Prescribed Benzodiazepines and Suicide Risk: A Review of the Literature

Prescribed Benzodiazepines and Suicide Risk:

A Review of the Literature

Tyler J. Dodds, MDa,*

ABSTRACT

Objective: To evaluate whether prescribed benzodiazepines affect one’s risk of suicide.

Data Sources: A PubMed search of English-language publications from database inception until October 11, 2016, was conducted using the terms benzodiazepine and suicide. References and related articles were also searched to yield additional publications.

Study Selection/Data Extraction: Studies were included if they addressed the relationship between suicidal behavior and the prescribed use of either specific benzodiazepines or benzodiazepines as a class. A total of 17 studies were included in this review.

Results: The majority of studies found that benzodiazepines were associated with increased suicide risk. This finding was consistent across various populations and different types of research, including a placebo-controlled crossover trial, a laboratory model of suicidal behavior, case-control studies regarding completed suicides on inpatient units, and large naturalistic studies.

Conclusions: Benzodiazepines appear to cause an overall increase in the risk of attempting or completing suicide. Possible mechanisms of prosuicidal effects may include increases in impulsivity or aggression, rebound or withdrawal symptoms, and toxicity in overdose.

Prim Care Companion CNS Disord 2017;19(2):16r02037

https://doi.org/10.4088/PCC.16r02037

© Copyright 2017 Physicians Postgraduate Press, Inc.

aThe Austen Riggs Center, Stockbridge, Massachusetts

*Corresponding author: Tyler J. Dodds, MD, The Austen Riggs Center, 25 Main St, PO Box 962, Stockbridge, MA 01262-0962 ([email protected]).

Brains of individuals who died by suicide display altered expression and regulation of genes involved in the γ-aminobutyric acid (GABA)–ergic system, including those coding for GABAA receptor subunits.1–5 In 1 study,6 GABA concentrations in the cerebrospinal fluid correlated with both impulsivity and prior suicidal behavior. Risk factors for suicide include the nonmedical use of GABAA receptor modulators such as alcohol and sedative-hypnotic medications.7 In the National Comorbidity Study Replication,8 the use of sleeping pills or other sedatives, many of which act on GABAA receptors, was associated with a 3-fold higher risk of suicide attempt even after adjusting for insomnia, substance use, anxiety, and mood disorders. Little attention has been paid, however, to the question of whether prescribing a benzodiazepine might raise a patient’s suicide risk. This question is becoming increasingly important to answer: benzodiazepine prescriptions in the United States have increased considerably over the past 2 decades,9 fatal overdoses involving benzodiazepines have become more frequent,9 and suicides in general are steadily rising.10

On the other hand, prescribing clinicians may expect benzodiazepines to protect against suicide by reducing anxiety and insomnia, 2 modifiable risk factors for suicide.11,12 Both symptoms are thought to exacerbate the psychological distress a suicidal person experiences, and insomnia may result in fatigue that then impairs emotional regulation and problem-solving abilities.11 For people who commit suicide, anguish, a state of excruciating mental distress, can lead to desperation, an urgent need for immediate relief of that suffering.13 If these individuals were able to obtain such relief from a rapidly calming medication, perhaps they would not resort to killing themselves. This review seeks to address the evidence regarding these 2 competing hypotheses.

METHODS

Figure 1 illustrates the strategy used to identify studies. A PubMed search of English-language publications from database inception until October 11, 2016, was conducted using the terms benzodiazepine and suicide. Additional publications were found through searching references and related articles (22 studies). Studies were included if they addressed the relationship between suicidal behavior and the prescribed use of either specific benzodiazepines or benzodiazepines as a class. Studies were not included if they addressed only suicidal ideation rather than behavior or reported only on more heterogeneous groups of medications such as sedatives, hypnotics, sedative-hypnotic medications, or sleeping pills. Three studies14–16 were excluded because they measured only lifetime history of suicide attempts without assessing whether participants were prescribed benzodiazepines around the time of those attempts. One study17 was excluded because too few participants were using benzodiazepines to draw any conclusions. Ultimately, 17 studies18–35 (1 study was described in 2 articles19,20) were included in this review.

