The cornerstone of PTSD treatment, according to the 2023 VA/DoD Clinical Practice Guideline (CPG) for PTSD, is specific trauma-focused psychotherapies. However, pharmacotherapy remains a vital option when these therapies are unavailable, not feasible, or when patients express a preference for medication. Furthermore, the high prevalence of psychiatric comorbidities, such as depression, alongside PTSD often necessitates the use of medication. This clinician’s guide provides an overview of medication options for PTSD treatment based on the latest evidence.
Overview of PTSD Medication
Medications for PTSD primarily target neurotransmitters involved in the brain’s fear and anxiety circuitry, including serotonin, norepinephrine, gamma-aminobutyric acid (GABA), glutamate, and dopamine. The strongest evidence supports the use of selective serotonin reuptake inhibitors (SSRIs) such as sertraline (Zoloft) and paroxetine (Paxil), and the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine (Effexor). Currently, sertraline and paroxetine are the only medications FDA-approved for PTSD, making all other uses “off-label.”
Medication Monotherapy for PTSD Treatment
The 2023 VA/DoD Clinical Practice Guideline provides specific recommendations for medication monotherapy based on the quality of evidence.
| Quality ofEvidence* | Recommend For | Suggest For | Suggest Against | Recommend Against | Recommend NeitherFor Nor Against |
|---|---|---|---|---|---|
| High | None | None | None | None | None |
| Moderate | paroxetine^, sertraline^, venlafaxine | None | None | None | None |
| Low | None | prazosin (only for the treatment of PTSD-associated nightmares) | None | None | None |
| Very Low | None | None | divalproex, guanfacine, ketamine, risperidone, tiagabine, vortioxetine, prazosin (for the treatment of PTSD) | benzodiazepines, cannabis (or cannabis derivatives)‡ | amitriptyline±, bupropion±, buspirone, citalopram±, desvenlafaxine, duloxetine, escitalopram, eszopiclone±, fluoxetine, imipramine±, lamotrigine±, mirtazapine±, nefazodone±, olanzapine±, phenelzine±, pregabalin±, quetiapine±, rivastigmine, topiramate |
| No Data | None | None | None | None | ayahuasca‡ , dimethyltryptamine‡ , ibogaine‡ , lysergic acid diethylamide (LSD) ‡ , psilocybin‡ |
| Key: * The Work Group determined there was no high-quality evidence regarding medication monotherapy. ^ FDA approved for PTSD. ± Clinicians should strongly consider potential adverse effects. ‡ Studies of these drugs did not meet the inclusion criteria for the systematic evidence review due to poor quality. |
Selective Serotonin Reuptake Inhibitors (SSRIs) for PTSD
The 2023 VA/DoD CPG highlights sertraline and paroxetine as SSRIs with the most substantial evidence for reducing PTSD symptoms, based on randomized controlled trials using clinician-rated assessments and considering potential harms. Other SSRIs like citalopram (Celexa), escitalopram (Lexapro), and fluoxetine (Prozac) had insufficient evidence to warrant a recommendation for or against their use.
Dosage Ranges:
- Sertraline (Zoloft): 50 mg to 200 mg daily
- Paroxetine (Paxil): 20 to 60 mg daily
Individual patient factors, such as side effect history, comorbidities (e.g., bipolar disorder), and personal preferences, may necessitate exceptions to these guidelines. For instance, in patients with PTSD and bipolar disorder, antidepressants might trigger mood instability. Tailoring medication and dosage to individual needs is crucial, considering factors like tolerability of side effects (e.g., sexual dysfunction, gastrointestinal issues).
The guideline advises against vortioxetine (Trintellix) use. A 2021 randomized, placebo-controlled trial showed no significant difference in CAPS-5 scores after 12 weeks of vortioxetine treatment for PTSD.
Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) for PTSD
Venlafaxine (Effexor) is a strongly recommended treatment for PTSD according to the 2023 VA/DoD CPG, based on data from large multi-site RCTs. At lower doses, it primarily inhibits serotonin reuptake, while higher doses affect both serotonin and norepinephrine.
Target Dosage:
- Venlafaxine (Effexor): 75 mg to 300 mg daily
The guideline found insufficient evidence to recommend for or against desvenlafaxine (Pristiq) and duloxetine (Cymbalta).
