Are High-Dose Antipsychotics More Deadly Than Fentanyl in Kids?
And other questions I'd rather not be asking.
The Frontier Psychiatrists is a daily health-themed newsletter. Today, it is about serious and avoidable risks to the health of the most vulnerable people. Antipsychotic medications, again, are under the microscope.
Antipsychotic medication can be profoundly helpful. It is also risky. New large-scale data highlights those risks. First, colleagues, including my first research mentor Christoph Correll, do a large-scale assessment of metabolic syndrome in depression…and find a risk of metabolic syndrome and other adverse metabolic outcomes. This is almost entirely attributable to antipsychotic medicines:
[authors included] 18 studies with interview-defined depression1. The overall proportion with MetS [Metabolic Syndrome] was 30.5% … using any standardized MetS criteria. Compared with…matched control groups, individuals with MDD had a higher Metabolic Syndrome prevalence [odds ratio (OR) 1.54, … p = 0.001]. They also had a higher risk for hyperglycemia (OR 1.33…p = 0.03) and hypertriglyceridemia (OR 1.17…p = 0.008). Antipsychotic use (p < 0.05) significantly explained higher MetS prevalence estimates in MDD. Differences in MetS prevalences were not moderated by age, gender, geographical area, smoking, antidepressant use, presence of psychiatric co-morbidity, and median year of data collection.
Now, I have made this point before…metabolic syndrome is “the real crisis,” and antipsychotics are a driver of this outcome. More than once, actually. A detractor even once highlighted my cheeky man-bear-pig meme as evidence that I am a bad guy who is presumably not saving anyone from serious adverse events! Man-Bear-Pig offers his response:
Next, youth treated with higher-dose antipsychotic medicines are at risk of increased death.2 Who was in this sample was especially important—it’s only older kids on Medicaid and without schizophrenia or severe somatic illnesses…
Design, setting, and participants: This was a US national retrospective cohort study of Medicaid patients with no severe somatic illness or schizophrenia or related psychoses who initiated study medication treatment. Study data were analyzed from November 2022 to September 2023.
These are poor kids who have conditions that have other options (presumably) in many cases. These are among the most vulnerable children in America.
Main outcome and measures: Total mortality, classified by underlying cause of death
This is not a debatable endpoint. There is no good dead child. This is the worst thing. It happened or it didn’t—it’s categorical.
It’s a massive sample:
Results: The 2,067,507 patients (mean [SD] age, 13.1 [5.3] years; 1,060,194 male [51.3%]) beginning study medication treatment filled 21,749,825 prescriptions during follow-up with 5,415,054 for antipsychotic doses of 100 mg or less, 2,813,796 for doses greater than 100 mg, and 13,520,975 for control medications.
And for young adults taking these medications…
[youth] aged 18 to 24 years had increased risk [of death] for doses greater than 100 mg3 (Hazard Ratio, 1.68; 95% CI, 1.23-2.29).4
This converts with a bit of math into the following excess morality…in the most vulnerable children:
For [higher dose medicine exposed individuals], young adults aged 18 to 24 years had significantly increased risk of death, with 127.5 additional deaths per 100,000 person-years.
This is a staggering number.
In 2021, 106,699 drug overdose deaths occurred, resulting in an age-adjusted rate of 32.4 per 100,000 standard population
And opioids, busted out, look like this:
….Around 25 (additional deaths in those 18-24) /100,000 in the population across all opioids in 2021. Yes, it is worse now.
500% More Deaths than Fentanyl.
Treating young adults with antipsychotic medicines at high doses—when they are poor and don't have a psychotic illness—is correlated to 5x as many additional deaths as fentanyl.
This might be correlation only—being so poor you are on Medicaid and so sick doctors are prescribing high-dose antipsychotic meds might be a marker for a different underlying death-causing problem. I made the same argument last week about benzodiazepine medicines. However—we can’t argue that these medicines are safer or better. Or that we should “just do something” in non-psychotic youth or depressed adults because the risk is that we are causing MORE harm up to and including metabolic syndrome and, of course, death.
Compared to a classic pulled-from-the-market-entirely disaster with additional mortality—Vioxx—and it’s not quite that bad
the relative risk of developing a confirmed adjudicated thrombotic cardiovascular event (myocardial infarction, unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or unexplained death, ischemic stroke, and transient ischemic attacks) with rofecoxib treatment compared with naproxen was 2.38 (95% confidence interval, 1.39-4.00; P = .002). There was no significant difference in cardiovascular event (myocardial infarction, stroke, and death) rates between celecoxib and nonsteroidal anti-inflammatory agents …5
The risk from antipsychotics is not that elevated…but in a younger cohort with lower baseline risk, and the Vioxx data includes sub-death endpoints, as cited. I’d be curious to hear what now-fellow sub-stacker Eric Topol at
would have to say about the above comparison…given he’s a coauthor of the Vioxx papers.The only argument we really can’t get away with? We don’t need better options for the most vulnerable youth.
Prior articles about antipsychotic medicines include great reasons to subscribe to this amazing resource for your life and or practice:
Risperdal (with a podcast version)
Clozapine, Part 1.
A Review of Tardive Dyskinesia
Finally, some of my own journey with obesity treatment after concluding antipsychotic treatment.
(n = 5531, 38.9% male, mean age = 45.5 years).
Ray WA, Fuchs DC, Olfson M, Patrick SW, Stein CM, Murray KT, Daugherty J, Cooper WO. Antipsychotic Medications and Mortality in Children and Young Adults. JAMA Psychiatry. 2023 Nov 29:e234573. doi: 10.1001/jamapsychiatry.2023.4573. Epub ahead of print. PMID: 38019523; PMCID: PMC10687711.
they standardized all the meds to “chlorpromazine equivalents” to figure our what is high vs low dose.
Hazard ratio can be converted to odds ratio, which I’ve presented before, as follows:
The probability of healing first can easily be derived from the odds of healing first, which is the probability of healing first divided by the probability of not healing first: hazard ratio (HR) = odds = P/(1 − P); P = HR/(1 + HR). A hazard ratio of 2, therefore, corresponds to a 67% chance of the treated patient's healing first, and a hazard ratio of 3 corresponds to a 75% chance of healing first.
It takes into account the drug might also help, not only risk killing you.
Stephenson J. Vioxx Controversy. JAMA. 2004;292(23):2827. doi:10.1001/jama.292.23.2827-a
Mukherjee D, Nissen SE, Topol EJ. Risk of Cardiovascular Events Associated With Selective COX-2 Inhibitors. JAMA. 2001;286(8):954–959. doi:10.1001/jama.286.8.954
Yes! Now we need Gov’t to put forth more rules to protect kids! Foster Kids (all kids) deserve so much better! As a teen, if I had had a psychiatrist like you to begin with I wouldnt have gone down the antipsychiatry path.
I think I have reached a point where I dont hate psychiatry anymore... but we need change. The system (between foster care and psychiatry) caused way too much harm. I would rather have stayed in the trailer park.
Thank you for speaking out! Foster youth are routinely warehoused in subpar facilities and given these drugs! UHS is one of the worst offenders. They own a lot of the troubled teen industry facilities!