RESULTS

The majority of the 17 studies (Table 1) found that benzodiazepines were associated with increased suicide risk. The most striking illustration comes from a small placebo-controlled crossover trial19,20 comparing several classes of medications in the outpatient treatment of women with borderline personality disorder. The alprazolam arm of the study was stopped early because of a 58% rate of “severe behavioral dyscontrol” compared to a rate of 14% on placebo (7 of 12 participants vs 2 of 14, P = .025). Examples included overdosing, jumping in front of a car, or throwing a chair at a child. Participants in the study took alprazolam at a mean daily dose of 4.7 mg for up to 6 weeks (mean = 30 days), and the authors19,20 were unable to identify any pattern as to when in the course of the trial these acts occurred. Those who exhibited violent or suicidal behavior generally only displayed minor evidence of dyscontrol in the preceding weeks, and, in some cases, they even reported feeling less depressed or anxious beforehand (on a modified Bunney-Hamburg Rating Scale administered weekly).19,20

Researchers18 demonstrated similar effects under laboratory conditions using a measure known as the self-aggression paradigm, which has previously been shown to correlate with levels of suicidal ideation and past suicidal and self-injurious behavior. In the experiment, 46 healthy young adults were randomized to receive a single dose of either placebo or diazepam 5 mg or 10 mg and then participate in a competitive reaction time task. Each participant selected the intensity of electric shock that would be delivered if he or she “lost” the round. Those who had received diazepam 10 mg self-administered shocks of higher intensity than the control group, and they were about 6 times as likely to select an intensity that they believed would be severe. At a dosage of 5 mg, this effect was not statistically significant.18

Among naturalistic research, the most informative may be a 5-year longitudinal study27 of 21,492 patients with schizophrenia, which found that high-dose benzodiazepines (eg, > 15 mg/d of diazepam) were associated with roughly 2-fold increased suicide rates, even after adjusting for proxy measures of illness severity and treatment adherence. In comparison, antidepressants showed no association, and high-dose antipsychotics (eg, > 7.5 mg/d of risperidone) were associated with lower suicide rates. This comparison between classes of medications helps to mitigate confounding by indication, to some degree, because antidepressants and antipsychotics also may be used to manage anxiety or insomnia.

A similar study26 involving 2,588 patients with first-episode schizophrenia also found a strong association between benzodiazepine use and suicide (hazard ratio [HR] = 3.83; 95% CI, 1.45–10.12). Antidepressants were associated with markedly lower suicide risk (HR = 0.15; 95% CI, 0.03–0.77), and concurrent use of 2 or more antipsychotics showed no association.

Other naturalistic studies of outpatient prescribing consistently confirm this association between benzodiazepines and suicidal behavior in a variety of populations, including patients with schizophrenia,22 adolescents with major depressive disorder,21 and the general population of Saskatchewan, Canada.23 In a case-control study25 of adults with deliberate self-poisoning, these risks were consistent between acute benzodiazepine treatment (eg, less than a week) or longer-term use (eg, 6–12 months). A study28 of suicides among seniors found increased risk with benzodiazepine types and dosages that conformed to Beers Criteria recommendations and with those that did not. US veterans receiving opioid analgesics have also shown higher rates of fatal drug overdoses when concurrently prescribed benzodiazepines, although the authors24 did not distinguish between intentional and accidental overdoses.

Case-control studies comparing inpatients who completed suicide during hospitalization to matched controls have yielded similar results. Two30,32 of 429,30,32,33 such studies found that benzodiazepines were prescribed to more of the patients in the suicide groups than in the control groups, and the other 2 studies29,33 showed nonsignificant trends in that direction. In comparison, antipsychotics displayed either a negative correlation with suicide32,33 or no overall association.29,30 However, 1 additional related study,31 a retrospective chart review involving patients hospitalized on an inpatient unit, found no association between the use of alprazolam or clonazepam and self-injurious or assaultive behavior.

Case-control studies comparing the medications of inpatients who either had or had not attempted suicide just prior to admission yielded mixed results. One such study35 found greater benzodiazepine use among the suicide attempt group, and the other34 found the opposite. Both studies were considerably limited, however, by not controlling for diagnosis35 or not controlling for rates of outpatient psychiatric treatment as a whole.34

CONCLUSIONS

Benzodiazepines have been shown to increase aggression36 and impair behavioral inhibition.37,38 In particular, benzodiazepines may promote a dissociated type of aggression in which users view themselves as friendlier and less hostile but then respond in more aggressive ways to provocation.39 Alcohol, another GABAA receptor modulator, has also been well established to enhance aggression,40 and 1 animal study41 found that benzodiazepine receptor antagonists such as flumazenil can block alcohol’s proaggressive effects.

