Selective serotonin reuptake inhibitors (SSRIs) and suicide in adults:
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《英国医生杂志》
1 Department of Social Medicine, University of Bristol, Bristol BS8 2PR, 2 Wolfson Institute of Preventive Medicine, Queen Mary, University of London, London EC1M 6BQ
Correspondence to: D Gunnell D.J.Gunnell@bristol.ac.uk
Abstract
Depression affects around one in 38 adults in Britain at any point in time.1 The most serious and distressing consequence of depression is suicide, and concerns have arisen that the very drugs used to treat depression, and by implication reduce the risk of suicide, may in some susceptible individuals cause suicidal feelings, self harm, and suicide.2 3 4 5 This concern is borne out by recent reviews of evidence from randomised controlled trials of selective serotonin reuptake inhibitors (SSRIs) compared with placebo in children.6 2 However, it is uncertain whether such a risk is present in adults and whether risks are increased for suicide as well as non-fatal suicidal end points. A meta-analysis of data for fluoxetine (an SSRI), funded by its manufacturer, found no evidence that suicidal acts were more common among adults receiving active treatment, but the review lacked power (n = 32 episodes of suicide and non-fatal self harm) to identify important risks.7 Khan et al synthesised clinical trial data for nine antidepressants and found, if anything, that suicide rates in people treated with placebo were lower than in those taking SSRIs or other antidepressants.8 Their findings are difficult to interpret as they had not conducted a formal meta-analysis.
We used data from the review of the safety of SSRIs that was recently published by the Medicine and Healthcare products Regulatory Agency (MHRA)9 to carry out a meta-analysis of data from placebo controlled, randomised controlled trials in adults to assess whether adults prescribed the SSRIs have an increased risk of suicide, non-fatal self harm, or suicidal thoughts.
Methods
The MHRA's report presents summary data from 342 placebo controlled trials of SSRIs including 40 826 subjects and 16 suicides. An estimated 172 episodes of non-fatal self harm were reported in data from 477 trials including 52 503 subjects. For suicidal thoughts, data are presented from 477 trials of 45 704 subjects and an estimated 177 episodes (table).
Summary of clinical trial data abstracted from the Medicine and Healthcare products Regulatory Agency's review of the safety of SSRIs9
The pooled odds ratio (with 95% credible intervals) for all SSRIs compared with placebo treated subjects in relation to suicide was 0.85 (0.20 to 3.40). For non-fatal self harm, excluding paroxetine, the odds ratio was 1.57 (0.99 to 2.55), and for suicidal thoughts, excluding paroxetine, it was 0.77 (0.37 to 1.55). The I2 values were 27%, 3%, and 37%, respectively, indicating relatively little heterogeneity across the individual drugs for the first two outcomes. Three suicides in placebo treated patients (all in paroxetine trials) and one suicide among people treated with an SSRI (escitalopram) occurred after they had stopped treatment. Exclusion of these events from our meta-analysis resulted in a revised odds ratio for suicide of 1.24 (0.21 to 6.71). When we included paroxetine data for non-fatal self harm and suicidal thoughts in the meta-analysis, assuming half the events in each arm of the trial were non-fatal self harm and half were suicidal thoughts, the respective odds ratios were 1.29 (0.90 to 1.91) and 0.79 (0.48 to 1.28). These odds ratios may be biased towards null effects as our assumption of an even distribution of episodes of self harm and suicidal thoughts across placebo and control groups is not supported by our meta-analysis of these end points excluding paroxetine data.
All 95% credible intervals are compatible with no increase in risk. The 95% credible interval for suicide is wide because of the small number of events. However, while the credible intervals for the risk of non-fatal self harm are also compatible with at least a doubling of risk and little evidence of risk reduction, those for suicidal thoughts are compatible with up to a two thirds reduction or a modest increase in risk. For non-fatal self harm, the number needed to treat to harm, using the odds ratio without paroxetine, is 759 (based on the weighted prevalence of self harm in the placebo groups of 1 in 433). As the 95% credible intervals for the odds ratio for non-fatal self harm span 1.0 they are compatible with both harm and benefit. Following Altman's suggestion,13 the 95% credible intervals around the numbers needed to treat to harm are 759 (95% credible interval number needed to treat to harm 279 to to number needed to treat to benefit 43 300).
The figure shows the risk estimates for each SSRI in relation to suicide (a), non-fatal self harm (b), and suicidal thoughts (c). Because of the small number of suicides, the confidence intervals for the risk estimates are very wide. Of note, the Bayesian intervals are slightly wider than those in the figures, which have been calculated by using a classical approach, as the bayesian estimates reflect uncertainty about the precision between products.
