PSYCHOPHARMACOLOGY FOR CHILDREN AND ADULTS WITH AUTISM AND OTHER DEVELOPMENTAL DISORDERS: AN UPDATE

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1 PSYCHOPHARMACOLOGY FOR CHILDREN AND ADULTS WITH AUTISM AND OTHER DEVELOPMENTAL DISORDERS: AN UPDATE Drugs Approved and Commonly Used Off-Label for Treating Autism Spectrum Disorders (ASDs) James O Hanlon Ph.D. Staff Psychopharmacologist, Tri-Counties RC The Current Armamentarium Eleventh Annual Developmental Disabilities Conference, UCSF, March 2012 Risperidone for Irritability Pivotal DBPC-PG trials 1,2 101 & 79 children, 5-17y & 5-12y, respectively 8-wk treatment with drug or placebo flexible doses, M = 1.8 & 1.5 mg/d, respectively Results Irritability, Hyperactivity, Stereotypy (ABC) responders (drug vs placebo, CGI-I): 69% vs 12% & 54% vs 18%, respectively AEs more frequent after drug than placebo : appetite increase/weight gain, somnolence, fatigue, tremor Aripiprazole for Irritability Pivotal DBPC-PG trials: flexible 3 & fixed dose 4 98 & 218 children, 6-17y 8-wk treatment with drug or placebo flexible doses: 2 mg/d (5%), 5 mg/d (33%) 10 mg/d (41%) 15 mg/d (21%) fixed doses: 5, 10, 15 mg/d Results Irritability, Hyperactivity, Stereotypy (ABC) responders: flexible - 67% (drug) vs 16% (placebo); fixed - ~ 50% (drug, every dose) vs 35% (placebo) AEs: profile similar to risperidone s with less weight gain and somnolence but more tremor and other EPS 1

2 Lingering Questions About Antipsychotic Drugs and Autism Pharmacological Rationale? Long-term side effects? tardive dyskinesia, dystonia, akathisia hyperprolactinemia (risperidone) weight gain and metabolic syndrome Effects on learning? Same effects in adults as children? Safer, more tolerable alternatives? Tip: Metformin Attenuates Weight Gain Attributable to Antipsychotic Use Meta-analysis of 6 DBPC trials with children, adolescents and adults (n = 336) who had gained weight during treatment with antipsychotics 5 Metformin vs placebo (M difference after 3-4 mo) weight: kg, p =.0002 BMI: kg/m 2, p =.0001 waist circumference: cm, p =.005 insulin resistance (HOMA-IR): -1.71, p =.004 Psychostimulants for Hyperactivity Amphetamines 6 seldom beneficial, poorly tolerated in early studies not subsequently studied for the last 37 years Methylphenidate (MPH) 7 4-wk DBPC-CO trial; 72 children, ages 5-14y mean doses: 0.0,.125,.25,.50 mg/kg/dose, tid MPH superior to placebo; small-medium effect sizes, depending on dose and rater responders: 49% to MPH - any dose, 20% to placebo drop-outs from intolerable drug effects: 18% Nonstimulant Drugs for Hyperactivity Atomoxetine 8 small (n = 16, 5-15y) DBPC-CO, flexible dosing trial final mean dose after 6 wk = 44.2 mg/d, divided bid. drug superior to placebo, medium effect size serious AE: violence leading to hospitalization Guanfacine (immediate release) 9 prospective open trial involving 25 (5-14y) nonresponders to methylphenidate final doses after 8 wk = 1-3 mg/d, divided bid or tid 48% responders (CGI-I), large effect size drop-outs from intolerable drug effects: 12% 2

