A 2023 study finds a dose-dependent association between chlorpromazine equivalents and death in non-psychotic young adults.

A team of researchers led by epidemiologists and health policy experts at Vanderbilt University Medical Center found an increased risk of sudden death for patients ages 18 to 24 taking chlorpromazine-type antipsychotic medications.

Young adults taking thioridazine and other chlorpromazine equivalents in doses at or above 100 mg had higher death rates than control-group subjects, who also were being treated for mental illness, according to study principal investigator William Cooper, M.D., M.P.H. and first author Wayne A. Ray, Ph.D.

“As antipsychotics have been prescribed more and more for youth over time, sudden deaths are increasing in this population,” Ray said. “The unexpected rise in drugs not approved by the FDA and lack of alternative resources for the patient remains a major problem in the psychiatric community.”

The information this study provides is important to clinicians prescribing these medications, as well as to their patients and family members, Cooper said. “Being able to consider the full range of risks and benefits is an essential element in making decisions about using certain medications – certainly for antipsychotics.”

Antipsychotics on the Rise

First-generation antipsychotics chlorpromazine and thioridazine were rarely used in children and young adults due to the low prevalence of schizophrenia and psychotic disorders in that population. This class of drugs also has severe side effects, predominantly movement disorders, such as trembling, shaking and jaw grimacing.

Risperidone, which has a much lower incidence of movement disorders, was introduced around 1988.

Lately, Ray said, “what we have seen, interestingly enough, is a dramatic increase in antipsychotic prescription in children and young adults. Practitioners started to prescribe them to children with autism spectrum disorders, intellectual disabilities or adjustment disorders. Because they were displaying problematic behavioral symptoms, lots of doctors started handing out antipsychotics, despite there being no increase in psychiatric disorder diagnoses in that age group.”

Several other drugs with similar purpose but not officially approved by the FDA were introduced after risperidone.

“Imagine you have a child whose behavioral symptoms prevent them from being allowed to attend school – what’s the parent going to do? They are probably less worried about FDA indications than getting a solution quickly,” Ray said.

Risk Assessment 

Due to the uncertainty of drug outcomes in the younger demographic, as well as data they earlier generated about cardiovascular and metabolic hazards, the investigators knew they had to further elucidate the risks.

Their new study focused on mortality risk in more than 2 million patients between 5 and 24 years old, none of whom had severe somatic or psychiatric illness but were treated with antipsychotics due to behavioral or other problems.

The chlorpromazine equivalents were split into doses at or below 100 mg and doses above 100 mg. Other, second-generation antipsychotics were converted to the equivalent strength of chlorpromazine to enable head-to-head comparison.

Their outcomes were compared with those of control patients taking psychiatric medications prescribed for traditionally approved conditions.

Deviation at 100 mg

Upon analyzing the data for this study, the researchers found that chlorpromazine doses at or below 100 mg were not associated with increased risk of death in either children ages 5 to 17 or in young adults 18- to 24-years-old.

Death was rare in children aged 5 to 17, less than one-fifth of that for young adults, and not elevated over controls at either dosage.

However, young adults taking doses above 100 mg equivalency underwent a significant increase in mortality risk, with 127.5 additional deaths per 100,000 person-years of exposure.

Cause of Death

Ray says these results appear to add weight to concerns about the adverse effects antipsychotic drugs like risperidone can have on cardiac health and breathing.

“They can cause potentially lethal arrhythmias and impaired respiration. For anyone at risk, these drugs can lead to fairly sudden deaths,” he said.

In the young adult group, there was an additional association of deaths with drug overdoses and unintentional injuries. Some patients had taken opioids in conjunction with the antipsychotics, creating a more lethal combination.

“The FDA actually has a black box warning for use of opioids and antipsychotics together because they both impair breathing,” Ray said.

Parsing Circumstances

The authors say future research should focus on specific categories of injury. How and why the injuries occur in isolation needs to be explored, although they say the way in which the information is gathered in the databases requires more specificity.

“I think one problem is that you have to use different approaches in these large databases,” Ray said. “If you look at antipsychotics and opioid overdoses, for example, the only topic explored is the combination leading to death – not whether the patient was hospitalized from taking one extra pill or came to the ED unconscious. The gap in that information needs to be filled.”

About the Expert

Wayne Ray, Ph.D.

Wayne Ray, Ph.D., is a professor of health policy at Vanderbilt University Medical Center. Ray has had a long-standing research interest in population-based studies of therapeutic interventions and pioneered the methodology for using large, automated databases for these types of studies. His research focuses on the health impacts of oral anticoagulants, non-steroidal anti-inflammatory drugs, COX-2 inhibitors, psychotropics and other medications.

William O. Cooper, M.D.

William O. Cooper, M.D., M.P.H., is professor of pediatrics and health policy at Vanderbilt University Medical Center. He is a pharmacoepidemiologist with a focus on the effects of psychotropic medications in children and adverse effects of prescription medication use during pregnancy. He has achieved international recognition for his work in using computerized databases to ask and answer important questions of drug safety.