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doi:10.1111/jpc.12655
VIEWPOINT
Do antidepressants make children and adolescents suicidal? Michael S Gordon1 and Glenn A Melvin2 1 Child and Adolescent Stream, Early in Life Mental Health Service, Monash Medical Centre and 2Centre for Developmental Psychiatry and Psychology, Department of Psychiatry, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia
Key words:
adolescent; antidepressive agent; review; suicide.
Antidepressants are widely used to treat a range of mental illnesses experienced by children and adolescents. Treatment guidelines vary on the place of antidepressants in the treatment hierarchy for children and adolescents with depressive disorders but all agree that antidepressants have a place in the prescriber’s armamentarium.1–3 Case studies identified that high doses of fluoxetine were associated with suicidal behaviour in adolescents dating back to 1991.4 Investigation at this time with available data suggested no link between antidepressants and treatment-emergent suicidal ideation or behaviour.5 In May 2003, GlaxoSmithKline advised the Food and Drug Administration (FDA) in the USA that paroxetine use was associated with suicide-related adverse events in paediatric patients in a clinical trial.6 At the end of 2003, the Medicines and Health Products Regulatory Agency, the UK’s counterpart to the FDA, sent a letter to all doctors in the UK to warn them against using all but one of the antidepressants (fluoxetine) in children and adolescents. In October 2004, the FDA reached a split decision (15 yes, eight no) ordering that pharmaceutical companies add a ‘black box warning’ (BBW) on all antidepressant medication warning of the heightened risk of suicidal thoughts and behaviours.7 For a review of the history of the BBW, see Licinio and Wong.8 The Royal Australian and New Zealand College of Psychiatry, the Royal Australian College of General Practitioners and the Royal Australian and New Zealand College of Physicians released a joint statement in response in 2005 arguing for the continued access of children and adolescents to antidepressants but for their use within the context of a comprehensive management plan and careful monitoring mindful of the increased risk of suicidal thinking and behaviour.9 The FDA expanded its BBW about increased suicidal ideation and behaviour to include young adults 18–24 at the start of treatment (first 1–2 months) in 2007.10 Prior to the BBW, two-thirds of adolescents diagnosed with depression were treated with an antidepressant.11 Following the BBW, the rates of antidepressant dispensing in the USA fell to 58% lower than would have been expected from pre-BBW trends, with a decrease in the new diagnoses of paediatric depression.11 In the USA, paediatricians and primary care phyCorrespondence: Dr Michael S Gordon, Early in Life Mental Health Service, Southern Health, 246 Clayton Road, Clayton, Melbourne, Vic. 3168, Australia. Fax: 03 9594 6333; email: [email protected] Conflict of interest: None declared. Accepted for publication 21 February 2014.
sicians demonstrated the greatest reduction in prescription of antidepressants following the introduction of the BBW.11,12 This paper provides a narrative review of the link between suicide and antidepressant use in children and adolescents and reports on the breadth of evidence since the BBW. It is the aim of this paper to provide a range of reports and views in order to inform practitioners about the risks when prescribing.
Method We identified the relevant studies by searching the Ovid Medline and Cochrane Reviews using the search terms ‘Adolescent Psychology/’ or ‘Child Psychology/’ or ‘Child Psychiatry/’ or ‘Adolescent Psychiatry/’ or ‘adolescent’ or ‘child.mp’ or ‘youth.mp’ AND ‘suicide.mp’ or ‘suicidal.mp’ or ‘suicidal ideation.mp’ or ‘suicide, attempted.mp’ or ‘Self-Injurious behavior.mp’ or ‘exp Self-injurious Behavior/’ AND ‘antidepressive agents’ or ‘Serotonin Uptake Inhibitors.mp’ or ‘SSRI.mp’ or ‘escitalopram.mp’ or ‘citalopram.mp’ or ‘fluvoxamine.mp’ or ‘paroxetine.mp’ or ‘sertraline.mp’ or ‘venlafaxine.mp’ or ‘mirtazapine.mp’ or ‘nefazodone.mp’ or ‘bupropion.mp’ AND ‘meta-analysis.mp’ or ‘Case-Control Studies/.mp’ or ‘Case-control.mp’ or ‘Epidemiological Methods/’ or ‘Epidemiological Studies.mp’ or ‘Epidemiological Studies/’ or ‘clinical trial.mp’ or ‘Clinical Trial/’ or ‘Toxicology/’ or ‘toxicology.mp’. The databases were searched for studies from December 1991 to December 2013. We also consulted bibliographies of other reviews. The focus of this narrative review was as follows: (i) meta-analyses of randomised controlled trials (RCTs); (ii) pharmacoepidemiological; and (iii) toxicological studies. The age of interest was 6–18 years. Studies that spanned across this age but overlapped with older cohorts of participants were considered for inclusion.
Results The search of the databases revealed 153 papers. From these, the authors removed the duplicates, non-English papers and those that related to adult studies. Only those meta-analyses that assessed for placebo-controlled RCT were included. Metaanalyses that assessed for efficacy but not suicidal thoughts and behaviours were also excluded. From those remaining, 11 meta-analyses of placebo-controlled trials, 17 pharmacoepidemiological studies, one meta-analysis of observational studies and six post-mortem studies are reported.
Journal of Paediatrics and Child Health 50 (2014) 847–854 © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).