Forest plots of suicide, non-fatal self harm, and suicidal thoughts in placebo controlled trials of SSRIs
The overall risk of suicide in both arms of the trials combined was 39 per 100 000 (16 suicides among 40 826 subjects). The risk of non-fatal self harm was about 10 times higher than that for suicide (328/100 000 (172 episodes of self harm among 52 503 subjects)); the risk of suicidal thoughts was similar to that for non-fatal self harm (387/100 000 (177 episodes of suicidal thoughts among 45 704 subjects)). As the mean duration of the trials included in the synthesis was eight to 10 weeks,9 the overall rates of suicidal behaviour and thoughts per person year at risk are likely to be some five times higher than the risks calculated here.
Size of trials needed to detect impact of SSRIs on risk of suicide and non-fatal self harm
We based our sample size estimates on the risk of suicide (39/100 000) and non-fatal self harm (328/100 000) among those taking part in the randomised trials of SSRIs, assuming a 20% decrease in risk is considered clinically important. About 1.9 million subjects would need to be recruited to a trial to detect a 20% decrease in suicide risk (assuming 80% power and 5% level of significance). For non-fatal self harm, the total sample size would need to be about 220 000. To detect a halving of risk of suicide and self harm, the sample sizes required would be 262 000 and 31 000 respectively.
Discussion
Singleton N, Bumpstead R, O'Brien M, Lee A, Meltzer H, and Office for National Statistics. Psychiatric morbidity among adults living in private households, 2000. London: Stationery Office, 2001.
Gunnell D, Ashby D. Antidepressants and suicide: what is the balance of benefit and harm? BMJ 2004;329: 34-8.
Healy D, Langmaak C, Savage M. Suicide in the course of the treatment of depression. J Psychopharmacol 1999;13: 94-9.
Healy D. Lines of evidence on the risks of suicide with selective serotonin reuptake inhibitors. Psychother Psychosomat 2003;72: 71-9.
Nutt D. Death and dependence: current controversies over the selective serotonin reuptake inhibitors. J Psychopharmacol 2003;17: 355-64.
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.
Beasley CM Jr, Dornseif BE, Bosomworth JC, Sayler ME, Rampey AH Jr, Heiligenstein JH, et al. Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression. BMJ 1991;303: 685-92.
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.
Report of the CSM Expert Working Group on the safety of selective serotonin reuptake inhibitors. 2004. www.mhra.gov.uk/news/2004/SSRIfinal.pdf (accessed 28 Jan 2005).
Spiegelhalter DJ, Abrams KR, Myles JP. Bayesian approaches to clinical trials and health-care evaluation. Chichester: Wiley, 2003.
Spiegelhalter DJ, Thomas A, Best NG. WinBUGS version 1.2 user manual. Cambridge: MRC Biostatistics Unit, 1999.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327: 557-60.
Altman DG. Confidence intervals for the number needed to treat. BMJ 1998;317: 1309-12.
Kelly S, Bunting J. Trends in suicide in England and Wales, 1982-96. Population Trends 1998;92: 29-41.
Hawton K, Fagg J, Simkin S, Bale E, Bond A. Trends in deliberate self-harm in Oxford, 1985-1995. Implications for clinical services and the prevention of suicide. Br J Psychiatry 1997;171: 556-60.
Gunnell D, Harbord R, Singleton N, Jenkins R, Lewis G. Factors influencing the development and amelioration of suicidal thoughts in the general population. Cohort study. Br J Psychiatry 2004;185: 385-93.
Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med 2004;23: 1351-75.
Als-Nielsen B, Chen W, Gluud C, Kjaergard LL. Association of funding and conclusions in randomized drug trials. JAMA 2003;290: 921-6.
Jick SS, Dean AD, Jick H. Antidepressants and suicide. BMJ 1995;310: 215-8.
Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA 2004;292: 338-43.
Freemantle N, Long A, Mason J, Sheldon T, Song F, Watson P, et al. Effective health care: the treatment of depression in primary care. Leeds: University of Leeds, Department of Health, 1993.
MacGillivray S, Arroll B, Hatcher S, Ogston S, Reid I, Sullivan F, et al. Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care: systematic review and meta-analysis. BMJ 2003;326: 1014-9.
Bech P, Cialdella P, Haugh MC, Birkett MA, Hours A, Boissel JP, et al. Meta-analysis of randomised controlled trials of fluoxetine v. placebo and tricyclic antidepressants in the short-term treatment of major depression. Br J Psychiatry 2000;176: 421-8.
