Principles of Disease Management for Bipolar Disorder

1

• Principles of Disease Management for Bipolar
  Disorder

2

• Accurate Treatment
• Follows Accurate Diagnosis

3
PrinciplesApplication to Individualized
Treatments

• Formulate a clear impression about the disease
  phenomenology and clinical state for which a
  treatment is being devised
• Distinguish comorbid disorders from differential
  diagnoses
• Avoid treatments that visibly worsen either phase
  of the illness
• Assure adequate duration of medication trials
  prior to determining that a treatment lacks
  efficacy
• Adjunctive antidepressants have shown no greater
  efficacy than mood stabilizers alone for bipolar
  depression
• Know which medications have or have not been
  studied in bipolar disorder
• Do not presume psychotropic class effect
  generalizations

Goldberg J, et al. J Clin Psychiatry.
200768(12)1982-1983.
4
PrinciplesApplication to Individualized
Treatments (cont)

• Differentiate psychotropic effects other than
  mood stabilization for anticonvulsants and other
  psychoactive agents
• Favor pharmacologic parsimony when feasible
• Certain psychotropic agents may exert targeted
  benefits for specific symptoms or psychopathology
  dimensions, regardless of efficacy for affective
  syndromes
• Use antipsychotic medications at appropriate
  dosages to treat psychosis
• Consider the extent to which mood stabilizing
  agents exert relative antimanic versus
  antidepressant effects
• Exercise caution when combining potentially
  redundant medications or medications that may
  exert undesirable pharmacokinetic or
  pharmacodynamic interactions

Goldberg J, et al. J Clin Psychiatry.
200768(12)1982-1983.
5
Drug ResponseDependent on 3 Variables
2. Drug Concentration Absorption Distribution Meta
bolism Elimination
1. Affinity Receptors Enzymes Uptake Pumps
3. Patient Genetics Age Disease Environment
Clinical Response
Adapted from Preskorn S. J Pract Psychiatry Behav
Health. 1999550-55.
6
Drug SpecificityComparative Receptor Binding
Profiles
Clozapine
Olanzapine
Quetiapine
Risperidone
Ziprasidone
Aripiprazole
Haloperidol
Adapted from Gareri P, et al. Clin Drug Invest.
200323(5)287-322. BMS Data on file.
7
Rationale-based PharmacotherapyImportant
Principles
Values represent Ki (nM) values in blue reflect
the highest binding affinity for a given drug
values in green reflect the lowest affinity
Adapted from Weiden P, et al. J Clin Psychiatry.
200768(7)5-46.
8
Binding Affinities for Atypical Antipsychotics
and Tricyclic Antidepressants for Norepinephrine
Transporter (NET)
Compound / drug
NET Ki (nM)
Quetiapine Norquetiapine Clozapine Olanzapine Risp
eridone Paliperidone Aripiprazole Ziprasidone Nort
riptyline Amitriptyline Imipramine Desipramine
gt 10000 35 3168 gt 10000 gt 10000 gt
10000 2093 44 2 13.3-35 52 0.55
Data from NIMH Psychoactive Drug Screening
Program Goldstein J, et al. Eur Psychopharmacol.
200717(S4)S401. Using ex vivo methodology
there was no inhibition of norepinephrine
reuptake with ziprasidone at serum
concentrations typically observed during
treatment (Owens and Nemeroff, personal
communication).
9
Mood Stability andAtypical Antipsychotics

• HypothesisAntidepressant effect is mediated by
• Downregulation of 5-HT2 receptors
• Inhibition of the norepinephrine transporter
• 5-HT2C antagonism which should lead to dopamine
  release in the frontal cortex
• Antimanic effect mediated by D2 blockade

10
Rationale-based PharmacotherapyImportant
Principles

• Agonist full activation of a receptor acts in a
  similar manner to the endogenous neurotransmitter
  or protein/hormone
• Antagonist no activation receptor is in a
  resting state
• An antagonist has affinity, but not signal
  transduction or efficacy
• Partial agonist partial receptor activation
• In the absence of an intrinsic agonist, a partial
  agonist will produce partial receptor activation
• In the presence the intrinsic agonist, a partial
  agonist acts like an antagonist, but it cannot
  block the receptor more than its intrinsic
  activity
• The net effect of a partial agonist is a function
  of the concentration of both the partial agonist
  and the endogenous full agonist