847
Antidepressants and suicidal events
MS Gordon and GA Melvin
Table 1 Meta-analyses of randomised control trials of antidepressants for children and adolescents Study
Method
Findings
Whittington et al.13
Five RCTs (MDD) fluoxetine, paroxetine, sertraline and venlafaxine
Mosholder and Willy14
21 RCTs (14 MDD, seven non-MDD- OCD, GAD, SAD) paroxetine, sertraline, venlafaxine, fluoxetine, citalopram, mirtazapine, nefazodone and fluvoxamine 20 RCTs (MDD, OCD, GAD, SAD) citalopram, fluoxetine, fluvoxamine, mirtazapine, paroxetine, sertraline and venlafaxine 22 RCTs (MDD, OCD, GAD and social anxiety) SSRIs and SNRIs 4 RCT (MDD, OCD) sertraline
RR calculated for individual antidepressants. Venlafaxine was most likely to be associated with suicide-related events. Fluoxetine was least likely to be associated with suicidal behavior or attempted suicide. The results were qualified because of wide confidence intervals. There was an increase in the number of serious suicidal events when the antidepressants were pooled (incident rate ratio of 1.89 compared with placebo) and with the MDD trials only (incident rate ratio 1.95). There was no overall increase in serious suicidal events from the non-MDD studies.
Hammad, Laughren and Racoosin15 Wohlfarth et al.16
March, Klee and Kremer17
Kaizar et al.18
Dubicka, Hadley and Roberts19 Bridge et al.20
Hetrick, McKenzie and Merry21 Cochrane22
Julious23
24 RCTs (MDD, OCD, anxiety, ADHD) citalopram, fluvoxamine, paroxetine, fluoxetine, sertraline, venlafaxine, mirtazapine, nefazodone and bupropion 16 RCTs (MDD) fluoxetine, sertraline, citalopram, paroxetine, venlafaxine and mirtazapine 27 RCTs (MDD, OCD, non-OCD anxiety disorders) SSRIs, nefazodone, venlafaxine, mirtazapine 10 RCTs (depressive disorder) paroxetine, fluoxetine, sertraline, citalopram 17 RCTs (MDD) citalopram, escitalopram, fluoxetine, mirtazapine, paroxetine, sertraline and venlafaxine 35 RCTs (depression and other indications) SSRIs and atypical antidepressants
There were no suicides in the 4582 patients. The risk difference for suicidal ideas or behaviours across all the antidepressants was 2% (NNH 50). The relative risk was 1.95 across all the all drugs for all indications. When antidepressants were assessed individually, the finding of increased risk was only significant for venlafaxine. There were no suicides in the 3832 patients. Risk difference for those in the MDD studies was 1.4% (NNH 71.4). There was no risk difference found for those treated for anxiety disorders. In the two MDD studies, for suicidal thoughts and behaviours, the risk difference was increased on sertraline 1.56% (NNH 64.2). Suicidal thoughts and behaviours associated with sertraline were more frequently seen in depressed children than depressed adolescents. There was no increase in suicidal thoughts and behaviours associated with sertraline when used for the treatment of OCD. There was an increased risk of suicidal thoughts and behaviours for those with MDD (OR 2.3) and separately where the antidepressant was an SSRI (OR 2.2).
For self-harm and suicide-related events, there was a difference favouring placebo using fixed effects estimate of the pooled odds (OR 1.70) but not when using random effects analysis. In 4592 children, across all the RCTs, the risk difference 0.7% was significant when all the studies were pooled (NNH 143). However, the risk difference for antidepressants across each of the conditions (MDD, OCD, non-OCD anxiety disorder) was not associated with suicidal ideation and behavior. The RR of suicide-related outcomes (ideas and behaviours) with SSRIs was 1.80.
From 3229 participants, the RR was 1.58 in suicidal thoughts and behaviours across in those treated with antidepressants compared with a placebo.
In 6039 patients, the risk difference for suicidal thoughts and behaviours for antidepressants compared with placebo across all indications was 0.9%. For suicidal thoughts and behaviours, there was no risk difference for SSRIs overall. There was no risk difference for suicidal thoughts and behaviours in those antidepressants treated for depression.
ADHD, attention deficit hyperactivity disorder; GAD, generalised anxiety disorder; MDD, major depressive disorder; NNH, number needed to harm; OCD, obsessive compulsive disorder; OR, odds ratio; RCT, randomised control trial; RR, relative risk; SAD, social anxiety disorder; SNRI, serotonin noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.
