W. Vaughn McCall, MD, MSMedical College of GeorgiaAugusta UniversityAugusta, GA

Hypnotic Medications and Suicide: Risk, Mechanisms, Mitigation, and the FDA

W. Vaughn McCall, MD, MS

●Grants: American Foundation of Suicide Prevention; National Institute of Mental Health (NIMH)

●Consultant: Multiple Energy Technologies; Anthem Insurance

●Royalties: Wolters Kluwer Publishing

Disclosures

Evaluate the relationship between hypnotics and increased risk of suicide.

Learning Objective

FDA Warnings and “Alarm Fatigue”●Antidepressants and suicide●Antipsychotics and excess death in patients with

dementia●Hypnotics and suicide

Prior to 2006, FDA Required Hypnotic Labels to Include Risk Warning

●Warns of the risk of prescribing to severely depressed patients, “….particularly the recognition that suicidal tendencies may be present and protective measures may be necessary.”

The emphasis of risk was on the underlying mental illness, and pre-existing suicidal tendencies, not so much on the drug.

FDA label for flurazepam hydrocloride. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/016721s076lbl.pdf.

In 2006 the FDA Expressed Concern of Increased Risk Related to the Newer ‘Z-Drug’ Hypnotic●Resulted in new labeling for z-drugs (zolpidem,

zaleplon, eszopiclone) and subsequent hypnotics●“In primarily depressed patients, worsening of

depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of sedative/hypnotics.

The focus is still on the disease state, but now stipulates the possibility of induction of suicide.

Southworth MR. Division of Drug Risk Evaluation. ODS Postmarketing safety review drug(s) zaleplon (20-859), eszopiclone (21-476), zolpidem (19-908). Event: suicidal ideation and attempts (completed suicide). D050402 D050403 D050404. 8-31-2006. Center for Drug Evaluation and Research f the Food and Drug Administration.

More Specific Warnings for Suvorexant

●“.. In clinical studies, a dose-dependent increase in suicidal ideation was observed in patient taking [suvorexant] as assessed by questionnaires.”

Now the warning has moved to indicate a risk of hypnotics inducing suicidal ideation in persons who are not depressed or otherwise not thought to be at risk. The focus moves from the underlying disease state to the drug itself.

Package insert for suvorexant tablets. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204569s000lbledt.pdf.

Scope of the Problem

● Three percent of non-institutionalized adult Americans have used a prescription hypnotic within the last month1

– 10% have used OTC hypnotics but these have not been linked to suicide and will not be further considered.2

● Insomnia is an independent risk factor for suicidal ideation, suicidal behavior, and suicide death, after adjusting for other known risk factors

● Not clear whether it is riskier to provided targeted treatment for insomnia, or riskier to not provide targeted treatment for insomnia

● Prior reviews of this topic were inconclusive as to whether hypnotics increased the risk for suicide, but nevertheless speculated that disinhibition and/or impairment of judgment from hypnotics could promote risky or violent behavior.3– Prior reviews only considered epidemiologic reports and did not consider published case

report, or FDA post-marketing safety reviews, or FDA Adverse Event reports

1. Bertisch SM, et al. Sleep. 2014;37:343-349.; 2. Ancoli-Isreal S, et al. Sleep. 1999;22(Suppl 2):S347-S353.; 3. Kripke DF. Sleep Med Rev. 2000;4(1):5-20.

Results: Hypnotic Toxicology Studies in Suicide VictimsUSA Study– 187 consecutive suicide victims from San Diego coroner office

1981-1982– 137 men, 50 women, mean age 44

–Hypnotics found in 10.7% of cases– 1/3 also tested positive for alcohol–No cases found where benzodiazepine was the only drug

detected and judged to be sole cause of death–Conclusion: In cases of suicide related to benzodiazepines,

multi-drug overdoses are of primary concernMendelson WB, Rich CL. Act Psychiatr Scand. 1993;88:337-341.

Results: Hypnotic Toxicology Studies in Suicide VictimsTwo Studies Outside of the USA– Study 1: 1467 suicide deaths in Switzerland in 19901

– 22 cases (1.5%) in which benzodiazepine single agent – Flunitrazepam (n = 16), triazolam (n = 1), midazolam (n = 4)

– Conclusion: Role of alcohol may have been underestimated– Study 2: 2245 elderly suicides in Sweden in 2003 by poisoning2

– Single benzodiazepine cause of death in 155 cases– Flunitrazepam (n = 104), nitrazepam (n = 36), triazolam (n = 1)

– Conclusion: Modern hypnotics often involved in suicide deaths, but usually are taken in combination with other sedatives or alcohol

1. Michel K, et al. Pharmocopsychiatry. 1994;27:114-118.2. Carlsten A, et al. Scan J Public Health. 2003;31:224-228.

Results: Retrospective Cohort Studies on the Topic of Hypnotics and SuicideUSA Study– Secondary analysis of National Comorbidity Survey Replication (n = 5692)

2001-2003– 5.8% of respondents affirmed use of sleeping pills in past 12 mos.– 2.6% endorsed suicidal thinking (OR 1.5-3.3)– 0.07% endorsed suicide plans (OR 1.1-3.3)– 0.04% admitted to a suicide attempt (OR 1.1-3.3)

– Strengths: Sampling technique, large sample size, adjustment for insomnia, inclusion of z-drugs

– Weaknesses: Lack of consideration of high-risk personality disorders, lack of measurement of severity of depressive illness, possibility of collection bias, retrospective design

Brower KJ, et al. J Clin Psychiatry. 2011;71(4):515-521.

