Medication management in children and youth with ASD

Transcription

1 Medication management in children and youth with ASD Evdokia Anagnostou, MD Clinician Scientist, Bloorview Research Institute Assistant Professor, Department of Pediatrics University of Toronto

2 Disclosures Consulting without fees: Neuropharm, Proximagen Consulting with fees: Seaside therapeutics, Novartis Grants: DoD, CIHR, NeuroDevNet, ALVA, Autism Speaks, PSI, HRSA, OBI

3 Currently: The goals of using currently available medications is facilitate psycho-educational treatments to improve learning

4 Current approaches in Psychopharm Medications to target symptom domains based on phenotypic overlap of such domains with other disorders, i.e. SSRI for repetitive behaviors (from OCD) Atypical antipsychotics for maladaptive behaviors (irritability and aggression across several other disorders) Stimulants, non-stimulants for inattention (overlap with ADHD)

5 ` Anticonvulsants (e.g. depakote) Atypicals (e.g.) Atypicals (e.g. Risperdal) Anticonvulsants (e.g. depakote) Atypicals (e.g. Risperdal) SSRIs (e.g. fluoxetine) Affective instability Aggression / anxiety Impulsivity Repetitive behaviors / restricted interests Social Deficits ASD Communication Deficits EEG abnormalities epilepsy?oxytocin? ADHD-like symptoms Anticonvulsants (e.g. depakote) Stimulants (e.g. Concerta) Nonstimulants (e.g.straterra)

6 What we know:

7 Summary of clinical trials in autism Aggression / Irritability Repetitive behaviors Attention / hyperactivity Atypical neuroleptics SSRIs, SNRIs Stimulants α and β blockers Mood stabilizers

8 SRIs in Autism Clomipramine (Anafranil) Fluoxetine (Prozac) Fluvoxamine (Luvox, Faverin) Sertraline (Zoloft) Paroxetine (Paxil, Seroxat) Citalopram (Celexa, Cipramil, Actavis) Venlafaxine (Effexor) Escitalopram (Lexapro, Cipralex)

9 Serotonin receptor

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11 Consolidated Standards for Reporting of Trials (CONSORT) chart King, B. H. et al. Arch Gen Psychiatry 2009;66: Copyright restrictions may apply.

12 Demographics and Baseline Characteristics by Treatment Group (ITT Population) Characteristic Citalopram Placebo (n=73) (n=76) Age (at consent, yrs) Mean (Std Deviation) 9.1 (3.2) 9.6 (3.1) Median Min-Max Non-verbal IQ > than 70*, n (%) 43 (61.4%) 43 (60.6%) CGI Severity, n (%) 4 (Moderately ill) 21 (28.8%) 22 (29.0%) 5 (Markedly ill) 37 (50.7%) 37 (48.7%) 6 (Severely ill) 14 (19.2%) 16 (21.1%) 7 (Among the most extreme) 1 (1.4%) 1 (1.3%) Male, n (%) 64 (87.7%) 64 (84.2%) Hispanic**, n (%) 9 (12.5%) 8 (10.5%) Race, n (%) American Indian/Alaskan Native 0 (0%) 2 (2.6%) Asian 6 (8.2%) 8 (10.5%) Black 7 (9.6%) 10 (13.2%) Native Hawaiian 1 (1.4%) 0 (0%) White 53 (72.6%) 55 (72.4%) Other 6 (8.2%) 4 (5.3%) Tanner Stage, n (%) 1 52 (73.2%) 48 (63.2%) 2 10 (14.1%) 12 (15.8%) >3 9 (12.7%) 16 (21.1%)

13 Much Improved or Very Much Improved % 9 0 % 8 0 % P l a c e b o C i t a l o p r a m 7 0 % 6 0 % 5 0 % 4 0 % p = % 2 0 % 1 0 % 0 % Week Percentage of Children with a Rating of Much Improved or Very Much Improved on the Clinical Global Impressions Improvement Scale (CGI-I) During the 12-Week Trial. All children assigned to citalopram (n = 73) and to placebo (n = 76) are included. Week 2 is the first opportunity to assess change from baseline.

14 Repetitive Behaviours (CYBOCS-PDD Score) P l a c e b o C i t a l o p r a m p= Week Mean CYBOCS-PDD Scores Over Time for Citalopram and Placebo. Scores reflect frequency and intensity of repetitive behaviours and are shown with standard error. All children assigned to citalopram (n = 73) and to placebo (n = 76) are included.

