2. Improving Medication Prescribing for Arkansas Children Through Off-label Education IMPACT Off-label Education Update on Depression and Anxiety in Children and Adolescents UAMS College of Pharmacy Evidence-based Prescription Drug Program UAMS College of Medicine Division of Child and Adolescent Psychiatry

3. Goals  Review anxiety and depression prevalence and recommendations  Discuss recently completed clinical trials and consensus national treatment guidelines  Review FDA advisory on “suicidality”  Examine treatment patterns in Arkansas Medicaid  Provide points of access to useful resources

4. Anxiety in Children

5.  Fear and worry can be normal, but excessive anxiety causes impairment  Prevalence in children is reported between 6% and 20%  Anxiety can be recognized at young ages, and may recur or persist to adulthood  Association with poor problem-solving, low self-esteem, negative self perceptions Source: AACAP Practice Parameter for the Assessment and Treatment of Children and Adolescents With Anxiety Disorders, 2007

6. Anxiety in Children Anxiety in children predicts:  Adult anxiety  Major depression  Suicide attempts  Psychiatric hospitalization Source: APA Report of the Working Group on Psychotropic Medications for Children and Adolescents, 2007

7. Anxiety in Children  Includes, generalized anxiety, separation anxiety, social phobia (and selective mutism), obsessive compulsive disorder, specific phobias, panic disorder, PTSD  Separate guidelines for OCD and PTSD in children are available by the AACAP  Anxiety can be a family phenomenon Source: AACAP Practice Parameter for the Assessment and Treatment of Children and Adolescents With Anxiety Disorders, 2007

8. Anxiety in Children  Screening tools for children exist  A positive screen is not a diagnosis – but an indication for more formal assessment  Consider overlap or overlay of physical ills  Comorbid conditions should be evaluated and effectively treated  Early assessment and intervention may improve long-term outlook Source: AACAP Practice Parameter for the Assessment and Treatment of Children and Adolescents With Anxiety Disorders, 2007

9. Anxiety in Children - Treatments Treatment Guideline considerations:  Multiple treatment modalities  Severity of impairment  Psychotherapy – especially Cognitive Behavioral Therapy (CBT)  Pharmacotherapy with SSRIs  Short-term helpful, long-term unknown  Pharmacotherapy with other agents Source: AACAP Practice Parameter for the Assessment and Treatment of Children and Adolescents With Anxiety Disorders, 2007

10. Anxiety in Children - Treatments  Psychotherapy (CBT) is consensus first-line approach  56% remission vs. 34% remission on wait-list control  SSRI are helpful, but no comparisons  Sertraline and fluoxetine have supportive trials  Fluvoxamine more useful if no baseline depression  Paroxetine useful, but not recommended due to safety concerns/”suicidality” association  Combined CBT with sertraline trial is recently published – NIMH CAMS trial Source: APA Report of the Working Group on Psychotropic Medications for Children and Adolescents, 2007

11. Anxiety in Children - Treatments  TCAs – Imipramine has mixed data. Risks (esp. CV) limit use – no longer supported  Benzodiazepines – not supported alone in children or adolescents. Avoid with history of substance use  SNRIs – limited information on venlafaxine ER  Buspirone – no published data Sources: APA Report of the Working Group on Psychotropic Medications for Children and Adolescents, 2007. AACAP Practice Parameter for the Assessment and Treatment of Children and Adolescents With Anxiety Disorders, 2007

12. Anxiety in Children Major Points:  Screen, evaluate and intervene early  Refer for evaluation and psychotherapy  SRI role – likely second-line or adjunct:  Fluoxetine, fluvoxamine, sertraline supported  Paroxetine good anxiety data, but suicide warnings in teens  Some ER venlafaxine support, though less than SSRIs  New study from NIMH on CBT vs. sertraline vs. combination

13. Depression in Children

14.  Prevalence estimated at 2.5% of children, 8.3% of adolescents  Anxiety is often associated  Suicidal thoughts are reported by 40 to 80% of depressed youth; attempts may be as high as 35%  Depression marks significant risks for recurrence, substance abuse, teen pregnancy… Source: PhysiciansMedGuide The Use of Medication in Treating Childhood and Adolescent Depression: Information for Physicians, 2007

15. Depression in Children Younger Children  Somatic complaints  Psychomotor agitation  Mood-congruent hallucinations  School refusal  Anxiety related issues Older Children  Esteem issues, boredom, apathy  Substance use  Change in weight, eating, sleep  Excess sleep/depressed affect  Aggression/antisocial behavior Source: GLAD-PC Toolkit available at www.GLAD-PC.org