Impulsivity and aggression both appear to mediate suicide risk.42 While many completed suicides involve planning and preparation, impulsivity may distinguish those individuals who carry out suicidal plans from those who plan for suicide but then decide against it.42 A propensity toward impulsive aggression, which can be passed down between generations, may also be one factor in the intrafamilial transmission of suicidal behavior.43

The majority of studies identified in this review report a positive correlation between prescribed benzodiazepines and attempted or completed suicide. One possible interpretation is that anxiety and insomnia themselves (rather than the medications used to treat these symptoms) are responsible. Several factors, however, suggest that benzodiazepines may play a causal role44: the consistency across different studies and populations, the coherence between diverse lines of evidence (epidemiologic, clinical, laboratory-based, neurobiologic), the availability of experimental evidence,18–20 the plausibility of the proposed mechanisms, and the analogy between prescribed use of benzodiazepines and nonmedical substance use, which is considered an important risk factor for suicide.45 Moreover, some of the same studies linking benzodiazepines and suicide found that antidepressants and antipsychotics, which also may be used to manage anxiety and insomnia, either did not correlate with suicide or were associated with lower suicide rates.26,27

In some cases, benzodiazepines are used as an instrument of suicide. Taken in overdose, they can cause lethal respiratory suppression, particularly when combined with other depressants such as alcohol or opioids.46 In 2013, for example, benzodiazepines were involved in 31% of all fatal prescription drug overdoses in the United States.9 The US Food and Drug Administration47 has since issued a black box warning regarding concurrent prescribing of opioids and benzodiazepines.

Rebound or withdrawal symptoms also may contribute to suicide risk. While benzodiazepines are intended to treat anxiety and insomnia, discontinuation, reduction in dosage, or missed doses may lead to emergence or exacerbation of these same symptoms. Abruptly stopping alprazolam, for example, has been shown to impair sleep onset and quality in healthy volunteers after as little as 2 weeks of daily use.48 More research is needed to clarify the safest manner in which to taper benzodiazepines in patients at risk of suicide.

Several notes of caution are warranted in applying the results of this review to clinical practice. The prescribing of medications requires weighing possible risks against potential benefits for each individual patient. The results of this review also do not rule out the possibility that benzodiazepines may be safe or perhaps even protective for certain patients at certain dosages.

Indeed, effects of benzodiazepines on aggression,36 impulsivity,49 and suicide18,24,27 do appear to be dose dependent. In 1 study,27 for example, increased suicide risk in patients with schizophrenia was only statistically significant at daily dosages equivalent to more than 15 mg of diazepam.

Effects on impulsivity and aggression also vary on the basis of individual characteristics, with greater risk in those patients with low anxiety and high baseline impulsivity or aggression.36,49 Particular care should be used in those with histories of suicide attempts or violence. Disinhibition also may be more likely in children, seniors, those with degenerative central nervous system diseases such as dementia, and those with borderline or antisocial personality disorders compared to other groups.20,49 Of note, clinical impressions of individuals’ responses to benzodiazepines may be misleading, with some patients reporting benefit but then going on to behave more aggressively toward themselves or others.19,20,39

In theory, different benzodiazepines may vary in their level of risk, but the available evidence does not allow for clear comparisons. Most studies included in this review analyzed benzodiazepines as a class rather than separately. While Paton49 suggests greater risk of disinhibition from high-potency benzodiazepines with shorter half-lives (eg, alprazolam), increased aggression is also well documented in response to the longer-acting, lower-potency diazepam.36 The closely related “Z-drugs” (zolpidem, zaleplon, and eszopiclone) were not included in this review, but another recent article50 examines the interplay between insomnia, the use of such hypnotics, and suicide.

Nonpharmacologic approaches, such as attending to sleep hygiene,51 are important for clinicians to consider. Future research should also seek to identify safer medications for the acute management of insomnia and anxious distress in suicidal patients. Although a full review of the research regarding other classes of medications is beyond the scope of this article, several of the studies27,32,33 cited here point to atypical antipsychotics as potential candidates to alleviate these symptoms without increasing the likelihood of suicide.

Submitted: August 19, 2016; accepted November 28, 2016.

Published online: March 2, 2017.

Drug names: alprazolam (Xanax, Niravam, and others), carbamazepine (Tegretol, Epitol, and others), clonazepam (Klonopin and others), diazepam (Valium and others), eszopiclone (Lunesta), lorazepam (Ativan and others), risperidone (Risperdal and others), temazepam (Restoril and others), tranylcypromine (Parnate and others), zaleplon (Sonata and others), zolpidem (Ambien, Edluar, and others).

