14-07-2025
First New PTSD Drug in Two Decades On the Horizon?
The Psychopharmacologic Drugs Advisory Committee of the FDA is set to meet on July 18 to consider a supplemental new drug application for brexpiprazole (Rexulti, Otsuka Pharmaceutical Co., Ltd.), in combination with sertraline, for the treatment of adults with posttraumatic stress disorder (PTSD).
If approved, it would be the first new treatment for PTSD in more than 20 years.
'It is my hope that the FDA does approve this treatment for two related reasons — the data look positive and compelling, and there's a tremendous unmet need in PTSD,' Roger McIntyre, MD, professor of psychiatry and pharmacology and head of the Mood Disorders Psychopharmacology Unit, University of Toronto, Toronto, Ontario, Canada, told Medscape Medical News.
What's in the Treatment Toolbox Now?
PTSD is a 'common, severe, and nonremitting condition,' McIntyre noted. According to the National Center for PTSD, the condition affects roughly 13 million adults in the US in any given year. This represents about 5% of the adult population.
PTSD can develop following exposure to traumatic events such as combat, assault, disasters, or severe accidents. Core symptoms of PTSD include intrusive memories and flashbacks, avoidance behaviors, negative alterations in mood and cognition, and hyperarousal.
Currently, the selective serotonin reuptake inhibitors (SSRI), sertraline and paroxetine, are the only FDA-approved medications for PTSD, and while these medications can be effective, many patients fail to achieve remission or discontinue treatment due to side effects or lack of response.
Other medications used off-label to treat PTSD — including prazosin, mirtazapine, atypical antipsychotics, and mood stabilizers — have shown variable efficacy.
There has not been a new FDA-approved drug for PTSD in over two decades, underscoring the need for better therapeutic options, particularly for patients who do not fully respond to SSRI alone.
Why Brexpiprazole Plus Sertraline?
Brexpiprazole is an atypical antipsychotic currently approved as adjunctive treatment of major depressive disorder (MDD) in adults; treatment of schizophrenia in adults and adolescents aged 13 years or older; and treatment of agitation associated with Alzheimer's dementia.
The combination of brexpiprazole and sertraline could address the limitations of SSRI alone by working synergistically to treat PTSD.
Sertraline increases serotonin levels in the brain to improve mood and reduce anxiety. Brexpiprazole has a complex mechanism of action involving multiple neurotransmitter systems, including but not limited to serotonin and dopamine.
Together, they may target different aspects of PTSD, potentially leading to a more comprehensive reduction in symptoms.
What Do the Phase 3 Data Show?
In a pivotal, double-blind, randomized controlled, phase 3 trial, brexpiprazole plus sertraline provided significantly greater relief of PTSD symptoms than sertraline plus placebo.
The results were published late last year in JAMA Psychiatry and reported by Medscape Medical News at that time.
The trial enrolled 416 adults (mean age, 37 years; 75% women) aged 18-65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ( DSM-5 ) diagnosis of PTSD and symptoms for at least 6 months prior to screening.
At baseline, participants had a mean Clinician Administered PTSD Scale (CAPS-5) for DSM-5 total score of 38.4, indicating moderate to high severity PTSD. The average time from the index traumatic event was 4 years, and three fourths had no prior exposure to PTSD prescription medications.
Participants 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.
At week 10, brexpiprazole plus sertraline demonstrated statistically significant greater improvement in the CAPS-5 total score (primary outcome) than sertraline plus placebo (mean change, -19.2 points vs -13.6 points; P < .001).
Brexpiprazole plus sertraline also led to statistically significant greater improvement on all key secondary and other efficacy endpoints, both clinician-reported and patient-reported, including measures of anxiety, depression, intrusive symptoms, hyperarousal, and overall functioning.
Combining an atypical antipsychotic with an antidepressant for PTSD 'builds on what we've been doing in depression,' Elspeth Ritchie, MD, chair of Psychiatry, MedStar Washington Hospital Center, Washington, DC, noted in an interview with Medscape Medical News .
'We have found that a combination of a low-dose antipsychotic and an antidepressant is helpful for depression, so it makes sense that it will be helpful for PTSD. However, this has been mostly based on clinical decisions, without a heavy research background. Good science is always helpful to support those clinical decisions,' Ritchie told Medscape Medical News .
What About Safety?
In the phase 3 trial, brexpiprazole plus sertraline had a safety profile consistent with that of brexpiprazole in approved indications. The rate of discontinuation due to adverse events was low (3.9% for brexpiprazole plus sertraline vs 10.2% for sertraline plus placebo), indicating that most participants tolerated the brexpiprazole and sertraline combination treatment, the study team said.
In both treatment groups, the only treatment-emergent adverse event (TEAE) with incidence greater than 10% was nausea, a known adverse effect of sertraline treatment.
Weight gain was greater in participants receiving the combination. At the last visit, a weight gain of 7% or greater from week 1 was experienced by 8% of participants taking brexpiprazole with the sertraline group and 5% of those taking the sertraline plus placebo. Previous analyses in schizophrenia and MDD show that brexpiprazole is associated with moderate weight gain (+3 to 4 kg over 1 year).
The incidence of sedating TEAEs (a concern with some antipsychotics) was generally low, although fatigue (7% vs 4%) and somnolence (5% vs 3%) were more common with brexpiprazole plus sertraline than with sertraline alone.
There were no clinically meaningful between-group differences in changes in laboratory test parameters, vital signs, or ECG and participant-reported TEAEs related to suicidality.
Potential Concerns
As with any new drug application, several questions and issues are likely to be raised by the advisory committee. They could include whether the clinical benefit is substantial enough to warrant approval and how the observed effect sizes compare to existing approved therapies and evidence-based psychotherapies.
McIntyre told Medscape Medical News what's particularly noteworthy is that the magnitude of the improvement in PTSD symptoms with brexpiprazole plus sertraline is greater than with sertraline alone. 'That's a very important statement. And this high level of efficacy was consistent on the secondary outcome measures, and the overall tolerability and safety seemed very acceptable,' he said.
What's equally important, said McIntyre, is that most people with PTSD have depression and anxiety, and the brexpiprazole plus sertraline combination was more helpful than sertraline alone on the measures of anxiety and depression. 'This is really important, especially in light of the fact that this medication [brexpiprazole] is already approved for adults living with major depressive disorder and inadequate response to antidepressants,' McIntyre said.
McIntyre added he suspects some questions the committee may have could relate to the extent to which it's the case that brexpiprazole is effective in PTSD regardless of the antidepressant that is prescribed with it.
'There also will be the inevitable questions about the absence of long-term data which I think will need to be addressed given how chronic and relapse prone this condition is,' McIntyre said.
The committee may ask how trauma and PTSD will be screened in primary care and how outcomes related to this therapy will be evaluated in everyday clinical practice, McIntyre said.
Overall, McIntyre said brexpiprazole plus sertraline in PTSD is a 'very positive' development for the field.
'PTSD is a terrible condition. It's so darn common, and we just don't have enough treatments for it. The data look good for my perspective. My fingers are crossed for the patients with PTSD and their families,' said McIntyre.
