Every five years or so, we do an update on PTSD treatments; the most recent was our August 2011 issue of TCPR, in which we declared that psychotherapy was the gold standard for treatment. Recently, the US Veterans Health Administration (VA) and the Department of Defense made this their official position. In their just-published 2017 treatment guidelines, they recommend that treatment begin with “individual trauma focused psychotherapy” before using medications (https://www.healthquality.va.gov/guidelines/MH/ptsd). They included the following types of therapy in this effective category: prolonged exposure, cognitive processing therapy, and eye movement desensitization and reprocessing (EMDR). Although there have been few head-to-head comparisons of therapy vs medications, the VA concluded that gains from therapy are generally more long-lasting than those from medications, and that when given the choice, patients prefer therapy over medication.

Nonetheless, specialized trauma focused therapy is often not available, and in those cases medications are appropriate. Even when therapy is available, medications can often enable a patient to more easily face the tough work of exposure or other psychotherapies. Symptoms that are most easily addressed by medications include hyperarousal and nightmares.

Medications for PTSD
SSRIs. Sertraline (Zoloft) and paroxetine (Paxil) are still the only drugs that are FDA approved for the treatment of PTSD, although fluoxetine is also effective and is recommended as first-line treatment by the VA practice guidelines. Dose these SSRIs at the same levels you would use for depression.

Other antidepressants. Of all the many other antidepressants, venlafaxine seems to be leading the pack when it comes to evidence for PTSD efficacy. It is the only non-SSRI recommended as a first-line treatment by the VA. While just about all SSRIs, SNRIs, tricyclics, and miscellaneous antidepressants (such as mirtazapine and nefazodone) have some positive evidence, that evidence is not strong, and the VA lists all of these under the category “insufficient evidence to recommend for or against.” This doesn’t prevent you from making reasonable clinical decisions based on your experience or on evidence from smaller trials. For example, since disrupted sleep is a frequent complaint of patients with PTSD and it often does not completely improve with psychotherapy or SSRIs, mirtazapine or a sedating tricyclic such as doxepin (Sinequan) can be helpful, alone or in combination with an SSRI (van Liempt S et al, Internat Clin Psychopharmacol 2006;21(4):193–202).

What about a non-sedating antidepressant to address the dysphoric mood that is often seen in PTSD patients? It may not be of much use. In a placebo-controlled trial, bupropion (Wellbutrin) had no significant effect even as an adjunct for PTSD (Becker ME et al, J Clin Psychopharm 2007;27(2):193–197).

Atypicals. The atypical antipsychotics that have been studied the most as monotherapy in PTSD are risperidone and olanzapine, and a 2014 meta-analysis of 8 randomized controlled trials found that these medications were superior to placebo for most PTSD symptoms. Surprisingly, given the well-known side effects of these agents, the meta-analysis found that patients judged the atypicals just as acceptable as placebo. The doses used in these studies were lower than typical doses used for schizophrenia, so this dosing strategy may limit side effects. While intriguing, it’s not very common for us to use atypicals as monotherapy for PTSD. Adjunctive use, generally adding them to an antidepressant, is the more usual scenario. For this use, the studies are somewhat mixed, although the weight of the evidence is positive.

A review of such studies from 2009 found positive data in some studies for risperidone (Risperdal), quetiapine (Seroquel), and olanzapine (Zyprexa) (Berger W et al, Prog Neuropsychopharmacol Biol Psychiatry 2009;33(2):169–180). They conclude that it is “an effective add-on therapy when patients did not fully benefit from previous treatment with SSRIs.” However, since this review was published, an influential randomized controlled trial found that risperidone augmentation did not outperform placebo on the global measure of PTSD symptoms, although it did benefit patients on the Clinician Administered PTSD Scale (CAPS) subscales for reexperiencing and hyperarousal; there was no benefit for avoidance/numbing (Krystal J et al, JAMA 2011;306(5):493–502).

Interestingly, the latest VA practice guidelines came out very strongly against use of atypicals, on the basis of the relatively weak efficacy evidence and the high potential for dangerous side effects such as metabolic syndrome. We find this guidance somewhat harsh, and perhaps an example of erring on the side of caution. The evidence argues for the modest efficacy of atypicals used either as monotherapy or as adjuncts to antidepressants—especially for symptoms such as flashbacks, anxiety, and insomnia. But try to stick with low dosages and, as always with atypicals, monitor for weight gain, blood sugar, and lipids.

