Psychopharmacology of ADHD Psychopharmacology of ADHD Scott Carroll, MD Founder – Ayni Neuroscience Institute Author of Don’t Settle: How to Marry the Man You Were Meant For

DIAGNOSIS AND TREATMENT OPTIONS Written evaluations (Connor/Vanderbuilt) from teachers, parents and pt (10yo+) to make diagnosis No diagnosis by medication trial!!! (IT except) Educate parents/pt about the dxn and txt options Risk/benefit analysis, not everyone needs txt Get baseline ht, wt, vitals and labs (EKG ?) Repeat evals yearly and with dose increases

ADHD – Neurochemistry Dopamine depletion hypothesis (Shaywitz et al 1977) lower levels of homovanillic acid (HVA), dopamine metabolite in CSF of ADHD compared to controls Executive function impairments caused by hypofrontality secondary to structural, biochemical changes in prefrontal cortex Genetic studies showing associations with DAT1, DRD4 - 7 repeat alleles Norepinephrine clearly involved but poorly studied Serotonin - weak, inconsistent evidence of involvement GABA - no evidence of involvement N=54 children with ADHD and 18 psychiatric controls Spect at rest and during visual CPT Limitations: -qualitative analysis -Comorbid conditions and/or developmental/neurological complications not controlled for -lack of control group matched for age or IQ

ADHD - Medication Treatment The psychostimulants are the most effective Non-stimulants are mildly to moderately effective Large individual differences in doses and to specific medications (25/50/25 rule of thumb) Start with methylphenidate (no SCD, except w/Sz) Hyperactive may require higher doses than inattention

ADHD Medications Classes of Medication psychostimulants – regular, sustained-release -adrenergic agents (clonidine and guanfacine) atypical antidepressants (bupropion, mirtazapine) NE-specific reuptake inhibitors (atomoxetine) tricyclic antidepressants (no longer used) dopaminergic agents (modafinil but risk of SJS)

ADHD - The Psychostimulants methylphenidate (Ritalin) d-amphetamine (Dexedrine) amphetamine salt mixture (Adderall) amphetamines increase risk of sudden cardiac death with structural cardiac abnormalities and other serious heart problems, esp. Adderall Starting with long acting formulation is better

ADHD - Psychostimulants Methylphenidate (Ritalin) – 5, 10, 20mg Dosage/Schedule 0.3 - 0.7 mg/kg/dose (5 - 20 mg/dose) 0.3 - 2.0 mg/kg/day (10 - 80 mg/day) 5 - 10 mg usual starting dose

ADHD - Psychostimulants Methylphenidate Advantages clear positive effects on inattention, distractibility, hyperactivity short duration of action (3 - 4 hours) allows individual fine-tuning doesn’t show up in standard urine drug test can increase HR/BP, no clear risk of SCD

ADHD - Psychostimulants Methylphenidate Disadvantages short duration requires bid or tid dosing abuse potential FDA approval for 6yo and up slightly lowers seizure threshold

ADHD - Psychostimulants Methylphenidate (Ritalin) More common side effects loss of appetite weight loss insomnia irritability behavioral rebound GI upset

ADHD - Psychostimulants Methylphenidate (Ritalin) Less common side effects tics (likely increased rather than caused) growth retardation (due to low appetite) elevated heart rate and blood pressure psychosis depression and dysphoria hyperfocus decreased seizure threshold

ADHD - Psychostimulants Methylphenidate – Other Preparations Ritalin LA – 10, 20, 30, 40 mg; 4-8 hour duration Methylin – 5, 10, 20 mg; 5, 10 mg chewable; 5 mg/5ml, 10mg/5ml solutions Methylin ER – 10, 20 mg; 4-8 hour duration Focalin – 2.5, 5, 10 mg dex-methylphenidate (half dose) Focalin XR – 5, 10, 15, 20, 30 mg; 10-12 hour duration

