Antipsychotic Lecture Stark MHAR August 2023.pptx

Slides from Lunch and Learn Lectures by Stephen Grcevich, MD, sponsored by Stark County MHAR Board, August 2023.

Videos may be found here:

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1. Appropriate Use of Antipsychotic Medication in Children and Teens Stephen Grcevich, MD Child and Adolescent Psychiatry Family Center by the Falls, Chagrin Falls OH Associate Professor of Psychiatry, NEOMED Presented for Stark County MHAR Lunch and Learn August 2023

2. Learning objectives: Review evidence-based indications for antipsychotic use in children and teens Explore off-label indications for antipsychotics in youth with some research support Compare tolerability and adverse effect profiles of second-generation antipsychotics approved for use in children and adolescents Review best practices for monitoring potential side effects in youth treated with antipsychotics.

3. FDA-approved indications for SGAs in children, youth Bipolar Disorder Bipolar maintenance Bipolar Depressed Schizophrenia Aggression- Autism Aripiprazole >10 >10 ___ >13 >6 Asenapine >10 ___ ___ ___ ___ Lurasidone ___ ___ >10 ___ ___ Olanzapine >13 ___ >10 (with fluoxetine) >13 ___ Paliperidone ___ ___ ___ >12 ___ Quetiapine >10 ___ ___ >13 ___ Risperidone >10 ___ ___ >13 >5

4. What about first-generation antipsychotics? Presence of FDA approved indications is very confusing – conflicting information on different U.S. government websites Pimozide (Orap®) – indicated for Tourette’s Disorder (not simple tics) in patients > age 8 (12?) who fail to respond to standard treatment “Grandfathered” indications: Thorazine – ages 1-12 for severe behavior problems, schizophrenia, mania, restlessness before surgery Haldol – > age 3 for schizophrenia, psychosis, conduct disorder, severe behavior problems, poor frustration tolerance Stelazine - > age 6 for psychotic disorders

5. A major controversy in child and adolescent mental health Large spike in use with children, adolescents in 1990s, 2000s. Much of antipsychotic use in pediatric population is off-label Off-label use especially common in Medicaid population Increased scrutiny over prescribing from social service agencies

6. Clinical Characteristics of Antipsychotic Use in Texas Medicaid, 2013-16 Chen S, Barner JC, Cho E. J Manag Care Spec Pharm .2021;27(8):1035-45

7. On and off-label diagnoses for children, adolescents prescribed antipsychotics Chen S, Barner JC, Cho E. J Manag Care Spec Pharm.2021;27(8):1035-45

8. Clinical Characteristics of Antipsychotic Use in Texas Medicaid, 2013-16 Chen S, Barner JC, Cho E. J Manag Care Spec Pharm .2021;27(8):1035-45 Modest decrease in antipsychotic prescriptions noted from 2013-16. Percentage of “off-label” prescriptions decreased from 66.9% to 59.8% in that time. Approximately 2/3 of patients treated with antipsychotics were male Most common diagnosis was ADHD (31.8%) Distribution of “on-label” diagnoses: Bipolar Disorder (58.8-65.9%) Autism (30.6-37.6%) Schizophrenia/psychosis (3.1-3.6%)

9. Clinical Characteristics of Antipsychotic Use in Texas Medicaid, 2013-16 (continued) Chen S, Barner JC, Cho E. J Manag Care Spec Pharm .2021;27(8):1035-45 Majority of all “off-label” prescriptions (51.3-55.8%) are written for ADHD 98.6% of prescriptions were for SGAs Off-label use more common among children ages 5-9 (82.5%) than ages 10-14 (61.9%) and ages 15-17 (56.5%) Much “off-label” use is “supported” by practice guidelines, clinical trials with low strength of evidence

10. “Supported” but unapproved uses Risperidone suggested as second-line treatment by AACAP Practice Parameters, Texas Medication Algorithms only when patients are unresponsive to behavioral interventions, stimulants. Risperidone approved in EU for short-term use for aggression in conduct disorder in children ages 5 and up.

11. Antipsychotics in treatment of aggression “There is some limited evidence that risperidone reduces aggression (low-quality evidence) and conduct problems (moderate-quality evidence) in the short term in children and youths (ages 5-18 years) with disruptive behavior disorders.” “There is currently no evidence to support the use of quetiapine, ziprasidone or any other atypical antipsychotics for disruptive behavior disorders in children and adolescents.” “There are no research data for children under five years of age.” Loy JH, et al. Cochrane Database of Systematic Reviews 2017, Issue 8.

