Antidepressant treatment and the risk of fatal and non-fatal self harm
http://www.100md.com
《英国医生杂志》
1 General Practice Research Database Division, Medicines and Healthcare products Regulatory Agency, London SW8 5NQ, 2 Post-Licensing Division, Medicine and Healthcare products Regulatory Agency, 3 Wolfson Institute of Preventive Medicine, Queen Mary, University of London, 4 Department of Psychiatry, University of Edinburgh, Edinburgh, 5 Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London, 6 Department of Social Medicine, University of Bristol, Bristol BS8 2PR
Correspondence to: C Martinez carlos.martinez@gprd.de
Abstract
Since the introduction of selective serotonin reuptake inhibitor (SSRI) antidepressants, concerns have been that these drugs may increase the risk of suicidal behaviour.1-3 Although analyses of data in adults have not consistently shown any influence on suicide or self harm from use of SSRIs,4 randomised controlled trials in young people indicate that these drugs may increase the risk of suicidal thoughts and self harm in those aged under 19.5 6 Ecological studies provide mixed evidence on the risks and benefits of SSRIs—some show that increases in SSRI prescribing are associated with reductions in suicide rates in the population; others show the opposite.4
The most comprehensive studies of suicidal behaviour to date are based on the General Practice Research Database.7 8 The first study contrasted the risks of suicide in people taking antidepressants commonly prescribed between 1988 and 1993. Although this study found some evidence of an increased risk of suicide among people prescribed fluoxetine,7 it was difficult to interpret because the drug's safety in overdose may have led to selective prescription to people at risk of self harm. Another study8 compared the risks for suicide and non-fatal suicidal behaviour between people prescribed fluoxetine, paroxetine, amitriptyline, and dothiepin in 1993 to 1999. No notable differences were found between the drugs in risk for fatal or non-fatal suicidal behaviour. The study was not restricted to patients prescribed antidepressants for the treatment of depression, making comparisons between individual SSRIs and tricyclic antidepressants more liable to confounding.
We report a nested case-control study, based on the General Practice Research Database, of patients with a new diagnosis of depression who were prescribed antidepressants for the first time between 1995 and 2001. We compared the risk of non-fatal self harm and suicide in association with the use of SSRIs and tricyclic antidepressants.
Methods
Our study cohort included 146 095 patients with a first prescription for an antidepressant for depression. These patients contributed 62 224 person years of follow up to the cohort (see bmj.com). Table 1 lists the characteristics of the participants, classified according to the first antidepressant prescribed. Almost twice as many women as men received antidepressants. SSRIs were the most commonly prescribed antidepressants. People prescribed SSRIs tended to be younger and more often had a history of self harm and referral to psychiatrists than those prescribed tricyclic antidepressants.
Table 1 Characteristics of study cohort according to first antidepressant class prescribed. Values are numbers (percentages) unless otherwise indicated
Table 2 shows data on exposures to antidepressants by age group. The strongest predictors of non-fatal self harm were a history of self harm, referral to a psychiatrist, alcohol misuse, and drug misuse. The strongest predictors for suicide were a history of non-fatal self harm, antipsychotic therapy, number of antidepressants prescribed in the previous year, alcohol misuse, and referral to a psychiatrist (table 3).
Table 2 Age and sex distribution of cases of non-fatal self harm and suicide and their matched controls
Table 3 Odds ratios for the association of potential confounders with non-fatal self harm and completed suicides
Over the study period, 1968 people had a recorded an episode of non-fatal self harm: 1344 were exposed to antidepressant medication at the time, and 624 had stopped treatment before the episode. Drug overdose accounted for most episodes of non-fatal self harm (81%). The incidence rate of non-fatal self harm, standardised by age and sex, per 100 000 person years of follow up among people prescribed antidepressants was 2894 (95% confidence interval 2618 to 3170). The rate per 100 000 person years for men was 2834 (2579 to 3089) and for women was 2952 (2471 to 3432).
Overall, 69 suicides took place (56 men, 13 women); 36 of those people were taking antidepressants at the time of death. The overall standardised incidence rate for suicide was 62 (40 to 85) per 100 000 person years; in men this was 117 (72 to 163) and in women 9 (1 to 18).
Table 4 shows the association of current antidepressant use with non-fatal self harm and suicide for all ages. The adjusted odds ratio for non-fatal self harm among SSRI users compared with users of tricyclic antidepressants was 0.99 (0.86 to 1.14). We found no evidence that the risk of non-fatal self harm varied among the different individual SSRIs or tricyclic antidepressants (P = 0.35 and P = 0.69, respectively) and no evidence of an increased risk of suicide associated with use of SSRIs compared with tricyclic antidepressants (odds ratio 0.57, 0.26 to 1.25).
