Pharmacology Overview for ASD & ADHD Robert L. Hendren, D.O. Professor and Vice Chair of Psychiatry, Director, Child and Adolescent Psychiatry UC San Francisco Disclosures Clinical Trials (past year) Forest Laboratories, Inc. Otsuka & Bristol Meyer Squibb Janssen NIMH Autism Speaks Disclosure All medication suggestions for the treatment of ASD in this presentation are off-label uses except for risperidone (Risperdal) and aripiprazole (Abilify). All of the medications discussed for the treatment of ADHD in children are FDA approved Neuromodulators Dopamine - regulation of attention, movement, reward dependence with extensive innervation in frontal lobe and basal ganglia Serotonin - sleep, appetite, impulsivity, mood with extensive innervations in the basal ganglia Norepinepherine - fear and anxiety, vigilance, selective attention, arousal, memory Glutamate - excitatory amino acid GABA- inhibitory amino acid 1
ASD Associated Target Symptoms Inattention Impulsivity/Compulsivity Affective Instability Cognitive Disorganization Anxiety/ Hyperarousal Symptoms and Psychotropic Medications Distractible inattention improves with stimulants (dopamine, norepinepherine) Impulsivity improves with SSRIs (serotonin) Affective instability improves with mood stabilizers (glutamate, GABA) Cognitive disorganization improves with atypical neuroleptics (dopamine, serotonin) Hyperarousal improves with alpha adrenergic agonists (norepinepherine) (Sudgen et al., J Neuropsychiatry Clin Neurosci, 2006) Stimulant and Non-stimulants Symptoms - distractible inattention, conduct problems - Methylphenidate (Ritalin, Concerta Methylin, Metadate) - Dextroamphetamine (Dexedrine, Adderall) - Atomoxetine (Strattera) - Bupropion (Wellbutrin) Antidepressants Symptoms - anxiety, depression, impulsivity, obsessions, compulsions, irritability, easily frustrated & angry, separation anxiety, behavior problems. Fluoxetine (Prozac) Paroxetine (Paxil) Sertraline (Zoloft) Fluvoxamine (Luvox) Citalopram (Celexa) Escitalopram (Lexapro) Venlafaxine (Effexor) Duloxetine(Cymbalta) Bupropion (Wellbutrin) 2
Atypical Neuroleptics Symptoms - social awkwardness, inappropriateness, withdrawal, tics, obsessions, compulsions, disorganization, hallucinations, delusions, conduct problems. risperidone (Risperdal) aripiprazole (Abilify) quetiapine (Seroquel) ziprasidone (Geodon) olanzapine (Zyprexa) clozapine (Clozaril) Mood Stabilizers Symptoms - mood instability, temper tantrums, anger, depression, impulsivity. Valproic acid (Depakote, Depakane) Carbamazepine (Tegretol, Carbitrol, Trileptal) Lamotrigine (Lamictal) Lithium carbonate (Lithobid Lithobid, Lithostat) Gabapentin (Neurontin) Topiramate (Topamax) Tiagabine (Gabitril) Adrenergic Stimulating Agents Others Symptoms - anxiety, sleep disturbance, PTSD, hyperactivity, impulsivity Clonidine (Catapres) Guanfacine (Tenex) Buspirone (BuSpar) Anxiolytics (Alprazolam, Clonazepam, Lorazepam) Propranolol (Inderal) 3
Inattention Pharmacologic Approach to Target Symptom Impulsivity/ Compulsivity Anxious/ Hyperarousal Affective Instability Cognitive Disorganization Which Inattention? Distractible inattention (fronto-straital, dopamine) - stimulants Difficulty changing sets (cerebellum, basal ganglia, serotonin) SSRI, atypicals Low arousal (dopamine, serotonin) - Atypicals Hyper-Arousal vigilance (norepinepherine) anti-anxiety anxiety agents ADHD Pharmacological Response Stimulant Untoward Effects Methylphenidate Amphetamine TCAs Bupropion MAOIs Clonidine/ Psychosis Lower seizure threshold? Tachycardia, palpitations, hypertension (Gould, 2009) guanfacine 0 20 40 60 80 100. Response Rate (%) Wilens TE (2001), CNS News, Spencer TJ (2004), J Clin Psychiatry 65(suppl 3):22-26; Spencer TJ (2004),J Clin Psychiatry 65(suppl 3):22-26 4
Managing Adverse Effects From ADHD Treatment Decreased appetite Affects about 6-7% of children Monitor weight Administer with or after meals Give high-calorie snacks Consider drug holidays or cyproheptadine Growth suppresion Monitor weight Use lowest effective dose Drug holidays? Managing Adverse Effects From ADHD Treatment (Cont.) Insomnia (may be a manifestation of ADHD itself) If patient can nap on meds, add another dose Administer dose earlier in day or a small dose at bedtime Try longer-acting preparation Melatonin or Clonidine at bedtime Mirtazapine (Remeron) 7.5 mg or Trazedone (25 to 50 mg) at bedtime Avoid sedative/hypnotic medications Dulcan M (1997), J Am Acad Child Adolesc Psychiatry 36(10 suppl):85s-121s; Findling RL et al. (1998), J Clin Psychiatry 59(suppl 7):42-49 Dulcan M (1997), J Am Acad Child Adolesc Psychiatry 36(10 suppl):85s-121s; Findling RL et al. (1998), J Clin Psychiatry 59(suppl 7):42-49 Managing Adverse Effects From ADHD Treatment (Cont.) Tics (usually transient, only rarely do patients develop a chronic tic disorder) Medicolegal concern Many children with tics and ADHD can tolerate stimulants without an increase in tics Switch stimulants Try nonstimulant medication Rebound effects Smaller step-down afternoon dose Try longer-acting preparation Emerging Treatment Options Delivery Systems Daytrana - Methylphenidate transdermal system (MTS) (Findling et al., 2009) 10, 15, 20, 30 mg/ 9 hour patch Vyvanse - Lisdexamfetamine (L-lysine lysine-d-amphetamine) (prodrug of D-amphetamine) (Najib Najib, 2009 20 70 mg dissolves in liquid Dulcan M (1997), J Am Acad Child Adolesc Psychiatry 36(10 suppl):85s-121s; Findling RL et al. (1998), J Clin Psychiatry 59(suppl 7):42-49 5