National Collaborating Centre for Mental Health. Depression: management of depression in primary and secondary care. London: National Institute for Clinical Excellence, 2004.(David Gunnell, professor of epidemiology)
Correspondence to: D Gunnell D.J.Gunnell@bristol.ac.uk
Abstract
Depression affects around one in 38 adults in Britain at any point in time.1 The most serious and distressing consequence of depression is suicide, and concerns have arisen that the very drugs used to treat depression, and by implication reduce the risk of suicide, may in some susceptible individuals cause suicidal feelings, self harm, and suicide.2 3 4 5 This concern is borne out by recent reviews of evidence from randomised controlled trials of selective serotonin reuptake inhibitors (SSRIs) compared with placebo in children.6 2 However, it is uncertain whether such a risk is present in adults and whether risks are increased for suicide as well as non-fatal suicidal end points. A meta-analysis of data for fluoxetine (an SSRI), funded by its manufacturer, found no evidence that suicidal acts were more common among adults receiving active treatment, but the review lacked power (n = 32 episodes of suicide and non-fatal self harm) to identify important risks.7 Khan et al synthesised clinical trial data for nine antidepressants and found, if anything, that suicide rates in people treated with placebo were lower than in those taking SSRIs or other antidepressants.8 Their findings are difficult to interpret as they had not conducted a formal meta-analysis.
We used data from the review of the safety of SSRIs that was recently published by the Medicine and Healthcare products Regulatory Agency (MHRA)9 to carry out a meta-analysis of data from placebo controlled, randomised controlled trials in adults to assess whether adults prescribed the SSRIs have an increased risk of suicide, non-fatal self harm, or suicidal thoughts.
Methods
The MHRA's report presents summary data from 342 placebo controlled trials of SSRIs including 40 826 subjects and 16 suicides. An estimated 172 episodes of non-fatal self harm were reported in data from 477 trials including 52 503 subjects. For suicidal thoughts, data are presented from 477 trials of 45 704 subjects and an estimated 177 episodes (table).
Summary of clinical trial data abstracted from the Medicine and Healthcare products Regulatory Agency's review of the safety of SSRIs9
The pooled odds ratio (with 95% credible intervals) for all SSRIs compared with placebo treated subjects in relation to suicide was 0.85 (0.20 to 3.40). For non-fatal self harm, excluding paroxetine, the odds ratio was 1.57 (0.99 to 2.55), and for suicidal thoughts, excluding paroxetine, it was 0.77 (0.37 to 1.55). The I2 values were 27%, 3%, and 37%, respectively, indicating relatively little heterogeneity across the individual drugs for the first two outcomes. Three suicides in placebo treated patients (all in paroxetine trials) and one suicide among people treated with an SSRI (escitalopram) occurred after they had stopped treatment. Exclusion of these events from our meta-analysis resulted in a revised odds ratio for suicide of 1.24 (0.21 to 6.71). When we included paroxetine data for non-fatal self harm and suicidal thoughts in the meta-analysis, assuming half the events in each arm of the trial were non-fatal self harm and half were suicidal thoughts, the respective odds ratios were 1.29 (0.90 to 1.91) and 0.79 (0.48 to 1.28). These odds ratios may be biased towards null effects as our assumption of an even distribution of episodes of self harm and suicidal thoughts across placebo and control groups is not supported by our meta-analysis of these end points excluding paroxetine data.
All 95% credible intervals are compatible with no increase in risk. The 95% credible interval for suicide is wide because of the small number of events. However, while the credible intervals for the risk of non-fatal self harm are also compatible with at least a doubling of risk and little evidence of risk reduction, those for suicidal thoughts are compatible with up to a two thirds reduction or a modest increase in risk. For non-fatal self harm, the number needed to treat to harm, using the odds ratio without paroxetine, is 759 (based on the weighted prevalence of self harm in the placebo groups of 1 in 433). As the 95% credible intervals for the odds ratio for non-fatal self harm span 1.0 they are compatible with both harm and benefit. Following Altman's suggestion,13 the 95% credible intervals around the numbers needed to treat to harm are 759 (95% credible interval number needed to treat to harm 279 to to number needed to treat to benefit 43 300).
The figure shows the risk estimates for each SSRI in relation to suicide (a), non-fatal self harm (b), and suicidal thoughts (c). Because of the small number of suicides, the confidence intervals for the risk estimates are very wide. Of note, the Bayesian intervals are slightly wider than those in the figures, which have been calculated by using a classical approach, as the bayesian estimates reflect uncertainty about the precision between products.