Meta-analyses A meta-analysis of RCTs allows for the pooling of suicidal thoughts and behaviours across a number of different antidepressant trials resulting in an improved ability to determine a difference between antidepressant and placebo groups. Eleven 848
meta-analyses are reported in Table 1. The meta-analyses varied in the RCTs that were chosen and available for inclusion. Whittington et al. in their analysis assessed each agent individually for adverse events.13 Mosholder and Willy assessed drug manufacturer data as provided by the FDA.14 However, Hammad assessed the FDA data after the suicide
Journal of Paediatrics and Child Health 50 (2014) 847–854 © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
MS Gordon and GA Melvin
Antidepressants and suicidal events
events had been reclassified by Columbia University owing to the poor and inconsistent classification of suicidal and self-harm events.6 While suicide was not reported in any of these RCTs, overall, the meta-analyses all reported an increased risk of suicidal thoughts and behaviours compared with placebo in the early stages of treatment in children and adolescents on SSRIs and other antidepressant treatments. However, the studies varied in their specific findings. Bridge et al. and Julious reported this increase in suicide risk when all antidepressants were pooled but not when sub-analyses by psychiatric condition were undertaken.20,23 One study showed an increase in suicide risk when a more liberal fixed effects estimate was undertaken but not when a more conservative random effects regression was done.19 When individual antidepressants were considered, the risk ratio was consistently lowest for fluoxetine. Venlafaxine was the antidepressant most consistently found to be associated with suicidal thought and events.13,15,22 Children may be at higher risk of suicidal thoughts and behaviours when treated with antidepressants than adolescents.17 Those children and adolescents treated with antidepressants for anxiety disorders did not have an increased risk of suicidal thoughts and behaviours in three of the studies.16,17,20 The most recent Cochrane review (2012) included 19 published and unpublished RCTs (n = 3335 participants) that compared newer generation antidepressants with placebo in children and adolescents (6–18 years) who were diagnosed with a depressive disorder.22 This Cochrane review used two outcome measures: (i) suicide-related outcomes (thoughts and behaviours) as reported in Hammad6 and (ii) suicidal thinking as measured by the Suicidal Ideation Questionnaire-Junior High School Version (SIQ-Jr).22 For the suicidal-related outcomes, there was a 58% greater risk for those children and adolescents on the newer antidepressants versus placebo. When the data were further stratified by age, there was no statistical difference on suiciderelated outcomes between antidepressant and placebo for adolescents (13–18 years).22 The finding of an increased risk of suicide-related outcomes was not significant for any individual antidepressant except for venlafaxine, which had a very wide confidence interval.22 Meta-analysis of SIQ-Jr data found that there was no difference in proportion with suicidal ideas between antidepressant and placebo.22 The risk difference between antidepressants and placebo across the meta-analyses varied with the FDA study of Hammad, which was at the upper end of the risk estimate at 2%,15 compared with Bridge et al. of 0.7%20 and Julious at 0.9%.23 This suggests that there is an increased risk of antidepressant-related suicidal thoughts or behaviours of up to 20 events per 1000 patients compared with placebo.
Seventeen pharmacoepidemiological studies that included children and adolescents in ecological, case-control and cohortdesigned studies are summarised in Table 2. Antidepressants or SSRI prescription were inversely related to the suicide rate.24–28 Five observational studies reported a gradient of suicide attempt risk. The highest risk was found to be in the month before starting the antidepressant and the next highest risk in the weeks and month after starting the antidepressant, declining thereafter.29,33,34,36,38 Other studies reported varying findings regarding suicide attempts. One study found an increase in suicide attempts and suicide in children and adolescents who had been admitted and treated with antidepressants for depression.30 Another study found an increased risk of suicide attempts but not death for antidepressants other than paroxetine,32 while another found no link between SSRIs and suicide.31 SSRIs were found to have the same suicide risk as tricyclic antidepressant (TCA),39 a higher risk than TCA35 and a lower risk compared with TCA.26 A compelling finding from the observational and casecontrolled studies is the meta-analysis of Barbui, Esposito and Cipriani.41 Barbui, Esposito and Cipriani conducted a random effects meta-analysis of observation studies involving those patients treated for moderate or severe depression with SSRIs.41 They included eight studies of which five had child and adolescent participants.41 Barbui, Esposito and Cipriani found that exposure to SSRIs doubled the risk for suicide or attempted suicide in children and adolescents compared with those not exposed to any antidepressants (odds ratio 1.92), while for adults, the risk was decreased.41 For individual agents, paroxetine and venlafaxine increased the risk of suicide and suicide attempts, while citalopram, fluoxetine, fluvoxamine and sertraline were not significant.41
Pharmacoepidemiological studies
The meta-analyses described have consistently indicated that there is an increased risk of suicidal thoughts and behaviours in the order of between seven and 20 incidents per 1000 of those treated with an antidepressant compared with placebo. These findings occur most consistently when the data are pooled. With the exception of venlafaxine, subgroup analyses do not provide an association between specific antidepressant agents and suicidal thoughts and behaviours, a finding that may be related to small sample sizes resulting in analyses that are underpowered
Epidemiological studies aim to detect relatively rare outcomes, such as suicide, in large samples exposed to variables of interest (e.g. antidepressant treatment).24 By contrast, observational studies link administrative and clinical databases, allowing the investigation of possible links between antidepressant prescriptions and suicide attempts or suicide in very large samples from real-world clinical practice.24
Post-mortem studies If antidepressants cause adolescents to become suicidal, it has been reasoned that it is very likely that antidepressants will be present in toxicology assays of adolescent suicide victims (see Table 3). Six toxicology studies assessed for the presence of antidepressants in adolescents who were assessed by the coroner to have died by suicide. Collectively, these findings suggest that it is reasonably uncommon for adolescents who have died by suicide to have been taking newer antidepressants, such as SSRI at therapeutic doses. The infrequent presence or absence of antidepressants at autopsy suggests either the adolescent was not prescribed the antidepressant or was not taking it in the days prior to their suicide.
Discussion
Journal of Paediatrics and Child Health 50 (2014) 847–854 © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
849
Antidepressants and suicidal events
MS Gordon and GA Melvin
Table 2 Pharmacoepidemiological studies of antidepressants and suicidal behaviour Study
Age in years
Method
Findings
Olfson et al.
