BIPOLAR DEPRESSION

1
BIPOLAR DEPRESSION

• David L. Dunner, MD, FACPsych
• Director, Center for Anxiety and Depression
• Mercer Island, WA
• Professor Emeritus, Department of Psychiatry and
  Behavioral Sciences
• University of Washington

2
(No Transcript)
3
Clinical Clues to Bipolarity in Unipolar
Depressed Patients

• Loaded family history
• Early age of onset (lt25 y) with high episode
  rates
• Psychotic features
• Seasonal pattern
• Antidepressant misadventures
• Treatment-emergent hypomania or agitation
• Erratic or uneven antidepressant responses
• Multiple antidepressant failures?treatment-resist
  ant depression

Ghaemi SN, et al. J Psychiatr Pract.
20017287-297. Goodwin FK, Jamison KR.
Manic-Depressive Illness. New York, NY Oxford
University Press, Inc 199056-73.
4
Unipolar vs Bipolar Depression in the Community
Severity of Depression
Plt.001
40
35
30.7
30
25
21.5
Mean CES-D Total Scores
20
Clinical Depression
15
10
5
0
Bipolar Depression
Unipolar Depression
CES-D Centers for Epidemiologic
Studies-Depression Scale. Hirschfeld RMA.
Personal communication.
5
Unipolar vs Bipolar Depression Psychosocial
Impairment
Bipolar depression
Unipolar depression
Plt.001
Plt.0001
Plt.0001
43.9
42.1
With Disruption
30.1
19.9
19.1
13.3
Work/School
Social/Leisure
Family Life
Marked or extreme over past 4 weeks.
Hirschfeld RMA, et al. Poster presented at 156th
Annual Meeting of the American Psychiatric
Association May 17-22, 2003 San Francisco,
California.
6
Bipolar Disorder

• Lifetime prevalence1,2
• BP I 1-1.6
• BP II 0.5
• Bipolar spectrum 5-8
• 90 recurrence3
• Number of episodes correlates with residual
  symptoms between episodes and treatment response1
• 25 of patients attempt suicide1 and about 15
  suicide
• High comorbidity eg, substance abuse2

1. Keck PE Jr, et al. Med Clin North Am.
200185645-661. 2. Evans DL. J Clin Psychiatry.
200061(suppl 13)26-31. 3. Muller-Oerlinghausen
B, et al. Lancet. 2002359241-247.
7
Depression Is the Predominant Mood in Bipolar I
Disorder
Based on the 12.8-year NIMH natural history study
(n 146), of the 47 of time spent
symptomatically ill, patients experienced
depressive symptoms 3 times more than manic
symptoms1
Cycling/ mixed
13
20
67
Manic
Depressed
Time spent symptomatically ill ()

• In another naturalistic study, patients treated
  for bipolar disorder experienced 121 days ill
  with depression, versus 40 with mania, in a
  single year (76 of patient cohort were patients
  with bipolar I disorder)2

1. Judd LL et al. Arch Gen Psychiatry.
200259530537. 2. Post RM et al. Clin Neurosci
Res. 20022142157.
8
ComorbiditiesThe Rule Not the ExceptionThe
Multidimensionality of Bipolar Disorder
DiabetesMellitus
Cardio-vascular
PainDisorders
Obesity
Migraine
BipolarDisorder
Substance Abuse
PersonalityDisorders
Comorbidities Medical Psychiatric
EatingDisorders
ADHD
AnxietyDisorders
ImpulseControl
McIntyre RS, Konarski JZ et al. Human
Psychopharmacol. 200419369-386.
9
Anxiety Disorder Comorbidity in Bipolar Disorder
McIntyre RS, Soczynska JK. Brodbar K, Bottas A,
Konarski JZ, Kennedy SH. Bipolar Disorder 2006
8665-676
10
Medical Comorbidity in Bipolar Disorder
N 37 984
 
No bipolar
Bipolar
Diabetes
5.8
6.6
Cancer
2.0
2.3
Heart disease
4.8
8.3
Effects of stroke
0.8
0.6
17.8
16.8
High blood pressure
Migraine
11.6
20.3
14.7
Asthma
7.1
Significantly higher than estimate for people
without bipolar (Plt.05)
McIntyre RS, et al. Psychiatric Services APPI
2006.
11
Mortality in Bipolar Disorder

• Excess mortality weighted averageof 16
  studies 2.28
• Suicide 4.7 - 52

Goodwin FK, Jamison KR. Manic-Depressive Illness.
New York, NYOxford University Press 1990.
12
Bipolar Disorders Are RecurrentRecurrence Rate
for Bipolar II Disorder

