Drugs for Bipolar Disorders
Kaukab Azim, MBBS, PhD
Drug List
For Treatment of Acute Mania
For Maintenance Treatment
First Line Drugs
Second Line Drugs
First Line Drugs
Second Line Drugs
Lithium
Carbamazepine*
Lithium
Carbamazepine*
Valproate*
Lamotrigine*
Valproate*
Olanzapine*
Lamotrigine*
Quietapine*
Olanzapine*
Risperidone*
Aripiprazole*
Haloperidol*
Clozapine*
* These drugs have been mentioned in other lectures
Learning Outcomes
By the end of the course the students should be able to
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Explain the mechanism of action of drugs used in acute mania
Explain the mechanism of action of lithium
Describe the main pharmacokinetics of lithium
Describe the adverse effects of lithium.
Outline the main drug interactions of lithium.
Outline the main contraindications of lithium
Describe the main therapeutic uses of lithium.
Outline the therapeutic uses of valproate, an carbamazepine in
bipolar disorder.
Outline the use of neuroleptics in bipolar disorder.
Classification of Bipolar Disorders*
Type
Features
Bipolar disorder type 1
A manic episode ± major depressive or
mixed episode
Bipolar disorder type 2
A major depressive episode ± hypomanic
episode
Cyclothymic disorder
Chronic fluctuation between
subsyndromal and hyomanic episodes (at
least 2 years for adults)
Bipolar disorder not other wise specified
Any bipolar disorder that does not meet
criteria for any specific bipolar disorder
* From DSM iV text revision
Theories of Bipolar Disorder
Genetic factors
• 80-90% of patients with bipolar disorder have a biologic
relative with a mood disorder.
• The concordance rate of mood disorders is 60-80% for
monozygotic twins and 14-20% for dizygotic twins.
Non-genetic factors
• Stressful life events often precede mood episodes and can
increase recurrence rate of them.
• Changes in sleep -wake cycle can precipitate episodes of
mania.
• Bright light therapy, used in the treatment of winter
depression can precipitate ipomania.
Neurotransmitter/neuroendocrine theories
Monoamine hypothesis
• An excess of catecholamines (primarily NE an DA)
can cause mania.
• Deficit of monoamines (primarily NE , DA and/or 5HT) can cause depression.
Cholinergic hypothesis
• Drug that increase cholinergic activity can decrease
manic symptoms
Dysregulation of amino acid neurotransmitters
• Drugs that increase GABA activity or decrease
glutamate activity are used for treatment of mania
(lithium, lamotigrine, valproic acid)
Theories for Bipolar Disorder
Dysregulation of secondary messenger system
• Abnormal adenyl cyclase activity, abnormal
phosphoinositide responses, abnormal Na+, K+
and Ca++ channel exchanges.
Dysregulation of hypothalamic, pituitary, thyroid
axis.
• Hyperthyroidism can precipitate manic symptoms
• Hypothyroidism can trigger depression and is a risk
factor for rapid cycling.
Sensitization and kindling
• Recurrences of mood episodes causes
electrophysiological kindling an can result in rapid
or continuous mood cycling.
Lithium
Drug
• Lithium is a small monovalent cation (MW:
6.9).
Main mechanisms of action
• Li+ is classified as a mood-stabilizing drug
because it can reduce both manic and
depressive symptoms of bipolar disorder.
The precise mechanism of its therapeutic effect is unknown
but is likely related to inhibition of two signal transduction
pathways:
1) Inositol signaling
• Li+ inhibits inositol monophosphatase, the rate-limiting
enzyme involved in inositol recycling. This leads to:
– Depletion of phosphatidylinositol-4,5-bisphosphate (
PIP2) which is the precursor of IP3 and DAG
– Inhibition of the synthesis of IP3 and DAG
– Inhibition of the activity of many receptors that are
IP3/DAG linked.
This is the major current working hypothesis for lithium
therapeutic mechanism of action
Lithium
2) Glycogen synthase kinase-3 signaling
– Li+ inhibits glycogen synthase kinase-3, a
protein-kinase that regulate signal pathways
involved in apoptosis.
– suppression of the expression of pro-apoptotic
genes and increase expression of anti-apoptotic
genes.
– The ultimate effect is neuro-protection which
could underlie long term mood stabilization
(increased neurogenesis has been found in the
hippocampus after lithium treatment)
Additional mechanisms of action
1) Actions on other second messenger systems
• Li+ inhibits norepinephrine-sensitive adenyl cyclase, which
results in a decrease of cAMP.
• Li+ enhances GABAergic activity and reduces glutamatergic
activity
2. Actions on electrolytes and ion transport
• Li+ can mimic the role of Na+ in excitable tissues.
• It goes across cell membranes an Na+ sodium in action
potential.
• It is not pumped out by Na+/K+ ATPase and therefore it
tends to accumulate inside the cells, displacing Na+.
• Ca++/Na+ exchanger is not significantly affected at
therapeutic concentration
Lithium
Effect of lithium on the IP3 (inositol trisphosphate) and DAG (diacylglycerol) secondmessenger system. The schematic diagram shows the synaptic membrane of a neuron.
(PIP2, phosphatidylinositol-4,5-bisphosphate; PLC, phospholipase-C; G, coupling protein;
Effects, activation of protein kinase C, mobilization of intracellular Ca2+, etc.) Lithium, by
inhibiting the recycling of inositol substrates, may cause depletion of the secondmessenger source PIP2 and therefore reduce the release of IP3 and DAG. Lithium may
also act by other mechanisms. (Katzung 2011)
Lithium
Pharmacological effects
CNS effects
• At therapeutic doses Li+ has no mental effects on normal
individual.
• The calming effect in manic patients develops slowly
(several day or weeks).