10–19
Regional suicide rate linked with national antidepressant prescriptions, 1990–2000
Hall and Lucke24
15 and over
Australian prescription data in general practice matched to suicide rates, 1991–2001 US regional suicide rate linked with national antidepressant prescriptions, 1996–1998
An inverse relationship between antidepressant medication and suicide. A 1% increase in use of antidepressant in adolescents was associated with a reduction in suicides by 0.23/100 000 adolescents per year Suicide rate was inversely related to antidepressant prescribing
25
Gibbons et
al.26
Gibbons et al.27 Gibbons et
al.28
All ages
5–14 Up to 19
US regional suicide rate linked with national antidepressant prescriptions, 1996–1998 Regional suicide rate linked with national antidepressant prescriptions, 2003–2005
Jick, Kaye and Jick29
10–69
Olfson, Marcus and Shaffer30
6–64
Søndergård et al.31
10–17
Tiihonen, et al.32
10 and older
Cohort study of Finnish patients hospitalised for a suicide attempt (n = 15 390) follow-up for 3.4 years, 1997–2003
Simon et al.33
5–105
Valuck et al.34
12–18
Managed care claims linking new episodes of depression, antidepressant prescription, treatment type with suicide attempts and suicide (n = 65 103), 1992–2003. Observations commenced 90 days prior to starting treatment and 180 days following the commencement of treatment Retrospective cohort study of Managed Care plans linking antidepressant treatment and suicide attempts in adolescents with MDD (n = 24 119)
Martinez, Rietbrock and Wise35
10–89
Nested case-control study in primary care (n = 146 095) for first prescription of antidepressant for depression linked with suicide and self-harm
Simon and Savarino36
7 and older
Olfson and Marcus37
Overall 6–64 with a paediatric subgroup (6–18 years) 5–89; paediatric sample 5–18 years
Managed care claims linking new episodes of depression, antidepressant prescription, treatment type with suicide attempts (n = 131 788), 1996–2005. Observations commenced 90 days prior to starting treatment and 180 days following the commencement of treatment A nested, matched case-control study on outpatients with MDD using 2 years of Medicaid data 1999–2000. Outcome of interest was a suicide attempt
Valuck, Orton and Libby38
Schneeweiss et al.39
10–18
Hysinger et al.40
10–18
Case-control study in UK general practice 1993–1999 (n = 159 810). First prescription of amitriptyline, fluoxetine, paroxetine or dothiepin matched with suicidal behavior or suicide Case-control study of patients who had been hospitalised and treated for depression, matched for suicide attempts (n = 784) and suicide (n = 94), 1999–2000 Danish pharmacoepidemiological register linkage study (n = 2569) of prescriptions and suicide, 1995–1999
Retrospective, nested case-control study of patient with depression in managed care database in USA 1999–2006 matched to controls. Outcome of interest was a suicide attempt British Columbia 9-year observational study (n = 20 906) of those who initiated a script for an antidepressant with recorded depression matched with hospitalisation for self-harm and suicide This was a retrospective cohort study of Tennessee Medicaid programme claims (outpatient and emergency department files, hospital admissions) and death certificates 1995–2006 inclusive to identify those adolescents with suicidal behaviours who had been prescribed antidepressant medication (n = 250)
No overall relationship between antidepressants and suicide rate. Non-TCA (including SSRIs) was negatively associated with the suicide rate. TCA was positively associated with suicide rate Counties with higher levels of SSRI prescribing had fewer suicides In the USA and the Netherlands, the decline in prescribing of antidepressants in youth declined was inversely associated the youth suicide rate The highest risk of non-fatal suicidal behaviour was in the first 9 days, with the risk dropping thereafter. No suicides in the 10- to 19-year-old group In those 6–18 years, there were 263 suicide attempts and eight suicides. Antidepressant treatment was significantly associated with suicide attempts (OR 1.52) and suicide (OR 15.62) in the children and adolescent group No link between SSRI treatment and suicide when adjusted for severity of illness. It was estimated that none of the suicides (n = 42) had been treated with an SSRI 2 weeks prior to their suicide For those subjects 10–19 years, the adjusted relative risk for suicide attempts in those using antidepressant was significant (1.84). There were 44 deaths (all causes) in those 10–19 years with no differences in those on and off antidepressants, except for paroxetine where the relative risk was 5.44 For adolescents, there were three suicides and 17 serious suicide attempts over 10.5 years. The risk of suicide attempt was highest in the month before starting antidepressant treatment and dropped away in the months after starting treatment
Antidepressants were not associated with an increased risk of suicide attempt. Those adolescents treated with an antidepressant for 6 months had fewer suicide attempts than those treated for only 2 months. Adolescents (10–18 years) who were given a first prescription of an antidepressant had higher odds of non-fatal self-harm when currently using an SSRI (adjusted OR 1.59) compared with TCA. There were no suicides among any of the adolescent subjects The risk of suicide attempt was highest in the month before starting antidepressant treatment and dropped in the months after starting treatment regardless of whether they are receiving antidepressants from primary care physician or psychiatrist or psychotherapy
Initiating antidepressant treatment increased the risk of suicide attempts in children and adolescents (OR 2.08) but not adults
Across all ages, antidepressants had a protective effect for suicide attempts. Initiation of antidepressants followed by changing the dosage up or down was associated with a suicide attempt. The paediatric subgroup had an elevated risk of suicide attempts compared with the adults Of those adolescents with a new diagnosis of depression, 266 attempted suicide, and three died of suicide in the first year of use. There were no differential effects of any of the individual SSRIs and TCAs There were two suicides. Previous suicide attempts were reported in 46% of the younger adolescents (10–14 years) and 51% of the older adolescents (15–18 years). The younger group (compared with the older group) was more likely to have had a history of sexual abuse, interpersonal conflict, have a history of a psychotic disorder or had experienced hallucinations prior to the attempt. While the older adolescents were more likely to have had alcohol or illicit substance use that the younger adolescents
MDD, major depressive disorder; OR, odds ratio; SSRI, selective serotonin re-uptake inhibitor; TCA, tricyclic antidepressant.