Other Antidepressants for PTSD
The 2023 VA/DoD CPG does not recommend for or against other antidepressants with various mechanisms of action, considering their potential harms. This group includes amitriptyline, bupropion, and mirtazapine. Nefazodone, phenelzine (Nardil), and imipramine (Tofranil) are also not recommended for or against, downgrading from a weak recommendation in 2017. Given the high comorbidity of major depressive disorder in PTSD patients, antidepressants beyond the three specifically recommended may be necessary to treat co-occurring depression.
While the 2023 VA/DoD CPG doesn’t address esketamine (Spravato) specifically for PTSD, it recommends against ketamine (of which esketamine is an enantiomer). Clinical trials of ketamine for PTSD have not shown a clear benefit. The lack of efficacy evidence, combined with risks and side effects, led to the recommendation against ketamine. However, ketamine and esketamine may be indicated for treatment-resistant comorbid major depressive disorder (MDD).
Mood Stabilizers for PTSD
The 2023 VA/DoD CPG suggests neither for nor against lamotrigine and topiramate while recommending against divalproex and tiagabine for PTSD. Topiramate showed promising results in RCTs with civilians and Veterans, but findings are mixed. Considering its potential cognitive side effects, a neutral stance is taken. Topiramate may benefit PTSD patients with co-occurring alcohol use disorder by reducing alcohol consumption.
Two negative RCTs for divalproex and one for tiagabine in treating PTSD, coupled with risks and potential side effects, led to the recommendation against their use. A small trial of lamotrigine in 15 individuals with PTSD showed possible benefit, but was insufficient to recommend it. Some of these agents may be warranted for treating comorbid bipolar disorder in PTSD patients.
Atypical Antipsychotics for PTSD
The 2023 VA/DoD CPG recommends against risperidone for PTSD but suggests neither for nor against quetiapine and olanzapine. Early studies suggested atypical antipsychotics were effective adjunctive treatment for PTSD patients with poor SSRI or SNRI response. However, a large-scale multi-site trial of risperidone as an adjunctive agent for SSRI non-responders showed no benefit compared to placebo. Quetiapine and olanzapine have weak evidence of benefit but carry a substantial risk of negative metabolic effects on weight, glycemic control, and lipid abnormalities.
Prazosin for PTSD
The 2023 VA/DoD CPG recommendations for prazosin depend on the outcome:
- Prazosin is suggested for treating nightmares associated with PTSD.
- Prazosin is suggested against for global PTSD symptoms.
Prazosin has been found effective in reducing nightmares in PTSD. However, it has not been associated with improvement in overall PTSD symptoms, leading to the suggestion against its use for general PTSD treatment.
Cannabis and PTSD
The 2023 VA/DoD CPG recommends against using cannabis or cannabis derivatives for PTSD treatment. This recommendation is based on significant harm associated with cannabis use (as cited in the 2017 CPG edition) and a lack of well-designed RCTs evaluating efficacy and side effects in individuals with PTSD.
Other Medications for PTSD
Small studies suggest benefit for adjunctive buspirone in treating PTSD, but no randomized placebo-controlled trials support its use. Beta-blockers have also been suggested as potential adjuncts, but available data do not support their use. The 2023 VA/DoD CPG recommends neither for nor against buspirone and beta-blockers for treating PTSD.
Benzodiazepines and PTSD: A Risky Combination
Studies haven’t shown benefit for benzodiazepines in treating PTSD. Concerns about benzodiazepine use include potential disinhibition, difficulty integrating traumatic experiences, interference with psychotherapy benefits, increased falls and mental clouding in the elderly, addiction, and increased mortality. A study combining Prolonged Exposure (PE) and alprazolam showed the alprazolam group had poorer PTSD symptom reduction compared to PE alone. A recent meta-analysis found benzodiazepines worsen symptom outcomes for PTSD patients. Therefore, benzodiazepine use is recommended against in PTSD treatment.
Booklet highlighting the risks of benzodiazepine use for PTSD patients
Combination and/or Adjunctive Medication for PTSD Treatment
The 2023 VA/DoD CPG recommends neither for nor against using any medication in combination with or as adjuncts to psychotherapy or other medications for PTSD treatment. Unlike in MDD treatment, there is no evidence to support combining recommended pharmacotherapy (sertraline, paroxetine, venlafaxine) with recommended psychotherapy for PTSD. No data support any other medication combination with any other medication for PTSD treatment, including adjunctive atypical antipsychotics with recommended pharmacotherapy.
