Attention Deficit Hyperactivity Disorder - ADHD

Attention Deficit Hyperactivity Disorder- ADHD Laneurodevelopmentaldisorder PHAR 835 –Fall 2024 Nadia Khartabil , PharmD, BCGP, Aph, MAS Learning Objectives Collect: • Describe the clinical features of attention-deficit hyperactivity disorder (ADHD); differentiate different types of ADHD per the DSM-5 criteria. • List risk factors for ADHD Assess: • Indications for pharmacotherapy (stimulant and non-stimulant) and nonpharmacologic strategies • Drug therapy problems for patient on stimulant • Compare and contrast the efficacy and limitations associated with non-pharmacologic and alternative treatment options for ADHD. • Compare and contrast the mechanisms of action, major pharmacokinetic properties, dosing, adverse effects, black box warnings, and drug interactions of stimulant and non-stimulant medications. Plan/Implement: • Design a treatment plan for a patient with ADHD [not responsible for doses] • Educate patients and caregivers about ADHD, monitoring parameters and medications used for ADHD. Follow-Up/Monitoring: • Identify monitoring parameters Patient Case • Chris is an 11-year-old boy who is often distracted during class and has difficulty finishing her work at school. She frequently makes careless mistakes and does not listen to instructions. She rarely remembers to bring her books from school or leaves them on the bus. At home, she has difficulty with organizing her homework and has difficulty starting or finishing her tasks. Her symptoms started about 3 years ago but her parents and teachers have noticed worsening of her symptoms. They are concerned that she will not be able to move onto 6th grade as planned. She has no personal or family history of cardiac disease but does have a tic disorder. • Does Chris meet DSM-5 criteria for ADHD? • What would you recommend as the initial treatment option? Pathophysiology • Functional MRIs show lower activation in memory areas of the brain • Brain Imaging reveal smaller volumes in the cerebellum, frontal cortex & striatum • Hypothesized neurochemical pathophysiology of ADHD • Increased postsynaptic receptors for dopamine (DA) and norepinephrine (NE) • Stimulants and SNRIs block presynaptic reuptake of DA and NE, leading to increased neurotransmitters in synaptic cleft • Dopamine in prefrontal cortex important for attention, focus, vigilance • Norepinephrine in prefrontal cortex important for decreasing distractibility, executive functioning, inhibits behaviors and cognitive functions that are undesirable Abb Etiology and risk factors • Etiology is multifactorial , genetics and environment work together to shape the disease. • Genetics: 5-9-fold increased risk if ADHD in 1st degree relatives. • Genes: DRD4, DAT, DRD5, SNAP-25, 5-HTT • Environmental: Toxins • Nutritional: Zinc, Mg Deficiencies • Psychosocial: Low income, family adversity • Perinatal: Injuries, stress, low birthweight, prematurity Diagnosis (DSM-5) • AAP guideline for diagnosis and evaluation for ADHD in adolescents and children recommends evaluation of any child 4-18 years of age with Inattention hyperactive impulsivity 6 symptoms of inattention or hyperactivity-impulsivity for 5 symptoms if age >17 years). Symptoms present for at least 6 months. symptoms • Screening for comorbid conditions ( anxiety, depression, conduct disorder, etc.…) , developmental conditions as autism, physical conditions as tics and sleep apnea. • Validated rating scales as Connors Rating scale (CRS-revised) or Vanderbilt ADHD diagnostic i symptom scale are recommended for objective ratings from parents and teachers. Symptoms present in 2 or more settings ( at home, work, school). was Symptoms interfere with functioning and not caused by another disorder. e Symptoms present before age 12. justrecognize them 8.35 Adopted from Dr. Michael Pondrom . May 2022 0 ta 55 ADHD Subtypes: to • Predominantly Inattentive Presentation: predominant symptoms of inattention, but not hyperactivity-impulsivity, were present for the past six months; and • Predominantly Hyperactive-Impulsive Presentation: predominant symptoms of hyperactivity-impulsivity but not inattention were present for the past six months. • Combined Presentation: symptoms of both criteria inattention and hyperactivity-impulsivity were present for the past 6 months; Treatment desired outcomes • Stimulants are considered first line therapy in most cases of ADHD. B conditions • Treatment plan depends on age, comorbid , family preference. • ADHD-specific educational, cognitive, and behavioral interventions are recognized as necessary components of an overall treatment plan. • Desired outcomes : In general : • Reduce frequency of symptoms • Reduce pervasiveness of the disease • Reduce degree of impairment • Minimize concomitant symptoms or comorbidities • Improve social interactions • Reduce disability short & long-term • Improve quality of life was • Specific goals must be identified • Examples for children: • Able to sit in chair for 20 minutes • Completes homework assignments • No longer blurts out comments in class without being called upon • Examples for adults: • Read entire newspaper before starting another project • Improved safety while driving • Successful completion of tasks on time at work s Treatment Guideline by age: AvoidAmphetamine American Academy of Pediatrics (AAP) - 2019 Children 4-5 Children 6-11 • 1st: Parent- and/or teacher-administered behavioral therapy • 2nd line: consider MPH only if behavioral interventions do not lead to improvement and if there is moderatesevere functional disturbance • FDA-approved medications • Best evidence for stimulants • Sufficient but less strong evidence for atomoxetine, guanfacine ER, clonidine ER • Parent- or teacher-based behavioral therapy only3drugscanbegiven or Amphetamines MPH: Methylphenidate methylphenidate Adolescents 12-18 • FDA approved medications • Behavioral therapy T NE as SardiovaguerPBI entity AAP – Medication recommendation Stimulants are 1st line therapy • MPH or AMPH group • LA and short-acting MPH appear equally efficacious • May not be associated with increased risk of serious CV events, but screening ECG suggested Non-stimulants are 2nd-line SSRI • Selective serotonin reuptake inhibitors : 1-Atomoxetine (STRATTERA) 2-Viloxazine (Qelbree) • Alpha-2 adrenergic agonists – as monotherapy or adjunct to stimulants 1-Guanfacine ER (INTUNIV) 2-Clonidine ER (KAPVAY) • Antidepressants and anxiolytics – unclear benefit Pharmacotherapy: Stimulants • Mode of Action: • Block pre-synaptic dopamine (DA) and norepinephrine (NE) reuptake • Two main classes : 1. Methylphenidate ( include dexmethylphenidate) 2. Amphetamines ( include dextroamphetamine, mixed amphetamine salts) • Most effective treatments for children, adolescents and adults • Quick onset of action and effect • Side effects are generally similar across stimulants with subtle differences • All classified as CII – may present challenges for adults Pharmacotherapy : Stimulants Categories • Categories of stimulants can be described by • Chemical compound • Duration of action • Formulation • What are the advantages and disadvantages of short or long-acting products? wedge • Duration of action: • Methylphenidate Products • Short-Acting • Elimination half-life ranges 2-4 hours • Long-Acting • Elimination half-life ranges 3-7 hours • Amphetamine Products • Short-Acting • Elimination half-life ranges 7-15 hours • Long-Acting • Elimination half-life ranges 10-13 hours • IR stimulants require BID-TID dosing. • IR stimulants : lower cost, less insomnia, potential fewer growth effects. • LA stimulants may require once daily dosing. • LA stimulants : provide 8-12 hours of symptom control, better adherence. • Does food have an impact ? • Food delays absorption, delay onset (0.5-1 h IR, 1-2h ER) • 10-30% reduction in bioavailability with food • Any dosing principles? • Dose is titrated based on individual needs and duration of action, no optimal dose that fits based on age, gender, etc.. thatdoesnothaveLAI IR ER or SA Anything p 0 Generic Name il