ADHD - Psychostimulants Methylphenidate – Other Preparations Concerta – 18, 27, 36, 48, 54 and 72 mg tablets; 14 hour duration, allows once a day dosing for most patients Metadate-ER – 10, 20 mg; 4-8 hour duration Metadate-CD – 10, 20, 30 mg; 8-12 hour duration Daytrana - methylphenidate patch (pediatric absorption?) Quillivant XR – liquid, 12 hour duration (in theory)

ADHD - Psychostimulants Concerta 18, 27, 36, 54, 72 mg no noon (at school) dose usual starting dose 18 mg do not crush or chew

ADHD - Psychostimulants Methylphenidate - Metadate CD 10, 20, 30 mg SR; ~ 8-12 hour duration may open capsule and sprinkle on/in non-chewed food immediately prior to administration; do not crush or chew Difucaps

ADHD - Psychostimulants D-amphetamine (Dexedrine) 5, 10 mg; 5, 10, 15 mg spansule Dosage/Schedule 0.15 - 0.5 mg/kg/dose (2.5 - 15 mg/dose) 0.15 - 1.5 mg/kg/day (5 - 40 mg/day) 2.5 - 10 mg usual starting dose

ADHD - Psychostimulants D-amphetamine (Dexedrine) Advantages clear positive effects on inattention, distractibility, and hyperactivity longer duration of action (6 - 8 hours) long-acting spansules available (6-10 hours) FDA approved for 3 years old and up preferable in patients with seizure disorders

ADHD - Psychostimulants D-amphetamine (Dexedrine) Disadvantages street reputation/diversion potential abuse potential longer action may complicate schedule

ADHD - Psychostimulants D-amphetamine (Dexedrine) Side effects as with methylphenidate (Ritalin), except for d-amphetamine’s mild antiepileptic effect

ADHD - Psychostimulants Other Amphetamine Preparations Adderall – 5, 7.5, 10, 12.5, 15, 20, 30 mg dextroamphetamine saccharate + amphetamine aspartate + dextroamphetamine sulphate + amphetamine sulphate 2.5 – 40 mg usual daily dose 1-2x/day dosing start 5 mg qAM/bid 4-8 hours duration

ADHD - Psychostimulants Other Amphetamine Preparations Adderall-XR – 5, 10, 15, 20, 25, 30 mg SR 10-12 hours duration start 5-10 mg qAM; max 30 mg/d may switch Adderall patients to same total daily dose qAM do not cut, crush or chew capsules may sprinkle on non-chewed food

ADHD - Psychostimulants Other Amphetamine Preparations Vyvanse – 10, 20, 30, 40, 50, 60 and 70 mg caps pro-drug, must be metabolized via 1st pass non-oral admin leads to slow activation 3.5 hour half life, but 1-2 hours to onset start 20 - 30 mg qAM; max 70 mg/d roughly equivalent to ½ the mg of Adderall indicated for ADHD (6yo+) and binge eating only appropriate if risk of abuse/diversion

Adderall, Adderall XR and Vyvanse

ADHD - Psychostimulants Side Effect Management Anorexia adjust timing of dosage – with or after meal adjust amount of dosage ask parents to provide an always-available snack consider medication holidays (hours, days, weeks) monitor weight, consider Remeron for wt gain.

ADHD - Psychostimulants Side Effect Management Insomnia adjust timing of dosage adjust amount of dosage reinforce good sleep hygiene reassess diagnosis (ADHD, comorbidity) consider a small evening stimulant dose (no research substantiation; use with caution) sleep med (melatonin, Benedryl, clonidine, trazodone)

ADHD - Psychostimulants Side Effect Management Irritability reassess diagnosis (ADHD, comorbidity) assess timing of doses- peak?, rebound?, nutrition? adjust dosage or try long acting/short acting form switch stimulants, try/stop drug holidays ?add α-adrenergic agent or antidepressant

ADHD - Psychostimulants Side Effect Management Rebound adjust amount of dosage (up or down, usually down) adjust timing of dosage switch to long-acting stimulant small dose of short-acting stimulant after long-acting reassess diagnosis (ADHD, comorbidity)

