Psychopharmacology in Developmental Disabilities

Michelle M. Macias, MD, FAAPCo-Director, SC LEND

Professor of PediatricsDirector, Division of Developmental-Behavioral

PediatricsMedical University of South Carolina

Faculty Disclosure Information

In the past 12 months, I have no relevant financial relationships with the manufacturer(s) of any commercial product(s) and/or provider(s) of

commercial services discussed in this CME activity.

I do intend to discuss unapproved/investigative use of a commercial product(s) in my presentation,

which will be disclosed at the time of discussion.

Learning Objectives

• Recognize indications for use of psychotropic medications for youth with developmental disabilities; will focus on intellectual disabilities and autism spectrum disorder.

• Implement objective monitoring of youth with DD on psychotropic medications.

Question

What is the extent of your current psychopharmacologic prescribing?

1. Stimulants only2. Stimulants, other ADHD meds3. Stimulants, other ADHD meds, SSRIs4. Stimulants, other ADHD meds, SSRIs, Atypical

antipsychotics

CASE 1: 5-year old Michael

• CC: hyperactivity, extreme tantrums, aggressive behavior• History:

– Medical: Dx with Soto syndrome at 9 months after being hospitalized for seizures (none for 3 years)

– Developmental: cognitive scores in the high 60s on recent testing, uses 4-5 word sentences, follows single step commands, poor fine motor skills

– Social: lives with mom, dad, 3 year old brother– FH: negative

• Can’t sit still at home or school• Tantrums several times a day• Mother ignores tantrums, tries to set limits. Has been working with

a behavior therapist.

Challenging Behavioral Symptoms

• ADHD sx– Hyperactivity– Impulsivity– Inattention

• Irritability:– Aggressive outbursts– Mood lability– Self-injurious behavior

• Anxiety• Depression• Repetitive behaviors:

– Stereotypic movements– Repetitive play– Inflexible routines– Perseverative speech

• Sleep disturbances

Clinical Approach to Challenging Behaviors

• Careful assessment of target behaviors– Timing, intensity, triggers, response to interventions– Use of behavioral scales– Obtain input from multiple sources (home, school)

• Assess existing and available supports – Behavioral services– Educational program– Family supports

Why Do Behaviors Occur?

• To communicate wants and needs• To get attention• To escape boring or aversive demands• To provide stimulation or sensory regulation

Also occur:• Due to skill deficits (don’t understand expectations)• Due to performance deficits (has skills but won’t

comply with requests)• Neurologic or psychiatric symptoms

Assessment: HPI

• Should be well documented in chart!• Describe:

– Presenting behaviors– Frequency, context– Duration– Impact on functioning– Impact on safety of self and others– Behavioral ROS– Comorbidities– Rating Scales, including collateral information

Assessment

• ROS– Anything on ROS contributing to presentation?– Sleep– Meds/medication history

• Family history– Developmental, behavioral/mental health disorders,

neurologic disorders, use of psychotropic medications • Social history/stressors

– Including guardian’s mental health

Psychotropic Medication Treatment

Should be based on:• An accurate, specific psychiatric diagnosis -

OR-• Target symptom approach

Identify Target Symptoms

With multiple complaints, list in order of severity and impact:• Inattention• Hyperactivity/Impulsivity • Agitation/Irritability/Aggression• Anxiety/Depression• Repetitive behaviors• Sleep problems

Clinical Approach to Challenging Behaviors: Medication

• Behavior is having a negative impact on functioning– Safety is an issue

• Poor response to non-pharmacological intervention• Medical factors causing or exacerbating symptoms

ruled out• Choose medication based on

– Likely efficacy for target symptoms– Potential adverse effects– Practical considerations (dosing, monitoring, cost)

Psychotropic Medication Use in DD

• Goal is to reduce challenging behaviors and improve response to behavioral and educational interventions

• Psychotropic medication use in individuals with ASD and ID is common

‒ Frequency: studies range from 35-75%‒ Consistent findings: ↑ use with older age, presence of

intellectual disability or psychiatric co-morbidity, Southern U.S.

