ADHD: Diagnosis and Treatment of More Than One Disorder

Steven R. Pliszka, MD

Faculty Disclosure

Steven R. Pliszka, MD, was a member of the Speakers Bureau for Shire US Inc. and Ortho-McNeil Pharmaceuticals, Inc. He has received grants/research support from Shire US Inc., Cephalon, Inc., McNeil, and Eli Lilly and Company, and is a consultant for Shire US Inc. He has received honoraria from Shire US Inc., McNeil and Cephalon, Inc.

Topics To Be Covered

ADHD “simplex” Adverse events of treatment (e.g.,

cardiovascular, psychiatric)

ADHD with comorbidity ODD/CD Tics Aggression Bipolar Disorder

CD = conduct disorder

Adverse Events of Stimulants

Update on the Controversy

Estimated Reporting Rates (1992-2004): Pediatric Sudden Death (18 Years Old)

Drug

All Age GroupsPediatric Age Group

0-18 Years

Total Prescriptions1

Pediatric Exposure (p-y)2 N3

Reporting Rate per 100,000 p-y

Methylphenidate (Concerta, Ritalin)

110,734,000 7,127,432 11 0.2

Amphetamine (Adderall) and dextroamphetamine (Dexedrine)

70,699,000 3,817,929 13 0.3

Atomoxetine (Strattera) 9,419,000 601,246 3 0.51IMS Health, National Prescription Audit Plus, January 1992 through December 2004. Data Extracted April 2005; 2Total person-years (p-y) times the percentage of drug appearances in the pediatric subgroup population (IMS Health, National Disease and Therapeutic Index, January 1993 to December 2004, Data Extracted June 2005); 3N = sudden death cases identified in FDA AERS database received from January 1992 through February 2005; Available at: www.fda.gov/ohrms/dockets/AC/06/briefing/2006_42106_06_Gelperin.pdf. Accessed Jan. 29, 2007

Psychiatric Side Effects of Stimulants?

Gelperin K (2006). Available at: www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4210B-Index/htm. Accessed Feb. 1, 2007

DrugsType of

trialNo. of trials

Duration of trials (range)

Category of exposure N

Patient-years

Psychosis /mania events

Suicidal events

Aggression events

Concerta DB 4 6-28 dys Placebo 317 10.20 0 0 0Drug DB 321 12.68 0 0 0

OL 7 < 12 mos. Drug OL 2824 1397.40 8 6 52Metadate CD DB 4 7-21 dys Placebo 572 19.44 0 0 3

Drug DB 493 19.13 0 0 3OL 2 NS Drug OL 322 19.55 0 0 6

MTS DB 8 1-49 dys Placebo 464 23.84 0 0 1Drug DB 471 30.26 4 0 6

OL 4 NS Drug OL 617 341.97 6 1 7Modafinil DB 6 1-9 wks Placebo 366 39.87 0 0 5

Drug DB 722 85.50 2 4 9OL 3 < 1 yr Drug OL 924 383.53 2 0 14

Adderall XR DB 7 1-4 wks Placebo 678 28.00 0 0 6Drug DB 1236 77.18 0 1 20

OL 6 < 2yrs Drug OL 5177 1767.47 14 8 166Atomoxetine DB 20 < 78 wks Placebo 1443 350.73 0 4 18

Drug DB 2459 654.87 4 9 49OL 10 < 96 wks Drug OL 5270 5095.27 12 44 198

Ritalin LA DB 5 1-14 dys Placebo 259 11.31 0 1 0Drug DB 383 25.66 2 0 2

OL 1 NS Drug OL 125 25.95 0 1 0d-MPH DB 8 < 49 dys Placebo 468 53.24 0 0 0

Drug DB 588 64.75 4 0 1OL 5 < 1 yr Drug OL 740 362.09 3 1 13

Growth and Stimulants

Spencer (1996) compared growth in 3 cross-sectional samples of patients with ADHD controls: children, early pubertal adolescents and young adults

No difference in height in child and young adult samples, adolescents with ADHD were shorter than control ADHD; no relationship of treatment history to height

This study lead to view that stimulants do not effect growth at all, drug holidays not necessary

Spencer TJ et al. (1996), J Am Acad Child Adolesc Psychiatry 35(11):1460-1469

Growth and Stimulants (Cont.)

