Antidepressants and suicide: what is the balance of benefit and harm
http://www.100md.com
《英国医生杂志》
1 Department of Social Medicine, University of Bristol, Bristol BS8 2PR, 2 Wolfson Institute of Preventive Medicine, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, London EC1M 6BQ
Correspondence to: D Gunnell d.j.gunnell@bristol.ac.uk
Introduction
SSRIs and tricyclic antidepressants account for over 90% of antidepressant prescribing in Britain. Systematic reviews confirm that both these classes of antidepressant are effective in adults,10 although SSRIs are better tolerated by patients.11 The effectiveness of antidepressants in childhood and adolescence is less clear.12
As depression is the main psychiatric condition leading to suicide, it seems reasonable to infer that rises in antidepressant prescribing, which indicate improved management of depression, should have a beneficial effect on suicide rates. Indeed, an intervention to improve general practitioners' management of depression in a Swedish community resulted in increased antidepressant prescribing and a short term reduction in suicide.13
Summary points
Concern is growing that serotonin reuptake inhibitors (SSRIs) may precipitate suicidal behaviour, especially in children
Reassuringly, although antidepressant prescribing in Britain has more than doubled in the past 15 years, population suicide rates have fallen.
If the risks of SSRI associated suicidal behaviour seen in children were to apply to suicide in adults, the number of "antidepressant induced" suicides would be small enough to be masked by currently favourable suicide trends
Long term studies are required to assess the risks and benefits to population health of recent large scale rises in antidepressant prescribing.
Surprisingly, direct evidence that antidepressants prevent suicide is hard to find. A meta-analysis of data on the SSRI fluoxetine, funded by its manufacturer, found no evidence that suicidal acts were less frequent among adults taking antidepressants; the pooled incidences were 0.3% for fluoxetine, 0.2% for placebo, and 0.4% for tricyclics.14 In the most comprehensive synthesis of data from randomised trials, Khan and colleagues found no evidence of a beneficial effect of antidepressants on suicide.15 These findings are difficult to interpret as this was not a formal meta-analysis and relative risks were not derived separately for each trial on an intention to treat basis.
Suicide is rare, even among people with depression.16 Thus, most clinical trials have insufficient power to provide clear evidence on the effect of antidepressants on suicide.
Time trends
In the absence of clear evidence from clinical trials, researchers have investigated whether rises in antidepressant prescribing are associated with reductions in population suicide rates.2-6 17-19 With some exceptions,3 17 18 such studies conclude that recent rises in prescribing have contributed to falls in suicides. Interpretation of these findings is not straightforward. A range of factors influence population suicide rates.19 It is therefore challenging to distinguish the discrete effects of increased antidepressant prescribing from changes in other risk factors.
Furthermore, declining overall suicide trends may mask rises in some age and sex groups.19 In Australia, recent rises in antidepressant prescribing were associated with falls in suicide among some age and sex groups but increases in others.4 In Britain, declines in suicide preceded increases in prescribing (see fig A on bmj.com) and rises in antidepressant prescribing since 1991 in different age and sex groups do not consistently coincide with clear changes in previous suicide trends (fig 1). The levelling out of suicide trends in young men is probably due to a fall in suicide by self poisoning with car exhaust because of reductions in the carbon monoxide content of exhaust gases.20
Fig 1 Trends in suicide and undetermined death rates (England and Wales) and prescribing of antidepressants (United Kingdom) by age and sex
Toxicity
Soon after the launch of fluoxetine, the most commonly prescribed SSRI, a series of reports were published suggesting worsening of depression and emergence of suicidal thoughts in some people.23 24 The issue has been hotly debated.7 8 Disentangling the evidence is problematic as much of the research is sponsored by the pharmaceutical industry.25 Review of data from paediatric trials of SSRIs shows that published findings present a more favourable risk-benefit profile than unpublished trials sponsored by industry.12
Table 1 summarises the evidence from clinical trials on the adverse effects of SSRIs on suicidal behaviour in children, abstracted from information recently released by the Medicines and Healthcare Products Regulatory Agency.26 No suicides occurred in these trials. The pooled estimate of increased risk of suicidal thoughts or behaviour from these data is 1.66 (95% credibility interval 0.83 to 3.50). Interpretation of this apparent increase in risk is problematic as people taking SSRIs may be more likely to report adverse effects, perhaps because the drugs could have a disinhibiting effect. In addition, response to treatment may lead to reactivation among people whose depression previously prevented them from acting on suicidal impulses.27 Furthermore, any increased risk may be counterbalanced by a longer term reduction in suicidal behaviour; such benefits would not detected in the trials as they generally lasted 10 weeks or less, whereas the mean duration of treatment in clinical practice is three to four months.28
