Dr. Crismon has no potential conflicts of interest to disclose with regard to this presentation. M. Lynn Crismon, Pharm.D., FCCP, BCPP Dean James T. Doluisio Regents Chair & Behrens Centennial Professor of Pharmacy Off label uses may be discussed during this presentation. If so, it will be based upon the best available evidence at the time of the presentation. By the end of this presentation, the participant should be able to: Discuss recent developments in the child psychopharmacology literature. Identify specific controversies that need to be addressed in using psychotropic medications in youth. Review parameters that indicate that medication treatment needs to be further evaluated for appropriateness D I A G N O S I S ADD/ADHD Conduct Disorder Oppositional Defiant Disorder Anxiety Disorder Adjustment Disorder Depressive Disorder Bi-polar Disorder Obsessive Compulsive Disorder PTSD Anger/ Aggression Impulsive Withdrawn Sad Destructive Defiant Anxious Difficulty with Focus Manipulative Teenagers Foster Care ADHD Conduct disorder Oppositional Defiant Disorder Anxiety Disorders Depression Bipolar Disorder Obsessive Compulsive Disorder Schizophrenia Autism (behavioral sequelae) PTSD Co-occurring disorders Courtesy of Peter Jensen, The REACH Institute, updated 10/8/14 www.thereachinstitute.org 1
Prevalence per 1,000 enrollees 1/13/2016 The most thoroughly studied psychotropic medication group in children is: A. Antipsychotics B. Antidepressants C. Mood stabilizers D. Stimulants Lorberg B, et al. JAACAP 2014; 53:716-19. The most studied medication for the treatment of aggression in children is: A. Methylphenidate B. Risperidone C. Haloperidol D. Lithium E. Aripiprazole Across the USA, increase in the use of psychotropic medication in children (particularly low socioeconomic), beginning in the mid-1990s. Of most concern, an increase in antipsychotic use By and large, antipsychotics being used to treat adverse behaviors & not psychosis Weight increase with SGAs and metabolic effects further fueled this Also, increase in psychotropic polypharmacy 18 16 14 12 10 8 6 4 2 0 Antipsychotic Use in Children and Adolescents: 1996 to 2001 Texas Ohio California Managed Care Org. 1996 1997 1998 1999 2000 2001 Year Patel NC, Crismon ML, et al. JAACAP 2005 Antipsychotic medication Most studies in aggression are with second generation antipsychotics (SGAs) Most data with risperidone In varying degrees, SGAs cause weight gain Olanzapine causes the most Weight gain associated with increased risk of glucose intolerance & increased lipids De Hert M, et al. European Psychiatry 2011,26:144-158. 2
De Hert M, et al. European Psychiatry 2011,26:144-158. Correll C, et al. JAMA 2009;302(16):1765-1773 Bobo WV, et al. JAMA Published online, August 21, 2013 Aman MG, et al. JAACAP 2014;53:47-61 Which of the following medications should be avoided as first line treatment for aggression in children because of excessive weight gain A. Fluoxetine B. Methylphenidate C. Guanfacine D. Aripiprazole E. Olanzapine TEAM Study Efficacy and tolerability of risperidone, lithium, and divalproex in 279 medication naïve children Risperidone superior to either other drug Particularly effective with comorbid ADHD Discontinuation rate higher with lithium Risperidone adverse effects: Weight gain, BMI increase, and hyperprolactinemia. Geller B, et al. Arch Gen Psychiatry 2012:69:515-28. Vitiello B, et al. JAACAP 2012;51:867-78 3
