Association between suicide attempts and selective serotonin reuptake
http://www.100md.com
《英国医生杂志》
1 Ottawa Health Research Institute, Clinical Epidemiology Program, 501 Smyth Road, Box 201, Ottawa, Ontario, Canada K1H 8L6, 2 Departments of Human Genetics and Pediatrics and Biomedical Ethics Unit, McGill University, Montreal, Quebec, Canada, 3 Department of Epidemiology and Biostatistics, McGill University, 4 Department of Psychological Medicine, University of Wales College of Medicine, Bangor
Correspondence to: D Fergusson dafergusson@ohri.ca
Abstract
Worldwide, selective serotonin reuptake inhibitors (SSRIs) are prescribed for the treatment of depression and an expanding list of additional conditions. SSRIs rank among the most commonly prescribed medications in the world, in large part because they have been marketed as safe and effective in treating common conditions.1-3 Concerns related to safety were raised in the early 1990s, with reports describing a possible association with suicidality.4-6 However, inferences regarding the plausibility and strength of the association between suicidality and the use of SSRIs have been divergent.7-9 An early meta-analysis showed that SSRIs potentially decreased suicidal ideation as measured by a single question on the Hamilton depression score.7 A more recent review of data from 77 trials submitted to the US Food and Drug Administration (FDA) found a non-significant increase in suicide rates between patients allocated to SSRIs and those allocated to placebo or other antidepressants.8 Because suicides and suicide attempts are rare events, the inability to document an important difference may be a function of the small number of patients in single studies and meta-analyses published to date. Nevertheless, the UK Committee on Safety of Medicines and the Food and Drug Administration (FDA) have issued public health advisories concerning the use of antidepressants and suicidality.10 11
Given the controversy, we undertook a systematic review of all published randomised controlled trials regardless of treatment indication, to evaluate the association between suicide attempts and the use of SSRIs.
Methods
The literature search identified a total of 3717 citations. After initial review by at least two authors (SD, BH, DF), 999 trials were deemed potentially eligible. Of these, we excluded 375 for the following reasons: duplicate publication (n = 125), not a randomised controlled trial (n = 118), SSRI control only (n = 62), no SSRI arm (n = 13), subgroup analysis (n = 20), foreign language other than French or English (n = 13), short trial duration (n = 12), incomplete or inaccessible data (n = 10), and population of suicidal patients (n = 2). We identified an additional 78 trials meeting eligibility criteria by the electronic search of the Cochrane Collaboration register of controlled trials (Cochrane depression, anxiety, and neurosis group) and the manual review of the bibliographies of three published systematic reviews and of all eligible trials (fig 1). 13-15 The 702 trials comprised 411 comparisons between SSRIs and placebo, 220 comparisons between SSRIs and tricyclic antidepressants, and 159 comparisons between SSRIs and active therapies other than placebos or tricyclic antidepressants. As some trials had more than one comparison arm, the total number of comparisons exceeds the number of published trials. Of the 159 comparisons, the most common comparative treatments were moclobemide (21 trials), psychotherapy (20), maprotiline (18), and mianserin (16).
Fig 1 Identification and inclusion of trials
Four hundred and thirty seven trials (62.3%) randomised less than 100 patients. Forty nine trials (7.0%) went on for longer than six months. Of the 493 trials that reported dropout information, 227 (46.0%) had a dropout rate of more than 25%. One hundred and four trials (14.8%) reported adverse events beyond thresholds of 3%, 5%, or 10% of enrolled patients or occurring in more than a defined number of patients, without any detail of adverse events related to suicidality.
Of the 702 trials including 87 650 patients, 414 (59.0%) were conducted in patients with a diagnosis other than major depressive conditions. Sixty eight per cent of trials (n = 475) included more than 50% women, and 91% (n = 638) of trials were conducted in participants with an average age of less than 60 years.
