Practical Psychotropic Drug Management in Developmental Disabilities Craig A. Erickson, M.D. Director, Developmental Disability Research and Treatment in Psychiatry Director, Fragile X Research & Treatment Center Medical Director, P3 Southwest Neurodevelopmental Disorders Inpatient Unit Director of Research, The Kelly O’Leary Center for Autism Spectrum Disorders Associate Professor of Psychiatry Cincinnati Children’s Hospital Medical Center University of Cincinnati College of Medicine- Affiliated

Conflicts of Interest Source Consultant (past* or present^) Stock or Equity Interest Speakers Bureau Research Support (past* or present^) Honorarium/ Support for this Talk Bristol-Myers Squibb X* Roche/Genentech Seaside Therapeutics Novartis Confluence Pharmaceuticals X^ X US Dept of Defense AACAP FRAXA Research Foundation Alcobra Neuren Simons Research Foundation Autism Speaks Cincinnati Children’s Hospital Research Foundation John Merck Fund National Fragile X Foundation

Roadmap Target symptom approach to treatment PRN medications Polypharmacy Medication Discontinuation Vignette Examples

Target Symptoms for Medication Motor hyperactivity and inattention Interfering ritualistic behavior Aggression, self-injury, property destruction

Target Symptoms Continued: Mood disturbances: depression, bipolar Anxiety: panic attacks, agoraphobia, general anxiety, phobia, PTSD Others: sleep disturbances, pica, inappropriate sexual behavior

Motor Hyperactivity and Inattention Psychostimulants: methylphenidate, dextroamphetamine, mixed amphetamine salts Alpha-2 agonists: guanfacine, clonidine Non-stimulants: atomoxetine, bupropion, tricyclic antidepressants

Psychostimulants Work quickly Side effects: reduced appetite, insomnia, tics, increased pulse/blood pressure May cause behavioral worsening May need to be given multiple times per day Need new prescription each month

Alpha-2 Agonists Need to monitor blood pressure and heart rate Can be sedating Generally don’t make symptoms worse Need to be given 2-3 times per day

Non-Stimulants Atomoxetine: effective in ADHD; preliminary studies in developmental disabilities. May take longer to work than stimulants. Generally won’t make tics worse. May help with comorbid mood and/or anxiety.

Non-Stimulants (Cont’d) Bupropion: has been shown to be effective for ADHD. Not well-studied in developmental disabilities. Can lower the seizure threshold and should NOT be given to a patient with a history of seizures or active seizure disorder. Can make tics worse.

Non-Stimulants (Cont’d) Tricyclic antidepressants: not well-studied in developmental disabilities. Associated with side effects including: dry mouth, blurry vision, constipation. Can lower the seizure threshold. Can affect cardiac rhythm.

Ritualistic Behavior Selective Serotonin Reuptake Inhibitors (SSRIs) Fluoxetine Fluvoxamine Sertraline Paroxetine Citalopram Escitalopram

SSRIs Data indicate SSRIs may be more effective in post-pubertal vs. pre-pubertal individuals with developmental disabilities Side effects: insomnia, sedation, stomach upset, sexual dysfunction, weight gain Can generally be given once a day Concern about increasing suicidal thinking/behavior

Irritability: Aggression, Self-Injury, Severe Tantrums Typical antipsychotics Atypical antipsychotics Mood stabilizers Alpha-2 agonists Naltrexone

Irritability (Cont’d) Typical Antipsychotics Haloperidol Thioridazine (rare use, sudden death) Chlorpromazine Trifluoperazine Fluphenazine

Irritability (Cont’d) Typical Antipsychotics Side-Effects acute extrapyramidal symptoms (EPS), tardive dyskinesia (TD), sedation, weight gain, drooling

Irritability (Cont’d) Atypical Antipsychotics Clozapine Risperidone Olanzapine Quetiapine Ziprasidone Aripiprazole Paliperidone

Clozapine Common side effects include weight gain, sedation, drooling Can lower the seizure threshold Agranulocytosis and need for careful blood monitoring

Risperidone Well-studied in autism (FDA approval) and mental retardation associated with behavioral dyscontrol Common side effects: weight gain, sedation (transient), drooling, elevated prolactin

Olanzapine Only small controlled studies in developmental disabilities Common side effects: weight gain (at times significant), has been associated with glucose and lipid dysregulation, sedation

Quetiapine No controlled studies in developmental disabilities Common side effects: weight gain (may be less prominent than with clozapine and olanzapine), sedation, orthostatic hypotension if dose increased too quickly

Ziprasidone No controlled studies in developmental disabilities Common side effects: sedation (transient), occasional insomnia or behavioral activation. Not associated with significant weight gain Should not be given to patients with cardiac problems

Aripiprazole Positive controlled study in youth with autism spectrum disorders Common side effects: EPS and nausea/vomiting if given at too high a starting dose. Akathisia. Occasionally transient sedation or activation. Not associated with significant weight gain or prolactin elevation

