Do antidepressants make children and adolescents suicidal?

Authors

  • Michael S Gordon,

    Corresponding author
    1. Child and Adolescent Stream, Early in Life Mental Health Service, Monash Medical Centre, Melbourne, Victoria, Australia
    • Correspondence: 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: michael.gordon@monashhealth.org

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  • Glenn A Melvin

    1. Centre for Developmental Psychiatry and Psychology, Department of Psychiatry, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia
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  • Conflict of interest: None declared.

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 physicians 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. Meta-analyses 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.

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 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 events had been reclassified by Columbia University owing to the poor and inconsistent classification of suicidal and self-harm events.[6]

Table 1. Meta-analyses of randomised control trials of antidepressants for children and adolescents
StudyMethodFindings
  1. 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.
Whittington et al.[13]

Five RCTs (MDD)

fluoxetine, paroxetine, sertraline and venlafaxine

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.
Mosholder and Willy[14]

21 RCTs (14 MDD, seven non-MDD- OCD, GAD, SAD)

paroxetine, sertraline, venlafaxine, fluoxetine, citalopram, mirtazapine, nefazodone and fluvoxamine

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 Racoosin[15]

20 RCTs (MDD, OCD, GAD, SAD)

citalopram, fluoxetine, fluvoxamine, mirtazapine, paroxetine, sertraline and venlafaxine

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.
Wohlfarth et al.[16]

22 RCTs (MDD, OCD, GAD and social anxiety)

SSRIs and SNRIs

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.
March, Klee and Kremer[17]

4 RCT (MDD, OCD)

sertraline

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.
Kaizar et al.[18]

24 RCTs (MDD, OCD, anxiety, ADHD)

citalopram, fluvoxamine, paroxetine, fluoxetine, sertraline, venlafaxine, mirtazapine, nefazodone and bupropion

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).
Dubicka, Hadley and Roberts[19]

16 RCTs (MDD)

fluoxetine, sertraline, citalopram, paroxetine, venlafaxine and mirtazapine

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.
Bridge et al.[20]

27 RCTs (MDD, OCD, non-OCD anxiety disorders)

SSRIs, nefazodone, venlafaxine, mirtazapine

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.
Hetrick, McKenzie and Merry[21]

10 RCTs (depressive disorder)

paroxetine, fluoxetine, sertraline, citalopram

The RR of suicide-related outcomes (ideas and behaviours) with SSRIs was 1.80.
Cochrane[22]

17 RCTs (MDD)

citalopram, escitalopram, fluoxetine, mirtazapine, paroxetine, sertraline and venlafaxine

From 3229 participants, the RR was 1.58 in suicidal thoughts and behaviours across in those treated with antidepressants compared with a placebo.
Julious[23]

35 RCTs (depression and other indications)

SSRIs and atypical antidepressants

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.

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 Hammad[6] 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 suicide-related 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.

Pharmacoepidemiological studies

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]

Seventeen pharmacoepidemiological studies that included children and adolescents in ecological, case-control and cohort-designed studies are summarised in Table 2. Antidepressants or SSRI prescription were inversely related to the suicide rate.[24-28]

Table 2. Pharmacoepidemiological studies of antidepressants and suicidal behaviour
StudyAge in yearsMethodFindings
  1. MDD, major depressive disorder; OR, odds ratio; SSRI, selective serotonin re-uptake inhibitor; TCA, tricyclic antidepressant.
Olfson et al.[25]10–19Regional suicide rate linked with national antidepressant prescriptions, 1990–2000An 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
Hall and Lucke[24]15 and overAustralian prescription data in general practice matched to suicide rates, 1991–2001Suicide rate was inversely related to antidepressant prescribing
Gibbons et al.[26]All agesUS regional suicide rate linked with national antidepressant prescriptions, 1996–1998No 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
Gibbons et al.[27]5–14US regional suicide rate linked with national antidepressant prescriptions, 1996–1998Counties with higher levels of SSRI prescribing had fewer suicides
Gibbons et al.[28]Up to 19Regional suicide rate linked with national antidepressant prescriptions, 2003–2005In the USA and the Netherlands, the decline in prescribing of antidepressants in youth declined was inversely associated the youth suicide rate
Jick, Kaye and Jick[29]10–69Case-control study in UK general practice 1993–1999 (n = 159 810). First prescription of amitriptyline, fluoxetine, paroxetine or dothiepin matched with suicidal behavior or suicideThe 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
Olfson, Marcus and Shaffer[30]6–64Case-control study of patients who had been hospitalised and treated for depression, matched for suicide attempts (n = 784) and suicide (n = 94), 1999–2000In 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
Søndergård et al.[31]10–17Danish pharmacoepidemiological register linkage study (n = 2569) of prescriptions and suicide, 1995–1999No 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
Tiihonen, et al.[32]10 and olderCohort study of Finnish patients hospitalised for a suicide attempt (n = 15 390) follow-up for 3.4 years, 1997–2003For 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
Simon et al.[33]5–105Managed 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 treatmentFor 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
Valuck et al.[34]12–18Retrospective cohort study of Managed Care plans linking antidepressant treatment and suicide attempts in adolescents with MDD (n = 24 119)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.
Martinez, Rietbrock and Wise[35]10–89Nested case-control study in primary care (n = 146 095) for first prescription of antidepressant for depression linked with suicide and self-harmAdolescents (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
Simon and Savarino[36]7 and olderManaged 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 treatmentThe 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
Olfson and Marcus[37]Overall 6–64 with a paediatric subgroup (6–18 years)A nested, matched case-control study on outpatients with MDD using 2 years of Medicaid data 1999–2000. Outcome of interest was a suicide attemptInitiating antidepressant treatment increased the risk of suicide attempts in children and adolescents (OR 2.08) but not adults
Valuck, Orton and Libby[38]5–89; paediatric sample 5–18 yearsRetrospective, 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 attemptAcross 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
Schneeweiss et al.[39]10–18British 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 suicideOf 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
Hysinger et al.[40]10–18This 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)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