Table 1 Risk of suicidal behaviour associated with use of SSRIs to treat depression in children and adolescents26
Reassuringly, time trends for suicide (England and Wales)29 and non-fatal self harm (Oxford)30 in children and adolescents provide no consistent evidence of adverse trends paralleling increased prescribing in the 1990s, although there is some evidence of a rise in non-fatal self harm in young females. Furthermore, in the United States, recent research suggests that areas with the largest increases in antidepressant prescribing to 10-19 year olds experienced the greatest falls in suicide.6
Modelling the effect
There are two reasons why an adverse effect of antidepressants on suicide risk may have been overlooked in adult clinical trials. Firstly, self harm, and fatal self harm in particular, is relatively rare, and most clinical trials lack power to detect any increased risk. Secondly, as it seems counterintuitive that treatments for depression might increase suicide risk, the possibility may not have been specifically investigated in the clinical trials. The increased risk in children may have been detected either because of the increased prevalence of suicidal thoughts and self harm in young people (giving greater power) or because the absence of beneficial effects12 meant that adverse effects dominated the clinical picture.
If rare adverse effects of antidepressants on suicide exist, recent large scale increases in prescribing might be expected to affect suicide trends. But, as detailed above, recent suicide trends have generally been favourable, and so it is likely either that benefits outweigh the risks in adults or that any excess risk is small. Nevertheless, antidepressants may have precipitated some suicides in susceptible individuals, and it is important to estimate the number of such deaths. Table 2 outlines a model to estimate the number of excess deaths that may have occurred in 2002 compared with 1991 as a result of their increased use in England.
Table 2 Model of possible excess suicides in 2002 compared to 1991 as a result of increased antidepressant prescribing (assumes findings from paediatric trials apply to adults and additional assumptions listed in text)
The model is based on the worst case scenario that the findings in relation to non-fatal self harm in paediatric trials are applicable to suicide deaths in adults. Under the model's assumptions (see bmj.com) an excess of 388 suicides (95% credibility interval-202 to 704) (233 men and 155 women) may have occurred in 2002 compared with 1991 as a result of increased anti-depressant prescribing. This is equivalent to an annual increase of around 35 suicides since 1991 (0.8% of the roughly 4500 annual suicides in England). Such a small increase may have been masked by other favourable influences on suicide.
The credibility intervals of our estimated increase in suicides (-202 to 704) include the possibility of a null or beneficial effect of SSRIs. Furthermore, some of our model assumptions are likely to result in us overestimating possible SSRI associated suicides. Firstly, there is no evidence that the findings from the paediatric trials can be extrapolated to adults, nor indeed that the strength of associations are the same for fatal and non-fatal self harm. Furthermore, the relative risk we used in our main model is based on findings from trials generally lasting 10 weeks or less, whereas the recommended duration of treatment is six months or more.32 Any increased suicide risk early in treatment may be offset by longer term improvements in suicide risk.
Secondly, we will have overestimated person time at risk because not all dispensed prescriptions are used and we have not taken account of the fact that (any) antidepressant associated increased risk of suicide may be concentrated in the early weeks of treatment. A sizeable proportion of people prescribed the drugs are long term users or have been taking antidepressants for two months or more and may therefore not be at risk of side effects.
Lastly, we assumed that suicide rates among those receiving antidepressants in 2002 are similar to those in the late 1980s and early 1990s.16 Recent increases in prescribing are likely to have occurred among people with less severe depressive illness and therefore a lower absolute suicide risk. The balance of risk and benefits may be different in this patient group. Our estimate of suicide rates among those treated with antidepressants is, however, some five times lower than that reported in one study.15 A sensitivity analysis of our model assumptions is presented on bmj.com.
Conclusions
Middleton N, Gunnell D, Whitley E, Dorling D, Frankel S. Secular trends in antidepressant prescribing in the UK, 1975-1998. J Public Health Med 2001;23: 262-7.
Isacsson G. Suicide prevention—a medical breakthrough? Acta Psychiatr Scand 2000;102: 113-7.
