Res. 2016;5(2):17–24. CrossRef
  59. Ben Barnes J, Presseau C, Jordan AH, et al. The Consortium to Alleviate PTSD. Common data elements in the assessment of military-related PTSD research applied in the Consortium to Alleviate PTSD. Mil Med. 2019;184(5-6):e218–e226. PubMed CrossRef
  60. Herron AJ, Mariani JJ, Pavlicova M, et al. Assessment of riboflavin as a tracer substance: comparison of a qualitative to a quantitative method of riboflavin measurement. Drug Alcohol Depend. 2013;128(1-2):77–82. PubMed CrossRef
  61. Habukawa M, Uchimura N, Maeda M, et al. Differences in rapid eye movement (REM) sleep abnormalities between posttraumatic stress disorder (PTSD) and major depressive disorder patients: REM interruption correlated with nightmare complaints in PTSD. Sleep Med. 2018;43:34–39. PubMed CrossRef
  62. Reist C, Streja E, Tang CC, et al. Prazosin for treatment of post-traumatic stress disorder: a systematic review and meta-analysis. CNS Spectr. 2021;26(4):338–344. PubMed CrossRef
  63. Hendrickson RC, Millard SP, Pagulayan KF, et al. The relative effects of prazosin on individual PTSD symptoms: evidence for pathophysiologically-related clustering. Chronic Stress (Thousand Oaks). 2021;5:2470547020979780. PubMed CrossRef
  64. Hoskins MD, Bridges J, Sinnerton R, et al. Pharmacological therapy for post-traumatic stress disorder: a systematic review and meta-analysis of monotherapy, augmentation and head-to-head approaches. Eur J Psychotraumatol. 2021;12(1):jcm1802920. PubMed CrossRef
  65. Martin A, Naunton M, Kosari S, et al. Treatment guidelines for PTSD: a systematic review. J Clin Med. 2021;10(18):4175. PubMed CrossRef
  66. Zhang Y, Ren R, Sanford LD, et al. The effects of prazosin on sleep disturbances in post-traumatic stress disorder: a systematic review and meta-analysis. Sleep Med. 2020;67:225–231. PubMed CrossRef
  67. Coventry PA, Meader N, Melton H, et al. Psychological and pharmacological interventions for posttraumatic stress disorder and comorbid mental health problems following complex traumatic events: systematic review and component network meta-analysis. PLoS Med. 2020;17(8):e1003262. PubMed CrossRef
  68. Raskind MA, Millard SP, Petrie EC, et al. Higher pretreatment blood pressure is associated with greater posttraumatic stress disorder symptom reduction in soldiers treated with prazosin. Biol Psychiatry. 2016;80(10):736–742. PubMed CrossRef
  69. Wilson SM, Krenek M, Dennis PA, et al. Daily associations between PTSD, drinking, and self-appraised alcohol-related problems. Psychol Addict Behav. 2017;31(1):27–35. PubMed CrossRef
  70. Simpson TL, Stappenbeck CA, Luterek JA, et al. Drinking motives moderate daily relationships between PTSD symptoms and alcohol use. J Abnorm Psychol. 2014;123(1):237–247. PubMed CrossRef
  71. Cohen J. Statistical Power for the Behavioral Sciences. 2nd ed. Hillsdale, NJ: Lawrence Erlbaum; 1988.
  72. Cramer H. The two-dimensional case. In: Mathematical Methods of Statistics. Princeton University Press; 1946.
Purchase PDF for $40

Members enjoy free PDF downloads on all articles. Join today

Save Save

Share Share

Cite Cite

Vol 85 • 2024 • Number 3

Read the Current Issue

Editorial

Focus on Women’s Mental Health: Twenty Years and Counting

Original Research

Esmethadone in Patients With Major Depressive Disorder and Inadequate Response to Standard Antidepressants

Commentary

Can Our Collective Experiences As Clinicians Improve Mental Health Care?

Original Research

Prescription Opioid Use Disorder in US Adults Reporting Prescription Opioid Use

Original Research

Symptomatic Disorders Comorbid with Borderline Personality Disorder Over Time

Original Research

Aripiprazole Lauroxil Initiation Regimens
View current Issue

Celebrating
85 Years

Read the Journal of Clinical Psychiatry

Subscribe to read
more articles

Subscribe