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 TCA[35] and a lower risk compared with TCA.[26]

A compelling finding from the observational and case-controlled 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]

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.

Table 3. Toxicological studies (n = 6) of children and adolescents who died by suicide
StudyAge, number of people who died by suicideSite, yearFinding
  1. SSRI, selective serotonin re-uptake inhibitor.
Isacsson, Holmgren and Ahlner[42]<15 years old (n = 52)Sweden, 1992–2000No SSRI was found in toxicological screening of those who died by suicide.
Isacsson, Holmgren and Ahlner[42]15–19 years (n = 326)Sweden, 1992–2000An antidepressant was found in 13 of those who died by suicide (9.8%). In only six of the 13 adolescents was the antidepressant an SSRI.
Leon et al.[43]10–17 years (n = 54)New York City, 1993–1998Imipramine (n = 2) and fluoxetine (n = 2) was found in four adolescents who had died by suicide.
Leon et al.[44]<18 years (n = 36)New York City, 1999–2002Thirty-six adolescents who had died by suicide had toxicology and had an injury to death interval of 3 days or less; only one subject was found to have bupropion and sertraline detected on post-mortem assay.
Singh and Lathrop[45]9–17 years (n = 433)New Mexico, 1979–2005Less than 5% of subjects had any detectable psychiatric drug at autopsy.
Moskos et al.[46]13–21 years (n = 151)Utah, 1996–1998They found no therapeutic or sub-therapeutic levels of psychotropic medications across a sample of 151 consecutive deaths from suicide in youth aged 13–21 years.
Cortes et al.[47]<25 years old (n = 253)Miami-Dade County, 1990–2007Antidepressants were found in 6% (n = 15) of those adolescents who died by suicide.

Discussion

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 to detect a difference. It has been accepted by the FDA that a 2% increase in risks of suicidal thoughts and behaviours for children and adolescents enrolled in an RCT can be extrapolated to an increased risk of suicide of a depressed adolescent medicated in the community.[7]

It is however difficult to know how this suicide risk in clinical trials translates in office-based prescribing. The participants from predominantly pharmaceutical industry-sponsored RCTs used for the meta-analyses are different from those adolescents treated in the real world. In many of the RCTs, those adolescents who were suicidal at assessment or who had serious psychiatric comorbidity were excluded from the studies.[48] Depressed adolescents enrolled in an RCT have been estimated to have half the rate of suicidal thoughts and behaviours of depressed youth in the community.[49]

There are methodological issues in pooling RCTs for a meta-analysis. The RCTs are predominantly studies in which suicidal thoughts and behaviours were not assessed prospectively. A review of a number of the controlled trials for the treatment of depression with antidepressants has found that the RCTs are quite heterogeneous with respect to recruitment, inclusion and exclusion criteria, study design, and outcome measures.[48] Gibbons has argued that pooling of intent-to-treat person-level longitudinal data is a superior statistical method than meta-analysis.[50] When this was done for RCT studies using fluoxetine, there was no increase in youth suicide risk over placebo.[50]

The main outcome measure used in the meta-analyses, the composite outcome of suicidal thoughts and behaviours, may not be the best single measure for assessing future risk for death by suicide. It has been argued that suicidal thoughts alone are a poor proxy for suicide. Baldessarini, Pompili and Tondo have opined that ‘suicidal ideation, as ascertained incidentally in trials, is a convenient but probably unreliable, nonequivalent, and potentially misleading surrogate for suicidal behavior (attempts or suicide)’ p. 246.[51] Suicidal thoughts in older adolescents poorly identify those adolescents who will die by suicide. Mann et al. in a review estimated that for older adolescent boys, the ratio of suicidal thoughts to death by suicide is 9000:1, and for older adolescent girls, it is 19 000:1.[5]

