BIPOLAR DISORDER

Dr. D. Phani Bhushan, Prof & H. O. D

Department of Psychiatry
NRI Medical College & GH

overview

History
Genetics
Neuroimaging
Neurobiology
What is
Mania
Hypomania
Depressive episode

Bipolar I disorder
Bipolar ll disorder
Cyclothymic disorder
Rapid cycling
Substance induced
CANMAT guideline for
BPAD
Mood Stabilizers
ECT in BPAD

BIPOLAR DIORDER
Chronic, reclusive & recurrent major mood
disorder
Often misdiagnosed
Has high rates of psychiatric & medical
morbidity
Has high risk of suicide
Management can be a constant challenge

Historical perspective
Known since Hippocrates times described
mania and depression as amic and
melancholic
Clear connections between mania and
melancholia established only in 19th century by
jules Baillarger
Emil krapelin Manic- depressive insanity
1st introduced in DSM-3(1980), ICD10 (1992)

Bipolar people in history

Abraham Lincoln

Winston Churchill

Past UK prime
Past US President Minister

Colonel Gaaddafi
Expresident
Libia

Genetics
Genome- wide association studies which are
more powerful than linkage studies, have been
used to assess for multiple causative disease
genes
Family, twin and adoption studies all support a
significant genetic burden in bipolar disorder
Genetic variants near the ADRENOMEDULLIN
(ADM) gene on chromosome11 p15 may be
specific to Bipolar II Disorder

Contd
Bipolar Disorder is phenotypically
heterogeneous
Lithium responders may have a unique genetic
make-up that is distinct from that of individuals
with other bipolar disorder
Epigentetics( Gene expression) investigates
gene and Environment (GXE) interplay.

Neuroimaging
BPD associated with
lateral ventricle enlargement
White matter changes
in total cortical volume

More evidence is emerging to support the use

of imaging markers for the Diagnosis of BPD
and for differentiation of BPD from UPD

Neuroimaging Contd
Higher rates of Deep white matter
hyperintensities
Smaller Cerebral Cortex
Bigger Hippocampus and Basal Ganglia
Interplay between immune system and
BPD is very complex at multiple levels

Neurobiology
Mechanism of mood stabilisers may involve the
Inhibition of Cyclooxygenase-2( COX2)and or
reduction in proinflammatory cytokines.
BDNF crosses Blood Brain barrier, its levels in
serum are highly correlated with its levels in
CSF.
Peripheral BDNF may serve as a Biomarker of
mood states and disease progression for
Bipolar Disorder.

Neurobiology.
Neurobiological correlates of BPD
Limbic hyperactivity
Frontal Hypoactivity

Brain glutamate levels are elevated in BD

patients- supports the idea that glutamate play
an important role in the pathophysiology of BD
Negative Effects of illness burden on Prefrontal
NAA( n-acetyl aspartate). Li treated patients
improve NAA levels to that of Healthy controls.

Manic Episode
Period of
Abnormally & persistently elevated,
expansive, or irritable mood
abnormally and persistently increased
goal-directed activity or energy,

lasting at least 1 week and present

most of the day, nearly every day (or
any duration if hospitalization is
necessary).

Three or more of
1.Inflated self-esteem or grandiosity.
2.Decreased need for sleep
3.More talkative than usual or pressure to keep
talking.
4.Flight of ideas or subjective experience that
thoughts are racing.
5.Distractibility
6.Increase in goal-directed activity, psychomotor
agitation
7.Excessive involvement in activities that have a high
potential for painful consequences (buying sprees,
sexual indiscretions, or foolish business
investments)

 Causing marked impairment in social or

occupational functioning
not due to the physiological effects of a
substance or to another medical
condition.

Hypomanic Episode
A distinct period of abnormally and persistently
elevated, expansive, or irritable mood and
abnormally and persistently increased activity
or energy, lasting at least 4 consecutive days
and present most of the day, nearly every day.

 The episode is not severe enough to cause

marked impairment in social or occupational
functioning or to necessitate hospitalization. If
there are psychotic features, the episode is, by
definition, manic.
The episode is not attributable to the
physiological effects of a substance, Other
medical Condition.

