Psychotropic Medication Management in Children and Adolescents

Drug Use Research & Management Program DHS Division of Medical Assistance Programs, 500 Summer Street NE, E35; Salem, OR 97301-1079 Phone 503-947-5220 Fax 503-947-1119 Psychotropic Medication Management in Children and Adolescents Changes in FDA regulations in 2000 have led to more pediatric studies. FDA mandates that any new medication expected to be prescribed to anyone under 18 years old must undergo safety and efficacy studies as part of the formal FDA approval process. 1 This review will summarize the available evidence for pediatric psychotopic drug use. Stimulants The stimulants are the most studied class of drugs in children and adolescents, but it is important to note that more than 80% of the world's use of stimulant medications occurs in the USA. 2 Over decades of use, multiple studies have demonstrated significant short-term efficacy of stimulants on target symptoms of attention deficit hyperactivity disorder (ADHD), specifically inattention, impulsivity, and hyperactivity. 1,3 Four types of medications are approved for use in children: methylphenidate (over 6 yrs old), mixed amphetamine salts (over 3 yrs old), lisdexamfetamine (6-12 yrs old), and atomoxetine (over 6 yrs old). To date, there are no data to suggest superiority of one stimulant over another. 1,3 One child may not respond to or tolerate one stimulant, yet may do well with another formulation. The most important differences have to do with convenience in dosing (number of doses per day) and price. 1 Systematic reviews recognize that some children need both short acting and long acting stimulants, given at different times of day. 1,3 Evidence of Effectiveness: There are two well documented long term studies 1, and multiple small, open label studies, case reports and retrospective chart reviews in preschoolers and older children with stimulants. The majority of studies showed significant and sustained improvement throughout the course of the studies. In the early 1990s, the National Institute of Mental Health embarked on the first large multi-modal psychiatric treatment intervention study involving children. This six-site, study enrolled 579 children, ages 7-10 yrs, with ADHD, and followed them for 14 months on active treatment in four different arms of the study. After the 14 months of active treatment, they were followed for an additional 10 months. The greatest improvement was seen in groups who received both medication and behavioral treatment (counseling). 4 The other long term study published was a double-blind, placebo controlled trial in Sweden which studied 62 children (6-11yrs) and randomized them to placebo or amphetamine for 15 months. The children in the active treatment arm showed a significant and sustained improvement on ADHD symptoms throughout the study. 5 The Drug Effectiveness Review Project (DERP) report on ADHD drugs found fair quality evidence that methylphenidate (MPH) is superior to placebo, but could not find Created on 9/5/2008 11:15:00 AM Modified on 11/25/2008

significant differences between the immediate release and long release formulations. 3 Evidence of Adverse Effects: Limited evidence from the DERP review suggests weight loss is greater with the amphetamine salts compared to methylphenidate (from short term trials). 3 Limited evidence suggests atomoxetine caused more vomiting and drowsiness than methylphenidate or amphetamine salts; methylphenidate caused more "abnormal thinking" than atomoxetine and the amphetamine mixtures caused more insomnia than atomoxetine in children (6-12 yrs). 3 Growth suppression has been a concern, yet most studies show growth suppression during stimulant treatment, but then a height catch-up period later in adolescence, or when the child is off stimulants. 1 There are current cardiac concerns with stimulants and more long term studies are needed. The American Academy of Pediatrics and the American Heart Association have been clarifying recommendations for children using stimulants. Their recommendations come from a review of data which show that children with heart conditions have a higher incidence of ADHD, and it is prudent to carefully assess children for heart conditions when assessing the need for stimulant medication. 29 Overuse and inappropriate use of stimulants is also a common concern. DeBarr, et al, found only 60% of the children given a stimulant had an actual diagnosis of ADHD. The authors point out that an additional 35% had "associated behavior symptoms" that seemed related to ADHD. 6 Mood Stabilizers Controversy exists surrounding the diagnosis of juvenile bipolar disorder (BPD). 1 Nonspecific aggression and explosive behavior are frequently the targeted symptoms for these drugs, whether or not there is the clear presence of a mood disorder. 