• 0.45 episodes of depression/ patient-year
  (placebo-treated bipolar II patients who had
  prior episodes)

Dunner et al. Arch Gen Psychiatry.
198239(11)1344-1345.
13
Principles of Bipolar Disorder Care

• Treat the illness, not just the episodes
• Help the patient learn about destabilizing
  factors
• Be empathetic, but blunt, about illness and
  denial
• Work to achieve recovery, not limited improvement
• Use regimens that yield excellent tolerability
  and adherence
• Acute episode drug needs are often different from
  maintenance, but they interact significantly

14
Mood Stabilization

• Acute Maintenance
• Mania/
• Hypomania
• Depression

15
Treatment of Acute Bipolar Depressive Episodes
16
Treatment of Bipolar Depressive Episode

• Lithium
• Antidepressants
• -MAOIS
• -(TCAs)
• SSRIs
• Others
• Some anti-epileptic drugs
• Olanzapine, Quetiapine, OFC
• Dopamine agonists, Omega 3 fatty acids
• ECT
• Psychotherapy

17
Antidepressant Response Linking Non-response to
the Patient with Bipolar Disorder
Initially fail to respond to antidepressant
therapy
51.3
31.6
Initially respond to antidepressant but then lose
response
53.8
15.8
Have a manic switch after starting antidepressant
therapy
48.8
0
0 10 20 30 40 50 60
Patient with Bipolar Disorder Patients with MDD
Ghaemi Am J Psych 2004
18
Treatment of Acute Bipolar I DepressionEfficacy
of Olanzapine
0

-5


Mean Change in MADRS Score


-10

Placebo (n377)
OLZ (n370)
-15



OLZ FLU (n86)
-20
0
2
4
6
8
Week
Plt0.05 vs OLZ FLU P lt0.05 vs OLZ.
OLZolanzapine FLUfluoxetine. Tohen et al. Ann
Meeting APA 2002 Philadelphia, Pa.
19
Summary Primary Outcome Analyses for BOLDER I
AND II
MADRS Total Score
P lt 0.001 vs placebo
ITT, LOCF
Calabrese J, et al. Am J Psychiatry.
20051621351-1360 Thase ME, et al. 2006. In
press.
20
EMBOLDEN IPrimary endpoint change in MADRS
total score
Study week
1
2
4
3
6
5
7
8
LSM change from baseline





plt0.05 plt0.01 plt0.001 vs placebo ITT, LOCF
Young et al 2008
21
EMBOLDEN IIPrimary endpoint change in MADRS
total score
Study week
1
2
4
3
6
5
7
8
LSM change from baseline


Improvement


plt0.05 plt0.01 plt0.001 vs placebo ITT, LOCF
McElroy et al 2008
22
Depressive Episodes Other Atypical Antipsychotics

• Risperidone
• Limited anecdotal experience
• Some evidence of reduction in depressive symptoms
  during augmentation of lithium or valproate in
  mania1
• Clozapine
• Is a mood stabilizer in addition to an
  antipsychotic
• Used as add-on therapy associated with
  significant clinical improvement vs
  treatment-as-usual2
• Aripiprazole
• Two placebo controlled studies showed positive
  results early but failed at endpoint
• Ziprasidone
• Open label study positive

1. Vieta E, et al. Collegium Internationale
Neuro-Psychopharmacologium (CINP), Brussels,
Belgium 2000. 2. Suppes T, et al. Am J
Psychiatry. 19991561164-1169.
23
Depressive Episodes Bupropion Treatment
BP II bipolar II disorder DMI desipramine
BUP bupropion. Haykal RF, Akiskal HS. J Clin
Psychiatry. 199051450-455. Sachs GS, et al. J
Clin Psychiatry. 199455391-393. Guille C, et
al. Bipolar Disord. 19991(suppl 1)33.
24
Depressive Episodes Topiramate and Bupropion SR

• 36 bipolar depressed patients on mood stabilizers
  received topiramate or bupropion SR for 8 weeks
• Response rates of 56.2 and 58.7 for topiramate
  and bupropion SR, respectively
• Remission rates of 24.8 and 27.5 for
  topiramate and bupropion SR, respectively
• Statistically significant reductions in CGI and
  YMRS for both drugs
• Weight loss observed in both groups