12. Cochrane review: Atypical antipsychotics for disruptive behavior disorders in children and youth “Though there is a reasonable level of evidence for the use of antipsychotics in young people with comorbid ADHD and DBDs, there is as of yet, no substantial evidence for the use of this drug class in DBDs alone.” “Risperidone led to a reduction of aggression (low‐quality evidence) and conduct problems (moderate‐quality evidence), to some extent, after six weeks of treatment.” “There is a lack of studies of medications other than risperidone.” Cochrane Library: https://doi.org/10.1002/14651858.CD008559.pub3

13. Systemic reviews of antipsychotics in disruptive behavior disorders Most recent review: (Rajkumar 2022) – “Though there is a reasonable level of evidence for the use of antipsychotics in young people with comorbid ADHD and DBDs, there is, as of yet, no substantial evidence for the use of this drug class in DBDs alone.” Rajkumar RP. Biomedicines 2022,10,2818. https://doi.org/10.3390/biomedicines10112818

14. Why such concern with using antipsychotics with kids? Weight gain notably higher than reported in adult studies Risk of metabolic syndrome, need for adjunctive medication for prediabetic conditions Increased vulnerability to EPS Impacts of prolactin elevation associated with most agents Near-complete absence of any long-term safety data (almost all studies have been short-term)

15. Weight gain associated with first-time initiation of antipsychotics Correll, CU et al., JAMA. 2009;302:1765–1773.

16. Weight gain with SGAs: #1 Clozapine comparable with olanzapine Quetiapine comparable to risperidone Ziprasidone > aripiprazole Relationship between weight gain and dosage still unclear Some propensity for less weight gain on lower doses? Difficult to interpret data from study patients with previous antipsychotic exposure Claims of aripiprazole being “weight neutral” came from FDA studies in which most patients had already been treated with SGA with higher propensity for weight gain. Correll CU. J Am Acad Child Adolesc Psychiatry 2008;47(1):9-20

17. EPS a greater risk in younger patients?

18. Extrapyramidal Symptoms Higher rates in pediatric patients than adults RCT comparing RIS, OLZ, HAL rates of EPS in youth: Risperidone - 53% Olanzapine - 56% Haloperidol - 67% EPS may be more severe, if not more frequent with first generation agents Withdrawal dyskinesias more likely reversible in kids TD rate of 0.4%/year reported in pediatric studies of risperidone (underestimate?) Correll CU. J Am Acad Child Adolesc Psychiatry 2008;47(1):9-20

19. Hyperprolactinemia Relative risk hierarchy:  Risperidone Haloperidol Olanzapine Ziprasidone Quetiapine Aripiprazole More likely with EOS vs. other indications  More likely in patients with personal, family history of autoimmune disease Not clear whether bone density, sexual maturation, risk of breast CA, development of prolactinomas affected Routine prolactin monitoring not recommended Correll CU. J Am Acad Child Adolesc Psychiatry 2008;47(1):9-20. Margari L et al. Int Clin Psychopharmacol. 2015 Mar; 30(2): 103–108.

20. Adjunctive medication for adverse effects in EOS: Metformin resulted in modest weight loss in open-label pediatric trial in kids with SGA’s No pediatric studies on anticholinergic use in EPS, bromocriptine for hyperprolactinemia Shin L et al. J Child Adolesc Psychopharmacol. 2009 Jun;19(3):275-9 J. Am. Acad. Child Adolesc Psychiatry, 2013;52(9):976–990 .

21. Suggested monitoring strategies in youth treated with antipsychotics : Tardive dyskinesia: AIMS at 3 months, annually Height, weight, BMI-at 4, 8, 12 weeks, at least every three months thereafter Blood pressure, glucose: Baseline, 3 months, annually if normal after three months Lipids, cholesterol: Baseline, 3 months, every six months thereafter Liver functions: 3 months, annually Prolactin: only if symptomatic Electrolytes, CBC: annually EKG: ziprasidone or clozapine, during titration, at maximum dose Correll CU, J Am Acad Child Adolesc Psychiatry 2008;47(1):9-20.

22. Second generation antipsychotics in pediatric bipolar disorder: As of February 2012: 11 RCTs published –all in 2007 or later Aside from TEAM, RCTs evaluated kids ages 10 and older Response rates in acute RCTs 45-89%, remission achieved in 25-72% Treatment-refractory nature of patients enrolled at academic medical centers attenuated magnitude of AEs Little data examining long-term course on SGAs, efficacy in preventing relapse Hamrin V, Ienacco J. Expert Rev Neurother. 2010;10(7):1053-1088.