ADHD - Psychostimulants Side Effect Management Overfocus (‘hyperfocus’) reduce dosage switch to longer-acting preparation reassess diagnoses (comorbidity, especially OCD, ASD)

ADHD - Psychostimulants Side Effect Management Headache, GI Sx reduce dosage switch to longer-acting preparation assess for migraine, other pathology switch to alternate stimulant hydration, give with food

ADHD - Psychostimulants Magnesium pemoline (Cylert) 18.75, 37.5, 75 mg; 37.5 mg chew Dosage/Schedule single daily dose 1.0 - 3.0 mg/kg/dose (18.75 - 75 mg/dose) do not use due to risk of liver failure

ADHD -Adrenergic Agents originally mediocre antihypertensives clonidine (Catapres), guanfacine (Tenex) effective for impulsivity, impulsive aggression clonidine available as a transdermal patch not effective for hyperactivity/inattention

ADHD - -Adrenergic Agents Clonidine (Catapres) 0.1, 0.2, 0.3 mg tab;0.1/24h, 0.2/24h, 0.3/24h patch Dosage/Schedule 0.05 - 0.2 mg/dose (0.3mg max/dose in teens) 0.1 - 0.6 mg/day (1.0mg max/day in teens) (usually 0.05 mg bid to 0.1 mg tid) 0.05 - 0.1 mg usual starting dose at qhs patch max 0.6mg/24h; ~5d duration in children

ADHD - -Adrenergic Agents Clonidine (Catapres) Advantages effective for impulsivity (and possibly for emotional hyper-reactivity) available as transdermal patch if switching from PO to patch, continue PO for 1-2d, monitoring VS

ADHD - -Adrenergic Agents Clonidine (Catapres) Disadvantages must be slowly titrated up to effective dose while monitoring blood pressure danger of rebound HTN if stopped suddenly shorter half-life for children – esp. the patch baseline and repeat EKG’s

ADHD - -Adrenergic Agents Clonidine (Catapres) Side effects sedation low blood pressure lightheadedness, dizziness dysphoria (feeling bad) headache stomach upset rebound HTN if stopped at high dose local irritation from patch (rotate site)

ADHD - -Adrenergic Agents Guanfacine (Tenex) 1, 2 mg Dosage/Schedule 0.5 - 2.0 mg/dose 1.0 - 6.0 mg/day (usually 1 mg qAM to 1 mg tid) 0.5 - 1.0 mg usual starting dose

ADHD - -Adrenergic Agents Guanfacine (Tenex) Advantages effective for impulsivity (and possibly for emotional hyper-reactivity less sedating than clonidine lowers blood pressure less than clonidine somewhat longer duration than clonidine

ADHD - -Adrenergic Agents Guanfacine (Tenex) Advantages extended release oral prep (Intuniv) Side effects as with clonidine, except for less sedation and less lowering of blood pressure

ADHD - Bupropion (Wellbutrin) Bupropion (Wellbutrin) 75, 100 mg ($) Dosage/Schedule 37.5 - 100 mg initial dose 75 - 450 mg day IN DIVIDED DOSES 150 mg max single dose for adolescents 100 mg max single dose for children

ADHD - Bupropion (Wellbutrin) Wellbutrin-SR 100, 150, 200 mg ($$) Dosage/Schedule 100 mg initial dose… single am dose may be sufficient 200 mg max single dose for adolescents 150 mg max single dose for children XL form expensive, not tested in children

ADHD - Bupropion (Wellbutrin) Advantages also treat other conditions such as depression, drug abuse and smoking also available as Wellbutrin-SR effective alternative to stimulants not a controlled substance safe to combine with a stimulant

ADHD - Bupropion (Wellbutrin) Disadvantages risk of seizures (4/1,000) not FDA approved for < 18 years old black box warning for suicide

ADHD - Bupropion (Wellbutrin) Side effects agitation stomach upset headache dizziness constipation dry mouth tremor seizures (rare liver toxicity) tinnitus CAUTION: Wellbutrin = Zyban = bupropion