HDRS Hamilton Depression Rating Scale. 7.50
reduction in baseline HDRS17.Final HDRS17
?7. McIntyre RS, et al. Bipolar Disord.
20024207-213.
25
Depressive Episodes SSRI Treatment
Fluoxfluoxetine IMIimipramine PBOplacebo
Paroxparoxetine. Cohn JB, et al. Int Clin
Psychopharmacol. 19894313-322. Simpson SG,
DePaulo JR. J Clin Psychopharmacol.
19911152-54. Nemeroff CB, et al. Am J
Psychiatry. 2001158906-912.
26
Depressive Episodes SSRI Treatment (Contd)
Fluoxfluoxetine Paroxparoxetine
Venlafaxvenlafaxine Sertsertraline. Baldassano
C, et al. Depression. 19953182-186.Vieta E,
et al. J Clin Psychiatry. 200263508-512.Kroenke
K, et al. JAMA. 20012862947-2955.
27
Risks Associated With Antidepressant Use in
Bipolar Depression

• Antidepressant monotherapy (eg, TCAs, MAOIs,
  SSRIs, SNRIs) are associated with risk of
• Mania induction
• Cycle acceleration
• SSRIs and bupropion may be relatively safer with
  regard to these risks than TCAs

El-Mallakh RS, Karippot A. Psychiatr Serv.
200253580-584.Wehr TA, Goodwin FK. Am J
Psychiatry. 19871441403-1411.Vieta E, et al. J
Clin Psychiatry. 200263508-512.
28
Depressive Episodes Lithium (Li) Treatment

• Li gt placebo in 5/7 studies (N158)
• Pooled data
• 19 little or no antidepressant effect
• 81 significant antidepressant effect
• Li vs TCA studies1-3
• Some included unipolar depressions
• TCA ? Li in 3 studies (N98)1,2
• Potential antisuicide effect independent of
  mood-stabilizing effect3

1. Mendels J. Am J Psychiatry. 1976133373-378. 2
. Watanabe S, et al. Arch Gen Psychiatry.
197532659-668. 3. Nilsson A. J Clin Psychiatry.
199960(suppl 2)85-88.
29
Lamotrigine vs Placebo in Bipolar I Depression
(MADRS)
LOCF
Observed
0 -5 -10 -15 -20
0 -5 -10 -15 -20
Change from Baseline

Change from Baseline






PBO (n65) LTG 50 mg/day (n64) LTG 200 mg/day
(n63)








0 1 2 3 4 5 6 7 Time (Weeks)
0 1 2 3 4 5 6 7 Time (Weeks)
Plt.10Plt.05
Calabrese JR, et al. J Clin Psychiatry.
199960(2)79-88.
30
Depressive Episodes Treatment With
First-Generation Antiepileptic Drugs

• Valproic acid
• Effective in 5 open trials (n195) in bipolar
  depression1
• Effective as monotherapy or as an augmenting
  agent in an open trial of rapid cycling2
• Longer time to depressive relapse than with
  lithium or placebo3
• Effective in 78 of bipolar offspring (n24)
  experiencing mood and behavioral disorders4
• Carbamazepine
• Moderate or better improvement in 44 to 48 of
  patients in controlled trials with unipolar or
  bipolar depression5,6
• Full remission obtained in 63 (n27) in an open
  acute trial7

1. McElroy SL, et al. J Clin Psychopharmacol.
199212(suppl 1)42S-52S. 2. Calabrese JR,
Delucchi GA. Am J Psychiatry. 1990147431-434. 3.
Bowden CL, et al. Arch Gen Psychiatry.
200057481-489. 4. Chang KD, et al. J Clin
Psychiatry. 200364936-942. 5. Ballenger JC,
Post RM. Commun Psychopharmacol.
19782159-175. 6. Post RM, et al. Arch Gen
Psychiatry. 198340673-676. 7. Ballenger JC,
Post RM. Am J Psychiatry. 1980137782-790.
31
Depressive Episodes Electroconvulsive Therapy
(ECT)

• ECT gt TCAs, MAOIs in 5 studies1-5
• ECT TCAs, MAOIs in 1 study6
• ECT recommended after failure of gt2 mood
  stabilizers gt2 antidepressants in revised
  Expert Consensus Guidelines7

1. Greenblatt M, et al. Am J Psychiatry.
1982139977-984. 2. Bratfos O, Haug JO. Acta
Psychiatr Scand. 19684489-112. 3. Avery D,
Winokur G. Biol Psychiatry. 197712507-523. 4.
Avery D, Lubrano A. Am J Psychiatry.
1979136559-562. 5. Black DW, et al. Compr
Psychiatry. 198728169-182. 6. Homan S, et al.
Psychol Med. 198212615-624. 7. Sachs GS, et al.
Postgrad Med. 2000Spec No1-104.
32
Maintenance Treatment of Bipolar Depressive
Episodes
33
Management of Bipolar Disorder
A Treatment Challenge
34
Mood Stabilizers Lithium
STRENGTHS
WEAKNESSES

