“Antidepressants and Suicidality in Youth,” Halifax, Nova Scotia, Canada; May 15, 2006, IWK Research Celebration, IWK Health Centre *Discuss suicide risk associated with antidepressants in youth *Discuss FDA post-hoc analysis of SSRI (Selective Serotonin Reuptake Inhibitor) youth studies *Future Research Directions

1. SSRIs and Suicidality inSSRIs and Suicidality in
YouthYouth
Carlo G. Carandang, M.D.Carlo G. Carandang, M.D.
Mood Disorders GroupMood Disorders Group
IWK Health CentreIWK Health Centre
Halifax, NSHalifax, NS
CANADACANADA

2. DisclosureDisclosure
Research GrantsResearch Grants
• Maine Medical Center Research InstituteMaine Medical Center Research Institute
• GlaxoSmithKlineGlaxoSmithKline
CommitteesCommittees
• Member, NIMH Antidepressants andMember, NIMH Antidepressants and
Suicidality Review Panel, 2006Suicidality Review Panel, 2006

3. ObjectivesObjectives
 Discuss suicide risk associated withDiscuss suicide risk associated with
antidepressants in youthantidepressants in youth
 Discuss FDA post-hoc analysis ofDiscuss FDA post-hoc analysis of
SSRI (Selective Serotonin ReuptakeSSRI (Selective Serotonin Reuptake
Inhibitor) youth studiesInhibitor) youth studies
 Future Research DirectionsFuture Research Directions

4. FDA Blackbox WarningFDA Blackbox Warning
 FDA: SSRIs associated withFDA: SSRIs associated with
increased risk of suicide in youthincreased risk of suicide in youth
 UK: SSRIs banned in youthUK: SSRIs banned in youth
 Columbia pooled analysis of 24Columbia pooled analysis of 24
clinical trials involving 4,400 youthclinical trials involving 4,400 youth
• 4% suicidal events on medication versus4% suicidal events on medication versus
2% on placebo2% on placebo
• Statistically significant p<0.05Statistically significant p<0.05
• No completed suicides in trialsNo completed suicides in trials

5. SSRI Clinical Trials in YouthSSRI Clinical Trials in Youth
 Methodological problemsMethodological problems
• Most trials: spontaneous reporting of adverseMost trials: spontaneous reporting of adverse
events such as suicidalityevents such as suicidality
• Definition of suicide not uniform across studiesDefinition of suicide not uniform across studies
 Includes activation, agitation, in addition to actualIncludes activation, agitation, in addition to actual
suicidal ideations/behaviorssuicidal ideations/behaviors
• Focus has been on efficacy to the detriment ofFocus has been on efficacy to the detriment of
treatment-emergent adverse effectstreatment-emergent adverse effects
 Standards for efficacy well-defined (i.e. CDRS)Standards for efficacy well-defined (i.e. CDRS)
 No standard method to assess adverse eventsNo standard method to assess adverse events
• Underpowered; short trial duration; highUnderpowered; short trial duration; high
placebo response; PI conflicts of interestplacebo response; PI conflicts of interest

6. SSRI Clinical Trials in YouthSSRI Clinical Trials in Youth
 Safety Design ProblemsSafety Design Problems
• Some studies did not have Data SafetySome studies did not have Data Safety
Monitoring Boards (DSMB)Monitoring Boards (DSMB)
• For studies with no DSMB, noFor studies with no DSMB, no
systematic way to address suicidalitysystematic way to address suicidality
 IRB/IEB oversight not adequate aloneIRB/IEB oversight not adequate alone
• Depressed youth samples alwaysDepressed youth samples always
considered high-risk studies givenconsidered high-risk studies given
suicide is part of the illnesssuicide is part of the illness
• PI conflicts of interestPI conflicts of interest

7. FDA Blackbox on SSRIsFDA Blackbox on SSRIs
 Blackbox on all antidepressants inBlackbox on all antidepressants in
youth <18 years old for ANYyouth <18 years old for ANY
indicationindication
 Includes all antidepressants: SSRIs,Includes all antidepressants: SSRIs,
bupropion, venlafaxine, mirtazepine,bupropion, venlafaxine, mirtazepine,
nefazodone and TCA’snefazodone and TCA’s

