PTSD Awareness Month Brings Mixed Bag News for PTSD Treatment

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Just in time for National Posttraumatic Stress Disorder Awareness Day on June 27, the US Food and Drug Administration accepted a supplemental new drug application (sNDA) for brexpiprazole in combination with sertraline for adults with PTSD. The acceptance was based on data from 3 randomized clinical trials (RCTs) evaluating the safety and efficacy; the FDA set a target review date of February 8, 2025.^1,2

The data came from both a fixed and a flexible phase 3 study as well as a flexible phase 2 RCT. Efficacy was determined by changes in the Clinician-Administered PTSD Scale (CAPS-5) total score from randomization to the primary endpoint (weeks 1 and 10, respectively). Both flexible dose studies found the combination of brexpiprazole and sertraline was associated with a statistically significant reduction (p<0.05) in PTSD symptoms via the CAPS-5 when compared with sertraline plus placebo. The primary endpoint was not met in the fixed dose trial, but researchers noted improvements consistent with the other 2 studies, including improvement in reexperiencing, avoidance, negative cognition/mood, and arousal/reactivity symptoms as measured by the CAPS-5.

Additionally, the 3 studies also demonstrated a relatively good safety profile, with the combination well-tolerated by participants. Investigators noted a 55.5% incidence rate of treatment-emergent adverse events in the combination brexpiprazole and sertraline group compared with 56.2% for the placebo plus sertraline group.

“Brexpiprazole in combination with sertraline could represent an important advancement over current standard of care, and we look forward to working with the FDA in the process of seeking approval of this combination,” Johan Luthman, PhD, executive vice president of research and development at Lundbeck, said in a statement to the press.¹

MDMA-Assisted Therapy Hits Setback

The announcement from Otsuka Pharmaceutical, Co. Ltd. and H. Lundbeck A/S about the sNDA was considered good news after June—PTSD Awareness Month—opened with what could have been a landmark decision and the possibility of the first newly approved medication to treat PTSD in 20 years. Yet, amidst cries about clinical trial design issues and other critical public comments, the FDA Psychopharmacologic Drugs Advisory Committee voted overwhelmingly against recommending midomafetamine (MDMA)-assisted therapy.³ The FDA's final decision is expected in August.

Leading up to the decision, Psychiatric Times asked experts to weigh in on their thoughts on MDMA-assisted therapy. Although our experts agreed that more was needed to support patients with PTSD, there was a spectrum of opinions on this approach and whether the time was right for approval.

Fernando Forcen, MD, having attended a 5-day educational event, felt the treatment held promise. “It became clear to me that MDMA-assisted psychotherapy can become a powerful, pleasant, and effective way of helping patients with PTSD,” he told Psychiatric Times. “Psychotherapy played a key role in [patients'] recovery, and the role of the therapists was essential. I cannot conceptualize a safe way of treating patients with MDMA without psychotherapy.”

Meanwhile, editorial board member David N. Osser, MD, said he remained skeptical about psychedelics. “I will not be giving any patients MDMA in the near term,” he told Psychiatric Times. “I do work full time at a VA, where I think it unlikely that it will be adopted any time soon. However, if it is I will educate myself about it and probably use it, but not eagerly. I would want to see patients have an adequate trial of prazosin, our most evidenced medication treatment for PTSD, before considering it.”

Many with whom we spoke fell into a middle ground—they were unsure of the treatment strategy but still intrigued. For instance, Psychiatric Times Editor in Chief John J. Miller, MD, noted that with only 2 drugs currently approved to treat PTSD, there is a huge unmet need in this population. "This is uncharted territory for us in psychiatry and for the FDA,” he added in an interview with Psychiatric Times. “It's an exciting time, and there is a lot of promise moving forward in medication-assisted psychotherapy."

Readers similarly seemed cautiously curious. When polled, 50% of Psychiatric Times readers said that, if approved, they would consider psychedelics for patients as a novel approach. Furthermore, 57% of Psychiatric Times readers said that, if approved, they might recommend MDMA-assisted psychotherapy to patients with PTSD, but first they would like to see it used in everyday practices. On the other hand, 42% said they were against recommending it.