Major Depressive Episode

Five or more of in two week period
1.Depressed mood most of the day( feels sad, empty, or hopeless
tearful).
2. Markedly diminished interest or pleasure in almost all activities
3. Significant weight loss or weight gain ( a change > 5% of body
weight in a month
4. Insomnia or hypersomnia.
5. Psychomotor agitation or retardation
6. Fatigue or loss of energy
7. Feelings of worthlessness or excessive or inappropriate guilt
8.Diminished ability to think or concentrate, or indecisiveness,
nearly every day
9. Recurrent thoughts of death (recurrent suicidal ideation without
a specific plan, or a suicide attempt or a specific plan for
committing suicide)

 The symptoms cause impairment in social,

occupational, or other important areas of
functioning.
Not attributable to substance or another
medical condition.

Unipolar vs Bipolar
Bipolar depression was associated with
Bipolar family history.
Earlier age of onset.
Greater number of previous depressive episodes.
Co morbities were more common in bipolar
depression.
Atypical features.
Loss of response during antidepressant
treatment.

Bipolar I Disorder
at least one manic episode
not better explained by schizoaffective disorder,
schizophrenia, schizophreniform disorder,
delusional disorder or other specified or
unspecified schizophrenia spectrum and other
psychotic disorder
Severity
Mild, Moderate and Severe

Modifiers

Anxious distress
Mixed features
Rapid cycling
Melancholic features
Atypical features
Mood-congruent psychotic features
Mood-incongruent psychotic features
Catatonia
Peripartum onset
Seasonal pattern

Bipolar I disorder

Prevalence rate- 0.6%

Male to female ratio 1.1:1
Mean age of onset 18 years
Late onset manic Sx -suspect medical condition
More common in high income countries than low
income countries
Females more likely to express rapid cycling and
mixed episodes and depressive episodes
15 times more suicide risk than genral population

Differential Diagnosis
Major Depressive Disorder
Other Bipolar disorders (1)
Anxiety disorders
GAD, Panic Disorder, PTSD,

Substance/ medication Induced

Attention- Deficit/ Hyperactivity Disorder
Personality Disorder
Disorders with prominent irritability

Bipolar II Disorder

Hypomania + Depressive Episode

Never been a Manic Episode
12 month prevalence 0.3 %
Average age of onset mid 20s
Most often begins with depressive episode
Risk is high among relatives of Bioplar II disorder
Suicide risk in bipolar II > Bipolar I
Most of patients become functional in between
episodes

Differential Diagnosis
Major Depressive disorder
Cyclothymic Disorder
Schizophrenia spectrum & other related
psychotic disorder.
Panic or other anxiety disorder
Substance use disorder
ADHD
Personality Disorder

Cyclothymic Disorder
Numerous periods of hypomanic Sx that do not
meet criteria for hypomanic episode
Numerous periods with depressive Sx that do
not meet criteria for a major depressive episode
Duration- 2 years ( 1 year in children and
adolescents)
Sx not due to drugs/ other medical condition
Significant impairment in social and
occupational functioning

Rapid Cycling
Four or more distinct
episodes of mania,
hypomania, or
depression within a 12month period.
Risk factors:
Female
Antidepressant use
Younger age of onset
Thyroid disease (overt
or subclinical)

Good response with

valproate rather than
Li
Avoid antidepressants
First line
Valproate in Bipolar 1
Lamotrigine in Bipolar
II

Reccurent Depressive Disorder

Repeated Episodes of Depression
With out any history of Independent episodes of
mood elevation or over activity that fulfill the
criteria Mania.

Substance induced

Alcohol
Phencyclidine and other hallucinogens
Sedative,hypnotic & anxiolytic
Amphetamine or Other stimuli
Cacaine

Bipolar Disorder types

Bipolar 0 disorder Schizophrenia
Bipolar

1/2

disorder Schizobipolar disorder

Bipolar I disorder "Classic" bipolar disorder

Bipolar I 1 /2

Depression with protracted hypomania

Bipolar II disorder Hypomania plus major depression

Bipolar II1/2
Depression superimposed on cyclothymic temperement
disorder
Bipolar III disorder Recurrent depression plus hypomania occurring solely in
association with antidepressant or other somatotherapy
Bipolar III 1/2
Mood swings that persist beyond stimulant and/or alcohol
abuse
Bipolar IV disorder Depression superimposed on a hyperthymic temperament
Bipolar V disorder Recurrent depressions without discrete hypomania, but
mixed hypomanic episodes (irritability/agitation/racing
thoughts) during depression
Bipolar VI
Disorder