Weiden P, et al. J Clin Psychiatry.
200768(7)5-46.
11
Initial Treatment of Bipolar Disorders in the
United States 20022003
Antidepressant monotherapy twice as common as
mood stabilizers
70
50
60
First prescribed drug class ()
50
40
17
30
15
11
8
20
10
0
Lithium
Sedative
Antipsychotic
Antidepressant
Anticonvulsant
N 7,760 patients with bipolar disorder 69 BP
I, 16 BP II, 14 BP NOS Data from US national
MarketScan research databases
Baldessarini R, et al. Psychiatr Serv.
200758(1)85-91.
12
Treatment of Bipolar Disorders Psychotropic
Drugs at Study Midpoint
80
70
60
Antidepressant
Lithium
50

Antipsychotic
40
Anticonvulsant
30
Sedative-anxiolytic
20
Subtotal
10
0
Bipolar I
Bipolar II
Bipolar I
Bipolar II
One drug
Two or more drugs
Bipolar I (N 4,375 patients)
Bipolar II (N 1,001 patients)
Baldessarini R, et al. Psychiatr Serv.
200758(1)85-91
13
Medication Use in Children/Adolescents With
Psychosis or Mood Disorders

• Great public concern about use of medications in
  vulnerable populations
• Regulatory concern about off-label use of
  medications
• Clinicians need to be vigilant as to what is and
  is not approved for use in pediatric populations
• Need to justify rationale as well as document
  decisions
• Family involvement critical
• Careful re-evaluation of risk-benefit
• Black box safety concerns regarding suicidality
  in youth

14
National Trends in Outpatient Treatment of
Children/Adolescents With Antipsychotic Drugs

• Office-based visits by children and adolescents
  that included antipsychotic treatment
• 201,000 in 1993
• 1,224,000 in 2002
• Antipsychotic treatment included in
• 9.2 of mental health visits
• 18.3 visits to psychiatrists
• From 20002002, 92.3 of prescriptions for an
  antipsychotic included a second-generation
  medication

1600
1400
1200
1000
800
Visits per 100,000 Population
600
400
200
0
1993-1995
1996-1997
1998
1999
2000
2001
2002
Year
Olfson M, et al. Arch Gen Psychiatry.
200663(6)679-685.
15
Outcome of First-episode Manic Adolescents
Syndromic recovery 0.86 Poor predictors ADHD,
DBD, anxiety disorders, nonadherence, low
socioeconomic status Symptomatic recovery
0.43 Functional recovery 0.41 Syndromic
recurrence 0.54 Predictors Alcohol use, no
psychotherapy, antidepressants
DelBello M, et al. Am J Psychiatry.
2007164(4)582-590.
16
Adherence to Pharmacotherapy in First-episode
Bipolar Adolescents
Percent
50
45
40
35
30
25
20
15
10
5
0
Full adherence
Partial
Nonadherence
(gt 75)
(2575)
(lt 25)
DelBello M, et al. Am J Psychiatry.
2007164(4)582-590.
17
Youth/AdolescentsEarly Phases of Bipolar Disorder

• Challenges
• Poor insight in young patients having a first
  episode may lead to difficulty with medication
  adherence
• Comorbidity with alcohol and substance abuse,
  suicidal behavior, psychotic symptoms
• Illness interference with educational, social,
  and sexual development
• Rapid relapse with medication discontinuation
• Greater symptom severity with early-onset illness
• Impact on families
• Advantages of Early Intervention
• Resilience of youth
• Medication efficacy in first episode
• Potential for neuroprotection with mood
  stabilizers
• Psychoeducational and psychosocial interventions
  particularly effective early in illness
• Prevention of secondary sequelae (family
  relationships, psychosexual development,
  vocational implications)