23. Second-generation antipsychotics in acute mania:

24. Medication Effect Sizes in Pediatric Trials Effect sizes robust in acute treatment Higher for SGAs than lithium Hobbs BA et al. J Child Adolesc Psychopharmacol 2022;32(10): 507-521

25. Treatment of Early-Age Mania (TEAM) study: Randomized, 8-week multicenter study of 279 patients ages 6-15 with Bipolar I Disorder Patients received lithium, divalproex sodium, risperidone Mean lithium level 1.09 (0.34) mEq/L Mean divalproex sodium level: 113.6 (23.0) ug/ml Mean titrated risperidone dose 2.57 (1.21) mg/day Geller et al. Arch Gen Psychiatry 2012 May;69(5):515-28

26. TEAM Results: Geller et al. Arch Gen Psychiatry 2012 May;69(5):515-28

27. Treatment of Early-Age Mania (TEAM) study Risperidone was more efficacious than lithium or divalproex sodium for the initial treatment of childhood mania Discontinuation rate higher for lithium than for risperidone Increased weight gain, body mass index, and prolactin level occurred with risperidone vs lithium and divalproex sodium Thyrotropin level increased in subjects taking lithium Geller et al. Arch Gen Psychiatry 2012 May;69(5):515-28

28. Risperidone vs. Divalproex Pavuluri MN et al. Bipolar Disord . 2010 Sep;12(6):593-605

29. Quetiapine vs. Divalproex Delbello MP et al. J Am Acad Child Adolesc Psychiatry. 2002 Oct;41(10):1216-23

30. Quetiapine vs. Lithium Patino LR et al. J Child Adolesc Psychopharmacol 2021;31(7):485-93

31. Quetiapine vs. Lithium 6-week, DB-RCT – patients randomized to quetiapine (400-600 mg/day) or lithium (serum level 1.0-1.2 mEq/L) Significantly greater improvement in YMRS scores on quetiapine vs. lithium Response rates – 72% on quetiapine, 49% on lithium More somnolence, weight gain, dizziness on quetiapine, more headaches, nausea, tremor on Lithium Patino LR et al. J Child Adolesc Psychopharmacol 2021;31(7):485-93

32. Other pediatric bipolar studies… Paliperidone: open-label study (N=15), improvement in YMRS, severity of ADHD, psychotic sx. significant Quetiapine: open label monotherapy in preschoolers (n=30), school age (N=19) children P reschooler r esponse comparable to school-age children Joshi G et al. Psychopharmacology 2013 Jun;227(3):449-58 Joshi G et al. J Affect Disord 2012 Feb;136(3):1143-53

33. Pharmacotherapy of Autism Spectrum Disorders No drug has been shown to be effective for “core symptoms” of ASD Risperidone (ages 5-17) and aripiprazole (ages 6-17) are FDA-approved for treatment of irritability associated with ASDs. Treatment is typically focused on target behaviors associated with autism Aggression Repetitive behaviors Irritability

34. Antipsychotics in Autism Spectrum Disorders Randomized trials have demonstrated benefit for irritability with risperidone, aripiprazole, paliperidone Dose range is lower than for other pediatric indications 0.5-3 mg/day for risperidone 2-15 mg/day for aripiprazole Weight gain, sedation, fatigue most common side effects Farmer C, Thurm A, Grant P.  Drugs  2013 March;73(4):303-314

35. Biomarkers in Autism of Aripiprazole and Risperidone Treatment (BAART) Study: 80 children ages 6–17 with ASDs enrolled, 61 randomized to study drug. No more than two-week exposure to either study drug in past three years 51 completed the 10-week trial 31 completed an optional 12-week blinded extension phase. Improvement greatest in RIS group at every assessment period, statistically significant vs. ARI at weeks 3 and 6 (p<0.05) Mean weight gain in ARI group significantly less than RIS at week 4 (0.62 vs 1.38 kg, p=0.033), week 10 (1.61 vs 3.31 kg, p<0.001 Difference became nonsignificant for the 31 patients completing the 3-month extension phase (4.36 vs 5.55 kg, p=0.26). Devane CL et al. Pharmacotherapy . 2019 June ; 39(6): 626–635.

36. Biomarkers in Autism of Aripiprazole and Risperidone Treatment (BAART) Study: Devane CL et al. Pharmacotherapy . 2019 June ; 39(6): 626–635.

37. Biomarkers in Autism of Aripiprazole and Risperidone Treatment (BAART) Study: Devane CL et al. Pharmacotherapy . 2019 June ; 39(6): 626–635.