Bipolarity in the frame of dementia

Management
Management involves treatment of acute episodes &
maintenance therapy
After the resolution of acute episodes, maintenance
treatment is aimed at prevention of future episodes
When a 1st line treatments are unsuccessful try
alternate first line treatments before proceeding to 2 nd
line Rx
Judicious use of psychosocial interventions, alternate
somatic treatments such as ECT, and the numerous
experimental agents offer additional promise for
management of Bipolar Disorder

CANMAT GUIDELINES FOR BPD

Introduction
Foundations of management
Acute management of bipolar mania
Acute management of bipolar depression
Maintenance therapy for bipolar disorder
Special populations
Acute and maintenance management of bipolar II
disorder
Safety and monitoring

Criteria for Rating strength of

Evidence
1

Meta analysis or replicated double

blind( DB), Randomized controlled trial
( RCT) that include placebo as control

At least one DB- RCT with placebo or

active comparison condition

Prospective uncontrolled trial with at

least 10 or more subjects

Anecdotal reports or expert opinion

Treatment Recommendations
1st line

Level 1 or level 2 evidence plus clinical

support for efficacy and safety

2nd line

Level 3 evidence or higher plus clinical

support for efficacy and safety

3rd line

Level 4 evidence or higher plus clinical

support for efficacy and safety

Not
Recommen
ded

Level 1 or 2 evidence of lack of efficacy

Acute mania Phrmacotherapy

1st line

2nd line

3rd line

Mono therapy:
Monotherapy
Monotherapy
Lithium
Carbamazepine
Chlorpromazine
Divalproex
Carbamazepine ER
Clozapine
Olanzapine
ECT
Oxcarbamazepine
Risperidone
Haloperidol
Tamoxifen
Quetiapine
Combination Therapy Cariprazine
Ariparazole
Li + Divalproex
Combination therapy
Ziprasidone
Li/ Divalproex + haloperidol
Asenapine
Li+ Carbamazepine,
Paliperidone
adjunctive tamoxifen
Adjunctive therapy with
Li or Divalprox
Not Recommended Monotherapy
Risperidone
Gabapentin,Topiramate,lamotrigine,verapamil, Tiagabine
Quetiapine
Not Recommended Combination Therapy
Aripaprazole
Risperidone+ Carbamazepine, Olanzapine + Carbazepine

Acute bipolar I Depression

1st line
Mono therapy:
Lithium
Lamotrigine
Quitiapine
Quitiapine XR
Combination Therapy
Li or Divalprox + SSRI
Olanzapine + SSRI
Li + Divalproex
Li or Divalproex +
Bupropion

2nd line

3rd line

Monotherapy
Divalproex
Lurasidone
Combination Therapy
Quitiapine+SSRI,
adjunctive modafinil
Li / Divalproex +
Lamotrigine
Li / Divalproex +
Lurasidone

Monotherapy
Carbamazepine
Olanazapine
ECT
Combination therapy
Li+ Carbamazepine,
Li + Pramipexole
Li / Divalproex +venlafaxine
Li + MAOI, Li/ DV +AAP
+TCA,
Li / Divalproex /
Carbazepine + SSRI
Quitiapine +Lamotigine

Not Recommended Monotherapy

Gabapentin,Aripaprazole, Ziprasidone
Not Recommended Combination Therapy
Adjunctive ziprasidone, adjunctive levitricetam

Acute bipolar II Depression

1st line
Quitiapine
Quitiapine XR

2nd line
Li
Lamotrigine
Divalproex
Combination Therapy
Li / Divalproex +
antidepressants
Li / Divalproex + atypical
antipsychotics +
antidepressants

3rd line
Monotherapy
Antidepressants
Combination therapy
Quitiapine +Lamotigine
Adjunctive ECT, N- acetyl
cysteine, T3,

Maintainance of Bipolar Disorder

1st line

2nd line

3rd line

Mono therapy:
Monotherapy
Monotherapy
Lithium
Carbamazepine
Asenapine
lamotrigine
Paliperodone
Adjunctive therapy
Divalproex
Combination Therapy Phenytoin
Olanzapine
Li + Divalproex
Clozapine
Risperidone
Li + Carbamazepine
ECT
Quetiapine
Li/ Divalproex +
Topiramate
Ariparazole
Olanzapine
Omega 3 fattyacids
Adjunctive therapy with
Li + Resperidone
Oxcarbazepine
Li or Divalprox
Li + lamotrigine
Gabapentin
Risperidone
Olanzapine +Fluoxetine asenapine
Quetiapine
Not Recommended Monotherapy
Aripaprazole
Gabapentin,Topiramate, antidepressants
ziprasidone
Adjunctive Therapy
Flupenthixol