1-2 year trials of long-acting stimulants showed small, but generally clinically insignificant effects on height z score1

Poulton (2005) reviewed all studies, concluded that stimulants induce a 1-3 cm deficit in expected height early in treatment2

1Faraone SV et al. (2005), J Child Adolesc Psychopharmacol 15(2):191-202; 2Poulton A (2005), Arch Dis Child 90(8):801-806

Growth and Stimulants: Recent Studies

140 preschoolers started treatment with methylphenidate (MPH) at a mean age of 4.4 for 1 year

z height and z weight assessed serially, no control group

Preschoolers with ADHD were bigger than average at baseline (z height = +0.45, z weight = +0.78)

Swanson et al. (in press), J Am Acad Child Adolesc Psychiatry

Preschool ADHD Treatment Study (PATS)

Growth and Stimulants: Recent Studies (Cont.)

Annual growth rates were reduced compared to that predicted by growth charts: -1.38 cm/year lower expected height -1.32 kg/year lower expected weight

Cannot say this pattern will continue

Swanson et al. (in press), J Am Acad Child Adolesc Psychiatry

Growth and Stimulants: Recent Studies (Cont.)

Multimodal Treatment Study of Children with ADHD (MTA)

Followed MTA sample 3-year follow up: 65 children with ADHD never medicated 70 children with ADHD consistently medicated 147 children with ADHD inconsistently medicated 88 children with ADHD newly medicated

Swanson et al. (in press), J Am Acad Child Adolesc Psychiatry

Growth and Stimulants: Recent Studies (Cont.)

BSL = baseline; MTA data; Swanson et al. (in press), J Am Acad Child Adolesc Psychiatry

-0.2

-0.1

0

0.1

0.2

0.3

0.4

0.5

0.6

BSL 14 Mo. 24 Mo. 36 Mo.

No meds

Controls

New meds

Incons

Cons meds

z H

eig

ht

Growth and Stimulants: Recent Data

66 children treated with mixed amphetamine salts (MAS) and 113 treated with MPH for at least 1 year (mean 2.7 years of treatment)

Treated with stimulant monotherapy, no switching from 1 stimulant to another

No effect of z height or weight, no difference between medications on height

Drug holidays averaging 31% of the time during treatment

Pliszka SR et al. (2006), J Am Acad Child Adolesc Psychiatry 45(5):520-526

Revised CMAP Algorithm for Pharmacotherapy of ADHD

Consensus conference of academic clinicians and researchers, practicing clinicians, administrators, consumers, families

Revised algorithms based upon new research developed for treatment of ADHD, with and without common comorbid conditions

Children treated according to earlier algorithms achieved better outcomes and were exposed to less polypharmacy than controls Pliszka SR et al. (2006), J Am Acad Child Adolesc Psychiatry 45(6):642-657; Pliszka SR et al. (2003), J Am Acad Child Adolesc Psychiatry 42(3):279-287

CMAP Algorithm for Pharmacologic Management of ADHD

Pliszka SR et al. (2006), J Am Acad Child Adolesc Psychiatry 45(6):642-657

Multimodal Treatment of ADHD Multimodal Treatment of ADHD Study: Change Scores Study: Change Scores

Combined Combined TreatmentTreatment

Medication Medication OnlyOnly

Behavioral Behavioral OnlyOnly

Community Community ComparisonComparison

Baseline-to-14-mo Baseline-to-14-mo changechange

ADHD (-) betterADHD (-) better -0.97-0.97 -0.95-0.95 -0.64-0.64 -0.57-0.57

14 to 24 mo change14 to 24 mo change

ADHD (+) worseADHD (+) worse +0.23+0.23 +0.21+0.21 +0.03+0.03 +0.02+0.02

14 mo to 14 mo to 24 mo 24 mo

MedicationMedicationMedicationMedication

No MedicationNo MedicationNo MedicationNo Medication

Medication Medication No MedicationNo Medication

No MedicationNo MedicationMedicationMedication

n=255n=255 n=139n=139 n=76n=76 n=51n=51

ADHD ChangeADHD Change(-) better(-) better(+) worse(+) worse

+0.15+0.15 +0.10+0.10 +0.33+0.33 -0.15-0.15

Jensen PS, et al. J Am Acad Child Adolesc Psychiatry. 2004;43(11):1334-1344.

