ADHD:Updates and Practical Suggestions

Transcription

1 :Updates and Practical Suggestions Elizabeth Reeve MD HealthPartners Medical Group Disclosure I have no financial disclosures I may be talking about non FDA approved indications for medications Elizabeth.A.Reeve@HealthPartners.com Arousal and alertness Processing Memory A disorder of the ability to modulate and maintain appropriate attention for the task at hand, not a disorder of inattention Impulsivity and distractibility result from this inappropriate modulation Lack of inhibition and focus Hyperactivity Focus, filtering, inhibition What is Attention? Accessing and retrieval Neurochemistry Changes with DSM 5 Desire, pleasure, interest Dopamine Filter information and sustain attention Norepinephrine Alertness, arousal, cognition Symptoms must exist before the age of 12 rather than 7 Half of adults do not recall symptoms before the age of 7 but 95% reported symptoms before the age of 12 Kessler et al, Arch Gen Psychiatry. 2005;62(6) Prevalence in one UK study only changed by 0.1% by changing the onset to 12 but increased by 27% (2.8% to 3.55%) in another study Matte et al, Psyhol Med. 2015;45(2) 1

2 Changes with DSM 5 Decreases the number of symptoms needed for persons 17 and older to 5 rather than 6 for each symptom category Inattentive Hyperactive/Impulsive The previous use of subtypes is now noted as presentations to capture the idea that symptoms may change over time The diagnosis of can now be made in the presence of comorbid autism Inattentive subtype Hyperactive impulsive subtype Combined subtype Adult Self Report Scale High degree of consistency between the self report and the clinician administered versions Concluded to be a reliable and valid instrument 18 question original version 6 question screening version Developmental Differences Research Updates 2

3 Long term open label study of Edivoxetine Monotherapy in Children and Adolescents with Nery et al, JCAP 10/17 Open label study for up to 5 years Highly selective and potent NE reuptake inhibitor Previous shorter studies had shown safety and efficacy No plans to proceed with further development and Aggression Extended release molidone (SPN 810) 6 12 years of age with with aggression diagnosis Double study Sedation, weight gain, increased appetite AEVI 001 Novel glutamate modulator in phase two trials Failed overall to show benefit but in a subset of subjects with specific key genesis a 9 gene panel significant benefit was obtained CNTN4 was the most associated with robust clinical response Contactin 4 is a cell adhesion molecule Second study showed 20 26% of subjects of 1013 tested positive for CNTN4, those subjects were much more likely to show disruptive behaviors Dasotraline Dopaminergic/NE reuptake inhibitor Long half life incurs 24 hour coverage Significantly improved symptoms of both inattention and hyperactivity/impulsivity Side effects of decreased appetite and insomnia Mazindol CR (NLS 1) Phase 2 study on 85 adults, placebo controlled, showed efficacy Worked in the first week of dosing Increase dopamine and NE Approved in Europe for weight loss and to modulate sleep Anti obesity benefits were not sustained and drug caused significant anxiety Ironshore pharmaceuticals HLD200 (methylphenidate) and HLD100 (amphetamine) Both are delayed release products to be taken at night for release in the morning Release is delayed 8 10 hours and peak levels achieved 14 hours after ingestion Delayed release hydrophobic outer layer over an extended release hydrophilic layer which covers the drug containing core DELEXIS delivery system 3

4 DELEXIS After a $200M financing, Highland Therapeutics falls silent on drug s fate as PDUFA sails by (Aug 2017) Early Morning Functional Impairment in Stimulant Treated Children versus Controls Farone et al, JCAP 10/2017 On line survey questionnaire of 3oo caregivers of subjects and 50 caregivers of non subjects subjects were on stable stimulant medications EMF was significantly greater in subjects Earlier article JCAP 2015, Sallee is first reference to EMF (funded by Ironshore) Single Dose Pharmacokinetics of HLD200 HLD200: JCAP 2/2018 ClinicalTrials.gov 1045 studies listed 393 are listed as placebo controlled trials Of those 39 are currently active and recruiting Three were novel agents other than those already discussed OPC (dopamine modulator, adults) KP 415 (methylphenidate prodrug) Tipepidine (potassium channel modulator) 4

5 Cannabis Treatment for Neurofeedback for Neurofeedback for : Meta Analysis of Clinical and Neuropsychological Outcomes From Randomized Controlled Trials JAACAP June 2016 Cortese et al 13 Trials, 520 participants Significant effects were found by assessor most proximal to the treatment setting No significance in trials that had blinded ratings or sham controls Combined Stimulant and Guanfacine Combined Stimulant and Guanfacine Administration in : A Controlled, Comparative Study JAACAP August 2016 McCracken et al 8 week double blind randomized three arm study Guanfacine1 3 mg, DMPH ER 5 20 mg daily, combination with flexible dosing 207 subjects Combination TX showed small but consistently greater reductions in inattention sub scales and overall benefit No serious CV side effects, more sedation in the guanfacine groups Long term use of Medications: MTA Study J of Child Psychology and Psychiatry March year FU data for over 90% of the and non subjects 23.5% of group had negligible med use, 61.9% inconsistent use, 7.4% consistent use Cumulative dose of 2153 mg, 60,567 mg, 117,102 mg methylphenidate equivalents Long term MTA data show a 2 cm deficit in adult height related to long term stimulant use. Followed for up to 16 years No difference in symptom severity scores related to medication use but there was a difference between and non subjects in symptoms severity MTA 16 years later Roy et al Of 453 subjects 49.9 % met DSM 5 criteria, 34.7% if self report impairment is also required Persistence of symptoms was predicted by baseline symptom severity, comorbidity, and parental mental health problems IQ, family SES, parental income and education, and parenting style did not predict persisting Hechtman et al Persistent led to decreased educational and occupational success, decreased income and increased need for public assistance. Also had worse outcome on measure of mood, anxiety and substance use disorders Household Diversion of Prescription Stimulants Pham et al, JCAP 2/2018 Questionnaires completed by 1890 parents of youth currently taking stimulants for Asked whether they or another adult had every taken their child s stimulant medication or if they ever given it to another child in the home 16% admitted to diverting, mostly to themselves, another 13% admitted they were tempted by the meds 71% stored the medication in plain site or out of site but available to all 5

