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Day # 109: Medications for PTSD

Now that we have covered trauma-focused psychotherapy, we can move on to discuss pharmacological management of PTSD. We will discuss medication options for the core symptoms of PTSD, augmentation strategies, medications to avoid, and treatment of nightmares and insomnia.

Today's Content Level: Intermediate; Advanced


•The Veteran Affairs (VA) and Department of Defense (DoD) collaboratively develops unbiased evidence-based clinical practice guidelines (CPGs) on a number of topics. I have found their CPG for PTSD to be particularly helpful, and it will be heavily referenced in today's post. Other sources include NICE guidelines for PTSD, the Maudsley Prescribing Guidelines in Psychiatry, Pocket Psychiatry, and other articles referenced throughout the text.

•In this post we are discussing pharmacological management of PTSD, but keep in mind that trauma-focused psychotherapy is first-line treatment for PTSD. This is the number one and initial recommendation for treatment. If trauma-focused therapy is not available or not preferred by the patient, then medications or non-trauma focused psychotherapy is recommended. 1


First line options 2, 3, 4

  • Selective Serotonin Reuptake Inhibitors (SSRIs) and Venlafaxine (an SNRI) have the best efficacy and tolerability.

  • SSRIs: the preferred SSRIs in PTSD are sertraline, fluoxetine, or paroxetine. Like anxiety disorders, it typically requires high doses. There is weak evidence to recommend against citalopram. There is insufficient evidence to recommend for or against escitalopram, although it is commonly used.

  • SNRIs: venlafaxine is also considered a first-line option. There is insufficient evidence to recommend for or against duloxetine, however two small open studies suggest efficacy.

Second line options 5, 6

  • Effective options, however second-line primarily due to worse side effect profiles.

  • Tricyclic antidepressants (TCAs): imipramine (recommended by VA/DoD), desipramine, and amitriptyline (recommended by NICE; recommended against by VA/DoD). Start at a low dose and increase according to tolerability.

  • Monoamine oxidase inhibitors (MAOIs): phenelzine (recommended by VA/DoD and NICE). Be cautious due to higher risk of serotonin syndrome and food/drug interactions.

  • Nefazodone: atypical antidepressant (related to trazodone) with evidence in PTSD. Rarely used as it carries a black box warning for rare but serious liver failure.

Third line options 7

  • Mirtazapine: recommended by NICE, particularly if comorbid insomnia. Data is less robust and according to VA/DoD there is currently insufficient evidence to recommend for or against.

  • Consider SSRIs/SNRIs with less robust data to include escitalopram and duloxetine.

Experimental or Mixed evidence 8, 9, 10, 11, 12 15

  • Second Generation Antipsychotics (SGAs): the use of SGAs in PTSD as monotherapy or adjunctive treatment is controversial. There is some evidence that quetiapine, olanzapine, and risperidone are effective for intrusive symptoms (flashbacks and nightmares) but not the avoidance and hyperarousal symptoms of PTSD. However, the VA/DoD guidelines make a weak recommendation against using quetiapine, olanzapine, and other SGAs (except for risperidone which is a "strong against"). This is due to lack of strong evidence for their efficacy and known associated adverse effects.

  • Prazosin: α1-receptor blocker (technically an inverse agonist at α1 adrenergic receptors). Commonly used to treat nightmares and sleep disturbance in PTSD. Sometimes used as augmentation for symptoms of hyper-vigilance. There are a number of studies that have shown reduction in nightmares, however a large 2018 multisite clinical trial sponsored by VA demonstrated no signifiant benefit over placebo. 13 According to the VA/DoD guidelines there is insufficient evidence to recommend for or against its use as monotherapy, augmentation, and nightmares.

  • Lamotrigine: limited data (small double blind study in 15 patients) showed significant improvement in re-experiencing and avoidance/numbing symptoms compared to placebo patients. Larger studies are warranted for primary treatment and augmentation of antidepressants. 14

  • Ketamine: ongoing studies for rapid reduction in symptom severity. Controversial and strongly recommended against in the VA/DoD guidelines.

  • Neither for or against-> escitalopram, duloxetine, desvenlafaxine, fluvoxamine, bupropion, doxepin, mirtazapine, trazodone, hydroxyzine, buspirone, zolpidem, and eszopiclone.

Medications to avoid 16, 17, 18, 19

  • Benzodiazepines: addictive medications, including BDZs, should be avoided in PTSD because of the high rate of comorbid substance use disorders. Also, BDZs have been shown to be ineffective or even potentially harmful in PTSD.

