Medications for Treatment of Bipolar Disorders

Choice of pharmacologic agents to treat bipolar disorders can be difficult because all medications can potentially have significant adverse effects, drug interactions are common, and no medication is universally effective. Selection should be based on what has previously been effective and well-tolerated in a given patient. If there is no prior experience (or it is unknown), choice is based on the patient’s medical history (in relation to the adverse effects of the specific mood stabilizer) and the severity of symptoms.

(See also Bipolar Disorders.)

For severe manic psychosis, in which immediate patient safety and management is compromised, urgent behavioral control usually requires a sedating second-generation antipsychotic, sometimes supplemented initially with a benzodiazepine such as lorazepam or clonazepam (see table Benzodiazepines).

For less severe acute episodes in patients without contraindications (eg, renal disorders), lithium is a good first choice for both mania and depressive episodes. Because its onset is slow (4 to 10 days), patients with significant symptoms may also be given an antiseizure medication or a second-generation antipsychotic.

For bipolar depression, the best evidence suggests using quetiapine, cariprazine, lumateperone, or lurasidone alone or the combination of fluoxetine and olanzapine (1, 2).

Once remission is achieved, preventive treatment with mood stabilizers is indicated for all patients with bipolar I disorder (bipolar I is defined by the presence of at least one full-fledged manic episode). If episodes recur during maintenance treatment, clinicians should determine whether adherence is poor and, if so, whether nonadherence preceded or followed recurrence. Reasons for nonadherence should be explored to determine whether a change in mood stabilizer type or dosing would render treatment more acceptable.

Lithium attenuates bipolar mood swings but has no effect on normal mood. Patients with a family history of typical bipolar disorders are more likely to respond to lithium.

Whether lithium or another mood stabilizer is being used, breakthroughs are more likely in patients who have mixed states, rapid-cycling forms of bipolar disorder (usually defined as ≥ 4 episodes/year), comorbid anxiety, substance use disorder, or a neurologic disorder.

Lithium carbonate is typically titrated based on blood levels, tolerance, and response. Higher maintenance levels are more protective against manic (but not depressive) episodes but have more adverse effects. Adolescents, whose glomerular function is excellent, need higher doses; older patients need lower doses.

Lithium can cause sedation and cognitive impairment directly or indirectly (by causing hypothyroidism) and often exacerbates acne and psoriasis. The most common acute, mild adverse effects are fine tremor, fasciculation, nausea, diarrhea, polyuria, polydipsia, and weight gain (partly attributed to drinking high-calorie beverages). These effects are usually transient and often respond to decreasing the dose slightly, dividing the dose (eg, 3 times a day), or using slow-release forms. Once dosage is established, the entire dose should be given after the evening meal. This once-daily dosing may improve adherence and possibly reduce renal toxicity. A beta-blocker (eg, atenolol 25 to 50 mg orally once a day) can control severe tremor; however, some beta-blockers (eg, propranolol) may worsen depression.

Acute lithium toxicity is manifested initially by gross tremor, increased deep tendon reflexes, persistent headache, vomiting, and confusion and may progress to stupor, seizures, and arrhythmias. Toxicity is more likely to occur in the following:

• Older patients

• Patients with decreased creatinine clearance

• Those with sodium loss (eg, due to fever, vomiting, diarrhea, or use of diuretics)

Thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin may contribute to hyperlithemia. Lithium blood levels should be measured every 6 months and whenever the dose is changed.

Long-term adverse effects of lithium include

• Hypothyroidism, particularly when there is a family history of hypothyroidism

• Hypercalcemia and hyperparathyroidism

• Renal damage involving the distal tubule that appears after ≥ 15 years of lithium treatment

Therefore, thyroid-stimulating hormone (TSH) levels should be monitored when lithium is started and annually thereafter if there is a family history of thyroid dysfunction or every other year for all other patients. Levels should also be measured whenever symptoms suggest thyroid dysfunction (including when mania recurs) because hypothyroidism may blunt the effect of mood stabilizers. Blood urea nitrogen (BUN) and creatinine should be measured at baseline, 2 or 3 times during the first 6 months, and then once or twice a year. Serum calcium and parathyroid hormone should be measured annually. Cumulative dose is a risk factor for renal damage so the minimal effective dose for effective prophylaxis should be used (1, 2, 3).

