BIPOLAR DISORDER

• Bipolar disorder (mania depresi) adalah suatu

penyakit yang ditandai dengan perubahan ekstrem
dari mood, pikiran, energi, dan tingkah laku.

• Bipolar disorder-
– Suasana hati seseorang dapat berubah antara mania
(highs) dan depresi (rendah)
– Perubahan mood ini dapat bertahan selama berjam-
jam, berhari-hari, berminggu-minggu atau bahkan
berbulan-bulan.
 What is bipolar disorder?
NICE Bipolar disorder guidelines 2006 www.nice.org.uk

Mania

Euthymia

Depression

• A chronic relapsing and remitting • Bipolar I – one or more manic or

disorder
• Abnormally elevated mood or
irritability alternates with
depressed mood
• In most cases depressive episodes
are more frequent than manic
ones
mixed episode, often
accompanied by one or more
major depressive episode
• Bipolar II – one or more major
depressive episode, accompanied
by one or more hypomanic
episode
 Types of Bipolar Disorder

• Bipolar Disorder 1
– Most severe, obscures normal functioning,
hospitalization common
• Bipolar Disorder 2
– Hypomanic,Full manic episodes rare. Depression
often still severe
• Cyclothymia
– Milder form of BP II, “Bipolar Spectrum
Disorder”. numerous periods with manic and
depressive symptoms not severe enough to
meet criteria for major episodes.
• NOS
 Some background information
NICE Bipolar disorder guidelines 2006 www.nice.org.uk
• Early onset
– usually before 30
years (peak in late
teens)
• Cause unclear
– although there is a
genetic component;
there is no cure
• Co-morbidity common
– e.g. anxiety,
personality disorder,
drug/alcohol abuse
• High risk of suicide
• Correct diagnosis difficult
– but is essential for effective
treatment
– often misdiagnosed as
depression initially
– frequently only recognised only
after several periods of
psychological or social
disturbance
• Recognition needs improving
– to enable early
diagnosis/referral and
appropriate treatment
– GPs have important role to play
in this
 RAPID CYCLING
 4 atau lebih episode dalam periode 12 bulan
 Rapid cycling=4 episode/tahun
 Ultrarapid cycling=5-364 episode/tahun
 Ultradian cycling=>365 episode/tahun
 Bipolar I Disorder
• Manic
*Maniaepisode*
– grandiosity,
lasts over
increased
one week
self-esteem,
or
requires hospitalization
decreased need for sleep, flight of ideas,
• agitation, excessive
Not secondary involvement
to substance abusein
• pleasurable activity of
Causes impairment -buying spree,
normal sex,
functioning
business investments
 Bipolar I Disorder
• May
Majorhave
depressive
psychotic
episodes
symptoms
often
when
precede
manic
oror
depressed
follow manic episodes
• 80%
No psychotic
will havesymptoms
multiple episodes
when stable
• Kindling
(distinguishes
effectfrom
of multiple
schizophrenia
episodesor
schizoaffective disorder)
 Mixed Episode
• Symptoms
*Excitable or
of agitated
both mania
but and
irritable
majorand
depression*
depressed instead of feeling euphoric
• Symptoms may alternate during the day
• Often more disabling and difficult to treat
 Rapid Cycling
• At
Mayleast
be triggered
four episodes
by taking
a yearantidepressants
of manic, for
hypomanic,episodes
depressive mixed or depressive episodes
• Present in 5% to 15% of patients with bipolar
disorder
 Bipolar II Disorder
• Hypomanic
*Hypomaniaepisode*
- elevated,
lasting
expansive
4 daysor
orirritable
longer
not requiring
mood but nothospitalization
as severe as mania
• Major
Not secondary
depressiveto substance
episodes often
abuseprecede or
• follow hypomanic
No impairment of episodes
normal functioning
 Cyclothymia
• Chronic
No episodes
moodmeet
disturbance
criteria for
with
mania
manyorperiods
major
of hypomania
depressive disorder
and depressed mood
• 15%
Episodes
to 50%
arerisk
generally
of developing
shorter bipolar
than in Ibipolar
or II I
or II
disorder
 Klasifikasi berdasarkan episode;
1. Mania
2. Depresi
3. Campuran
Mania
4. Hypomania Hypomania
Polarity of Symptoms