0 10 20 30 40 50 60

Oppositional defiant disorder

Conduct disorder

Mood disorders

Anxiety disorders

Learning disorders

ADHD—Childhood Common Comorbid Diagnoses

Approximate Prevalence Rate in Children With ADHD (%)

Biederman J et al. (1996), J Am Acad Child Adolesc Psychiatry 35(3):343-351; Pliszka SR (1998), J Clin Psychiatry 59(suppl 7):50-58; Biederman J et al. (1999), J Am Acad Child Adolesc Psychiatry 38(8):966-975; Spencer T et al. (1999), Pediatr Clin North Am 46(5):915-927

Male

Female

Nature of ODD and CD

A descriptive diagnosis, does not imply etiology

ODD may be secondary to ADHD

ODD or CD may occur even without ADHD

ODD/CD are sometimes due to environmental factors (late onset)

Most likely has multiple causes

Meta-Analyses of the Effects of Stimulants on Aggression

Connor et al. (2002) 1970-2001, 28 studies Mean effect size of stimulants—0.84 for overt

and 0.69 for covert aggression

Pappadopulos et al. (2006) 1989-2004, 19 studies, >1,000 participants Mean effect size of 0.78

Connor DF et al. (2002), J Am Acad Child Adolesc Psychiatry 41(3):253-261; Pappadopulos E et al. (2006), J Cdn Acad Child Adolesc Psychiatry 15(1):27-39

Psychopharmacology of ODD/CD

ADHD children with ODD/CD respond to stimulants as well at those without ODD/CD

No evidence that stimulants increase aggression at appropriate doses

Relative to placebo, ADHD children on stimulants engage in less antisocial behavior

ADHD-ODD/CD Issues With Stimulants

Fear: stimulant therapy may lead to substance abuse

Fact: untreated ADHD is a significant risk factor for substance abuse in adolescence

Pharmacotherapy for ADHD may have protective effects

Pharmacotherapy and Substance Abuse

Pharmacotherapy and Substance Abuse: Adolescents With ADHD

Ab = alcohol or drug abuse; Dep = dependence; Wilens TE et al. (2002), Annu Rev Med 53:113-131

Rat

e o

f S

A (

%)

0

5

10

15

20

25

30

35

40

45

EtOH Ab/Dep Drug Ab/Dep

Unmedicated Medicated

Treatment Plan for ADHD/ODD

Optimize treatment of ADHD Stimulants, atomoxetine, bupropion

(Wellbutrin) If good response of ADHD, add behavioral

interventions If behavior interventions fail, consider

guanfacine, clonidine (Catapres) Severe aggression, mood lability, consider

mood stabilizers and SGAs

Risperidone in Conduct Disorder:Study Design

6-week, double-blind, placebo-controlled study

110 children aged 5-12 with subaverage IQ (5-12 years)

0.02-0.06 mg/kg/day (0.98 mg/kg/day) mean dose

Snyder R et al. (2002), J Am Acad Child Adolesc Psychiatry 41(9):1026-1036

Efficacy of Risperidone in Conduct Disorder: Change in Aggression Score

Mea

n R

edu

ctio

n in

C

on

du

ct S

core

s

Snyder R et al. (2002), J Am Acad Child Adolesc Psychiatry 41(9):1026-1036

-18

-16

-14

-12

-10

-8

-6

-4

-2

0Baseline Wk. 1 Wk. 2 Wk. 3 Wk. 4 Wk. 5 Wk. 6

Placebo (N=57)

Risperidone (N=52)

Treatment Plan for ADHD/ODD

Serotonin reuptake inhibitors (e.g., fluoxetine [Prozac], paroxetine [Paxil]) not helpful for ADHD per se, rarely help ODD in absence of depression

Rational and irrational polypharmacy

CMAP Algorithm for Pharmacologic Management of ADHD and Aggression

Pliszka SR et al. (2006), J Am Acad Child Adolesc Psychiatry 45(6):642-657

Tics and ADHD

Many children with tics and ADHD can tolerate stimulants without an increase in tics Law and Schachar (1999): 12-month study, 91 children

MPH treatment did not produce significantly more tics than placebo in children with or without mild-to-moderate pre-existing tic disorder

Gadow et al. (1999): 24-month study, 34 children with ADHD and tic disorder or Tourette’s syndrome Stimulant treatment was effective in controlling ADHD symptoms

without adversely affecting tics Lipkin et al. (1994), in a review of 122 children treated with

stimulant medication found 9% developed transient tics and <1% developed chronic tics

