RSS
_-The-Breakthrough-Antipsychotic-That-Could-Change-Everything.webp?t=1729528747 "KarXT (Cobenfy)_ The Breakthrough Antipsychotic That Could Change Everything.jpg")
He would smile briefly when I greeted him, sit down, and glance furtively around my office, all the while mumbling something to himself.
“So how have you been, John?” I ask, but often he seems oblivious to the fact that I am addressing him.
“John?”
“Oh—yes, Dr. Carlat?”
“What’s going on in your head right now?”
“Oh, I don’t know, Dr. Carlat.”
“Were you hearing voices?”
“Yes, I hear voices.”
“What are they saying to you?”
“All kinds of things. Bad things. ‘You’re a bad person. You can’t do anything. You don’t know what you’re doing.’”'
“Do they make you feel bad?” But he doesn’t respond. He’s already been pulled back into the current of his inner world.
▸ And yet, this was a huge improvement.
→ A few years earlier, John had been cycling in and out of hospitals, sometimes for erratic or aggressive behavior. Clozapine helped a great deal.
He stabilized.
He got his own apartment.
We found a rhythm.
But over the years, he also gained nearly 100 pounds. Despite metformin.
Then I retired from practice.
I hadn’t seen John in years—until I came across his obituary. He had died of heart disease in his early 60s.
▸ Did I help him or fail him?
Clozapine gave him peace. But maybe it also took 20 years off his life. The truth is, people with schizophrenia lose an average of 14–15 years of life, mostly from preventable medical conditions like cardiovascular disease and diabetes—not suicide. Their risk of early death is about three times higher than the general population. And clozapine, while often the most effective option, adds to that cardiometabolic burden.
⟶ Which is why we have to do better at managing clozapine’s side effects. In the June 2025 issue of The Carlat Psychiatry Report, Dr. Jonathan Leung, PharmD, shared practical, clinic-tested strategies for doing just that. We turned his insights into a visual summary (below), covering:
→ Constipation (the most dangerous side effect)
→ Weight gain and metabolic risk
→ Sialorrhea, sedation, orthostasis, and dry mouth
→ How to use meds like metformin, topiramate, and GLP-1 agonists (semaglutide)
→ When to slow titration and what to screen for One recent RCT in The Lancet Psychiatry found that semaglutide led to a 13.8% weight loss in clozapine-treated patients—without worsening psychosis or raising safety issues. If we can treat clozapine’s side effects—and start doing so proactively—then maybe we can stop treating it like a drug of last resort.
Clozapine doesn’t fail. We fail to support it.
What’s the biggest barrier you face in using clozapine confidently?
Share this with a colleague who may be wrestling with the same tension.
Follow me (Daniel Carlat, MD) for reflections on practical psychiatry, grounded in real life.