Euthymia

Subsyndromal
Depression
Depression
Depression
 Bipolar Disorder
Manic Depressive Illness
• Mania • Depression
– Mood yang tinggi dan lekas marah • Mood yang turun
– Grandiosity • Loss of interest or pleasure
(bersikap
berlebih-lebihan) • Change in appetite or weight
– Kebutuhan untuk tidur menurun • Insomnia or hypersomnia
– Berbicara dengan cepat dan • Letih,lelah
intonasi yang keras • Merasa tidak berguna
– Flight of ideas or racing thoughts • Konsentrasi dan memori yang
– Risk taking terganggu
– Functional impairment • Suicidality
• Clinically significant distress or
impairment

1-2% population prevalence worldwide

Symptoms of mania - the "highs" of bipolar
disorder
• Increased physical and mental activity.

• Heightened mood and self-confidence.

• Racing speech.

• Decreased need for sleep.

• In the most severe cases, delusions and

hallucinations may occur.
Symptoms of depression - the "lows"
of bipolar disorder
• Prolonged sadness.

• Social withdrawal.

• Feelings of guilt, worthlessness.

• Irritability and anger.

• Recurring thoughts of death or suicide.

 DIGFAST:
Symptoms of Hypomania and Mania
D Distractibility: poorly focused
I Insomnia: decreased need for sleep
G Grandiosity: inflated self-esteem
F Flight of ideas: c/o racing thoughts
A Activities: increased activities
S Speech: pressured or more talkative
T Thoughtlessness: “risk-taking” behaviors
sexual, financial, travel, driving
Ghaemi et al, World J Biol Psych 2: 65, 2000
 Patofisiologi?
• Teori Genetic.
• Teori Neurotransmitter.
• Teori Elektrolit.
• Teori Lingkungan.
• Kondisi medis, pengobatan, perawatan kejiwaan yang
dapat mengiduksi terjadinya mania.
 etiologi?

– Biochemical imbalances in the brain have a

role in the disorder.

– Genes also play a role in the disorder. The risk

for developing bipolar disorder is seven times
higher in families with a history of the illness
than in the general population (Sheslow, D.)

– Environmental factors may also play a role. A

traumatic event such as a death or divorce
could trigger the first episode of mania or
depression.
 prevalensi
• Age of onset early twenties
• 1-2% of the population worldwide
• Male and Female rates equal and it is
found in all ages, races, ethnic groups and
social classes
• 60-80% of cases begin with mania
• 4-18% of those with depression later
have mania
• Alcohol and substance abuse
 Social impact of Bipolar Disorder
• Affects more than 2.5 million Americans every year.

• Up to 90 percent of bipolar disorders start before age 20,

although the illness can start in early childhood or as late as
the 40's and 50's.

• An equal number of men and women develop bipolar illness

and it is found in all ages, races, ethnic groups and social
classes.

• A person with the disorder becomes extremely removed and

unable to perform with anyone around them.
 Social Impact contd.

• When they are in spells of mania they cannot work with

others because they become very argumentative and bossy.

• It is impossible to imagine the pain and stress experienced by

a family member or friend of a person with the disorder.

• Often people with the disorder lose all ability to communicate

with others and become completely unattached.
 Economic Impact
• In 1990, the World Health Organization identified bipolar disorder
as the sixth leading cause of disability-adjusted life years in the
world among people aged 15 to 44 years (Woods, SW 2004)

• There is typically a five to ten year delay between onset of the

illness and the time of first proper treatment or first hospitalization
(Stimmel, GL)

• Individuals with bipolar disorder often see multiple doctors and seek
treatment for many years before receiving a proper diagnosis.
 Economic Impact contd.
• Often job is lost

