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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)
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
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
Manic Episode
Period of
Abnormally & persistently elevated,
expansive, or irritable mood
abnormally and persistently increased
goal-directed activity or energy,
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)
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.
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
Differential Diagnosis
Major Depressive Disorder
Other Bipolar disorders (1)
Anxiety disorders
GAD, Panic Disorder, PTSD,
Bipolar II Disorder
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)
Substance induced
Alcohol
Phencyclidine and other hallucinogens
Sedative,hypnotic & anxiolytic
Amphetamine or Other stimuli
Cacaine
1/2
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
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
Treatment Recommendations
1st line
2nd line
3rd line
Not
Recommen
ded
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
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
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,
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.
Adverse Effects
GI side effects like
Nausea and Vomitting
Weight gain
Tremor
usually 8 to 12 Hz
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
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 :
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
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
Atypical antipsychotics
Risperidone(2-6mg)
Paliperidone(3-12mg)
Olanzapine(10-20 mg)
Quetiapine(400-800mg)
Ziprasidone(80-160mg)
Aripiprazole(15-30mg).
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.
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