Adolescents contemplate suicide more than adults. It remains unclear what the risk of dying by suicide is for those adolescents who are medicated for depression and who have suicidal thoughts. The ratio of suicide attempt to suicide in the older adolescent group was estimated to be 400:1 for boys and 3000:1 for girls.[5] Those meta-analyses that have pooled suicidal thoughts and behaviours may have inadvertently mixed different risk factors (by an order of up to 20 times) for suicide. Further, if suicidal thoughts and behaviours are increased by antidepressant use by 20 per 1000 compared with placebo, then it may be very difficult to detect if antidepressants are increasing child and adolescent suicides.

A problem with the meta-analyses described is that they use data from studies of up to 19 weeks.[14] Valuck, Orton and Libby have reported on antidepressant risk for a suicide attempt noting that initiation of antidepressants refers to the first 55 days and early maintenance refers to days 56–179.[38] Given that the pharmacoepidemiological studies suggest that the risk of suicide is highest prior to and following initiation of treatment, it is possible that the findings of increased risk from RCTs might have overestimated the risk during treatment that occurs beyond 19 weeks of antidepressant treatment.

Studies that compare the treatment of depression in children and adolescents using medication and cognitive behavioural therapy have longer observation periods. The most recent Cochrane review comparing psychological therapies with antidepressants did not combine the suicidal-related adverse-related events in a meta-analysis owing to the diversity of assessment instruments used.[52] However, with respect to suicidal thoughts, there was a higher level of suicidal thinking in the antidepressant-treated group compared with psychological-treated group following treatment and at 6–9 months of follow-up.[52] It is unclear what the significance of this means other than to possibly reinforce the message of psychological interventions to be considered as first-line treatment for adolescent depression over antidepressant medication.

Outcomes of the ecological studies suggest that there is an inverse effect with increased antidepressant prescription rates associated with a declining rate of suicide at a population level. The inference however is that antidepressants are not increasing suicide rate as would be expected if these medications indeed have suicide-inducing qualities. However, antidepressants are prescribed for a multitude of indications, and it cannot be assumed that all those antidepressant prescriptions are for depressed children and adolescents. The prescriptions might be in the main for use in conditions with a lower suicide risk than depression such as chronic fatigue or autism, thereby muddying the findings. Given that suicide is a final common pathway for a myriad of diagnoses, interacting risk factors, compliance with medication and individual dosing, it is a challenge to know how to extrapolate the finding of an inverse relationship between antidepressants and suicide rate at a population perspective to explain a given individual's risk of treatment with an antidepressant.

The meta-analysis of observational studies found an increased risk of suicide and attempted suicide of nearly twice that of those not on an SSRI.[41] This doubling of the risk is the same as the finding by Hammad from the FDA data.[15] While these findings are reasonably convincing of an increased suicide risk, it must be remembered that there are limitations with observational studies. Unlike RCTs, patients in observational studies are not randomised. Those adolescents in observational studies with higher levels of depression are more likely to be given an antidepressant medication.[24, 53]

While toxicological studies have not found, or infrequently found, antidepressant medication at autopsy, there are a number of problems with the post-mortem toxicology studies. Not all those who died by suicide had toxicology assays. In some of the studies, they did not exclude those who had an injury to death period of less than 3 days.[46] Antidepressants with a short half life (such as fluvoxamine or sertraline) may substantively been metabolised if the injury to death interval is more than 72 h.[54] Further, it has been suggested that antidepressant withdrawal may be a mechanism that increases suicidal behaviours.[55] It can also be argued that those who are on antidepressants are less likely to die if they overdose only on their prescribed antidepressants, given the low overall lethality of newer antidepressant agents.

A further unanswered question concerns the possibility of subgroups of children and adolescents who may be more vulnerable to treatment-emergent suicidal events. There is some preliminary evidence that those children and adolescents who had more severe suicidal behaviours at initial assessment or suffered with borderline personality disorder or psychotic features were more likely to experience suicide-related events.[56] Clarifying which groups of children and adolescents are more at risk is a challenge for the future.

Clinical implications

There are several implications arising from the literature on suicidal effects of antidepressants in children and adolescents for the prescribing clinician. The clinician should carefully weigh up the risks and benefits before starting an antidepressant. The child or adolescent and their parents should be involved in informed and shared decision-making[57] with the risk of increased risk of approximately twofold being explained to them prior to initiating an antidepressant. Venlafaxine and paroxetine have been implicated more than the other newer antidepressants and are not recommended as a first-line treatment.