• Gold standard (for classic mania)
• Established efficacy in maintenance therapy
• Efficacy in augmenting antidepressants
• Suicide prevention

• Less effective in rapid cycling and (?) mixed
  states
• Limited efficacy against depression?
• Slow onset of action
• Need for plasma-level monitoring
• Low therapeutic index

American Psychiatric Association. Am J
Psychiatry. 2002159(4 suppl)1-50.Carney SM,
Goodwin GM. Acta Psychiatr Scand Suppl.
20054267-12. Nolen WA, Bloemkolk D.
Neuropsychobiology. 200242 suppl 111-17.Swann
AC, et al. Arch Gen Psychiatry.
19975437-42.Goodwin GM, et al. J Clin
Psychiatry. 200465432-441.
35
Lithium Reduces Frequencyand Severity of Bipolar
Episodes
Lithium
Placebo
Stallone et al. Am J Psychiatry.
1973130(9)1006-1010.
36
Pattern of Phases (M,D) and Intervals (I)
Li-Responsive!
Mania-Depression Interval (MDI)
Depression-(Hypo)Mania Interval (DMI)
Kukopulos A, et al. Pharmakopsychiatr
Neuropsychopharmakol. 198013156-167.
37
Lithium and Suicide

• Published studies 28
• Patients 17,000
• Suicide/suicide attempt rate
• 3.2 vs 0.37 per 100 patient-years
• After lithium discontinuation, rates of suicidal
  acts rose 7-fold, fatalities 9-fold

Tondo L, et al. Ann NY Acad Sci. 1997836339-351.
38
Mood Stabilizers and Suicide
39
Maintenance Treatment With Valproate, Lithium, or
Placebo (1 Year)
39
33
24
23
22
Percent
17
18
10
6
Bowden CL, et al. Arch Gen Psychiatry.
200057(5)481-489.
40
Mood Stabilizers Divalproex
STRENGTHS
WEAKNESSES

• Effective against mania
• Superior to lithium in mixed states
• Useful in comorbid substance abuse
• Can be started at a therapeutic dose
• Less cognitive dysfunction than lithium?

• Limited efficacy against depression?
• Weight gain and hair loss
• Teratogenesis
• Thrombocytopenia
• Polycystic ovary syndrome
• Pancreatitis
• Need for plasma-level monitoring
• Long-term efficacy not clearly established

American Psychiatric Association. Am J
Psychiatry. 2002159(4 suppl)1-50.Albanese MJ,
et al. J Clin Psychiatry. 200061916-921.Gyulai
L, et al. Neuropsychopharmacology.
2003281374-1382. Hirsch E, et al. Acta Neurol
Scand Suppl. 200318023-32.Stoll AL, et al. J
Clin Psychiatry. 199657356-359.Polifka JE,
Friedman JM. CMAJ. 2002167265-273.
41
Patients Without Relapse After 2.5 Years of
Prophylactic Treatment With Lithium vs
Carbamazepine
Percent
Greil W, et al. J Affect Disord.
199743(2)151-161.
42
Lithium vs Carbamazepine

• 2.5-year study N 171 patients with bipolar
  disorder
• Lithium statistically superior to carbamazepine
  in classical euphoric bipolar I disorder, but
  less well tolerated
• Carbamazepine better than lithium for
  mood-incongruent, atypical, nonclassical bipolar
  disorder
• Patient satisfaction statistically higher in
  carbamazepine group

Kleindienst N, Greil W. Neuropsychobiology.
200042(suppl 1)2-10.
43
Mood Stabilizers Carbamazepine
STRENGTHS
WEAKNESSES

• Limited efficacy against depression?
• Complex pharmacokinetics (many drug-drug
  interactions)
• Lowers steroidal contraceptive blood levels
• Hyponatremia, agranulocytosis, Stevens-Johnson
  syndrome

• Effective against mania
• Useful with comorbid substance abuse
• Relatively little weight gain

