The mood stabilizers most commonly used are lithium, valproate, and carbamazepine. Table 13-3 lists mood stabilizers and their dosage and therapeutic levels. Other medications, such as calcium channel blockers, benzodiazepines, and antipsychotics, have some utility in refractory bipolar disorder.

Indications

Mood stabilizers are indicated acutely (in conjunction with antipsychotics) for the treatment of mania.

They are indicated for long-term maintenance prophylaxis against depression and mania in bipolar individuals. Anticonvulsant medications (valproate and carbamazepine) may also be useful in individuals having seizure-related mood instability. Mood stabilizers are also used for treatment of impulsive behavior in individuals without bipolar disorders.

The choice of mood stabilizer is based on a patient’s particular psychiatric illness (i.e., subtype of bipolar disorder) and other clinical factors such as side effects, metabolic routes, patient tolerance, and a history of patient or first-degree relative drug responsiveness. Table 13-1 lists the major mood stabilizers and their most common indications. Some common and more serious side effects of mood stabilizers are listed in Table 13-2.

The mechanism of action of mood stabilizers in bipolar illness is unclear. The range of neurotransmitters affected by these medications and their disparate modes of action suggest that mania may be controlled by altering the function of several different neurotransmitter systems. Conversely, they may share a common mechanism of action that is yet to be elucidated.

Lithium

Mechanism of Action
The mechanism of action of lithium in the treatment of mania is not well determined. Lithium alters at least two intracellular second messenger systems (the adenyl cyclase, cyclic AMP system, and the G protein-coupled phosphoinositide systems) and as an ion, can directly alter ion channel function. Because norepinephrine and serotonin in the central nervous system (CNS) use G protein-coupled receptors as one of their mechanisms of action, their function is altered by lithium. Lithium also alters GABA (gamma-amino-butyric acid) metabolism.

Choice of Medication
Lithium is indicated as a first-line treatment for regular cycling bipolar disorder in individuals with normal renal function. Lithium also is used to augment other antidepressants in unipolar depression. Lithium is renally cleared and can easily reach toxic levels in persons with altered renal function (e.g., especially the elderly). It is less effective in the treatment of the rapid cycling variant of bipolar disorder.

Therapeutic Monitoring
Lithium levels should be monitored regularly until a stable dosing regimen has been obtained. Additional monitoring is necessary in a patient with variable compliance or altered renal function. In addition, patients should be warned about toxicity and be regularly assessed for side effects. Thyroid-stimulating hormone and creatinine should also be monitored at regular intervals to check thyroid and kidney function, respectively.

Side Effects
Lithium has several minor but troublesome side effects, including tremor, polyuria, gastrointestinal distress, minor memory problems, acne exacerbation, and weight gain. Approximately 5% of patients on long-term lithium therapy develop hypothyroidism because the lithium interferes with thyroid hormone production. At toxic levels, ataxia, coarse tremor, confusion, coma, sinus arrest, and death can occur.

Lithium has a narrow therapeutic window, and patients can become toxic at prescribed doses, especially if they undergo an abrupt change in renal function.

Valproate

Mechanism of Action

The mechanism of action of valproate is thought to be due in part to augmentation of GABA function in the CNS. Valproate increases GABA synthesis, decreases GABA breakdown, and enhances its postsynaptic efficacy.

Choice of Medication
Valproate is indicated in acute mania and in Rrophylaxis against mania in bipolar disorder (Table 13-1). It is more effective than lithium for the rapidcycling and mixed variants of bipolar disorder. It may not provide prophylaxis against depression in bipolar disorder or augment antidepressants. It is used in treating impulse dyscontrol.

Therapeutic Monitoring
Valproate levels should be monitored regularly until a stable blood level and dosing regimen have been obtained. Liver function tests should be checked at baseline and frequently during the first 6 months, especially because the idiosyncratic reaction of fatal hepatotoxicity is most frequent in this time frame.

Side Effects
At therapeutic levels, valproate produces a variety of side effects, including sedation, mild tremor, mild ataxia, and gastrointestinal distress. Thrombocytopenia and impaired platelet function may also occur. At toxic levels, confusion, coma, cardiac arrest, and death can occur. Valproate usage carries with it the risk of idiosyncratic but serious side effects. These include fatal hepatotoxicity, fulminant pancreatitis, and agranulocytosis.

