A new medication is knocking on the door for FDA approval in PTSD, and it isn’t MDMA. We cover that, and 8 other off label medications.

Publication Date: 09/23/2024

Duration:  27 minutes, 18 seconds

CHRIS AIKEN: A new medication is knocking on the door for FDA approval in PTSD, and it isn’t MDMA.

Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. Last week, we looked at first line medications for PTSD, but before we venture too far off label let’s recap.

1. Medications take second place to therapy in PTSD, as therapy has a bigger short and long-term effects.

2. When it comes to medications, some experts recommend SSRIs first line, while others recommend a personalized approach, favoring prazosin first-line if insomnia, nightmares, and nocturnal hyperarousal are prominent, and SSRIs first line for others.

3. The debate doesn’t end there. When choosing an SSRI, some recommend the FDA approved options – sertraline and paroxetine – while others argue that fluoxetine has a better risk/benefit profile, with better efficacy data that sertraline and better tolerability than paroxetine.

There’s a reason the experts can’t agree – the data just isn’t clear in either direction. Today we’re going to look at what to do when those first line options fail, and the data is even less clear down these paths.

Here’s a rule of thumb. Collaborative care is a spectrum. The clearer the data, and the bigger the risks, the less collaborative you should be. There’s no ambiguity about whether clozaspine causes neutropenia, or lamotrigine causes Stevens-Johnson syndrome, and these are big risks, so there’s zero collaboration on whether to stop those meds when the patient comes in with a rash or a low blood count. But should you use topiramate for PTSD? For that kind of decision, collaboration ought to be high. I’ll talk to the patient about the meaning of off label use, the promising but uncertain studies, and the risks so they can decide with me. 

Let’s start with topiramate. In 2020 we published an article in Carlat that recommended it for treatment resistant PTSD, and we have an update that takes it down a notch. At the time, topiramate rose to the top with an effect size of 0.6 in a network metaanalysis that compared effect sizes for 26 medications across 58 studies. That sounds impressive, but there’s a catch – the certainty of this finding is very low because it is based on just 2 small trials with a total of 73 patients. There is other data supporting topiramate – and here the story gets more interesting. At least five trials were left out of that analysis: one was unpublished, one came out after the metaanalysis, and three were excluded because they involved unique populations – but populations that we often see in practice: Treatment resistant PTSD and PTSD with alcoholism. So altogether topiramate has 5 small randomized trials, totaling over 300 patients – many involving military trauma and some that ventured into areas where most other treatments fail. The glass is half full and half empty on this one – half the studies were positive and half were negative. When it did work, topiramate was most helpful for the “reexperiencing” symptoms—flashbacks, intrusive memories, and nightmares, with less benefit for avoidance and numbing.

We’re not exactly changing our recommendation on topiramate, but the newly published negative trial and the discovery of the unpublished trial – also negative from 2016 – dampen our enthusiasm. Looking through the trials, many failed because of high drop out rates, which means tolerability may be the elephant in the room. In those failed trials, if we just look at the patients who stayed on the topiramate, the results are positive. In my experience topiramate is hit or miss – it is either very well tolerated or not at all – and the reasons are many – cognitive, dizziness, visual changes, paresthesias, fatigue, and all kinds of psychiatric changes – topiramate for example can cause or treat depression and it can cause or treat psychosis. This drug is a wild card, so I would only use it when nothing else has worked in PTSD, or if alcohol use was part of the picture; in those trials topiramate lowered alcohol use by 55% compared to placebo. Topiramate does reduce drinking – both in PTSD and non-PTSD populations. Besides alcohol, topiramate improves other comorbidities that might go along with PTSD – migraines, obesity, borderline personality disorder, cocaine use, and impulse control disorders (Nourredine M et al, CNS Drugs 2021;35(2):177–213; Varghese BS et al, Indian J Pharmacol 2010;42(3):135–141).

Another off label option is to augment an antidepressant with an antipsychotic, much as we do in depression. This is a popular strategy and it works, but it’s questionable whether this is the right thing to do for patients who haven’t tried the standard treatment – psychotherapy – given the risks of antipsychotics. When it comes to choosing an antipsychotic, the experts agree – risperidone has the best evidence, but things are about to change. We’ll get to that after this pause for a preview of the CME quiz for this podcast.

1. Which supplements are effective in PTSD?

A. Omega-3 fatty acids

B. St. John’s Wort

C. SAM-e

D. No supplements are known to work in PTSD

On June 11, 2024, the FDA accepted a new drug application for brexpiprazole (Rexulti) in combination with sertraline in adult PTSD. The manufacturers - Otsuka and Lundbeck pharmaceuticals – submitted 3 large randomized controlled trials, two of which were positive. The dose was 1-3 mg per day, and it was added to sertraline in patients who did not recover on the antidepressant. We haven’t seen the trials, but the FDA usually approves meds that passed in 2 trials, so this may change the game. Brexpiprazole improved re-experiencing, avoidance, negative cognition, depression, hyperarousal, and reactivity. You’ll notice sleep is missing from that list. A lot of people add a sedating antipsychotic like quetiapine to improve sleep in PTSD, but I’d caution against that. In the words of a new analysis of meds for insomnia in PTSD: “Risperidone and Quetiapine carry a high risk of causing somnolence without having a clear therapeutic benefit.” In other words, it's meaningful sleep benefit we are after – sleep quality – not just sedation. For insomnia in PTSD, the recent review in American Journal of Psychiatry recommends trazodone over benzos and z-hypnotics, and sees promise in the orexin antagonists like suvorexant. 

