Sleeping Pills May Cut Risk for Suicidal Thoughts in Depression

Pauline Anderson

October 04, 2019

Prescribing a sleeping pill in tandem with an antidepressant medication may help improve sleep quality and reduce the risk of developing suicidal thoughts for patients with insomnia and depression, new research suggests.

Dr W. Vaughn McCall

"This study provides support for the idea that targeted treatment of insomnia may be a useful way to reduce suicidal ideation in depressed folk who are suicidal and have insomnia," lead investigator W. Vaughn McCall, MD, Case Distinguished University Chair, Department of Psychiatry and Health Behaviour, Medical College of Georgia, Augusta, told Medscape Medical News.

The researchers note, "Although the results do not support the routine prescription of hypnotic medication for mitigating suicidal ideation in all depressed outpatients with insomnia, they suggest that coprescription of a hypnotic during initiation of an antidepressant may be beneficial in suicidal outpatients, especially in patients with severe insomnia."

Alternative insomnia treatments, such as targeted psychotherapy, may work as well as a hypnotic, McCall added.

The study was published online September 20 in the American Journal of Psychiatry.

Rising Rates

Suicide rates are on the rise in the United States. Between 2001 and 2015, the rate increased from 12.5 to 15.0 per 100,000 annually.

Insomnia is a risk factor for suicide, but to date, no randomized clinical trial has examined whether targeted pharmacologic treatment of insomnia lowers suicide risk.

The new randomized clinical trial, called Reducing Suicidal Ideation Through Insomnia Treatment (REST-IT), included 103 patients (mean age, 40.5 years). Study participants had major depression, as indicated by the Hamilton Depression Rating Scale (HAM-D); insomnia, as measured by the Insomnia Severity Index (ISI); and suicidal ideation, as measured by Scale for Suicide Ideation (SSI).

Although participants had suicidal thoughts, they did not have suicidal plans or intent, as indicated by the Columbia–Suicide Severity Rating Scale (C-SSRS). McCall noted that it would be unethical to include in an outpatient study those "who wanted to kill themselves tomorrow."

Most participants (62%) were women, and 39% of the sample represented minorities.

There were no significant differences between treatment groups at baseline.

At the start of the study, the patients had not been taking a psychiatry medication for at least a week, and in many cases, for much longer, said McCall.

All patients were offered a selective serotonin reuptake inhibitor (SSRI); most chose fluoxetine. They were randomly assigned to also receive either the lowest available dose (6.25 mg) of controlled-release zolpidem (zolpidem-CR) or placebo at bedtime. Treatment continued for 8 weeks.

At the end of week 1, the zolpidem-CR or placebo dose could be increased if there were no side effects.

The primary outcome was suicidal ideation. Researchers used the SSI, a self-rated scale that evaluates suicidal desire and planning, and the suicidal ideation dimension of the C-SSRS.

In contrast to the SSI, the C-SSRS is completed by physicians, who may use their own interpretation and other information in addition to patient input, said McCall.

Insomnia, Suicide: A Direct Link?

For participants in both study groups, the researchers determined the least square mean scores on the ISI, the SSI, and the C-SSRS.

The zolpidem-CR group showed more improvement in insomnia than the group that received placebo. On average, the least squares mean score on the ISI during the study period was 11.2 for the zolpidem-CR group and 13.8 for the placebo group (P = .004).

Improvements with zolpidem-CR were better for those whose insomnia was more severe.

"It was striking that the subjects with the really bad insomnia seemed to be exactly the group that got the most sleep benefit out of the drug," said McCall.

There was no significant effect of the treatment on suicidal ideation, as measured by the SSI (P = .50). However, for patients who received zolpidem-CR, the suicidal ideation scores on the C-SSRS improved more so than for the patients who received placebo (P = .035).

McCall noted that the zolpidem-CR intervention was associated with a numerically greater reduction in C-SSRS suicidal ideation scores in participants with severe baseline insomnia relative to those with mild to moderate insomnia.

There may be a psychological explanation for why treatment of insomnia reduces suicidal ideation in some patients, said McCall.

There may also be a biological explanation. According to the so-called hyperarousal theory, insomnia is not caused so much by broken sleep machinery as by "an arousal machinery that is functioning in overdrive," which diminishes the ability to make good decisions, he said.

Secondary outcomes included depression severity scores on the HAM-D. The analysis showed that there were significant improvements in depression scores (P < .001), but no significant differences between groups.

This finding dispels the idea that for the patients who received zolpidem, suicide scores improved because depression scores improved, said McCall. "This tells us that maybe there is a link between insomnia and suicide," he said.

Durable Effect

Study participants kept sleep diaries during the study. Among those who completed at least 50% of their diaries, zolpidem-CR yielded numerical advantages for sleep latency, wake after sleep onset, and total sleep time.

Both groups experienced improved quality of life, with reductions in hopelessness and dysfunctional beliefs and in attitudes about sleep and nightmares.

"Across the board, patients in both groups profited," said McCall.

No deaths or suicide attempts occurred during the study. About 61% of the zolpidem-CR group and 71% of the placebo group experienced a nonserious adverse event, the most common of which were cold symptoms and flu, followed by nausea and diarrhea, and then headache.

The authors believe the safety findings are as important as the efficacy findings.

"When pharmaceutical companies develop a new medication like an antidepressant or sleeping pill, suicidal patients are routinely excluded, so we don't have much information on how to treat suicidal problems," said McCall.

"To be able to conduct a clinical trial, albeit of modest size, and have everybody get through it safely is a sort of indication that we can conduct clinical trials in suicidal patients and learn something useful without causing undue harm," he said.

The researchers followed up with the patients 1 and 2 weeks after the end of the study. This follow-up was important, said McCall, because "we felt we were in unfamiliar territory" and that the patients may have been "vulnerable."

The investigators found that improvements in suicidality and insomnia persisted after discontinuation of the bedtime medication.

A limitation of the study was that polysomnography was not an outcome measure. Also, the study did not compare a hypnotic agent against cognitive-behavioral therapy for insomnia, which has proved helpful for insomnia in patients with depression.

An Appropriate Approach?

Commenting on the study for Medscape Medical News, Wilfred R. Pigeon, PhD, professor of psychiatry and public health sciences and director of the Sleep and Neurophysiology Research Laboratory, University of Rochester Medical Center, New York, said it was well designed.

Pigeon agreed that the study procedures "provide a model for enrolling and retaining patients at increased risk for suicide."

In addition, the findings "clearly support a strong relationship between reductions in severity of insomnia and reductions in severity of suicidal ideation," he said.

However, Pigeon had some reservations about the study.

Given that there was no effect of the hypnotic in comparison with placebo for the SSI measure and there was a small effect for the C-SSRS measure, "the overall findings do not support zolpidem-CR in reducing suicidal ideation any more than placebo when added to an SSRI in patients with major depression and insomnia," he said.

Although managing insomnia is a valid and important target for suicide prevention among depressed patients, "it remains unclear whether hypnotic management of insomnia in such patients is the appropriate therapeutic lever," said Pigeon.

He noted that epidemiologic evidence links some hypnotics with increased safety risk, although no such adverse events occurred in the current study.

The study was supported by grants from the National Institute of Mental Health. McCall has received honoraria from Anthem, CME Outfitters, and Wolters Kluwer and research support from MECTA, Merck, and VistaGen; he is an adviser for Jazz and Sage. Pigeon is a consultant for CurAegis Technologies.

Am J Psychiatry. Published online September 20, 2019. Abstract

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