‒ Stimulants, alpha2 agonists, 2nd gen antipsychotics, and SSRIs most common (depends on age)

Tenets of Psychotropic Medication Use

• “Start low and go slow”• Avoid frequent drug and/or dose changes• Identify specific behavioral indices• Collect baseline data!• Track behavior and monitor doses objectively• Give prn prescriptions with caution

Pharmacokinetics in Pediatrics

• Liver mass effects– Liver mass is greater in toddlers and children than an adult,

relative to body weight– Children clear drugs more rapidly than adults– May require higher mg/kg concentrations to achieve same

plasma levels

• Renal filtration– GFR and renal tubular mechanisms for secretion at adult

levels by age 1– Fluid intake may be greater in children– Therefore, may have more rapid renal clearance in children

ID/Autism Spectrum Pharmacotherapy

• NO medications approved for core symptoms • Medications often used to treat related sx, such as

depression, anxiety, and aggression• Stimulants, long acting alpha2 agonists approved

for ADHD• Risperidone and aripiprazole are FDA approved for

irritability in ASD• Anxiety: none FDA approved (only for OCD)• Depression: fluoxetine, escitalopram FDA approved• Individuals with disabilities are often very sensitive

to adverse effects, even at low doses

Target Behaviors

• With multiple complaints, list in order of severity and impact

• Rating scales for baseline and to follow effects of medication– ADHD: Vanderbilt, Conner’s, ADHD IV, Child Attention Problems

Scale– Anxiety: Screen for Child Anxiety Related Emotional Disorders

(SCARED), Generalized Anxiety D.O. (GAD-7)– Depression: Center for Epidemiologic Studies Depression Scale (CES-

D), Patient Health Questionnaire-9 (PHQ-9 Modified), PHQ2– Aggression: Modified Overt Aggression Scale (MOAS)– Broad band: Aberrant Behavior Checklist, Child Behavior

Checklist, Behavior Assessment System for Children-2

Identify Target Symptoms

• ADHD type sx→ Stimulants, ATX, Alpha agonists

• Aggression/Irritability→ Stimulants, Atypical antipsychotics, alpha agonists

• Anxiety, depression → SSRIs, atypical antidepressants

• Repetitive behaviors (OCD) → SSRIs, clomipramine

CASE 1: 5-year old Michael

• CC: hyperactivity, extreme tantrums, aggressive behavior• History:

– Medical: Dx with Soto syndrome at 9 months after being hospitalized for seizures (none for 3 years)

– Developmental: cognitive scores in the high 60s on recent testing, uses 4-5 word sentences, follows single step commands, poor fine motor skills

– Social: lives with mom, dad, 3 year old brother– FH: negative

• Can’t sit still at home or school• Tantrums several times a day• Mother ignores tantrums, tries to set limits. Has been working with

a behavior therapist.

CASE 1: 5-year old Michael

What would you recommend?

1. Therapy2. Methylphenidate3. Guanfacine4. Clonidine5. Selective Serotonin Reuptake Inhibitor (SSRI)6. Risperidone

Classes of Medication Used to Treat ADHD

• FDA-approved – Stimulants (methylphenidate, amphetamine)– Selective noradrenergic reuptake inhibitor (atomoxetine)– Long acting -adrenergic agonists (clonidine, guanfacine)

• Off-label– Antidepressants (tricyclics, bupropion)– Short acting -adrenergic agonists (clonidine, guanfacine)– Modafinil (>18 only)

ADHD Medication Guide available at www.ADHDMedicationGuide.com(courtesy of Andy Adesman, MD)

CASE 1: 5-year old Michael

What I did• Recommended PCIT and discussed medication• Mom called in < 1 month, ready to start meds• Guanfacine ½ mg q HS X 3 days then ½ mg BID• Increased to 1 mg BID after 1 month • Did well, with improved Child Attention Problems

Scale (CAPS) scores and markedly decreased aggression

Short Acting Alpha-Adrenergics

Dose Range Target symptoms

Side effects

Clonidine(Catapres®)

0.25-0.1 mg bid-qid

Impulsivity, hyperactivity, aggressive outbursts, tics

Sedation, hypotension, dry mouth, irritability

Guanfacine (Tenex ®)

0.25 -1 mg bid-tid

Same Less sedation; hypotension

Must titrate/wean!

Long Acting Alpha-Adrenergics

• Evidence vs. placebo: significant ↓in ADHD Rating Scale-IV scores• Has not been studied in ID/ASD• Intuniv: Guanfacine ER

– Must swallow– 1,2,3,4 mg

• Kapvay: clonidine ER– Must swallow– 0.1, 0.2 mg

Total Daily Dose Morning Dose Bedtime dose0.1 mg/day 0.1 mg

0.2 mg/day 0.1 mg 0.1 mg0.3 mg/day 0.1 mg 0.2 mg0.4 mg/day 0.2 mg 0.2 mg

KAPVAY Dosing Guidance

Michael Part 2Age 6

• Still taking guanfacine 1 mg BID• Not working as well-more impulsive• Unable to focus in school

What would you do now??

