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ADHD: Diagnosis and Treatment of More Than One Disorder. Steven R. Pliszka, MD. Faculty Disclosure.

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faculty disclosure
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
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

Adverse Events of Stimulants

Update on the Controversy

estimated reporting rates 1992 2004 pediatric sudden death 18 years old
Estimated Reporting Rates (1992-2004): Pediatric Sudden Death (18 Years Old)

1IMS 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
Psychiatric Side Effects of Stimulants?

Duration

Psychosis

Type of

No. of

of trials

Category

Patient-

/mania

Suicidal

Aggression

trial

trials

(range)

of exposure

N

years

events

events

events

Drugs

Concerta

DB

4

6-28 dys

Placebo

317

10.20

0

0

0

Drug DB

321

12.68

0

0

0

<

12 mos.

OL

7

Drug OL

2824

1397.40

8

6

52

Metadate CD

DB

4

7-21 dys

Placebo

572

19.44

0

0

3

Drug DB

493

19.13

0

0

3

OL

2

NS

Drug OL

322

19.55

0

0

6

MTS

DB

8

1-49 dys

Placebo

464

23.84

0

0

1

Drug DB

471

30.26

4

0

6

OL

4

NS

Drug OL

617

341.97

6

1

7

Modafinil

DB

6

1-9 wks

Placebo

366

39.87

0

0

5

Drug DB

722

85.50

2

4

9

<

1 yr

OL

3

Drug OL

924

383.53

2

0

14

Adderall XR

DB

7

1-4 wks

Placebo

678

28.00

0

0

6

Drug DB

1236

77.18

0

1

20

<

2yrs

OL

6

Drug OL

5177

1767.47

14

8

166

<

78 wks

Atomoxetine

DB

20

Placebo

1443

350.73

0

4

18

Drug DB

2459

654.87

4

9

49

<

96 wks

OL

10

Drug OL

5270

5095.27

12

44

198

Ritalin LA

DB

5

1-14 dys

Placebo

259

11.31

0

1

0

Drug DB

383

25.66

2

0

2

OL

1

NS

Drug OL

125

25.95

0

1

0

<

49 dys

d-MPH

DB

8

Placebo

468

53.24

0

0

0

Drug DB

588

64.75

4

0

1

<

1 yr

OL

5

Drug OL

740

362.09

3

1

13

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

growth and stimulants
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
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
Growth and Stimulants: Recent Studies

Preschool ADHD Treatment Study (PATS)

  • 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

growth and stimulants recent studies cont
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 cont11
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 cont12
Growth and Stimulants: Recent Studies (Cont.)

0.6

0.5

0.4

No meds

0.3

Controls

z Height

0.2

New meds

Incons

0.1

Cons meds

0

BSL

14 Mo.

24 Mo.

36 Mo.

-0.1

-0.2

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

growth and stimulants recent data
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
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
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 study change scores
Multimodal Treatment of ADHD Study: Change Scores

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

adhd childhood common comorbid diagnoses
ADHD—Childhood Common Comorbid Diagnoses

Approximate Prevalence Rate in Children With ADHD (%)

Male

Female

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

nature of odd and cd
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
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
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
ADHD-ODD/CD Issues With Stimulants

Pharmacotherapy and Substance Abuse

  • 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 adolescents with adhd
Pharmacotherapy and Substance Abuse: Adolescents With ADHD

Unmedicated

Medicated

45

40

35

30

25

Rate of SA (%)

20

15

10

5

0

EtOH Ab/Dep

Drug Ab/Dep

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

treatment plan for adhd odd
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
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
Efficacy of Risperidone in Conduct Disorder: Change in Aggression Score

Baseline

Wk. 1

Wk. 2

Wk. 3

Wk. 4

Wk. 5

Wk. 6

0

-2

Placebo (N=57)

-4

Risperidone (N=52)

-6

Mean Reduction in Conduct Scores

-8

-10

-12

-14

-16

-18

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

treatment plan for adhd odd26
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
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
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
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 clonidine
Controlled Trial of MPH and Clonidine

Week 0

Week 4

Week 8

Week 12

Week 16

0

-2

-4

PLA

Change in Y-GTSSTotal Score

-6

MPH

CLON

-8

MPH + CLON

-10

-12

-14

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

cmap algorithm for pharmacologic management of adhd with comorbid tic disorder
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
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?
slide33

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

Adjusted Mean CDRS-R Score

Visit Week

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

important issues
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
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
TADS—Suicidal Ideation

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

tads harm and suicide related events
TADS—Harm and Suicide Related Events

No SSRI

SSRI

12

10

8

Intent to Treat Cases

6

4

2

0

Harm

Suicide Related

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

fda meta analysis
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
Relationship of Suicide and SSRI Prescription Rate

1.8

1.6

1.4

1.2

Number of Suicides per 100,000

1.0

0.8

0.6

0.4

0.2

0

1

2

3

4

5

6

7

8

9

10

Higher SSRI Prescription Rate

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

trends in completed suicide since boxed warning
Trends in Completed Suicide Since Boxed Warning

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

recent meta analysis
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
Recent Meta Analysis (Cont.)

