FDA Rejects Rexulti for PTSD, Noting Insufficient Evidence of Effectiveness

Through a complete response letter, the FDA rejected Otsuka and Lundbeck’s request to approve Rexulti (brexpiprazole) in combination with sertraline for treating adults with post-traumatic stress disorder (PTSD), noting the submitted data didn’t provide enough evidence that the drug is effective.

Otsuka Pharmaceutical Co., Ltd. and H. Lundbeck A/S announced the FDA’s letter on September 20 regarding the companies’ supplemental New Drug Application (sNDA) for the combination treatment. The letter stated that the FDA had completed its review but could not approve the application in its current form, citing a lack of substantial evidence of effectiveness to support approval.

The application for Rexulti in combination with sertraline for adults with PTSD was first accepted for FDA review in June 2024. It was based on data from three randomized clinical trials evaluating the safety and efficacy of the drug combination in adult patients with PTSD.

In the phase 3 trial, 416 adults with PTSD were randomly assigned to receive the drug with sertraline or sertraline plus placebo for 11 weeks from October 2019 to August 2023. The primary measure—a change in PTSD symptom severity on the CAPS-5 scale—showed significantly greater improvement for the combination treatment than for sertraline alone. In this phase trial, the combination was generally well tolerated, with common side effects including nausea, fatigue, weight gain and sleepiness. Fewer participants discontinued treatment due to adverse events in the combination group than in the placebo group.

The recent FDA decision followed a July 18, 2025 meeting of the Psychopharmacologic Drugs Advisory Committee. Committee members voted 1-10, noting that the efficacy of the drug, when started at the same time as sertraline, has not been established for the treatment of PTSD based on the available data.

The FDA noted that not all submitted studies contributed to substantial evidence of effectiveness and said that additional positive, adequate and well-controlled trials would be needed if Otsuka and Lundbeck wish to pursue the indication.

John Kraus, M.D., Ph.D., executive vice president and chief medical officer at Otsuka responded to the FDAs decision by respecting the agency’s decision, though their belief in the potential of the drug remains.

“Otsuka and Lundbeck will take time to review the contents of the letter with the FDA to determine the appropriate path forward,” Kraus said in their announcement.

PTSD is one of the most common mental health disorders in the U.S. About 5% of the population experiences the condition during a given year, and most patients are in the civilian population. PTSD can occur in those who have experienced or witnessed traumatic events that are emotionally or physically harmful or life-threatening.

Examples include physical or sexual assault, natural disasters, serious accidents, terrorist acts, war, historical trauma, intimate partner violence and bullying.

Symptoms of PTSD are generally grouped into four categories: intrusion or re-experiencing, avoidance, negative alterations in mood and cognition and heightened arousal and reactivity. Symptom intensity can fluctuate over time and between individuals.

On average, symptoms appear 2.2 years after the trauma and the average time to diagnosis is about 8.7 years. Symptoms must last longer than one month and be severe enough to interfere with daily life, such as work or relationships, and they must not be caused by medications, substance use, or another medical condition.

Guideline-recommended first-line treatment for PTSD includes psychotherapy, such as trauma-focused cognitive behavioral or processing therapy. Pharmacotherapy with certain antidepressants is recommended when these therapies are unavailable, not feasible, or if patients prefer medication.

Rexulti was first approved in the U.S. in 2015 as an adjunctive therapy for adults with major depressive disorder and as a treatment for schizophrenia in adults. In May 2023, the drug was also approved for treating agitation associated with dementia due to Alzheimer’s disease. Rexulti has been approved in more than 60 countries including the European Union, Canada and Japan.

The drug was developed by Otsuka and Lundbeck. Researchers aren’t clear as to how it works, but it affects certain brain chemicals, including norepinephrine, serotonin and dopamine. It blocks some of their receptors and partially activates others, which may help balance brain activity.

Rexulti is currently approved for use along with antidepressants to treat major depressive disorder in adults, to treat schizophrenia in adults and children 13 years and older and to treat agitation associated with dementia due to Alzheimer’s disease. It should not be used as an as-needed treatment for agitation in dementia, and its safety and effectiveness in children with MDD or in children under 13 with schizophrenia are unknown.

Otsuka and Lundbeck have not announced the next steps for the PTSD indication but said they will review the FDA’s letter to determine an appropriate path forward.