8. Risk Ratio of Serious Suicide-Risk Ratio of Serious Suicide-
Related Event on SSRIsRelated Event on SSRIs
DrugDrug N (drug)N (drug) N (PBO)N (PBO) Risk RatioRisk Ratio
FluoxetineFluoxetine 249249 209209 0.920.92
ParoxetineParoxetine 642642 549549 2.652.65
SertralineSertraline 281281 279279 1.481.48
CitalopramCitalopram 210210 197197 1.371.37
VenlafaxineVenlafaxine 339339 342342 4.974.97
MirtazepineMirtazepine 170170 8888 1.581.58
NefazodoneNefazodone 279279 189189 No eventsNo events
Total allTotal all
trialstrials
1.781.78

9. Risk Ratio of Serious Suicide-RelatedRisk Ratio of Serious Suicide-Related
Event: All Indications vs. MDD TrialsEvent: All Indications vs. MDD Trials
DrugDrug Relative RiskRelative Risk
(95% CI), all trials,(95% CI), all trials,
all indicationsall indications
Relative RiskRelative Risk
(95% CI),(95% CI),
MDD trialsMDD trials
FluoxetineFluoxetine 0.92 (0.39, 2.19)0.92 (0.39, 2.19) 0.89 (0.36, 2.19)0.89 (0.36, 2.19)
ParoxetineParoxetine 2.65 (1.00, 7.02)2.65 (1.00, 7.02) 2.15 (0.71, 6.52)2.15 (0.71, 6.52)
SertralineSertraline 1.48 (0.42, 5.24)1.48 (0.42, 5.24) 2.16 (0.48, 9.62)2.16 (0.48, 9.62)
CitalopramCitalopram 1.37 (0.53, 3.50)1.37 (0.53, 3.50) 1.37 (0.53, 3.50)1.37 (0.53, 3.50)
VenlafaxineVenlafaxine 4.97 (1.09, 22.72)4.97 (1.09, 22.72) 8.84 (1.12, 69.51)8.84 (1.12, 69.51)
MirtazepineMirtazepine 1.58 (0.06, 38.37)1.58 (0.06, 38.37) 1.58 (0.06, 38.37)1.58 (0.06, 38.37)

10. SSRI Treatment in YouthSSRI Treatment in Youth
DepressionDepression
 Younger age of treatment associated with moreYounger age of treatment associated with more
adverse effects, less efficacyadverse effects, less efficacy
• Compared to adults, youth have differentCompared to adults, youth have different
pharmacokinetics and more impacted by psychosocialpharmacokinetics and more impacted by psychosocial
environmentenvironment
 SSRIs may induce mania, hypomania, behavioralSSRIs may induce mania, hypomania, behavioral
activation (impulsive, silly, agitated, daring)activation (impulsive, silly, agitated, daring)
• Increases risk for acting on suicidal ideationsIncreases risk for acting on suicidal ideations
 Early case reports described association betweenEarly case reports described association between
SSRI and increased suicidal tendencies, possiblySSRI and increased suicidal tendencies, possibly
linked to behavioral activation or akathisia (Kinglinked to behavioral activation or akathisia (King
et al, 1991; Teicher et al., 1990)et al, 1991; Teicher et al., 1990)

11. SSRI Efficacy for MDD in Youth:SSRI Efficacy for MDD in Youth:
Published Controlled StudiesPublished Controlled Studies
 Fluoxetine has proven efficacy (4/4 studies)Fluoxetine has proven efficacy (4/4 studies)
 Citalopram (1/3 studies) and Sertraline (2 studiesCitalopram (1/3 studies) and Sertraline (2 studies
when data aggregated), have weak evidence forwhen data aggregated), have weak evidence for
efficacyefficacy
 Paroxetine has very weak evidence for efficacyParoxetine has very weak evidence for efficacy
 Virtually no data for other SSRIsVirtually no data for other SSRIs
 SSRIs have response rate of 50-60% forSSRIs have response rate of 50-60% for
depression in youth (Birmaher 2004)depression in youth (Birmaher 2004)
 SSRIs have low effect size (about 0.26) in youthSSRIs have low effect size (about 0.26) in youth
(Jureidi et al., 2004)(Jureidi et al., 2004)
 Treatment-resistant depression associated withTreatment-resistant depression associated with
poor prognosis and high suicide riskpoor prognosis and high suicide risk