  • Cannabis: VA/DoD recommends against due to lack of evidence for efficacy, known adverse effects, and associated risks. This is controversial, however, as some argue there is limited data to support reduction of PTSD symptoms.

  • Valproate: VA/DoD strongly recommends against valproate in PTSD due to low quality evidence and known adverse effects. A 2007 systematic review and met-analysis (one single-blinded study, four open-label studies and three case reports) showed modest benefit in reducing hyperarousal, improving irritability and anger outbursts, and improving mood.


  • Nightmares: Image rehearsal therapy (IRT) preferred. Prazosin is commonly used, however there is mixed data (see above). Typically initiated at 1mg and gradually increased due to risk of hypotension. Doses of 2-15mg have had positive results. Clonidine can be considered as an alternative with limited data for effectiveness. 20 Hydroxyzine has also been used. 21

  • Insomnia: Cognitive behavioral therapy for insomnia (CBT-i) preferred. Low-dose trazodone may be used. Avoid benzodiazepines. VA/DoD guidelines neither for or against zolpidem and eszopiclone. Suvorexant (orexin antagonist) is promising for trauma-related insomnia and currently being studied at the time of this writing. 22 Other potential medications in development include endocannabinoids including fatty acid amide hydrolase (FAAH) inhibitors, nabilone and cannabidiol, and other novel targets including glutamate, brain-derived neurotrophic factor (BDNF), and the oxytocin receptor. 23

  • Intrusive thoughts: second generation antipsychotics (SGAs) can be used as an adjunct to treat intrusive thoughts with or without psychosis. May consider when symptoms are very severe and exist with disorganized behavior and marked dissociative symptoms. 24 VA/DoD guidelines make a weak recommendation against using quetiapine, olanzapine, and other SGAs (except for risperidone which is a "strong against"). This is due to lack of strong evidence for their efficacy and known associated adverse effects.


  • Psychedelic assisted exposure therapy: this could be an entire post by itself and is an area of significant research interest. MDMA, psilocybin, lysergic acid (LSD), D-cycloserine, ketamine, and cannabinoids are all compounds of interest. The rational behind using psychedelics combined with exposure therapy is that "these drugs can catalyze the psychotherapeutic process, for example, by increasing the capacity for emotional and cognitive processing through pharmacologically diminishing fear and arousal, by strengthening therapeutic alliance through increased trust and rapport, or by targeting processes of fear extinction and memory consolidation." If you are interested this is a great 2020 review article on the subject. 25

  • Prevention: there has been an interest in preventive psychopharmacological interventions administered soon after trauma exposure, based on the findings that arousal and noradrenergic hyperactivity may promote consolidation of trauma memories. Agents that have been studied with some evidence for prevention of symptoms include hydrocortisone (moderate), benzodiazepines (limited), morphine (moderate), and propranolol (limited). There is insufficient evidence to recommend these interventions outside of the research setting. 26, 27

  • Electroconvulsive therapy (ECT): there is some data that demonstrates effectiveness of ECT in PTSD, however current data does not separate conclusively the effects of ECT on PTSD symptoms from those on depression. Further studies are needed to examine the use of ECT in PTSD patients with and without comorbid depression. 28, 29

  • Transcranial magnetic stimulation (TMS): limited but growing evidence for the use of TMS in anxiety disorders and trauma-related disorders. 30 The placement of the electric coils and the stimulation parameters are different than the depression protocols.

  • Stellate ganglion block (SGB): SBG is a procedure that involves injection of local anesthetic in and around the stellate ganglion (located at the base of the neck) to temporarily block its function. The mechanism by which temporary interruption of the cervical sympathetic chain could improve PTSD symptoms is not well understood. Data for effectiveness is mixed, but there are limited studies that show a clinically significant reduction in symptoms. 31


There was a lot of information in this post. I hope this is a helpful guide to medication options in PTSD. Feel free to comment below your experiences in treating PTSD and if you would add anything to the post.

Congratulations. You have now finished the topics in the trauma/stressor disorders theme. Next post will be the last quiz for this section before we move on to dissociative disorders.

Resources used today include the VA/DoD CPG, NICE guidelines, the many articles linked in the body of this post, as well as the following books: Pocket psychiatry and the Maudsley Prescribing Guidelines in Psychiatry.

Bullet Psych is an Amazon Associate and we receive a small commission if you use our links for the purchase of recommended resources.

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