To explain pathogenesis of Bipolar Disorders To classify drugs used for treatment of Bipolar Disorders To describe mechanism of action of drugs used for treatment of Bipolar Disorders To enlist side effects of drugs used for treatment of Bipolar Disorders. Indications: Bipolar, cyclothymia, schizoaffective, impulse control and intermittent explosive disorders. Classes: Lithium, anticonvulsants, antipsychotics Which you select depends on what you are treating and again the side effect profile.

1. 3rd Year
Neurosciences II
Treatment of Bipolar disorders
Fazaia Ruth Pfau Medical College
Department of Pharmacology 1

2. Objectives:
 To explain pathogenesis of Bipolar Disorders
 To classify drugs used for treatment of Bipolar Disorders
 To describe mechanism of action of drugs used for
treatment of Bipolar Disorders
 To enlist side effects of drugs used for treatment of
Bipolar Disorders.
Fazaia Ruth
Pfau Medical
College
Department of Pharmacology 2

3. Sulaiman
AlRajhi
Colleges
Department of Pharmacology 3
Indications: Bipolar,
cyclothymia, schizoaffective,
impulse control and
intermittent explosive
disorders.
Classes: Lithium,
anticonvulsants,
antipsychotics
Which you select depends on
what you are treating and
again the side effect profile.
Mood stabilizers

4. Mood
stabilizers
&
drugs
for
bipolar
disorders
MOOD STABILIZERS
LITHIUM
CARBONATE
Bipolar affective
disorder,
Sodium Valporate
Carbamazapine: /
Oxcarbamezapine
Lamotrigine:
Topiramate:
TOPAMAX
Sulaiman
AlRajhi
Colleges
Department of Pharmacology 4
Classification

5. Generic name Trade name Manic Mixed Depressed
ARIPIPRAZOLE Abilify
x x
ZIPRASIDONE Geodon
x x
RISPERDONE Risperdal
x x
QUETIAPINE Seroquel
x
QUETIAPINE XR Seroquel XR
x x
CHLORPROMAZINE Thorazine
x
OLANZAPINE Zyprexa
x x
OLANZAPINE
FLUOXETINE COMB
Symbyax
x
FDA approved indications in Bipolar disorder
Sulaiman
AlRajhi
Colleges
Department of Pharmacology
5

6. Lithium – mood stabilizer
Mechanism of action
Effect on ion
exchange
• Lithium can substitute for Na+ (Li+ - Na+) & inhibits action
potential across the membrane.
• At therapeutic concentrations (~1 m Eq/L), it does not affect
Na+ - Ca2+ exchanger or Na+ / K+-ATPase pump.
Effects on
Second
Messengers
PIP2 - phosphatidylinositol-4,5-bisphosphate
PLC phospholipase C
G coupling protein
activation of protein kinase C &
mobilization of intracellular Ca2+
Lithium inhibits recycling of
inositol substrates & cause
depletion of second-
messenger source PIP2 ,
therefore reduce release of
IP3 & DAG.
IP3 (inositol) trisphosphate & DAG
diacylglycerol are second
messengers for beta adrenergic &
muscarinic transmission.
The activity of these pathways is increased during a
manic episode. Treatment with lithium would be
expected to diminish activity in these circuits.
Studies of noradrenergic effects in isolated brain tissue indicate that
lithium can inhibit norepinephrine-sensitive adenylyl cyclase. Such an
effect could relate to both its antidepressant and its antimanic effects.
Alterations of protein kinase C-mediated signaling alters gene expression
& production of proteins implicated in long-term neuroplastic events
Sulaiman
AlRajhi
Colleges
Department of Pharmacology 6

7. Lithium directly inhibits two signal transduction pathways
Insulin/insulin-like growth factor
Brain-derived neurotrophic factor (BDNF)
Wnt pathway.
Inositol signaling Glycogen synthase kinase 3 (GSK-3)
↓ intracellular inositol
GSK-3 phosphorylates b-catenin interaction with
transcription factors modulate energy metabolism,
provide neuroprotection, and increase neuroplasticity.
Valproic acid indirectly ↓ GSK-3
activity up-regulate gene
expression through inhibition of histone
deacetylase and also ↓ inositol
signaling through an inositol
depletion mechanism.
* Blockade of NMDA receptor-
mediated excitation
Carbamezapine
*↓ intracellular inositol
* Potentiation of a voltage-gated K+
current
** blocks Na+ channels & inhibits
high-frequency repetitive firing in
neurons in culture
It can substitute for Na+ in action potential involving Na+ - Na+
exchange across membranes.
Sulaiman
AlRajhi
Colleges
Department of Pharmacology 7