Results: Retrospective Cohort Studies on the Topic of Hypnotics and SuicideStudies Outside the USA– Study 1: Finnish psychiatric patients (n = 25) who died by suicide during

hospitalization compared to controls (n = 25) with match psychiatric diagnosis1

– Suicide victims more likely to have received benzodiazepine (72%) compared to controls (44%), p < .05.

– Limitations: Lack of detail whether benzodiazepine prescribed for anxiety or insomnia, lack of matching groups on severity of symptoms, small sample size

– Study 2: Taiwanese nationwide register reported association between zolpidem and suicide 2002-2011 compared to 10 matched controls

– Adjusted OR for exposure to zolpidem was 2.08 (1.83-2.36) and remained significant regardless of presence of psychiatric comorbidity

– Limitations: Imprecision in establishing psychiatric diagnosis and lack of measurement of severity of symptoms

– Conclusion: Authors noted zolpidem dreamlike confusion state lead to potentially harmful behavior

1. Taiminen T. Acta Psychiatr Scand. 1993;87:45-47.; 2. Sun Y, et al. Mayo Clin Proc. 2016;91:308-315.

Retrospective Cohort Studies Regarding Hypnotics and SuicideCountry N Outcome Odds Ratio

UnitedStates1 5,692 community-dwelling

adults

Suicide ideation 2.2

Suicide plan 1.9

Suicide attempt 3.4

Finland2 25 psychiatric inpatients Suicide death N/A

Taiwan3 10 adults from nationwide register

Suicide death + hospitalization for suicide attempt 2.08

1. Brower KJ, et al. J Clin Psychiatry. 2011;72:515-521.; 2. Taiminen TJ. Acta Psychiatr Scand. 1993;87:45-47.; 3. Sun Y, et al. Mayo Clin Proc. 2016;91:308-315.

Clinical trials are required to show causality between hypnotics and suicide. The sample size required to identify a difference between hypnotics and placebo in rates of suicide attempts in a sample of insomniacs is 1,068 (534 per group)

Prospective Cohort Studies Regarding Hypnotics and Suicide

Country N Outcome Odds Ratio (OR) or Hazard Ratio (HR)

UnitedStates1 1,099,830 Suicide death Men HR = 1.32

Women HR = 1.22Sweden2 26,952 Suicide death OR = 2.6Canada3 225,796 Suicide attempt or death OR = 6.2Sweden4 1,750 Men

1,773 Women Suicide deathMen HR = 21.2

Women HR = 24.3

1. Kripke DF, et al. Biol Psychiatry. 1998;43:687-693.; 2. Allgulander C, et al. Psychosom Med. 1991;53:101-108.; 3. Neutel CI, et al. Ann Epidemiol. 1997;7:568-574.; 4. Mallon L, et al. Sleep Med. 2009;10:279-286

Illustrative Cases on the Topic of Hypnotics and Suicide: Zolpidem

● Spontaneous adverse event reports from Australia 2001-2008 indicated that zolpidem had higher odds for “parasomnia, amnesia, hallucinations, and perhaps suicidality compared to either all other drugs or hypnotics”.1– OR = 8.3 for suicidality related to zolpidem vs. other psychotropic drugs in

survey● 91 coroner cases from New South Wales 2001-2010 noted 2

cases of “bizarre, dissociative” behavior leading to suicide deaths– Person dancing from high ledge before falling – In another, person impulsively jumped out of a window during an argument

1. Ben-Hamou M, et al. J Sleep Res. 2011;20:559-568.2. Hejri SM, et al. Daru. 2013;21:77.

Illustrative Cases on the Topic of Hypnotics and Suicide in US: Z-Drugs

From FDA post-marketing safety review of Z-drugs in 2006● 33 year-old man with no history of mental illness took zolpidem for 4

or 5 nights, on last night took 10 mg of zolpidem at 2:30 AM. Awoke at 6:AM, went to work and next thing he remembered was “standing on a pile of boxes with a noose around his neck."

● 39 year-old man, with no history of mental illness, took 10 mg of zolpidem for 3 nights. On 3rd night, his wife “found him sleep walking in the closet with no memory of how he got there.” The next morning he “could not focus” and walked into the woods and shot himself

Southworth MR. Division of Drug Risk Evaluation. ODS Postmarketing safety review drug(s) zaleplon (20-859), eszopiclone (21-476), zolpidem (19-908). Event: suicidal ideation and attempts (completed suicide). D050402 D050403 D050404. 8-31-2006. Center for Drug Evaluation and Research f the Food and Drug Administration.

Allocation of Suicidal Ideation as Measured by C-SSRS Across Suvorexant Trials

Group Frequency of SuicidalIdeation per C-SSRS

% With Suicidal Ideation

Placebo (n = 1,025) 1 0.1

Low dosage (n = 493) 1 0.2

High dosage (n = 1,291) 9 0.7

C-SSRS = Columbia-Suicide Severity Rating ScalePooled data across all Phase III trialsPeripheral and Central Nervous System Drugs Advisory Committee, US FDA: Suvorexant Tablets Insomnia Indication: NDA 204569. 2013. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM352970.pdf.

Call to Action

●Closely monitor all patients prescribed hypnotics to uncover any changes to mood or emergence of suicidal ideation

Thank You to Our Team of Contributing Authors!● Ruth M. Benca, MD, PhD● Peter B Rosenquist, MD● Mary Anne Riley, MS● Laryssa McCloud, PhD● Jill C. Newman, MS● Doug Case, PhD● Meredith Rumble, PhD● Andrew D. Krystal, MD, MS● W. Vaughn McCall, MD, MS

Questions Answers &

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