850
Journal of Paediatrics and Child Health 50 (2014) 847–854 © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
MS Gordon and GA Melvin
Table 3
Antidepressants and suicidal events
Toxicological studies (n = 6) of children and adolescents who died by suicide
Study
Age, number of people who died by suicide
Site, year
Finding
Isacsson, Holmgren and Ahlner42 Isacsson, Holmgren and Ahlner42
doi:10.1111/jpc.12655
VIEWPOINT
Do antidepressants make children and adolescents suicidal? Michael S Gordon1 and Glenn A Melvin2 1 Child and Adolescent Stream, Early in Life Mental Health Service, Monash Medical Centre and 2Centre for Developmental Psychiatry and Psychology, Department of Psychiatry, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia
Key words:
adolescent; antidepressive agent; review; suicide.
Antidepressants are widely used to treat a range of mental illnesses experienced by children and adolescents. Treatment guidelines vary on the place of antidepressants in the treatment hierarchy for children and adolescents with depressive disorders but all agree that antidepressants have a place in the prescriber’s armamentarium.1–3 Case studies identified that high doses of fluoxetine were associated with suicidal behaviour in adolescents dating back to 1991.4 Investigation at this time with available data suggested no link between antidepressants and treatment-emergent suicidal ideation or behaviour.5 In May 2003, GlaxoSmithKline advised the Food and Drug Administration (FDA) in the USA that paroxetine use was associated with suicide-related adverse events in paediatric patients in a clinical trial.6 At the end of 2003, the Medicines and Health Products Regulatory Agency, the UK’s counterpart to the FDA, sent a letter to all doctors in the UK to warn them against using all but one of the antidepressants (fluoxetine) in children and adolescents. In October 2004, the FDA reached a split decision (15 yes, eight no) ordering that pharmaceutical companies add a ‘black box warning’ (BBW) on all antidepressant medication warning of the heightened risk of suicidal thoughts and behaviours.7 For a review of the history of the BBW, see Licinio and Wong.8 The Royal Australian and New Zealand College of Psychiatry, the Royal Australian College of General Practitioners and the Royal Australian and New Zealand College of Physicians released a joint statement in response in 2005 arguing for the continued access of children and adolescents to antidepressants but for their use within the context of a comprehensive management plan and careful monitoring mindful of the increased risk of suicidal thinking and behaviour.9 The FDA expanded its BBW about increased suicidal ideation and behaviour to include young adults 18–24 at the start of treatment (first 1–2 months) in 2007.10 Prior to the BBW, two-thirds of adolescents diagnosed with depression were treated with an antidepressant.11 Following the BBW, the rates of antidepressant dispensing in the USA fell to 58% lower than would have been expected from pre-BBW trends, with a decrease in the new diagnoses of paediatric depression.11 In the USA, paediatricians and primary care phyCorrespondence: Dr Michael S Gordon, Early in Life Mental Health Service, Southern Health, 246 Clayton Road, Clayton, Melbourne, Vic. 3168, Australia. Fax: 03 9594 6333; email: [email protected] Conflict of interest: None declared. Accepted for publication 21 February 2014.
sicians demonstrated the greatest reduction in prescription of antidepressants following the introduction of the BBW.11,12 This paper provides a narrative review of the link between suicide and antidepressant use in children and adolescents and reports on the breadth of evidence since the BBW. It is the aim of this paper to provide a range of reports and views in order to inform practitioners about the risks when prescribing.
Method We identified the relevant studies by searching the Ovid Medline and Cochrane Reviews using the search terms ‘Adolescent Psychology/’ or ‘Child Psychology/’ or ‘Child Psychiatry/’ or ‘Adolescent Psychiatry/’ or ‘adolescent’ or ‘child.mp’ or ‘youth.mp’ AND ‘suicide.mp’ or ‘suicidal.mp’ or ‘suicidal ideation.mp’ or ‘suicide, attempted.mp’ or ‘Self-Injurious behavior.mp’ or ‘exp Self-injurious Behavior/’ AND ‘antidepressive agents’ or ‘Serotonin Uptake Inhibitors.mp’ or ‘SSRI.mp’ or ‘escitalopram.mp’ or ‘citalopram.mp’ or ‘fluvoxamine.mp’ or ‘paroxetine.mp’ or ‘sertraline.mp’ or ‘venlafaxine.mp’ or ‘mirtazapine.mp’ or ‘nefazodone.mp’ or ‘bupropion.mp’ AND ‘meta-analysis.mp’ or ‘Case-Control Studies/.mp’ or ‘Case-control.mp’ or ‘Epidemiological Methods/’ or ‘Epidemiological Studies.mp’ or ‘Epidemiological Studies/’ or ‘clinical trial.mp’ or ‘Clinical Trial/’ or ‘Toxicology/’ or ‘toxicology.mp’. The databases were searched for studies from December 1991 to December 2013. We also consulted bibliographies of other reviews. The focus of this narrative review was as follows: (i) meta-analyses of randomised controlled trials (RCTs); (ii) pharmacoepidemiological; and (iii) toxicological studies. The age of interest was 6–18 years. Studies that spanned across this age but overlapped with older cohorts of participants were considered for inclusion.
Results The search of the databases revealed 153 papers. From these, the authors removed the duplicates, non-English papers and those that related to adult studies. Only those meta-analyses that assessed for placebo-controlled RCT were included. Metaanalyses that assessed for efficacy but not suicidal thoughts and behaviours were also excluded. From those remaining, 11 meta-analyses of placebo-controlled trials, 17 pharmacoepidemiological studies, one meta-analysis of observational studies and six post-mortem studies are reported.
Journal of Paediatrics and Child Health 50 (2014) 847–854 © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).