A total of 345 trials representing 36 445 patients reported the number of suicide attempts (143 in total) and were included in the analysis. Of the 345 trials reporting suicide attempts as adverse events, 64 reported at least one suicide attempt. In comparing trial characteristics between trials that reported suicide attempts and those that did not, the only significant difference was that larger trials tended not to report (2 test, df = 2, P = 0.001). The overall rate of suicide attempts was 3.9 (95% confidence interval 3.3 to 4.6) per 1000 patients treated in clinical trials. When we used study duration as exposure time, we found an incidence of 18.2 suicide attempts per 1000 patient years. For the trials conducted in patients with depression, the overall rate of suicide attempts was 4.9 (95% confidence interval 4.2 to 5.6 per 1000 patients). Table 1 provides the reported numbers of fatal and non-fatal suicide attempts.
Fatal and non-fatal suicide attempts in the analysed trials
We found a significant increase in the odds of suicide attempts (odds ratio 2.28, 1.14 to 4.55, number needed to treat to harm 684; P = 0.02) for patients receiving SSRIs compared with placebo (fig 2). Given reduced sample sizes, our ability to detect significant differences within subgroups was limited. However, all odds ratios exceeded 1.0 except for trials whose participants had a mean age of over 60 (fig 2). In comparing non-fatal suicide attempts, a significant difference overall remained (2.70, 1.22 to 5.97; P = 0.01). In comparing fatal suicide attempts, we did not detect any differences between SSRIs and placebo (0.95, 0.24 to 3.78).
Fig 2 Fatal and non-fatal suicide attempts in SSRI trials and placebo trials
In the pooled analysis of SSRIs compared with tricyclic antidepressants, we did not detect differences in the odds of suicide attempts (0.88, 0.54 to 1.42; fig 3). We found no clinically or statistically important differences in any subgroup analyses. The odds ratio of non-fatal suicide attempts was 0.85 (0.51 to 1.43) and the odds ratio of fatal suicide attempts for SSRIs compared with tricyclic antidepressants was 7.27 (1.26 to 42.03).
Fig 3 Fatal and non-fatal suicide attempts in SSRI trials and trials studying tricyclic antidepressants
We found an increase in the odds of suicide attempts when comparing SSRIs with therapeutic interventions other than tricyclic antidepressants (1.94, 1.06 to 3.57, number needed to treat to harm 239; fig 4). Again with smaller sample sizes, we found no subgroup specific differences that reached significance. All odds ratios exceeded 1.0, except for trials in which the proportion of women exceeded 75%. The odds ratio for fatal suicide attempts was 0.59 (0.16 to 2.24) and that for non-fatal suicide attempts 2.25 (1.16 to 4.35).
Fig 4 Fatal and non-fatal suicide attempts in SSRI trials and trials studying other therapies
Discussion
Stafford RS, MacDonald EA, Finkelstein SN. National patterns of medication treatment for depression, 1987 to 2001. Prim Care Companion J Clin Psychiatry 2001;3: 232-5.
Vanderhoff BT, Miller KE. Major depression: assessing the role of new antidepressants. Am Fam Physician 1997;55: 249-54, 259-60.
Guze BH, Gitlin M. New antidepressants and the treatment of depression. J Fam Pract 1994;38: 49-57.
Teicher MH, Glod C, Cole JO. Emergence of intense suicidal preoccupation during fluoxetine treatment. Am J Psychiatry 1990;147: 207-10.
Rothschild AJ, Locke CA. Reexposure to fluoxetine after serious suicide attempts by three patients: the role of akathisia. J Clin Psychiatry 1991;52: 491-3.
Masand P, Gupta S, Dewan M. Suicidal ideation related to fluoxetine treatment. N Engl J Med 1991;324: 420.
Baldwin D, Bullock T, Montgomery D, Montgomery S. 5-HT reuptake inhibitors, tricyclic antidepressants and suicidal behaviour. Int Clin Psychopharmacol 1991;6(suppl 3): 49-55.
Khan A, Khan S, Kolts R, Brown WA. Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. Am J Psychiatry 2003;160: 790-2.
Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviours. JAMA 2004;292: 338-43
Center for Drug Evaluation and Research, United States Food and Drug Administration. Worsening depression and suicidality in patients being treated with antidepressant medications. www.fda.gov/cder/drug/antidepressants/AntidepressanstPHA.htm (accessed 11 May 2004).