Cardiovascular effects
• Depression of the SA node
• T wave depression or inversion (likely due to intracellular
myocardial K+ depletion by displacement with Li+).
Renal effects
• Inhibition of vasopressin action on the kidney (likely due to
inhibition of adenyl cyclase)
Lithium
Endocrine and metabolic effects
• Inhibition of thyroid hormone synthesis (TSH-induced
production of cAMP in thyroid cells is inhibited, due to
inhibition of adenylyl cyclase)
• ECF expansion (during the first days of therapy. Li+ tends to
accumulate inside the cells, displacing Na+).
Pharmacokinetics
• Oral bioavailability: 100%
• Distribution in total body water (Vd . 45 L)
• No metabolism
• Excretion: 97% in the urine (80% is reabsorbed in the
proximal tubule, some is reabsorbed in the collecting duct).
• Half -life: 20 hours
(Accumulation can be a problem due to the long half life)
Lithium Adverse effects
CNS
• Fine hand tremor (up to 50%. Beta-blockers can
be useful)
• Memory impairment, mental confusion, poor
concentration (up to 40%)
• Muscle weakness, lethargy (up tp 30%)
• Motor hyperactivity, ataxia, aphasia, seizures
(with high doses).
Metabolic/Endocrine system
• Hypothyroidism (5-8%)
• Weight gain (up to 30%)
Urinary system
• Polyuria, polydipsia (up to 70%)
• Nephrogenic diabetes insipidus (12% after long term
treatment).
Gastrointestinal system
• Nausea, epigastric bloating, diarrhea (6-20%).
Adverse effects Cardiovascular system
• Edema, frequent during the first 5-7 days of therapy (likely
due to increased NA+ in the ECF).
• Hypotension, arrhythmias sinus bradycardia, SA / AV block
Other systems
• Leukocytosis (very frequent)
• Acneiform skin eruptions
Overdosage
• Li+ has a narrow therapeutic index (about 2-3) and
Li+ plasma levels must always be monitored.
• Symptoms of overdosage include lethargy, apathy,
unsteady gait, mental confusion, muscle twitches,
seizures, stupor, coma and cardiovascular collapse.
Pregnancy
• Disagreement exists about the importance of
teratogenic effects of Li+
• However the drug is rated pregnancy category D
by FDA
• Ebstein’s anomaly of the tricuspid valve is the
main teratogenic effect.
Drug interactions of Clinical Importance
Drug
Type of Interaction
Thiazides, Loop diuretics
Increased Li+ plasma levels (increased Na+
elimination enhances Li+ reabsorption in
the proximal tubules)
NSAIDs
Increased Li+ plasma levels (reduced renal
prostaglandin production decreases renal
elimination of Li+)
ACE inhibitors, angiotensin blockers Increased Li+ plasma levels (mechanism is
(ARBs)
unknown)
SSRIs
Serotonin syndrome may occur
(mechanism is unknown)
Carbamazepine
Increased neurotoxicity of Li+ (ataxia,
tremor, hyperreflexia. Mechanism is
unknown
Iodide salts
Risk of Li+ induced hypothyroidism is
increased
Lithium Therapeutic uses
Main uses
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Manic phase of bipolar disorders (often with concurrent use of
antipsychotics or benzodiazepines during the first few days)
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Maintenance treatment of bipolar disorder (maintenance
treatment can prevents or diminishes the intensity of
subsequent episodes of both mania and depression.
Treatment must be continued for at least 6-9 months; in severe
cases even for life).

Schizoaffective disorder (together with antipsychotic drugs).
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Depressive disorder (augmenting agent for antidepressants).
Unlabeled/Investigational uses
 Aggression,
post-traumatic stress disorder,
conduct disorder in children
Anticonvulsants for Bipolar Disorder
Drugs
• Valproate, lamotigrine and carbamazepine are the main
anticonvulsant drugs with mood stabilizing properties.
Mechanism of action
• Still uncertain. Actions similar to those of Li+, which seems
to mediate the mood stabilizing properties include:
a. Inhibition of adenylyl cyclase
b. Reduction of inositol generation in the inositol signaling
pathway
c. Activation of neuroprotective genes
Pharmacological and adverse effects
(these are discussed under antiseizure drugs)
Therapeutic uses in bipolar disorders
• As monotherapy in acute mania or mixed
states
• As monotherapy in acute bipolar depression
• As maintenance therapy
Atypical Neuroleptics for Bipolar
Disorder
Drugs
• Aripiprazole, olanzapine, quetiapine, risperidone.
Mechanism of action, pharmacological and adverse effects
• (these are discussed under neuroleptic drugs)
Therapeutic uses in bipolar disorders
• As monotherapy or adjunctive therapy in acute mania or
mixed states
• As adjunctive therapy in acute bipolar depression
(risperidone, olanzapine)
Therapy for Bipolar Disorder
Disorder
First Line Drugs
Second Line Drugs
Acute Mania or mixed
states
Lithium
Valproate
Carbamazepine
Aripiprazole
Olanzapine
Quetiapine
Risperidone
Lamotrigine (for rapid
cycling)
Acute bipolar depression
Lithium
Lamotrigine
Carbamazepine
Valproate
Maintenance therapy
Lithium
Valproate
Lamotrigine
Olanzapine
Carbamazepine
Therapy for Bipolar Disorder
Hypomania
Lithium or valproate or carbamazepine
(if response is inadequate)
Lithium plus an anticonvulsant or an
atypical neuroleptic
Mania
Lithium or valproate plus lorazepam
(if response is inadequate)
Lithium plus an anticonvulsant plus an
atypical neuroleptic
Mild bipolar depression
Severe bipolar depression
Lithium or lamotrigine
Lithium plus an SSRI
(if response is inadequate)
Lithium plus lamotrigine plus an SSRI