Review of: Davis LL et al, J Clin Psychiatry 2020;81(6):20m13267; Spangler PT et al, J Clin Psychiatry 2020;81(6):20m13233

Type of Studies: Randomized, placebo-controlled trial; randomized controlled trial

Medications for posttraumatic stress disorder (PTSD) don’t have a great track record, particularly in combat-related trauma. Prazosin, risperidone, psychotherapy, and the FDA-approved sertraline have all failed in this population (Raskind MA et al, NEJM 2018;378(6):507–517). These two trials shed light on the struggle to find more effective treatments.

Davis’ team hypothesized that mirtazapine, which has both noradrenergic and serotoninergic effects, would improve PTSD by decreasing sleep problems and, maybe, fear and arousal. Mirtazapine has some evidence of efficacy in PTSD, with support from a few controlled but flawed trials (ie, they lacked randomization and placebo). Spangler’s team looked at riluzole, a glutamatergic modulator, as an augmenter to an SSRI. Riluzole has open-label data in treatment-resistant depression and anxiety, and is related to glutamatergic agents we already use in psychiatry like lamotrigine, ketamine, and N-acetylcysteine.

Both studies were done with American veterans with combat-related PTSD, mostly men; only 3 subjects in the mirtazapine trial had PTSD from other trauma. Other psychiatric and substance diagnoses were excluded from the riluzole trial, but the mirtazapine study allowed comorbid depressive, anxiety, or substance use disorders.

In the riluzole study, 79 subjects already on SSRIs or SNRIs for 8 weeks were randomized to receive riluzole augmentation (mean dose 126 mg/day) or placebo. The mirtazapine study randomized 78 subjects to get the active drug (mean dose 39 mg/day) or placebo for 8 weeks as monotherapy. The primary outcome measure in both was change in PTSD symptoms as measured by the Clinician-Administered PTSD Scale (CAPS) (for riluzole) or the Structured Interview for PTSD (for mirtazapine). Both studies used standard rating scales to track secondary outcomes for depression, anxiety, sleep, disability, and global function.

Both drugs failed on the primary PTSD measures. Among secondary measures, riluzole was only positive on the hyperarousal subscale of the CAPS, and mirtazapine only made a significant difference on global functioning. Surprisingly, mirtazapine did not help sleep and appeared to increase nightmares in some subjects. Both medications were well tolerated. Riluzole’s main side effects were impaired concentration and fatigue, while mirtazapine tended to cause sedation, nightmares, and irritability.

TCPR’s TAKE
We note no significant flaws with these studies, which found no significant benefits for riluzole or mirtazapine in PTSD. It’s worth noting that riluzole was tested in a more treatment-resistant population, and both studies were conducted in combat-related PTSD, a group that tends to be less responsive to medication.