• Cost of medicine and therapy

sessions

• Loss of medical Insurance

• Person has no money to put back into economy

 diagnosis? Clinical Self-report
Form
• Diagnosa penyakit bipolar disorder
– laporan pribadi kejadian yang dialami
oleh penderita dan juga laporan
mengenai kelainan perilaku penderita
dari anggota keluarga, teman atau teman
Clinical Monitoring
kantor Form
– observasi sekunder oleh psikiater,
perawat, pekerja social, psikolog klinis
atau klinisi lainnya dengan penilaian klinis
Screening for Mania and Mixed States
The Mood Disorder
Questionnaire (MDQ) is a
validated screening
instrument for bipolar I
and II disorders
Hirschfeld RM, et al. Am J
Psychiatry. 157:1873, 2000
The Questionable Quad –the 4 I’s
George Winokur, Classification of Mania & Depression, 1991

Irritability
Insomnia
Impulsivity
Impaired Social/Vocational Life

>4 Days – Hypomania

<4 Days – Bipolar NOS
 How is bipolar disorder treated?

• Can be treated by a family doctor.

• Treated with medicines to stop the mood swings
• Mood stabilizers are used to even out highs and lows
• Counseling is strongly encouraged.
 TREATMENT APPROACHES
• Non farmakologi
– Psikoedukasi kepada penderita dan keluarga mengenai
bipolar disorder, pengobatan,dan monitoring penyakit.
– Psikoterapi (individual, kelompok, atau keluarga)
– Kurangi stress, terapi relaksasi (pijat, yoga)
– Tidur yang cukup dan terjadwal, hindar alkohol dan
kafein menjelang tidur.
– Nutrisi dan asupan protein dan asam amino esensial,
suplemen vitamin dan mineral yang cukup
– Olah raga.
 Therapies With Bipolar Disorder Indications
Bipolar Bipolar
Therapy Maintenance Mixed States
Mania Depression
Valproate Yes No* No Yes
Lithium Yes No* Yes No
Carbamazepine Yes No No Yes
Lamotrigine No No Yes No
Aripiprazole Yes No Yes Yes
Olanzapine Yes No Yes Yes
Quetiapine Yes Yes No No
Risperidone Yes No No Yes
Ziprasidone Yes No No Yes
Olanzapine+fluoxetine (OFC) No Yes No No

Limited data
*

Physicians’ Desk Reference®. 61st ed. Montvale, NJ: Medical Economics

Co; 2007.
 Algorithm and Guidelines for the Acute Treatment of
Mood Episodes in Patients with Bipolar I Disorder

 General Guidelines
 Monitor penyebab terjadinya mania/mixed/depresi (eg alkohol,
penyalahgunaan obat)
 Kurangi sedikit demi sedikit antidepresan,stimulan/kafein jika
memungkinkan
 Obati ketergantungan obat
 Cukupi asupan nutrisi,olahraga,tidur yang cukup,kurangi stres dan
terapi psikososial
 Optimalkan terapi mood stabilizer sebelum menggunakan
BZ,Antidepresan.
 Gunakan antipsikotik bila muncul gejala psikosis
 ECT digunakan untuk kejadian yang berat atau terapi sudah resisten
pada pasien
 Episode Mania/Mixed

Mild-Moderate Moderate-Severe

Lithium/Valproate/atypical Kombinasi 2 obat : -

antipsikotik. Alternatif : Litium/valproat +
antikonvulsant antipsikotik.
Alternatif :antikonvulsan
Jika respon tidak
Jika respon tidak cukup +kan BZ
cukup +kan BZ (terapi jangka
Jika respon
pendek). Lorazepam
(terapi jangka tidak
direkomendasikan
pendek)
Respon tidak cukup,gunakan
untuk terapi
cukup maka kombinasi
katatonia3
gunakan obat: -
kombinasi 2 Litium+antikonv
obat : a. litium + ulsan+antipsikot
antikonvulsan/a ik, atau –
ntipsikotik antikonvulsan+a
Jika respon
ntikonvulsan+a
tidak cukup,
ntipsikotik
gunakan
terapi ECT
 Episode Depresi

Mild-Moderate Moderate-Severe

Kombinasi 2 obat : -
Mood Stabilizer : Litium/Lamotrigin +
litium/Lamotrigin. antidepresan atau
Alternatif : antikonvulsan Litium+Lamotrigine.
Alternatif antikonvulsan
Jika respon tidak
cukup
Jika +kan
respon
antipsikotik
tidak (terapi
jangka pendek).
cukup,gunakan
kombinasi 3
obat: -
Litium+antikonv
ulsan+antidepre
san, atau –
Lamtrigine+anti
Jika respon
konvulsan+anti
tidak cukup,
depresan
gunakan
terapi ECT
 No benefit with antidepressants for
bipolar depression with manic symptoms