38. Dose response to aripiprazole in children with autism Marcus RN et al. J Am Acad Child Adolesc Psychiatry 2009;48(11), 1110-1119

39. Impact of prior antipsychotic exposure on weight gain – aripiprazole for autism Mankoski R et al. J Child Adolesc Psychopharmacol 2013;24(8), 572-576

40. Impact of prior antipsychotic exposure on metabolic parameters – aripiprazole for autism Mankoski R et al. J Child Adolesc Psychopharmacol 2013;24(8), 572-576

41. Challenges in treating kids with EOS, COS… Medication typically helps with positive symptoms, ongoing impairment results from negative symptoms Most kids continue to have significant functional impairment despite treatment Long-term adherence to medication is very poor Practically no long-term studies of either traditional or atypical neuroleptics Less data on psychosocial treatments than medication

42. Psychopharmacology of EOS, VEOS: Use of antipsychotics considered a “primary treatment” Antipsychotics considered “first-line treatment of choice for schizophrenia spectrum disorders in youth, with second-generation agents typically being the treatments of first choice” Antipsychotics should be used in conjunction with psychotherapeutic interventions J Am Acad Child Adolesc Psychiatry 2013;52(9):976-990

43. Comparative effectiveness of antipsychotics in EOS: “ No significant differences were detected in risk of either adverse outcome (medication discontinuation, psychiatric hospitalization) across five commonly prescribed antipsychotic medications ” Olfson et al. Schizophrenia Bulletin 2012;38(4) 845-853

44. Time to discontinuation with antipsychotics in EOS From Olfson et al. Schizophrenia Bulletin 2012;38(4) 845-853

45. Clinical Trials of Traditional Neuroleptics in EOS: Spencer (1992): haloperidol (0.02-0.12 mg/kg) superior to placebo in reducing symptoms of thought disorder, hallucinations, persecutory ideation in youth with schizophrenia Spencer et al. Psychopharmacol Bull (1992) 28:183-186

46. Risperidone in EOS: Sikich (2004), RCT: risperidone (mean dose 4.0 mg), olanzapine (12.3 mg), haloperidol (5.0 mg) N=50 Diagnoses not homogeneous % of patients “ improved ” : 74% with risperidone, 88% olanzapine, 54% haloperidol More severe EPS, weight gain reported than in adult trials Sikich L et al, Neuropsychopharmacology. 2004;29:133-145.

47. Low/High-Dose Risperidone in EOS Haas M et al, J Child Adolesc Psychopharmacology 2009;19(Dec)6:611-621

48. Low vs. High-Dose Risperidone in EOS Haas (2007) R isperidone (1-3 mg/day), R isperidone (4-6 mg/day) PBO Six-week duration, mean age=15.6, N=160 Both RIS groups >PBO in PANSS total score Increased EPS, dizziness on high dose RIS Haas M et al, J Child Adolesc Psychopharmacology 2009;19(Dec)6:611-621

49. Aripiprazole in EOS: Findling RL et al, Am Journal Psychiatry 2008 Nov;165(11):1432-41

50. Aripiprazole in EOS: Robb and Findling: aripiprazole 10 mg, aripiprazole 30 mg vs. PBO Six-week duration Mean age=15.5 N=302 ARI>PBO in BPRS-C, CGI-S, 37.5% response rate to ARI, 25.7% PBO (non-significant) Findling RL et al, Am Journal Psychiatry 2008 Nov;165(11):1432-41

51. Low/High-Dose Quetiapine in EOS Findling RL et al, J Child Adolesc Psychopharmacology 2012;22(Oct)5:327-342

52. Low/High-Dose Quetiapine in EOS Randomized trial… Quetiapine 400 mg (n=73) Quetiapine 800 mg (n=74) placebo (n=73) Six-week duration Both QUE groups>PBO in PANSS total score No significant differences in efficacy, AEs between low-dose and high dose groups Findling RL et al, J Child Adolesc Psychopharmacology 2012;22(Oct)5:327-342

53. Ziprasidone in EOS Findling RL et al, J Child Adolesc Psychopharmacology 2013 Oct;23(8):531-544

54. Ziprasidone in EOS Six-week RCT followed by 26 week open-label extension Planned interim analysis led to early termination of study due to lack of efficacy N=283 (193 on active drug) No QT prolongation >500 ms Well-tolerated metabolically One completed suicide in open-label extension Findling RL et al, J Child Adolesc Psychopharmacology 2013 Oct;23(8):531-544