Committee on Safety of Medicines, Medicines and Healthcare products Regulatory Agency, United Kingdom. Use of selective serotonin reuptake inhibitors (SSRIs) in children and adolescents with major depressive disorder (MDD)—only fluoxetine (Prozac) shown to have a favourable balance of risks and benefits for the treatment of MDD in the under 18s. http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/cemssri_101203.pdf (accessed 30 June 2004).
Dickersin K, Scherer R, Lefebvre C. Systematic reviews: Identifying relevant studies for systematic reviews. BMJ 1994;309: 1286-91.
North of England Evidence Based Guideline Development Project. Evidence based clinical practice guideline: the choice of anti-depressants for depression in primary care. Report 91. Newcastle upon Tyne: Centre for Health Services Research, 1998.
Barbui C, Hotopf M, Freemantle N, Boynton J, Churchill R, Eccles MP, et al. Treatment discontinuation with selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs). Cochrane Database Syst Rev 2000;(4): CD002791.
Geddes JR, Freemantle N, Mason J, Eccles MP, Boynton J. SSRIs versus other antidepressants for depressive disorder. Cochrane Database Syst Rev 2000;(2): CD001851.
Alderson P, Green S, Higgins JPT, eds. Cochrane reviewers' handbook 4.2.2 . Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley.
Deeks J, Bradburn M, Bilker W, Localio R, Berlin J. Much ado about nothing: statistical methods for meta-analysis with rare events. Proceedings of the Sixth Cochrane Colloquium, Baltimore, USA, 1998: 50.
Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of rare events. 4th Symposium on Systematic Reviews: Pushing the Boundaries. Oxford, July 2002
Healy D, Whitaker C. Antidepressants and suicide: risk-benefit conundrums. J Psychiatry Neurosci 2003;28: 331-7.
Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 2004;363: 1341-5.
Steiner M, Steinberg S, Stewart D, Carter D, Berger C, Reid R, et al. Fluoxetine in the treatment of premenstrual dysphoria. Canadian Fluoxetine/Premenstrual Dysphoria Collaborative Study Group. N Engl J Med 19958; 332: 1529-34.
Haynes RB, Dantes R. Patient compliance and the conduct and interpretation of therapeutic trials. Control Clin Trials 1987;8: 12-9.
((Dean Fergusson, scientist1, Steve Doucet)
Correspondence to: D Fergusson dafergusson@ohri.ca
Abstract
Worldwide, selective serotonin reuptake inhibitors (SSRIs) are prescribed for the treatment of depression and an expanding list of additional conditions. SSRIs rank among the most commonly prescribed medications in the world, in large part because they have been marketed as safe and effective in treating common conditions.1-3 Concerns related to safety were raised in the early 1990s, with reports describing a possible association with suicidality.4-6 However, inferences regarding the plausibility and strength of the association between suicidality and the use of SSRIs have been divergent.7-9 An early meta-analysis showed that SSRIs potentially decreased suicidal ideation as measured by a single question on the Hamilton depression score.7 A more recent review of data from 77 trials submitted to the US Food and Drug Administration (FDA) found a non-significant increase in suicide rates between patients allocated to SSRIs and those allocated to placebo or other antidepressants.8 Because suicides and suicide attempts are rare events, the inability to document an important difference may be a function of the small number of patients in single studies and meta-analyses published to date. Nevertheless, the UK Committee on Safety of Medicines and the Food and Drug Administration (FDA) have issued public health advisories concerning the use of antidepressants and suicidality.10 11
Given the controversy, we undertook a systematic review of all published randomised controlled trials regardless of treatment indication, to evaluate the association between suicide attempts and the use of SSRIs.