Brand Name Duration Dexmethylphenidate HCl Focalin® 3 to 5 hours Methylin® Chewable Methylin® Solution Ritalin® 3 to 5 hours Methylphenidate HCl Methylphenidate Ritalin SR®, Metadate ER® Methylin ER® 3- 8 hours who Ritalin LA® (50%IR, 50% beads) children Long Acting Methylphenidate Interme Short-Acting diate (ImmediateActing Release) Class Type combi Metadate CD® (30% IR, 70% beads) 10-12 hours Concerta (OROS controlled release delivery) 10-12 hours stiff Dytrana® (Transderma) Methylphenidate Take atnight working 8-10 hours cry Focalin XR (50%IR, 50% beads) 12 hrs (worn for Needtoknow tuet sapota Quillivant® ER suspension (20%IR, 80% ER) Journay PM® (dosed in pm, dual layer morning microbeads) Serdexmethylphenidate (SDX) Azstarys® ( 70% SDX, 30% IR dMPH) 9 hours) 10-12 hours 10-12 hours 14-16 hrs after dosing 10-12 hours Short-Acting (Immediate Release) Interme -diate Acting Generic Name Brand Name Amphetamine (dextro:levo 3:1 ratio) Adderall® Amphetamine (dextro:levo 1:1 ratio) Dextroamphetamine Dextroamphetamine Amphetamine (dextro : levo 3:1 ratio) Long Acting Amphetamines Class Type Mixed Amphetamine salts ( triple beads) Dextroamphetamine Lisdexamfetamine ( prodrug to dextroamphetamine) Duration 4 to 6 hours Evekeo® Evekeo® ODT Dexedrine® Zenzedi® 4 to 6 hours 3-5 hours 5-8 hours Dexedrine® Spansule Adderall® XR 10-12 hours Adzenys XR ODT, ER suspension 10-12 hours Mydayis® 12-16 hours Xelstrym® Transdermal 12 hours (worn for 9 hours) Vyvanse® 10-12 hours Pharmacotherapy : Stimulants Categories • Formulation: • Methylphenidate Products • Capsules, liquid/suspension, tablets, chewable tablets, transdermal patch • Amphetamine Products • Capsules, liquid/suspension, tablets, orally disintegrating tablets, chewable tablets • Pharmacist consultation ,dosage form pearls: Formulation Counselling tip Adderall XR, Ritalin LA Capsule can be sprinkled on small amount of applesauce. (Don’t chew beads, or warm food) Vyvanse Capsule content can be mixed in water , juice or yogurt. Chewable tablets, Oral disintegrating tablets Handle with dry hands Liquids , suspensions Special instructions , stability specific to each formulation. Transdermal patch Caution with heat sources, disposal, remove after 9 hours and apply to alternate hips daily Concerta® Not recommended for patients with GI narrowing Counsel patient they may notice “Ghost tablet in stool” A Stimulants – Most common adverse effects: Management strategy a Appetite suppression Give high-calorie meal when stimulant effects are low (breakfast or bedtime) Take with food or after meals 2 Abdominal pain Administer on a full stomach Lower dose if possible AAAS 4 3 5 Headaches Irritability Sleep disturbance Divide dose Assess for comorbid condition Give dose earlier in the day Give with food Reduce dosage Lower the last dose of the day Give analgesic Consider mood stabilizer or atypical antipsychotic Consider sedating medication at bedtime (guanfacine, clonidine, melatonin, or cyproheptadine) GIE Adverse Effects - Stimulants • • Growth suppression: • Overall, 1 cm per year growth deceleration. ( Amphetamines> Methylphenidates) • Not clinically significant by late adolescence. Less Common • Tics ( reduce dose, alternative medication) • Priapism (Obtain medical assistance) • Zombie-like state ( Reduce dose, alternative medication) • Alcohol and substance use disorders (BBW for stimulants) • Skin discoloration ( chemical leukderma) , counsel regarding risk prior to use of methylphenidate patch. • Psychiatric – considered rare, warnings on labeling (3 categories: psychosis, mood disturbance, severe anxiety/panic attacks): reduce dose, supportive treatment • Cardiovascular (Not significant for most youth, may be intolerable with existing cardiac/CV disease). Use caution in peds and adults with known structural cardiac abnormalities. A • Black box warning for Adderall products. • Baseline ECG and cardiology consult before initiation in patients with PMH or FH of cardiovascular disease. PMH : Past medical history, FH : Family history, ECG : electrocardiogram, CV: cardiovascular Pharmacotherapy: Non-Stimulants • Selective Norepinephrine Reuptake Inhibitor • Atomoxetine (Straterra) • Viloxazine (Qelbree) • Alpha-2a Adrenergic Agonists • Clonidine (IR, Catapres [Unlabeled]; Kapvay) • Guanfacine (IR, Tenex [Unlabeled]; XR, Intuniv) • Norephinephrine & Dopamine Reuptake Inhibitor • Bupropion (Wellbutrin) • Antipsychotics use for mood disorders, tics, comorbid aggression. Pharmacotherapy: Non-Stimulants • What is non-stimulant place in therapy? • Less effective than stimulants. • FDA approved as monotherapy or adjunct to stimulants • Advantages: • Less potential for growth effects • Less sleep disturbances • No abuse potential Non-Stimulants: Selective Norepinephrine Reuptake Inhibitor (SNRI) Generic Name Brand Name Atomoxetine Strattera Qelbree Titration FDA approve d yrs ADR Urinary hesitancy/retention Potential for severe liver injury ,dry mouth, fatigue, headache, insomnia, sedation, dizziness, aggressive behavior, orthostasis, cardiovascular events. is BBW Notes Suicidal thoughts • • • • • • Viloxazine Qelbree Decreased appetite, increased HR/BP, insomnia, irritability. (Need to monitor HR/BP after initiation and dose titration) Suicidal thoughts and behaviors (irritability, anger) • • • • Don’t open capsule Slower onset than stimulants (6-12 weeks) Weight based dosing Beneficial for comorbid anxiety (not depression) Contraindicated to use within 14 days of MAO inhibitor CYP2D6 substrate, dose adj. Can open capsule Possible quicker onset of effect compared to atomoxetine ( 1 week) CI : 14 days from MAOi CI : CYP1A2 substrate concomitant use. Anti-depressants: depression use if pthaestopusingit smoke we Bupropion (Wellbutrin) Advantages • Adjunctive therapy : • Reduce disruptive behavior • Improve sleep in youth (dose-dependent sedation) • Beneficial in comorbid depression, or nicotine use disorder pt met Seis Betis Disadvantages • May decrease seizure threshold • May exacerbate tics • Avoid in patients with eating disorders , seizure disorders. • Suicidal behavior warning Non-Stimulants: Alpha-2a Adrenergic Agonists Generic Brand FDA approved ADR BBW Notes Clonidine Kapvay® 6-17 yr old (mono and adjunct) Dose-dependent sedation, hypotension, constipation Sedation usually subsides after 2-3 weeks of therapy Heart block and sudden death have been reported rarely with None • Gruseat night • • • Onyda XR® suspension Guanfacine it'sa ae E5 Intuniv® 6-17 yr old (mono and adjunct) CNS: Sedation, drowsiness, depression, agitation, anxiety, headache, fatigue GI: Dry mouth, constipation, weight gain Cardiac: Orthostatic hypotension, decreased BP/HR, rebound hypertension w/abrupt D/C None Less selectivity for alpha-2a receptor (compared to guanfacine) Few reports of sudden death in children seen when clonidine + methylphenidate Useful + stimulants (Tics, aggression, conduct disorder) Need to taper slowly • Bedtime dosing with 0.1 mg increments/day at weekly interval max 0.4 mg • Selective for alpha-2a receptor • Less sedation than clonidine • No RCT in adults (monotherapy) • Longer half-life and duration of action compared to clonidine. • Don’t take with high fat meal ( absorption) Non-Stimulants drug interaction Medication Drug interaction Atomoxetine • • • It is a CYP 2D6 substrate , inducers or inhibitors require change in atomoxetine dosing Max of 80 mg daily if combined with CYP2D6 inhibitor as paroxetine MAOI (14 days) Clonidine • • CNS depressants : Additive sedation Beta blockers, non-DHP CCBs : caution with decrease blood pressure and heart rate Guanfacine • • CYP 3A4 inducers: double the dose of Guanfacine CYP 3A4 inhibitors: decrease dose by 50% Viloxazine • • Concomitant use + CYP1A2 substrate MAOI (14 days) MAOI : monoamine oxidase inhibitor. Non-Stimulants: Lithium and Valproate Lithium Valproate • Used to control aggression, explosive behavior ( co-diagnosis of ODD, CD) • Ineffective for ADHD alone. • To control aggression and explosive behavior. • Well-studied for aggression associated with ADHD. • Slow