16. Depression in Children Recent Trial Information TADS Study Results: Source: TADS Team Treatment for Adolescents with Depression Study (TADS) – Long- term Effectiveness and Safety Outcomes. Arch Gen Psychiatry. 2007; 64(10) 1132-1144 Therapy Improvement/Response Rate Week 12Week 18Week 36 CBT+Fluoxetine71%85%86% Fluoxetine61%69%81% CBT43%65%81% Placebo35%

17. Depression in Children Recent Trial Information TADS Study Suicide Event Screening Results Source: TADS Team Treatment for Adolescents with Depression Study (TADS) – Long- term Effectiveness and Safety Outcomes. Arch Gen Psychiatry. 2007; 64(10) 1132-1144 Treatment Positive Suicide Event Screening BaselineWeek 12Week 36 CBT+Fluoxetine42/1068/902/79 Fluoxetine28/10718/9710/73 CBT27/1075/913/76 Fluoxetine differed significantly from both other treatments at weeks 12 and 36

18. Depression in Children Recent Trial Information  TORDIA trial – resistant depression/poor treatment response in adolescents  Entering subjects had prior SSRI treatment +/- CBT, high rate of suicidal thoughts  Tested changing medication vs. changing medication with CBT  Postulated changing to an SNRI after an SSRI may increase response rate Source: Brent, et. al. Switching to Another SSRI or to Venlafaxine With or Without Cognitive Behavioral Therapy for Adolescents With SSRI-ResistantDepression. JAMA. 2008;299(8):901-913

19. Depression in Children Recent Trial Information  Initially treated with at least 40mg fluoxetine (or equivalent)  Switched to SSRI, SSRI+CBT, SNRI, or SNRI+CBT  SNRI was venlafaxine ER  Initial SSRIs were fluoxetine or paroxetine  After FDA warnings, paroxetine was dropped, and citalopram was substituted. Source: Brent, et. al. Switching to Another SSRI or to Venlafaxine With or Without Cognitive Behavioral Therapy for Adolescents With SSRI-ResistantDepression. JAMA. 2008;299(8):901-913

20. Depression in Children Recent Trial Information  Best responses occurred with switch from SSRI to either arm with CBT  ER venlafaxine was no better than a change from one SSRI to another  CBT showed site variations, but robust and durable improvement  ER venlafaxine had higher rates of cardiovascular and other side effects. Source: Brent, et. al. Switching to Another SSRI or to Venlafaxine With or Without Cognitive Behavioral Therapy for Adolescents With SSRI-ResistantDepression. JAMA. 2008;299(8):901-913

21. Depression in Children - Treatments  Fluoxetine plus CBT has best evidence of success. Consistent benefits and FDA approved down to age 8 (7 for OCD)  Non-responders to SSRI alone, may benefit from addition of CBT with change in SSRI  Most medication trials have serious flaws/ limitations  Several psychotherapy approaches may help Sources: APA Report of the Working Group on Psychotropic Medications for Children and Adolescents, 2007. Brent, et. al. Switching to Another SSRI or to Venlafaxine With or Without Cognitive Behavioral Therapy for Adolescents With SSRI-ResistantDepression. JAMA. 2008;299(8):901-913

22. Depression in Children Major Points:  Screen, evaluate and intervene early  Refer for evaluation and psychotherapy  SRI role – likely first-line in combination:  Fluoxetine was the only approved agent, still a good starting point  Monitoring is key  Shorter half-life agents seem problematic  Watch for more from NIMH:  Antidepressant Safety in Kids (ASK)  Treatment of Adolescent Suicide Attempters (TASA)

23. FDA “Suicidality” Warnings, Antidepressants, and Young People

24. FDA and “Suicidality”  “Suicidality” links thoughts of suicide and suicide attempts  60% of completed suicides are thought to be in patients with depression  FDA warning based on 23 studies of nine medications, none with a completed suicide  Monitoring for thoughts, plans and attempts is important with any treatment Source: PhysiciansMedGuide The Use of Medication in Treating Childhood and Adolescent Depression: Information for Physicians, 2007

25. FDA and “Suicidality” Timeline  June 2003 – FDA issues warnings specific to paroxetine and increased rate of suicide reports  December 2003 – EU/UK agencies advise not to use most SSRI/SNRIs in patients under 18  October 2004 – FDA “black box” warning relating to children and adolescents on all agents  December 2006 – FDA warning extended to young adults