Law SF, Schachar RJ (1999), J Am Acad Child Adolesc Psychiatry 38(8):944-951; Gadow KD et al. (1999), Arch Gen Psychiatry 56(4):330-336; Lipkin PH et al. (1994), Arch Pediatr Adolesc Med 148(8):859-861

Induction or Exacerbation of Tics

Tics are usually transient; only very rarely do patients develop a chronic tic disorder

When tics occur or increase Decrease dose Switch to another stimulant Adjunct agent to treat tics Try nonstimulant medication

Controlled Trial of MPH and ClonidineC

ha

ng

e in

Y-G

TS

ST

ota

l Sco

re

Y-GTSS = Yale Global Tic Severity Scale; Tourette Syndrome’s Study Group (2002), Neurology 58(4):527-536

-14

-12

-10

-8

-6

-4

-2

0Week 0 Week 4 Week 8 Week 12 Week 16

PLA

MPH

CLON

MPH + CLON

CMAP Algorithm for Pharmacologic Management of ADHD With

Comorbid Tic Disorder

Pliszka SR et al. (2006), J Am Acad Child Adolesc Psychiatry 45(6):642-657

Depressive Disorders

Major depressive disorder

Dysthymia

Adjustment disorder with depressed mood

Chronic dysphoria of adolescence (Non-DSM)

Ethical aspects of diagnosis—do really help people by broadening or ignoring our diagnostic criteria?

CDRS-R = Children’s Depression Rating Scale-Revised; Wagner KD et al. (2003), JAMA 290(8):1033-1041

Children and Adolescents With MDD: Score on the CDRS-R

Ad

just

ed M

ean

CD

RS

-R S

core

Visit Week

Important Issues

Only mildly depressed patients in trials

Suicidal patients/inpatients excluded

Drugs studied long after they have been on the market

Enrollment pressures

Treatment of Adolescent Depression Study (TADS)

FLX + CBT: 71% response

FLX alone: 61%

CBT alone: 43%

Placebo: 35%

SI present in 29% at baseline, all groups improved significantly

March J et al. (2004), JAMA 292(7):807-820

TADS—Suicidal Ideation

March J et al. (2004), JAMA 292(7):807-820

TADS—Harm and Suicide Related Events

March J et al. (2004), JAMA 292(7):807-820

Inte

nt

to T

reat

Cas

es

0

2

4

6

8

10

12

Harm Suicide Related

SSRI No SSRI

FDA Meta-Analysis

Pooled all studies, published and unpublished

Blinded reviewers at Columbia assessed each adverse event as to its self harm potential

N ~4,000

No suicides

4% SI on drug, 2% on placebo, statistically significant

Hammad TA et al. (2006), Arch Gen Psychiatry 63(3):332-339

Relationship of Suicide and SSRI Prescription Rate

Gibbons RD et al. (2006), Am J Psychiatry 163(11):1898-1904

Higher SSRI Prescription Rate

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

1 2 3 4 5 6 7 8 9 10

Nu

mb

er o

f S

uic

ides

p

er 1

00,0

00

Trends in Completed Suicide Since Boxed Warning

0

500

1000

1500

2000

2500

2003 2004

Ages 10-14 Ages 15-19 All ages

Hamilton BE et al. (2007), Pediatrics 119(2):345-360

Recent Meta Analysis

Reviewed 27 studies of MDD, OCD and anxiety disorders in children and adolescents 15 MDD studies 6 OCD studies 6 anxiety studies

Included studies not in FDA review

Number of participants MDD: 3,430 OCD: 718 Anxiety: 1,162

Bridge JA et al. (2007), JAMA 297(15):1683-1696

Recent Meta Analysis (Cont.)

DisorderTreatment

Response (%)Placebo

Response (%) p-Value

MDD 61 50 0.001

OCD 52 32 0.001

Anxiety 69 39 0.001

Treatment SI (%) Placebo SI (%)

MDD 3 2 0.08

OCD 1 0 0.57

Anxiety 1 0 0.21

Bridge JA et al. (2007), JAMA 297(15):1683-1696

Clinical Guidelines

Based on FDA meta-analysis, we tell families there is a 2-4% of SI vs. 1-2% on placebo; TADS study shows 60-70% chance of improvement of MDD

Tell families to watch for and report increase in agitation or SI

Use alternative SSRI (sertraline, citalopram) if fluoxetine fails, NRI after that1

1CMAP: Hughes et al. (in press), J Am Acad Child Adolesc Psychiatry

Algorithm for ADHD and depression

Issues in Pediatric Bipolar Disorder

What is the prevalence of BD in childhood and adolescence?