titration to therapeutic response. Anti-psychotics • Second Generation Antipsychotics (SGAs) used to control aggression in refractory ADHD • Lower risk of extrapyramidal S.Es, metabolic side effects. ODD = oppositional defiant disorder, CD = Conduct disorder , S.E = side effect du Non- pharmacological Interventions grow • Educational, Psychosocial, Cognitive, and Behavioral Interventions: Hoo , education of biological basis of ADHD. a Il • De-stigmatization • Individualized educational program (IEP) at school. • Combined behavioral and stimulant therapy resulted in greater academic and conduct improvements. • Start with behavioral therapy in preschoolers (3-5 years) with ADHD before starting stimulants. • EndeavorRX : first video game FDA approved to treat ADHD for children 8-12 years. (adjunct therapy) • New devices under study : not FDA approved Mendi Dietary Interventions • Correct iron, zinc deficiencies • Supplementation enhances stimulant benefit • Gingko, vitamin D • Variable efficacy, tolerability • Omega-3 fatty acids • May be beneficial, few side effects • Inconsistent studies • Healthy diet recommended • Avoidance of sugar and artificial sweeteners • Balance of protein, fresh produce, fiber Treating Comorbid Conditions Algorithm Monitoring of Therapeutic Outcomes Document: • Baseline symptoms and complaints over 1-month pre-drug period • Investigate family history of psychiatric disorders and cardiac disease to determine risk for ADRs and implement appropriate monitoring • Height, weight, eating, sleeping patterns – baseline, Q3 months • Assess overall functioning using standardized scales • Benefits must outweigh potential for ADRs Monitoring: Monitor: Atomoxetine & bupropion • Monitor for changes in appetite, weight, sleep patterns • Pulse, BP • Therapeutic trial – 6 weeks at max tolerated dose Guanfacine, clonidine • Monitor for fatigue, dizziness, autonomic changes • AHA – ECG monitoring not required • Withdraw slowly if discontinuing • Therapeutic trial – 1-2 months Antipsychotics • Baseline weight, lipids, fasting glucose, then Q6 months • Extrapyramidal symptoms and hyperprolactinemia Cardiovascular monitoring frequency: Medication Children, Adolescents, Adults Children, Adolescents Adults >50 yo or CV risk Adults <50 without CV risk Stimulants BP, HR Baseline ECG Baseline ECG No ECG Atomoxetine BP, HR Baseline ECG Baseline ECG No ECG Viloxazine BP, HR Unknown but baseline ECG ideal Unknown but baseline ECG ideal Unknown but probably no ECG Alpha adrenergic agonists BP, HR Baseline ECG not required ( but usually done by many clinicians) Baseline ECG No ECG Bupropion BP, HR Baseline ECG Baseline ECG No ECG Vetter et al. Circulation 2008;117:2407-2423 Patient Case 1: 6 • Chris is an 11-year-old boy who is often distracted during class and has difficulty finishing her work at school. He frequently makes careless mistakes and does not listen to instructions. He rarely remembers to bring his books from school or leaves them on the bus. At home, he has difficulty with organizing her homework and has difficulty starting or finishing her tasks. His symptoms started about 3 years ago but his parents and teachers have noticed worsening of her symptoms. They are concerned that he will not be able to move onto 6th grade as planned. He has no personal or family history of cardiac disease but does have a tic disorder. Beharenaltherapy wanovadbatrror Bupropion • Does Chris meet DSM-5 criteria for ADHD?49 a • What would you recommend as the initial treatment option? • What if he fails therapy ? What is the next step? Atomot don Gaut Vil Amphiphenyl monitor EE BRIAR don wagut Patient Case 1 • Diagnosis : • Meet DSM-5 : 1. Distracted during class 2. Difficulty finishing her work 3. He frequently makes careless mistakes 4. He rarely remembers to bring his books 5. Difficulty with organizing 6. Failing his class 7. Input from teachers and parents 8. Having symptoms for 3 years • Recommendations: • Behavioral therapy • MPH • If he fails MPH at max tolerated dose then AMPH