Dealing with Difficulties

in Treating Bipolar
Disorder
Suryo Dharmono
Department of Psychiatry, Faculty
of Medicine, University of Indonesia

oBipolar traits: 66% of awardwinning writers, poets, painters

and sculptors
oMood disorder 40 % artists
oMood disorder 80% of creative
writers

Ludwig AM. Creative achievement and psychopathology: comparison among professions. Am J

Ilustrasi Kasus
Tn S, 35 tahun, Wiraswasta, tidak
menikah
Ditegakkan diagnosis MDD episode
berulang sejak 4 tahun yang lalu
Riwayat tidak patuh berobat, hampir
setiap tahun mengalami kekambuhan
Setiap kali kambuh respons terhadap
obat antidepresan sangat baik,
pemberian sertraline 50mg per hari
remisi gejala dalam waktu kurang dari 2
minggu pasien menghentikan obat

 Pada kekambuhan yang terakhir gejala

depresi lebih berat dan tidak berespons
terhadap pemberian sertralin sampai
dengan 100mg/hari
Terapi diubah dengan Venlavaxin 150mg.
Pada minggu kedua muncul perubahan
gejala pasien menjadi agitasi, irritable
dan cenderung agresif. Sempat mencoba
bunuh diri dengan meminum semua obat.

Questions .
Treatment Resistant
Depression ?
Mall-Treatment ?
Miss-Diagnosis ?
What should we do ?

Self Awareness'
10 status dengan diagnosis akhir
Gangguan Bipolar , dilakukan kajian
terhadap stabilitas diagnosis pada
evaluasi awal:
- 3 status pernah didiagnosis depresi berat
- 2 status pernah didiagnosis skizofrenia
- 1 status pernah didiagnosis skizoafektif
- 1 status pernah diagnosis anxietas panik
- Hanya 3 status yang di diagnosis bipolar
dari sejak awal

Miss-Diagnosis Bipolar
Base on Initial Assessments
60%
60

Depresion
Persentasi (%)

50

Anxiety

40
30

Schizophrenia

26%
18% 17%

20
10

14%

Borderline personality

Alkohol Abuse

0
NDMDA = National Depressive and Manic-Depressive Association; N = 400
Hirschfeld RM, et al. J Clin Psychiatry. 2004;65(suppl 15):5-9.

Diagnosis of Bipolar Disorder:

Often Made Years After Initial
Presentation
Professional consultation
Within 6 months of symptom onset = 23%

Consultations before correct diagnosis

3 = 48%
7 = 10%

Diagnosis >10 years after presentation

of bipolar illness
24%
National Depressive & Manic-Depressive Association (NDMDA) Survey of Bipolar Illness.
Lish, et al. 1994.

Think Bipolar
When..

Think Bipolar
When
Treatment resistant to
antidepressants
Antidepressants cause
agitation,irritability
Perugi, Toni, et al., 2003

Think Bipolar
When
History of + response to
antidepressants, but
loss of efficacy after
a month or two

Think Bipolar
When?
Clear Seasonal Pattern
MDD with racing
thoughts

Think Bipolar
When?
Psychotic Symptoms
Frequent recurrence
more than one a year
.almost 100%
Atypical Symptoms of
Depression

Treatment challenges in
bipolar disorder
Initial diagnosis

Bipolar disorder is often unrecognised

and undiagnosed

Comorbidities

Common, can hinder diagnosis

Depression

Predominant symptomatic phase,

can lead to misdiagnosis

Chronic disorder

Need for long-term symptom stability

across both poles

Phenotypes

Bipolar I vs bipolar II, rapid cycling, mixed states

Evans. J Clin Psychiatry 2000; Hirschfeld et al. J Clin Psychiatry 2003; Judd et al. Arch Gen Psychiatry 2002;
Judd et al. J Affect Disord 2003; Citrome & Goldberg. Postgrad Med 2005; Kupka et al. Bipolar Disord 2007

Objectives of treatment
Functionalit
y
Remission
Improvement

Outcomes in mania are not as

good as commonly believed
Symptomatic remission
(70%)

n=34

n=79

Remission sustained
8 weeks
(35%)

n=40

Remission sustained
1 year
(19%)

n=22

Open-label continuation study of olanzapine treatment;