1 Evidence of Effectiveness: Most evidence with mood stabilizers comes from fair quality evidence (6 RCTs, 6 open label studies) in older children (7-18 yrs), even though many case reports and retrospective chart reviews, and at least one open-label 8 week trial identify mood stabilizer use in preschool children also. 7 Biederman, et al, evaluated short term safety and efficacy in 31 preschoolers (4-6 yrs) in an open-label prospective study and found both risperidone (at 1 week) and olanzapine (at 2 weeks) resulted in a rapid reduction of symptoms of mania in children with BPD, however there were substantial adverse effects and the benefit may not out weigh the risk in this population. 8 Four case reports/retrospective chart reviews using valproate, lithium or carbamazepine in preschoolers showed positive results, but some also showed adverse events. 9 Six case reports of bipolar illness in preschool children (3-5 yrs) showed positive improvements when treated with lithium. 10 Trials show valproate is generally well tolerated in children and adolescents with BPD when given as monotherapy and when used in combination with risperidone, lithium and quetiapine, although the incidence of sedation is higher when combined with quetiapine. 7 Lithium has been shown effective in children and adolescents (ages 5-17) with mood disorder and conduct

disorder in at least 2 RCTs (4 weeks long), and 1 uncontrolled study, plus case reports and 1 retrospective review. 7 Oxcarbazepine and topiramate have not shown efficacy in this population, even though a few case reports describe symptom improvements. 11,12 National consensus guidelines for treating type I BPD with or without psychotic features, recommend valproate alone, lithium alone, or either in combination with an atypical antipsychotic as a first line treatment option even though evidence supporting combination therapy is limited. 7 Valproate also shows effectiveness in reducing aggression. 7 Long term studies are needed. Evidence of adverse effects: Concerns with liver toxicity (fatality risk highest in children under 2 years of age), pancreatitis, thrombocytopenia and polycystic ovary disease in girls is a concern with valproate and other anti-epileptic drugs used for mood stability in children. 1,7 Lithium also has concerning side effects and risks, yet side effects in children from lithium or valproate are typically mild to moderate. 7 Atypical Antipsychotics Atypical antipsychotics have limited, but growing evidence for use in conduct disorder (CD), oppositional defiant disorder (ODD), disruptive behavior disorder (DBD), BPD (mania and/or psychotic symptoms), and autism spectrum disorders (including pervasive developmental disorder). Evidence of Effectiveness: Most evidence is still from small, short term trials (up to 6 weeks). A systematic review conducted by Ipser et al, found one open-label trial with olanzapine and risperidone for BPD in preschoolers, and a fair amount of open label studies, retrospective chart reviews or case studies using risperidone, olanzapine, haloperidol and quetiapine in older youths. 13 Risperidone has fair quality evidence for effectiveness in pervasive developmental disorders (two 6 month RCTs, one 8 week open label trial), including autism and has FDA approval for use in this disorder for age 5 years and older. The DERP review on atypical antipsychotics found risperidone and olanzapine were superior to placebo for improving behavioral symptoms in children with autism and other pervasive developmental disorders, and found risperidone superior to placebo in children and adolescents with DBD. 14 There are 3 larger studies with risperidone in DBD (6 week RCTs in 5-12 years old) and one 6 month RCT using risperidone in children (5-17 years old) with ODD and CD associated with ADHD. 30,31,32,33 All showed significant improvement in behavioral symptoms when compared to placebo. Evidence of adverse effects: Side effects from atypicals are concerning since long term studies have not been completed in children. Weight gain, sedation, metabolic and endocrine issues are the most common concerns. In short term studies (mostly open-label), serious side effects have been reported only rarely in children. 13

Antidepressants Currently, fluoxetine is the only second-generation antidepressant approved by the FDA for treating major depressive disorder (MDD) in children 2-18 yrs old. Published evidence is based on controlled trials in children 7-18 years of age. Fluvoxamine and sertraline are approved for the treatment of obsessivecompulsive disorder (OCD) in pediatric patients, although they are not approved for treating MDD. Evidence for Effectiveness: There are over 11 RCTs using SSRIs in older children and adolescents. Many studies include a 1 yr open label follow-up. 1 They have not been well studied in preschool age children. There are 3 case reports and 1 open label trial (n=7) using buspirone, fluoxetine, or clonidine in children ages 2-10 for anxiety disorders. 