3 Tip: Cyproheptadine for Managing Hyperactivity in Very Young Children Cyproheptadine is approved for treating hypersensitivity reactions & migraine prophylaxis in children 2y. Drug has multiple mechanisms of action, most important being histamine H 1 & serotonin 5-HT 2A/2C receptor antagonism (or inverse agonism). Cyproheptadine, 0.2 mg/kg/d + haloperidol, 0.05 mg/kg/d was superior (p <.003) to placebo + haloperidol for reducing aberrant behavior (ABC) in an 8-wk DBPC-PG trial involving 40 children, aged 3-11y. 10 Valproate (divalproex) for Irritability 1 ST DBPC-PG trial: 30 non-epileptics (6-20y) treated with valproate or placebo for 8 wk 11 final mean serum concentration: 77.7 mcg/dl no significant difference between groups weight gain: valproate > placebo (1.98 vs 1.10 kg) 2 nd DBPC-PG trial: 27 non-epileptics (5-17y) treated with valproate or placebo for 12 wk 12 final mean serum concentration: 80.2 mcg/dl valproate superior to placebo, 62.5% vs 9.1% response rates (CGI-I), moderate effect size weight gain: valproate placebo (1.37 vs 1.34 kg) Lamotrigine 13 Other Mood Stabilizers DBPC-PG; n = 28, 3-11y; dose titrated (8-wk) to 5.0 mg/kg/d (4 wk); no significant clinical benefits. Levetiracetam 14 DBPC-PG; n = 20, 5-17y; dose titrated (4 wk) to mg/kg/d (6 wk); no significant clinical benefits. Topiramate (adjunctive to risperidone 2-3 mg/d) 15 DBPC-PG; n = 40, 4-12y; topiramate, titrated to 100 or 200 mg/d, significantly improved risperidone effects on irritability, hyperactivity and stereotypy (ABC) SSRIs for Repetitive Behavior: Adults Fluvoxamine 16 DBPC-PG; n = 30, 18-53y; ~ 3-wk dose titration to M = mg/d for additional 9 wk global responders: 53% drug vs 0 placebo (CGI-I) M repetitive behavior: 36% drug vs 0 placebo (Y- BOCS), large effect size Fluoxetine 17 DBPC-PG; n = 34, 18-60y; ~ 3 wk dose titration to M = 64.8 mg/d for additional 9 wk global responders: 35% drug vs 0 placebo (CGI-I) M repetitive behavior: 16% drug vs 6% placebo (Y- BOCS, actual data), medium effect size 3

4 SSRIs for Repetitive Behavior: Children Fluvoxamine 18 DBPC-PG; n = 34, 5-18y; started at 25 mg q2d, increased by 25 mg every 3-7d to mean mg/d 14/18 (78%) of drug group dropped out due to AEs Fluoxetine 19 DBPC-CO; n = 39, 5-16y; 8-wk treatments separated by 4-wk washout; slow (4-wk) dose titration to mean final dose 0.36 mg/kg/d (9.9 mg/d) Improvement in CY-BOCS significantly greater with fluoxetine than placebo; medium effect size No difference in AEs but 16% required dose reduction while on fluoxetine due to emerging agitation SSRIs for Repetitive Behavior: Children (cont.) Citalopram 20 DBPC-PG, 12 wk; n = 149, 5-17y dose/d: starting, 2.5 mg; < 40 kg, biweekly titration by +2.5 mg (6 wk), thereafter biweekly titration by +5mg; 40 mg, weekly titration by +2.5 mg (5 wk) thereafter biweekly titration by +5 mg maximum 20 mg/d No significant drug-placebo difference in response rates (CGI-I) or mean CY-BOCS ratings Significantly more AEs after drug: increased energy, decreased concentration, hyperactivity, stereotypy, diarrhea, insomnia, nightmares, prolonged seizure (1) Buspirone for Anxiety Few studies of pharmacotherapy for anxiety Prospective 6-8 wk open trial with buspirone 21 n = 22, 6-17y; starting dose = 15 mg/d; final dose = mg/d, divided bid or tid. much improved 41% and moderately improved 32% (CGI-I: anxiety) no serious side effects (none at all, 73%) improvement sustained in 2-12 mo follow-up one case of reversible dyskinesia after 10 mo Melatonin for Sleep Onset Insomnia Evidence for pineal hypofunction in children with autism that resolves with puberty. 22 Deficit in melatonin secretion correlates with symptom severity: r =.45 Three PCDB-CO studies including 79 children (2-18y) treated with melatonin 3-15 mg for up to 3 mo have shown drug significantly Shortens M latency to sleep onset by min Lengthens M total sleep duration by min But does not significantly affect awakenings; i.e., does not manage sleep maintenance insomnia. 4

