The antipsychotic clozapine appears to guard against suicide for patients with treatment-resistant schizophrenia, results of an autopsy study suggest.
Investigators reviewed over 53,000 autopsy records, including over 600 from individuals whose autopsies revealed the presence of the antipsychotics clozapine or olanzapine, and found that those who took clozapine were significantly less likely to have died by suicide compared to their counterparts who were taking olanzapine.
“Clozapine is an important and effective antisuicide medicine and should be strongly considered for treatment-resistant psychotic disorders, especially when the patient may be at risk for suicide,” study investigator Paul Nestadt, MD, associate professor, Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland, told Medscape Medical News.
The study was published online March 15 in The Journal of Clinical Psychiatry.
Clozapine is the only medication indicated for treatment-resistant schizophrenia and is considered “the most efficacious antipsychotic,” the investigators note. Unfortunately, it has “long been underutilized” for several reasons, including prescriber hesitancy and concerns about side effects.
The authors note that its mechanism of action and the basis for superior efficacy are “still poorly understood” but “may extend beyond neurotransmitter receptor binding.”
Importantly, it may have a beneficial impact on domains other than positive symptoms of schizophrenia, including suicidality. Several studies have shown that it’s beneficial in this regard, but it is “unclear whether the unique antisuicidal properties of clozapine are related to better symptom control…or to the closer monitoring and follow-up mandated for clozapine use,” they note.
A previous trial, the International Suicide Prevention Trial (InterSePT), demonstrated that clozapine is associated with a greater reduction in suicidality, and the findings “led to an FDA indication for clozapine in reducing the risk of recurrent suicidal behavior.”
However, the authors note, “in the severely ill populations in these studies, it is difficult to be certain about patients’ adherence to prescribed clozapine.”
“Other studies, such as InterSePT, have shown some evidence of clozapine working to reduce suicide-related outcomes, such as attempts or suicidal ideation, but few have been sufficiently powered to measure an effect on actual suicide deaths,” said Nestadt.
“As a suicidologist, I feel it is very important that we understand what treatments and interventions can actually prevent suicide deaths, as most suicides are not associated with past attempts or ideation, with suicide decedents usually looking very different from characteristic nonfatal attempters, from a clinical or epidemiological standpoint,” he added.
“If we could show that clozapine actually decreases the likelihood of suicide deaths in our patients, it gives us more reason to choose it over less effective neuroleptics in our clinics — especially for patients at high risk of suicide,” he said.
For the study, the researchers reviewed 19-year state-wide autopsy records of Maryland’s Office of the Chief Medical Examiner, which “performs uniquely comprehensive death investigations.” Data included in these investigations are full toxicologic panels with postmortem blood levels of antipsychotics.
The researchers compared decedents who tested positive for clozapine and decedents who tested positive for olanzapine. They evaluated demographics, clinical features, and manner-of-death outcomes.
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 (OR, 0.47; 95% CI, 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 to 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).
Nestadt outlined several hypotheses regarding the mechanism of clozapine’s antisuicidal properties.
“Most theories stem from the differences in its receptor affinity, compared to 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 Hoffman.
“Strongly Suggestive” Data
Commenting for Medscape Medical News, 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 Oquendo, past president of the American Psychiatric Association.
Nevertheless, some questions remain, said 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 Oquendo.
The study received no funding or support. 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. 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.
J Clin Psychiatry. Published online March 15, 2023. Abstract
Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).
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