Atomoxetine (Strattera) – 10, 18, 25, 40, 60 mg ADHD – Atomoxetine Atomoxetine (Strattera) – 10, 18, 25, 40, 60 mg name changed from tomoxetine to avoid confusion with anti-cancer drug tamoxifen hypothesized to act via highly-selective blockade of the presynaptic NE transporter (increases synaptic NE) specific FDA approval for Rx adult and child ADHD

ADHD – Atomoxetine Dosage Adult - begin at 40 mg PO qAM x 3d; maximum of 100 mg/day Child – start at 0.5 mg/kg PO qAM x 3d; maximun of 1.4 mg/kg/d adjust dose for hepatic impairment, CYP2D6 competition Initially given bid, but qd dosing equally effective.

black box warning for SI can induce mania and psychosis ADHD – Atomoxetine Side Effects serious: black box warning for SI can induce mania and psychosis HTN, ↑HR, orthostasis, palpitations angioedema and increased narrow-angle glaucoma more common: dry mouth, blurred vision urinary hesitancy/retention abdominal pain, nausea, constipation, dyspepsia insomnia, fatigue impotence, dysmorrhea, ↓libido

ADHD – Atomoxetine Advantages Disadvantages no known addictive potential; not a controlled substance selective inhibitor of NE uptake half-life (T1/2) of 5 hours → QD dosing Disadvantages Expensive (~$1,000/mo), but Wellbutrin is cheap slower onset of positive effects noradrenergic side effect profile

Modafinil (Provigil/Sparlon) a wakefulness-producing non-stimulant drug, highly effective in ADHD less risk of appetite suppression starting dose 100mg qam 300mg max/day, divided bid/tid 200mg average effective daily dose caused Steven-Johnson syndrome in children

ADHD - Tricyclic Antidepressants imipramine (Tofranil) desipramine (Norpramin) nortriptyline (Pamelor) amitriptyline and protriptyline are also available, but the above three tricyclics are preferable based on side effect profile and research base

ADHD - Tricyclic Antidepressants Imipramine/Desipramine Dosage/Schedule 25 - 150 mg final dose (2 - 3 mg/kg/day) 10 - 50 mg qhs usual starting dose

ADHD - Tricyclic Antidepressants Nortriptyline Dosage/Schedule 10 - 100 mg final dose 10 mg qhs usual starting dose

ADHD - Tricyclic Antidepressants Advantages concomitant treatment of comorbid conditions (depression, panic disorder, enuresis) once-twice daily dosing blood levels available

ADHD - Tricyclic Antidepressants Disadvantages cardiac effects reports of sudden death on desipramine subgroup of slow metabolizers delayed onset of action potentially lethal overdose

ADHD - Tricyclic Antidepressants More common side effects sedation orthostatic hypotension lightheadedness, dizziness dry mouth blurred vision constipation elevated heart rate (tachycardia)

ADHD - Tricyclic Antidepressants Less common side effects urinary retention easy sunburn EKG changes (prolonged PR, widened QRS, increased QTc) decreased seizure threshold rash agranulocytosis hypomania/mania

ADHD - Tricyclic Antidepressants Side Effects - Special Considerations obtain a baseline ECG; repeat with each dose increase above 2 mg/kg for imipramine or desipramine, and above 1 mg/kg for nortriptyline; repeat for any cardiac symptoms warning signs: PR interval > 200 ms; QRS > 30% above baseline, or > 120 ms; QTc > 450 ms resting pulse rate > 120; resting systolic BP > 130 or diastolic > 85 risk of sudden death roughly 8 per million per year

ADHD - Tricyclic Antidepressants Side Effects - Special Considerations, continued obtain intermittent CBC, LFT’s blood levels - therapeutic range 150 - 300 ng/ml for total of imipramine + desipramine; therapeutic window of 50 - 150 ng/ml for nortriptyline taper off gradually to avoid cholinergic rebound potentially dangerous interactions with MAO inhibitors, methylphenidate, and other medications (including over-the-counter medications)