Goldberg et al. Am J Psychiatry 2007:164:1348-1355

 Lithium
 Direkomendasikan untuk terapi Bipolar Disorder
 60-80% success in reducing acute manic and
hypomanic states
 Menurunkan reuptake 5-HT dan meningkatkan
sensitivitas reseptor postsinaptik 5-HT
 Menginhibisi sintesis Dopamine, menurunkan jumlah
reseptor β-adrenergik
 Meningkatkan aktivitas GABAergik dan
menormalkan kadar GABA.
 Menurunkan aktivitas glutaminergik
 Menurunkan transport kalsium dalam sel,
 Lithium vs Placebo in Maintenance
1.2
Lithium
Probability of Remaining Well

1 Placebo

0.8

0.6

0.4

0.2

0
0 10 20 30 40 50 60
Follow-Up (weeks)

Keck PE Jr, et al. Biol Psychiatry. 2000;47:756-761.

 Lithium Reduces Mortality

Cochrane Controlled Trials Registry: 32 Randomized Trials

1389 patients randomized to lithium; 2069 randomized to active comparators

Odds 95% Confidence

Outcome
Ratio Interval
Suicide 0.26 0.09–0.77

Suicide and Deliberate

Self-Harm 0.21 0.08–0.50

All Causes of Death 0.42 0.21–0.87

riani A, et al. Am J Psychiatry. 2005;162:1805-1819.

 Side Effects and Toxicity
• Relate to plasma concentration levels, so constant
monitoring is key
• Konsentrasi tinggi ( ≥1.0 mEq/L menimbulkan efek yang
buruk, > 2 mEq/L menimbulkan efek serius atau fatal)
• Symptoms can be neurological, gastrointestinal, enlarged
thyroid, rash, weight gain, memory difficulty, kidney
disfunction, cardiovascular
• Tidak dianjurkan penggunaan selama kehamilan, dapat
mempengaruhi perkembangan jantung dari janin.
 If Lithium Doesn’t Work
• 40% dari penderita Bipolar resisten terhadap litium
atau efek samping dapat menghalangi efektifitas dari
litium
• Therefore, we must consider alternative agents for
treatment
 Valproic Acid (Depakote)
 Antikonvulsan, banyak digunakan sebagai obat anti
mania
 Meningkatkan aktivitas post-synaptic dari GABA pada
reseptornya (meningkatkan sintesis dan pelepasannya)
 Baik untuk rapid cycling dan mania akut
 Therapeutic blood levels: 50-100 Mg/L
 Side effects include GI upset, sedation, lethargy,
tremor, metabolic liver changes and possible loss of hair
 Can also be used for anxiety, mood, and personality
disorders
 Lamotrigine
 Reported effective with Bipolar, Borderline Personality,
Schizoaffective, Post-Traumatic Stress Disorders
 98% of administered drug reaches plasma
 Waktu paruh 26 jam
 Blocks voltage-sensitive Na channels
 Mengatur atau menurunkan pelepasan presinaptik
aspartat dan glutamat
 Inhibits neuronal excitability and modifies synaptic
plasticity
 Efek samping berupa pusing, tremor, sakit kepala, mual
dan ruam
 Carbamazepine (Tegretol)
 Superior to lithium for rapid-cycling, regarded as a
second-line treatment for mania
 Menstimulasi pelepasan hormon antidiuretik dan
menurunkan konsentrasi serum Na+
 Correlation between therapeutic and plasma levels
(estimated between 5-10 Mg/L)
 Side effects may include GI upset, sedation, ataxia
and cognitive effects
 Gabapentin
• Merupakan anti konvulsan, belum diakui oleh FDA
sebagai terapi Bipolar
• GABA analogue
• not bound to plasma proteins, not metabolized, few drug
interactions
• Half-Life is 5-7 hours
• Side Effects include sleepiness, dizziness, ataxia and double
vision
 Topiramate and Tiagabine