847
Antidepressants and suicidal events
MS Gordon and GA Melvin
Table 1 Meta-analyses of randomised control trials of antidepressants for children and adolescents Study
Method
Findings
Whittington et al.13
Five RCTs (MDD) fluoxetine, paroxetine, sertraline and venlafaxine
Mosholder and Willy14
21 RCTs (14 MDD, seven non-MDD- OCD, GAD, SAD) paroxetine, sertraline, venlafaxine, fluoxetine, citalopram, mirtazapine, nefazodone and fluvoxamine 20 RCTs (MDD, OCD, GAD, SAD) citalopram, fluoxetine, fluvoxamine, mirtazapine, paroxetine, sertraline and venlafaxine 22 RCTs (MDD, OCD, GAD and social anxiety) SSRIs and SNRIs 4 RCT (MDD, OCD) sertraline
RR calculated for individual antidepressants. Venlafaxine was most likely to be associated with suicide-related events. Fluoxetine was least likely to be associated with suicidal behavior or attempted suicide. The results were qualified because of wide confidence intervals. There was an increase in the number of serious suicidal events when the antidepressants were pooled (incident rate ratio of 1.89 compared with placebo) and with the MDD trials only (incident rate ratio 1.95). There was no overall increase in serious suicidal events from the non-MDD studies.
Hammad, Laughren and Racoosin15 Wohlfarth et al.16
March, Klee and Kremer17
Kaizar et al.18
Dubicka, Hadley and Roberts19 Bridge et al.20
Hetrick, McKenzie and Merry21 Cochrane22
Julious23
24 RCTs (MDD, OCD, anxiety, ADHD) citalopram, fluvoxamine, paroxetine, fluoxetine, sertraline, venlafaxine, mirtazapine, nefazodone and bupropion 16 RCTs (MDD) fluoxetine, sertraline, citalopram, paroxetine, venlafaxine and mirtazapine 27 RCTs (MDD, OCD, non-OCD anxiety disorders) SSRIs, nefazodone, venlafaxine, mirtazapine 10 RCTs (depressive disorder) paroxetine, fluoxetine, sertraline, citalopram 17 RCTs (MDD) citalopram, escitalopram, fluoxetine, mirtazapine, paroxetine, sertraline and venlafaxine 35 RCTs (depression and other indications) SSRIs and atypical antidepressants
There were no suicides in the 4582 patients. The risk difference for suicidal ideas or behaviours across all the antidepressants was 2% (NNH 50). The relative risk was 1.95 across all the all drugs for all indications. When antidepressants were assessed individually, the finding of increased risk was only significant for venlafaxine. There were no suicides in the 3832 patients. Risk difference for those in the MDD studies was 1.4% (NNH 71.4). There was no risk difference found for those treated for anxiety disorders. In the two MDD studies, for suicidal thoughts and behaviours, the risk difference was increased on sertraline 1.56% (NNH 64.2). Suicidal thoughts and behaviours associated with sertraline were more frequently seen in depressed children than depressed adolescents. There was no increase in suicidal thoughts and behaviours associated with sertraline when used for the treatment of OCD. There was an increased risk of suicidal thoughts and behaviours for those with MDD (OR 2.3) and separately where the antidepressant was an SSRI (OR 2.2).
For self-harm and suicide-related events, there was a difference favouring placebo using fixed effects estimate of the pooled odds (OR 1.70) but not when using random effects analysis. In 4592 children, across all the RCTs, the risk difference 0.7% was significant when all the studies were pooled (NNH 143). However, the risk difference for antidepressants across each of the conditions (MDD, OCD, non-OCD anxiety disorder) was not associated with suicidal ideation and behavior. The RR of suicide-related outcomes (ideas and behaviours) with SSRIs was 1.80.
From 3229 participants, the RR was 1.58 in suicidal thoughts and behaviours across in those treated with antidepressants compared with a placebo.
In 6039 patients, the risk difference for suicidal thoughts and behaviours for antidepressants compared with placebo across all indications was 0.9%. For suicidal thoughts and behaviours, there was no risk difference for SSRIs overall. There was no risk difference for suicidal thoughts and behaviours in those antidepressants treated for depression.
ADHD, attention deficit hyperactivity disorder; GAD, generalised anxiety disorder; MDD, major depressive disorder; NNH, number needed to harm; OCD, obsessive compulsive disorder; OR, odds ratio; RCT, randomised control trial; RR, relative risk; SAD, social anxiety disorder; SNRI, serotonin noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.
