Journal Mobile Options
Table of Contents
Vol. 72, No. 2, 2003
Issue release date: March–April 2003
Psychother Psychosom 2003;72:71–79

Lines of Evidence on the Risks of Suicide with Selective Serotonin Reuptake Inhibitors

Healy D.
North Wales Department of Psychological Medicine, University of Wales College of Medicine, Bangor, UK

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Background: There has been a long-standing controversy about the possibility that selective serotonin reuptake inhibitor (SSRI) antidepressants might induce suicidality in some patients. Methods: Starting from the clinical studies that gave rise to this issue, this paper reviews an unselected cohort of randomized clinical trials (RCTs), a series of meta-analyses undertaken to investigate aspects of the problem, studies in recurrent brief depressive disorders, epidemiological studies and healthy volunteer studies using SSRIs to shed light on this issue. Results: The original clinical studies produced evidence of a dose-dependent link, present on a challenge, dechallenge and rechallenge basis, between SSRIs and both agitation and suicidality. Meta-analyses of RCTs conducted around this time indicate that SSRIs may reduce suicidal ideation in some patients. These same RCTs, however, yield an excess of suicides and suicide attempts on active treatments compared with placebos. This excess also appears in the best-controlled epidemiological studies. Finally, healthy volunteer studies give indications that SSRIs may induce agitation and suicidality in some individuals. Conclusions: The data reviewed here, which indicate a possible doubling of the relative risk of both suicides and suicide attempts on SSRIs compared with older antidepressants or non-treatment, make it difficult to sustain a null hypothesis, i.e. that SSRIs do not cause problems in some individuals to whom they are given. Further studies or further access to data are indicated to establish the magnitude of any risk and the characteristics of patients who may be most at risk.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Teicher MH, Glod C, Cole JO: Emergence of intense suicidal preoccupation during fluoxetine treatment. Am J Psychiatry 1990;147:207–210.
  2. King RA, Riddle MA, Chappell PB, Hardin MT, Anderson GM, Lombroso P: Emergence of self-destructive phenomena in children and adolescents during fluoxetine treatment. J Am Acad Child Adolesc Psychiatry 1991;30:171–176.
  3. Masand P, Gupta S, Dwan M: Suicidal ideation related to fluoxetine treatment. N Engl J Med 1991;324:420.
  4. Rothschild AJ, Locke CA: Reexposure to fluoxetine after serious suicide attempts by three patients: The role of akathisia. J Clin Psychiatry 1991;52:491–493.
  5. Creaney W, Murray I, Healy D: Antidepressant induced suicidal ideation. Human Psychopharmacol 1991;6:329–332.
  6. Wirshing WC, Van Putten T, Rosenberg J, Marder S, Ames D, Hicks-Gray T: Fluoxetine, akathisia and suicidality: Is there a causal connection? Arch Gen Psychiatry 1992;49:580–581.
  7. Lane RM: SSRI-induced extrapyramidal side-effects and akathisia: Implications for treatment. J Psychopharmacol 1998;12:192–214.
  8. Preda A, MacLean RW, Mazure CM, Bowers MB: Antidepressant-associated mania and psychosis resulting in psychiatric admission. J Clin Psychiatry 2001;62:30–33.
  9. Hill AB: The environment and disease: Association or causation. Proc Roy Soc Med 1966;58:295–300.
  10. Karch FE, Lasagna L: Toward the operational identification of adverse drug reactions. Clin Pharmacol Ther 1977;21:247–253;
  11. Kazdin A: Single-Case Research Designs. New York, Oxford University Press, 1982.
  12. Stevens M: Deliberate drug rechallenge. Hum Toxicol 1983;2:573–577.
  13. Beasley CM Jr: Fluoxetine and suicide. BMJ 1991;303:1200.
  14. Girard M: Conclusiveness of rechallenge in the interpretation of adverse drug reactions. Br J Clin Pharmacol 1987;23:73–79.
  15. Dukes MNG: Responsibility for Drug-Induced Injury. Amsterdam, Elsevier, 1988.
  16. Federal Judicial Center: Reference Manual on Scientific Evidence. Washington, Federal Judicial Center, 1994, pp 160–161.
  17. Committee on Safety of Medicine’s ‘Current Problems’ (No 21). Guidance on Benzodiazepines, January 1988.
  18. Healy D: Let Them Eat Prozac. Toronto, Lorimer, 2003.
  19. Khan A, Warner HA, Brown WA: Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials. Arch Gen Psychiatry 2000;57:311–317.
  20. Storosum JG, van Zwieten BJ, van den Brink W, Gersons BP, Broekman AW: Suicide rate in placebo-controlled studies of major depression. Am J Psychiatry 2001;158:1271–1275.
  21. Laughren TP: The scientific and ethical basis for placebo-controlled trials in depression and schizophrenia: An FDA perspective. Eur Psychiatry 2001;16:418–423.
  22. Brecher M: FDA Review and Evaluation of Clinical Data Original NDA 20–021, Paroxetine Safety Review, June 19, 1991 (available from author).
  23. Lee H: Statistical reviews on Sertraline for FDA, August 14, 1990 (available from author).
  24. Khan A, Khan SR, Leventhal RM, Brown WA: Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: A replication analysis of the Food and Drug Administration Database. Int J Neuropsychopharmacol 2001;4:113–118.
  25. Von Keitz B: Suicide Report for the BGA, December 1986. Brickler G: Exhibit 1 in Fentress vs Eli Lilly, 1994. Hardison CD: Summary of Suicide Attempt Rate, April 10, 1985. Ashbrook E: Exhibit 5 in Fentress vs Eli Lilly, 1994 (all available from the author).
  26. Kasper S: The place of milnacipran in the treatment of depression. Human Psychopharmacol 1997;12:S135–S141.