Nonstimulants: Atomoxetine (Strattera) Blocks presynaptic norepinepherine transporter with no significant dopamine effect Similar improvement in ADHD symptoms to methylphenidate, but perhaps less improvement in inattention Modest improvement in depression and anxiety if present Dosage: 18-100100 mg once/day Maybe of benefit to stimulant partial responders (Hammerness P, 2009, JCAP) Kratochvil CJ et al. (2002), J AACAP; Donnelly, C (2009) JAACAP Nonstimulants: Atomoxetine (Cont.) Adverse effects in children: decreased appetite, nausea, abdominal pain, dizziness, somnolence Adverse effects in adults: constipation, dry mouth, urinary retention and sexual dysfunction Possible decreased height and weight with longer term treatment Caution with poor CYP2D6 metabolizers FDA warnings: liver toxicity, suicidal thoughts in children Well tolerated in youth with ADHD and Bipolar (Chang K, 2009, JCAP) Brown University Child and Adolescent Psychopharmacology Update (2003), 5:1-8; Prescribing information. Available at: www.accessdata.fda.gov Unproven (but maybe effective) (but maybe effective)treatments EEG biofeedback training Dietary manipulation: oligoantigenic diet Megavitamin therapy Herbal treatments Manipulation: body and craniosacral Sensory integration training Antiyeast medications Supplements (acetyl carnitine, essential fatty acids, Ginko biloba) Stimulants and ASD Evidence for effectiveness mixed with less information for amphetamines Early studies suggest ineffectiveness and poor tolerability (Campbell, 1972, 1976) RUPP DBPC study (2005) of 72 youth using methylphenidate suggest improvement in some but with lower rates of improvement and more adverse events than in children with ADHD without ASD. Decrease in appetite; sudden cardiac death Atomoxetine-small studies suggest improvement but less than children with ADHD without ASD Arnold LE (2001), Ann N Y Acad Sci 931:310-341; Kidd PM (2000), Altern Med Rev 5(5):402-428 6
Inattention Pharmacologic Approach to Symptom Domains Impulsivity/ Compulsivity Anxious/ Hyperarousal Affective Instability Cognitive Disorganization Impulsivity - Treatment Prolong thinking before action Educational and behavioral focus practicing delay, response inhibition, and reflection. CBT Removal from high-risk situations & strengthen cultural container Pharmacologic Interventions Stimulants SSRIs Mood stabilizers SSRI s and Autism Serotonin consistently shown to be disregulated in ASD (Cook, 1997). (Posey 2006; Henry 2006) Fluvoxamine and sertraline demonstrate improvement in aggression, and social relations (McDougle, 1996, 1998). Retrospective review of 15 children treated with citalopram reported improvement in anxiety and mood in 11 with mild side effects in 5 (Namerow, 2003) Perhaps improved language and correlation with family hx affective disorder (Delong, 2002) DBPC trial of fluoxetine in children found significant improvement in repetitive behaviors (Hollander, 2005) Lack of Efficacy of Citalopram for Repetitive Behaviors in ASD DBPC trial with 149 children (5 to 17 years) with ASD, mean dose 16.5 mg/da) No significant difference on CGI-I I or CY- BOCS Citalopram more likely to cause increased energy, impulsiveness, hyperactivity, decreased concentration, stereotypy, diarrhea and insomnia. 30% placebo response rate (King et al, 2009) 7
Inattention Pharmacologic Approach to Symptom Domains Impulsivity/ Compulsivity Anxious/ Hyperarousal Affective Instability Cognitive Disorganization Anxious Hyperarousal - Treatment Stress management Stress reduction Stress anticipation Pharmacologic interventions SSRIs Alpha adrenergic blockers (e.g. clonidine) Anxiolytics Tricyclics Alpha-2 Adrenergic Agonists Clonidine 2 DBPC (Jaselskis et al, 1992; Fankhauser et al, 1992) modest benefit for overactivity, sensory responses, affectual reactions and decreased irritability, stereotypy, and oppositional behavior Sedation, fatigue, decreased activity Guanfacine retrospective 80 ss with ASD; prospective 23 ss (Posey et al, 2004, Handan et al., 2008) decreased hyperactivity Sedation, constipation, sleep disruption, irritability Inattention Pharmacologic Approach to Symptom Domains Impulsivity/ Compulsivity Anxious/ Hyperarousal Affective Instability Cognitive Disorganization 8