Berk M, et al. Med J Aust. 2007187(S7)S11-S14.
18
Treatment of Youth/Adolescent Bipolar Disorder
Aripiprazole and risperidone are FDA approved
for mania in youth ages 10 and up. Lithium is
FDA approved for mania in youth ages 12 and up.
19
Lithium for Adolescent BP and SUD

• 6-week, double-blind, placebo-controlled
• N 25 adolescents with BP and SUD
• 60 vs 9 response rate, CGAS ? 65

CGAS
Urine Drug Assays

60
60
50
50
40
40
Positive
Mean CGAS Score
30
30
20
20
10
10

0
0
6
4
5
6
3
2
4
5
1
3
Baseline
Weeks
Weeks
P 0.03 P 0.04 SUD substance use
disorders CGAS Childrens Global Assessment
Scale Geller B, et al. J Am Acad Child Adolesc
Psychiatry. 199837(2)171-178.
20
Open-Label Lithium for Adolescent Bipolar
Depression
Mean (SD) CDRS-R Total Score
80
70

60


P Value
Endpoint Mean (SD)
Baseline Mean (SD)



50
40
lt 0.001
38.5 (17.6)
64.0 (12.1)
CDRS-R
30
20
0.008
10.7 (7.1)
15.1 (7.0)
YMRS
10
0.02
1.2 (1.7)
2.6 (3.2)
SAPS
0
0
7
14
21
28
35
42
Day
CDRS-R Childrens Depression Rating
Scale-Revised YMRS Young Mania Rating Scale
SAPS Scale for the Assessment of Positive
Symptoms
P lt 0.001 compared with baseline score
Patel N, et al. J Am Acad Child Adolesc
Psychiatry. 200645(3)289-297.
21
Open-Label Trial of Lamotrigine for Adolescent
Bipolar Depression
70
60

50

CDRS-R
40
30
20
10
0
1
7
6
0
5
4
2
3
8
Week
P 0.04 vs baseline P 0.001 vs baseline
P lt 0.001 vs baseline
CDRS-R Childrens Depression Rating
Scale-Revised
Chang K, et al. J Am Acad Child Adolesc
Psychiatry. 200645(3)298-304.
22
Oxcarbazepine for Pediatric Mania
0
Oxcarbazepine (N 55)
Placebo (N 55)
-5
Change in Mean Score on Young Mania Rating Scale
-10
-15
14
21
28
35
42
7
Day
Wagner K, et al. Am J Psychiatry.
20061631179-1186.
23
Adolescents With Bipolar ManiaYMRS Change from
Baseline Olanzapine vs Placebo
0
Olanzapine
Placebo
-2
-4
Primary Efficacy Analysis
-6

-8
-10
LS Mean Change

-12
P 0.062 P 0.002 P lt 0.001 P lt 0.001

-14

-16

-18
-20
LOCF
0.5
1
2
3
Weeks
Tohen M, et al. Am J Psychiatry.
2007164(10)1547-1556.
24
Quetiapine and Divalproex for Adolescent Mania
40
Divalproex

• Repeated measures analysis of variance (LOCF)
  No significant group differences in YMRS scores
  across 28 days of study (P 0.30)
• Mixed Regression analysis Improvement in YMRS
  occurred more rapidly in the quetiapine group
  vs divalproex (P 0.03)
• Response and remission rates were significantly
  greater in the quetiapine than divalproex group
  (P lt 0.03)

35
Quetiapine
30
25
20
YMRS Score
15
10
5
0
0
7
21
28
14
Day
DelBello M, et al. J Am Acad Child Adolesc
Psychiatry. 200645(3)305-313.
25
YMRS Change From Baseline Quetiapine vs Placebo
in Children/Adolescents
0
4
7
14
21
0
400 mg Quetiapine 600 mg Quetiapine Placebo
-4
-8
LS Mean

-12

-16


-20
Days
P lt 0.001 vs placebo P 0.035 NS
DelBello M, et al. AACAP Annual Meeting, October
23-28, 2007. Abstract B10.
26
Aripiprazole for Pediatric Bipolar Disorder