15 Compulsive and Repetitive Behaviors Over Time in the Trial by Treatment Group Copyright restrictions may apply.

16 Copyright restrictions may apply. Compulsive and Repetitive Behaviors Over Time in the Trial by Treatment Group

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18 Conclusions Citalopram was not superior to placebo in this sample of children with autism spectrum disorders. Neither the rate of positive global response to citalopram, nor dimensional scores of repetitive behaviors on the blinded clinician-rated CYBOCS-PDD nor the parent-rated RBS-R suggested any difference between groups.

19 Significant predictors at baseline

20 Distribution of ABC Irrit (High/Low) High N = 71 Low N = 71

21 % Responders at 12 weeks (High Baseline CSQ & ABC Irrit) 35% 30% 25% 20% 15% 10% 5% 0% N=20 N=25 PBO CITAL

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23 Factor 1: disruptive behaviors

24 Factor 2: autism severity / mood

25 Factor 3: Caregiver strain

26 Conclusions These findings suggest that it may be possible to reduce the likelihood of nonspecific responses to treatment in clinical trials by identifying and controlling for symptom burden and other factors at study entry. Is it possible to identify groups where Citalopram is actually effective?

27 Serotonin Reuptake inhibitors Medication Common Side Effects Evidence Citalopram, Escitalopram Decreased appetite, insomnia, agitation, hyperactivity, restlessness, disinhibition, dry mouth, headache, polyuria, sexual dysfunction irritability Child +++ Fluoxetine (SSRI) Decreased appetite, insomnia, agitation, hyperactivity, restlessness, disinhibition, dry mouth, headache, polyuria, sexual dysfunction irritability Child +++ Fluvoxamine (SSRI) Decreased appetite, insomnia, agitation, hyperactivity, restlessness, disinhibition, dry mouth, headache, polyuria, sexual dysfunction irritability Adult +++ Sertraline (SSRI) Decreased appetite, insomnia, agitation, hyperactivity, restlessness, disinhibition, dry mouth, headache, polyuria, sexual dysfunction irritability Adult ++ Child ++ Clomipramine (tricyclic antidepressant) Increased aggression, increased irritability, sedation, EKG changes, urinary retention. Adult +++ Child ++ Venlafaxine (SNRI) Hyperactivity, irritability, aggression, agitation. Adult + Child + Modified from Schapiro et al 2007

28 Measurement (from CBT studies) Chalfant et al 28 M age = 10.8 years Reaven et al. 7 male 3 female M age = 11 years Sofronoff et al. 44 males, 6 females M age = 10 years Wood et al. N=40, age 9 years ADIS, RCMAS, SCAS, CATS, and SDQ SCARED James and the Math Test, SCAS and SWQ ADIS, CGI and MASC 71.4% of the children in CBT group no longer meet definition for diagnosis of an Anxiety disorder as compared to 0% of the control group (p<0.05). Statistically significant improvements were found all dependent variables significant decrease in the severity of anxiety symptoms over time in treatment group and no significant decreases in the control group. Child report on the SCARED found no significant differences in either group Significant reduction in parent-rated symptoms on SCAS-P and SWQ. James and the Math Test showed a significant increase in the number of strategies to deal with anxiety-producing situations 92.9% (13 out of 14) met CGI criteria for positive treatment response compared to 9.1% (2 out of 22) on waitlist; 9 of 14 no longer met criteria for any anxiety disorder vs. 2 of 22 on placebo. Parent MASC scores were significantly lower in the post treatment group, but not for the child-reported MASC scores White et al: 2009: Multimodal Anxiety and Social Skills Intervention: MASSI, CASI

29 Atypical Antipsychotics No convincing evidence for primary involvement of the dopamine system in autism. However Typical antipsychotics have been shown to be effective in this population

30 Atypical neuroleptics Effect wider range of neurotransmitter systems (dopamine, serotonin, etc.) Improve overall functioning in other neuropsychiatric disorders Lower incidence of side effects Decreased severity of side effects

31 Atypical Antipsychotics Clozapine (Clozaril) Olanzapine (Zyprexa) Risperidone (Risperdal) Quetiapine (Seroquel) Ziprasidone (Geodon) Aripiprazole (Abilify)

32 Atypical Antipsychotics McPheeters ML, Warren Z, Sathe N, Bruzek JL, Krishnaswami S, Jerome RN, Veenstra-Vanderweele J. A systematic review of medical treatments for children with autism spectrum disorders. Pediatrics May;127(5):e Evidence for effectiveness only in the case of risperidone and aripiprazole

33 RUPP risperidone study

34 RUPP risperidone study

35 RUPP risperidone study

36 Pharmacogenetics of risperidone (Hoekstra et al 2010) In a 8 week open label study Carriers of the HTR2C promoter T allele gained an average of ± body mass index-standardized z scores (1.84 ± 1.51 kg) versus 0.64 ± 0.35 z (3.23 ± 1.47 kg) for non-t-allele carriers (p < 0.001). Weight gain appeared to be associated with younger age and higher doses of risperidone.