113 patients with acute mania followed for up to 1 year
(mean duration 27.9 20.1 weeks)
Adapted from Chengappa et al. Bipolar Disord 2005

Remission versus functional

recovery:
pan-european EMBLEM study
1,656 bipolar I patients
2-year follow-up

Percentage of patients

64%

34
%

Clinical remission:
6 months
asymptomatic
Functional recovery:
clinical remission
+ good social
function
(work, independence, social
activities and relationships)
Haro et al; EMBLEM Advisory Board. Eur
Neuropsychopharmacol 2011

An ideal treatment will

achieve clinical AND functional
remission
Acute symptom
control

Coping with stigma/

social exclusion

Relapse prevention
Insight
Subsyndromal
symptom control
Personal autonomy

Improved
functioning

Physical health
Sleep
Cognition

Improvements in all
dimensions of bipolar
disorder are extremely
important for improving
quality of life

Three Phases of
Treatment

Episode

0-2 months
Symptomatic

Continuation

2-12 months
Functional

Maintenance

Indefinite
Stability/adaptive

Each phase has specific goals

Each phase has specific pharmacological and nonpharmacolo
Treatment must be harmonized across phases
Nicol Ferrier, Psyhobiology

Issues in Treatment of Bipolar Disorder

Lithium
More effective against classic mania than mixed mania or rapid cycling
Slow onset of action
Tolerability issues

Conventional antipsychotics Atypical antipsychotics

Effective against mania, but not
against depressive symptoms
Tolerability issues, particularly EPS

Effective against mania and emerging

efficacy data in depressive symptoms
Fewer motor side effects than
conventional antipsychotics

Anticonvulsants
No class effect in severe mania
Tolerability problems

Drug interactions

Antidepressants
May exacerbate or even promote mania symptoms

Agents Approved for Bipolar I Disorder

in the U.S.
Acute Mania

Maintenance

Acute Depression

Year Drug

Year Drug

Year Drug

1970 Lithium

1974 Lithium

1973 Chlorpromazine

2003 Lamotrigine

1994 Divalproex

2004 Olanzapine

2003 Olanzapinefluoxetine
combination

2000 Olanzapine*

2005 Aripiprazole

2006 Quetiapine

2003 Risperidone*
2004 Quetiapine*

*Adjunctive as well as monotherapy

2004 Ziprasidone
2004 Aripiprazole
2004 Carbamazepine

Ketter TA (ed). Advances in the Treatment of Bipolar

Disorders. Am Psychiatric Press, Inc. 2005:2.

Broad Efficacy Spectra of Atypical

Antipsychotics
Agent

Mixed

Psychotic

Rapid
Cycling

Olanzapine1,2

Risperidone3,

Quetiapine5,p

Ziprasidone6,

Aripiprazole7,
p

Tohen M, et al. Am J Psychiatry 1999;156:702-9; 2Tohen M, et al. Arch Gen Psychiatry 2000;57:841-9;
3
Sachs G et al. Am J Psychiatry. 2002;159:1146-1154; 4Hirschfeld RM, et al. Am J Psychiatry
2004;161:1057-65; 5Yatham LN, et al. J Clin Psychopharmacol 2004;24:599-606; 6Potkin SG, et al. 157th
APA Ann Mtg, New York, May 1-6, 2004; 7Jody D, et al. 157th APA Ann Mtg. New York, NY, May 1-6, 2004. p
1

FDA-approved Bipolar Disorder Treatments

Agents

Manic

Mixed

Maintenance

Depression

Lithium
Lithium

Divalproex
Divalproex DR
DR

Divalproex
Divalproex ER
ER

Carbamazepine
Carbamazepine ER
ER

MOOD
MOOD STABILiseR
STABILISER

ANTYPICALS
ATYPICALS

Risperidone
Risperidone

Olanzapine

Quetiapine

Ziprasidone

Aripiprazole
Aripiprazole

Lamotrigine

Olanzapine/fluoxetine

OTHER

Drugs listed in order of approval for a bipolar disorder indication.

This chart does not imply comparable efficacy or safety profiles.
Physicians Desk Reference. 60th ed. Montvale, NJ: Medical Economics Co; 2006.