6 Omega 3 Fatty Acid Supplementation. In Medicated Children with and Deficits in Emotional Self Regulation Wilens et al, JCAP 2/2018 Small 12 week open label pilot study with subjects aged 6 17 with All were receiving stimulants and had prominent dive it s in emotional self regulation 973 mg EPA Showed rapid improvement in emotional self regulation and no change in MEDICATIONS Presynaptic dopamine and norepinephrine reuptake blockade How do Medications Work Stimulants Atomoxetine Guanfacine and clonidine Increase noradrenergic efflux particularly in the prefrontal cortex Primarily noradrenergic reuptake inhibitor but also transport of serotonin and dopamine in to presynaptic terminals Alpha 2 adrenergic receptor agonist, exact mechanism for treating is unknown Stimulants Methylphenidate products Mixed amphetamine salts products Dexedrine products All come short and long acting Increasing variability but all have equal efficacy New products are no better and most are not paid for by insurance Guanfacine is highly selective for the alpha 2a receptor in the prefrontal cortex Tidbits to Know Amphetamine Containing Products All stimulants have the same potential efficacy and side effects Most people respond to whatever stimulant you give them Most common side effects are decreased appetite, insomnia, headaches, tics The presence of tics does not preclude the use of stimulants Stimulant response can be seen immediately, there is no need to wait weeks to see the benefit It is permitted by the FDA to give 90 days at time, either in one 90 day prescription or three 30 day prescriptions with the appropriate fill dates (insurance dependent) Zenzedi Procentra Evekeo Adderall Vyvanse Dexedrine spansules Dynavel Adzenys Mydayis 6

7 Adzenys XR ODT : amphetamine extended release dissolving tablet. Comes in a blister pack. 3.1 mg, 6.3, 9.4, 12.5, 15.7, mg is equivalent to 30 mg Adderall XR. Duration of hours Dynavel : Extended releases liquid Dexedrine. 2.5 mg amphetamine/ml, max dose of 20 mg Evekeo : short acting amphetamine, 5,10 mg tablets. 50% d amphetamine and l amphetamine. Adderall is 75%/25% ProCentra : a colorless bubble gum flavored short acting oral solution 5 ml/5mg dextroamphetamine Aptensio XR : Methylphenidate XR, one hour onset, 12 hour duration, may be sprinkled, mg Quillivant : Extended release liquid methylphenidate Mydayis : 16 hour extended release mixed amphetamine salt Stimulant Side Effects Nonstimulants Decreased appetite Tics Rebound irritability Impact on growth Maybe greatest if started younger, female, and on higher doses Atomoxetine Target dose is about 1.4 mg/kg or a max dose of 100 mg Nausea and sedation are the most common side effects It take 6 or more weeks to fully work Not a controlled substance Does not work as an antidepressant Must be taken daily Alpha adrenergics Both clonidine and guanfacine come in long and short acting Clonidine ER is still twice daily dosing Only guanfacine XR has FDA approval for adults Sedation is the most common side effect Take 4 6 weeks to work Must be taken daily Taper when discontinuing Not a controlled substance Alpha Adrenergics Combinations Start guanfacine at 0.5 mg twice daily and increase to 1 mg bid, then 1.5 mg bid and then 2 mg bid as clinically indicated. Clonidine IR need tid dosing. More sedating, shorter half life Can increase weekly, or a bit quicker if no side effects OK to use a stimulant with a nonstimulant Alpha 2 plus stimulant Atomoxetine plus a stimulant Ok to use two nonstimulants Alpha 2 plus atomoxetine OK to use bupropion with either a stimulant or a nonstimulant Avoid tricyclic with and alpha 2 agent Increased cardiovascular side effects 7

8 Comorbidity of and Depression/Anxiety What Do I Treat First, Depression/Anxiety or? OK to use stimulants plus SSRI OK to use alpha 2 agent and SSRI Strattera is 2D6 metabolized so avoid using with fluoxetine, paroxetine, bupropion and venlafaxine all of which require 2D6 OK to use stimulant or alpha 2 agent with bupropion, mirtazapine, venlafaxine If planning to use a stimulant for the start that medication first Reassess mood/anxiety after stable on stimulant Are other medications still needed? ARE appropriate nonpharmaceutical therapies in place? Chicken and the egg Is it truly inattention due to or inattention due to mood/anxiety? Is depression/anxiety secondary to untreated? After School Dosing Special Concerns Consider adding an after school dose if there is rebound irritability After school dose depends on the product used during the day Adderall XR 20 mg with 10 mg short acting after school Metadate 20 mg with mg short acting methylphenidate after school College students Convert to long acting agents and avoid short acting Discuss your refill policy in detail Have student purchase a safe for the dorm room Discuss abuse potential Chemical Dependency First choice treatment is a non stimulant Use of stimulants in sober patients who have supportive environments can be cautiously considered 8