26. Selective Reuptake Inhibitors  Uses are anxiety and depression  Reasonable evidence, some very recent  Recent controversy – “suicidality” link  FDA statements in 2003 and 2004  Subsequent drop in youth SSRI use of 22% from 2003 to 2005 reported  2003 to 2004 suicide rate increases  10-14 YO females – 56 to 94 or.95/100K (+75%)  15-19 YO females – 265 to 365 or 3.52/100K (+32%)  15-19 YO males – 1,222 to 1,345 or 12.65/100K (+9%) Sources: Gibbons, et al. Early Evidence on the Effects of Regulators’ Suicidality Warnings on SSRI Prescriptions and Suicide in Children and Adolescents. Am J Psychiatry 2007; 164:1356–1363. CDC Suicide Trends among Youths and Young Adults aged 10 to 24 years – United States,1990 to 2004. MMWR. 2007 56(35);905-908.

27. “Suicidality” Warning Impact  Gibbons commercially available data show:  no prescribing gain or drop between 2003 and 2004  22% prescribing drop between 2004 and 2005  Olfson reported on pharmacy claims data:  Rapid annualized increases in SSRI use in children prior to paroxetine warnings (May 2002 to June 2003)  Significant drop (mostly due to paroxetine) seen after paroxetine warning (June 2003 to October 2004)  Stable/no significant drop after black box warning (October 2004 through Dec 2005) Sources: Gibbons, et al. Early Evidence on the Effects of Regulators’ Suicidality Warnings on SSRI Prescriptions and Suicide in Children and Adolescents. Am J Psychiatry 2007; 164:1356–1363. Olfson, et. al. Effects of Food and Drug Administration Warnings on Antidepressant Use in a National Sample, Arch Gen Psychiatry 2008;65(1): 94-101.

28. “Suicidality” in Practice  Screening does not increase risks or cause suicidal thoughts  Failing to screen may lead to missing vital information

29. “Suicidality” in Practice  When starting Tx, FDA recommends  weekly assessment for first four weeks  twice weekly assessment for four weeks,  then (minimally) at the end of 12 weeks  Practically, this can be individualized  Formal assessment tools available  Suicide risk and assessment plan should be documented

30. Anxiety and Depression Treatment Trends in Arkansas Medicaid

31. Treatment Pattern Trends  Arkansas Medicaid claims data are robust (half of all children in the state)  We include only continuously enrolled Medicaid and ARKids recipients which corrects for variations in total enrollment over time.  Prevalence can be grouped by recipient age:  Preschool – one year to age six  Primary School – six years to age 12  Adolescent – 12 years to age 18

32. Recent Initial Treatment Trends  777 newly diagnosed/ treated Medicaid recipients under 18 from April – Oct 2008  Treatment patterns identified by CPT codes and pharmacy claims paid  No severity indicator, but all had no treatment in prior six months

33. Persistence Of Treatment  Same 777 newly diagnosed/treated children  Question: How many received more than two claims for either intervention?  Answer: About 70% -  Possibly better persistence with counseling Counseling Visits Prescriptions Dispensed None1-2 3 or more None 122406 1-2 892343 3 or More 68927

34. Preschool Prevalence Trends Source: Arkansas Medicaid claims data, EBRx analysis

35. Grade School Prevalence Trends Source: Arkansas Medicaid claims data, EBRx analysis

36. Adolescent Prevalence Trends Source: Arkansas Medicaid claims data, EBRx analysis

37. Newer Antidepressant Use Patterns Four Groups of SSRI/SNRI medications  FDA approved – fluoxetine*  Supported with some evidence:  Anxiety – sertraline, fluvoxamine  Depression – citalopram, ER venlafaxine  No adequate/supportive trials  Buproprion, duloxetine, escitalopram*, mirtazepine, nefazodone  Negative information – paroxetine * During the periods reviewed. Escitalopram was FDA approved in March 09, but at this time, studies are not yet available.