Methods
The literature search identified a total of 3717 citations. After initial review by at least two authors (SD, BH, DF), 999 trials were deemed potentially eligible. Of these, we excluded 375 for the following reasons: duplicate publication (n = 125), not a randomised controlled trial (n = 118), SSRI control only (n = 62), no SSRI arm (n = 13), subgroup analysis (n = 20), foreign language other than French or English (n = 13), short trial duration (n = 12), incomplete or inaccessible data (n = 10), and population of suicidal patients (n = 2). We identified an additional 78 trials meeting eligibility criteria by the electronic search of the Cochrane Collaboration register of controlled trials (Cochrane depression, anxiety, and neurosis group) and the manual review of the bibliographies of three published systematic reviews and of all eligible trials (fig 1). 13-15 The 702 trials comprised 411 comparisons between SSRIs and placebo, 220 comparisons between SSRIs and tricyclic antidepressants, and 159 comparisons between SSRIs and active therapies other than placebos or tricyclic antidepressants. As some trials had more than one comparison arm, the total number of comparisons exceeds the number of published trials. Of the 159 comparisons, the most common comparative treatments were moclobemide (21 trials), psychotherapy (20), maprotiline (18), and mianserin (16).
Fig 1 Identification and inclusion of trials
Four hundred and thirty seven trials (62.3%) randomised less than 100 patients. Forty nine trials (7.0%) went on for longer than six months. Of the 493 trials that reported dropout information, 227 (46.0%) had a dropout rate of more than 25%. One hundred and four trials (14.8%) reported adverse events beyond thresholds of 3%, 5%, or 10% of enrolled patients or occurring in more than a defined number of patients, without any detail of adverse events related to suicidality.
Of the 702 trials including 87 650 patients, 414 (59.0%) were conducted in patients with a diagnosis other than major depressive conditions. Sixty eight per cent of trials (n = 475) included more than 50% women, and 91% (n = 638) of trials were conducted in participants with an average age of less than 60 years.
A total of 345 trials representing 36 445 patients reported the number of suicide attempts (143 in total) and were included in the analysis. Of the 345 trials reporting suicide attempts as adverse events, 64 reported at least one suicide attempt. In comparing trial characteristics between trials that reported suicide attempts and those that did not, the only significant difference was that larger trials tended not to report (2 test, df = 2, P = 0.001). The overall rate of suicide attempts was 3.9 (95% confidence interval 3.3 to 4.6) per 1000 patients treated in clinical trials. When we used study duration as exposure time, we found an incidence of 18.2 suicide attempts per 1000 patient years. For the trials conducted in patients with depression, the overall rate of suicide attempts was 4.9 (95% confidence interval 4.2 to 5.6 per 1000 patients). Table 1 provides the reported numbers of fatal and non-fatal suicide attempts.
Fatal and non-fatal suicide attempts in the analysed trials
We found a significant increase in the odds of suicide attempts (odds ratio 2.28, 1.14 to 4.55, number needed to treat to harm 684; P = 0.02) for patients receiving SSRIs compared with placebo (fig 2). Given reduced sample sizes, our ability to detect significant differences within subgroups was limited. However, all odds ratios exceeded 1.0 except for trials whose participants had a mean age of over 60 (fig 2). In comparing non-fatal suicide attempts, a significant difference overall remained (2.70, 1.22 to 5.97; P = 0.01). In comparing fatal suicide attempts, we did not detect any differences between SSRIs and placebo (0.95, 0.24 to 3.78).
Fig 2 Fatal and non-fatal suicide attempts in SSRI trials and placebo trials
In the pooled analysis of SSRIs compared with tricyclic antidepressants, we did not detect differences in the odds of suicide attempts (0.88, 0.54 to 1.42; fig 3). We found no clinically or statistically important differences in any subgroup analyses. The odds ratio of non-fatal suicide attempts was 0.85 (0.51 to 1.43) and the odds ratio of fatal suicide attempts for SSRIs compared with tricyclic antidepressants was 7.27 (1.26 to 42.03).
Fig 3 Fatal and non-fatal suicide attempts in SSRI trials and trials studying tricyclic antidepressants
We found an increase in the odds of suicide attempts when comparing SSRIs with therapeutic interventions other than tricyclic antidepressants (1.94, 1.06 to 3.57, number needed to treat to harm 239; fig 4). Again with smaller sample sizes, we found no subgroup specific differences that reached significance. All odds ratios exceeded 1.0, except for trials in which the proportion of women exceeded 75%. The odds ratio for fatal suicide attempts was 0.59 (0.16 to 2.24) and that for non-fatal suicide attempts 2.25 (1.16 to 4.35).