• Double-blind, placebo controlled trial
• N 302, Low dose 10 mg, High dose 30 mg
• Ages 1017 years
• 4-week trial
• Change YMRS Low dose 14, High dose 17,
  Placebo 8
• 50 drop in YMRS 26 placebo, 45 10 mg, 64 30
  mg
• Side effects EPS, weight gain
• FDA approval for pediatric patients (1017 years)
  with bipolar disorder February 2008

Chang K, et al. AACAP Annual Meeting, October
23-28, 2007. Abstract B6. Correll C, et al. AACAP
Annual Meeting, October 23-28, 2007. Abstract B7.
27
Other Atypical Antipsychotics for Youth With
Bipolar Disorder

• Positive double-blind placebo-controlled studies
  in acute manic or mixed episodes associated with
  BP in adolescents (ages 10-17 years)
• Risperidone-FDA approval
• Ziprasidone

http//www.fda.gov/bbs/topics/news/2007/NEW01686.h
tml. Pandina G, et al. AACAP Annual Meeting,
October 23-28, 2007. Abstract F21. DelBello M, et
al. Biol Psychiatry. 200863(7)283S, Abstract
892.
28
Treatment of Youth/Adolescent Bipolar Disorder
Side Effects

• Weight gain
• EPS
• Sedation
• Dyslipidemia
• Prolactin elevation

Patel N, et al. J Child Adolesc Psychopharmacol.
200717(3)303-311. DelBello M, Kowatch R. Dev
Psychopathol. 200618(4)1231-1246.
29
Treatment of Adult Bipolar Disorder
30
Effectiveness of Adjunctive Antidepressant
Treatment for Bipolar Depression Primary
Effectiveness Outcome
30
20

10
0
Durable recovery 8 wks euthymia (no more than 2
depressive or 2 manic symptoms) Switch DSM
criteria for hypomania or mania or required
treatment Powered to detect an absolute
difference of 15 in recovery rates No
differences between patients with BP I and BP II
Sachs G, et al. N Eng J Med. 2007356(11)1711-172
2.
31
Effectiveness of Adjunctive Antidepressant
Treatment for Bipolar Depression Outcomes
According to Treatment Group
Outcome
Transient remission (P 0.40)
50
48.7
45
Durable recovery (primary outcome) (P 0.40)
41.3
40
38
35
32.4
Transient remission of durable recovery (P 0.23)

30
27.3
25
23.5
Treatment-effectiveness response (P 0.27)
21.4
20
17.9
12.3
15
Treatment-emergent affective switch (P 0.84)
10.7
10.1
10
9.1
5
Discontinuation of study medication because of
adverse event (P 0.32)
0
Mood Stabilizer Placebo (N 187)
Mood Stabilizer Antidepressant (N 179)
Sachs G, et al. N Eng J Med. 2007356(11)1711-172
2.
32
Self-Reported History of Manic/Hypomanic Switch
Associated With Antidepressant Use (Adults)

• Retrospective study of STEP-BD Patients (first
  500 enrolled)
• 338 patients with prior antidepressant
  treatment and complete data on switch outcomes
• 44 reported at least 1 switch occurrence
• Results/Conclusions
• High risk of switch for
• BP patients with short duration of illness
• Multiple antidepressant trials
• Past experience of switch with at least 1
  antidepressant
• Treatment of bipolar patients with
  antidepressants is associated with potential risk
  for treatment-emergent mania or hypomania
• Important to assess patient-specific
  vulnerabilities when considering risk-benefit for
  treatment of bipolar depression