Meta-analyses A meta-analysis of RCTs allows for the pooling of suicidal thoughts and behaviours across a number of different antidepressant trials resulting in an improved ability to determine a difference between antidepressant and placebo groups. Eleven 848
meta-analyses are reported in Table 1. The meta-analyses varied in the RCTs that were chosen and available for inclusion. Whittington et al. in their analysis assessed each agent individually for adverse events.13 Mosholder and Willy assessed drug manufacturer data as provided by the FDA.14 However, Hammad assessed the FDA data after the suicide
Journal of Paediatrics and Child Health 50 (2014) 847–854 © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
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Antidepressants and suicidal events
events had been reclassified by Columbia University owing to the poor and inconsistent classification of suicidal and self-harm events.6 While suicide was not reported in any of these RCTs, overall, the meta-analyses all reported an increased risk of suicidal thoughts and behaviours compared with placebo in the early stages of treatment in children and adolescents on SSRIs and other antidepressant treatments. However, the studies varied in their specific findings. Bridge et al. and Julious reported this increase in suicide risk when all antidepressants were pooled but not when sub-analyses by psychiatric condition were undertaken.20,23 One study showed an increase in suicide risk when a more liberal fixed effects estimate was undertaken but not when a more conservative random effects regression was done.19 When individual antidepressants were considered, the risk ratio was consistently lowest for fluoxetine. Venlafaxine was the antidepressant most consistently found to be associated with suicidal thought and events.13,15,22 Children may be at higher risk of suicidal thoughts and behaviours when treated with antidepressants than adolescents.17 Those children and adolescents treated with antidepressants for anxiety disorders did not have an increased risk of suicidal thoughts and behaviours in three of the studies.16,17,20 The most recent Cochrane review (2012) included 19 published and unpublished RCTs (n = 3335 participants) that compared newer generation antidepressants with placebo in children and adolescents (6–18 years) who were diagnosed with a depressive disorder.22 This Cochrane review used two outcome measures: (i) suicide-related outcomes (thoughts and behaviours) as reported in Hammad6 and (ii) suicidal thinking as measured by the Suicidal Ideation Questionnaire-Junior High School Version (SIQ-Jr).22 For the suicidal-related outcomes, there was a 58% greater risk for those children and adolescents on the newer antidepressants versus placebo. When the data were further stratified by age, there was no statistical difference on suiciderelated outcomes between antidepressant and placebo for adolescents (13–18 years).22 The finding of an increased risk of suicide-related outcomes was not significant for any individual antidepressant except for venlafaxine, which had a very wide confidence interval.22 Meta-analysis of SIQ-Jr data found that there was no difference in proportion with suicidal ideas between antidepressant and placebo.22 The risk difference between antidepressants and placebo across the meta-analyses varied with the FDA study of Hammad, which was at the upper end of the risk estimate at 2%,15 compared with Bridge et al. of 0.7%20 and Julious at 0.9%.23 This suggests that there is an increased risk of antidepressant-related suicidal thoughts or behaviours of up to 20 events per 1000 patients compared with placebo.
Seventeen pharmacoepidemiological studies that included children and adolescents in ecological, case-control and cohortdesigned studies are summarised in Table 2. Antidepressants or SSRI prescription were inversely related to the suicide rate.24–28 Five observational studies reported a gradient of suicide attempt risk. The highest risk was found to be in the month before starting the antidepressant and the next highest risk in the weeks and month after starting the antidepressant, declining thereafter.29,33,34,36,38 Other studies reported varying findings regarding suicide attempts. One study found an increase in suicide attempts and suicide in children and adolescents who had been admitted and treated with antidepressants for depression.30 Another study found an increased risk of suicide attempts but not death for antidepressants other than paroxetine,32 while another found no link between SSRIs and suicide.31 SSRIs were found to have the same suicide risk as tricyclic antidepressant (TCA),39 a higher risk than TCA35 and a lower risk compared with TCA.26 A compelling finding from the observational and casecontrolled studies is the meta-analysis of Barbui, Esposito and Cipriani.41 Barbui, Esposito and Cipriani conducted a random effects meta-analysis of observation studies involving those patients treated for moderate or severe depression with SSRIs.41 They included eight studies of which five had child and adolescent participants.41 Barbui, Esposito and Cipriani found that exposure to SSRIs doubled the risk for suicide or attempted suicide in children and adolescents compared with those not exposed to any antidepressants (odds ratio 1.92), while for adults, the risk was decreased.41 For individual agents, paroxetine and venlafaxine increased the risk of suicide and suicide attempts, while citalopram, fluoxetine, fluvoxamine and sertraline were not significant.41
Pharmacoepidemiological studies
The meta-analyses described have consistently indicated that there is an increased risk of suicidal thoughts and behaviours in the order of between seven and 20 incidents per 1000 of those treated with an antidepressant compared with placebo. These findings occur most consistently when the data are pooled. With the exception of venlafaxine, subgroup analyses do not provide an association between specific antidepressant agents and suicidal thoughts and behaviours, a finding that may be related to small sample sizes resulting in analyses that are underpowered
Epidemiological studies aim to detect relatively rare outcomes, such as suicide, in large samples exposed to variables of interest (e.g. antidepressant treatment).24 By contrast, observational studies link administrative and clinical databases, allowing the investigation of possible links between antidepressant prescriptions and suicide attempts or suicide in very large samples from real-world clinical practice.24
Post-mortem studies If antidepressants cause adolescents to become suicidal, it has been reasoned that it is very likely that antidepressants will be present in toxicology assays of adolescent suicide victims (see Table 3). Six toxicology studies assessed for the presence of antidepressants in adolescents who were assessed by the coroner to have died by suicide. Collectively, these findings suggest that it is reasonably uncommon for adolescents who have died by suicide to have been taking newer antidepressants, such as SSRI at therapeutic doses. The infrequent presence or absence of antidepressants at autopsy suggests either the adolescent was not prescribed the antidepressant or was not taking it in the days prior to their suicide.
Discussion
Journal of Paediatrics and Child Health 50 (2014) 847–854 © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
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Table 2 Pharmacoepidemiological studies of antidepressants and suicidal behaviour Study
Age in years
Method
Findings
Olfson et al.