Barbui C, Campomori A, D'Avanzo B, Negri E, Garattini S. Antidepressant drug use in Italy since the introduction of SSRIs: national trends, regional differences and impact on suicide rates. Soc Psychiatry Psychiatr Epidemiol 1999;34: 152-6.
Hall WD, Mant A, Mitchell PB, Rendle VA, Hickie IB, McManus P. Association between antidepressant prescribing and suicide in Australia, 1991-2000: trend analysis. BMJ 2003;326: 1008.
Rihmer Z, Belso N, Kalmar S. Antidepressants and suicide prevention in Hungary. Acta Psychiatr Scand 2001;103: 238-9.
Olfson M, Shaffer D, Marcus SC, Greenberg T. Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry 2003;60: 978-82.
Healy D. Lines of evidence on the risks of suicide with selective serotonin reuptake inhibitors. Psychother Psychosom 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.
SSRI and venlafaxine use in children. Curr Prob Pharmacovig 2003;29: 4.
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.
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.
Rutz W, von Knorring L, Walinder J. Long-term effects of an educational program for general practitioners given by the Swedish committee for the prevention and treatment of depression. Acta Psychiatr Scand 1992;85: 83-8.
Beasley CM Jr, Dornseif BE, Bosomworth JC, Sayler ME, Rampey AH, Heiligenstein JH. 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.
Jick SS, Dean AD, Jick H. Antidepressants and suicide. BMJ 1995;310: 215-8.
Oravecz R, Czigler B, Leskosek F. Correlation between suicide rate and antidepressant use in Slovenia. Arch Suicide Res 2003;7: 279-85.
Helgason T, Tomasson H, Zoega T. Antidepressants and public health in Iceland. Time series analysis of national data. Br J Psychiatry 2004;184: 157-62.
Gunnell D, Middleton N, Whitley E, Dorling D, Frankel S. Why are suicide rates rising in young men but falling in the elderly?—a time-series analysis of trends in England and Wales 1950-1998. Soc Sci Med 2003;57: 595-611.
Amos T, Appleby L, Kiernan K. Changes in rates of suicide by car exhaust asphyxiation in England and Wales. Psychol Med 2001;31: 935-9.
Shah R, Uren Z, Baker A, Majeed A. Deaths from antidepressants in England and Wales 1993-1997: analysis of a new national database. Psychol Med 2001;31: 1203-10.
Freemantle N, House A, Song F, Mason JM, Sheldon TA. Prescribing selective serotonin reuptake inhibitors as strategy for prevention of suicide. BMJ 1994;309: 249-53.
Teicher MH, Glod C, Cole JO. Emergence of intense suicidal preoccupation during fluoxetine treatment. Am J Psychiatry 1990;147: 207-10.
Masand P, Gupta S, Dewan M. Suicidal ideation related to fluoxetine treatment. N Engl J Med 1991;324: 420.
Als-Nielsen B, Chen W, Gluud C, Kjaergard LL. Association of funding and conclusions in randomized drug trials. JAMA 2003;290: 921-6.
Medicines and Healthcare Products Regulatory Agency. Selective serotonin reuptake inhibitors (SSRIs): overview of regulatory status and CSM advice relating to major depressive disorder (MDD) in children and adolescents including a summary of available safety and efficacy data. http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/ssrioverview_101203.htm (accessed 16 May 2004).
Nutt D. Death and dependence: current controversies over the selective serotonin reuptake inhibitors. J Psychopharmacol 2003;17: 355-64.
MacKay FR, Dunn NR, Martin RM, Pearce GL, Freemantle SN, Mann RD. Newer antidepressants: a comparison of tolerability in general practice. Br J Gen Pract 1999;49: 892-6.
McClure GMG. Suicide in children and adolescents in England and Wales 1970-1998. Br J Psychiatry 2001;178: 469-74.
Hawton K, Hall S, Simkin S, Bale L, Bond A, Codd S, et al. Deliberate selfharm in adolescents: a study of characteristics and trends in Oxford, 1990-2000. J Child Psychol Psychiatry 2003;44: 1191-8.
Donoghue JM, Tylee A. The treatment of depression: prescribing patterns of antidepressants in primary care in the UK. Br J Psychiatry 1996;168: 164-8.
Paykel ES, Priest RG. Recognition and management of depression in general practice: consensus statement. BMJ 1992;305: 1198-202.
Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiatry 1998;173: 11-53.(David Gunnell, professor )
Correspondence to: D Gunnell d.j.gunnell@bristol.ac.uk
Introduction
SSRIs and tricyclic antidepressants account for over 90% of antidepressant prescribing in Britain. Systematic reviews confirm that both these classes of antidepressant are effective in adults,10 although SSRIs are better tolerated by patients.11 The effectiveness of antidepressants in childhood and adolescence is less clear.12
As depression is the main psychiatric condition leading to suicide, it seems reasonable to infer that rises in antidepressant prescribing, which indicate improved management of depression, should have a beneficial effect on suicide rates. Indeed, an intervention to improve general practitioners' management of depression in a Swedish community resulted in increased antidepressant prescribing and a short term reduction in suicide.13
Summary points
Concern is growing that serotonin reuptake inhibitors (SSRIs) may precipitate suicidal behaviour, especially in children
Reassuringly, although antidepressant prescribing in Britain has more than doubled in the past 15 years, population suicide rates have fallen.
If the risks of SSRI associated suicidal behaviour seen in children were to apply to suicide in adults, the number of "antidepressant induced" suicides would be small enough to be masked by currently favourable suicide trends
Long term studies are required to assess the risks and benefits to population health of recent large scale rises in antidepressant prescribing.
Surprisingly, direct evidence that antidepressants prevent suicide is hard to find. A meta-analysis of data on the SSRI fluoxetine, funded by its manufacturer, found no evidence that suicidal acts were less frequent among adults taking antidepressants; the pooled incidences were 0.3% for fluoxetine, 0.2% for placebo, and 0.4% for tricyclics.14 In the most comprehensive synthesis of data from randomised trials, Khan and colleagues found no evidence of a beneficial effect of antidepressants on suicide.15 These findings are difficult to interpret as this was not a formal meta-analysis and relative risks were not derived separately for each trial on an intention to treat basis.
Suicide is rare, even among people with depression.16 Thus, most clinical trials have insufficient power to provide clear evidence on the effect of antidepressants on suicide.
Time trends
In the absence of clear evidence from clinical trials, researchers have investigated whether rises in antidepressant prescribing are associated with reductions in population suicide rates.2-6 17-19 With some exceptions,3 17 18 such studies conclude that recent rises in prescribing have contributed to falls in suicides. Interpretation of these findings is not straightforward. A range of factors influence population suicide rates.19 It is therefore challenging to distinguish the discrete effects of increased antidepressant prescribing from changes in other risk factors.
Furthermore, declining overall suicide trends may mask rises in some age and sex groups.19 In Australia, recent rises in antidepressant prescribing were associated with falls in suicide among some age and sex groups but increases in others.4 In Britain, declines in suicide preceded increases in prescribing (see fig A on bmj.com) and rises in antidepressant prescribing since 1991 in different age and sex groups do not consistently coincide with clear changes in previous suicide trends (fig 1). The levelling out of suicide trends in young men is probably due to a fall in suicide by self poisoning with car exhaust because of reductions in the carbon monoxide content of exhaust gases.20
Fig 1 Trends in suicide and undetermined death rates (England and Wales) and prescribing of antidepressants (United Kingdom) by age and sex
Toxicity
Soon after the launch of fluoxetine, the most commonly prescribed SSRI, a series of reports were published suggesting worsening of depression and emergence of suicidal thoughts in some people.23 24 The issue has been hotly debated.7 8 Disentangling the evidence is problematic as much of the research is sponsored by the pharmaceutical industry.25 Review of data from paediatric trials of SSRIs shows that published findings present a more favourable risk-benefit profile than unpublished trials sponsored by industry.12
Table 1 summarises the evidence from clinical trials on the adverse effects of SSRIs on suicidal behaviour in children, abstracted from information recently released by the Medicines and Healthcare Products Regulatory Agency.26 No suicides occurred in these trials. The pooled estimate of increased risk of suicidal thoughts or behaviour from these data is 1.66 (95% credibility interval 0.83 to 3.50). Interpretation of this apparent increase in risk is problematic as people taking SSRIs may be more likely to report adverse effects, perhaps because the drugs could have a disinhibiting effect. In addition, response to treatment may lead to reactivation among people whose depression previously prevented them from acting on suicidal impulses.27 Furthermore, any increased risk may be counterbalanced by a longer term reduction in suicidal behaviour; such benefits would not detected in the trials as they generally lasted 10 weeks or less, whereas the mean duration of treatment in clinical practice is three to four months.28
Table 1 Risk of suicidal behaviour associated with use of SSRIs to treat depression in children and adolescents26
Reassuringly, time trends for suicide (England and Wales)29 and non-fatal self harm (Oxford)30 in children and adolescents provide no consistent evidence of adverse trends paralleling increased prescribing in the 1990s, although there is some evidence of a rise in non-fatal self harm in young females. Furthermore, in the United States, recent research suggests that areas with the largest increases in antidepressant prescribing to 10-19 year olds experienced the greatest falls in suicide.6
Modelling the effect
There are two reasons why an adverse effect of antidepressants on suicide risk may have been overlooked in adult clinical trials. Firstly, self harm, and fatal self harm in particular, is relatively rare, and most clinical trials lack power to detect any increased risk. Secondly, as it seems counterintuitive that treatments for depression might increase suicide risk, the possibility may not have been specifically investigated in the clinical trials. The increased risk in children may have been detected either because of the increased prevalence of suicidal thoughts and self harm in young people (giving greater power) or because the absence of beneficial effects12 meant that adverse effects dominated the clinical picture.