How should diagnostic criteria differ from adults, if at all?

What is the role of the comorbidity of ADHD with pediatric BD?

Aggression and BD

Controversies in treatment

Different Developmental Trajectories?

0 2 4 6 8 10 12 14 16 18 20 220 2 4 6 8 10 12 14 16 18 20 22

Mo

od

S

tate

Mo

od

S

tate

EuthymicEuthymic

ManicManic

DepressedDepressed

Adult SubtypeAdult Subtype

Adolescent SubtypeAdolescent SubtypeBP II or IBP II or I

BP NOS?BP NOS?

ADHD RxADHD Rx

??Pediatric Euphoric BPsPediatric Euphoric BPs

Age/YearsAge/Years

Mood Stabilizers

Classic mood stabilizers Lithium, divalproex, carbamazepine—despite use in

adults, limited studies in children

Negative studies Gabapentin (Neurontin) Tiagabine (Gabitril) Oxcarbazepine (Trileptal) Topiramate (Topamax)

Lamotrigine (Lamictal)—an emerging treatment

Study Week

Baseline

% P

os

itiv

eM

ea

n C

GA

S S

core

UrineDrug Assays

Children’s Global Assessment Scale (CGAS)

Scores

Lithium vs. Placebo Efficacy for Acute Treatment of Adolescents With BD and

Substance Dependency

Geller B et al. (1998), J Am Acad Child Adolesc Psychiatry 37(2):171-178

35

45

55

65

1 2 3 4 5 6

Lithium

Placebo

0

20

40

60

3 4 5 6

Lithium

Placebo

Lithium, Divalproex Sodium and Carbamazepine in the Treatment of

Bipolar Disorder: Study Design

42 outpatient participants

Mean age = 11.4 ± 3.0 years

6-8 week monotherapy period Randomized to lithium, divalproex or

carbamazepine Assessed weekly for 6-8 weeks Low dose chlorpromazine allowed as

“rescue medication”Kowatch RA et al. (2000), J Am Acad Child Adolesc Psychiatry 39(6):713-720

Lithium, Divalproex Sodium and Carbamazepine in the Treatment of BD:

Response Rates and Effect Size

1.0034Carbamazepine

1.0642Lithium

1.6346Valproate

Effect SizeITT

Response Rate (%)Medication

p=0.66; Kowatch RA et al. (2000), J p=0.66; Kowatch RA et al. (2000), J Am Acad Child Adolesc PsychiatryAm Acad Child Adolesc Psychiatry 39(6):713-720 39(6):713-720

Lithium, Divalproex Sodium and Carbamazepine in the Treatment of BD:

Responder’s Pattern of ResponseM

ean

Y-M

RS

Sco

re

Week

Kowatch RA et al. (2000), J Kowatch RA et al. (2000), J Am Acad Child Adolesc PsychiatryAm Acad Child Adolesc Psychiatry 39(6):713-720 39(6):713-720

0

5

10

15

20

25

30

35

1 2 3 4 5 6 7 8

Carbamazepine

Valproate

Lithium

Randomized

Lithium in Adolescents With Bipolar Depression

27 adolescents (12-18 years old), BD-I current episode depressed

6-week open-label trial of lithium monotherapy, titrated to serum level of 1-1.2 mEq/L

Response rate: 48%

Remission rate: 30%

Patel NC et al. (2006), J Am Acad Child Adolesc Psychiatry 45(3):289-297

Lithium (Li) and Risperidone (Risperdal)

38 children and adolescents, mean age 11.4, all with early onset BD, mixed or manic

All participants received Li monotherapy first

17 responded to Li monotherapy, remaining 21 were augmented with risperidone, response rate rose to 85.7%

Predictors of nonresponse to Li monotherapy: ADHD, severity, history of abuse, preschool age at start

of treatment

Pavuluri MN et al. (2006), J Child Adolesc Psychopharmacol 16(3):336-350

Divalproex Treatment for Youth With Explosive Temper and Mood Lability: A Double-Blind,