Potential conflicts of interest: None.

Funding/support: None.

Acknowledgements: Dr Dodds thanks Elizabeth Weinberg, MD, for her clinical insights regarding this topic and Gregory Farr, MLIS, for his assistance with conducting the literature search. Dr Weinberg and Mr Farr are both affiliated with the Austen Riggs Center (Stockbridge, Massachusetts) and report no conflicts of interest related to the subject of this article.

REFERENCES

1. Poulter MO, Du L, Weaver IC, et al. GABAA receptor promoter hypermethylation in suicide brain: implications for the involvement of epigenetic processes. Biol Psychiatry. 2008;64(8):645–652. PubMed doi:10.1016/j.biopsych.2008.05.028

2. Klempan TA, Sequeira A, Canetti L, et al. Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression. Mol Psychiatry. 2009;14(2):175–189. PubMed doi:10.1038/sj.mp.4002110

3. Sequeira A, Mamdani F, Ernst C, et al. Global brain gene expression analysis links glutamatergic and GABAergic alterations to suicide and major depression. PLoS One. 2009;4(8):e6585. PubMed doi:10.1371/journal.pone.0006585

4. Choudary PV, Molnar M, Evans SJ, et al. Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci U S A. 2005;102(43):15653–15658. PubMed doi:10.1073/pnas.0507901102

5. Merali Z, Du L, Hrdina P, et al. Dysregulation in the suicide brain: mRNA expression of corticotropin-releasing hormone receptors and GABA(A) receptor subunits in frontal cortical brain region. J Neurosci. 2004;24(6):1478–1485. PubMed doi:10.1523/JNEUROSCI.4734-03.2004

6. Lee R, Petty F, Coccaro EF. Cerebrospinal fluid GABA concentration: relationship with impulsivity and history of suicidal behavior, but not aggression, in human subjects. J Psychiatr Res. 2009;43(4):353–359. PubMed doi:10.1016/j.jpsychires.2008.04.004

7. Schneider B. Substance use disorders and risk for completed suicide. Arch Suicide Res. 2009;13(4):303–316. PubMed doi:10.1080/13811110903263191

8. Brower KJ, McCammon RJ, Wojnar M, et al. Prescription sleeping pills, insomnia, and suicidality in the National Comorbidity Survey Replication. J Clin Psychiatry. 2011;72(4):515–521. PubMed doi:10.4088/JCP.09m05484gry

9. Bachhuber MA, Hennessy S, Cunningham CO, et al. Increasing benzodiazepine prescriptions and overdose mortality in the United States, 1996–2013. Am J Public Health. 2016;106(4):686–688. PubMed doi:10.2105/AJPH.2016.303061

10. Curtin S, Warner M, Hedegaard H. Increase in suicide in the United States, 1999–2014. National Center for Health Statistics Data Brief No 241. April 22, 2016. CDC website. http://www.cdc.gov/nchs/products/databriefs/db241.htm. Accessed August 12, 2016.

11. Malik S, Kanwar A, Sim LA, et al. The association between sleep disturbances and suicidal behaviors in patients with psychiatric diagnoses: a systematic review and meta-analysis. Syst Rev. 2014;3(1):18. PubMed doi:10.1186/2046-4053-3-18

12. Fawcett J. Treating impulsivity and anxiety in the suicidal patient. Ann N Y Acad Sci. 2001;932(1):94–102, discussion 102–105. PubMed doi:10.1111/j.1749-6632.2001.tb05800.x

13. Maltsberger JT. The descent into suicide. Int J Psychoanal. 2004;85(pt 3):653–667. PubMed doi:10.1516/3C96-URET-TLWX-6LWU

14. Xiang Y-T, Weng Y-Z, Leung C-M, et al. Socio-demographic and clinical correlates of lifetime suicide attempts and their impact on quality of life in Chinese schizophrenia patients. J Psychiatr Res. 2008;42(6):495–502. PubMed doi:10.1016/j.jpsychires.2007.06.001

15. Weinstock LM, Gaudiano BA, Epstein-Lubow G, et al. Medication burden in bipolar disorder: a chart review of patients at psychiatric hospital admission. Psychiatry Res. 2014;216(1):24–30. PubMed doi:10.1016/j.psychres.2014.01.038