Truman C, et al. J Clin Psychiatry.
200768(10)1472-1479.
33
No Faster Recovery From Mixed Depression With
Adjunctive Antidepressants
288 BP I or II patients with full depression plus
2 manic symptoms
1.0
Log Rank Statistic P 0.651
0.8
Interaction Effect Antidepressant use x of
mania symptoms at baseline higher YMRS score
after 3 months (F 4.22, P 0.006)
0.6
Proportion of Patients Not Recovering
0.4
0.2
0.0
100
0
20
40
80
60
Time to Recovery or Recovering (days)
Goldberg J, et al. Am J Psychiatry.
2007164(9)1348-1355.
34
Is Past Year Antidepressant Use Associated with
Rapid Cycling Over a One-Year Prospective Period?
Antidep (n 720) No Antidep (n 471)
Percent
1
2 or 3
4
0
Number of Episodes
X2 69.1, df 3, P lt 0.0001
Schneck C, et al. Am J Psychiatry.
2008165370-377.
35
MADRS Response Rates Across Six Lamotrigine
Multicenter Acute Bipolar Depression Studies
P 0.005
PBO
LTG
P 0.21
P 0.03
P 0.89
P 0.36
P 0.42
Percentage of Subjects
Calabrese et al 1999
LamLit Study
SCAA2010
SCA40910
SCA30924
SCA100223
2003-2006 BP 1 2
1996-1997 BP 1
1996-1998 BP 1 2
2000-2002 BP 1
2003-2005 BP 1
2003-2005 BP 2
Response 50 improvement over
baseline Calabrese J, et al. Bipolar Disord.
200810323-333. Geddes J, et al. BMJ.
200633232-33. Van der Loos M, et al. J Clin
Psychiatry. In Press.
36
Acute Treatment of Bipolar DepressionLamotrigine
Monotherapy - Adverse Events

• Combined safety population of 5 studies
• N 515 placebo N 531 lamotrigine

Includes mania, hypomania, mixed episodes
Calabrese J, et al. Bipolar Disord.
200810323-333.
37
Quetiapine Monotherapy for the Treatment of
Bipolar Depression
MADRS Total Score
Study Week
Study Week
1
2
4
3
6
5
7
8
0
1
2
4
3
6
5
7
8
0
0
0
Placebo (n 169)
Placebo (n 161)
Mean Change From Baselinea
QTP 300 mg/d (n 172)
QTP 300 mg/d (n 155)
QTP 600 mg/d (n 151)
QTP 600 mg/d (n 170)
-4
-4

-8
-8





-12
-12

Improvement















-16
-16










BOLDER I N 511
BOLDER II N 467
-20
-20
P lt 0.01 vs placebo, P lt 0.001 vs placebo
aValues are least squares mean
Calabrese J, et al. Am J Psychiatry.
20051621351-1360.
Thase M, et al. J Clin Psychopharmacol.
200626600-609.
38
Common Adverse Events Leading to
WithdrawalBOLDER I II Safety Population
Calabrese J, et al. Am J Psychiatry.
20051621351-1360. Thase M, et al. J Clin
Psychopharmacol. 200626(6)600-609.
39
EMBOLDEN STUDIESEfficacy of Monotherapy
Quetiapine in BipOLar DEpressioN

• Two similarly designed acute quetiapine trials
  except each had different active comparators
• EMBOLDEN I lithium (6001800 mg/d 0.61 mEq/L)
• EMBOLDEN II paroxetine (20 mg/d)
• Each study had two phases
• Acute Phase replicated BOLDER design
• Continuation Phase
• Remitters on quetiapine were re-randomized to
  either quetiapine (300 mg) or placebo and studied
  for an additional 2652 weeks

Young A, et al. 3rd Biennial Conf Int Soc Bipolar
Disorders January 2008 New Delhi,
India. McElroy S, et al. 3rd Biennial Conf Int
Soc Bipolar Disorders January 2008 New Delhi,
India.
40
EMBOLDEN STUDIESPrimary Endpoint Change in
MADRS Total Score
EMBOLDEN II Study week
EMBOLDEN I Study week
1
2
4
3
6
5
7
8
2
4
3
5
1
6
7
8
0
0
Quetiapine 600 mg (n 263)
Quetiapine 600 mg (n 232)
Quetiapine 300 mg (n 255)
Quetiapine 300 mg (n 229)
Placebo (n 129)
Placebo (n 121)
-5
-5
Lithium (n 136)
Paroxetine (n 118)