American Psychiatric Association. Am J
Psychiatry. 2002159(4 suppl)1-50.Weisler RH,
et al. J Clin Psychiatry. 200566323-330.Goldber
g JF, et al. J Clin Psychiatry.
199960733-740.Goldberg JF, Citrome L. Postgrad
Med. 200511725-26, 29-32, 35-36.Wilbur K,
Ensom MH. Clin Pharmacokinet. 200038355-365.
44
Lamotrigine Time to Intervention for Depression
LTG v. PBO, p 0.015 Li v. PBO, p 0.167 LTG
v. Li, p 0.355
Index Mania
Bowden et al., Arch. Gen. Psych. 2003
45
Mood Stabilizers Lamotrigine
STRENGTHS
WEAKNESSES

• Effective as depression prophylaxis and (to a
  lesser extent) as mania prophylaxis
• Little cognitive dysfunction
• Generally well tolerated, little or no adverse
  effect on weight

• Acute antidepressant effect less established
• Very slow titration rate
• Drug interactions (eg, valproate, carbamazepine,
  OCs)
• Rash, Stevens-Johnson syndrome

American Psychiatric Association. Am J
Psychiatry. 2002159(4 suppl)1-50.Goodwin GM,
et al. J Clin Psychiatry. 200465432-441.
Goldberg JF, Burdick KE. J Clin Psychiatry.
200162(suppl 14)27-33.Bowden CL, et al. Drug
Saf. 200427173-184.Sabers A, et al. Neurology.
200361570-571.
46
52-Week Olanzapine vs. Placebo MaintenanceTime
to Relapse Based on Hospitalization and/or
Symptomatic Rating Scale Criteria
Mania
Mania or Depression
100
Olanzapine 12.5 mg/day (n225)
Placebo (n136)
80
plt.001
plt.001
23.1
60
Probability of Remaining in Remission
55.1
Probability of Remaining in Remission
40
Plt.001
86.8
62
Olanzapine 12.5 mg/day (n225)
20
Placebo (n136)
plt.001
0
0
50
100
150
200
250
300
400
0
100
150
200
250
300
350
400
50
350
Time to Relapse of Mania (Days)
Time to Relapse of Mania or Depression (Days)
Depression
100
Olanzapine 12.5 mg/day (n225)
Placebo (n136)
80
plt.001
45.6
60
Probability of Remaining in Remission
40
71.9
20
0
0
50
100
250
300
350
400
150
200
Time to Relapse of Depression (Days)
YMRS or HAMD-21 Total scores ?15.
Tohen M, et al. 156th APA Annual Meeting May
17-22, 2003 San Francisco, CA. Abstract NR197.
47
26-Week Aripiprazole vs Placebo
MaintenanceAripiprazole Compared to Placebo
After Manic/Mixed Episodes
1.0
0.9
0.8
0.7
0.6
Proportion of patients without relapse
0.5
Log-rank P value 0.02
0.4
Relative ARI relapse risk 0.52 0.30, 0.91
0.3
Aripiprazole
0.2
Placebo
0.1
0.0
0
14
25
42
55
70
84
95
112
125
140
154
168
182
195
210
Days
Pts 48 less likely to relapse on aripiprazole
Keck PE, et al. 157th APA Annual Meeting May
1-6, 2004 New York, NY. Abstract NR746.
48
Issues in Selecting Treatment Rapid Cycling

• Avoid TCAs, which induce reversible rapid cycling
  in double-blind, placebo-controlled studies1
• Poor response to lithium monotherapy
• Thyroid (T4) may be helpful
• May respond to anticonvulsants
• Lamotrigine significant response (Plt.05) vs
  placebo and gabapentin2
• Carbamazepine has emerged as an adjunct or
  alternative therapy3

1. Wehr TA, Goodwin FK. Am J Psychiatry.
19871441403-1411. 2. Frye MA, et al. J Clin
Psychopharmacol. 200020607-614. 3. Post RM, et
al. Bipolar Disord. 20002305-315.
49
Principles of Bipolar Disorder Care

• Treat the illness, not just the episodes
• Help the patient learn about destabilizing
  factors
• Be empathetic, but blunt, about illness and
  denial
• Work to achieve recovery, not limited improvement
• Use regimens that yield excellent tolerability
  and adherence
• Acute episode drug needs are often different from
  maintenance, but they interact significantly

50
Bipolar I DisorderLong-term Maintenance Goals

• Provide effective maintenance therapy so as to
• Reduce cycling frequency and mood instability
• Prevent relapse
• Minimize subthreshold symptoms
• Maximize patient functioning
• Reduce suicidality
• Minimize adverse effects of treatment
• Enhance patient adherence to pharmacotherapy

