Benzodiazepines Do Not Cause Suicide or Suicide Attempts

See reply by Dodds and article by Dodds

Benzodiazepines Do Not Cause Suicide or Suicide Attempts

To the Editor: It is unfortunate that a recent literature review published in the Primary Care Companion for CNS Disorders concluded that "benzodiazepines appear to cause an overall increase in the risk of attempting or completing suicide."1(p1) As the authors of a study2 that found no such relationship, which was cited in the review, we feel it is important to point out to your readers the serious flaws in the author’s methodology, which led him to unwarranted conclusions. The majority of the studies cited in the literature review were unable to control for confounding variables including severity of anxiety, severity of depression, or that benzodiazepines are more likely to be prescribed to patients who are already at an increased risk for suicide because of their anxiety disorder.3-5 Of the 17 studies included in the review,1 only 2 were placebo controlled. The first,6 in healthy volunteers, was not a study of attempted or completed suicide. The second,7 which the author states is "the most striking illustration"1(p1) that benzodiazepines are associated with an increased risk of suicide was a small 16-patient study of patients suffering from severe borderline personality disorder, which reported higher rates of disinhibition, not suicide. Furthermore, Gardner and Cowdry7 pointed out in their article that "since there was no standardized benzodiazepine comparison group, it is impossible to determine whether the incidence of disinhibition was higher for patients taking alprazolam"(p99) and that higher than usual doses of alprazolam were used.

In his review, Dr Dodds failed to include or cite several important published literature reviews8,9 that do not substantiate the argument that benzodiazepines are associated with rage attacks, physical assault, self-destructive behavior, or depression.

Studies such as ours2 and others,10 which allowed for the assessment of behavioral disturbances in a high-risk population under 24-hour observation, found no increased risk of suicide or suicide attempts in patients taking benzodiazepines. A third study11 done in 47 psychiatric hospitals in Germany, which Dr Dodds mistakenly used to support his opinion that benzodiazepines are associated with an increased risk of suicide or suicide attempts, also did not conclude that there was an increased risk of suicide or suicide attempts in patients taking benzodiazepines.

The invocation by Dr Dodds of the Bradford-Hill criteria for causation12 is inappropriate because no statistically significant association of benzodiazepines with an increased risk of suicide or suicide attempts was reported by Dr Dodds. No meta-analysis was done. If no statistically significant positive association is found, it cannot be said that exposure to the drug is associated in any way with the outcome, much less that cause and effect has been established. The analysis of potential causality would be over; there is no causality.13

In conclusion, benzodiazepines play an important role in decreasing symptoms of anxiety, which in turn reduces the risk of suicide.14 The totality of the reliable scientific evidence does not support the conclusion that benzodiazepines are associated with, let alone causally associated with, an increased risk of suicide or suicide attempts.

References

1. Dodds TJ. Prescribed benzodiazepines and suicide risk: a review of the literature. Prim Care Companion CNS Disord. 2017;19(2):16r02037. PubMed doi:10.4088/PCC.16r02037

2. 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

3. Fawcett J. Suicide and anxiety in DSM-5. Depress Anxiety. 2013;30(10):898-901. PubMed

4. Khan A, Leventhal RM, Khan S, et al. Suicide risk in patients with anxiety disorders: a meta-analysis of the FDA database. J Affect Disord. 2002;68(2-3):183-190. PubMed doi:10.1016/S0165-0327(01)00354-8

5. Busch KA, Fawcett J, Jacobs DG. Clinical correlates of inpatient suicide. J Clin Psychiatry. 2003;64(1):14-19. PubMed doi:10.4088/JCP.v64n0105

6. 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

7. 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

8. Jonas JM, Hearron AE Jr. Alprazolam and suicidal ideation: a meta-analysis of controlled trials in the treatment of depression. J Clin Psychopharmacol. 1996;16(3):208-211. PubMed doi:10.1097/00004714-199606000-00003

9. Rothschild AJ. Disinhibition, amnestic reactions, and other adverse reactions secondary to triazolam: a review of the literature. J Clin Psychiatry. 1992;53(suppl):69-79. PubMed

10. 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

11. 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

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

13. Reference Manual on Scientific Evidence. 2nd ed. Washington, DC: Federal Judicial Center; 2000.

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

Anthony J. Rothschild, MDa

[email protected]

Judith A Shindul-Rothschild, PhD, MSN, RNb

aDepartment of Psychiatry, University of Massachusetts Medical School and UMass Memorial Health Care, Worcester, Massachusetts

bWilliam F. Connell School of Nursing, Boston College, Chestnut Hill, Massachusetts

Potential conflicts of interest: Dr Rothschild has received grant or research support from Allergan, Janssen, the National Institute of Mental Health, and Takeda; is a consultant to Eli Lilly and Company, GlaxoSmithKline, Pfizer, and Sanofi-Aventis; and has received royalties from UpToDate, UMass Medical School for the Rothschild Scale for Antidepressant Tachyphylaxis (RSAT), and American Psychiatric Press, Inc for Psychoneuroendocrinology: The Scientific Basis of Clinical Practice (2003), Clinical Manual for Diagnosis and Treatment of Psychotic Depression (2009), The Evidence-Based Guide to Antipsychotic Medications (2010), and The Evidence-Based Guide to Antidepressant Medications (2012). Dr Shindul-Rothschild reports no conflicts of interest related to the subject of this letter.

Funding/support: The work was supported in part by the Irving S. and Betty Brudnick Endowed Chair of Psychiatry at the University of Massachusetts Medical School.

Role of the sponsor: The sponsor played no role in the design and conduct of the study; collection, management, analysis, and interpretation of data; and preparation, review, or approval of the manuscript.

Published online: October 5, 2017.

Prim Care Companion CNS Disord 2017;19(5):17lr02171

https://doi.org/10.4088/PCC.17lr02171

© Copyright 2017 Physicians Postgraduate Press, Inc.