The prescribing clinician should consider slow increases in medication mindful that the highest risk is likely to be in the early phase of treatment and when the dose is changed (up or down).

Suicidal thoughts and behaviours should be monitored prior to starting the medication and early in the treatment. The UK NICE guidelines suggest weekly medication review for the first month and at least monthly review for the first 3 months.[3] The likely mechanisms by which antidepressants might increase suicidal thoughts and behaviours are summarised in Table 4. Monitoring for disinhibition, impulsivity, increased aggression and hypomanic symptoms in addition to suicidal thoughts and behaviours should be conducted at each review. Should the medication need to be stopped, then gradual tapering to avoid discontinuation syndrome is advised.[59] A case study incorporating the monitoring of suicidal events is presented in Appendix I.

Table 4. Potential mechanisms of increased suicidal thought and behavior adapted from Teicher, Glod and Cole[58]
Possible mechanism
Increased energy to overcome lethargy and psychomotor retardation to act on suicidal plans
Worsening of depression
Increases mental and physical restlessness (akathisia)
Increased anxiety
Hypomanic, manic or mixed manic states
Worsening of insomnia and increased disturbance of sleep architecture
Obsessional suicidal pre-occupation
Hostility
Change to electroencephalogram with increased impulsivity

Conclusions

Different experts have argued opposite interpretations of the same available studies regarding the risk of suicidal events during antidepressant treatment. Part of the challenge is that suicide, the adverse event of concern, is (fortunately) relatively rare, and each of the methodological tools used to evaluate the risk have their limitations. Taken together, the extant literature overall suggests that there is a small but increased risk of suicidal thoughts and behaviours when using antidepressants in children and adolescents, particularly early in treatment.

This review recommends the frequent monitoring of an adolescent over the initial weeks after commencing an antidepressant and inquiring about the emergence of suicidal thoughts and behaviours. The joint advisory of the Colleges of Psychiatry, General Practice and Physicians on the use of antidepressants recommending prudent use, clear communication of the potential risks involved with treatment, frequent early monitoring for suicidal thought and behaviours, and use within the context of comprehensive management plan remains a very relevant guide.[9]

Appendix: Appendix I

Case study: Monitoring for suicidal events

Dr. Smith is asked to assess Oscar, a 14-year-old boy, who presents with a 4-month history of school refusal and social anxiety. On further questioning, Dr. Smith elicits a history of a 6-month history of lowered mood, sleep disturbance, poor concentration, daytime lethargy, anorexia without loss of weight, with fleeting suicidal thoughts but no suicide plans or past attempts. There is a family history of major depression in Oscar's mother and maternal grandmother. Dr. Smith diagnoses Oscar with major depressive disorder and social anxiety and refers Oscar to a private psychologist for cognitive behavioural therapy (CBT).

Dr. Smith reviews Oscar after eight sessions of weekly CBT. While there is some limited improvement, Oscar is still struggling with sleep problems, anorexia, lowered mood, lack of concentration and school refusal. Oscar now denies suicidal ideation.

Dr. Smith suggests a trial of fluoxetine for the treatment of MDD and Social Anxiety after the limited response to CBT over 8 weeks. Dr. Smith has a discussion with Oscar and his mother about the options of further CBT, family therapy, interpersonal therapy or a day programme. The risks and benefits of each are discussed. Oscar and his mother decide to trial the fluoxetine, as Oscar's mother has had a good response in the past to this antidepressant. Dr. Smith discusses the common and rare side effects of fluoxetine with Oscar and his mother including manic switching, serotonin syndrome and potential for increased suicidal thoughts and behaviours. Dr. Smith indicates that the risk of this is approximately 3%. Fluoxetine is commenced at 10 mg mane in conjunction with further CBT.

Dr. Smith reviews Oscar after a week, and he reports mild headache and nausea, side effects that had settled spontaneously after 4 days without a change in his dose. At this review, there are no suicidal thoughts or behaviours. On questioning, Oscar does not have any hypomanic symptoms, or increased irritability or anger. Dr. Smith increases the dose to 20 mg daily and reviews Oscar until the end of the month. At this review, Oscar's mother reports that Oscar's anxiety has decreased somewhat to allow him to return to school for two periods per day. There is also some improvement in Oscar's overall mood and sleep pattern. Dr. Smith increases the fluoxetine at the 1-month review to 30 mg daily. Oscar is reviewed after 2 weeks and continues to improve. Oscar is reviewed monthly for the next 12 months, when a trial off the fluoxetine is undertaken. The fluoxetine is reduced gradually, and the medical reviews are at fortnightly intervals over the tapering period.