5 Naltrexone for SIB? Reviews of drug s effects on SIB in mental retardation in general 26 and autism in particular 27 Positive results from many case studies and open trials, probably reflecting publication bias Conflicting results from controlled trials, probably reflecting methodological differences & deficiencies Conclusion: drug probably effective in a minority Best evidence: 5-y retrospective survey of all institutionalized adult DD patients in Texas cases, 19 (34%) with autism; M dose = 97 mg/d responders: 57% (clinical staff) & 25% (blind review) course of improvement: continuous for 30 mo Oxidative Stress and Neuroinflammation in Autism Spectrum Disorders Emerging Concepts and Pharmacotherapy Oxidative Stress Causes toxicant exposure? mitochondrial defect? deficient defense? Effects reactive O 2 species lipid peroxidation Purkinje cell apoptosis? axonal degeneration? Pathophysiology 29?? Neuroinflammation Cause dysregulated innate immune response? Effects glial activation & proliferation (gliosis) Inflammatory cytokines & matrix metaloproteinases edema/hypoprofusion? L-Carnosine 30 Antioxidants design: 8-week, DBPC-PG; n = 31, 3-12y dose: 400 mg bid results: global behavior, receptive language on carnosine but not placebo. No serious AEs. N-Acetylcysteine (NAC) 31 design: 12-week, DBPC-PG; n = 28, 3-12y dose: 900 q.d bid tid, each for 4 weeks results: NAC vs placebo - irritability (ABC), repetitive behavior, sociability. No serious AEs. 5

6 Anti-inflammatory Microglia Stabilizers Pioglitazone (PPARγ inhibitor - antidiabetic) 32 design: 4-mo prospective open trial; n = 25, 3-17y dose: 30 mg/d (3-5y) or 60 mg/d (6-17y) results: irritability, lethargy, stereotypy, hyperactivity (ABC), inversely age-related (r = ) Pentoxifylline (PDE inhibitor - hemorrheologic) 33 design: 10-wk, DBPC-PG, adjunctive to risperidone (2-3 mg/d); n = 40, 4-12y doses: & mg/d ( 40 & > 40kg) results: add-on effect - irritability, lethargy, stereotypy, hyperactivity, inappropriate speech (ABC) Also Minocycline see Appendix C Conclusions Presently approved antipsychotics: effective for controlling irritability but can cause serious side effects. Psychostimulants: limited efficacy, can exacerbate hyperactivity, (guanfacine better?). Mood stabilizers: not consistently beneficial. SSRIs: high probability of AEs before puberty, effective after puberty for controlling repetitive behavior. Buspirone: less than ideal but may reduce anxiety in some patients with ASDs. Melatonin: safe hypnotic with limited efficacy. Antioxidants & anti-inflammatory drugs: await further developments but do not be surprised by a breakthrough Appendices A. Abbreviations B. Down Syndrome New Developments C. Fragile X Syndrome New Developments D. References Appendix A: Abbreviations Not Defined in Text or Commonly Used Aβ: amyloid beta (peptide) ABC: Aberrant Behavior Checklist AE: adverse event BMI: Body Mass Index CGI-I: Clinical Global Impression - Improvement CY-BOCS: Children s Yale-Brown Obsession- Compulsion Scale DBPC-CO: double-blind, placebo-controlled-crossover DBPC-PG: double-blind, placebo-controlled-parallel group DD: developmentally disabled 6