Maintainance Rx of Bipolar II
Disorder
1st line
Lithium
Lamotrigine
Quitiapine

2nd line

3rd line

Li
Divalproex
Combination Therapy
Li / Divalproex /atypical
antipsychotic+antidepress
ants
Adjunctive
Quitiapine
Lamotrigine

Carbamazepine
Oxcarbazepine
Atypical antipsychotic agent
ECT
Fluoxetine

Not Recommended
Gabapentin

Mood stabilizers
Lithium
Anticonvulsants
Valproic acid
Carbamazepine
Oxcarbamazepine
Lamotrigine
Topiramate
Zonisamide
Gabapentin
Pregabalin

Atypical antipsychotics
Risperidone
Olanzepine
Quetiapine
Ziprasidone
Aripiprazole

Other agents
Benzodiazepines
Omega 3 fatty acids
Thyroid hormone

Lithium
used for short-term, long-term, and prophylactic
management
as an adjunctive medication in the treatment of major
depressive disorder.
Lithium is rapidly and completely absorbed after oral
administration and is excreted through kidneys.
Usual Dosage Range
1800 mg/day in divided doses (acute)
9001200 mg/day in divided doses (maintenance)
46

 Mechanism of action
through Neurotropic
properties.
Supposed to act through
modulating G- proteins or
inhibiting 2nd messenger
such as Inositol mono
phosphate which effect
signal transduction for
neurotransmitters.

Lithuim efficacy is best established for treating and

preventing mania than depression
It is also effective in preventing Suicide
Less effective for Rapid Cycling or mixed episodes

Adverse Effects
GI side effects like
Nausea and Vomitting
Weight gain
Tremor
usually 8 to 12 Hz

Renal Diabetes insipidus

Interstitial fibrosis.

Thyroid
Hypothyroidism

Cardiac
Resembles like
Hypokalemia on EKG
T wave flattening /
inversion
Dermotologic
Acneiform, follicular
and Maculopapular
eruptions, pretibial
ulcerations
Worsening 48
of Psoriasis

Li in special population
Elderly persons should initially be given low
dosages, their dosages should be switched less
frequently than are those of younger persons.
Li administered in 1st trimester of pregnancy
child is prone to Cardiovascular anomalies
(most common- Ebsteins anomaly)
Lithium is excreted into breast milk and should
be taken by a nursing mother only after careful
evaluation of potential risks and benefits.
Li is Contraindicated in Cardiac and Renal
49
Patients

SODIUM VALPROATE
Used for
Acute mania
Mixed episodes
Seizure Disorder
Migraine prophylaxis

Therapeutic action due to

Enhancemnet of
GABA ,Glutamate and
modulation of Na+ and
Ca+2 chanells

Metabolised by Liver
Hepatic
glucoronidation
Mitochondrial Beta
oxidation
50

SODIUM VALPROATE
Better tolerated than li or carbamazepine
Adverse effects-teratogenicity and hepatotoxicity,
pancreatitis, thrombocytopenia and somnolence in
elderly.
PCOD, weight gain , hirsutism, alopecia.
Contraindicated in Patients with Hepatic failure and frequent
monitoring of Liver function tests in 1st few months of treatment.

CARBAMAZEPINE
Mood stabilizer
Antiepileptic
Trigeminal neurolgia
Auto inducer- increares its
own metabolism by
inducing cytochromal
enzymes
On Chronic administration
T1/2 devreases from 26 to Acts on GABA, Na+,
12 hours
Ca+,k+.with particular site
of action on unit of Na
Chanell.