16. Lekka NP, Paschalis C, Beratis S. Suicide attempts in high-dose benzodiazepine users. Compr Psychiatry. 2002;43(6):438–442. PubMed doi:10.1053/comp.2002.35912

17. Fleischhacker WW, Kane JM, Geier J, et al. Completed and attempted suicides among 18,154 subjects with schizophrenia included in a large simple trial. J Clin Psychiatry. 2014;75(3):e184–e190. PubMed doi:10.4088/JCP.13m08563

18. Berman ME, Jones GD, McCloskey MS. The effects of diazepam on human self-aggressive behavior. Psychopharmacology (Berl). 2005;178(1):100–106. PubMed doi:10.1007/s00213-004-1966-8

19. Cowdry RW, Gardner DL. Pharmacotherapy of borderline personality disorder: alprazolam, carbamazepine, trifluoperazine, and tranylcypromine. Arch Gen Psychiatry. 1988;45(2):111–119. PubMed doi:10.1001/archpsyc.1988.01800260015002

20. Gardner DL, Cowdry RW. Alprazolam-induced dyscontrol in borderline personality disorder. Am J Psychiatry. 1985;142(1):98–100. PubMed doi:10.1176/ajp.142.1.98

21. Brent DA, Emslie GJ, Clarke GN, et al. Predictors of spontaneous and systematically assessed suicidal adverse events in the treatment of SSRI-resistant depression in adolescents (TORDIA) study. Am J Psychiatry. 2009;166(4):418–426. PubMed doi:10.1176/appi.ajp.2008.08070976

22. Fontanella CA, Campo JV, Phillips GS, et al. Benzodiazepine use and risk of mortality among patients with schizophrenia: a retrospective longitudinal study. J Clin Psychiatry. 2016;77(5):661–667. PubMed doi:10.4088/JCP.15m10271

23. Neutel CI, Patten SB. Risk of suicide attempts after benzodiazepine and/or antidepressant use. Ann Epidemiol. 1997;7(8):568–574. PubMed doi:10.1016/S1047-2797(97)00126-9

24. Park TW, Saitz R, Ganoczy D, et al. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study. BMJ. 2015;350:h2698. PubMed doi:10.1136/bmj.h2698

25. Shih H-I, Lin M-C, Lin C-C, et al. Benzodiazepine therapy in psychiatric outpatients is associated with deliberate self-poisoning events at emergency departments: a population-based nested case-control study. Psychopharmacology (Berl). 2013;229(4):665–671. PubMed doi:10.1007/s00213-013-3127-4

26. Tiihonen J, Suokas JT, Suvisaari JM, et al. Polypharmacy with antipsychotics, antidepressants, or benzodiazepines and mortality in schizophrenia. Arch Gen Psychiatry. 2012;69(5):476–483. PubMed doi:10.1001/archgenpsychiatry.2011.1532

27. Tiihonen J, Mittendorfer-Rutz E, Torniainen M, et al. Mortality and cumulative exposure to antipsychotics, antidepressants, and benzodiazepines in patients with schizophrenia: an observational follow-up study. Am J Psychiatry. 2016;173(6):600–606. PubMed doi:10.1176/appi.ajp.2015.15050618

28. Voaklander DC, Rowe BH, Dryden DM, et al. Medical illness, medication use and suicide in seniors: a population-based case-control study. J Epidemiol Community Health. 2008;62(2):138–146. PubMed doi:10.1136/jech.2006.055533

29. Gaertner I, Gilot C, Heidrich P, et al. A case control study on psychopharmacotherapy before suicide committed by 61 psychiatric inpatients. Pharmacopsychiatry. 2002;35(2):37–43. PubMed doi:10.1055/s-2002-25027

30. Neuner T, Hübner-Liebermann B, Haen E, et al; AGATE. Completed suicides in 47 psychiatric hospitals in Germany—results from the AGATE-study. Pharmacopsychiatry. 2011;44(7):324–330. PubMed doi:10.1055/s-0031-1284428

31. Rothschild AJ, Shindul-Rothschild JA, Viguera A, et al. Comparison of the frequency of behavioral disinhibition on alprazolam, clonazepam, or no benzodiazepine in hospitalized psychiatric patients. J Clin Psychopharmacol. 2000;20(1):7–11. PubMed doi:10.1097/00004714-200002000-00003