Fig 4 Fatal and non-fatal suicide attempts in SSRI trials and trials studying other therapies
Discussion
Stafford RS, MacDonald EA, Finkelstein SN. National patterns of medication treatment for depression, 1987 to 2001. Prim Care Companion J Clin Psychiatry 2001;3: 232-5.
Vanderhoff BT, Miller KE. Major depression: assessing the role of new antidepressants. Am Fam Physician 1997;55: 249-54, 259-60.
Guze BH, Gitlin M. New antidepressants and the treatment of depression. J Fam Pract 1994;38: 49-57.
Teicher MH, Glod C, Cole JO. Emergence of intense suicidal preoccupation during fluoxetine treatment. Am J Psychiatry 1990;147: 207-10.
Rothschild AJ, Locke CA. Reexposure to fluoxetine after serious suicide attempts by three patients: the role of akathisia. J Clin Psychiatry 1991;52: 491-3.
Masand P, Gupta S, Dewan M. Suicidal ideation related to fluoxetine treatment. N Engl J Med 1991;324: 420.
Baldwin D, Bullock T, Montgomery D, Montgomery S. 5-HT reuptake inhibitors, tricyclic antidepressants and suicidal behaviour. Int Clin Psychopharmacol 1991;6(suppl 3): 49-55.
Khan A, Khan S, Kolts R, Brown WA. Suicide rates in clinical trials of SSRIs, other antidepressants, and placebo: analysis of FDA reports. Am J Psychiatry 2003;160: 790-2.
Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviours. JAMA 2004;292: 338-43
Center for Drug Evaluation and Research, United States Food and Drug Administration. Worsening depression and suicidality in patients being treated with antidepressant medications. www.fda.gov/cder/drug/antidepressants/AntidepressanstPHA.htm (accessed 11 May 2004).
Committee on Safety of Medicines, Medicines and Healthcare products Regulatory Agency, United Kingdom. Use of selective serotonin reuptake inhibitors (SSRIs) in children and adolescents with major depressive disorder (MDD)—only fluoxetine (Prozac) shown to have a favourable balance of risks and benefits for the treatment of MDD in the under 18s. http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/cemssri_101203.pdf (accessed 30 June 2004).
Dickersin K, Scherer R, Lefebvre C. Systematic reviews: Identifying relevant studies for systematic reviews. BMJ 1994;309: 1286-91.
North of England Evidence Based Guideline Development Project. Evidence based clinical practice guideline: the choice of anti-depressants for depression in primary care. Report 91. Newcastle upon Tyne: Centre for Health Services Research, 1998.
Barbui C, Hotopf M, Freemantle N, Boynton J, Churchill R, Eccles MP, et al. Treatment discontinuation with selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs). Cochrane Database Syst Rev 2000;(4): CD002791.
Geddes JR, Freemantle N, Mason J, Eccles MP, Boynton J. SSRIs versus other antidepressants for depressive disorder. Cochrane Database Syst Rev 2000;(2): CD001851.
Alderson P, Green S, Higgins JPT, eds. Cochrane reviewers' handbook 4.2.2 . Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley.
Deeks J, Bradburn M, Bilker W, Localio R, Berlin J. Much ado about nothing: statistical methods for meta-analysis with rare events. Proceedings of the Sixth Cochrane Colloquium, Baltimore, USA, 1998: 50.
Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of rare events. 4th Symposium on Systematic Reviews: Pushing the Boundaries. Oxford, July 2002
Healy D, Whitaker C. Antidepressants and suicide: risk-benefit conundrums. J Psychiatry Neurosci 2003;28: 331-7.
Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published versus unpublished data. Lancet 2004;363: 1341-5.
Steiner M, Steinberg S, Stewart D, Carter D, Berger C, Reid R, et al. Fluoxetine in the treatment of premenstrual dysphoria. Canadian Fluoxetine/Premenstrual Dysphoria Collaborative Study Group. N Engl J Med 19958; 332: 1529-34.
Haynes RB, Dantes R. Patient compliance and the conduct and interpretation of therapeutic trials. Control Clin Trials 1987;8: 12-9.
((Dean Fergusson, scientist1, Steve Doucet)