    External Resources

  27. Montgomery SA, McAulay R, Rani SJ, Roy D, Montgomery DB: A double-blind comparison of zimelidine and amitriptyline in endogenous depression. Acta Psychiatr Scand 1981;63(suppl 290):314–327.
  28. Wakelin JS: The role of serotonin in depression and suicide. Do serotonin reuptake inhibitors provide a key? in Gastpar M, Wakelin JS (eds): Selective Serotonin Reuptake Inhibitors: Novel or Commonplace Agents. Basel, Karger 1988, pp 70–83.
  29. Lopez-Ibor JJ: Reduced suicidality on paroxetine. Eur Psychiatry 1993;1(suppl 8):17S–19S.
  30. Montgomery SA, Dunner DL, Dunbar G: Reduction of suicidal thoughts with paroxetine in comparison to reference antidepressants and placebo. Eur Neuropsychopharmacol 1995;5:5–13.
  31. Beasley CM, Dornseif BE, Bosomworth JC, Sayler ME, Rampey AH, Heiligenstein JH, et al: Fluoxetine and suicide: A meta-analysis of controlled trials of treatment for depression. BMJ 1991;303:685–692.
  32. Healy D: A failure to warn. Int J Risk Saf Med 1999;12:151–156.
  33. American Psychiatric Association: Diagnostic and Statistical Manual revised (DSM-IV-TR). Washington, American Psychiatric Association, 2000.
  34. Montgomery DB, Roberts A, Green M, Bullock T, Baldwin D, Montgomery SA: Lack of efficacy of fluoxetine in recurrent brief depression and suicidal attempts. Eur Arch Psychiatry Clin Neurosci 1994;244:211–215.
  35. Exhibit 21 in the deposition of J Wernicke in Fentress vs Eli Lilly, 1994.
  36. Baldwin D: The treatment of recurrent brief depression. Eur Coll Neuropsychopharmacol Meet, London, September 1999.
  37. Verkes RJ, Van Der Mast RC, Hengeveld MW, Tuyl JP, Zwinderman AH, Van Kempen GM: Reduction by paroxetine of suicidal behavior in patients with repeated suicide attempts but not major depression. Am J Psychiatry 1998;155:543–547.
  38. Ashleigh EA, Fesler FA: Fluoxetine and suicidal preoccupation. Am J Psychiatry 1992;149:1750.
  39. Fava M, Rosenbaum JF: Suicidality and fluoxetine: Is there a relationship? J Clin Psychiatry 1991;52:108–111.
  40. American College of Neuropsychopharmacology: Suicidal behavior and psychotropic medication. Neuropsychopharmacology 1992;8:177–183.
  41. Teicher MH, Glod CA, Cole JO: Antidepressant drugs and the emergence of suicidal tendencies. Drug Saf 1993;8:186–212.
  42. Warshaw MG, Keller MB: The relationship between fluoxetine use and suicidal behavior in 654 subjects with anxiety disorders. J Clin Psychiatry 1996;57:158–166.
  43. Leon AC, Keller MB, Warshaw MG, Mueller TI, Solomon DA, Coryell W: Prospective study of fluoxetine treatment and suicidal behavior in affectively ill subjects. Am J Psychiatry 1999;156:195–201.
  44. Fisher S, Bryant SG, Kent TA: Postmarketing surveillance by patient self-monitoring: Trazodone versus fluoxetine. J Clin Psychopharmacol 1993;13:235–242.
  45. Fisher S, Kent TA, Bryant SG: Postmarketing surveillance by patient self-monitoring: Preliminary data for sertraline versus fluoxetine. J Clin Psychiatry 1995;56:288–296.
  46. Donovan S, Kelleher MJ, Lambourn J, Foster R: The occurrence of suicide following the prescription of antidepressant drugs. Arch Suicide Res 1999;5:181–192.

