Finding the right medication or combination of medications for a patient with bipolar disorder is an incredibly important task, as many individuals with bipolar disorder will require life-long treatment with a mood stabilizer.

Mood stabilizer treatment goals should include resolving active symptoms of mania or depression, minimizing adverse effects, preventing future episodes, and enhancing treatment adherence, according to treatment guidelines from the American Psychiatric Association (APA) (Guideline Watch: Practice Guide-line for the Treatment of Patients With Bipolar Disorder, 2nd Edition, 2005).
A mood stabilizer is a medication used to treat the depressive and manic symptoms of bipolar disorder. In addition, a mood stabilizer should prevent or extend the duration between episodes, therefore maintaining euthymia (a stable mood that is neither depressed nor manic).

Medications commonly used as mood stabilizers include lithium (Lithobid), divalproex (Depakote), lamotrigine (Lamictal), and atypical antipsychotics—also referred to as “second generation” antipsychotics.

So how do clinicians choose among these agents? It’s helpful to select medication based on the following two factors:

1. The phase of bipolar disorder being treated—mania or depression; and
   
2. Tolerability and side effect concerns.
   

Let’s take a look at the different phases of bipolar disorder and the medications used to treat them.

Acute Mania and Mood Stabilizer Selection
For the treatment of acute mania, there is a large body of evidence supporting monotherapy with lithium, divalproex, or an atypical antipsychotic. At least in the short term, atypical antipsychotics may provide a modest but statistically significant advantage over divalproex and lithium. This was demonstrated in an analysis of nine randomized double-blind trials. The researchers proposed that the small difference in efficacy may have occurred due to the quicker onset of action of the atypical antipsychotics and the short length of the trials (Tarr GP et al, J Affect Disord 2011;134(1–3):14–9).

Lithium can take as long as two to three weeks to work, compared to a few days with an atypical antipsychotic. When choosing an antipsychotic for acute mania, a more sedating one, such as quetiapine (Seroquel) or olanzapine (Zyprexa), may be advantageous for symptoms of irritability, agitation, psychosis, and insomnia. If treatment adherence is a concern, consider the long-acting injectable form of risperidone (Risperdal Consta).

Dosing is important when initiating mood stabilizer therapy. For extended-release divalproex, a nice clinical pearl is to add a “0” to the patient’s weight in pounds to achieve the correct anti-manic dose. For example, a 150-pound person should get an initial daily dose of 1500 mg.

Mixed manic episodes, when patients experience both mania and major depression at the same time, can be even more difficult to treat. Atypical antipsychotics, divalproex, and carbamazepine (Equetro) are the most effective treatment options. Often, patients are prescribed a combination of medications (eg, an atypical antipsychotic plus lithium or divalproex) to treat their bipolar disorder.

Bipolar Depression and Mood Stabilizer Selection
Most people with bipolar disorder will identify more with the depressive phase of their illness. In fact, many individuals will present for treatment reporting only depression. This may lead to a misdiagnosis of major depressive disorder and consequently treatment with only an antidepressant. Treatment with an antidepressant may be inadequate, given that the findings of recent randomized controlled trials of antidepressant treatment for bipolar depression have generally not yielded favorable results (Sidor MM and Macqueen GM, Curr Psychiatry Rep 2012;14(6):696–704).

Once an accurate diagnosis of bipolar depression is made, the most efficacious treatments include lithium, lamotrigine, and atypical antipsychotics. There are no large, double-blind, placebo-controlled studies supporting the use of divalproex for bipolar depression (Baldassano CF et al, Curr Psychiatry Rep 2011;13(6):483–487).

There is extensive evidence indicating that lithium reduces the risk of suicide among patients with bipolar disorder (for example, Baldessarini RJ et al, Bipolar Disord 2006;8(5 Pt 2):625–639; and Cipriani A et al, Am J Psychiatry 2005;162(10):1805–1819). Lamotrigine, although not FDA-approved for bipolar II, is often the preferred agent by clinicians due to its tolerability. There is also some evidence for its efficacy in the treatment of bipolar II disorder (eg, Nierenberg AA et al, Am J Psychiatry 2006;163(2):210–216).

Dosing for lamotrigine typically should begin at 25 mg and gradually increase in strength to a goal of 200 mg daily, in accordance to a schedule outlined in the Prescribing Information. It is important to note that the initial and goal doses vary (higher or lower) depending on the concomitant use of other medications as outlined in the Prescribing Information. Using a higher than recommended initial or goal dose can increase the risk of developing a potentially fatal skin rash.

Quetiapine and olanzapine are the only two atypical antipsychotics with FDA approval for the treatment of bipolar depression. Selection of these agents must be weighed against their negative metabolic side effect profiles.

Mood Stabilizer Tolerability
Roughly 75% of people who take lithium will experience side effects. Side effects include fine hand tremor, nausea, and an increase in thirst and urination (due to diabetes insipidus). One of the biggest concerns with lithium treatment, however, is its narrow therapeutic window. This means that drug level monitoring is required, because it is fairly easy for toxicity to occur.

Lithium should be given cautiously to people who report poor medication adherence, those with established renal disease, chronic consumers of alcohol, and those who take any of a number of other medications, including NSAIDs and blood pressure medication. Lithium is considered a safer treatment option for a person with liver disease, as it bypasses liver metabolism.

Divalproex is the preferred agent in someone with chronic kidney disease. More common side effects associated with divalproex use include drowsiness, weight gain, tremor, and transient elevations in liver enzymes. Carbamazepine has a similar side effect profile to divalproex, but it can also cause the more rare and serious side effects of anemia, cardiac conduction abnormalities, and a decrease in sodium levels. Both carbamazepine and lamotrigine have been implicated in causing a rare and potentially life-threatening rash (Malhi G S et al, Bipolar Disord 2012;14(Suppl 2):1–21).

The most concerning side effects associated with the atypical antipsychotics include significant weight gain, development of diabetes, and elevated cholesterol. Olanzapine and quetiapine carry the greatest metabolic risk. Ziprasidone (Geodon) and aripiprazole (Abilify) are associated with the lowest metabolic side effect risk. All antipsychotics also have the potential to cause extrapyramidal side effects or movement disorders. Aripiprazole is more likely to cause akathisia (restlessness), and risperidone is more likely to cause parkinsonian side effects such as a resting tremor and muscle rigidity.

TCRBH’s Take: Bipolar disorder requires long-term (often lifetime) treatment with mood-stabilizing medications. Yet all of the medications available for treatment of bipolar disorder carry the potential for serious adverse effects. Special attention should be given to educating patients and their families in a way that both emphasizes the importance of the pharmacotherapy and also respects their right to know about the risks (and how to lower them).