12. Why Prescribe SSRIs in Youth withWhy Prescribe SSRIs in Youth with
these Suicide Risks?these Suicide Risks?
 For Fluoxetine, need to treat just 3For Fluoxetine, need to treat just 3
patients to see significant responsepatients to see significant response
 In contrast, need to treat over 50In contrast, need to treat over 50
patients in order to see SSRI-inducedpatients in order to see SSRI-induced
suicidalitysuicidality
 American Academy of Child &American Academy of Child &
Adolescent Psychiatry finds this anAdolescent Psychiatry finds this an
acceptable risk-benefit ratio for theacceptable risk-benefit ratio for the
treatment of pediatric depression.treatment of pediatric depression.

13. Recommendations for SSRIs inRecommendations for SSRIs in
Youth DepressionYouth Depression
 Monitor weekly for 1Monitor weekly for 1stst
monthmonth
• Watch for worsening depression and suicidality (esp. 1Watch for worsening depression and suicidality (esp. 1stst
month and dose changes)month and dose changes)
• Watch for anxiety, agitation, impulsivity, akathisia,Watch for anxiety, agitation, impulsivity, akathisia,
maniamania
 May be harbingers of emerging suicidalityMay be harbingers of emerging suicidality
 Screen for potential switch to mania prior to SSRIScreen for potential switch to mania prior to SSRI
treatmenttreatment
• Includes family history of bipolar disorder,Includes family history of bipolar disorder,
multigenerational loading of depression, suicidemultigenerational loading of depression, suicide
• Acute onset of depression, psychotic depression, andAcute onset of depression, psychotic depression, and
early-onset depression associated with high risk ofearly-onset depression associated with high risk of
bipolaritybipolarity

14. Recommendations for SSRIs inRecommendations for SSRIs in
Youth DepressionYouth Depression
 Mild to moderate depression: CBTMild to moderate depression: CBT
 Moderate to severe depression: SSRI +Moderate to severe depression: SSRI +
CBTCBT
 Fluoxetine: first-line treatmentFluoxetine: first-line treatment
 Citalopram and Sertraline as 2Citalopram and Sertraline as 2ndnd
-line-line
• Weak evidence for efficacyWeak evidence for efficacy
 Paroxetine very weak evidenceParoxetine very weak evidence
 Virtually no data for other antidepressantsVirtually no data for other antidepressants
 Monitor weekly, watching for anxiety,Monitor weekly, watching for anxiety,
agitation, impulsivity, akathisia, maniaagitation, impulsivity, akathisia, mania

15. Effect of Blackbox on Public HealthEffect of Blackbox on Public Health
 Questions:Questions:
• Effect on youth suicide rates?Effect on youth suicide rates?
• Effect on treatment delivery?Effect on treatment delivery?
 Will families avoid seeking treatment?Will families avoid seeking treatment?
 Will Pediatricians and Family Physicians stopWill Pediatricians and Family Physicians stop
prescribing SSRIs to youth?prescribing SSRIs to youth?
 Can Child Psychiatrists handle the burden ofCan Child Psychiatrists handle the burden of
treating youth depression alone?treating youth depression alone?

16. Effect of Blackbox on Public HealthEffect of Blackbox on Public Health
 Youth prescribed less antidepressantsYouth prescribed less antidepressants
 Medco Health Solutions, Inc. coversMedco Health Solutions, Inc. covers
12,374,932 patients under 1812,374,932 patients under 18
• 10% DECREASE in antidepressant Rx in 200410% DECREASE in antidepressant Rx in 2004
to youth under 18to youth under 18
• This contrasts to almost 9% INCREASE inThis contrasts to almost 9% INCREASE in
antidepressant Rx in 2003 to youth under 18antidepressant Rx in 2003 to youth under 18
(start of controversy in May 2003)(start of controversy in May 2003)
• Only a 0.66% prescribing rate ofOnly a 0.66% prescribing rate of
antidepressants in youthantidepressants in youth
• Expect continued decrease in prescribing, withExpect continued decrease in prescribing, with
possible increase in suicide rate in youthpossible increase in suicide rate in youth