Paliperidone Major active metabolite of risperidone Potentially fewer drug-drug interactions Once daily dosing Potentially less weight gain and prolactin elevation

Irritability (Cont’d) Mood Stabilizers Valproic acid Lithium Carbamazepine Gabapentin Topiramate Oxcarbazapine

Valproic Acid The only controlled study in autism found no drug vs. placebo difference Common side effects: sedation, weight gain Need to monitor blood level for therapeutic range and to follow liver function tests May be useful in patients with seizures and aggression

Lithium No controlled studies in developmental disabilities Common side effects: tremor, polydipsia, polyuria, weight gain Need to monitor blood for therapeutic range and to follow kidney and thyroid function

Carbamazepine No controlled studies in developmental disabilities Common side effects: dizziness Need to monitor blood level for therapeutic range and to follow blood count and sodium level

Oxcarbazepine Not well studied in developmental disabilities Negative study in adolescent bipolar disorder Need to monitor serum sodium

Gabapentin No controlled studies in developmental disabilities Common side effects: some sedation, some weight gain No need to monitor blood levels Not particularly effective on a clinical basis

Topiramate No controlled studies in developmental disabilities Common side effects: sedation, cognitive dulling. Not associated with weight gain No need to monitor blood levels

Irritability (Cont’d) Alpha-2 Agonists Guanfacine: not particularly effective for aggression Clonidine: can be effective for aggression. Need to balance sedation vs. clinical benefit Need to monitor blood pressure and heart rate

Irritability (Cont’d) Naltrexone Not effective on a clinical basis No significant side effects, except: Need to monitor liver function

Irritability: Conclusion Best evidence based treatments in persons with developmental disabilities: Risperidone Aripiprazole

Mood - Depression SSRIs: fluoxetine, paroxetine, citalopram, escitalopram, fluvoxamine etc. Bupropion SNRIS: Venlafaxine (elevated blood pressure), duloxetine Mirtazapine (weight gain, sedation) Tricyclic antidepressants

Mood – Bipolar Disorder Valproic acid Lithium Carbamazepine Gabapentin Topiramate Lamotrigine (Steven’s Johnson Syndrome)

Anxiety SSRIs/SNRIs generally most effective Cautious use/avoid benzodiazepines Lorazepam, alprazolam, clonazepam, diazepam etc.

Anxiety Buspirone: few side-effects combined with limited benefit Consider mirtazapine (dosed at bedtime) Commonly associated with sedation and increased appetite

Sleep Disturbance - Insomnia Diphenhydramine (paradoxical rxt’n) Clonidine Trazodone (priapism) Chloral hydrate Benzodiazepines (paradoxical rxt’n) Melatonin Mirtazapine

Pica SSRIs Antipsychotics Behavioral strategies All strategies may hinge on framing what drives pica: anxiety/impulsivity/something else/unknown

Inappropriate Sexual Behavior SSRIs Hormonal strategies Behavioral strategies

PRN Medications “As needed” drugs “Chemical restraints” Common in mental health outside of MR/DD world Beta blockers for social anxiety Benzodiazepines and hydroxyzine for anxiety/panic Antipsychotics for agitation associated with psychotic and bipolar illness

PRN Medications Acute Inpatient Psychiatry Units About 50% of all inpatients receive at least one PRN medication during course of hospital stay Most frequently antipsychotics and/or benzodiazepines Classic PRN combo for agitation: 5mg haloperidol + 2mg lorazepam IM Usher K, Luck L. Psychotropic PRN: a model for best practice management of acute psychotic behavioural disturbance in inpatient psychiatric settings. J Ment Health Nurs. 2004 Mar;13(1):18-21

PRN Medications Long-term state psychiatric facilities In one study, 23% of residents received at least one PRN medication in last month Craig TJ, Bracken J. An epidemiologic study of prn/stat medication use in a state psychiatric hospital. Ann Clin Psychiatry 1995 Jun;7(2):57-64

PRN Medications Nursing homes 35% of all psychotropic drugs prescribed for PRN use Stokes J.A.; Purdie D.M.; Roberts M.S. Factors influencing PRN medication use in nursing homes. Pharmacy World and Science, Volume 26, Number 3, June 2004 , pp. 148-154(7)

PRN Medications Supervised living environments No systematic studies look at % of patients with PRN orders? Clinically we see minority of patients with behavioral PRNs

PRN Medications Issues: Chronic, frequent use: If you need it all the time is it really a PRN? Who makes the call: Who/Whom are the appropriate personnel to decide if PRN needed?

PRN Medications Issues Continued: Aren’t you just sedating someone? Risk of falls/hypotension/dystonic reaction/disinhibition: ie side effects.

