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Nicole Bennett MN PMHNP-BC

Thinking outside of the ‘FDA Box’: History and Update on SSRIs, suicide risk, and treatment practices in youth. Nicole Bennett MN PMHNP-BC. No disclosures. Disclosure Statement. Understand history of FDA warning on SSRIs for suicidal thinking youth

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Nicole Bennett MN PMHNP-BC

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  1. Thinking outside of the ‘FDA Box’: History and Update on SSRIs, suicide risk, and treatment practices in youth • Nicole Bennett MN PMHNP-BC

  2. No disclosures Disclosure Statement

  3. Understand history of FDA warning on SSRIs for suicidal thinking youth Understand the current FDA warnings on SSRIs for suicidality Examine practice changes that accompanied the FDA warning Review current research of treatment and risks for depression and suicide in youth Develop a framework for decision making about educating and treating families and youth for depression and suicide risk Goals

  4. Suicide risk in youth Many families and clinicians have misinformation about SSRIs and depression treatment which may delay seeking treatment choices and effect decision making Much has been learned since 2004 warning FDA warning has changed since the 2004 Understanding the full scope of risk will help us select treatment and educate families and youth that provide best options for successful treatment rather than out of fear or lack of knowledge Considerable amount of research done since 2004 Why discuss this now?

  5. Injury is #1 cause of death MVT injury death is 1st Suicide is 2nd Leading Causes of Death in OregonYouth 10-24 (Noonan, 2012)

  6. Suicide Rates among Youth Aged 10-24 in Oregon & the US, 1990-2009 (Noonan, 2012)

  7. Mental & Behavioral Health Status among Youth Who Died by Suicide in Oregon (Noonan, 2012)

  8. Prevalence of suicidal ideation in teens: 15-25% With intent or plan: 6% teen girls 2.3% in boys Lifetime risk of attempt: 1.3-3.8% in males 1.5-10.1% in females Attempts needing medical attention 1-3% Risk is multifactorial: Mood DO and impulsivity being most highly correlated with suicidal behavior Epidemiology of suicide Risk in teens (Bridge et al, 2006)

  9. Background of FDA WARNING

  10. Internal memos from GlaxoSmithKline released showed manipulation of paroxetine study results NY Attorney General files suit against GSK UK Committee on Safety of Medications prohibits use of SSRIs except fluoxetine FDA releases warning against use of Paxil and close monitoring of youth on SSRIs FDA requests internal study to review safety of SSRIs in pediatric patients http://www.fda.gov/NewsEvents/Testimony/ucm113265.htm 2003 (Howland, 2006)(Whittington et al, 2004)( FDA Summary, 2004)(Mann et al, 20034)

  11. FDA internal study finds increased risk Results from external study inconclusive Re-analysis of internal study ordered by FDA FDA Advisory meeting held FDA Advisory meeting votes for Black Box Warning for 9 ADs including all SSRIs http://www.fda.gov/NewsEvents/Testimony/ucm113265.htm 2004 (Hammad, 2004)

  12. BOXED WARNING This type of warning is also commonly referred to as a “black box warning.” It appears on a prescription drug’s label and is designed to call attention to serious or life-threatening risks. (http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/ucm107976.pdf, retrieved May 2013.) OFF LABEL PRESCRIBING Off-label use of a prescription drug or device refers to the ability of licensed health care providers to prescribe or use the drug for indications, conditions, patients, dosages or routes of administration not yet evaluated and approved by the FDA. The decision to prescribe a prescription drug or use a device off-label should be based upon emerging science and clinical evidence and may or may not differ from the evidence used for the FDA to approve the product being on the market. http://www.ama-assn.org/resources/doc/cme/fact-sheet-4.pdf, retrieved May 26,2013 Off label prescribing vs. Black box warnings

  13. Fluoxetine (Prozac) Escitalopram (Lexapro) Currently Approved SSRIs for Depression for Youth

  14. Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. http://www.fda.gov/NewsEvents/Testimony/ucm113265.htm 2004 FDA Warning

  15. 2004 FDA Warning Anyone considering the use of [Drug Name] or any other antidepressant in a child or adolescent must balance this risk with the clinical need. http://www.fda.gov/NewsEvents/Testimony/ucm113265.htm

  16. 2004 FDA Warning Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. http://www.fda.gov/NewsEvents/Testimony/ucm113265.htm

  17. [Drug Name] is not approved for use in pediatric patients except for patients with [Any approved pediatric claims here]. (See Warnings and Precautions: Pediatric Use)

  18. fluoxetine: Prozac sertraline: Zoloft paroxetine: Paxil fluvoxamine: Luvox citalopram: Celexa, escitalopram: Lexapro bupropion: Wellbutrin, venlafaxine: Effexor nefazodone: Serzone mirtazapine: Remeron Required to have FDA Warning