Affective Instability - Treatment Strengthen the cognitive path from the perception of emotion to action CBT & DBT Pharmacologic Treatments Atypical neuroleptics (e.g. risperidone) Mood stabilizers (e.g. divalproex) Inhibit through GABA; inhibit glutamate Divalproex and ASD (inhibit through GABA) Retrospective review of 14 patients 5 to 40 years of age. 10 (71%) reported sustained, positive response to treatment. Mean dose 768 mg.da (range 125-25002500 mg) Affective instability, impulsivity, and aggression most likely to respond. All with abnormal EEG responded. (Hollander, 2001) Repetitive behavior improved in DBPC study (Hollander, 2006) Topiramate and ASD (Inhibit glutamate) Retrospective review of 15 patients 8 to 18 years of age. 8 were judged to be responders with a score of 1 or 2 on the CGI-I Mean dose 235 mg.da (range 100-400 mg) Conduct, hyperactivity and inattention most likely to respond. Side effects leading to discontinuation include cognitive difficulties and skin rash (Hardan, 2004) Inattention Pharmacologic Approach to Symptom Domains Impulsivity/ Compulsivity Anxious/ Hyperarousal Affective Instability Cognitive Disorganization 9
Cognitive Disorganization- Treatment Improve executive function and memory Social skills, behavioral interventions and CBT D2 blocking helps with positive symptoms 5-HT2A enhancers improve negative symptoms Pharmacologic interventions Neuroloptics Anxiolytics A Double-Blind Placebo Controlled Trial of Risperidone in Autistic Disorder 101 children between 5 and 17 years with AD and mental age > 18 mo. No other psychotropics. 8 weeks of treatment associated with statistically significant decrease in self-injury, aggression, agitation, sterotypy and hyperactivity. (McCracken, 2002) A Double-Blind Placebo Controlled Trial of Risperidone in Autistic Disorder - (cont.) Average weight gain of 2.5 kg after 8 weeks compared with.2 kg in placebo group. Mean dose 1.8 mg Other AEs include increased appetite, sedation, tremor and hypersalivation. No EPS or TD reported in longer term follow-up (Aman, 2005). Second double blind study completed (Shea et al., 2004) Aripiprazole in the Treatment of Irritability in Youth with Autism 8 week DBPC fixed and flexible dose study of over 300 children & adolescents 6 to 17 yrs 85% completion; Average dose 8.1mg; 50 52% responders based on ABC-I and CGI=I of much or very much improve Somnolence, sedation and drooling most common side effects. EPS 12 to 14% which was dose dependent; Weight gain.9 vs..5 kg placebo; curve flattens at 6 to 9 months Marcus RN (2009) JAACAP; Owen R (2009) Pediatrics 10
Olanzapine, Quetiapine, Ziprazidone Decreased temper tantrums, impulsivity, social withdrawal and autism symptoms including social relations and language but not repetitive behaviors (Potenza, 1999; Kemner, 2002, Masi, 2009). Olanzapine vs. haloperidol in children demonstrated CGI response in both, but broader response with olanzapine (Malone, 2001). Reviews suggest quetiapine useful and well tolerated (Findling, 2002) Ziprazidone shows modest improvement with weight loss (McDougle, 2002; Cohen 2004) Concern about rapid metabolic changes in children (Nicol, 2009) Rationale Memantine (Namenda) - Excitatory neurotransmitter glutamate may play a role in neurodegeneration mediated by NMDA. - Memantine is a low to moderate affinity, uncompetitive NMDA receptor antagonist - Aberrant functioning of NMDA receptor and/or altered glutamate may play a role in autism Evidence - Case series demonstrating significant improvement in language and socialization in children with autism. (Chez, 2006) - Open label, retrospective study of 18 patients, 6 to 19 years, 11 improved in social withdrawal and inattention at doses between 2.5 and 20 mg/day (Erickson et al., Psycopharmacology, 2007) Procedure - Titrate in 5 mg increments to 10 to 20 mg in divided BID dose Safety - Well tolerated in children. Some experience fatigue, modest increase in LFTs Melatonin for Sleep DBPC trial of 5 mg CR melatonin in 51 children, 2 18 years, found significant improvement in 30 min and improvement in family stress (Wasdell, 2008) Open trial of 3 mg in 15 children 6 to 17 years found excellent sleep response in half and improvement in behavioral measures (Paavonen et al., 2003) Naltrexone and Autism Modest improvements in self injurious behavior Moderate improvement in hyperactivity and restlessness (Desjardins, 2009) No improvement in core symptoms (Symons, 2004) Suggestion that low dose (2.5 mg/ day) may affect immune system and improve core symptoms (McCandless, personal communication) 11
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