LSM Change from Baseline
-10
-10




-15
-15




-20
-20
P lt 0.05 P lt 0.01 P lt 0.001 vs.
placebo. ITT, LOCF
Young A, et al. 3rd Biennial Conf Int Soc Bipolar
Disorders January 2008 New Delhi,
India. McElroy S, et al. 3rd Biennial Conf Int
Soc Bipolar Disorders January 2008 New Delhi,
India.
41
EMBOLDEN I and IIAcute Tolerability Summary

• Both doses of quetiapine were generally well
  tolerated
• The most common adverse events with quetiapine
  included
• Somnolence, dry mouth, dizziness in EMBOLDEN I
• Dry mouth, sedation, somnolence, dizziness in
  EMBOLDEN II
• Clinical laboratory test results showed a greater
  increase in triglyceride levels with quetiapine
  than placebo
• Quetiapine showed a low incidence of
• EPS (including akathisia)
• Treatment-emergent mania/hypomania
• Suicidal behavior and ideation

Young A, et al. 3rd Biennial Conf Int Soc Bipolar
Disorders January 2008 New Delhi,
India. McElroy S, et al. 3rd Biennial Conf Int
Soc Bipolar Disorders January 2008 New Delhi,
India.
42
DepressionNot Responding to Treatment
25

• Open-label randomized trial
• Adults
• Prior nonresponse to MS AD
• LTG 150250 mg/day
• INO 1025 gms/day
• RIS up to 16 mg/day
• Up to 16 weeks
• Recovery lt 2 sxs for 2 mos

20
15
Recovery Rate ()
10
5
0
Lamotrigine (N 21)
Inositol (N 23)
Risperidone (N 23)
Nierenberg A, et al. Am J Psychiatry.
2006163210-216.
43
Burden of Treatment

• Side effect burden of treatments for depressive
  symptoms in bipolar disorder
• Treatments
• Lamotrigine, olanzapine, quetiapine
• Common adverse events in depression studies
• Lamotrigine headache, nausea, rash
• Olanzapine somnolence, weight gain, increased
  appetite, asthenia
• Quetiapine dry mouth, sedation/somnolence,
  dizziness, constipation

Calabrese J, et al. Eur Neuropsychopharmacol.
200717(S4)S355.
44
Monotherapy Treatment for Acute ManiaCategory A
Evidence
80
70
Placebo
Lithium
60
Divalproex
Carbamazepine
50
Olanzapine
Monotherapy Response Rates
40
Risperidone
Quetiapine
30
Ziprasidone
Aripiprazole
20
10
0
Weisler, 2004
Bowden, 1994
Tohen, 1999
Tohen, 2000
Khanna, 2005
Hirschfeld, 2004
Vieta, 2005
Keck, 2003
Keck, 2003
Sachs, 2006
N 179
N 204
N 139
N 115
N 290
N 259
N 403
N 210
N 262
N 272
Category A Evidence Derived from randomized,
double-blind, placebo-controlled studies with
adequate sample size
Adapted from Sachs G. FOCUS. 20075(1)3-13.
45
Adjunctive Treatment for Acute ManiaCategory A
Evidence
Neuroleptic Placebo
80
Lithium or Valproate Placebo
70
Valproate
60
Risperidone
50
Haloperidol
Response Rates
40
Olanzapine
30
Quetiapine
20
Overall Atypical antipsychotic
10
0
Muller-Olinghausen, 2000
Sachs, 2002
Yatham, 2003
Tohen, 2002
Sachs, 2004
Yatham, 2004
Ketter, 2005
Adjunctive Treatment
N 934
N 136
N 156
N 151
N 344
N 191
N 402
Category A Evidence Derived from randomized,
double-blind, placebo-controlled studies with
adequate sample size
Adapted from Sachs G. FOCUS. 20075(1)3-13.
46
Treatment for Acute Bipolar Depression Category
A Evidence
70
Placebo
60
Lamotrigine (50 mg/day)
50
Lamotrigine (200 mg/day)
Olanzapine (5-20 mg/day)
40
Response Rates
Olanzapine Fluoxetine Combination (6 25,
6 50 or 12 50 mg/day)
30
20
Quetiapine (300 mg/day)
10
Quetiapine (600 mg/day)
0
Calabrese, 1999
Tohen, 2003
Calabrese, 2005
Thase, 2006
N 195
N 833
N 542
N 509
Category A Evidence Derived from randomized,
double-blind, placebo-controlled studies with
adequate sample size
Adapted from Sachs G. FOCUS. 20075(1)3-13.
47
Maintenance Treatment for Bipolar Disorder
Category A Evidence
90
Placebo
80
Valproate
70
Lithium
60
Lamotrigine
50
Recurrence Rates
Olanzapine
40
Aripiprazole
30
20
10
0
Bowden, 2000
Goodwin, 2004
Tohen, 2006
Keck, 2006
N 372
N 638
N 361
N 160
Category A Evidence Derived from randomized,
double-blind, placebo-controlled studies with
adequate sample size Maintenance of effect,
based on 6 month data
Adapted from Sachs G. FOCUS. 20075(1)3-13.
48
Treatment of Bipolar Disorders and Psychiatric
Comorbidities
Antidepressants may trigger mania or destabilize
bipolar disorder
Keck P, et al. J Clin Psychiatry. 200667(Suppl
1)8-15.
49
Bipolar Disorder and Substance Abuse Treatment
Response