Adverse Events

Dosage-Related :

Watch for fever, sore

Double/ blurred vision,
throat, rash,petechiae,
Vertigo,
bruising, and easy
GI distrubances
bleeding
Hematologic effects
Steven jhonson
Idiosyncratic:
syndrome discontinue
Agranulocytosis
the drug start
Aplastic aneamia
Prednisolone.
Maculo popular Rash Secreted renally lower
Steven-jonhsons
dose in Renal
syndrome
impairment
Hepatic failure
Pancreatitis

53

Drug Interactions
Cytochrome enzyme inducer
decreases the blood concentrations of oral
contraceptives, resulting in breakthrough bleeding and
uncertain prophylaxis against pregnancy.
should not be administered with monoamine oxidase
inhibitors (MAOIs), which should be discontinued at least
2 weeks before initiating treatment with carbamazepine. .
When carbamazepine and valproate are used in
combination, the dosage of carbamazepine should be
decreased, because valproate displaces carbamazepine
binding on proteins, and the dosage of valproate may
need to be increased.
54

OXCARBAMAZEPINE May be effective in acute

mania.
Dosages are 50% higher
than carbamazepine.
Starting 300-600mg/d,
increasing 300mg/d and
max. 900-2400mg/d.

Better tolerated than

carbamazepine, less
neurotoxicity and rash,
less induction of
enzymes.
Adverse Effects ataxia,
rash,
hyponatremia.

LAMOTRIGINE
uses
maintenance treatment
particularly preventing
depressive episodes
Acute bipolar depression
Rapid cycling disorders
Treatment resistant mood
disorders.

Adverse Effects
Rash.

Drug interactions
Significant and well
charecterised interactions
with other anti convusants

Valproate lamotrigine
levels in serum
Lamotigine valproate
levels by 25%
Carbamazepine,
phenytoin
phenobarbital
lamotrigine
concentrations

Topiramate
Bipolar Disorder
Alcohol / smoking
Deaddiction
Seizures
Migraine Prophylaxis
Possible actions on GABA,
Glutamate,Ca+ and NA+
Channels
Also a weak Carbonic
anhydrase inhibitor

Topiramate
Adverse effects
Metabolic acidosis
Secondary narrow angle glaucoma

Use with caution in Cardiac and hepatic

impairment
Excreted by kidney lower the dose in renal
impairment

Atypical antipsychotics

Risperidone(2-6mg)
Paliperidone(3-12mg)
Olanzapine(10-20 mg)
Quetiapine(400-800mg)
Ziprasidone(80-160mg)
Aripiprazole(15-30mg).

 Atypicals are highly preferred over typicals because of

low risk of EPS.
Risk of weight gain ,metabolic side effects with
atypicals.
Clozapine & olanzapine high risk for weight gain
followed by risperidone & quitiapine.
Ziprasidone & aripiprazole are weight neutral.
Children & adolescence are more susceptable to EPS
and other side effects of atypicals than are adults.

Electroconvulsive therapy Patients with treatment refractory bipolar depression

or in those who are suicidal, ECT remains the best
option.
Also useful in pregnant women with severe bipolar
depression.
Risk of memory impairment, acute confusion.
Anticonvulsants are withdrawn prior to ECT

Prophylaxis in BPAD

Lithium
Valproate
Carbamazepine
Lamotrigine
Atypical antipsychotics.
Gabapentin/topiramate.
Calcium channel blockers.

Bipolar disorders in child and adolescence Extreme irritablity that is severe & persistent and may
include aggressive outbursts and violent behavior.
In between outbursts children may continue to be
angry or dysphoric.
High rates of comorbid ADHD, conduct disorder,
anxiety disorder.
Treatment-mood stabilizers, antipsychotics.
Stabilize mania before treating comorbid ADHD.

BIPOLAR DISORDER IN WOMEN

Bipolar II and rapid cycling more in women.

More depressive and mixed episodes.
Higher risk of antidepressant induced mania.
Risperidone and typical antipsychotics
significantly elevated prolactin levels.
Valproate- risk of PCOD.
Carbamazepine- decrease efficacy of OCPs.

PREGNANCY
Pregnancy itself does not have a therapeutic or
preventive effect on episode recurrence.
Discontinuation of medications during pregnancy
decreases the duration of recurrence latency.
Teratogenic effectsvalproate>carbamazepine>lithium>lamotrigine.
Pharmacotherapy should be avoided particularly first
trimester.
Folate supplementation 3 months before conception
reduces risk of neural tube defects.
ECT may be useful.

LACTATION

Breast feeding while taking lithium is not

recommended
Breast feeding while taking valproate,
carbamazepine, lamotrigine or atypical
antipsychotics can be cautiously
considered with careful monitoring of the
infant and if necessary obtain infant blood
drug levels.