Dr. Diana Zuckerman, July 18, 2025
I’m Dr. Diana Zuckerman, president of the National Center for Health Research. Thank you for the opportunity to share my views today. Our nonprofit think tank conducts, analyzes, and scrutinizes research focusing on the safety and effectiveness of medical products. We do not accept funding from any entities that have a financial interest in our work and therefore have no conflicts of interest.
My perspective is as a scientist trained in psychiatric and psychosocial epidemiology at Yale Med School and I previously held research positions at Yale and Harvard before moving to DC to work in the US Congress, HHS, and the White House. PTSD is a terrible condition and there are numerous treatments, some more effective than others. Veterans tell us that medications often create more problems than they solve, so any treatment should be based on clear evidence that its benefits outweigh the risks. This meeting is very important and I thank you for your service.
The company designed 2 adequate and well-controlled studies, and Study 00071 showed a benefit for the proposed combination of Rexulti and Zoloft, but Study 00072 did not. FDA sometimes approves drugs based on just one study, but the problem here is that a 2 nd study does not show any benefit and is nonsignificant with a p> .90. For those unsure about p values, that means there is a 90% chance that the drug combination was NOT beneficial in that 2nd study.
The sponsor wants the FDA and this Committee to consider its phase 2 exploratory study, # 00061 instead of #00072. We agree with FDA that Study 00061 did not appropriately control for the numerous statistical comparisons. The sponsor’s evidence is also based on several post-hoc analyses, and those are not kosher from a scientific perspective. And of course, Study 00061 is even less persuasive because the larger, better designed Study 00072 did not show any benefit, or even a hint of a benefit.
What about risks?
The serious risks of these drugs are well established. We should especially be concerned about the risk of suicidal thoughts and behavior for youth and young adults
for each of these drugs, because:
#1 Many veterans and abuse patients with PTSD are teenagers or young adults.
#2 PTSD patients and veterans are already at high risk of suicide. I’ve spoken with veterans groups that have stated that the use of multiple psychotropic drugs concurrently are contributing to very serious mental health problems, with rebounding when patients try to reduce their use. In contrast to what we’ve heard, these combinations are often NOT well tolerated.
#3 PTSD patients often self-medicate with alcohol and other drugs, and so FDA should be even more cautious when considering approval for PTSD. There are other serious risks as well, and although the agency says there were “no new safety signals,” they found there was a “clinically relevant difference in weight gain” when the two drugs are combined. Weight gain, metabolic disorders, suicidal thoughts, and other side effects could become more obvious in the months after these 12-week studies were completed and could be greater when the drugs are given at the same time.
In conclusion, the FDA previously approved these drugs despite the risks because the agency determined that the evidence of benefits for patients with schizophrenia, depression, and other indications outweigh the risks. In your review today, there is not clear evidence that there is any benefit for PTSD, and for that reason, it seems impossible to conclude that the unproven benefits of these combined drugs for PTSD outweigh the well-established risks. And those risks will not be as well monitored in the real world as they were in these clinical trials – and that’s especially true in rural areas with less access to medical care.
The Advisory Committee agreed and voted 10-1 against Rexulti for PTSD. The patient representative was the only voting in favor.