Mood stabilizers. Because hyperarousal can include mood lability, you might think of using a mood stabilizer for these patients. Although results are mixed, in general, mood stabilizers have surprisingly often been shown to be ineffective in PTSD, especially as monotherapy. Among others, a double-blind randomized trial of divalproex (Depakote) as monotherapy in combat veterans showed no difference from placebo (Davis L et al, J Clin Psychopharm 2008;28(1):84–88).

Benzodiazepines. Benzodiazepines are probably the most commonly prescribed unproven drugs for PTSD. Although there is surprisingly little direct research on this topic, one small prospective study found no improvement on multiple PTSD scales compared to the placebo group after 1 or 6 months of treatment (Gelpin E et al, J Clin Psychiatry 1996;57(9):390–394). In addition to the poor evidence base, benzos seem tailor-made for abuse in this population, since there is significant comorbidity of substance use disorders in people with PTSD—up to 40% and even perhaps as high as 75% for combat veterans with PTSD (Jacobsen LK et al, Am J Psychiatry 2001;158(8):1184–1190).

Another potential disadvantage of benzos is that they might contribute to the emotional numbing of PTSD and prevent integration of the traumatic event. While there is not much actual clinical evidence of this, benzodiazepines given after a stressor in animal models are found to inhibit normal HPA-axis response to stress and even increase vulnerability to future stressors (Matar MA et al, European Neuropsychopharm 2009;19(4):283–295).

However, with these caveats, we often still find benzos useful when prescribed at low doses for insomnia. Just be careful of dosage creep; many PTSD patients seem to end up on a TID dosing of clonazepam, which can be very hard to taper.

Prazosin: Did its bubble burst?
TCPR has traditionally been quite bullish on prazosin (Minipress), the alpha-1 antagonist, for PTSD-associated nightmares—and for good reason. Four studies have been published, and all have shown prazosin’s efficacy. However, the latest VA guidelines have a tepid statement that there’s not enough evidence to definitively rule for or against prazosin. Why? Because there is a very large well-designed yet unpublished study in which 326 veterans were randomly assigned to prazosin vs placebo, and prazosin did not beat placebo on any PTSD symptom measures, including nightmares. The size of this study dwarfed all four published studies combined—326 subjects vs 167 subjects. But the catch is that these results have not yet been published, and are available only online at clinicaltrials.gov

(https://clinicaltrials.gov/ct2/show/results/NCT00532493?sect=X70156#outcome1). From our perspective, we don’t really trust study results until they have survived the rigorous peer review process for journal publication, so at this point we are standing by our drug. Dose it initially at 1 mg at bedtime and increase gradually, watching for orthostasis.

While on the subject of nightmares and insomnia, a thorough (if dated) meta-analysis of drug treatment for sleep disruption in PTSD found an astounding number of medications that have been effective in studies ranging from case reports to clinical trials, including buspirone, gabapentin (Neurontin), topiramate (Topamax), imipramine (Tofranil), phenelzine (Nardil), mirtazapine (Remeron), prazosin, clonidine, and multiple atypical antipsychotics (van Liempt S et al, op. cit.).

In our experience, topiramate (25 mg–100 mg at bedtime), clonidine (0.1 mg–0.2 mg at bedtime), and quetiapine (as low as 25 mg at bedtime) are particularly helpful for nightmares. Warn patients of orthostasis when getting up in the morning, especially with clonidine or quetiapine.

Other potentially effective medications
Much of the pharmacologic treatment of PTSD involves addressing particular symptoms. For hypervigilance and activation symptoms, try a beta blocker such as propranolol (Inderal) or an alpha-2-agonist such as clonidine (Catapres)—these can be quite helpful and do not carry the stigma that patients new to psychiatric treatment can associate with classic psychiatric meds. A good starting dose of propranolol is 10 mg, taken 3 or 4 times daily. While you do not need to monitor heart rate or blood pressure in the typical patient, check for interaction with other cardiac meds.