8. Lithium was preferred treatment for bipolar disorder,
especially in the manic phase.
With approval of valproate, aripiprazole, olanzapine,
quetiapine, a smaller percentage of bipolar patients now
receive lithium.
This trend is reinforced by the slow onset of action of
lithium, which has often been supplemented with concurrent
use of antipsychotic drugs or potent benzodiazepines in
severely manic patients
These considerations have led to increased use of
combined treatment in severe cases.
After mania is controlled, the antipsychotic drug may be
stopped and benzodiazepines and lithium continued as
maintenance therapy.
The depressive phase of manic-depressive
disorder often requires concurrent use of
antipsychotics.
Selective serotonin reuptake inhibitors are less
likely to induce mania but may have limited
efficacy.
Antidepressants have not shown consistent
utility and have been linked to precipitation of
mania.
SNRI agents have been associated with higher
rates of switching to mania than some
antidepressants.
The prophylactic use of lithium can prevent both mania and depression.
Indications for Lithium & supportive therapy.
Sulaiman
AlRajhi
Colleges
Department of Pharmacology 8

9. Side effects of Lithium
A. Neurologic and Psychiatric Adverse Effects: Tremor, choreoathetosis, motor
hyperactivity, ataxia, dysarthria, and aphasia.
B. Decreased Thyroid Function: Decreases thyroid function, which is reversible,
non-progressive. TSH must be monitored every 6–12 months.
C. Nephrogenic Diabetes Insipidus and Other Renal Adverse Effects: Polydipsia
and polyuria are common due to loss of responsiveness to antidiuretic hormone.
D. Edema is related to sodium retention.
E. Cardiac Adverse Effects: The bradycardia-tachycardia (“sick sinus”) syndrome
is a definite contraindication to the use of lithium
F. Use During Pregnancy: Renal clearance of lithium increases during pregnancy
and reverts to lower levels immediately after delivery. Serum levels need to be
monitored
Sulaiman
AlRajhi
Colleges
Department of Pharmacology 9

10. Carbamazepine, Valproate & Lamotrigine
all affect membrane excitability by an
action on voltage-dependent sodium
channels which carry the inward
membrane current necessary for the
generation of an action potential.
They block preferentially the excitation
of cells that are firing repetitively, and
the higher the frequency of firing, the
greater the block produced.
Valproate and Lamotrigine also effects T –
type Calcium channels and Valproate in
addition has significant on GABAA
receptors & Increases brain
concentrations of gamma aminobutyric
acid (GABA) António F. Ambrósio, Patrício Soares-da-Silva, Caetana M. Carvalho, and Arsélio P. Carvalho’
Mechanisms of Action of Carbamazepine and Its Derivatives, Oxcarbazepine, BIA 2-093, and
BIA 2-024*Neurochemical Research, Vol. 27, Nos. 1/2, February 2002 , pp. 121–130
Sulaiman
AlRajhi
Colleges
Department of Pharmacology 10

11. Valproate, has anti manic effects and shows efficacy equivalent to that of lithium during early weeks of
treatment although its efficacy in maintenance therapy not proven.
Valproic acid is effective in patients who have failed to respond to lithium - mixed states & rapid
cycling forms of bipolar disorder and more responsive to valproate than to lithium.
Side-effect profile allows to rapidly increase dosage over a few days to produce blood levels in the apparent
therapeutic range. Nausea is the limiting factor in some patients.
Combinations of valproic acid with other psychotropic medications to be used in either phase of bipolar illness
are generally well tolerated.
The interactions of carbamazepine and enzyme inducer of CYP3A4 substrates makes it a difficult
drug to use with other treatments for bipolar disorder.
Adverse effects include blood dyscrasias and CBC needs to be repeated .
Carbamazepine may be used alone or, in refractory patients, in combination with lithium or, rarely,
valproate. Is used to treat acute mania and prophylactic therapy.
Lamotrigine is approved as a maintenance treatment for bipolar disorder and is not effective in
treating acute mania.
It is effective in reducing the frequency of recurrent depressive cycles and may have some utility in
the treatment of bipolar depression.
Sulaiman
AlRajhi
Colleges
Department of Pharmacology 11

12. Take home points
 Be clear on the diagnosis you are treating
and any comorbid diagnoses when you are
selecting an agent to treat- often can get 2
birds with 1 stone!
 Select the agent based on patients history,
current symptom profile and the side effect
profile of the medication- there is no one
correct answer in most cases.
 Monitor for efficacy and tolerance and
adjust as indicated.
 If the patient does not improve step back,
rethink your diagnosis and treatment plan!
 Keep an eye on drug-drug interactions
Sulaiman
AlRajhi
Colleges
Department of Pharmacology 12
1. Basic & Clinical Pharmacology by Katzung 13th
edition.
2. Rang & Dale Pharmacology 8th edition.
3. Pharmacology by Brenner 3rd edition.
4. Board review series Pharmacology 5th edition.
5. Netters Pharmacology.
6. Stahl’s Psychopharmacology 4th edition.