9 There is sparse evidence for use of antidepressants in children under 6 years, except possibly for fluoxetine in autism spectrum disorders. According to the DERP review on second generation antidepressants, both published and unpublished data suggests that only fluoxetine has a favorable risk-benefit profile in pediatric populations, but that in children and adolescents, placebo controlled evidence supports the efficacy of fluoxetine and citalopram in major depressive disorder. 16 One published multi-national study pooled data from two double-blind RCTs conducted in 53 centers and sertraline treated pediatric patients showed a greater improvement in symptoms versus placebo, but neither trial had demonstrated a consistent advantage for sertraline over placebo by itself, before the pooling. 16 Evidence from two trials reported no difference between paroxetine and placebo or venlafaxine and placebo. 16 Evidence is inconclusive about the efficacy of escitalopram, fluvoxamine, mirtazapine, venlafaxine, bupropion, duloxetine and nefazodone. 16 A meta-analysis by Tsapakis et al, concluded antidepressants of all types show limited efficacy in juvenile depression, but fluoxetine might be more effective, especially in adolescents. 17 A systematic review from the National Institute for Health and Clinical Excellence looked at 46 studies of depression in children and young people (ages 5-18 yrs) and concluded that tricyclic antidepressants should not be used, but fluoxetine, particularly combined with cognitive behavior therapy seems efficacious. 18 Evidence of adverse effects: There are reports of increased suicidal thoughts and behavior for citalopram, paroxetine, sertraline, and venlafaxine, but not for fluoxetine according to the DERP systematic review. 16 In 2005, the FDA added black box warnings for suicidal precautions in children and adolescents taking all classes of antidepressants. From pooled analysis of short-term (4-16 weeks) trials of 9 different antidepressants (24 trials, more than 4,400 patients), the average risk of adverse suicidal reactions was 4%, twice the placebo risk of 2%. Polypharmacy Zito et al, referenced the increase of polypharmacy in children over the decade: in July 2004, 72% of psychotropic agent-medicated youth in foster care received > 2 different classes of medication and 41.3% received >3, compared to figures in 1996 in which 46% received >2 and 26.9% received over 3 meds. 19

Comorbidity with ADHD is very common (30-50%) and multiple medications are often used. 20 About 50% of children with ADHD are comorbid for ODD and/or CD. 20 Co-occuring diagnoses in children are increasingly frequent and include (but are not limited to) the following: ADHD, CD, ODD, anxiety, OCD, depression, BPD, autism, intermittent explosive disorder, post-traumatic stress disorder, tics, Tourettes, epilepsy, psychosis, and mixed states. 19,20,21 Most psychotropic combinations lack adequate evidence of effectiveness or safety in youth. Typically, they are adopted based on knowledge generalized from adult studies or assume that the combination is as safe and effective as each component of the regimen. Data reveal that children and adolescents differ from adults in adverse drug reactions to psychotropic medications. 19a,19b In addition, pediatric research shows that increasing the number of concomitant medications increases the likelihood of adverse drug reactions. 19a,19b In a study reviewing psychotropic medication utilization, patients receiving antipsychotics were most likely to receive polypharmacy, but a diagnosis of ADHD was also strongly related to use of polypharmacy. 24 Those receiving polypharmacy were also more likely to have a co-diagnosis of anxiety disorder and a history of abuse or neglect. 24 For co-occurring diagnoses, consensus panels strongly recommend that whenever possible, initiate one medication for the most severe disorder first, then assess the need for pharmacotherapy with the co-occurring disorder, making one medication change at a time. 21,22 International consensus statement on ADHD and disruptive behavior disorders suggest stimulants plus other pharmacotherapy as add-on for ADHD with co-morbid conduct disorder when aggression/impulsivity is marked and persistent. 20 The presence of psychosis with BPD in adolescents has sometimes shown to be lithium refractory, requiring adjunctive antipsychotic treatment. 23 There are emerging data from adolescent studies showing that the addition of an atypical antipsychotic to a mood stabilizer may decrease BPD symptoms and improve overall response rates compared with monotherapy. There are no studies in preschoolers, but four studies involving adolescent children with BPD (one study included children 5 years old) have been published and all showed significant improvements with adjunctive therapy, even when the patient was considered a non-responder to monotherapy. 23,25,26,27 Zito, JM, in her testimony before the House Committee on Ways and Means in May 2008, examined the Texas Dept. of State Health Services, one of the more comprehensive consensus groups on medication utilization for foster children. Texas implemented criteria for review when five or more psychotropic medications were prescribed concomitantly, if antipsychotics or antidepressants were prescribed for children under 4 years old, stimulants under 3 years, and if 2 21, 21a or more drugs from the same class were prescribed concomitantly. Five months after promulgating these criteria, there was a 31% drop in use of 5 or more psychotropic classes among foster care youth. They now recommend criteria for triggering a review be set at 3 or more concomitant psychotropic medications classes in youth given that such drug use lacks supportive evidence and systematic safety studies, and is off-label in almost all instances.

