Hypnotics Linked to Increased Suicide Risk

Liam Davenport

October 05, 2016

Hypnotic medications such as benzodiazepines appear to be associated with an increased risk for suicide and suicidal ideation, although the impact of comorbid depression and substance use remains unclear.

In a review of published literature and US Food and Drug Administration (FDA) data examining the link between hypnotics and suicide, W. Vaughn McCall, MD, Department of Psychiatry and Health Behavior, Medical College of Georgia, in Augusta, showed that the risk for suicide or suicidal ideation associated with the drugs was doubled in some studies.

However, the investigators note that these studies did not adequately control for comorbid depression and other psychiatric disorders that may be linked to insomnia and that suicide deaths in patients who take hypnotics are commonly associated with exposure to multiple drugs.

The study was published online September 9 in the American Journal of Psychiatry.

"Complicated Picture"

In an interview with Medscape Medical News, Dr McCall said that the evidence all together paints a "very complicated picture."

"When people want to commit suicide, they often use sleeping pills to make that happen. That doesn't mean that the sleeping pill...made them suicidal. It was simply the agent of the suicidal behavior. But that's not news.

"[T]he most worrisome thing is these rare, unexpected, paradoxical outbursts of suicidal behavior and suicide death that seem to come early in the course of treatment with a sleeping pill...and it seems to cause disinhibition and acting out of character in a way that would put [patients] at risk of suicide.

"Then the last thing, which kind of turns everything completely upside down, is that there's so much research showing that insomnia is a risk factor for suicide, it could make you think: 'Well, gosh, maybe if we treat insomnia intelligently, we might push people in the opposite direction.'

"So, if I was in an elevator and someone asked me, 'Do sleeping pills make people suicidal?,' the most honest response would be, it just sort of depends," said Dr McCall.

For the current analysis, the researchers focused on studies of US Food and Drug Administration (FDA)–approved hypnotics, beginning with the introduction of benzodiazepines and including flurazepam, temazepam, triazolam, estazolam, quazepam, zolpidem, zaleplon, eszopiclone, ramelteon, doxepin 3 mg and 6 mg, and suvorexant.

They conducted a PubMed search for the literature relating to the drugs using the terms "suicide" and "suicidal." In addition, they searched the FDA website for postmarketing safety reviews and commentaries on adverse event reporting for each of the drugs and submitted Freedom of Information Act requests to the FDA Adverse Event Reporting System for reports of hypnotic-related suicide deaths. They divided the data sources into different categories.

The team notes that hypnotic toxicology studies in suicide victims indicated that, although hypnotics are commonly involved in suicide deaths, they are usually part of multidrug combinations, including sedatives and alcohol.

Several retrospective cohort studies from the United States and elsewhere indicated that the use of hypnotics was associated with an approximate doubling of the risk for suicidal ideation and suicide attempts/death. However, the researchers note that these studies did not adequately control for the severity of depressive illness and the impact of insomnia.

A similar picture was derived from the four prospective cohort studies that the researchers identified. In those studies, hypnotics were associated with a significantly increased risk for suicide, at hazard ratios ranging from 1.22 to 24.3. However, again the findings were confounded by psychiatric and substance abuse diagnoses.

The researchers also listed a series of case reports in which suicidal behaviors and deaths occurred during a period of confusion, amnesia, hallucination, or paranoia shortly after taking hypnotics. These reports suggest that in rare cases, parasomnia may lead to suicidal ideation and suicide during the peak drug effect.

Whether there will ever be definitive research into the link between hypnotics and suicide risk seems doubtful, owing to the large number of participants that would be required to show causality.

"It seems unlikely that such a large trial would ever be attempted; therefore, there is justification for trials to detect a proxy risk factor, such as suicidal ideation, rather than suicide attempts," the investigators write.

For example, pooled data from all phase 3 trials of suvorexant (Belsomra, Merck Sharp Dohme) obtained from the FDA showed that suicidal ideation, as measured on the Columbia–Suicide Severity Rating Scale, occurred in 0.1% of patients given placebo, in 0.2% of those given low-dose suvorexant, and in 0.7% of those receiving a high dose of the drug.

Despite all this, the team suggests that, given the fact that insomnia is itself associated with an increased suicide risk, "judicious prescription of hypnotics, when taken appropriately, might reduce (not increase) the risk of suicide."

They also presented a series of steps to decrease the risk for suicide when prescribing hypnotics, such as prescribing the lowest effective dose, avoiding coprescription with medications that have similar effects, and instructing the patient to take the drugs in the appropriate setting, when they are ready to sleep.

As to his own clinical practice, Dr McCall said: "Having reviewed the data, I'm thinking maybe people's first prescription for a sleeping pill should be for no more than a weeks' worth, and maybe we should get back together with them at the end of the week to see how it went and make sure that nothing weird happened."

Causality "Seems Likely"

Approached for comment, Daniel F. Kripke, MD, from the University of California, San Diego, in La Jolla, said that although it has not been proven that hypnotics cause suicide, "the associations are so strong and logical that causality seems likely.

"The burden of proof is on the manufacturers and advocates of sleeping pills to prove that they are safe. Responsible medical judgment requires avoiding probable risks, even if they are not certain," Dr Kripke told Medscape Medical News.

"The exact same argument was made that the association of smoking with cancer and deaths does not prove that smoking causes cancer, but no sane physician would recommend smoking."

Dr Kripke highlighted a study that he conducted using FDA data, which indicated that hypnotics are associated with an increased incidence of depression. "I don't think anybody questions if depression causes suicide," he added.

Dr Kripke also described the notion put forward by Dr McCall and colleagues that the appropriate treatment of insomnia with hypnotics may reduce the risk for suicide as "fanciful speculation for which there is no scientific evidence whatsoever.

"Moreover, Sanofi has told FDA...that the currently recommended dose is 'ineffective' for treating insomnia, and Merck made similar statements about the recommended dose of suvorexant," he added.

The study was supported by grants from the National Institute of Mental Health and the American Foundation for Suicide Prevention. Dr McCall and several coauthors have reported relationships with industry, which are listed in the original article.

Am J Psychiatry. Published online October 5, 2016. Abstract

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