37 Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Owen R, Sikich L, Marcus RN, Corey-Lisle P, Manos G, McQuade RD, Carson WH, Findling RL. Pediatrics Dec;124(6):

38 Aripiprazole randomized controlled trial in ASD

39 Aripiprazole randomized controlled trial in ASD

40 Aripiprazole randomized controlled trial in ASD

41 Line-item analysis of the Aberrant Behavior Checklist: results from two studies of aripiprazole in the treatment of irritability associated with autistic disorder. (Aman et al 2010) Statistically significantly greater improvement was seen with aripiprazole versus placebo (p < 0.05) for all arms in both trials on the ABC-Irritability total subscale score and on the following individual ABC-Irritability items: Mood changes quickly, cries/screams inappropriately, stamps feet/bangs objects. Several additional items measuring tantrum-like behaviors improved in the flexibly dosed trial and at least one arm of the fixed-dose trial (p < 0.05). Measures of self-injurious behavior, demonstrated numerical, but not statistically significant, improvement in both trials.

42 1 year open label (continuation and novo) (Marcus et al 2011) Table 1. Subject Disposition n (%) De novo (n = 86) Prior placebo (n = 70) Prior aripiprazole (n = 174) Completed 55 (64.0) 37 (52.9) 107 (61.5) Discontinued 31 (36.0) 33 (47.1) 67 (38.5) Lack of 8 (9.3) 5 (7.1) 7 (4.0) efficacy Adverse event 9 (10.5) 11 (15.7) 15 (8.6) Withdrew 7 (8.1) 5 (7.1) 15 (8.6) consent Lost to followup 2 (2.3) 8 (11.4) 21 (12.1) 2 (2.3) 1 (1.4) 2 (1.1) Poor/noncompli ance Administrative 1 (1.2) 1 (1.4) 2 (1.1) reason by sponsor Other 2 (2.0) 2 (2.9) 5 (2.9)

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45 Mood Stabilizers & Anticonvulsants Lithium Valproic acid (Depakote, Confulex, Epival, Depakene)) Carbamazepine (Tegretol, Garbagel) Lamotrigine (Lamictal) Gabapentin (Neurontin) Levetiracetam (Keppra)

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47 Anticonvulsants Medication Side effects Recommended blood monitoring Evidence Valproate irritability, restlessness, rush, headaches, Weight gain, ataxia, alopecia, GI disturbance, hyperammonemic encephalopathy, sedation, thrombocytopenia, PCOS, pancreatitis, liver failure, teratogenic effects CBC / platelets, LFT, VPA levels If there is a change in mental status, then ammonia testing is Indicated, Therapeutic blood levels: cg/ml +++ Lamotrigine Levetiracetam dizziness, ataxia, somnolence, headache, diplopia, blurred vision, nausea, vomiting, rash Drowsiness, dizziness, weakness, headache, loss of coordination e.g., difficulty walking, muscle control, agitation, disinhibition none +++ (negative) none +++ (negative) Carbamazepine Drowsiness, diplopia, headache, ataxia, nausea, vomiting, dizziness, abdominal pain, diarrhea constipation, loss of appetite, serious rash, Low Na, agranulocytosis, liver dysfunction CBC with platelets, LFTS, carbamazepine levels, Therapeutic blood levels: 5-12 mcg/ml + Topiramate paresthesia, weight decrease, somnolence, anorexia, nausea, weakness, tiredness, drowsiness, dizziness, tingling sensations, dry mouth, constipation, and memory difficulties None +

48 ADHD like symptoms and autism Stimulants Dextro-amphetamine (Dexedrin), Methylphenidate (Ritalin, Concerta), amphetamine (Adderral) Atomoxetine

49 Randomized, Controlled, Crossover Trial of Methylphenidate in Pervasive Developmental Disorders With Hyperactivity Research Units on Pediatric Psychopharmacology (RUPP) Autism Network, Arch Gen Psychiatry 2005;62: Copyright restrictions may apply.