38. Pattern of Medication Treatment in Arkansas

39. What we know now  Some decrease in prevalence of medication use after FDA warnings – but now stable  Almost half of Arkansas children treated with medication did not receive an evidence- supported SSRI/SNRI  Still need more data on children and adolescents receiving counseling alone or combined with SSRI

40. Depression and Anxiety in Children and Adolescents Take Home Points

41. Depression and Anxiety in Children and Adolescents  Anxiety and depression are common in children and adolescents  Earlier awareness/intervention may prevent negative events  Screening tools are available, easy to use, and facilitate recognition  Practice guidelines and recent evidence should inform treatment decisions

42. Anxiety Recommendations  Counseling can help define diagnosis and is a first-line treatment  Limited SSRI/SNRI support  Fluoxetine appears to be best supported  Sertraline with CBT for anxiety  Fluvoxamine (only if no depression present)  Maybe ER venlafaxine, but CV effects are limiting  Paroxetine good for anxiety, but specific suicide risk  Other pharmacotherapy not supported

43. Depression Recommendations  Counseling can help define diagnosis and is a first-line treatment  Frequent suicidality screening  CBT plus fluoxetine – best practice  Fluoxetine alone caries suicidality risk  Other SSRI/SNRI agents with published data  Citalopram  Venlafaxine ER – higher side effects than SSRIs  Other pharmacotherapy not supported

44. SSRI/SNRI Adverse Effects Serious Adverse Effects  Serotonin Syndrome  Akathisia  Hypomania  Discontinuation syndromes Common Adverse Effects  GI effects (dry mouth, constipation, diarrhea)  Sleep disturbance  Irritability  Disinhibition  Agitation/jitteriness  Headache

45. Recommendations  CBT is a first-line approach with or without medication  Foster a relationship with a psychologist to refer and communicate about your patients  Identify and use screening tools  Remember fluoxetine dosing:  Younger children - 10mg daily, cautious titration  Older children - 10mg initially with titration to 20mg after 2 weeks  Limited experience above 20mg

46. Recommendations  Use GLAD-PC materials for depression or other screening tools for anxiety  If treating with SSRIs, establish, document and monitor a safety/suicidal thoughts plan  ParentsMedGuide.org has useful information on pharmacologic treatment for obtaining informed consent

47. IMPACT Off-label Education If this was helpful to you:  Make time for AFMC to bring you more materials/resources  AFMC will have tool-kit items and other free resources  Web-based curricula/resource pages available at: COP.UAMS.EDU/OffLabel

48. Hows and Whys of the Project

49. Project Funding  Attorney General Consumer Prescriber Education Grant Program  Settlement paid for off-label promotion of Neurontin(gabapentin)  Arkansas received $370,000 of this grant.  Focus: SSRI and SNRI medication use in children and adolescents

50. IMPACT Off-label Education  The concept:  Use techniques and tools of the industry  Provide up-to-date evidence-based information on off-label medication uses in children  Report our results  Pharmaceutical representative discussion of uses not FDA approved is prohibited by federal law  Physician-to-physician communication is not restricted, but usually only available with corporate sponsorship

51. Off-label Uses:  Finding information on appropriate, safe and helpful off-label uses is a challenge  Sometimes, national meetings have reasonably authoritative presentations  Usually manufacturers have more information, but they don’t always share  Pediatric medication trials have special challenges, so there is much off-label use

52. Why SSRI/SNRIs?  Mental health medications stand out for off- label uses in children  2006 Medicaid data analysis revealed high use of SSRIs/SNRIs in children  General interest, need and utility:  Current controversy/new data  Low industry noise level – only a few brand players  Stable category for analysis of our program

53. IMPACT Off-label Education Drug Category Children Treated Prescriber Count Prescription Count Paid Amounts SSRIs/SNRIs12,2971,46556,395$3,533,620 Tri/Tetra6,48698923,607$273,276 Newer Antipsychotic 11,97494569,229$19,672,764 Older Antipsychotic 3271321,654$48,921 Newer Sleep Aids 9723532,555$231,427 Source: Arkansas Medicaid MIS, Calendar Year 2006, Children under age 18 years.

54. Our Information Sources  American Academy of Child and Adolescent Psychiatry  American Psychiatric Association  American Psychological Association  Agency for Healthcare Research and Quality  Centers for Disease Control  NIMH funded Treatment for Adolescents with Depression Study (TADS)  GLAD-PC project  Other recent peer-reviewed reports

55. Thank you for your interest

56. Screening/Monitoring Tools Anxiety (for 8 yo and up)  Multidimensional Anxiety Scale for Children  Screen for Child Anxiety Related Emotional Disorders Depression  Columbia Depression Scale  Beck Depression Inventory  Children’s Depression Rating Scale – Revised  Reynold’s Adolescent Depression Scale