Carbamazepine

Mechanism of Action
The mechanism of action of carbamazepine in bipolar illness is unknown. Carbamazepine blocks sodium channels in neurons that have just produced an action potential, blocking the neuron from repetitive firing. In addition, carbamazepine decreases the amount of transmitter release at presynaptic terminals. Carbamazepine also appears to indirectly alter central GABA receptors.

Choice of Medication
Carbamazepine is generally considered to be a second-line drug (after lithium and valproate) for the treatment of mania (Table 13-1). It is used in acute mania, prophylaxis against mania in bipolar disorder, and may be more effective than lithium in rapidcycling and mixed mania. Carbamazepine’s efficacy in the prophylaxis and treatment of depression is not clear. It is also used in treating impulse dyscontrol.

Side Effects
Carbamazepine, at therapeutic levels, produces similar CNS side effects to lithium and valproate. Nausea, rash, and mild leukopenia are also common.
At toxic levels, autonomic instability, atrioventricular block, respiratory depression, and coma can occur.
Carbamazepine has idiosyncratic side effects of agranulocytosis, pancytopenia, and aplastic anemia.

Therapeutic Monitoring
Carbamazepine levels should be monitored regularly until a stable dosing regimen has been obtained.
Patients should be carefully monitored for rash, signs of toxicity, or evidence of severe bone marrow suppression.

Novel Mood Stabilizers
Several new agents are being used as mood stabilizers for bipolar disorder. Like valproic acid, they are all FDA-approved anticonvulsants that are now being studied for use in treatment of acute manic episodes and for maintenance of bipolar disorder (see Table 13-3).

Lamotrigine

Mechanism of Action

The mechanism of action of lamotrigine in bipolar disorder is unknown. Lamotrigine is approved by the FDA for use as an anticonvulsant and is used off-label in mood disorders. Lamotrigine in vitro has been shown to inhibit voltage-sensitive sodium channels.
This effect is believed to stabilize neuronal membranes and modulate presynaptic excitatory neurotransmitter release.

Choice of Medication
Although studies are still ongoing regarding the use of lamotrigine in bipolar disorder, it appears to have some antidepressant as well as mood stabilizing properties. Since its efficacy is not yet certain, it is currently only used after a patient has failed or been allergic to more traditional therapies.
Dosages are generally altered for the elderly, those with renal or other organ impairment, or when combined with interacting agents.

Therapeutic Monitoring
The development of serious allergic reactions to lamotrigine appears to be related to rapid dose escalation and/or drug interactions. A clinically useful assay for serum levels of lamotrigine is not available.
Generally, this medication should only be prescribed by a qualified psychiatrist, neurologist, or other physician who is aware of the complex drug interactions that exist particularly between valproic acid and lamotrigine.

Side Effects
Lamotrigine can commonly cause ataxia, blurred vision, diplopia, dizziness, nausea, and vomiting.
Severe, potentially life-threatening allergic rashes have been reported with the use of lamotrigine. The allergic reaction can begin as a simple rash and lead to Stevens-Johnson syndrome.

Gabapentin

Mechanism of Action
The mechanism of action of gabapentin in bipolar disorder and in seizure disorders is unknown.
Gabapentin inhibits induced seizures in rats and mice. Although it is structurally related to the neurotransmitter GABA, it has no binding affinity to the GABA receptor or to any other known brain receptors.

Choice of Medication
Studies indicate that gabapentin may be a useful adjunctive medication for mood stabilization and anxiolysis in bipolar disorder, but it appears to lack sufficient efficacy for use as monotherapy for bipolar disorder episode prophylaxis. It is generally used as an adjunct to more traditional agents such as lithium or valproic acid or to address particular target symptoms such as anxiety.

Therapeutic Monitoring
A similar dosage range is used for seizure and bipolar disorders, although the drug is not FDA approved for this use. The drug is excreted renally and unchanged.
There is no clinically available assay for serum gabapentin.