Stimulants: Evidence of Effect

Research Unit on Pediatric Psychopharmacology (RUPP) Autism Network trial of Methylphenidate (2005)• DBPC crossover trial• Primary outcome: Reduction of Hyperactivity subscale score on

ABC (Aberrant Behavior Checklist) • ABC Hyperactivity scores lower at all MPH dosages vs. placebo• 49% were “responders” to MPH vs. 13% to placebo

• vs. 70-80%+ response rate in ADHD trials• 18% discontinued due to adverse effects• Irritability, decreased appetite, difficulty falling asleep,

emotional outbursts

ADHD and Non-Stimulants in DD: What’s the Evidence?

• Alpha2 Agonists– 2 positive small DBPC trials – clonidine→ ↓ hyperarousal– guanfacine → ↓ hyperactivity

• Atomoxetine– Noradrenergic reuptake inhibitor– 2 positive RCT

• ↓ hyperactivity• No change in stereotypic behavior, irritability

Case 2. Simone: a 13 year old with ID/ASD

• Cognitive functioning in the moderate range of intellectual disability

• Attends public middle school in a self-contained special education class

• Described as ‘out of control’ this school year, increasing difficulty with transitions, hits others, worsening self-injury

• Has to be watched ‘constantly’• On OROS methylphenidate (now on 72 mg) for

hyperactivity since 7 years of age• No other changes in the home or school, no abuse concerns

What would you do?

• Increase methylphenidate• Add clonidine• Change stimulant medications• Replace one/both with risperidone• Replace one/both with aripiprazole• Run…

Aggression

Experts support the use of psychosocial interventions and parent education/training

before the use of medication for maladaptive aggression at every stage of medication

treatment, from diagnosis to maintenance to medication discontinuation.

Maladaptive Aggression

• No official medications approved by FDA for treatment.• Treatment guidelines for pediatric aggression in

primary care largely (completely?) neglected.• Significant gaps in published, randomized, controlled

evidence re: efficacy, safety, long-term use of meds for aggression.

• Lack of consensus on “best practice” is the source of high treatment variability.– Including inappropriate or overprescribing

• Leads to poor outcomes in this population.

Treatment for Aggression: Systematic Review of the Literature

• Treatment of Maladaptive Aggression in Youth (T-MAY) systematic review articles

• Most studies focus on disruptive behavior disorders.– ODD, ADHD, CD

• 17% focus on aggression in autism spectrum d.o.• “Moving target” which requires ongoing

assimilation of new evidence as it emerges.

Treatment for Aggression: Systematic Review

• Antipsychotics have the largest efficacy for aggression (Effect size for aggression 0.72)

• Stimulants have the next largest mean effect size (ES 0.60)– Both methylphenidate and amphetamines

• Mood stabilizers: highly varied results, largely inpatient studies (ES 0.47)– Lithium best (ES 0.63) and carbamazepine worst (ES 0.06)– 1 outpatient study with valproate, inferior to placebo (ES

0.13)

Atypical Antipsychotics: MOA

• Block D2 receptors• Used to control symptoms of agitation,

aggression, and SIB• Try meds with fewer SE first• All similar in efficacy, differ in potency & side

effects• Atypical antipsychotics: more specific dopamine

antagonists, less SE

Treatment for Aggression: Expert Consensus Opinion

• Indications: unsuccessful behavioral intervention with continued serious risk of harm to self or others

• ADHD + severe aggression: – maximize stimulant (ensure adequate dose),

assess for compliance, assess side effects– Alpha agonist (guanfacine, clonidine) as adjunct

• Severe aggression without ADHD: best evidence for atypical antipsychotics

Atypical Antipsychotics: Clinical Use

Generic Brand Name Approval Dose

Aripiprazole Abilify 6-17 years with autism 2-30 mg/day

Olanzapine Zyprexa 2.5-20 mg/day

Quetiapine Seroquel 25-600 mg/day

Risperidone Risperdal 5-16 yrs with autism 0.5-6 mg/day

Ziprasidone Geodon 20-160 mg/day

Antipsychotics: Evidence of Effect

• Various RCT of risperidone and aripiprazole in ASD (+/- ID)• Only 2 small RCT of risperidone in ID• Clinically significant improvement in: irritability,

hyperactivity• Inconsistent improvement in: anxiety, RRB, social

withdrawal • No improvements in: social relatedness,

communication/language, sensory problems• 2009 RUPP study: risperidone + parent training superior to

risperidone alone

Antipsychotics: Side Effects & Monitoring

• Increased appetite and weight gain

• Dyslipidemia• Diabetes• Sedation• Constipation• Extrapyramidal symptoms• Prolactin elevation• Increased liver enzymes (less common)