PRN" or as needed PRN use of psychotropic drugs is growing without supported evidence in the outpatient setting. There is fair quality evidence of as PRN use of psychotropics in the "inpatient" setting, given by medically trained providers to prevent/contain agitation, physical aggression, disruptive and aggressive behavior to protect other patients and staff members. 28 In one inpatient setting study, PRN doses occurred most often in the early evening, when the transition to more unstructured time was evident. The authors did say it was unclear if this was the reason, or if diurnal variation in biological factors contributed to the diurnal patterns in PRN use. 28 Patients in this study had a positive opinion of, and response to the PRN therapy. 28 There is a significant lack of data in the "outpatient" or home setting use of PRN medications where it is difficult to identify outcomes or interactions, know timing in relation to trials of behavioral techniques, etc., even though PRN use in the home setting is growing significantly and adding to the polypharmacy dilemma in children. Summary There is limited evidence to support the use of psychotropics in pre-school children (stimulants for ADHD, risperdal for autism, lithium for BPD). There is fair evidence to support the use of up to 2 psychotropic drugs in children over 6 years old for co-occurring diagnoses (ADHD + ODD, CD; ADHD + depression, OCD; BPD + psychosis, CD, etc). There is very limited evidence to support the use of two mood stabilizers (valproate, lithium) used concomitantly when refractory illness is present in older children, but not in children under 6 yrs old. There is no evidence to support the use of more than 1 antidepressant or antipsychotic drug used concomitantly. There is evidence to support the use of a short acting plus a long acting stimulant drug concomitantly. There is insufficient evidence to support the efficacy and safety of using a psychotropic drug as a "PRN" in the outpatient/home setting, even though this practice is increasing without published case-reports of adverse events associated with the practice. There is no literature evidence to support the use of safely administering a psychotropic drug PRN >2 times in any 7 day period in an outpatient setting, but this may be a reasonable, tightly controlled guideline to set.

Drug Class Level of Evidence for preschool age (3-5 yrs) Level of Evidence for older children (7-18 yrs) Stimulants fair Good Mood Stabilizers poor Fair Atypical antipsychotics poor fair (autism, CD, DBD) Antidepressants poor fair only for fluoxetine, citalopram Polypharmacy (2 psychotropic drugs used concomitantly) Polypharmacy (3 or more psychotropic drugs used concomitantly) poor none fair only for: 1. stimulants-short/long acting 2. ADHD or BPD plus co-occurring diagnosis 3. refractory BPD Poor PRN use of psychotropics none Poor Recommendations: From review of the best available literature evidence, and reviewing national consensus statements and guidelines (Texas, Ohio, Tennessee) the following situations are suggested for further review of the patient's case: 1. Absence of a thorough assessment of DSM-IV (or current) diagnosis in the child's medical record. 2. A diagnosis other than ADHD, uncomplicated depression, uncomplicated anxiety disorder and not evaluated or consulted by a psychiatrist. 3. A child under 6 year of age has been prescribed a psychotropic medication. 4. More than 3 psychotropic medications are administered to a child <18 years. 5. Prescribing of the following but not including a "tapering off or down" time period: A. Two or more concomitant antidepressants. B. Two or more concomitant antipsychotic medications C. Two or more concomitant stimulant medications. Exception: A long acting and short acting stimulant concomitantly is allowed. D. Two or more concomitant mood stabilizer medications. 6. The psychotropic medication dose exceeds usually recommended doses. 7. Psychotropic polypharmacy is prescribed BEFORE utilizing psychotropic monotherapy. 8. When a psychotropic medication is prescribed PRN (as needed). 9. When the child's monthly medication log reflects administration of a psychotropic medication prescribed PRN more than two times in any seven day period.