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

clinical guidelines
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

issues in pediatric bipolar disorder
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
Different Developmental Trajectories?

Pediatric Euphoric BPs

Mood State

?

Adult Subtype

Manic

BP NOS?

Euthymic

ADHD Rx

Adolescent Subtype

BP II or I

Depressed

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

Age/Years

mood stabilizers
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
lithium vs placebo efficacy for acute treatment of adolescents with bd and substance dependency
Lithium vs. Placebo Efficacy for Acute Treatment of Adolescents With BD and Substance Dependency

60

UrineDrug Assays

40

% Positive

20

Lithium

Placebo

0

3

4

5

6

65

Lithium

Children’s Global Assessment Scale (CGAS)Scores

Placebo

55

Mean CGAS Score

45

35

Baseline

1

2

3

4

5

6

Study Week

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

lithium divalproex sodium and carbamazepine in the treatment of bipolar disorder study design
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
Lithium, Divalproex Sodium and Carbamazepine in the Treatment of BD: Response Rates and Effect Size

Medication

ITT Response Rate (%)

Effect Size

Valproate

46

1.63

Lithium

42

1.06

Carbamazepine

34

1.00

p=0.66; 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 responder s pattern of response
Lithium, Divalproex Sodium and Carbamazepine in the Treatment of BD: Responder’s Pattern of Response

35

Carbamazepine

Valproate

30

Lithium

25

20

Mean Y-MRS Score

15

10

5

0

Randomized

1

2

3

4

5

6

7

8

Week

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

lithium in adolescents with bipolar depression
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
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

slide54
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
Divalproex Treatment for Youth With Explosive Temper and Mood Lability: Response to Treatment

Phase 1:Initial Treatment (N=20)

Phase 2:Completed Treatment (N=15)

Improvement

Improvement

Treatment

N

N

%

N

N

%

Divalproex

10

8

80

7

6

86

Placebo

10

0

0

8

2

25

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

divalproex and lithium for pediatric mania
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
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
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
Valproate and PCOS (Cont.)

12

10

8

Valproate

6

Rate of PCOS (%)

Non-Valproate

4

2

0

Type of Mood Stabilizer

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

risk of rash with lamotrigine
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
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
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
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

SGA Antipsychotics
comparative pharmacology of sga antipsychotics
Comparative Pharmacology of SGA Antipsychotics

Ziprasidone

Risperidone

5-HT2A

5-HT2A

D2

D2

5-HT2C

5-HT1A

Clozapine

1

5-HT1D

5-HT2C

5-HT2A

m1

H1

H1

1

D2

5-HT1A

Quetiapine

Olanzapine

5-HT2C

H1

1

5-HT2A

m1

5-HT2A

m1

D2

H1

D2

1

5-HT1A

5-HT2C

5-HT2C

H1

1

olanzapine in pediatric mania
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
Quetiapine in pediatric mania
  • 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
Aripiprazole in pediatric mania

N = 296

4 week study

Remission rates

Low EPS

Little wt gain

Chang et al, (2006) presented at AACAP

comparison of divalproex quetiapine or placebo in children with bd
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/day

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

slide70
Comparison of Divalproex + Quetiapineor Placebo in Children With BD Change in YMRS Score From Baseline to End

Baseline

Endpoint

35

30

25

p=0.006

20

Remission

p<0.0001

15

10

5

0

DVPX + Pbo

DVPX + QUE

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

comparison of quetiapine and divalproex for adolescent mania
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 mania72
Comparison of Quetiapine and Divalproex for Adolescent Mania

90

p=0.03

80

p=0.02

70

p=0.02

60

50

Divalproex

Percent Response

40

Quetiapine

30

20

10

0

CGI-Overall

CGI Mania

YMRS

Remission

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

antipsychotic weight gain meta analysis
Antipsychotic Weight Gain: Meta-Analysis
  • 95% CI for weight change after 10 weeks on standard drug doses, estimated from a random effects model

6

5

4

3

2

1

0

-1

-2

-3

Placebo

Conventional antipsychotics

Novel antipsychotics

95% CI for Weight Change (kg)

Placebo

Clozapine

Haloperidol

Olanzapine

Risperidone

Ziprasidone

Chlorpromazine

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

algorithm for adhd and bp
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
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