‘Untapped resource’
Of 53,133 decedents, olanzapine or clozapine was detected in the blood of 621 persons (n = 571 and n = 50, respectively).
There were no significant differences in age, sex, race, or urban residence between the decedents who were treated with olanzapine and those who received clozapine.
The odds of a death by suicide in those treated with clozapine were less than half of the odds among decedents who had been treated with olanzapine (odds ratio, 0.47; 95% confidence interval, 0.26-0.84; P = .011).
In sensitivity analyses, the investigators reanalyzed the data to compare clozapine with other antipsychotics, including chlorpromazine, thioridazine, quetiapine, and olanzapine, and the results were similar. The odds of suicide (compared with accident) in those taking clozapine were much lower than in those taking any other tested antipsychotics individually or in combination (OR, 0.42; 95% CI, 0.24-0.73; P = .002).
Dr. Nestadt outlined several hypotheses regarding the mechanism of clozapine’s antisuicidal properties.
“Most theories stem from the differences in its receptor affinity, compared [with] the other neuroleptics,” he said. “In addition to the more typical dopaminergic blockade seen in neuroleptics, clozapine enhances serotonin release and greatly increases peripheral norepinephrine.”
This has been shown to “grant clozapine a greater antidepressant effect than other neuroleptics while also potentially decreasing aggression and impulsivity, which are both strongly associated with suicide risk,” he said.
Clozapine may also “work to reduce the inflammation-triggered activation of the kynurenine pathway, which otherwise contributes to serotonin depletion,” he added.
He noted that some studies have shown that as many as 1 in 10 patients with schizophrenia die by suicide, “so addressing this risk is paramount,” and that clozapine can play an important role in this.
The authors note that the findings “also highlight the utility of state-wide autopsy records, an untapped resource for investigating the potential protective effect of psychiatric medications on suicide at a population level.
“Importantly, we can be certain that this was not an issue of nonadherence to treatment in either group, which is a common issue in the use of these drugs because, instead of prescription records or self-report, we used actual measurements of drug presence in decedents’ blood at death,” said Dr. Nestadt.
‘Strongly suggestive’ data
Commenting on the study, Maria Oquendo, MD, PhD, Ruth Meltzer Professor and chair of psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, said most work on antisuicidal psychopharmacologic approaches “focuses on suicidal ideation or suicide attempts, due to the rarity of suicide death, even in high-risk populations.”
“Showing that clozapine may decrease risk for the most dreaded outcome of schizophrenia – suicide – is critically important,” said Dr. Oquendo, past president of the American Psychiatric Association.
Nevertheless, some questions remain, said Dr. Oquendo, who was not involved with the study. “Comparison of suicides to only accidental deaths has limitations. Many individuals who die due to accidents, like many suicides, are not similar to the general population,” she added.
However, she acknowledged, the data are strongly suggestive that clozapine protects against suicide.
“While not definitive, ideally these findings will stimulate changes in prescribing practices which may be lifesaving both literally – in terms of preventing suicides – and figuratively, given the drug’s effect on symptoms that impact quality of life and functioning,” said Dr. Oquendo.
The study received no funding or support. Dr. Nestadt is supported by the American Foundation for Suicide prevention and the National Institute on Drug Abuse. The other authors’ disclosures are listed in the original article. Dr. Oquendo receives royalties from the Research Foundation for Mental Hygiene for the commercial use of the Columbia Suicide Severity Rating Scale. She serves as an advisor to Alkermes, Mind Medicine, Sage Therapeutics, St. George’s University, and Fundacion Jimenez Diaz. Her family owns stock in Bristol-Myers Squibb.