References: 1. Riddle MA, Kastelic EA, Frosch E. Pediatric Psychopharmacology. J. Child Psychol. Psychiat. 2001;vol 42(1): 73-90. 2. Vitiello, Benedetto. An international perspective on pediatric psychopharmacology. International Review of Psychiatry. Apr 2008; vol 20(2):121-126.. 3. McDonagh MS, Peterson KS, Dana T, Thakurta S. Drug Class Review on Pharmacologic Treatments for ADHD. Dec 2007. OHSU Evidence Practice Center, Drug Effectiveness Review Project (DERP) Report. 4. MTA Cooperative Group. A 14 month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Archives of General Psychiatry. 1999; 56:1073-1086. 5. Gillberg C, Melander H, von Knorring A, et al. Long-term stimulant treatment of children with ADHD symptoms. A randomized double-blind placebo controlled trial. Archives of General Psychiatry. 1997; 54:857-864. 6. Debarr LL, Lynch F, Powell J, Gale J. Use of psychotropic agents in preschool children: associated symptoms, diagnoses and health care services in a health maintenance organization. Arch Pediatr Adolesc Med 2003;157:150-157. 7. Azorin JM, Findling RL. Valproate Use in children and adolescents with bipolar disorder. CNS Drugs. 2007:21(12):1019-1033. 8. Biederman J, Mick E, et al. Open-Label, 8 week trial of olanzapine and risperidone for the treatment of bipolar disorder in preschool-age children. Biol Psychiatry. 2005;58:589-594. 9. Gleason MM, Egger HL, Emslie GJ, Greenhill LL, et al. Psychopharmacological Treatment for very young children: contexts and guidelines. J.Am. Acad. Child Adolescent Psychiatry. 2007; 46(12): 1532-1572. 10. Tumuluru RV, Weller EB, Fristad MA, Weller RA. Mania in six preschool children. Journal of Child & Adolescent Psychopharmacology. 2003, 13(4):489-494. 11. Correl. Clinical psychopharmacology of pediatric mood stabilizer and antipsychotic treatment, part 1: challenges and developments. J Clin Psychiatry. 2007; 68(8): 1301-1302. 12. Teitelbaum M. Oxcarbazepine in bipolar disorder. Am Acad of Child and Adolescent Psychiatry. 2001; 40(9):993-994. 13. Ipser J, Stein DJ. Systematic review of pharmacotherapy of disruptive behavior disorders in children and adolescents. Psychopharmacology. 2007; 191:127-140. 14. McDonagh MS, Peterson K, Carson S, Chan B, Thakurta S. Drug Class Review on Atypical Antipyschotic Drugs. OHSU Evidence Practice Center, Drug Effectiveness Review Project (DERP)Final Report. May 2008. 15. Hollander E, Phillips A, Chaplin W et al. A placebo controlled crossover trial of liquid fluoxetine on repetitive behaviors in childhood and adolescent autism. Neuropsychopharmacology 2005; 30:582-589. 16. Garlehner G, Hansen RA, Kahwati L. Second generation antidepressants: DERP Review. September 2006. 17. Tsapakis EM, Soldani F, Tono L, et al. Efficacy of antidepressants in juvenile depression: meta-analysis. The British Journal of Psychiatry. 2008; 193:10-17. 18. National Collaborating Centre for Mental Health. Depression in children and young people: identification and management in primary, community and secondary care. Leicester: British Psychological Society. 2005; 233. 19. Zito JM, Safer DJ, et al. Psychotropic medication patterns among youth in foster care. Pediatrics. Jan 2008; vol 121(1):157-163. 19a. Safer DJ, Zito JM, dosreis SM. Concomitant psychotropic medication for youths. American Journal of Psychiatry 2003;160:438-449. 