| Quality of Evidence ± | Recommend For | Suggest For | Suggest Against | Recommend Against | Recommend NeitherFor Nor Against |
|---|---|---|---|---|---|
| High | None | None | None | None | None |
| Moderate | None | None | None | None | None |
| Low | None | None | None | None | 3, 4-methylenedioxymethamphetamine (MDMA) |
| Very Low | None | None | aripiprazole, asenapine, brexpiprazole, cariprazine, iloperidone, lumateperone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone | None | None |
| No Data | None | None | None | None | None |
| Key: * Combination means 2 or more evidence-based treatments for PTSD are combined to improve outcomess. Augmentation means an intervention that has not demonstrated efficacy for PTSD itself is added to evidence-based treatment to enhance its effect. ± The Work Group determined there was no high- or moderate-quality evidence regarding medication augmentation. |
Conclusion
This clinician’s guide provides a summary of medication options for PTSD treatment based on the 2023 VA/DoD Clinical Practice Guideline. For a more in-depth discussion, refer to the full guideline. Individualized treatment planning, considering patient preferences, comorbidities, and potential side effects, remains paramount in effectively managing PTSD.
References
- Department of Veterans Affairs and Department of Defense. (2023). VA/DoD Clinical Practice Guideline for the Management of Posttraumatic Stress Disorder and Acute Stress Disorder. Author. Retrieved from: https://www.healthquality.va.gov/guidelines/MH/ptsd/
- Williams, T., Phillips, N. J., Stein, D. J., & Ipser, J. C. (2022). Pharmacotherapy for post traumatic stress disorder (PTSD). Cochrane Database Systematic Reviews, 3(3):Cd002795. https://doi.org/10.1002/14651858.CD002795.pub3
- Nuñez, N. A., Coombes, B. J., Melhuish Beaupre, L., Romo-Nava, F., Gardea-Resendez, M., Ozerdem, A., Veldic, M., Singh, B., Sanchez Ruiz, J. A., Cuellar-Barboza, A., Leung, J. G., Prieto, M. L., McElroy, S. L., Biernacka, J. M., & Frye, M. A. (2023). Antidepressant-associated treatment emergent mania: A meta-analysis to guide risk modeling pharmacogenomic targets of potential clinical value. Journal of Clinical Psychopharmacology, 43(5), 428-433. https://doi.org/10.1097/JCP.0000000000001747
- Dunlop, B. W., Rakofsky, J. J., Newport, D. J., Mletzko-Crowe, T., Barone, K., Nemeroff, C. B., & Harvey, P. D. (2021). Efficacy of vortioxetine monotherapy for posttraumatic stress disorder: A randomized, placebo-controlled trial. Journal of Clinical Psychopharmacology, 41(2): 172-179. https://doi.org/10.1097/jcp.0000000000001363
- Abdallah, C. G., Roache, J. D., Gueorguieva, R., Averill, L. A., Young-McCaughan, S., Shiroma, P. R., Purohit, P., Brundige, A., Murff, W., Kyung-Heup, A., Sherif, M. A., Baltutis, E. J., … & Krystal, J. H. (2022). Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in Veterans and active duty military: A double-blind, randomized, placebo-controlled multi-center clinical trial. Neuropsychopharmacology, 47(8):1574-1581. https://doi.org/10.1038/s41386-022-01266-9
- Feder, A., Parides, M. K., Murrough, J. W., Perez, A. M., Morgan, J. E., Saxena, S., Kirkwood, K., ann het Rot, M., Lapidus, K. A. B., Wan, L. Iosifescu, D., & Charney, D. S. (2014). Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: A randomized clinical trial. JAMA Psychiatry, 71(6): 681-688. https://doi.org/10.1001/jamapsychiatry.2014.62
- Varma, A., Moore, M. B., Miller, C. W. T., & Himelhoch, S. (2018). Topiramate as monotherapy or adjunctive treatment for posttraumatic stress disorder: A meta-analysis. Journal of Traumatic Stress, 31(1), 125-133. https://doi.org/10.1012/jts.22251
- Davis, L. L., Davidson, J. R., Ward, L. C., Bartolucci, A., Bowden, C. L., & Petty, F. (2008). Divalproex in the treatment of posttraumatic stress disorder: a randomized, double-blind, placebo-controlled trial in a Veteran population. Journal of Clinical Psychopharmacology, 28(1), 84-88. https://doi.org/10.1097/JCP.0b013e318160f83b
- Hamner, M. B., Faldowski, R. A., Robert, S., Ulmer, H. G., Horner, M. D., & Lorberbaum, J. P. (2009). A preliminary controlled trial of divalproex in posttraumatic stress disorder. Annals of Clinical Psychiatry, 21(2), 88-94. http://europepmc.org/article/MED/19439158.
