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SSRIs and Suicidality in Youth

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“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

Published in: Health & Medicine
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SSRIs and Suicidality in Youth

  1. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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!)

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