• Tohen et al (1990)
• 24 lithium-treated BP patients - alcoholism
  predicted shorter remission
• Weiss et al (1998)
• Self-report compliance 21 compliance lithium vs
  50 divalproex in 44 bipolar-SUD patients
• Goldberg et al (1999)
• 204 substance abusers who received valproate or
  carbamazepine had remission from acute mania more
  often than substance abusers who received lithium
  alone (P lt 0.05)
• Salloum IM (2005)
• VPA found to be effective with co-occurring
  alcohol dependence
• Weiss et al (2005)
• Patients with bipolar disorder who experience
  sustained recovery from SUDs have a better QOL
  than with an active SUD
• Patients with no SUD history had the best QOL

Tohen M, et al. J Affect Disord.
19901979-86. Weiss R, et al. J Clin Psychiatry.
199859172-174. Goldberg J, et al. J Clin
Psychiatry. 199960733-740. Salloum I, et al.
Arch Gen Psychiatry. 20056237-45. Weiss R, et
al. J Clin Psychiatry. 200566730-735.
50
Efficacy vs Effectiveness

• Efficacy treatment results under highly
  controlled experimental conditions
• Narrow focus and inclusion/exclusion criteria of
  clinical trials can limit applicability to
  clinical practice
• Primary outcome measures/endpoints
• Short duration
• Effectiveness treatment performance in general
  clinical practice
• Broad spectrum of patients (including those with
  coexisting medical illnesses, comorbid substance
  abuse, history of treatment resistance)
• Practical outcomes

Nasrallah H. J Clin Psychiatry. 200768(S1)3-11.
51
Optimizing Treatment OutcomesComplicating Factors

• Difficulty and delay in diagnosis
• High levels of comorbidity that directly and
  indirectly complicate the course of illness
• Frequent treatment non-adherence
• High risk of relapse and recurrence, particularly
  in association with residual symptoms

Goldberg J. J Clin Psychiatry. In press.
52
Summary

• Anterior limbic abnormalities are present in
  bipolar disorder and progress, some are
  developmentally specific
• May be useful as biomarkers of treatment effects
  and response
• Studies of treatment of youth/adolescent bipolar
  patients are limited, especially in mood states
  other than mania
• Important to monitor the side effects associated
  with treatment of youth/adolescent patients with
  bipolar disorder
• Adjunctive use of antidepressants may be
  associated with treatment-emergent
  mania/hypomania or long-term cycle acceleration
  particularly for patients at high risk for
  switch treatment with antidepressants in
  patients with co-occurring manic and depressive
  symptoms may lead to greater manic symptom
  severity
• Use clinical principles to select interventions
  based on sound rationales and strategies
• Carefully and consistently monitor outcomes