I agree – these orexin antagonists look safer than other hypnotics and in some studies show they improve sleep quality and next-day cognition – a feat that has evaded the benzos and z-hypnotics. But I was disappointed by the only randomized controlled trial in PTSD, a small one from 2022 which was negative, perhaps because of a high placebo response but negative none-the-less.

Benzos are controversial in PTSD. The American Journal concludes, “Evidence for the effectiveness of benzodiazepines is lacking, despite their continued use in clinical practice.” In fact, there is evidence that taking a benzodiazepine shortly after a trauma increases the risk of PTSD, and some therapists will advise your patient to stop their benzos out of concern that taking a benzo dampens the benefits of psychotherapy by interfering with exposure based learning.

Technically, they have a point, although the studies on this are mixed and the positive ones look at patients who started a benzo while starting psychotherapy – not people who were on them long term. My opinion – which is just an opinion as we don’t have definitive evidence here – is that we should not start a benzo while starting psychotherapy for PTSD, but if they have been on them long term it is probably not a good idea to attempt a taper. Coming off a benzo is likely to interfere with cognitive processing as much as starting one. I’ll also remind psychotherapists not to take an all-or-nothing approach. Even if benzos interfere with learning, it isn’t 100%. Alcohol and sleep deprivation also interfere, and few therapists are screening for sleep apnea or requiring the patient to abstain from red wine before starting exposure therapy. 

When patients don’t respond to standard antidepressants, tricyclics are an option. Some of these worked in combat related PTSD, and the three with the best evidence are imipramine, amitriptyline, and nortriptyline. The usual warnings about drug interactions, toxicity, and cardiac and anticholinergic effects apply here. 

I usually start with nortriptyline which is cleaner and less likely to cause hypotension, but will choose imipramine first if anxiety is the issue as it often is in PTSD. Evidence for MAOIs, however, is limited, so they are best reserved for comorbid treatment resistant depression.

What about Alternative and Complementary Treatments? The American Journal article recommends acupuncture, deep breathing, progressive muscle relaxation, mindfulness meditation, and yoga. I’ll add light therapy to the list – it has a positive randomized controlled trial from a few years back where it treated military PTSD regardless of the season, dose was 1 hour in the morning. I keep a list of effective lightboxes at www.chrisaikenmd/lighttherapy. You may wonder if they authors overlooked supplements in their list of complementary treatments, but no – I know of no natural supplements with positive controlled trials in PTSD.

Wait, Dr. Aiken you have on your shelf an Oxford textbook on Complimentary and Alternative Medicine in PTSD, and it includes a chapter on alternative medicines. Let’s see here, melatonin “may help, has yet to be supported by direct evidence”; omega-3’s – there was a small open label study but was cut short because patients got worse and dropped out; SAMe “may prove ideal” based on its mechanism of action, but no studies here; ok every vitamin and herb they list comes with the caveat that there are zero studies in PTSD. They even list magnesium as having positive studies of PTSD in mice, but go on to clarify that the study was in posttraumatic brain injury, not PTSD. That’s a stretch.

Maybe some of these are the future, or maybe that belongs to Ayahuasca, but what is in the pipeline for PTSD? Cannabis derivatives like CBD oil have pilot studies, and a phase II trial of CBD is underway. Cannabis has some positive pilot data, but some patients worsened with that drug. Cannabis is the full marijuana plant – a mix of nearly 100 cannabinoids – while CBD is just one of those cannabinoids.

MDMA assisted therapy may have failed to gain FDA approval in PTSD, but another medication assisted therapy is on the horizon, with a lot less controversy. Reconsolidation therapy combines written exposure with propranolol. Patients write out a detailed narrative of the trauma, and then take propranolol (dosed by weight at 1 mg/kg) 90 minutes reading it aloud to their therapist. The idea is aptly captured in this quote from the AJP paper: “propranolol decouples intense emotions from the recollection of the trauma and a new memory is formed, which is reconsolidated with a factual narrative but without terror, horror, and helplessness and other negative trauma-related emotions, and which replaces the original terror-fueled narrative.” The therapy is brief, requiring only 4-6 weekly sessions, and it improved PTSD with a large effect size in a double-blind placebo-controlled trial. This is an exciting avenue, dampened though by the fact that propranolol was unsuccessfully explored as a preventative treatment for PTSD, given shortly after a trauma. Its trials there were so mixed that meta-analyses gave it a thumbs down. 

Another way to enhance exposure based therapy is with the d-cycloserine, and old antibiotic that enhances learning at low doses and has glutamatergic, antidepressant effects at high doses. These studies use the low dose, 50-100 mg taken 1 hour before an exposure exercise. D-cycloserine has some positive – but also negative trials to enhance the effects of exposure therapy in OCD and various anxiety disorders including PTSD. D-cycloserine is generic but hard to get unless you find a pharmacist who is more determined than average.

Ketamine has a positive controlled trial in PTSD, and psilocybin and neurofeedback have trials in progress. TMS is reasonable but unlikely to inspire insurance approval – the magnetic treatment improved PTSD in a meta-analysis of 13 trials. 

Two procedures - vagal nerve stimulation, and stellate ganglion block – hope to treat PTSD by modulating the autonomic nervous system. They have promising pilot data but risks as well.

That wraps up our series on PTSD. I hope you enjoyed the journey.

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