Table 4 Risk of non-fatal self harm and completed suicide in people prescribed SSRIs, other antidepressants, or exposed to more than one antidepressant compared with people prescribed tricylic antidepressants and among specific SSRIs compared with paroxetine and specific tricyclic antidepressants compared with dothiepin (all ages)
We found borderline evidence that the risk of non-fatal self harm (P for interaction = 0.05), but not suicide (P for interaction = 0.73), differed between the different antidepressant categories in relation to time since starting therapy (table 5). This association showed no clear pattern.
Table 5 Risk of non-fatal self harm and suicide in relation to time since starting tricyclic antidepressant monotherapy or SSRI monotherapy (all ages)*
We found evidence of a difference in risk of non-fatal self harm for current SSRI users compared with current users of tricyclic antidepressants in relation to age (P for interaction = 0.02), with an increased risk associated with SSRI use among those aged 18 or younger (odds ratio 1.59, 1.01 to 2.50), but not in 19 to 30 year olds (1.04, 0.82 to 1.31) or those younger than 30 (0.86, 0.71 to 1.04; table 6).
Table 6 Risk of non-fatal self harm in people prescribed SSRIs compared with tricyclic antidepressants in relation to age
In people aged 18 or younger, we found no evidence of any difference in risk of non-fatal self harm between individual tricyclic antidepressants, but among SSRIs (figure), the greatest risk was in relation to paroxetine use.
Fig 1 Risk of non-fatal self harm in patients aged 10-18 currently exposed to citalopram, fluoxetine, fluvoxamine, and sertraline compared with paroxetine
The risk of non-fatal self harm or suicide did not seem to differ between or within antidepressant classes according to the time since stopping treatment (see bmj.com).
Discussion
Healy D. Lines of evidence on the risks of suicide with selective serotonin reuptake inhibitors. Psychother Psychosomat 2003;72: 71-9.
Medawar C, Herxheimer A, Bell A, Jofre S. Paroxetine, Panorama and user reporting of ADRs: Consumer intelligence matters in clinical practice and post-marketing drug surveillance. Int J Risk Saf Med 2002;15: 161-9.
Medawar C. The antidepressant web. Int J Risk Saf Med 1997;10: 75-126.
Gunnell D, Ashby D. Antidepressants and suicide: what is the balance of benefit and harm. BMJ 2004;329: 34-8.
Anonymous. SSRI and venlafaxine use in children. Curr Probl Pharmacovigilance 2003;29: 4.
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.
Jick SS, Dean AD, Jick H. Antidepressants and suicide. BMJ 1995;310: 215-8.
Jick H, Kaye J, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA 2004;292: 338-43.
Wood L; Martinez C: The General Practice Research Database: role in pharmacovigilance. Drug Saf 2004, 27:871-81. www.ingentaconnect.com/content/adis/dsf;jsessionid=t54q6ekj7s9s.Victoria (accessed 19 Jan 2005).
Breslow N, Day N. Statistical methods in cancer. Research, volume II: the design and analysis of cohort. studies. Lyons: International Agency for Research on Cancer, World Health Organization: 1987.
National Statistics Online. Census 2001. www.statistics.gov.uk/census2001/pop2001/united_kingdom.asp (accessed 19 Jan 2005).
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guideline. Clinical investigation of medicinal products in the pediatric population. E11. www.ich.org (accessed 28 Jan 2005.
Vandenbroucke J. When are observational studies as credible as randomised trials? Lancet 2004;363: 1728-31.
Buckley NA, McManus PR. Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data. BMJ 2002;325: 1332-3.
Zahl D and Hawton K. Repetition of deliberate self-harm and subsequent suicide risk: long term follow-up study of 11583 patients. Br J Psychiatry 2004;185: 70-75.
Hawton K, Harriss L, Hall S, Simkin S, Bale E, Bond A. Deliberate self-harm in Oxford 1990-2000: a time of change in patient characteristics. Psychol Med 2003;33: 987-95.
Gunnell D, Frankel S. Prevention of suicide: aspirations and evidence. BMJ 1994;308: 1227-33.
Brock A, Griffiths C: Trends in suicide by method in England and Wales, 1979 to 2001. Health Stat Q 2003;20: 7-17.
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.