32. Taiminen TJ. Effect of psychopharmacotherapy on suicide risk in psychiatric inpatients. Acta Psychiatr Scand. 1993;87(1):45–47. PubMed doi:10.1111/j.1600-0447.1993.tb03328.x

33. Taiminen TJ, Kujari H. Antipsychotic medication and suicide risk among schizophrenic and paranoid inpatients: a controlled retrospective study. Acta Psychiatr Scand. 1994;90(4):247–251. PubMed doi:10.1111/j.1600-0447.1994.tb01588.x

34. Barak Y, Olmer A, Aizenberg D. Antidepressants reduce the risk of suicide among elderly depressed patients. Neuropsychopharmacology. 2006;31(1):178–181. PubMed

35. Raja M, Azzoni A, Koukopoulos AE. Psychopharmacological treatment before suicide attempt among patients admitted to a psychiatric intensive care unit. J Affect Disord. 2009;113(1–2):37–44. PubMed doi:10.1016/j.jad.2008.04.024

36. Albrecht B, Staiger PK, Hall K, et al. Benzodiazepine use and aggressive behaviour: a systematic review. Aust N Z J Psychiatry. 2014;48(12):1096–1114. PubMed doi:10.1177/0004867414548902

37. Acheson A, Reynolds B, Richards JB, et al. Diazepam impairs behavioral inhibition but not delay discounting or risk taking in healthy adults. Exp Clin Psychopharmacol. 2006;14(2):190–198. PubMed doi:10.1037/1064-1297.14.2.190

38. Deakin JB, Aitken MR, Dowson JH, et al. Diazepam produces disinhibitory cognitive effects in male volunteers. Psychopharmacology (Berl). 2004;173(1–2):88–97. PubMed doi:10.1007/s00213-003-1695-4

39. Bond AJ, Curran HV, Bruce MS, et al. Behavioural aggression in panic disorder after 8 weeks’ treatment with alprazolam. J Affect Disord. 1995;35(3):117–123. PubMed doi:10.1016/0165-0327(95)00053-4

40. Heinz AJ, Beck A, Meyer-Lindenberg A, et al. Cognitive and neurobiological mechanisms of alcohol-related aggression. Nat Rev Neurosci. 2011;12(7):400–413. PubMed doi:10.1038/nrn3042

41. Weerts EM, Tornatzky W, Miczek KA. Prevention of the pro-aggressive effects of alcohol in rats and squirrel monkeys by benzodiazepine receptor antagonists. Psychopharmacology (Berl). 1993;111(2):144–152. PubMed doi:10.1007/BF02245516

42. Gvion Y, Apter A. Aggression, impulsivity, and suicide behavior: a review of the literature. Arch Suicide Res. 2011;15(2):93–112. PubMed doi:10.1080/13811118.2011.565265

43. Brent DA, Oquendo M, Birmaher B, et al. Familial pathways to early-onset suicide attempt: risk for suicidal behavior in offspring of mood-disordered suicide attempters. Arch Gen Psychiatry. 2002;59(9):801–807. PubMed doi:10.1001/archpsyc.59.9.801

44. Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58(5):295–300. PubMed

45. Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266–1277. PubMed doi:10.1176/appi.ajp.2011.10111704

46. Charlson F, Degenhardt L, McLaren J, et al. A systematic review of research examining benzodiazepine-related mortality. Pharmacoepidemiol Drug Saf. 2009;18(2):93–103. PubMed doi:10.1002/pds.1694

47. FDA requires strong warnings for opioid analgesics, prescription opioid cough products, and benzodiazepine labeling related to serious risks and death from combined use. August 31, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm518697.htm. Accessed November 13, 2016.

48. Barbanoj MJ, Clos S, Romero S, et al. Sleep laboratory study on single and repeated dose effects of paroxetine, alprazolam and their combination in healthy young volunteers. Neuropsychobiology. 2005;51(3):134–147. PubMed doi:10.1159/000085206

49. Paton C. Benzodiazepines and disinhibition: a review. Psychiatrist. 2002;26(12):460–462.

50. McCall WV, Benca RM, Rosenquist PB, et al. Hypnotic medications and suicide: risk, mechanisms, mitigation, and the FDA. Am J Psychiatry. 2017;174(1):18–25. PubMed doi:10.1176/appi.ajp.2016.16030336

51. Stepanski EJ, Wyatt JK. Use of sleep hygiene in the treatment of insomnia. Sleep Med Rev. 2003;7(3):215–225. PubMed doi:10.1053/smrv.2001.0246