AMAZE STUDY
ARIPIPRAZOLE EFFECTIVE TO IMPROVE
SYMPTOMS IN
BIPOLAR DISORDERS
Aripiprazole
0

N = 107 112

15

13

N = 44 45

78

80

10

12

14

12

14

Manic

Mixed

(aripiprazole vs placebo)
manic 28.2 vs 28.2
Mixed 28.9 vs 26.5

16

112 112

10

12

N = 10 13

10

16

Mean changes in YMRS total

score

Mean changes in YMRS total

score

LOCF Last observation Carried Forward)

Mean changes in YMRS total

score

Placebo

14
With
Without
psychot psychotic
ic
symptoms
sympto
(Aripiprazole
vs placebo)
ms
With
30.3 vs 30.0
Without 27.2 vs 26.9

Hori et al.: Japanese Journal of Clinical

16

Rapid cyclingNon-rapid
cycling
(Aripiprazole vs placebo)
rapid 32.7 vs 28.2
Non-rapid 27.9 vs 28.0

26-Week Double-Blind Aripiprazole vs Placebo

Continuation/Maintenance Monotherapy
Aripiprazole Compared to Placebo After Manic/Mixed Episodes

Percent of Patients

50

Superior
Episode
Prevention
43%

Equivalent
Depression
Prevention

Equivalent
Mixed
Prevention

Superior
Mania
Prevention

40
p=.013

30

25%

20

Aripiprazole 24.3 mg/d (n=77)

p=.009

12% 13%

10
0

5%
Overall
Relapse

23%

Placebo (n=83)

Relapse into
Depression

6%

Relapse into
Mixed

8%
Relapse into
Mania

Stabilized on open ARI before randomization (mean 12.7 weeks). Relapse criteria - hospitalized or medication added.
Keck PE, et al. J Clin Psychiatry 2006;67:626-37.

AMAZE study: Incidence of the most

frequent adverse events among patients
treated with Aripiprazole by period
Incidence of adverse event (%)

Adverse Events (occurring rate at 5 )

akathisia
insomunia
tremor

vomiting
nausea

constipation

diarrhoea

salivary hypersecretion
blood CPK increased

headache

1-4 5-7

8-10

11-14

15-28

endpoint*

Time period (day)

* Adverse events that I expressed to the day after the endpoint

Hori et al.: Japanese Journal of Clinical Psychiatry.2012

AMAZE study: weight and prolactin

levels
Mean change from baseline
(kg)

(ng/mL)

Kanba S. et al.: The World Journal of Biological Psychiatry, in press

Consensus on Antipsychotic Drugs on

Obesity &Diabetes
Antipsychotic

Weight Gain

Diabetes Risk

Dyslipidem

Clozapine

+++

Olanzapine

+++

Risperidone

++

Quetiapine

++

Aripiprazole

+/-

Ziprasidone

+/-

+ = increased effect - = no effect 0 = discrepant results

Table adapted from :
American Diabetes Association , American Psychiatric Association ,
American Association of Clinical Endocrinologist , North American Association For Study of Obesity ,
Consensus development conference on antipsychotic drugs and obesity and diabetes
J Clin Psychiatry 2004 ; 65:267-272

Conclusion
Bipolar disorder is a chronic,

recurrent, often life-long illness,

which often leads to a major
deterioration in the persons
quality of life and level of
functioning
The bipolar disorder are a
complicated and mixed set of
illnesses, with much shared
symptomatology

 Under-recognition and

misdiagnosis are very common in

bipolar disorder
A correct diagnosis is essential to
the management of people with
bipolar disorder
The management of bipolar
disorder is complicated because
of; often miss diagnosis,
polypharmacy standard of care,
and problem of non compliance

 Atypical antipsychotics are

increasingly used as mono
therapy or in combination with
mood stabilizer
Aripiprazole a novel antipsychotic
FDA-approved for acut mania and
maintenance

Lanjutan Kasus
Pasien menjalani rawat inap selama 4
minggu
Antidepresan dihentikan
Aripiprazole 15mg + Na Divalproat
500mg minggu ke 3 perawatan
gejala remisi minggu ke 4 pasien
dipulangkan
Diagnosis pulang Gangguan Bipolar
Episode kini campuran

Waiting a miracle
occur..???

Sometimes questions
are more important than answers
- David Baird-