• BMI• HbA1c• Fasting blood glucose• Fasting lipids• Prolactin (+/-, depends on

drug)• Baseline, Repeat labs at 3 m,

then annually– LFTs baseline, 3 m only

• Monitor for EPS (AIMS, DISCUS)

Potential Side Effects Recommended Monitoring (Varies)

Atypical Antipsychotics: Metabolic effects

• All carry a risk of metabolic disturbance– Clozapine, olanzapine >> quetiapine, risperidone– Weight gain: clozapine, olanzapine highest; aripiprazole,

ziprasidone lowest• If any parameter abnormal, consider the following:

– Switching to an agent that is less risky– Decreasing dose or discontinuing therapy– Recommend diet and exercise– Refer to clinician with expertise in weight management,

diabetes, or lipidsZeier K et al, Current Psychiatry 2013:12 (9): 51-56

SSRIs: Clinical Use

• Selective Serotonin Reuptake Inhibitors (SSRIs) primarily used in the treatment of depression and anxiety– Similarity between repetitive behaviors of ASD

and symptoms of OCD – Evidence of serotonin system abnormalities in

ASD• Liquid preparations available

Depression/Anxiety Treatment: FDA Approval

• Approved for Depression– Fluoxetine ≥ 8 years– Escitalopram ≥ 12 years

• Approved for OCD– Clomipramine ≥ 10 years– Fluvoxamine ≥ 8 years– Sertraline ≥ 6 years– Fluoxetine ≥ 7 years

• Approved for Anxiety (non-OCD)– None

SSRIs: Evidence of Effect

• ID: no RCT of SSRIs• Fluvoxamine (Posey & McDougle, 2000)

– Double-blind, placebo controlled study– 34 children with ASD ages 5-18, 12 weeks– Only 1 of 18 patients responded to treatment– 14 of 18 patients experienced adverse effects (hyperactivity,

insomnia, agitation, and aggression)• Fluoxetine (Hollander, 2005)

– Double-blind, placebo controlled crossover study– 44 children with ASD ages 5-17, 16 weeks– Fluoxetine superior to placebo in reducing repetitive behaviors– No difference in adverse effects between fluoxetine and

placebo

SSRIs: Evidence of Effect

• Citalopram (STAART Network, 2009)– 149 children with ASD ages 5-17– Randomized to citalopram or placebo for 12 weeks– No difference between groups on CGI-I (33% tx vs. 34%

pbo), CYBOCS-PDD, or repetitive behavior scale– Adverse effects: Increased energy level, impulsiveness,

decreased concentration, stereotypy, diarrhea, insomnia, dry skin, and nightmares

– Are repetitive behaviors in ASD fundamentally different from behaviors in OCD?

SSRIs: Evidence of Effect

• Conclusions:– Small, open-label studies with various SSRI’s have

shown some benefits– Placebo controlled studies to date show mixed

results– Largest study performed failed to show

improvement of repetitive behaviors with citalopram

– Side effects are common

SSRI Treatment Choices for Depression and Anxiety

SSRI Forms

Start Dose

+/- by

Max DoseDep/Anx

+RCT EvidenceDep/anx

FDA Approval

Fluoxetine(Prozac)

Tab, liquid

10 mg 5-10mg

60/40 mg Y/N 8-17

Sertraline(Zoloft)

Tab, liquid

25mg 12.5-25mg

200/150mg

Y/N N

Citalopram(Celexa)

Tab, liquid

10mg 10mg 40mg Y/N N

Escitalopram(Lexapro)

Tab, liquid

5mg 5mg 20mg Y/N 12-17

Paroxetine(Paxil)

Tab, liquid

10mg 10mg 60mg N/N N

Fluvoxamine(Luvox)

Tab, liquid

25mg BID 25mg 300mg N/N N

SSRIs: Side Effects & Monitoring

• Nausea and vomiting• Sedation• Weight gain• Dry mouth• Behavioral activation• Induction of mania• Insomnia• Suicidal ideation (FDA

black box warning)

• Baseline Hx & PE• No routine baseline

labs/studies needed• Careful monitoring,

especially for psychiatric side effects

Potential Side Effects Recommended Monitoring

SSRIs: Side Effects

• Behavioral activation is common: 10-15%– Early in course or after dose change– What to do? Stop if it doesn’t go away with time, switch to

second SSRI or non-activating antidepressant (mirtazapine (Remeron), nefazadone (Cymbalta), duloxetine (Serzone)

• GI issues (early)• Easy bruising• Nocturnal enuresis • SRI’s involve cytochrome P450: alter liver’s ability to

metabolize other medications• Drug interactions: TCA’s, AED’s, erythromycin, common

antihistamines

Case 3: Nicholas

• 9 year old with ASD and ID• Doing well on aripiprazole and guanfacine• Functioning at ~ 4-5 year level• Sleep is a big problem

– No real bedtime, falls asleep around 11 p.m., up at 2 a.m. for 1-2 hours, back to sleep until 6 a.m.