Forest plots of suicide, non-fatal self harm, and suicidal thoughts in placebo controlled trials of SSRIs
The overall risk of suicide in both arms of the trials combined was 39 per 100 000 (16 suicides among 40 826 subjects). The risk of non-fatal self harm was about 10 times higher than that for suicide (328/100 000 (172 episodes of self harm among 52 503 subjects)); the risk of suicidal thoughts was similar to that for non-fatal self harm (387/100 000 (177 episodes of suicidal thoughts among 45 704 subjects)). As the mean duration of the trials included in the synthesis was eight to 10 weeks,9 the overall rates of suicidal behaviour and thoughts per person year at risk are likely to be some five times higher than the risks calculated here.
Size of trials needed to detect impact of SSRIs on risk of suicide and non-fatal self harm
We based our sample size estimates on the risk of suicide (39/100 000) and non-fatal self harm (328/100 000) among those taking part in the randomised trials of SSRIs, assuming a 20% decrease in risk is considered clinically important. About 1.9 million subjects would need to be recruited to a trial to detect a 20% decrease in suicide risk (assuming 80% power and 5% level of significance). For non-fatal self harm, the total sample size would need to be about 220 000. To detect a halving of risk of suicide and self harm, the sample sizes required would be 262 000 and 31 000 respectively.
Discussion
Singleton N, Bumpstead R, O'Brien M, Lee A, Meltzer H, and Office for National Statistics. Psychiatric morbidity among adults living in private households, 2000. London: Stationery Office, 2001.
Gunnell D, Ashby D. Antidepressants and suicide: what is the balance of benefit and harm? BMJ 2004;329: 34-8.
Healy D, Langmaak C, Savage M. Suicide in the course of the treatment of depression. J Psychopharmacol 1999;13: 94-9.
Healy D. Lines of evidence on the risks of suicide with selective serotonin reuptake inhibitors. Psychother Psychosomat 2003;72: 71-9.
Nutt D. Death and dependence: current controversies over the selective serotonin reuptake inhibitors. J Psychopharmacol 2003;17: 355-64.
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.
Beasley CM Jr, Dornseif BE, Bosomworth JC, Sayler ME, Rampey AH Jr, Heiligenstein JH, et al. Fluoxetine and suicide: a meta-analysis of controlled trials of treatment for depression. BMJ 1991;303: 685-92.
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.
Report of the CSM Expert Working Group on the safety of selective serotonin reuptake inhibitors. 2004. www.mhra.gov.uk/news/2004/SSRIfinal.pdf (accessed 28 Jan 2005).
Spiegelhalter DJ, Abrams KR, Myles JP. Bayesian approaches to clinical trials and health-care evaluation. Chichester: Wiley, 2003.
Spiegelhalter DJ, Thomas A, Best NG. WinBUGS version 1.2 user manual. Cambridge: MRC Biostatistics Unit, 1999.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327: 557-60.
Altman DG. Confidence intervals for the number needed to treat. BMJ 1998;317: 1309-12.
Kelly S, Bunting J. Trends in suicide in England and Wales, 1982-96. Population Trends 1998;92: 29-41.
Hawton K, Fagg J, Simkin S, Bale E, Bond A. Trends in deliberate self-harm in Oxford, 1985-1995. Implications for clinical services and the prevention of suicide. Br J Psychiatry 1997;171: 556-60.
Gunnell D, Harbord R, Singleton N, Jenkins R, Lewis G. Factors influencing the development and amelioration of suicidal thoughts in the general population. Cohort study. Br J Psychiatry 2004;185: 385-93.
Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med 2004;23: 1351-75.
Als-Nielsen B, Chen W, Gluud C, Kjaergard LL. Association of funding and conclusions in randomized drug trials. JAMA 2003;290: 921-6.
Jick SS, Dean AD, Jick H. Antidepressants and suicide. BMJ 1995;310: 215-8.
Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA 2004;292: 338-43.
Freemantle N, Long A, Mason J, Sheldon T, Song F, Watson P, et al. Effective health care: the treatment of depression in primary care. Leeds: University of Leeds, Department of Health, 1993.
MacGillivray S, Arroll B, Hatcher S, Ogston S, Reid I, Sullivan F, et al. Efficacy and tolerability of selective serotonin reuptake inhibitors compared with tricyclic antidepressants in depression treated in primary care: systematic review and meta-analysis. BMJ 2003;326: 1014-9.
Bech P, Cialdella P, Haugh MC, Birkett MA, Hours A, Boissel JP, et al. Meta-analysis of randomised controlled trials of fluoxetine v. placebo and tricyclic antidepressants in the short-term treatment of major depression. Br J Psychiatry 2000;176: 421-8.
National Collaborating Centre for Mental Health. Depression: management of depression in primary and secondary care. London: National Institute for Clinical Excellence, 2004.(David Gunnell, professor of epidemiology)