PRN Medications Maybe best if narrowly defined PRN use prior to long trips or going to the doctor’s office/other appointments PRN for sleep if patient still awake after X number of hours/at a certain time

PRN Medications Frequency of administration is key If not needing it for months and months, consider getting rid of it If need it every other day, look at adjusting scheduled meds/behavioral intervention changes to try and limit need for PRN

Polypharmacy A chronic problem in our patient population “Layers of drugs” A drug gets added with no plans to remove a preexisting agent

Polypharmacy Can end up on drugs with opposite effects Stimulants and benzodiazepines: “Uppers and downers”

Polypharmacy In our clinic most commonly seen with borderline personality disorder May be do to fluctuating moods, severity of agitation, anxiety, psychotic-like phenomena Can almost read a med list and predict the diagnosis Antipsychotics, plus antidepressants, plus benzodiazepines, plus maybe a stimulant

Polypharmacy How To Avoid Target Symptom Approach Be sure each drug has defined target symptom(s) If a drug does not adequately treat a target symptom, discontinue it If adding a drug, always consider what the new drug could replace

Polypharmacy Cross-titration Slowly increasing a new drug while slowly decreasing the drug it replaces May takes weeks to a few months, but can in some cases be much faster Goal is to not exacerbate behavior/symptoms in the process

Medication Discontinuation Goal is least number of drugs at lowest doses

Medication Discontinuation Need behavioral/symptom stability before slowly removing effective agents Like to see at least 6-12 months of good symptom control before removing slowly a effective drug

Medication Discontinuation Good plan to at least try slow med reduction, especially if significant side-effects are at risk/developing Worst case is behavior worsens and dose need be restored Do run risk that behavioral control will not be duplicated when dose restored

Vignettes 13 year old male with autistic disorder, IQ=50 Reported failures/lack of significant response of/from aripiprazole, risperidone, quetiapine, guanfacine, Adderall BMI at >99% for age and gender Gained weight on all antipsychotics Also on Concerta 54mg, trazodone 50mg for sleep and quetiapine 200mg TID which is viewed as partially effective Admitted with increased physical aggression- grabs, hits, spits Sleep OK, no major medical issues

Vignettes 4 year old with autism, non verbal, intense hyperactivity, aggression and tantrums in developmental preschool BMI at 50% for age No major medical problems, no previous medications

Vignettes 14 year old with ASD, IQ 80, intensely fears fire drills, has outbursts going to school, attacks parents on school days, emesis in the morning at school, no medical problems Recently started aripiprazole 5mg daily, 50% reduction in agitation, but still missing 2 days of school per week

Vignettes 7 year with ASD, intermittent agitation controlled on risperidone, admitted due to running away from school in the street, hyperkinetic, cannot sit still, unable to stay in seat at school Current medication: risperidone .5mg BID, clonidine .2mg HS for sleep, melatonin 3mg QHS for sleep Previous medication trials: daytime clonidine too sedating, guanfacine non helpful Unable to swallow pills

Vignettes Age 12, ASD, explosive aggression, history of abnormal EEG, never treated for frank epilepsy No other medical problems, BMI 50% for age. Current meds: naltrexone, lithium, risperidone, clonidine .1mg TID and .2mg HS Past med failures: quetiapine, aripiprazole, guanfacine, olanzapine, haloperidol, fluoxetine, clonazepam

Vignettes Age 16, ASD, severe self-injury, history of retinal detachments, seizure disorder- last seizure 18 months ago, stable on valproic acid Current meds: haloperidol 10mg TID, trazodone 150mg HS for sleep, Depakote ER 1000mg BID, guanfacine 1mg TID BMI 50%, no other medical issues other than epilepsy Previous medication failures: aripiprazole, risperidone, quetiapine, olanzapine, chlorpromazine; was on aripiprazole and risperidone at same time before

Vignettes 17 year old developmental disability, no ASD, FAS, history of physical and sexual abuse Intermittent about 3 times per week major aggression, mainly towards mother Admitted 4 times in last 12 months Failed aripiprazole, risperidone, olanzapine, ziprasidone, guanfacine Current meds: Quetiapine 300mg BID, minimally effective; clondine .2mg HS for sleep, fluoxetine 20mg daily for history of anxiety BMI 25% for age, no medical problems

Vignettes 17 year old developmental disability, no ASD, FAS, history of physical and sexual abuse Intermittent about 3 times per week major aggression, mainly towards mother Admitted 4 times in last 12 months Failed aripiprazole, risperidone, olanzapine, ziprasidone, guanfacine Current meds: Quetiapine 300mg BID, minimally effective; clondine .2mg HS for sleep, fluoxetine 20mg daily for history of anxiety BMI 25% for age, no medical problems

Vignettes 15 year old with ASD, IQ 125, admitted with self-inflicted chest inflicted chest laceration from knife, bullied at school, suicidal ideation for six months, insomnia, has lost 15 pounds in six months No medication now or in the past

QUESTIONS? Craig.erickson@cchmc.org