17. Treatment-Resistant Mood Disorders inTreatment-Resistant Mood Disorders in
Adolescents: Clinical Characteristics andAdolescents: Clinical Characteristics and
Implications for TreatmentImplications for Treatment
 Collaborators (Portland, Maine)Collaborators (Portland, Maine)
• Douglas Robbins, MDDouglas Robbins, MD
• Carlo Carandang, MDCarlo Carandang, MD
• Sarah Minot, BASarah Minot, BA
• Mary Jane Call, PsyDMary Jane Call, PsyD
• Ellen Zimmerman, LCSWEllen Zimmerman, LCSW
• William Cook, PhDWilliam Cook, PhD
 MMCRI grantMMCRI grant

18. Project on Lamotrigine for Treatment –Project on Lamotrigine for Treatment –
Refractory Depression in AdolescentsRefractory Depression in Adolescents
 Collaborators (Portland, Maine)Collaborators (Portland, Maine)
• Carlo Carandang, MDCarlo Carandang, MD
• Douglas Robbins, MDDouglas Robbins, MD
• Betsy Mullany, RNBetsy Mullany, RN
• Sarah Minot, BASarah Minot, BA
• Mary Jane Call, PsyDMary Jane Call, PsyD
• Ellen Zimmerman, LCSWEllen Zimmerman, LCSW
• William Cook, PhDWilliam Cook, PhD
 Investigator-initiated studyInvestigator-initiated study
• GSK fundedGSK funded
• Contract clause: publication at discretion of PIContract clause: publication at discretion of PI

19. Future DirectionsFuture Directions
 NIMH RFA-MH-06-001 to study theNIMH RFA-MH-06-001 to study the
relationship between SSRIs andrelationship between SSRIs and
suicidality (2005)suicidality (2005)
• Need clinical/biological predictors ofNeed clinical/biological predictors of
response to SSRIsresponse to SSRIs
• Need clinical/biological predictors ofNeed clinical/biological predictors of
adverse effects to SSRIsadverse effects to SSRIs

20. Future Directions:Future Directions:
PharmacogeneticsPharmacogenetics
 Martin Alda’s Research GroupMartin Alda’s Research Group
• Clinical/biological predictors of response toClinical/biological predictors of response to
lithium in bipolar patientslithium in bipolar patients
 Will that paradigm work for SSRIs inWill that paradigm work for SSRIs in
depression?depression?
• 5-HTTLPR long polymorphism associated with5-HTTLPR long polymorphism associated with
treatment responsetreatment response
• Mutant alleles of cytochrome P450 genesMutant alleles of cytochrome P450 genes
associated with poor metabolizersassociated with poor metabolizers
 Predict initial dosing and hence less side effectsPredict initial dosing and hence less side effects
• Caveat: family/environmental variables mayCaveat: family/environmental variables may
explain the variance of response in youth whenexplain the variance of response in youth when
compared to adultscompared to adults

21. Future Directions:Future Directions:
PharmacogeneticsPharmacogenetics
 Time is nearing to consider genotypingTime is nearing to consider genotyping
(with clinical profiling) to predict who will(with clinical profiling) to predict who will
response and have side effects to SSRIsresponse and have side effects to SSRIs
• Decrease treatment-resistanceDecrease treatment-resistance
• Decrease depressive symptoms (includingDecrease depressive symptoms (including
suicidality from depression)suicidality from depression)
• Decrease adverse effects (i.e. SSRI-inducedDecrease adverse effects (i.e. SSRI-induced
suicidality)suicidality)
 More research with uniformity in designMore research with uniformity in design
and proper controls needed (placeboand proper controls needed (placebo
groups)groups)

22. Halifax CollaboratorsHalifax Collaborators
 Suzanne Zinck, MD (IWK Psychiatry)Suzanne Zinck, MD (IWK Psychiatry)
 Darcy Santor, PhD (Dal Psychology)Darcy Santor, PhD (Dal Psychology)
 Mark Samuels, PhD (IWK Genetics)Mark Samuels, PhD (IWK Genetics)
 Martin Alda, MD (Dal & McGillMartin Alda, MD (Dal & McGill
Psychiatry)Psychiatry)
 Sunlife Endowed Chair in AdolescentSunlife Endowed Chair in Adolescent
Mental Health (to be hired, soon!)Mental Health (to be hired, soon!)