7 Appendix A (cont.) EPS: extrapyramidal (motor) symptoms fmr1 KO: fragile x mental retardation-1 gene - Knockout HOMA-IR: Homeostatic-insulin resistance (model) M: mean mglur: metabotropic glutamate receptor PDE: phosphodiesterase PPARγ: paroxisome proliferator activated receptor gamma SIB: self-injurious behavior Y-BOCS: (adult) Yale-Brown Obsession-Compulsion Scale Appendix B: Down Syndrome (DS) DS: Cholinergic Hypothesis 34 triplication of gene for amyloid precursor protein excessive production of Aβ 1-42 peptide from birth binding of soluble peptide at α 7 nicotinic acetylcholine receptor during childhood & adolescence eventual formation of insoluble Aβ plaques with neurofibrillary tangles between neurons in 4 th decade early onset of Alzheimer's Disease in 5 th -6 th decade initial interference with cholinergic transmission may be countered with acetylcholinesterase inhibitors; e.g. donepezil Appendix B (cont.) Several open trials showed a positive effect of donepezil on cognitive functions in children, adolescents and young adults with DS Sharply contrasting results from more recent, methodologically divergent DBPC-PG trials children, n = 129, 10-17y, 10 wk with mg/d or placebo: no drug effect young adults: n = 123, 18-35y, 12 wk with 5-10 mg/d or placebo: equivocally positive drug effect severely impaired older adults: n = 21, 32-58y, 24 wk with 3mg/d or placebo: strongly positive drug effect Appendix C: Fragile X Syndrome (FXS) mglur Theory of pathophysiology in FXS 38 Mouse model (fmr1-ko) of FXS confirms theory Drug screening based on theory and model Minocycline identified as one agent (among others) that reverses FXS pathophysiology 39 drug: tetracycline antimicrobial that strongly inhibits microglial activation by an unknown mechanism. immediate effect: reduction in microglial release of inflammatory cytokines and expression of matrix metaloproteinase-9 ultimate effect: normalization of abnormal synapses 7

8 Appendix C (cont.) Retrospective parent reports of beneficial minocycline effects in 50 children with FXS 40 Prospective 8-wk open study of 20 adolescents & adults with FXS (13-32y), randomly assigned doses of 100 & 200 mg/d, divided b.i.d. 41 responders: 18/19 (CGI-I) Improvement (ABC): irritability,stereotypy, hyperactivity, inappropriate speech (all, p <.002) DBPC-CO trial ( 3 mo/condition) involving 50 children with FXS, 3 ½ -16y, nearing completion at MIND Institute (UC Davis) 42 Appendix D: References 1. McCracken JT, McGough J, Shah B, et al. N Engl J Med 2002; 347: Shea S, Turgay A, Carroll A, et al. Pediatrics 2004; 114: e634-e Owen R, Sikich L, Marcus RN, et al. Pediatrics 2009; 124: Marcus RN, Owen R, Kamen L, et al. J Am Acad Child Adolesc Psychiatry 2009; 48: Ehret M, Goethe J, Lanosa M, et al. J Clin Psychiatry 2010; 71: Campbell M, Fish B, David R, et al. J Autism Childhood Schizophrenia 1972; 2: Aman MG, Arnold LE, Ramadan Y, et al. Arch Gen Psychiatry 2005; 62: Arnold LE, Aman MG, Cook AM, et al. J Am Acad Child Adolesc Psychiatry 2006; 45: Scahill L, Aman MG, McDougle CJ, et al. J Child Adolesc Psychopharmacol 2006; 16: Akhondzadeh S, Erfani S, Mohammadi MR, et al. J Clin Pharm Thera 2004; 29: Hellings JA, Weckbaugh M, Nickel EJ, et al. J Child Adolesc Psychopharmacol 2005; 15: Hollander E, Chaplin W, Soorya L, et al. Neuropsychopharmacol 2010; 35: Belsito KM, Law PA, Kirk KS, et al. J Autism Dev Disord 2001; 31: Wasserman S, Iyengar R, Chaplin WF, et al. Int. Clin Psychopharmacol 2006; Rezaei V, Mohammadi MR, Ghanizadeh A, et al. Prog Neuropsychopharmacol 2010; 34:

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