adhd: diagnosis and treatment of more than one disorder steven r. pliszka, md
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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
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