Antiseizure medications that act as mood stabilizers, especially valproate and carbamazepine, are often used for acute mania and for mixed states (mania and depression). Lamotrigine is effective for mood-cycling and for depression. The precise mechanism of action for antiseizure medications in bipolar disorder is unknown but may involve gamma-aminobutyric acid mechanisms and ultimately G-protein signaling systems. Their main advantages over lithium include a wider therapeutic margin and lack of renal toxicity.

For valproate, the initial dose and route of administration may vary, but it requires adjustment based on target serum levels. A loading-dose protocol based on weight may result in earlier symptom improvement. Adverse effects include nausea, headache, sedation, dizziness, and weight gain; rare serious effects include hepatotoxicity and pancreatitis.

Carbamazepine should not be loaded; it should be increased gradually to achieve a target serum level. Adverse effects include nausea, dizziness, sedation, and unsteadiness. Very severe effects include aplastic anemia and agranulocytosis.

For lamotrigine, the initial dose and titration vary depending on possible interactions with concomitant medications. Dosage is lower for patients taking valproate and higher for patients taking carbamazepine. Lamotrigine can cause rash and, rarely, the life-threatening Stevens-Johnson syndrome, particularly if the dosage is increased more rapidly than recommended. While taking lamotrigine, patients should be encouraged to report any new rash, hives, fever, swollen glands, sores in the mouth and on the eyes, and swelling of the lips or tongue.

Acute manic psychosis is being increasingly managed with second-generation antipsychotics, such as

• Aripiprazole

• Cariprazine

• Lurasidone

• Olanzapine

• Quetiapine

• Risperidone

• Ziprasidone

In addition, evidence suggests that some of these medications may enhance the effects of mood stabilizers after the acute phase (1).

Although any of these medications may have extrapyramidal adverse effects and cause akathisia, risk is lower with more sedating medications such as quetiapine and olanzapine. Less immediate adverse effects include substantial weight gain and development of the metabolic syndrome (including weight gain, excess abdominal fat, insulin resistance, and dyslipidemia); risk may be lower with the least sedating second-generation antipsychotics, lurasidone, ziprasidone and aripiprazole.

For extremely hyperactive psychotic patients with poor food and fluid intake, an antipsychotic given IM plus supportive care in addition to lithium or an antiseizure medication may be appropriate.

Specific antidepressants (eg, selective serotonin reuptake inhibitors [SSRIs]) are sometimes added for severe depression, but their effectiveness is controversial; they are generally not recommended as monotherapy for depressive episodes, though there is evidence that an SSRI (specifically sertraline) may be safe and effective as monotherapy for bipolar II depression (1). A series of small studies have indicated that tranylcypromine may be more effective than other antidepressants in the treatment of bipolar depression (2).

Lithium use during pregnancy has been associated with an increased risk of cardiovascular malformations (particularly Ebstein anomaly). However, the absolute risk of this particular malformation is quite low (1). Taking lithium during pregnancy appears to increase the relative risk of any congenital anomaly by about 2-fold, a risk similar to the 2- to 3-fold increased risk of congenital anomalies associated with use of carbamazepine or lamotrigine and is substantially lower than the risk associated with use of valproate.

With valproate, risk of neural tube defects and other congenital malformations appears to be 2 to 7 times higher than that with other commonly used antiseizure medications and should not be used during pregnancy (2). Valproate increases the risk of neural tube defects, congenital heart defects, genitourinary anomalies, musculoskeletal abnormalities, and cleft lip or palate. Also, cognitive outcomes (eg, IQ scores) in children of women who took valproate during pregnancy are worse than those with other antiseizure medications; risk appears to be dose-related. Valproate also appears to increase risk of attention-deficit/hyperactivity disorder and autism spectrum disorders (3).

Extensive study of the use of first-generation antipsychotics and tricyclic antidepressants during early pregnancy has not revealed causes for concern. There is evidence that second-generation antipsychotics are safe as well, with the possible exception of risperidone (4). The risk of teratogenicity also appears to be low for selective serotonin reuptake inhibitors (SSRIs) (5). Some studies suggest there may be a small absolute increased risk of congenital heart defects with paroxetine (6), but the data are inconsistent. Data about the risks of second-generation antipsychotics to the fetus are sparse as yet, even though these medications are being more widely used for all phases of bipolar disorder.

Use of medications (particularly lithium and SSRIs) before parturition may have postpartum effects on neonates.

Treatment decisions are complicated by the fact that with unplanned pregnancy, teratogenic effects may already have taken place by the time clinicians become aware of the issue. Consultation with a perinatal psychiatrist should be considered. In all cases, discussing the risks and benefits of treatment with patients is important. (See also Antidepressants During Pregnancy.)