If rare adverse effects of antidepressants on suicide exist, recent large scale increases in prescribing might be expected to affect suicide trends. But, as detailed above, recent suicide trends have generally been favourable, and so it is likely either that benefits outweigh the risks in adults or that any excess risk is small. Nevertheless, antidepressants may have precipitated some suicides in susceptible individuals, and it is important to estimate the number of such deaths. Table 2 outlines a model to estimate the number of excess deaths that may have occurred in 2002 compared with 1991 as a result of their increased use in England.
Table 2 Model of possible excess suicides in 2002 compared to 1991 as a result of increased antidepressant prescribing (assumes findings from paediatric trials apply to adults and additional assumptions listed in text)
The model is based on the worst case scenario that the findings in relation to non-fatal self harm in paediatric trials are applicable to suicide deaths in adults. Under the model's assumptions (see bmj.com) an excess of 388 suicides (95% credibility interval-202 to 704) (233 men and 155 women) may have occurred in 2002 compared with 1991 as a result of increased anti-depressant prescribing. This is equivalent to an annual increase of around 35 suicides since 1991 (0.8% of the roughly 4500 annual suicides in England). Such a small increase may have been masked by other favourable influences on suicide.
The credibility intervals of our estimated increase in suicides (-202 to 704) include the possibility of a null or beneficial effect of SSRIs. Furthermore, some of our model assumptions are likely to result in us overestimating possible SSRI associated suicides. Firstly, there is no evidence that the findings from the paediatric trials can be extrapolated to adults, nor indeed that the strength of associations are the same for fatal and non-fatal self harm. Furthermore, the relative risk we used in our main model is based on findings from trials generally lasting 10 weeks or less, whereas the recommended duration of treatment is six months or more.32 Any increased suicide risk early in treatment may be offset by longer term improvements in suicide risk.
Secondly, we will have overestimated person time at risk because not all dispensed prescriptions are used and we have not taken account of the fact that (any) antidepressant associated increased risk of suicide may be concentrated in the early weeks of treatment. A sizeable proportion of people prescribed the drugs are long term users or have been taking antidepressants for two months or more and may therefore not be at risk of side effects.
Lastly, we assumed that suicide rates among those receiving antidepressants in 2002 are similar to those in the late 1980s and early 1990s.16 Recent increases in prescribing are likely to have occurred among people with less severe depressive illness and therefore a lower absolute suicide risk. The balance of risk and benefits may be different in this patient group. Our estimate of suicide rates among those treated with antidepressants is, however, some five times lower than that reported in one study.15 A sensitivity analysis of our model assumptions is presented on bmj.com.
Conclusions
Middleton N, Gunnell D, Whitley E, Dorling D, Frankel S. Secular trends in antidepressant prescribing in the UK, 1975-1998. J Public Health Med 2001;23: 262-7.
Isacsson G. Suicide prevention—a medical breakthrough? Acta Psychiatr Scand 2000;102: 113-7.
Barbui C, Campomori A, D'Avanzo B, Negri E, Garattini S. Antidepressant drug use in Italy since the introduction of SSRIs: national trends, regional differences and impact on suicide rates. Soc Psychiatry Psychiatr Epidemiol 1999;34: 152-6.