  19. 6 medications examined 19 studies selected among 23 from manufacturer trials Looked at SSRIs for MDD and other indications Pooled analyses of short-term studies (4 to 16 weeks) 4,400 patients No suicides occurred in these trials. Primary outcome behaviors of: Preparatory actions toward suicidal behavior Suicide attempt Suicidal ideation Examine FDA re-analysis (Hammad, 2004)(Hammad et al, 2006)

  20. 5.10.3.3 The primary outcome (outcome 3) by drug Only 19 out of the 23 trials were evaluable for the primary outcome (outcome 3). No individual trial showed a statistically significant signal but eight trials had a RR of 2 or more. The pooled overall estimates varied by drug. The following table summarizes the overall RR estimates of the primary outcome (outcome 3) by drug. Note that Effexor was the only drug that did not include “1” in the 95% CI of its risk estimate. Table 10: Summary of the overall risk estimates of the primary outcome (outcome 3) by drug across all indications and in MDD trials. (Hammad, 2004)

  21. May not reflect general population Flexible dosing in most trials leads to problems with understanding dose effect Difficulty when looking at adolescents who rarely take medications regularly Most events occurred in trials with patients with history of suicide attempt or SI at baseline Study did not allow a comparison of medications Limitations discussed by Dr. Hammad (Hammad, 2004)(Hammad et al, 2006)

  22. Research: 2004-20011

  23. TADS Study CBT & fluoxetine more effective treating depressive symptoms than placebo and either CBT or fluoxetine alone Fluoxetine alone more effective than CBT alone Other studies Fluoxetine effective treating depression The longer the trial the longer length of remission Efficacy of fluoxetine: Depression (March et al, 2004)(Henry, 2012)(Rosenberg & Gershon, 2012)(Emslie, 2002)(Emslie,1997)

  24. mixed results or lack of efficacy escitalopram: some studies show efficacy in adolescents, none in children citalopram: one positive and one negative sertraline: Some efficacy paroxetine: 3 studies, all negative Efficacy other SSRIs: Depression (Henry, 2012)(Rosenburg & Gershon, 2012)

  25. Therapy and Mediaction treatment Rates of suicide highest month before treatment and month after initiation of treatment, then decline Higher in those on ADs in Psych office Still high in those starting therapy Lowest in those getting ADs in primary care Attempts the same in all groups Psychotherapy only 12.5% incidence of emergent SI Higher for those who reported SI prior to intake even if they denied SI at intake Treatment effects on Suicide risk (Simon & Savarino, 2006)(Bridge, 2005)

  26. Some SSRIs have favorable risk benefit profile when only published studies reviewed Unpublished data reviewed indicate more risks for SSRIs except fluoxetine (Whittington et al 2004) Am. College of Neuropsycopharmacology Task Force (Mann et al, 2006) Fluoxetine shows efficacy May translate to other SSRIs SNRIs, tricyclics and other ADs not effective Non-FDA REVIEWS: efficacy & risk

  27. “practitioners are warned against withholding SSRI therapy from youth with well-defined emotional disorders such as MDD or OCD” SSRIs show reduction in symptoms of depression 4% risk if on SSRI vs. 2% risk placebo HOWEVER ½ could be considered spontaneous other ½ likely caused by underlying depression (Hammerness et al, 2006) Non-FDA REVIEWS: efficacy & risk

  28. “In our opinion, SSRI medication (in particular fluoxetine and citalopram) can reasonably be considered in therapeutic decision making for treatment of post-pubertal MDD” (Kutcher & Gardner, 2008) Non-FDA REVIEWS: efficacy & risk

  29. SSRIs efficacious for MDD, OCD and non-OCD anxiety, strongest in non-OCD. Modest effect for MDD Under 12y. only fluoxetine was efficacious for MDD SI risk less than 1% compared to placebo in pooled AD data NIMH meta-analysis 2007 (Bridge, 2007)

  30. FDA requests more study FDA completes expanded meta-analysis Increase in suicidal risk: 18-25years pooled 1.55(.91,2.70) FDA revises black box warning 2007 (Howland, 2007)(Leon, 2007)(Freidman & Leon, 2007)

  31. Suicidality and Antidepressant Drugs: Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of [Insert established name] or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. [Insert Drug Name ] is not approved for use in pediatric patients. http://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM173233.pdf Retrieved 5/31/13 2007 FDA WARNING

  32. Current Research

  33. Clinicians should consider: Patient preference Prior suicidal behavior/attempts SSRIs safer in non-depressed youth ADs used less with younger children ADs are beneficial and should be considered in treatment NIMH Review 2012 (Henry, 2012)