National Statistics Online. Trends in suicide by method in England and Wales, 1979 to 2001. www.statistics.gov.uk/downloads/theme_health/HSQ20.pdf (accessed 24 Jan 2005):7-18.(Carlos Martinez, epidemiologist1, Stepha)
Correspondence to: C Martinez carlos.martinez@gprd.de
Abstract
Since the introduction of selective serotonin reuptake inhibitor (SSRI) antidepressants, concerns have been that these drugs may increase the risk of suicidal behaviour.1-3 Although analyses of data in adults have not consistently shown any influence on suicide or self harm from use of SSRIs,4 randomised controlled trials in young people indicate that these drugs may increase the risk of suicidal thoughts and self harm in those aged under 19.5 6 Ecological studies provide mixed evidence on the risks and benefits of SSRIs—some show that increases in SSRI prescribing are associated with reductions in suicide rates in the population; others show the opposite.4
The most comprehensive studies of suicidal behaviour to date are based on the General Practice Research Database.7 8 The first study contrasted the risks of suicide in people taking antidepressants commonly prescribed between 1988 and 1993. Although this study found some evidence of an increased risk of suicide among people prescribed fluoxetine,7 it was difficult to interpret because the drug's safety in overdose may have led to selective prescription to people at risk of self harm. Another study8 compared the risks for suicide and non-fatal suicidal behaviour between people prescribed fluoxetine, paroxetine, amitriptyline, and dothiepin in 1993 to 1999. No notable differences were found between the drugs in risk for fatal or non-fatal suicidal behaviour. The study was not restricted to patients prescribed antidepressants for the treatment of depression, making comparisons between individual SSRIs and tricyclic antidepressants more liable to confounding.
We report a nested case-control study, based on the General Practice Research Database, of patients with a new diagnosis of depression who were prescribed antidepressants for the first time between 1995 and 2001. We compared the risk of non-fatal self harm and suicide in association with the use of SSRIs and tricyclic antidepressants.
Methods
Our study cohort included 146 095 patients with a first prescription for an antidepressant for depression. These patients contributed 62 224 person years of follow up to the cohort (see bmj.com). Table 1 lists the characteristics of the participants, classified according to the first antidepressant prescribed. Almost twice as many women as men received antidepressants. SSRIs were the most commonly prescribed antidepressants. People prescribed SSRIs tended to be younger and more often had a history of self harm and referral to psychiatrists than those prescribed tricyclic antidepressants.
Table 1 Characteristics of study cohort according to first antidepressant class prescribed. Values are numbers (percentages) unless otherwise indicated
Table 2 shows data on exposures to antidepressants by age group. The strongest predictors of non-fatal self harm were a history of self harm, referral to a psychiatrist, alcohol misuse, and drug misuse. The strongest predictors for suicide were a history of non-fatal self harm, antipsychotic therapy, number of antidepressants prescribed in the previous year, alcohol misuse, and referral to a psychiatrist (table 3).
Table 2 Age and sex distribution of cases of non-fatal self harm and suicide and their matched controls
Table 3 Odds ratios for the association of potential confounders with non-fatal self harm and completed suicides
Over the study period, 1968 people had a recorded an episode of non-fatal self harm: 1344 were exposed to antidepressant medication at the time, and 624 had stopped treatment before the episode. Drug overdose accounted for most episodes of non-fatal self harm (81%). The incidence rate of non-fatal self harm, standardised by age and sex, per 100 000 person years of follow up among people prescribed antidepressants was 2894 (95% confidence interval 2618 to 3170). The rate per 100 000 person years for men was 2834 (2579 to 3089) and for women was 2952 (2471 to 3432).
Overall, 69 suicides took place (56 men, 13 women); 36 of those people were taking antidepressants at the time of death. The overall standardised incidence rate for suicide was 62 (40 to 85) per 100 000 person years; in men this was 117 (72 to 163) and in women 9 (1 to 18).
Table 4 shows the association of current antidepressant use with non-fatal self harm and suicide for all ages. The adjusted odds ratio for non-fatal self harm among SSRI users compared with users of tricyclic antidepressants was 0.99 (0.86 to 1.14). We found no evidence that the risk of non-fatal self harm varied among the different individual SSRIs or tricyclic antidepressants (P = 0.35 and P = 0.69, respectively) and no evidence of an increased risk of suicide associated with use of SSRIs compared with tricyclic antidepressants (odds ratio 0.57, 0.26 to 1.25).