“While we were of course disappointed by the outcome, we were not surprised by the important questions raised,” Amy Emerson, the CEO of Lykos Therapeutics, said in a press statement shortly after the decision. “We are advancing a novel treatment and have worked closely with the FDA over the course of years to address these complex issues. Ultimately, the final decision for the potential approval of midomafetamine rests with the FDA, and we are deeply committed to providing any information needed to enable its thorough review. We have full confidence in the rigor and thoughtfulness that the FDA will give our application.”⁴

Awareness Day Shines Light on Limited Treatment Options, Support for Patients

In another Psychiatric Times poll, almost three-quarters of respondents noted the biggest challenge is the lack of FDA-approved treatments. In fact, one reader commented about the FDA Advisory Committee decision, "I feel this treatment could really help those suffering with PTSD, and I think it's unfortunate this treatment was not [endorsed]." Currently, only sertraline and paroxetine are FDA-approved medications for adults with PTSD. As a result, clinicians often use treatments off-label to support patients, especially when those medications fail to be successful or are not tolerated.

“There are other SSRIs a clinician might prescribe as an off-label treatment, and these decisions often come down to a discussion of the patient’s past response to these medications and the potential for certain side effects. For example, certain SSRIs cause more weight gain, stomach upset, or sexual side effects than others, and that impacts which treatments a patient is willing to try,” Alexa Hall, MD, medical director of NeuroWellness Spa told Psychiatric Times in an interview. “SNRIs can also be used at times. Several studies found venlafaxine to be effective in PTSD treatment.”

“Making sure other psychiatric comorbidities are adequately treated is important to improving the prognosis for any patient with PTSD,” Hall advised colleagues. She added that the specific comorbidities may steer treatment strategy discussions. For instance, she said she considers SSRIs and SNRIs useful if the patient also has an anxiety or depressive disorder. “When a patient has bipolar disorder in addition to PTSD, there is more caution with choosing treatments, since an antidepressant like a SSRI or SNRI can cause more unstable mood. [This] could be addressed proactively by making sure the patient is already on a mood stabilizing medication.”

For patients with sleep-related PTSD symptoms such as nightmares, Hall considers off-label use of prazosin. "Prazosin can often be used in addition to a SSRI or SNRI or by itself,” she added. Hall also considers trauma-focused psychotherapy.

Perhaps equally important is the need for awareness to support research and resources as well as to encourage individuals to seek care. “One of the biggest challenges involved with the treatment of PTSD is time,” Araceli Lozano, PMHNP, clinician at NeuroWellness Spa, told Psychiatric Times in an interview. “Unfortunately, and for a variety of reasons, many people with PTSD do not seek treatment until long after the trauma occurred. And the longer PTSD goes untreated, the poorer the prognosis.”

National PTSD Awareness Day was first recognized on June 27, 2010, after Senator Kent Conrad advocated for PTSD recognition as a tribute to National Guard Staff Sergeant Joe Biel of North Dakota. Biel, who's birthday was June 27, had PTSD after serving in Operation Iraqi Freedom and died of suicide in 2007.⁵ In 2014, the US Senate expanded the awareness to the full month of June.

Would you like to share clinical pearls for treating PTSD? Email article proposals to PTEditor@mmhgroup.com.

References

1. Otsuka and Lundbeck Announce FDA Acceptance of sNDA Filing for Brexpiprazole in Combination With Sertraline for the Treatment of Adults With Post-Traumatic Stress Disorder (PTSD). Press release. June 25, 2024. Accessed June 26, 2024. https://www.businesswire.com/news/home/20240625407910/en/Otsuka-and-Lundbeck-Announce-FDA-Acceptance-of-sNDA-Filing-for-Brexpiprazole-in-Combination-With-Sertraline-for-the-Treatment-of-Adults-With-Post-Traumatic-Stress-Disorder-PTSD

2. Duerr HA. Brexpiprazole + Sertraline Combination for PTSD Submitted for sNDA Review. Psychiatric Times. April 11, 2024. Accessed June 26, 2024. https://www.psychiatrictimes.com/view/brexpiprazole-sertraline-combination-for-ptsd-submitted-for-snda-review

3. Kuntz L. FDA Panel Votes Against MDMA-Assisted Therapy. Psychiatric Times. June 5, 2024. Accessed June 26, 2024. https://www.psychiatrictimes.com/view/fda-panel-votes-against-mdma-assisted-therapy

4. Kuntz L. Lykos Therapeutics Releases Statement on FDA Advisory Committee Meeting. Psychiatric Times. June 13, 2024. Accessed June 26, 2024. https://www.psychiatrictimes.com/view/lykos-therapeutics-releases-statement-on-fda-advisory-committee-meeting

5. Lefkowitz C. Staff Perspective: The History of PTSD Awareness Month. Uniformed Services University. June 8, 2022. Accessed June 26, 2024. https://deploymentpsych.org/blog/staff-perspective-history-ptsd-awareness-month