  34. Fluoxetine 24.1% response vs. 5.7% on placebo Remission 46.6%:16.5% No increased suicide risk as compared to placebo More efficacious in youth than adults Baseline severity not related to degree of advantage over placebo No clear benefits to use of venlafaxine NIMH Meta-analysis: 2012 (Gibbons, 2012a)(Gibbons, 2012b)

  35. Youth on Ads led to lower symptom severity compared to placebo Modest effect on overall depression Fluoxetine should be medication of choice Increased risk of SI 58% (25:1,000 placebo or 44:1,000 on AD) Cochrane Review Meta-analysis 2012 (McKenzie et al, 2012)

  36. SSRIs discovered: 1992: Suicide rate males 15-19y 17.6 per 100K 2002: Suicide rate males 15-19y 12.2 per 100K Study completed in 2003 prior to FDA change found that between 1990-2002 there was an inverse relationship between AD use in adolescents and suicides FDA Warning: Rates of suicide increase 18.2% from 2003-2004 Some studies showed rise of 14% after warning Through 2007: Rates have declined through 2007 to lowest in 25 years US Adolescent Suicide changes with change in use of SSRIs (McKeown et al, 2006)(Hammond, 2006)(Olfson, 2003)(Henry, 2012) (Hamilton, 2007)(Cuff & Hall, 2007)

  37. (Hammad & Mosholder, 2010)

  38. 2005 Swedish review of toxicology found no SSRI evidence in suicides under 15 and less SSRI than TCAs Utah study 2003 24% of youth had been prescribed SSRIs but none found in toxicology New York study 41 suicides 1999-2002 one with SSRI and was case of overdose, accidental deaths (N=269) 2 cases with imipramine and none found SSRI Toxicology studies of Suicides (Leon et al, 2006)(ACN, 2006)

  39. Practice Changes: Post-FDA warnings

  40. Decrease in diagnosis of depressive disorders in youth Change began to occur after 2004 warning according to 2 studies Decrease seen 2004-2009 and still trending down PRACTICE CHANGES: Diagnosis (Clarke et al, 2012)(Libby et al, 2007)

  41. 58% decrease in AD prescriptions in 2005 post FDA warning (Libby 2007) Pre-warning 30% increase in paroxetine prescription Prescription dropped by -44% after warning (Olfson,2008 ) Overall AD prescribing decreased (but more fluoxetine than paroxetine)(Busch, 2010) Decline in AD prescriptions (Clark 2012) Prescribing of SSRIs decreased in depressed youth Youth with severe depression : rates of SSRI did not change. (Valluri et al, 2010) Decrease in AD prescription in under 18 (Nemeroff, 2007) Practice changes: Prescriptions

  42. Primary care practices after warning 80% reported changed on practice because of FDA warning 31% followed patients more closely (2/3 did not follow more closely) (Chueng et al, 2008) Study of HMO records Not as many refills written (one month vs 2-3) (followed more closely?) Fewer refills picked up by family, (fewer follow up visits?)(Clark 2012) Privately insured data No increase in monitoring by providers after starting AD (Busch et al, 2010) Practice changes: Monitoring

  43. 24% pediatricians referred to psychiatrist to treat depression (Chueng et al, 2008) Reduction in treatment in primary care and increase in referral to psychiatry (Nemeroff, 2007) Practice changes: Setting of care

  44. Slight increase in psychotherapy (64% vs 67%) (Valluri,2008) Statistically significant increase in psychotherapy without AD (37% vs. 44%) (Valluri,2008) No increase in psychotherapy treatment (Libby 2007) Practice change: use of therapy

  45. Use both SSRI and therapy Not monitoring at as close frequency as recommended by FDA and ACAAP Treating with ADs for 6-12 months as recommended Using fluoxetine and sertraline Practice change: PSYCHIATRY

  46. Risk of non treatment Risk under diagnosis Risk of under treatment Risk for delays in treatment Risk of continues poor monitoring early in treatment May be more judicious use of ADs Potential Consequences of practice changes:

  47. Lifetime prevalence: Ideation=12.1% (1/3 will make plan & 1/3 attempt) Plan=4.0% (60% of these will make attempt) Attempt=4.1% 55.3%-73.2% have received some for of mental health treatment prior to suicidal ideation (school based or MH services) Of all MH disorders studied ONLY MDD /dysthymia were predictors of developing a suicidal plan 2013 Risk of suicide among Adolescents (Nock et al, 2013)

  48. (Noonan, 2012)

  49. Risks of suicidality in studies only shown in short term studies, we must balance with long term risks of depression. Don’t underestimate risk of suicide in any youth, especially those with depression! Appears to be evidence of difference among SSRIs for efficacy and risk of suicide though more research is needed. Follow clients more closely and treat longer !! Increase therapy referrals/access Treat with medication & therapy in most moderate/severe cases Talk about suicide risk with all depression clients and families (OCCAP materials) Apply this information to each individual in front of you measuring balance of risk and benefit Take aways:

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