Hall WD, Mant A, Mitchell PB, Rendle VA, Hickie IB, McManus P. Association between antidepressant prescribing and suicide in Australia, 1991-2000: trend analysis. BMJ 2003;326: 1008.
Rihmer Z, Belso N, Kalmar S. Antidepressants and suicide prevention in Hungary. Acta Psychiatr Scand 2001;103: 238-9.
Olfson M, Shaffer D, Marcus SC, Greenberg T. Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry 2003;60: 978-82.
Healy D. Lines of evidence on the risks of suicide with selective serotonin reuptake inhibitors. Psychother Psychosom 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.
SSRI and venlafaxine use in children. Curr Prob Pharmacovig 2003;29: 4.
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.
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.
Rutz W, von Knorring L, Walinder J. Long-term effects of an educational program for general practitioners given by the Swedish committee for the prevention and treatment of depression. Acta Psychiatr Scand 1992;85: 83-8.
Beasley CM Jr, Dornseif BE, Bosomworth JC, Sayler ME, Rampey AH, Heiligenstein JH. 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.
Jick SS, Dean AD, Jick H. Antidepressants and suicide. BMJ 1995;310: 215-8.
Oravecz R, Czigler B, Leskosek F. Correlation between suicide rate and antidepressant use in Slovenia. Arch Suicide Res 2003;7: 279-85.
Helgason T, Tomasson H, Zoega T. Antidepressants and public health in Iceland. Time series analysis of national data. Br J Psychiatry 2004;184: 157-62.
Gunnell D, Middleton N, Whitley E, Dorling D, Frankel S. Why are suicide rates rising in young men but falling in the elderly?—a time-series analysis of trends in England and Wales 1950-1998. Soc Sci Med 2003;57: 595-611.
Amos T, Appleby L, Kiernan K. Changes in rates of suicide by car exhaust asphyxiation in England and Wales. Psychol Med 2001;31: 935-9.
Shah R, Uren Z, Baker A, Majeed A. Deaths from antidepressants in England and Wales 1993-1997: analysis of a new national database. Psychol Med 2001;31: 1203-10.
Freemantle N, House A, Song F, Mason JM, Sheldon TA. Prescribing selective serotonin reuptake inhibitors as strategy for prevention of suicide. BMJ 1994;309: 249-53.
Teicher MH, Glod C, Cole JO. Emergence of intense suicidal preoccupation during fluoxetine treatment. Am J Psychiatry 1990;147: 207-10.
Masand P, Gupta S, Dewan M. Suicidal ideation related to fluoxetine treatment. N Engl J Med 1991;324: 420.
Als-Nielsen B, Chen W, Gluud C, Kjaergard LL. Association of funding and conclusions in randomized drug trials. JAMA 2003;290: 921-6.
Medicines and Healthcare Products Regulatory Agency. Selective serotonin reuptake inhibitors (SSRIs): overview of regulatory status and CSM advice relating to major depressive disorder (MDD) in children and adolescents including a summary of available safety and efficacy data. http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/ssrioverview_101203.htm (accessed 16 May 2004).
Nutt D. Death and dependence: current controversies over the selective serotonin reuptake inhibitors. J Psychopharmacol 2003;17: 355-64.
MacKay FR, Dunn NR, Martin RM, Pearce GL, Freemantle SN, Mann RD. Newer antidepressants: a comparison of tolerability in general practice. Br J Gen Pract 1999;49: 892-6.
McClure GMG. Suicide in children and adolescents in England and Wales 1970-1998. Br J Psychiatry 2001;178: 469-74.
Hawton K, Hall S, Simkin S, Bale L, Bond A, Codd S, et al. Deliberate selfharm in adolescents: a study of characteristics and trends in Oxford, 1990-2000. J Child Psychol Psychiatry 2003;44: 1191-8.
Donoghue JM, Tylee A. The treatment of depression: prescribing patterns of antidepressants in primary care in the UK. Br J Psychiatry 1996;168: 164-8.
Paykel ES, Priest RG. Recognition and management of depression in general practice: consensus statement. BMJ 1992;305: 1198-202.
Harris EC, Barraclough B. Excess mortality of mental disorder. Br J Psychiatry 1998;173: 11-53.(David Gunnell, professor )