Lithium N = 53; PCBO N = 28 Ages 7 17 yrs YMRS significantly more improved with Lithium (p = 0.03) Very much or much improved: 47% vs 21% Lithium Dose 7 11 YOs = 1,292 + 420 mg/d 12 17 YOs = 1,716 + 606 mg/d Findling RL, et al. Pediatrics 2015;136:885-94. Geller B, et al. Arch Gen Psychiatry 2012:69:515-28. FDA approved for ages 10 17 years 3 week study in 403 pediatric patients 2.5, 5, or 10 mg BID Black cherry SL tablets Available 2 nd quarter 2015. Findling RL, et al. Pediatrics 2015;136:885-94. Medscape, March 13, 2015 Pooled data from 15 clinical trials Risk of suicidal verbalizations or behavior in 4% of drug treated patients vs. 2% with placebo No completed suicides Close monitoring warranted Untreated depression is still the biggest risk factor for depression Bridge JA, et al. JAMA 2007;297:1683-1696 Drug Relative Risk (95% CI), all trials, all indications Relative Risk (95% CI), MDD trials Fluoxetine 0.92 (0.39, 2.19) 0.89 (0.36, 2.19) Paroxetine 2.65 (1.00, 7.02) 2.15 (0.71, 6.52) Sertraline 1.48 (0.42, 5.24) 2.16 (0.48, 9.62) Citalopram 1.37 (0.53, 3.50) 1.37 (0.53, 3.50) Venlafaxine 4.97 (1.09, 22.72) 8.84 (1.12, 69.51) Mirtazapine 1.58 (0.06, 38.37) 1.58 (0.06, 38.37) Hammond TA, et al. Arch Gen Psychiatry 2006;63:332-339 4
Fluoxetine no different from placebo with regard to suicide risk (primarily suicidal thoughts) in 4 RCTs in youths. Severity of depressive symptoms strongly correlated with suicide risk. Fluoxetine decreased depressive symptoms more rapidly than placebo Gibbons RD. Arch Gen Psych. 2012;69:572-9. Epidemiological study in 1.1 million adolescents 31% decrease in antidepressant Rxs in adolescents in 2 nd year after black box warning 21.7% increase in self poisonings in 2 nd year after black box warning Also an increase in self poisonings among young adults, but not among adults. No change in completed suicides. Lu CY, et al. BMJ 2014; published on-line June 14, 2014. Matched cohort study of 162,625 people ages 10-64 yrs prescribed either citalopram, fluoxetine, or sertraline. Rate of deliberate self-harm in 10 24 YO group was 2.2 times higher if dose started at higher than modal dose. Modal doses Citalopram = 20mg/d Fluoxetine = 20 mg/d Sertraline = 50 mg/d 1 additional event in every 150 treated patients. No relationship between self-harm & starting dose in the 25-64 YO group. Does not address dose titration. Miller M, et al. JAMA Int Med 2014 174:899-909. Brent DA, Gibbons R. JAMA Int Med 2014;174:909-12. Lu CY, et al. BMJ 2014. Predictors High baseline suicidal ideation Family conflict Drug and alcohol use Preliminary Venlafaxine Rx Adjunctive benzodiazepine Rx (small N) Brent DA, et al. Am J Psych 2009;166:418-26. Miller M, et al. JAMA Int Med 2014;174:899-909 5
CDRS - R Score 1/13/2016 Child Depression Rating Scale - Revised Detke HC, et al. JAACAP 2015; 54: 217-24. Richardson LP, et al. JAMA 2014;312:809-16. D. Antidepressants are contraindicated in youth A. Antidepressants increase the risk of completed suicide in youth B. Antidepressants have been associated with an increased risk of suicidality in youth C. Antidepressants have been associated with a decreased risk of suicidality in youth A. Divalproex B. Lithium C. Risperidone D. Lithium and Risperidone E. All of the above MTA Study: Rate of growth in height decreased by about 1-3 cm/year over the first 1-3 years of medication treatment if the child was actually adherent with treatment. No difference in adult height Clinically insignificant trend in Z score change among males No change in the peak height velocity (PHV) Maximum growth rate Later age for PHV in stimulant treated males 13.6 vs 12.9 years Vitiello B. Child and Adolescent Psychiatric Clinics of North America. 2008. 17(2):459-474. Harstad EB, et al. Pediatrics, published online 9/1/2014 6
Participants meeting response criteria (%) Prevalence of substance use disorder Prevalence of nicotine dependence Participants meeting response criteria (%) Change in height-for-age Z score 1/13/2016 Study in 1,200,438 individuals (age 2-24 yrs) found no difference between incident users and nonusers in the rate of sudden death, ventricular arrhythmia, or death from any cause. Cooper WO et al. N Engl J Med 2011;365:1896-904. Cumulative stimulant duration (y). Harstad EB, et al. Pediatrics, published online 9/1/2014 Healthy controls No stimulant GXR AM + psychostimulant GXR PM + psychostimulant Placebo + psychostimulant treatment Stimulant treatment 40% reduction in ADHD-RS-IV total score from baseline 50% reduction in ADHD-RS-IV total score from baseline Groenman AP, et al. Brit Jour Psych July 2013 (on-line). Cutler A, et al. JAACAP 2014;53:1092-1101. GXR AM + psychostimulant Symptomatic remission GXR PM + Placebo + psychostimulant psychostimulant A. Switch the stimulant to atomoxetine B. Add atomoxetine to the stimulant C. Switch the stimulant to guanfacine D. Add guanfacine to the stimulant Syndromal remission Cutler A, et al. JAACAP 2014;53:1092-1101. 7