50 Weight-Dependent Methylphenidate Dosing at Each Dosage Level Research Units on Pediatric Psychopharmacology (RUPP) Autism Network, Arch Gen Psychiatry 2005;62: Copyright restrictions may apply.

51 Parent-Rated and Teacher-Rated Aberrant Behavior Checklist Hyperactivity Subscale Scores During Crossover Phase Research Units on Pediatric Psychopharmacology (RUPP) Autism Network, Arch Gen Psychiatry 2005;62: Copyright restrictions may apply.

52 Mean Aberrant Behavior Checklist (ABC) hyperactivity subscale scores as rated by teachers and parents at baseline, at the best dose of methylphenidate during the crossover phase, and during the methylphenidate hydrochloride open-label continuation phase Research Units on Pediatric Psychopharmacology (RUPP) Autism Network, Arch Gen Psychiatry 2005;62: Copyright restrictions may apply.

53 Adverse Effects During Each Dose of Methylphenidate* Compared With Placebo Research Units on Pediatric Psychopharmacology (RUPP) Autism Network, Arch Gen Psychiatry 2005;62: Copyright restrictions may apply.

54 Atomoxetine cross over study Atomoxetine for Hyperactivity in Autism Spectrum Disorders: Placebo- Controlled Crossover Pilot Trial. ARNOLD, L; AMAN, MICHAEL; COOK, AMELIA; WITWER, ANDREA; HALL, KRISTY; THOMPSON, SUSAN; RAMADAN, YASER Journal of the American Academy of Child & Adolescent Psychiatry. 45(10): , October DOI: /01.chi a Copyright 2006 American Academy of Child and Adolescent Psychiatry. Published by Lippincott Williams & Wilkins, Inc. 3

55 ADHD like symptoms and autism and agonists/blockers 2 NE Receptor agonists: anti-hypertensive agents (Jaselskis et al., 1992) Clonidine: Open label and one placebo controlled studies blockers Improvement in hyperactivity, irritability, stereotypies, global severity SE: hypotension, bradycardia, sedation Propranolol: two open label studies improvements in aggression and irritability

56 Evidence for medications targeting hyperactivity ABC hyperactivity subscale N % change from baseline Evidence Ritalin 66 34% +++ Guanfacine 25 25% + Risperdal % +++ Haldol % +++ Clomiparmine % +++ Amantadine % +++ Atomoxetine % +++ Scahill et al 2007

57 Melatonin Produced in the pineal gland. Regulates sleep-wake cycle sets circadian clock induces sleep In ASD: suggestion of decreased melatonin synthesis (Melke et al 2008) Open label studies (3) Improvements in up to 85% of children Placebo controlled trial (Wassdell et al 2007): Improvements in sleep latency and CGI

58 Treatment Non-Pharmacological, biological treatments Data is still missing for both supplements, and manual treatments Still, these are biologically active compounds and treatments and have the potential for both desirable effects and side effects

59 NMDA inhibitors: memantine Arbaclofen Compounds by NOVARTIS ROCHE Seaside Therapeutics rapamycin IGF1

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61 STX209 for fragile X syndrome: Analysis in low sociability subgroup n=27 ABC-Social Withdrawal 8 at screening and baseline STX209 (mean ± SD) Placebo (mean ± SD) p-value ABC-Social Withdrawal -4.3 ± ± 7.1 < 0.05 Vineland Socialization (raw) 14.2 ± ± 10.8 < 0.05 CGI-I 2.7 ± ± 1.2 < 0.01 CGI-S -1.0 ± ± 0.9 = 0.01 Treatment preference (clinician) 63% 19% < 0.01 Treatment preference (parent) 67% 19% = Responders (CGI-I =1 or 2, and ABC-SW improvement 25%) 42% 7% <

62 Future approaches Based on new info on neurobiology of disorder Developmental studies Immunomodulation Steroids, IV IG, poor NNT for SE profile Other immunomodulators,?omega 3?, pioglitazone Glutamate/GABA modulation epilepsy Memantine, Riluzole, Valproate, metabotropic glutamate receptor modulation Neuropeptide modulation?oxytocin Target executive function abnormalities NE modulation vs. cognitive remediation programs Studies targeting specific mutations:?design issues, RCTs? Etc Widen the plasticity window

63 Future approaches COMPLEMENTARY AND ALTERNATIVE TREATMENTS Of interest: Omega 3 fatty acids, methylation/demethylation agents, GABA enhancing compounds

64 From disability to possibility Thank you