Finally, a New Option for Posttraumatic Stress Disorder?

A drug that combines the atypical antipsychotic brexpiprazole and the selective serotonin reuptake inhibitor sertraline provides significantly greater relief of posttraumatic stress disorder (PTSD) symptoms than sertraline plus placebo, results of a phase 3 trial showed.

The medication is currently under review by the US Food and Drug Administration (FDA) and if approved, will be the first pharmacologic option for PTSD in more than 20 years.

The trial met its primary endpoint of change in the Clinician Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) (CAPS-5) total score at week 10 and secondary patient-reported outcomes of PTSD symptoms, anxiety, and depression.

“And what is really cool, what’s really impactful is the combination worked better than sertraline plus placebo on a brief inventory of psychosocial functioning,” study investigator Lori L. Davis, a senior research psychiatrist, Birmingham Veterans Affairs Health Care System, Birmingham, Alabama, told Medscape Medical News.

“We can treat symptoms but that’s where the rubber meets the road, in terms of are they functioning better,” added Davis, who is also an adjunct professor of psychiatry, Heersink School of Medicine, The University of Alabama at Birmingham.

The findings were published online on December 18 in JAMA Psychiatry and reported earlier this year as part of a trio of trials conducted by Otsuka Pharmaceutical and Lundbeck Pharmaceuticals, codevelopers of the drug.

Clinically Meaningful

The FDA accepted the companies’ supplemental new drug application in June with a decision on approval expected in early February 2025.

“This study provides promising results for a medication that may be an important new option for PTSD,” John Krystal, MD, director, Clinical Neuroscience Division, National Center for PTSD, US Department of Veterans Affairs, who was not involved in the research, told Medscape Medical News. “New PTSD treatments are a high priority.”

Currently, there are two FDA-approved medication treatments for PTSD — sertraline and paroxetine.

“They are helpful for many people, but patients are often left with residual symptoms or tolerability issues,” noted Krystal, who is also professor and chair of psychiatry, Yale University, New Haven, Connecticut.

“New medications that might address the important ‘effectiveness gap’ in PTSD could help to reduce the remaining distress, disability, and suicide risk associated with PTSD.” 

The double-blind, phase 3 trial included 416 adults aged 18-65 years with a DSM-5 diagnosis of PTSD and symptoms for at least 6 months prior to screening. Patients underwent a 1-week placebo-run in period followed by randomization to daily oral brexpiprazole 2-3 mg plus sertraline 150 mg or daily sertraline 150 mg plus placebo for 11 weeks.

Participants’ mean age was 37.4 years, 74.5% were women, and mean CAPS-5 total score was 38.4, suggesting moderate to high severity PTSD, Davis said. The average time from the index traumatic event was 4 years and three fourths had no prior exposure to PTSD prescription medications.

At week 10, the mean change in CAPS-5 score from randomization was −19.2 points in the brexpiprazole plus sertraline group and −13.6 points in the sertraline plus placebo group (95% CI, −8.79 to −2.38; P 

Asked whether the 5.59-point treatment difference is clinically meaningful, Davis said there is no widely agreed definition for change in CAPS-5 total score but that a within-group reduction of more than 10-13 points is most-often cited as being clinically meaningful.

The key secondary endpoint of least square mean change in the patient-reported Brief Inventory of Psychosocial Function total score from baseline to week 12 was −33.8 with the combination vs −21.8 with sertraline plus placebo (95% CI, −19.4 to −4.62; P = .002).

“That’s clinically meaningful for me as a provider and a clinician and a researcher when you’re getting the PTSD symptom change differences in parallel with the improvement in functional outcome,” she said. “I see that as the clinically meaningful gauge.”

In terms of safety, 3.9% of the participants in the brexpiprazole/sertraline group and 10.2% of those in the sertraline/placebo group discontinued treatment due to adverse events.

In both the combination and control groups, the only treatment-emergent adverse event with an incidence of more than 10% was nausea (12.2% vs 11.7%, respectively).

At the last visit, the mean change in body weight from baseline was an increase of 1.3 kg for brexpiprazole plus sertraline vs 0 kg for sertraline alone. Rates of fatigue (6.8% vs 4.1%) and somnolence (5.4% vs 2.6%) were also higher with brexpiprazole plus sertraline.

A Trio of Clinical Trials

The findings are part of a larger program reported by the drug makers that includes a flexible-dose brexpiprazole phase 2 trial that met the same CAPS-5 primary endpoint and a second phase 3 trial (072 study) that did not.

“We’ve looked at that data and the sertraline/placebo response was a lot higher, so it was not due to a lack of response with the combination but due to a more robust response with the active control,” Davis said. “But we want to point out for that 072 study, there was still important separation between the combination and sertraline plus placebo on the functional outcome.”

All three trials ran for 12 weeks, so longer-term efficacy and safety data are needed, she said. Other limitations of the published phase 3 study are the patient eligibility criteria, restrictions on concomitant therapy, and lack of non-US sites, which many limit generalizability, the authors note.

“Specifically, the exclusion of patients with a current major depressive episode is both a strength (to show a specific effect on PTSD) and a limitation (given the high prevalence of comorbid depression in PTSD),” they added.

This study was funded by Otsuka Pharmaceutical Development & Commercialization, which was involved in the design, conduct, and data analysis. Davis reported receiving advisory board fees from Otsuka and Boehringer Ingelheim; lecture fees from Clinical Care Options; and grants from Alkermes, the Veterans Affairs, Patient-Centered Outcomes Research Institute, Department of Defense, and Social Finance. Several co-authors are employees of Otsuka.

Krystal reported serving as a consultant for Otsuka America Pharmaceutical, Aptinyx, Biogen, IDEC, Bionomics Ltd, Boehringer Ingelheim International, Clearmind Medicine, Cybin IRL, Enveric Biosciences, Epiodyne, EpiVario, Janssen, Jazz Pharmaceuticals, Perception Neuroscience, Praxis Precision Medicines, Springcare, and Sunovion Pharmaceuticals. Krystal also reported serving as a scientific advisory board member for several companies and holding several patents.