Placebo-Controlled Crossover Design

20 outpatients Mean age = 13.8 80% male 90% special education

Divalproex 6-week crossover trial

Donovan SJ et al. (2000), Am J Psychiatry 157(5):818-820

Divalproex Treatment for Youth With Explosive Temper and Mood Lability:

Response to Treatment

25280010Placebo

866780810Divalproex

%NN%NNTreatment

ImprovementImprovement

Phase 2:Completed Treatment

(N=15)

Phase 1:Initial Treatment

(N=20)

Donovan SJ et al. (2000), Am J Psychiatry 157(5):818-820

Divalproex and Lithium for Pediatric Mania

Kowatch et al. (2006), presented at AACAP meeting in Boston

150 patients aged 7-17 years randomized to divalproex, lithium or placebo for 8 weeks

Divalproex superior to placebo, trend for lithium to be superior to placebo

Depakote ER in pediatric mania

Wagner et al. (2006), presented at AACAP meeting, Boston

150 adolescents (10-17 years) with mania randomzied to placebo or Depakote ER for 4 weeks, then enrolled in 6 month open label study

Titrated to serum level of 80-125 µg/mL

No difference between Depakote ER and placebo in reducing symptoms of mania

Valproate and Polycystic Ovary Disease (PCOS)

230 women with bipolar disorder ages 18-45 in the Systematic Treatment Enhancement of Bipolar Disorder (STEP-BD) study

86 valproate users, 144 non-valproate users

On medication at least 3 months

Median 12 months for valproate, 17 months for other mood stabilizers (non-antipsychotic)

Joffe H et al. (2006), Biol Psychiatry 59(11):1078-1086

Valproate and PCOS (Cont.)

p=0.002; Joffe H et al. (2006), Biol Psychiatry 59(11):1078-1086

0

2

4

6

8

10

12

Type of Mood Stabilizer

Valproate

Non-Valproate

Rat

e o

f P

CO

S (

%)

Risk of Rash With Lamotrigine

1/10 rash; 3/1,000 serious rash; 1/100 pediatric patients1

Increased rash risk1, 2

Higher starting doses Faster initial titration Youth (age <18) Concurrent valproate (doubles lamotrigine levels)

1Package insert Lamotrigine (2006); Available at: www.fda.gov. Accessed Jan. 26, 2007; 2Calabrese JR et al. (1999), J Clin Psychiatry 60(2):79-88

Case Studies With Lamotrigine

16-year-old girl with severe, melancholic depression; unresponsive to 2 SSRIs and bupropion, partial response to venlafaxine, full response to venlafaxine + lamotrigine

11-year-old male with severe euphoric manner, pressured speech, flight of ideas, clanging, severely motor driven, no response or adverse event to lithium, valproate, all SGAs

Lamotrigine in Adolescents With Bipolar Depression

20 adolescents (mean age = 15.8), 7 boys, 13 girls—BD-I or -II in current depressive episode

Lamotrigine started at 12.5-25 mg/day, mean final dose 131.6 mg/day, 7 participants on other medications

19 participants completed trial

Response rate: 84%, remission rate: 63%

Chang K et al. (2006), J Am Acad Child Adolesc Psychiatry 45(3):298-304

Other Anticonvulsants

Gabapentin: no evidence for effectiveness as mood stabilizer in adults or children

Topiramate: negative study in adults, trend toward efficacy in children and adolescents; no plan for development as mood stabilizer—cognitive side effects; substance abuse agent?

Oxcarbazepine: no difference from placebo in child/adolescent mania trial1

A new antiepileptic does not a mood stabilizer make

Wagner KD et al. (2006), Am J Psychiatry 163(7):1179-1186

SGA Antipsychotics

Current agents Risperidone Olanzapine (Zyprexa) Quetiapine (Seroquel) Ziprasidone (Geodon) Aripiprazole (Abilify)

Powerful

Sometimes necessary

Limit use because of ... Sedation Weight gain

Comparative Pharmacology of SGA Antipsychotics

Ziprasidone Risperidone

Olanzapine Quetiapine

Clozapine

5-HT2A

m1

H1 5-HT2C

D21

H1

5-HT2A

D2

5-HT2C

15-HT1D

5-HT2A

D2

H1 1

5-HT2C

m1

5-HT2C1H1

5-HT2A

D25-HT1A

m1

1

H1 D2

5-HT2A

5-HT1A

5-HT2C

5-HT1A

Olanzapine in pediatric mania

Tohen et al. Am J Psychiatry 164: 1547

161 adolescents randomized to placebo or olanzapine

Difference from placebo noted in week 1, very significant difference by week 3

Very serious weight gain and increase in serum lipids, glucose

Quetiapine in pediatric mania

0

20

40

60

Remission (%)

