• Lithium, carbamazepine (CBZ), valproate, and lamotrigine are effective for monotherapy of

bipolar disorder, in treating both manic and depressive episodes in bipolar disorder, as
well as for bipolar prophylaxis.
• Lithium: first-line treatment for bipolar disorder
• The APA guideline lists lithium as a first-line agent for essentially every type and phase of
bipolar disorder, with perhaps one exception: for “mixed” manic episodes, valproate may
be preferred over lithium.
• For rapid cycling: Lithium or Valproate
• Prophalyaxis: the medications with the best empirical evidence to support their use in
maintenance treatment are lithium and valproate. However, the case for use of valproate as
a prophylactic agent is not as well established as the use of lithium
• For the initial treatment of an acute depressive episode in bipolar disorder, the APA
guideline recommends either lithium or lamotrigine
• Lithium: mineral, classic mood stabilizer, first to be approved by FDA. The most common
side effects are lethargy and weight gain. The less common side effects of using lithium are
blurred vision, a slight tremble in the hands, and a feeling of being mildly ill. Signs and
symptoms of toxicity include nausea, vomiting, diarrhea, and ataxia.
• The precise mechanism of action of lithium is still unknown, and it is suspected that it acts
at various points of the neuron between the nucleus and the synapse. Lithium is known to
inhibit the enzyme GSK-3B.1 This improves the functioning of the circadian clock―which
is thought to be often malfunctioning in people with bipolar disorder―and 2 positively
modulates gene transcription of brain-derived neurotrophic factor (BDNF). The resulting
increase in neural plasticity may be central to lithium's therapeutic effects. 3 Lithium may
also increase the synthesis of serotonin.

• Valproate – Available in extended release form. This drug can be very irritating to the stomach,
[5]
especially when taken as a free acid. Liver function and CBC should be monitored.
• Lamotrigine – Particularly effective for bipolar depression. The usual target dose is 100–200 mg daily,
[6]
titrated to by 25 mg increments every 2 weeks. The patient should be monitored for signs and
[7]
symptoms of Stevens–Johnson syndrome, a very rare but potentially fatal skin condition.
• Carbamazepine – CBC should be monitored, as carbamazepine can lower white blood cell count.
Therapeutic drug monitoring is required. Carbamazepine was approved by the US Food and Drug
Administration as a bipolar disorder treatment in 2005, but had been widely used previously.
• Most anticonvulsant mood stabilizers increase the ratio of γ-aminobutyric acid (GABA) to
glutamate to varying degrees and via differing mechanisms.
• Valproate produce antimanic effects by increasing concentration of GABA. It also has
antiglutamatergic effects; blocks sodium channels; and may decrease dopamine turnover,
possibly accounting for its modest antipsychotic effects.
• Lamotrigine leads to blockade of voltage-dependent sodium channels, which in turn may
prevent excessive release of glutamate (excitatory neurotransmitter).
• Lithium is one of the only psychotropic agents in common use that does not undergo
hepatic metabolism; rather, it is eliminated almost entirely via the kidneys.
• Lithium retention and excretion may be affected by sodium (salt) restriction or “loading.”
• Lithium increases urination and thirst. Excessive urination: polyuria. Excessive thirst:
polydipsia. Lithium causes loose stools (GI disturbance) and tremors. Hypothyroidism (low
BP). Cognitive dulling or slowed thinking.
• Valproate has fewer side effects than lithium. It causes GI disturbance, tremors, weight
gain. Impermanent hair loss (lithium also causes it). Thrombocytopenia (low platelet
count). Menstrual dysfunction and PCOS.
• Lamotrigine is usually well tolerated but may cause transient headache nearly in
treatment. It is not associated with weight gain. Steven Johnson syndrome.
• CBZ side effects: fatigue, gait instability, headache, lightheadedness, and rash. CBC should
be monitored, as carbamazepine can lower white blood cell count (leucopenia).
• Some drugs interact with lithium and increase its levels (like NSAIDs) and some decrease
lithium levels (eg. caffeine).
• In the treatment of refractory Bipolar disorder, mood stabilizers are used in combination. A
combination of lithium and valproate is used for rapid cycling or mixed mania is used
when the patient does not respond to lithium or valproate alone. Patients whose symptoms
remain refractory may have CBZ added to this regimen. The addition of lamotrigine to
other mood stabilizers has become more common in refractory cases, particularly in
bipolar depression.
• Pregnancy: Lithium is safest mood stabilizer. Lithium use during early pregnancy is
associated with the development of cardiac abnormalities, especially Ebstein’s anomaly (a
 congenital malformation of the heart). CBZ is associated with craniofacial defects,
developmental delay, and spina bifida.
• There are few controlled studies to support efficacy of mood stabilizers in children. Usually
lithium is used. Valproate and lithium valproate combinations are also used. Lamotrigine
risk of steven Johnson syndrome is higher.
• Valproate is the mood stabilizer of choice for many elderly bipolar patients. Valproate
appears to be relatively well tolerated in the elderly, though rates of thrombocytopenia are
substantial, and cognitive side effects may be seen. Lithium may have an increased
likelihood of neurotoxicity in elderly and dementia populations and must be used
cautiously in patients with reduced renal function (e.g., the elderly and medically ill).
• Lithium side effects: excessive thirst and urination, diarrhea, impaired memory,
drowsiness, tremors, weight gain, slowed thinking, acne, hair thinning and hair loss
• Lithium toxicity: ataxia, diarrhea, nausea, confusion, seizures, coma
• Carbamazepine: sedation, fatigue, nausea, leucopenia (low WBC count), Hyponatremia
(low sodium concentration in the blood), skin rash, GI disturbances, thyroid dysfunction,
liver enzyme elevation.
• Lamotrigine: dizziness, nausea, vomiting, rash, ataxia
• Valproate: elevated liver functions, increased appetite (weight gain), thrombocytopenia
(low platelet count).