- Davidson, J. R., Brady, K., Mellman, T. A., Stein, M. B., & Pollack, M. H. (2007). The efficacy and tolerability of tiagabine in adult patients with post-traumatic stress disorder. Journal of Clinical Psychopharmacology, 27(1), 85-88. https://doi.org/10.1097/JCP.0b013e31802e5115
- Hertzberg, M. A., Butterfield, M. I., Feldman, M. E., Beckham, J. C., Sutherland, S. M., & Connor, K. M. (1999). A preliminary study of lamotrigine for the treatment of posttraumatic stress disorder. Biological Psychiatry, 45(9), 1226-1229. https://doi.org/10.1016/S0006-3223(99)00011-6
- Pae, C. U., Lim, H. K., Peindl, K., Ajwani, N., Serretti, A., Patkar, A. A., & Lee, C. (2008). The atypical antipsychotics olanzapine and risperidone in the treatment of posttraumatic stress disorder: A meta-analysis of randomized, double-blind, placebo-controlled clinical trials. International Clinical Psychopharmacology, 23(1), 1-8. https://doi.org/10.1097/YIC.0b013e32825ea324
- Krystal, J. H., Rosenheck, R. A., Cramer, J.A., Vessicchio, J. C., Jones, K. M., Vertrees, J. E., Horney, R. A., Huang, G. D., & Stock, C. (2011). Adjunctive risperidone treatment for antidepressant-resistant symptoms of chronic military service-related PTSD. Journal of the American Medical Association, 306(5), 493-502. https://doi.org/10.1001/jama.2011.1080
- Crapanzano, C., Damiani, S., Casolaro, I., & Amendola, C. (2023). Quetiapine treatment for posttraumatic stress disorder: A systematic review of the literature. Clinical Psychopharmacology and Neuroscience, 21(1), 49-56. https://doi.org/10.9758/cpn.2023.21.1.94
- Reist, C., Streja, E., Tang, C. C., Shapiro, B., Mintz, J., & Hollifield, M. (2021). Prazosin for treatment of post-traumatic stress disorder: A systematic review and meta-analysis. CNS Spectrums, 26(4):338-344. https://doi.org/10.1017/s1092852920001121
- Zhang, Y., Ren, R., Sanford, L. D., Yang, L., Ni, Y., Zhou, J., Zhang, J., Wing, Y., Shi, J., Lu, L., & Tang, X. (2020). The effects of prazosin on sleep disturbances in post-traumatic stress disorder: A systematic review and meta-analysis. Sleep Medicine, 67: 225-231. https://doi.org/10.1016/j.sleep.2019.06.010
- Braun, P., Greenberg, D., Dasberg, H., & Lerer, B. (1990). Core symptoms of posttraumatic stress disorder unimproved by alprazolam treatment. Journal of Clinical Psychiatry, 51(6), 236-238.
- Gelpin, E., Bonne, O., Peri, T., Brandes, D., & Shalev, A. Y. (1996). Treatment of recent trauma survivors with benzodiazepines: A prospective study. Journal of Clinical Psychiatry, 57(9), 390-394.
- Rothbaum, B. O., Price, M., Jovanovic, T., Norrholm, S. D., Gerardi, M., Dunlop, B., Davis, M., Bradley, B., Duncan, E. J., Rizzo, A., & Ressler, K. J. (2014). A randomized, double-blind evaluation of D-cycloserine or alprazolam combined with virtual reality exposure therapy for posttraumatic stress disorder in Iraq and Afghanistan War Veterans. American Journal of Psychiatry, 171(6), 640-648. https://doi.org/10.1176/appi.ajp.2014.13121625
- Guina, J., Rossetter, S. R., DeRHODES, B. J., Nahhas, R. W., & Welton, R. S. (2015). Benzodiazepines for PTSD: A systematic review and meta-analysis. Journal of Psychiatric Practice, 21(4), 281-303. https://doi.org/10.1097/PRA.0000000000000091
- Tannenbaum, C., Martin, P., Tamblyn, R., Benedetti, A., & Ahmed, S. (2014). Reduction of inappropriate benzodiazepine prescriptions among older adults through direct patient education: The EMPOWER cluster randomized trial. JAMA Internal Medicine, 174(6), 890-898. https://doi.org/10.1001/jamainternmed.2014.949