19b. Safer DJ, Zito JM. Treatment emergent adverse events from selective serotonin reuptake inhibitors by age group: children versus adolescents. Journal of Child and Adolescent Psychopharmacology 2006; 24:429-436. 20. Kutcher S, Aman M, Brooks SJ, et al. International consensus statement on attention-deficit/hyperactivity disorder (ADHD) and disruptive behavior disorders (DBDs): Clinical implications and treatment practice suggestions. European Neuropsychopharmacology (2004); 14:11-28. 21. Advisory Committee on Psychotropic Medications. Psychotropic Medication Utilization Parameters for Foster Children. Texas Department of State Health Services.2004. 21a. Zito JM. Testimony to the House Committee on Ways and Means, Washington DC, May 2008. available at: https://waysandmeans.house.gov/hearings.asp?formmode=printfriendly&id=6907. 22. Birmaher B, Brent D, AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with depressive disorders. Washington DC: American Academy of Child and Adolescent Psychiatry; 2007: 36pages. Available at http://www.guideline.gov. Accessed 8/3/08. 23. Kafantaris V, coletti DJ, Dicker R, et al. Adjunctive antipsychotic treatment of adolescents with bipolar psychosis. J Am Acad Child Adolesc Psychiatry 2001;40(12):1448-56. 24. Dean AJ, McDermott BM, Marshall RT. Psychotropic Medication Utilization in a child and adolescent mental health service. Journal of Child and Adolescent Psychopharmacology Vol 16 (3) 2006. pp 273-285. 25. DelBello MP, Schwiers ML, Rosenberg HL, et al. A double-blind, randomized placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania. J Am Acad Child Adolesc Psychiatry 2002;41(10): 1216-23. 26. Pavuluri MN, Henry DB, Carbray JA, et al. Open-label prospective trial of risperidone in combination with lithium or divalproex sodium in pediatric mania. J Affect Disord 2004; 82 suppl. (1): S103-11. 27. Kowatch RA, Sethuraman G, Hume JH, et al. Combination pharmacotherapy in children and adolescents with bipolar disorder. Biol Psychiatry 2003; 53(11):978-984. 28. Dean AJ, McDermott BM, Marshall RT. PRN Sedation-patterns of prescribing and administration in a child and adolescent mental health inpatient service. Eur Child Adolesc Psychiatry 2006; 15:277-281. 29. American Heart Association news release May 16, 2008. Accessed at https://americanheart.mediaroom.com 30. Buitelaar JK, van der Gaag, RJ, Cohen-Kettenis P, Melman CT. A randomized controlled trial of risperidone in the treatment of aggression in hospitalized adolescents with subaverage cognitive abilities. J Clin Psychiatry 2001;62:239-248. 31 Aman MG, De Smedt G, Derivan A, Lyons B, Findling RL. Double blind, placebo-controlled study of risperidone for the treatment of disruptive behaviors in children and with subaverage intelligence. Am J Psychiatry 2002;159:1337-1346. 32.Snyder R, Turgay A, Aman M, Binder C, Fisman S, Carroll A. Risperidone Conduct Study Group. Effects of risperidone on conduct and disruptive behavior disorders in children with subaverage IQs. J Am Acad Child Adolsec Psychiatry. 2002; 41:1026-1036. 33. Reyes M, Buitelaar J, Tore P, Augustyns I, Eerdekens M. A randomized, double-blind, placebo-controlled study of risperidone maintenance treatment in children and adolescents with disruptive behavior disorders. Am J Psychiatry 163:402-410.