10–19
Regional suicide rate linked with national antidepressant prescriptions, 1990–2000
Hall and Lucke24
15 and over
Australian prescription data in general practice matched to suicide rates, 1991–2001 US regional suicide rate linked with national antidepressant prescriptions, 1996–1998
An inverse relationship between antidepressant medication and suicide. A 1% increase in use of antidepressant in adolescents was associated with a reduction in suicides by 0.23/100 000 adolescents per year Suicide rate was inversely related to antidepressant prescribing
25
Gibbons et
al.26
Gibbons et al.27 Gibbons et
al.28
All ages
5–14 Up to 19
US regional suicide rate linked with national antidepressant prescriptions, 1996–1998 Regional suicide rate linked with national antidepressant prescriptions, 2003–2005
Jick, Kaye and Jick29
10–69
Olfson, Marcus and Shaffer30
6–64
Søndergård et al.31
10–17
Tiihonen, et al.32
10 and older
Cohort study of Finnish patients hospitalised for a suicide attempt (n = 15 390) follow-up for 3.4 years, 1997–2003
Simon et al.33
5–105
Valuck et al.34
12–18
Managed care claims linking new episodes of depression, antidepressant prescription, treatment type with suicide attempts and suicide (n = 65 103), 1992–2003. Observations commenced 90 days prior to starting treatment and 180 days following the commencement of treatment Retrospective cohort study of Managed Care plans linking antidepressant treatment and suicide attempts in adolescents with MDD (n = 24 119)
Martinez, Rietbrock and Wise35
10–89
Nested case-control study in primary care (n = 146 095) for first prescription of antidepressant for depression linked with suicide and self-harm
Simon and Savarino36
7 and older
Olfson and Marcus37
Overall 6–64 with a paediatric subgroup (6–18 years) 5–89; paediatric sample 5–18 years
Managed care claims linking new episodes of depression, antidepressant prescription, treatment type with suicide attempts (n = 131 788), 1996–2005. Observations commenced 90 days prior to starting treatment and 180 days following the commencement of treatment A nested, matched case-control study on outpatients with MDD using 2 years of Medicaid data 1999–2000. Outcome of interest was a suicide attempt
Valuck, Orton and Libby38
Schneeweiss et al.39
10–18
Hysinger et al.40
10–18
Case-control study in UK general practice 1993–1999 (n = 159 810). First prescription of amitriptyline, fluoxetine, paroxetine or dothiepin matched with suicidal behavior or suicide Case-control study of patients who had been hospitalised and treated for depression, matched for suicide attempts (n = 784) and suicide (n = 94), 1999–2000 Danish pharmacoepidemiological register linkage study (n = 2569) of prescriptions and suicide, 1995–1999
Retrospective, nested case-control study of patient with depression in managed care database in USA 1999–2006 matched to controls. Outcome of interest was a suicide attempt British Columbia 9-year observational study (n = 20 906) of those who initiated a script for an antidepressant with recorded depression matched with hospitalisation for self-harm and suicide This was a retrospective cohort study of Tennessee Medicaid programme claims (outpatient and emergency department files, hospital admissions) and death certificates 1995–2006 inclusive to identify those adolescents with suicidal behaviours who had been prescribed antidepressant medication (n = 250)
No overall relationship between antidepressants and suicide rate. Non-TCA (including SSRIs) was negatively associated with the suicide rate. TCA was positively associated with suicide rate Counties with higher levels of SSRI prescribing had fewer suicides In the USA and the Netherlands, the decline in prescribing of antidepressants in youth declined was inversely associated the youth suicide rate The highest risk of non-fatal suicidal behaviour was in the first 9 days, with the risk dropping thereafter. No suicides in the 10- to 19-year-old group In those 6–18 years, there were 263 suicide attempts and eight suicides. Antidepressant treatment was significantly associated with suicide attempts (OR 1.52) and suicide (OR 15.62) in the children and adolescent group No link between SSRI treatment and suicide when adjusted for severity of illness. It was estimated that none of the suicides (n = 42) had been treated with an SSRI 2 weeks prior to their suicide For those subjects 10–19 years, the adjusted relative risk for suicide attempts in those using antidepressant was significant (1.84). There were 44 deaths (all causes) in those 10–19 years with no differences in those on and off antidepressants, except for paroxetine where the relative risk was 5.44 For adolescents, there were three suicides and 17 serious suicide attempts over 10.5 years. The risk of suicide attempt was highest in the month before starting antidepressant treatment and dropped away in the months after starting treatment
Antidepressants were not associated with an increased risk of suicide attempt. Those adolescents treated with an antidepressant for 6 months had fewer suicide attempts than those treated for only 2 months. Adolescents (10–18 years) who were given a first prescription of an antidepressant had higher odds of non-fatal self-harm when currently using an SSRI (adjusted OR 1.59) compared with TCA. There were no suicides among any of the adolescent subjects The risk of suicide attempt was highest in the month before starting antidepressant treatment and dropped in the months after starting treatment regardless of whether they are receiving antidepressants from primary care physician or psychiatrist or psychotherapy
Initiating antidepressant treatment increased the risk of suicide attempts in children and adolescents (OR 2.08) but not adults
Across all ages, antidepressants had a protective effect for suicide attempts. Initiation of antidepressants followed by changing the dosage up or down was associated with a suicide attempt. The paediatric subgroup had an elevated risk of suicide attempts compared with the adults Of those adolescents with a new diagnosis of depression, 266 attempted suicide, and three died of suicide in the first year of use. There were no differential effects of any of the individual SSRIs and TCAs There were two suicides. Previous suicide attempts were reported in 46% of the younger adolescents (10–14 years) and 51% of the older adolescents (15–18 years). The younger group (compared with the older group) was more likely to have had a history of sexual abuse, interpersonal conflict, have a history of a psychotic disorder or had experienced hallucinations prior to the attempt. While the older adolescents were more likely to have had alcohol or illicit substance use that the younger adolescents
MDD, major depressive disorder; OR, odds ratio; SSRI, selective serotonin re-uptake inhibitor; TCA, tricyclic antidepressant.
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Journal of Paediatrics and Child Health 50 (2014) 847–854 © 2014 The Authors Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians)
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Table 3
Antidepressants and suicidal events
Toxicological studies (n = 6) of children and adolescents who died by suicide
Study
Age, number of people who died by suicide
Site, year
Finding
Isacsson, Holmgren and Ahlner42 Isacsson, Holmgren and Ahlner42