55. TEOSS (Treatment of early-onset schizophrenia) study R andomized, eight-week trial of… O lanzapine (2.5-20 mg/day) R isperidone (0.5-6.0 mg/day) M olindone (10-140 mg/day, plus 0.5 mg bid benztropine) Age range of patients: 8-19 Positive response=CGI score of 1 or 2, and/or >20% improvement in PANSS score at 8 weeks 116 patients received drug NIMH funded Sikich L et al, Am J Psychiatry 2008 Nov; 165(11): 1369-1372

56. Clinical response in TEOSS: Sikich L et al, Am J Psychiatry 2008 Nov;165(11):1369-1372

57. Medication Tolerability in TEOSS: Mean weight gain at 8 weeks: olanzapine 6.1 kg risperidone 3.4 kg molindone 0.3 kg Significantly greater cholesterol elevation on olanzapine than other agents Olanzapine arm of study terminated early by monitors secondary to cholesterol elevation, elevated liver functions Sikich L et al, Am J Psychiatry 2008 Nov;165(11):1369-1372

58. How well do antipsychotics work? Effect sizes from a metanalysis of 212 RCTs of antipsychotics for schizophrenia in adults… Clozapine 0.88 (0.73-1.03) Olanzapine 0.59 (0.53-0.65) Risperidone 0.56 (0.50-0.63) Paliperidone 0.50 (0.39-0.60) Haloperidol 0.45 (0.39-0.51) Quetiapine 0.44 (0.35-0.52) Aripiprazole 0.43 (0.34-0.52) Ziprasidone 0.39 (0.30-0.49) Leucht S et al. Lancet 2013 Sep 14;382(9896) 351-362

59. Clozapine vs. Haloperidol in EOS: Clozapine: NIMH studies-Kumra, Frazier (1996) helpful in 50% of treatment-resistant patients S uperior to haloperidol (N=21), D iscontinuation due to seizures, neutropenia Kumra S, Frazier JA, Jacobsen LK et al. Arch Gen Psychiatry (1996), 53:1090-1097

60. Clozapine vs. Olanzapine in EOS Shaw P, Sporn A, Gotgay N et al, Arch Gen Psychiatry. 2006;63:721-730

61. Clozapine vs. Olanzapine in EOS: Shaw (2006) Clozapine (mean dose 327 mg/day) vs. olanzapine (18.1 mg) Eight-week duration Mean age=12 N=25 CLZ>OLZ in negative symptom improvement 6 of 15 patients had dyslipidemia at 2-year follow-up Shaw P, Sporn A, Gotgay N et al, Arch Gen Psychiatry. 2006;63:721-730

62. Clozapine vs. Olanzapine in EOS: Clozapine mean dose 403.1 mg, olanzapine 26.2 mg 12- week study, N=39 Mean age=15.6 CLZ superior to OLZ in negative symptom improvement, 66% response rate to CLZ, 33%OLZ Kumra S et al, Biol Psychiatry. 2007

63. Clozapine metanalysis in EOS: Short-term improvement of 69% on BPRS maintained in long-term follow-up to nine years Neutropenia occurred in 6-15% of patients, but agranulocytosis rare (<0.1%) Seizures were uncommon (<3%) Treatment-emergent diabetes infrequent (<6%) Long-term discontinuation rate low (3-6%) NO fatalities reported with CLZ use in EOS Schneider C et al. Eur Psychiatry 2013 Oct 9

64. When should we consider clozapine in EOS? Only drug with demonstrably greater efficacy in EOS Reserved for treatment-refractory cases (two or more failed trials of other antipsychotics) Second opinion recommended prior to treating kids ages 12 and under WBCs required weekly for first six months, biweekly in months 6-12, q4 weeks thereafter J Am Acad Child Adolesc Psychiatry 2013;52(9);976-990

65. Early-Onset Schizophrenia Other Controversies in Psychopharmacology Role of polypharmacy…adjunctive medications for depression, parkinsonian symptoms? Use of stimulants in treating executive functioning impairment, negative symptoms? One RCT demonstrated benefit to omega 3 ’ s in delaying onset of psychosis in high-risk patients Minocycline as add-on treatment to protect against gray matter loss in the midposterior cingulate cortex and in the precentral gyrus, significantly improved executive functioning vs. placebo J Am Acad Child Adolesc Psychiatry 2013;52(9);976-990 Chaves, C, Schizophr Res. 2015 Feb;161(2-3):439-45

66. Contact Information [email protected] [email protected] Twitter: @drgrcevich LinkedIn:https://www.linkedin.com/in/stephen-grcevich-md /