Table 4 Risk of non-fatal self harm and completed suicide in people prescribed SSRIs, other antidepressants, or exposed to more than one antidepressant compared with people prescribed tricylic antidepressants and among specific SSRIs compared with paroxetine and specific tricyclic antidepressants compared with dothiepin (all ages)
We found borderline evidence that the risk of non-fatal self harm (P for interaction = 0.05), but not suicide (P for interaction = 0.73), differed between the different antidepressant categories in relation to time since starting therapy (table 5). This association showed no clear pattern.
Table 5 Risk of non-fatal self harm and suicide in relation to time since starting tricyclic antidepressant monotherapy or SSRI monotherapy (all ages)*
We found evidence of a difference in risk of non-fatal self harm for current SSRI users compared with current users of tricyclic antidepressants in relation to age (P for interaction = 0.02), with an increased risk associated with SSRI use among those aged 18 or younger (odds ratio 1.59, 1.01 to 2.50), but not in 19 to 30 year olds (1.04, 0.82 to 1.31) or those younger than 30 (0.86, 0.71 to 1.04; table 6).
Table 6 Risk of non-fatal self harm in people prescribed SSRIs compared with tricyclic antidepressants in relation to age
In people aged 18 or younger, we found no evidence of any difference in risk of non-fatal self harm between individual tricyclic antidepressants, but among SSRIs (figure), the greatest risk was in relation to paroxetine use.
Fig 1 Risk of non-fatal self harm in patients aged 10-18 currently exposed to citalopram, fluoxetine, fluvoxamine, and sertraline compared with paroxetine
The risk of non-fatal self harm or suicide did not seem to differ between or within antidepressant classes according to the time since stopping treatment (see bmj.com).
Discussion
Healy D. Lines of evidence on the risks of suicide with selective serotonin reuptake inhibitors. Psychother Psychosomat 2003;72: 71-9.
Medawar C, Herxheimer A, Bell A, Jofre S. Paroxetine, Panorama and user reporting of ADRs: Consumer intelligence matters in clinical practice and post-marketing drug surveillance. Int J Risk Saf Med 2002;15: 161-9.
Medawar C. The antidepressant web. Int J Risk Saf Med 1997;10: 75-126.
Gunnell D, Ashby D. Antidepressants and suicide: what is the balance of benefit and harm. BMJ 2004;329: 34-8.
Anonymous. SSRI and venlafaxine use in children. Curr Probl Pharmacovigilance 2003;29: 4.
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.
Jick SS, Dean AD, Jick H. Antidepressants and suicide. BMJ 1995;310: 215-8.
Jick H, Kaye J, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA 2004;292: 338-43.
Wood L; Martinez C: The General Practice Research Database: role in pharmacovigilance. Drug Saf 2004, 27:871-81. www.ingentaconnect.com/content/adis/dsf;jsessionid=t54q6ekj7s9s.Victoria (accessed 19 Jan 2005).
Breslow N, Day N. Statistical methods in cancer. Research, volume II: the design and analysis of cohort. studies. Lyons: International Agency for Research on Cancer, World Health Organization: 1987.
National Statistics Online. Census 2001. www.statistics.gov.uk/census2001/pop2001/united_kingdom.asp (accessed 19 Jan 2005).
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH harmonised tripartite guideline. Clinical investigation of medicinal products in the pediatric population. E11. www.ich.org (accessed 28 Jan 2005.
Vandenbroucke J. When are observational studies as credible as randomised trials? Lancet 2004;363: 1728-31.
Buckley NA, McManus PR. Fatal toxicity of serotoninergic and other antidepressant drugs: analysis of United Kingdom mortality data. BMJ 2002;325: 1332-3.
Zahl D and Hawton K. Repetition of deliberate self-harm and subsequent suicide risk: long term follow-up study of 11583 patients. Br J Psychiatry 2004;185: 70-75.
Hawton K, Harriss L, Hall S, Simkin S, Bale E, Bond A. Deliberate self-harm in Oxford 1990-2000: a time of change in patient characteristics. Psychol Med 2003;33: 987-95.
Gunnell D, Frankel S. Prevention of suicide: aspirations and evidence. BMJ 1994;308: 1227-33.
Brock A, Griffiths C: Trends in suicide by method in England and Wales, 1979 to 2001. Health Stat Q 2003;20: 7-17.
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.
National Statistics Online. Trends in suicide by method in England and Wales, 1979 to 2001. www.statistics.gov.uk/downloads/theme_health/HSQ20.pdf (accessed 24 Jan 2005):7-18.(Carlos Martinez, epidemiologist1, Stepha)