• Two newer anti-convulsants that have potential for

use in the treatment of Bipolar disorder
 Atypical Anti-psychotics
• 3 types that may be used for BP- Clozapine,
Risperidone, and Olanzapine
• Risperidone seems more anti-depressant than anti-
psychotic
• Clozapine is effective, yet not readily used due to
potential serious side effects
• Olanzapine is approved for short-term use in acute
mania
 Olanzapine Versus Placebo:
Relapse Into Mania or Depression
1.0 1.0
Probability of Remaining Relapse Free

0.8 0.8

0.6 0.6

0.4 0.4

Subjects receiving 0.2 Subjects receiving

0.2
olanzapine (N = 225) olanzapine (N = 225)
Subjects receiving Subjects receiving
0.0 placebo (N = 136) 0.0 placebo (N = 136)

0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400
Days to Relapse Into Mania Only Days to Relapse Into Depression Only
P < 0.001 P < 0.001

hen M, et al. Am J Psychiatry. 2006;163:247-256.

 Calcium channel blockers
• Nimodipine dan verapamil
• Menurunkan aktivitas 5-HT, dopamine, dan
endhorpin.
• Digunakan sebagai third line agent untuk
kombinasi dengan obat lain seperti
carbamazepine, valproate, antipsikotik.
 Long-term management
NICE Bipolar disorder guidelines 2006; www.nice.org.uk

• Long-term treatment and • The primary long-term

support are required to
minimise the risk of
recurrence of manic and
depressive episodes and
optimise quality of life, social important
and personal functioning
• Important:
– collaborative relationship
with patients and families
– continuity of care
– crisis support
– an integrated (primary and
secondary) care plan are all
important
treatments are drugs, but
psychological/psychosocial
therapy/support are also
• Initiate long-term drugs:
– after a manic episode with
significant risk and adverse
consequences
– bipolar I: two or more acute
episodes
– bipolar II: evidence of significant
functional impairment or risk of
suicide or frequently recurring
episodes
Support long-term pharmacological treatment
www.nice.org.uk/nicemedia/pdf/implementation_tools/CG38presenterslides.ppt

• Prescribing advisers should be aware of NICE

guidance, and what to consider when choosing
treatment (update prescribing policies and
formularies accordingly)
• Focus on optimising appropriate long-term
treatment
• Support patient education and empowerment in
pharmacological treatment and management
decisions
• Make use of early intervention teams, regional
mental health trusts and CAMHS teams
• Raise awareness of effective antidepressant
prescribing
• Support patient fears about antidepressant
withdrawal
 Overview of the drug treatment of bipolar disorder
NICE Bipolar disorder guidelines 2006 www.nice.org.uk

Antimanic agents (“mood stabilisers”)

• Consider lithium, olanzapine or valproate for

long-term treatment

• If frequent relapses, or functional impairment,

switch to alternative monotherapy or add a
second drug (e.g. olanzapine plus lithium or
valproate)

• If trial of a combination of agents is ineffective,

consider consulting or referring to a bipolar
disorder specialist, or prescribing lamotrigine
(esp. if bipolar II disorder) or carbamazepine

• Be aware of side-effects, drug interactions and

requirements for monitoring
 Overview of the drug treatment of bipolar disorder
NICE Bipolar disorder guidelines 2006 www.nice.org.uk

Antidepressants
• Can be used to control depressive
episodes (with antimanic medications)
e.g. SSRIs
• After successful treatment of an acute
depressive episode, do not continue
long-term antidepressants routinely
• Stop antidepressant at the onset of an
acute episode of mania (abruptly or
slowly)
• NOTE. Patients with bipolar disorder who
are prescribed an antidepressant should
always be prescribed an antimanic drug
 Other considerations
NICE Bipolar disorder guidelines 2006 www.nice.org.uk

• Do not prescribe valproate routinely for women with childbearing

potential
• For women planning a pregnancy, valproate, carbamazepine, lithium
or lamotrigine should be stopped. A low dose antipsychotic may be
used with caution
• Normally continue prophylactic medication (not antidepressants) for
at least 2 years after an episode
• Provide regular reviews
• If long-term medication declined, offer regular contact and
reassessment with primary or secondary care services
• Long-acting IM antipsychotics (‘depots’) are not recommended for
routine use
Consider psychological therapy and psychosocial support
NICE Bipolar disorder guidelines 2006 www.nice.org.uk

