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 < .001).
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.
Kudos, Caveats
Reached
for comment, Vincent F. Capaldi, II, MD, ScM, professor and chair,
department of psychiatry, Uniformed Services University of the Health
Sciences School of Medicine, Bethesda, Maryland, said the exclusion of
these patients is a limitation but that the study was well designed and
conducted in a large sample across the United States.
“The findings suggest that brexpiprazole plus sertraline is a more effective treatment for PTSD than sertraline alone,” he told Medscape Medical News. “This finding is significant for our service members, who suffer from PTSD at higher rates than the general population.”
Additionally,
the significant improvement in psychosocial functioning at week 12 “is
important because PTSD is known to cause significant social and
occupational disability, as well as quality-of-life issues,” he said.
Capaldi
pointed out, however, that the study was conducted only at US sites and
did not specifically target military/veteran persons, which may limit
applicability to these unique populations.
“While
subgroup analyses were generally consistent with the primary analysis,
the study was not powered to detect differences between subgroups,” he
added. “These subgroup analyses are quite important when considering
military and veteran populations.”
Further research is needed to
explore whether certain traumas are more responsive to combination
treatment, the efficacy of augmenting existing sertraline therapy, and
the specific mechanisms of brexpiprazole driving the improved outcomes,
Capaldi said.
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.