Placebo controlled, double blind trials Aripiprazole*: 5 15 mg/d. Olanzapine: 7.5 12.5 mg/d. Risperidone*: 0.5 3.5 mg/d. Also superior to haloperidol Valproic Acid: Mean Cp = 89.8 mcg/ml. * FDA approved for this indication. Volkmar F, et al. Practice Parameters for ASD. JAACAP 2014;53:237-57. Piacentini J, et al. JAACAP 2014;53:297-310. Placebo controlled, double blind trials Atomoxetine: 1.2 mg/kg/d Methylphenidate: 7.5 50 mg/d. Note lower percent response rates than in ADHD trials (without ASD) Volkmar F, et al. Practice Parameters for ASD. JAACAP 2014;53:237-57. In a child receiving psychotropic medication: Absence of a thorough assessment of DSM-V diagnosis in the child s medical record 4 or more psychotropic medications prescribed concomitantly Side effect medications are not included in this count. Prescribing of: 2 or more concomitant antidepressants 2 or more concomitant antipsychotic medications 2 or more concomitant stimulant medications 3 or more concomitant mood stabilizer medications 2 or more alpha agonists 8
Prescribed psychotropic medication is not consistent with appropriate care for the patient s diagnosed mental disorder or with documented target symptoms usually associated with a therapeutic response to the medication prescribed. i.e., not clinically indicated Psychotropic polypharmacy for a given mental disorder is prescribed before utilizing psychotropic monotherapy. The psychotropic medication dose exceeds usual recommended maximum doses (either FDA maximum or literature supported maximum) Psychotropic medications are prescribed for children of very young age, including children receiving the following medications with an age of: Psychostimulants: Less than 3 years of age Alpha agonists: Less than 4 years of age Antidepressants: Less than 4 years of age Antipsychotics: Less than 4 years of age Mood stabilizers: Less than 4 years of age Prescribing by a primary care provider who has not documented previous specialty training for a diagnosis other than the following (unless medication recommended by a psychiatrist consultant): Attention Deficit Hyperactive Disorder (ADHD) Uncomplicated anxiety disorders Uncomplicated depression Gleason MM, et al. J Am Acad Child Adolesc Psychiatry 2007;46:1532-1572 Antipsychotic medication(s) prescribed continuously without appropriate monitoring of glucose and lipids at least every 6 months. A. Children prescribed antipsychotics medication should have monitoring of glucose and lipids at least every six months B. Children less than six years of age should not be prescribed a stimulant C. Psychotropic medication should not be prescribed by a primary care clinician D. Psychotropic medication dose should not exceed that listed in the FDA approved labeling E. Three or more psychotropic medication should not be prescribed concomitantly 9
A full spectrum of mental disorders occur in children and adolescents. Inadequate evidence exits to appropriately guide treatment for many disorders seen in children and adolescents. Clinicians need to combine available evidence with evidence in adults and clinical experience to guide treatment decisions. http://www.dfps.state.tx.us/child_protecti on/medical_services/guidepsychotropic.asp Acknowledgements: James Rogers, M.D. Medical Director, TDFPS Alan Shafer, Ph.D. Data Analyst, TDSHS Texas Foster Care Psychotropic Parameters Working Group Texas Department of Family and Protective Services 10