400 mg

600 mg

Placebo

Delbello et al. (AACAP, 2006)

277 randomized to quetiapine (400/600) or placebo for 3 weeks

Difference from placebo at days 4 and 7

Sedation common (28-30%)

1.7 kg (3.7 lbs) weight gain

Aripiprazole in pediatric mania

0

5

10

15

20

25

30

35

40

45

50

Week 1 Week 2 Week 3 Week 4

Placebo

10 mg

30 mg

N = 296

4 week study

Remission rates

Low EPS

Little wt gain

Chang et al, (2006) presented at AACAP

Comparison of Divalproex + Quetiapineor Placebo in Children With BD

30 inpatients participants BD-I Mean age = 14 Randomized for 42 days

DVPX + placebo DVPX + QUE Mean VPA level

DVPX + placebo = 93 μg/ml DVPX + QUE = 106 μg/ml

QUE titrated from 25 mg bid to 450 mg/day by day 7

Mean dose of QUE = 432 mg/dayDelBello MP et al. (2002), J Am Acad Child Adolesc Psychiatry 41(10):1216-1223

Comparison of Divalproex + Quetiapineor Placebo in Children With BD Change in

YMRS Score From Baseline to End

p=0.006

p<0.0001Remission

DelBello MP et al. (2002), J Am Acad Child Adolesc Psychiatry 41(10):1216-1223

0

5

10

15

20

25

30

35

DVPX + Pbo DVPX + QUE

Baseline Endpoint

Comparison of Quetiapine and Divalproex for Adolescent Mania

50 adolescents aged 12-18 with bipolar I disorder, manic or mixed

Randomized to quetiapine (400-600 mg/day) or divalproex (serum level 80-120 mcg/mL)

28-day inpatient study

Delbello MP et al. (2006), J Am Acad Child Adolesc Psychiatry 45(3):305-313

Comparison of Quetiapine and Divalproex for Adolescent Mania

Delbello MP et al. (2006), J Am Acad Child Adolesc Psychiatry 45(3):305-313

0

10

20

30

40

50

60

70

80

90

CGI-Overall CGI Mania YMRSRemission

Divalproex

Quetiapine

Per

cen

t R

esp

on

se p=0.02

p=0.03

p=0.02

Antipsychotic Weight Gain: Meta-Analysis

Allison DB et al. (1999), Am J Psychiatry 156(11):1686-1696

Zipr

asid

one

Halope

ridol

Chlor

prom

azin

e

Risper

idon

e

6

5

4

3

2

1

0

-1

-2

-3

Placeb

o

Olanza

pine

Cloza

pine

Placebo

Conventional antipsychotics

Novel antipsychotics

95%

CI f

or

Wei

gh

t C

han

ge

(kg

)• 95% CI for weight change after 10 weeks on standard drug doses, estimated from a

random effects model

Algorithm for ADHD and BP

If floridly manic, use SGA or classic mood stabilizer (lithium, valproate) as monotherapy- growing trend to prefer SGA first line

If ADHD symptoms persist, may add stimulant to mood stablizer or SGA

If diagnosis of BP unclear (hypomanic) proceed with ADHD treatment. As a general rule, little evidence that stimulants precipitate mania (Biederman et al, J Child Adolesc Psychopharmacol, 9:247, 1999

If ADHD treatment markedly improves hyperactivity/impulsivity but mood remains labile, irritable or elated, add SGS or classic mood stablizer

Algorithm for ADHD and BD: difficult cases

Has failed lithium, divalproex and SGA only, consider: (Stimulant or ATX) + SGA + lithium and/or divalproex (Stimulant or ATX) + lamotrigine* (Stimulant or ATX) + lamotrigine* + SGA (Stimulant or ATX) + lamotrigine + SGA + lithium

Avoid antidepressants

Little enthusiasm for novel anticonvulsants, might consider topiramate

Combining SGA’, SGA + clonidine not recommended