A combination of the atypical antipsychotic brexpiprazole and the selective serotonin reuptake inhibitor sertraline may reduce post-traumatic stress disorder (PTSD) symptoms to a greater extent than sertraline plus a placebo. This was shown in the results of a phase 3 trial.
The drug is currently under review by the U.S. Food and Drug Administration (FDA) and, if approved, would be the first pharmacological option for PTSD in more than 20 years.
This study examined the change in clinician-administered Diagnostic and Statistical Manual of Mental Disorders PTSD Scale-5 (DSM-5) (CAPS-5) total score at week 10 and the patient-reported The primary endpoint of the study was changes in PTSD symptoms and anxiety. , and depression.
“And what’s really impressive, and what’s really impactful, is that in a simple study of psychosocial functioning, this combination was more effective than sertraline and a placebo,” said the Birmingham Veterans Administration in Birmingham, Alabama. said study investigator Lori L. Davis, a senior research psychiatrist at the health system. , said Medscape Medical News.
“You can treat the symptoms, but that’s where the rubber plays an important role in terms of whether it works better or not,” said Dr. one Davis added.
It was discovered that Published online on December 18th JAMA Psychiatry and previously reported It was conducted this year as part of three trials conducted by the drug’s co-developers, Otsuka Pharmaceutical and Lundbeck Pharmaceuticals.
clinically meaningful
The FDA will accept the company’s supplemental new drug application in June, with an approval decision expected in early February 2025.
“This study provides promising results for a potentially important new drug option for PTSD,” said John Crystal, M.D., director of clinical neuroscience at the U.S. Department of Veterans Affairs National Center for PTSD. Although not involved in the study, said Medscape Medical News. “New PTSD treatments are a top priority.”
There are currently two FDA-approved medications for PTSD: sertraline and paroxetine.
“While they are beneficial for many people, patients often remain symptomatic or have tolerability issues,” said Dr. Schneider, a professor and chair of the department of psychiatry at Yale University in New Haven, Connecticut. As one crystal points out.
“New drugs that have the potential to address important ‘efficacy gaps’ in PTSD could help reduce the residual distress, disability, and risk of suicide associated with PTSD.”
double blind, Phase 3 study Subjects included 416 adults aged 18 to 65 years with a DSM-5 diagnosis of PTSD and symptoms for at least 6 months prior to screening. Patients received a 1-week placebo period and were then randomized to oral brexpiprazole 2 to 3 mg daily and sertraline 150 mg or daily sertraline 150 mg and placebo for 11 weeks.
Participants’ average age was 37.4 years, 74.5% were women, and their average CAPS-5 total score was 38.4, suggesting moderate to severe PTSD, Davis said. The average time to onset of the traumatic event was 4 years, and three-quarters had never been exposed to a prescription PTSD medication.
At week 10, the mean change in CAPS-5 score due to 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; 95% CI, -8.79 to -2.38). P < .001).
When asked if the 5.59-point treatment difference was clinically meaningful, Davis said that while there is no widely agreed upon definition of a change in CAPS-5 total score, what is clinically meaningful? The most frequently cited drop was 10 to 13 points or more within a group. meaningful.
The key secondary endpoint of least squares mean change in patient-reported short-form psychosocial functioning inventory total score from baseline to week 12 was -33.8 for combination therapy and -33.8 for combination therapy with sertraline and placebo. 21.8 (95% CI, -19.4 to -4.62; P = .002).
“The difference in PTSD symptom change that parallels improved functional outcomes is clinically meaningful to me as a health care provider, clinician, and researcher,” she said. . “I think that’s a clinically meaningful measure.”
From a safety perspective, 3.9% of participants in the brexpiprazole/sertraline group and 10.2% of participants in the sertraline/placebo group discontinued treatment due to adverse events.
The only treatment-emergent adverse event with an incidence >10% in both the combination and control groups was nausea (12.2% vs. 11.7%, respectively).
At the last visit, the mean change in weight from baseline was 1.3 kg with brexpiprazole and sertraline, compared with 0 kg with sertraline alone. Rates of fatigue (6.8% vs. 4.1%) and somnolence (5.4% vs. 2.6%) were also higher with brexpiprazole and sertraline.
3 clinical trials
The study results are part of a larger program reported by the drug manufacturer that includes flexible-dose brexpiprazole. Phase 2 study These trials met the same CAPS-5 primary endpoint, but the second phase 3 trial (Study 072) did not.
“When we looked at that data, the response for sertraline and placebo was much higher, so it was not due to a lack of response with the combination, but rather a stronger response with the active control,” Davis said. “However, we would like to point out that in the 072 study, there was still an important gap between combination therapy and sertraline plus placebo in terms of functional outcomes.”
All three trials were conducted for 12 weeks, so long-term efficacy and safety data are needed, she said. Other limitations of published phase 3 trials include patient eligibility criteria, limited combination therapy, and lack of sites outside the United States, many of which the authors say limit generalizability. have pointed out.
“In particular, excluding patients currently suffering from a major depressive episode is both a strength (indicating a specific effect on PTSD) and given the high prevalence of comorbid depression in PTSD. ) is also a limitation,” the researchers added.
Kudos and notes
When asked for comment, Vincent F. Capaldi II, M.D., professor and chair of the Department of Psychiatry at the Uniformed Services University School of Medicine in Bethesda, Maryland, said that while excluding these patients is a limitation, the study was carefully designed and It was conducted on a large sample across the United States.
“Study results suggest that the combination of brexpiprazole and sertraline is more effective in treating PTSD than sertraline alone,” he said. Medscape Medical News. “This finding is important for military personnel, who suffer from PTSD at higher rates than the civilian population.”
Additionally, the significant improvement in psychosocial functioning at 12 weeks is “important because PTSD is known to cause significant social and occupational impairment, as well as quality of life issues,” he said. said.
However, Capaldi noted that the study was conducted only at U.S. facilities and did not specifically target military personnel or veterans, which could limit its applicability to these special populations.
“Although the subgroup analyzes were generally consistent with the primary analyses, this study did not have the ability to detect differences between subgroups,” he added. “These subgroup analyzes are critical when considering military and veteran populations.”
Capaldi said further research is needed to explore whether certain injuries are more responsive to combination therapy, its effectiveness in augmenting existing sertraline therapy, and the specific mechanisms by which brexpiprazole leads to improved outcomes. said.
This study was funded by Otsuka Pharmaceutical Development and Commercialization, which was involved in design, implementation, and data analysis. Mr. Davis reported receiving advisory board fees from Otsuka Pharmaceutical and Boehringer Ingelheim. Lecture fees from Clinical Care Options. Also supported are grants from Alkermes, the Department of Veterans Affairs, the Patient-Centered Outcomes Research Institute, the Department of Defense, and Social Finance. Several co-authors are employees of Otsuka Pharmaceutical.
Mr. Crystal is a member of Otsuka America Pharmaceuticals, Aptinix, Biogen, IDEC, Bionomics, Inc., Boehringer Ingelheim International, ClearMind Medicine, Cybin IRL, Enveric Biosciences, Epiodyne, Epivario, Janssen, and Jazz Pharmaceuticals. , Perception Neuroscience, Praxis Precision Medicine, and SpringCare. , Sunovion Pharmaceuticals. Crystal also reported serving on scientific advisory boards for multiple companies and holding several patents.