– Sometimes naps in the day

What would you do for sleep?

1. Change sleep schedule2. Behavior plan3. Melatonin4. Clonidine5. Other?

Sleep

• Sleep problems are highly prevalent in ID/ASD (45-75%)– Evidence of abnormal melatonin regulation in ASD

• Sleep hygiene, behavioral management 1st line• Sleep hygiene

– Bedtime routine– Low arousal activities– Consistent schedule: same time to bed, same time waking up, same during

week/weekends– Move schedule ~15 minutes earlier every 5-7 days– Sleep education program:

http://www.autismspeaks.org/family-services/tool-kits• Medications

– Stimulants: give earlier, use shorter acting form– SSRI: change from AM to PM dose or vice-versa– Consider sleep medication

Sleep

• Limited data to support diphenhydramine, clonidine, mirtazapine, selective benzodiazepine receptor agonists

• Melatonin– Clinical studies have shown some benefit

• Small RCTs showed increased sleep duration and reduced sleep latency (Wirojanan, 2009, Garstang, 2006)

• Retrospective study of 107 children showed only 3 with side effects of daytime sleepiness and enuresis (Andersen, 2008)

– 0.5-10 mg/dose, onset 30-60 minutes– Unknown long term side effects– Lower seizure threshold, rare gynecomastia, hepatitis

Sleep

• Benzodiazepines– Reduces latency to sleep onset, # of

arousals/awakenings, increases sleep time– Side effects: daytime sedation, disinhibition,

memory impairment, dependence with long term use

– Clonazepam 0.25-0.5 mg at bedtime• Onset 20-40 min, peak 1-4 h

Psychopharmacology: Monitoring

• Careful follow-up for side effects– Atypical antipsychotics: extrapyramidal sx, tardive

dyskinesia (AIMS, DISCUS)• Use drugs only as long as there is clear evidence that

benefits outweigh SE• Except for stimulants, dose reduction and

discontinuation should be gradual– Especially antipsychotics (behavioral rebound, withdrawal

dyskinesia)

• No standard taper, generally 25% per week

Monitor Response

• Determine outcome parameters and time course of trial prior to treatment

• Ongoing collaboration among physicians, parents, schools, and child– Teacher and parent report important– Aberrant Behavior Checklist, Clinical Global Index, Child

Attention Problems Scale• Direct observation• Scheduled appointments to monitor course and

effects

Summary

• Consider educational, behavioral and pharmacological treatment alone and together

• Discuss evidence for the medications with the family, discuss target symptoms, responsibilities of each team member and how outcomes will be measured

Selected References

• Huffman LG, Sutcliffe TL, Tanner IS, Feldman HM. Management of symptoms in children with autism spectrum disorders: a comprehensive review of pharmacologic and complementary-alternative medicine treatments. J Dev Behav Pediatr 2011; 32 (1), 56-68.

• Munshi KR, Gonzalez-Heydrich J, Augenstein T, D’Angelo EJ. Evidence based treatment approach to autism spectrum disorders. Pediatr Ann; 40(11): 569-574.

• Leskovec et al. Pharmacological treatment options for autism spectrum disorders in children and adolescents. Harvard Review of Psychiatry 2008; 16:97-112.

• Rosato N, Correll C, Pappadopulos A, et al. Treatment of maladaptive aggression in youth: CERT Guidelines II. Treatments and Ongoing Management. Pediatrics 2012; 129:6 e1577-e1586.

• Sturmey P. Treatment of psychopathology in people with intellectual and other disabilities. Can J Psychiatry 2012; 57 (10): 593-600.

• Walkup, Child and Adolescent Psychopharmacology: Integrating Current Data into Clinical Practice. January 21, 2012.

Helpful Websites

• AAP: http://www.aap.org/cocwd; www2.aap.org/sections/dbpeds/resources.asp

• Autism Speaks: http://autismspeaks.org• CDC: http://www.cdc.gov/ncbddd/autism/index.html• http://www.fda.gov/Drugs/ResourcesForYou/Consumers/

ucm143565.htm• AIMS: http://www.psychiatrictimes.com/clinical-scales-

movement-disorders/clinical-scales-movement-disorders/aims-abnormal-involuntary-movement-scale

• DISCUS: http://cpnp.org/_docs/ed/movement-disorders/scale/discus.pdf