    External Resources

  47. Donovan S, Clayton A, Beeharry M, Jones S, Kirk C, Waters K, Gardner D, Faulding J, Madely R: Deliberate self-harm and antidepressant drugs. Investigation of a possible link. Br J Psychiatry 2000;177:551–556.
  48. MacKay FJ, Dunn NR, Wilton LV, Pearce GL, Freemantle SN, Mann RD: A comparison of fluvoxamine, fluoxetine, sertraline and paroxetine examined by observational cohort studies. Pharmacoepidemiol Drug Saf 1997;6(suppl 3):S5–S11.
  49. Biswas P, Wilton LV, Shakir SAW: Pharmacovigilance of mirtazapine: Results of a prescription event monitoring study of 13,554 patients in England. Royal Coll Psychiatr Annu Meet, London 2001.
  50. Jick S, Dean AD, Jick H: Antidepressants and suicide. BMJ 1995;310:215–218.
  51. Hagnell O, Lanke J, Rorsman B: Suicide rates in the Lundby study: Mental illness as a risk factor for suicide. Neuropsychobiology 1981;7:248–253.
  52. van Weel-Baumgarten E, van Den Bosch W, van Den Hoogen H, Zitman FG: Ten-year follow-up of depression after diagnosis in general practice. Br J Gen Pract 1998;48:1643–1646.
  53. Simon GE, VonKorff M: Suicide mortality among patients treated for depression in an insured population. Am J Epidemiol 1998;147:155–160.
  54. Boardman AP, Healy D: Modelling suicide risk in affective disorders. Eur Psychiatry 2001;16:400–405.
  55. Isacsson G: Suicide prevention – a medical breakthrough? Acta Psychiatr Scand 2000;102:113–117.
  56. Barbui C, Campmori A, D’Avanzo B, Negri B, Garattini S: Antidepressant drug use in Italy since the introduction of the SSRIs: National trends, regional differences and impact on suicide rates. Soc Psychiatry Psychiatr Epidemiol 1999;34:152–156.
  57. Donovan S, Kelleher MJ, Lambourn J, Foster R: The occurrence of suicide following the prescription of antidepressant drugs. Arch Suicide Res 1999;5:181–192.

    External Resources

  58. Hotopf M, Lewis G, Normand D: Are SSRIs a cost-effective alternative to tricyclics? Br J Psychiatry 1996;168:404–409.
  59. Tranter R, Healy H, Cattell D, Healy D: Functional effects on agents differentially selective to noradrenergic or serotonergic systems. Psychol Med 2002;32:517–524.
  60. Healy D: Antidepressant induced suicidality. Primary Care Psychiatry 2000;6:23–28.

    External Resources

  61. Healy D, Jaffar K, Tranter R: Antidepressant-associated suicidality. Royal Coll Psychiatr Meet, Edinburgh, July 2000.
  62. Saletu B, Grunberger J, Linzmayer L: On central effects of serotonin reuptake inhibitors: Quantitative EEG and psychometric studies with sertraline and zimelidine. J Neural Transm 1986;67:241–266.
  63. Warrington SJ, Dana-Haeri J, Sinclair AJ: Cardiovascular and psychomotor effects of repeated doses of paroxetine: A comparison with amitriptyline and placebo in healthy men. Acta Psychiatr Scand 1989;80(suppl 350):42–44.
  64. Kielholz P, Battegay R: Behandlung depressiver Zustandsbilder, unter spezieller Berücksichtigung von Tofranil, einem neuen Antidepressivum. Schweiz Med Wochenschr 1958;88:763–767.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50