• For those who are relatively stable, individual

structured psychological therapy (CBT, family
therapy) should include:
– at least 16 sessions over 6 to 9 months
– psychoeducation
– promotion of medication adherence
– monitoring of mood, detection of early
warnings and prevention strategies
– coping strategies
• Consider offering befriending to people who
would benefit from additional social support,
particularly those with chronic depressive
symptoms
Carry out regular health reviews/monitoring
www.nice.org.uk/nicemedia/pdf/implementation_tools/CG38presenterslides.ppt

• An annual review should include a review of mental and

physical health and social functioning
• Monitor the following (as a minimum):
– lipid levels, including cholesterol, in patients over 40 years
– plasma glucose levels
– weight
– smoking status and alcohol use
– blood pressure
• Support patients in controlling weight
– review risk of weight gain when prescribing
– offer early dietary advice and support
– advise to take exercise
• Careful monitoring of weight is needed with all
antipsychotics, lithium, valproate and carbamazepine

• Note see NICE guideline for more details and

recommendations for monitoring for specific drugs
(additional checks and serum levels)
 INTERAKSI OBAT
NO NAMA OBAT INTERAKSI
1 Lithium – Carbamazepin, Meningkatkan resiko neurotoksik
diltiazem, fluoxetine,
haloperidol, verapamil

2 Litium - NSAIDs Menurunkan eksresi litium dari ginjal sehingga konsentrasi serum
litium tinggi
3 Litium - Chlorpromazin Menurunkan konsentrasi serum kedua obat tersebut

4 Litium – ACEI Meningkatkan toksisitas litium

Litium – Phenytoin

5 Litium – Diuretik Thiazide Meningkatkan konsentrasi Litium

6 Carbamazepin -Asetaminofen Meningkatkan hepatotoksik dari asetaminophen

7 Carbamazepin Dapat menginduksi metabolisme dari BZ,

citalopram,clozapine,kortikosteroid,doksisiklin,haloperidol,kontra
sepsi oral,phenitoin, antidepresan trisiklik,valproat
 INTERAKSI OBAT
NO NAMA OBAT INTERAKSI
8 Valproate – Carbamazepin, Menginduksi metabolisme Na Valproat
Lamotrigin, phenytoin Na Valproate dapat menurunkan, meningkatkan atau
meniadakan efek carbamazepin atu phenytoin

9 Valproate - kolesteramin Kolesteramin dapat mengikat valproat di saluran GI

10 Valproate – Clarithromycin, Menghambat metabolisme Valproate

eritromisin, dan INH

11 Valproate - Lamotrigine Menghambat metabolisme lamotrigine

12 Lamotrigine – Carbamazepin, Menurunkan konsentrasi Lamotrigine

phenytoin dan phenobarbital
 Moody person vs bipolar disorder
 Perbedaan utama adalah dari onset lama mood tersebut
bertahan dan gejala-gejala yang dialami orang tersebt.
 Perubahan mood pada bipolar disorder dapat bertahan
selama beberapa menit sampai beberapa bulan,
terdapat periode depresi dan periode euphoria (mania).
Pada orang yang moody, perubahan mood tersebut
mungkin hanya bertahan 5 menit dan setelah itu selesai.
Pada bipolar disorder tidak hanya terjadi perubahan
mood tetapi juga dibarengi dengan gejala seperti
kesulitan tidur (insomnia), terganggu nafsu makan dan
jati diri
• Seseorang yang moody / mood-moodan
berpotensial untuk menjadi bipolar disorder
tetapi memerlukan suatu diagnosa utnuk
menentukkan orang tersebut mengidap
bipolar atau tidak. Apabila moody yang
dialami terus terjadi dan perubahan mood
berlangsung atau menetap lama maka orang
tersebut sebaiknya diperiksa oleh dokter
untuk didiagnosa lebih lanjut.
IF YOU CAN’T TAKE SOMEONE AT THEIR
WORST THEN YOU DON’T DESERVE
THEM AT THEIR BEST