Adapted from American Psychiatric Association. Am
J Psychiatry. 2002159(4 suppl)1-50.
51
Bipolar Disorder Long-term Pharmacotherapy
Nonadherence

• Range 20-66
• Median 41

Lingam R, Scott J. Acta Psychiatr Scand.
2002105164-172.
52
Mood Stabilizer Nonadherence

• Mood control by meds
• Missed highs
• A hassle
• Reminder of illness
• Felt well
• Felt less creative
• Felt less attractive
• Side effects
• Cost

Goodwin FK, Jamison KR. Manic-Depressive Illness.
New York, NY Oxford University Press
1990746-762. Breen R, Thornhill JT. CNS Drugs.
19989457-471.
53
Improving Treatment Adherence

• Therapeutic alliance
• Education
• Availability and support
• Psychotherapy
• Medication?minimize side effects, complexity, cost

Breen R, Thornhill JT. CNS Drugs. 19989457-471.
54
Bipolar Psychotherapies

• Family-focused
• Interpersonal and social rhythm
• Cognitive-behavioral
• Life goals program

55
Bipolar Relapse PreventionCognitive Therapy
Medication
1.0
Patients assigned to cognitive therapy (n48)
0.8
Patients assigned to control condition (n51)
0.6
Cumulative Proportion Without Episode
0.4
0.2
0
100
0
20
40
60
80
120
140
Time Until First Bipolar Episode (weeks)
Reproduced with permission from Lam DH, et al. Am
J Psychiatry. 2005162324-329.
56
Goals of Psychoeducation in Bipolar Patients

• Improve illness awareness
• Early identification of new episodes
• Enhance compliance
• Stress management
• Avoid substance abuse

Colom F, et al. Psychother Psychosom.
199867(1)3-9.
57
EducationEducationEducation
58
Depression and Bipolar Support Alliance (DBSA)
Formerly National Depressive and Manic-
Depressive Association (NDMDA)

• 730 N. Franklin Street, Suite 501
• Chicago, IL 60610
• [phone]
• www.dbsalliance.org
• and
• Moodswing by Ronald R. Fieve, MD
• Mood Charting

59
(No Transcript)
60
Symptom Domains of Bipolar Disorder
Manic Mood and Behavior
Dysphoric or NegativeMood and Behavior

• Euphoria
• Grandiosity
• Pressured speech
• Impulsivity
• Excessive libido
• Recklessness
• Social intrusiveness
• Diminished need for sleep

• Depression
• Anxiety
• Irritability
• Hostility
• Violence or suicide

BipolarDisorder
CognitiveSymptoms
Psychotic Symptoms

• Racing thoughts
• Distractibility
• Disorganization
• Inattentiveness

• Delusions
• Hallucinations

Goodwin FK, Jamison KR. Manic-Depressive Illness.
New York, NY Oxford University Press
199085-125.
61
Bipolar vs Unipolar DepressionDifferentiating
Characteristics
Adapted with permission from Akiskal HS. J Affect
Disord. 200584107-115.
62
The Natural Course of Depression in Bipolar
Disorder

• Average durations of phases of bipolar disorder
  (from NIMH Collaborative Depression Study1)
• Pure depression
• 19 weeks
• shorter duration than unipolar depression
• Pure mania 10 weeks
• Mixed states 36 weeks
• 20 remained depressed for ?1 year1

1. Keller MB, et al. JAMA. 19862553138-3142.
63
Bipolar Disorder Presents at an Early Age

• Age when symptoms begin to be a problem1
• lt15 years (33)
• 15-19 years (27)
• Age of onset (median) in a case registry2
  (n2308)
• 17.5 years

• Hirschfeld RMA, et al. J Clin Psychiatry.
  200364161-174.
• Kupfer DJ, et al. J Clin Psychiatry.
  200263120-125.

64
Bipolar DisorderLong-term Maintenance Goals
65
Maintenance Treatment to Help Maintain Stability
Against Depressive Episodes Is Particularly
Important
Depression a dominant next episode among
patients receiving placebo
during two 18-month maintenance trials
29
Mania
Patients currentlyor recently depressed
Depression
71
57
Mania
Patients currentlyor recently manic/hypomanic
Depression
43
Bowden CL et al. Arch Gen Psychiatry.
200360392400. Data on file, GlaxoSmithKline.
66
Medication Nonadherence (Noncompliance)
Medication-specific factors
Patient-specificfactors
Clinician-specificfactors
Breen R, Thornhill JT. CNS Drugs. 19989457-471.
67
Management of Bipolar Depression Challenges