Drugs in the pipeline
D-cycloserine (Seromycin). This drug, which is an antibiotic developed for the treatment of tuberculosis, showed some promise in some earlier trials. Since it demonstrated some efficacy when used for treatment of social phobia and acrophobia, the theory was that the drug could enhance the effectiveness of exposure therapy for PTSD. Unfortunately, definitive double-blind studies have now been done, and the results are negative for d-cycloserine. For example, in one study 156 Iraq and Afghanistan veterans with PTSD were randomly assigned to virtual reality exposure therapy with either D-cycloserine or placebo. There was no advantage of D-cycloserine over placebo (Rothbaum BO et al, Am J Psychiatry 2014;171(6):640–648).

Beta blockers after trauma. After the World Trade Center bombing, there was a lot of interest in immediate pharmacologic interventions that could be done in the emergency room after a traumatic exposure, with the idea that such interventions could lessen development of acute stress and then PTSD later. With the aim of decreasing initial activation, propranolol was one of the more common interventions, with the idea that it might block the consolidation of stress-related memories after a trauma. After some promising early results from non-randomized trials, however, placebo-controlled trials have not endorsed propranolol’s value.

Steroids after trauma. A couple of studies have shown that giving patients hydrocortisone immediately after a trauma may reduce the risk of PTSD symptoms. One trial involved a single intravenous high dose of hydrocortisone within 6 hours of the event, while the other study used a 10-day course of low-dose oral hydrocortisone (20 mg twice daily). Both studies were double-blind randomized trials, and cortisone was more effective than placebo in both cases (see Howlett JR and Stein MB, Neuropsychopharmacology 2016;41(1):357–369 for a review of these and other strategies used to prevent PTSD). The theory behind using cortisol is based on data showing that people who produce low levels of cortisol after a trauma are more likely to suffer PTSD; thus, adding exogenous cortisol might prevent this.

Interestingly, steroids have also been implemented to enhance extinction learning during exposure therapy, similar to D-cycloserine, with positive results. Veterans with PTSD underwent a single session of exposure therapy after being given either glucocorticoid or placebo, and a week later the subjects who received the glucocorticoid had a reduction in symptoms. This was transient, however, and the effect was gone by the 1-month assessment (Suris A et al, Ann Clin Psychiatry 2010;22(4):274–279).

MDMA. MDMA (street name “ecstasy”) is a Schedule I drug, often used as a “club drug,” that induces relaxation and a sense of well-being. This could help patients tolerate and benefit from exposure therapy. For example, in an open-label trial, 10 of 12 subjects with PTSD who received MDMA and exposure therapy had such a big drop in their CAPS scores that they no longer met criteria for PTSD, compared with 2 of 8 in the placebo group (Mithoefer MC et al, J Psychopharmacol 2011;25(4):439–452). The effects persisted for the 2-month duration of the study. In Phase 2 of that study, the clinical response rate was 100% in 7 subjects from the placebo arm who wanted to try active treatment—6 people who did not respond, and 1 who relapsed after an initial placebo response (Mithoefer MC et al, J Psychopharmacol 2013:27(1):28–39). Recently, the FDA reviewed these data and was so impressed it gave MDMA a “breakthrough designation” for PTSD treatment, paving the way for rapid review of larger clinical trials. As a substantial caveat, MDMA is not a fully benign drug (see Sarkar S & Schmued L, Curr Pharm Biotechnol 2010;11(5):460–499 for a review of its potential neurotoxicity). Of note, the study involved significant training of the therapists who worked with the patients while they were under the influence of MDMA.

Ketamine. Since we’re on the subject of “club drugs gone good,” IV ketamine (“special K”) has promise for PTSD. In one trial, 41 patients were randomly assigned to a single IV infusion of ketamine at 0.5 mg/kg (the typical antidepressant dose) vs an infusion of the benzodiazepine midazolam. 24 hours later, patients assigned to ketamine had significantly more improvement in PTSD symptoms than those who were given midazolam (Feder A et al, JAMA 2014;71(6):681–688). As with all things ketamine-related, we await more studies to learn how long the positive effects will last.

TCPR Verdict: Medications for PTSD? The research base remains pretty thin, but there are plenty of options to try. Psychotherapy is still the bedrock of treatment for most PTSD patients.