Bipolar Disorder Maintenance Treatment: Monitoring Effectiveness and Safety

Michael E. Thase, MD

Departments of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia Veterans Affairs Medical Center, and the University of Pittsburgh Medical Center, Philadelphia and Pittsburgh

Patients with bipolar I disorder typically suffer from periods of depression and mania, whereas the course of bipolar II disorder is usually characterized by recurrent depressive episodes and briefer, nonpsychotic hypomanic episodes. Although bipolar disorder cannot be cured, medications are available that can shorten the duration of mood episodes and help prevent new episodes, thus lengthening patients’ time spent well and improving functional outcomes. The long-term treatment goal for bipolar disorder is to protect against both poles of the illness without increasing cycle frequency (ie, medications that protect against or treat depressive episodes should not increase the risk of mania and vice versa).

Maintenance Treatments for Bipolar Disorder

Effective medications for bipolar disorder include mood stabilizers (lithium, divalproex, lamotrigine, and carbamazepine) and atypical antipsychotics. Carbamazepine is rarely used in primary care due to the possibility of severe side effects, including aplastic anemia, agranulocytosis, and sometimes fatal dermatologic reactions. However, all medications for bipolar disorder require long-term monitoring for adverse effects.1 (See long-term monitoring parameters.)

Mood stabilizers. Lithium, which was the only FDA-approved drug for bipolar disorder for more than 2 decades, was first demonstrated to be effective for acute mania and for prophylaxis against recurrent manic episodes; subsequently, lithium was shown to have some antidepressant effects. More than half a century of data support the efficacy, safety, and tolerability of lithium, and it is the least expensive pharmacotherapy for bipolar disorder. A meta-analysis2 of trials ranging from 1973 to 2003 found that lithium reduced the risk of becoming ill again by about 35%, although the preventive effect was greater for manic than for depressive episodes. In addition, lithium treatment has been shown to reduce the risk of suicidal behavior and completed suicide.3

Not all patients will respond to lithium, and some who do receive a therapeutic benefit cannot tolerate an adequate trial of the medication. Lithium’s side effects include diarrhea and other GI concerns, acne and exacerbation of psoriasis, tremor and changes in handwriting, and memory impairment and other cognitive complaints. Typically, higher doses of lithium are needed to treat mania but, once patients’ conditions are stabilized, their ability to tolerate those doses decreases; at that time, a slow reduction of blood lithium levels can reduce plasma-level dependent adverse events such as diarrhea, tremor, and memory impairment. With prolonged exposure, there is the risk of hypothyroidism and goiter and a tendency toward weight gain. Polyuria and excessive thirst are common side effects of lithium and can be associated with the development of renal insufficiency. Lithium therapy during pregnancy is associated with an increased risk of congenital hypothyroidism and a congenital cardiac malformation known as Epstein’s abnormality.

Divalproex has efficacy comparable to lithium for treatment of mania and is a useful alternative for patients who either do not respond to or who are unable to tolerate lithium.4,5 Common side effects of divalproex include upset stomach, weight gain, sedation, and changes in hair growth (eg, alopecia, hirsutism, male pattern baldness). A minority of patients will have reduced platelet counts or elevated liver enzymes. Some women may have menstrual irregularities and other changes suggestive of polycystic ovarian syndrome; divalproex therapy during pregnancy is associated with a risk of neural tube defects.

Lamotrigine has established efficacy for the prevention of relapse or recurrence of bipolar mood episodes, though—in contrast to lithium—it is more effective at prolonging the time to a recurrence of depression than mania.6 Lamotrigine is generally well-tolerated and has fewer side effects than lithium, although, like other anticonvulsants, it is associated with the risk of serious, sometimes fatal, skin rashes.

Atypical antipsychotics. For maintenance treatment for bipolar I disorder, aripiprazole, olanzapine, and the long-acting injectable form of risperidone are FDA-approved as monotherapy, while quetiapine and ziprasidone are approved as adjunctive treatments to mood stabilizers. In placebo-controlled maintenance monotherapy trials, aripiprazole7 and long-acting risperidone8 significantly delayed the time to relapse for manic (P ≤ .005 for both) but not depressive episodes; olanzapine9 significantly prolonged the time to relapse for both manic and depressive episodes (P < .001). Adjunctive quetiapine10 significantly reduced the risk of manic and depressive relapse (P < .0001), and adjunctive ziprasidone11 produced a significantly longer time to intervention for any mood episode compared with adjunctive placebo (P < .0104).

AV 1. Propensity for Metabolic and Neurologic Adverse Effects for Atypical Antipsychotics (00:27)

Reprinted with permission from McIntyre12
Circle size indicates likelihood of adverse event

Side effects associated with atypical antipsychotics include weight gain, sedation, dyslipidemia, diabetes, EPS, and hyperprolactinemia. This class of medications is not approved for treatment of psychosis associated with dementia in the elderly, for whom increased mortality has been documented. Weight gain and other metabolic disturbances during long-term treatment are the greatest safety and tolerability concerns of the atypicals, and, despite the apparent low risk, ongoing monitoring for signs of tardive dyskinesia is necessary. There are important differences in the side effects of these medications. For example, among the medications approved for longer-term therapy, olanzapine is associated with more weight gain and a greater risk of metabolic side effects, whereas aripiprazole and ziprasidone are associated with the least (AV 1).12 Typically, people who are likely to gain weight during therapy often begin to do so within the first 4 to 8 weeks, so attention to minimizing weight gain should begin from the outset of therapy. Additionally, the risk for developing dyslipidemia is more closely linked to weight gain than is the risk for developing either hyperglycemia or diabetes.


Managing Complex Medication Regimens

Patients with bipolar disorder, even with comprehensive treatment, are symptomatically ill about half of the time.13 In current practice guidelines,14 monotherapy with 1 of 2 mood stabilizers—lithium and divalproex—is generally considered to be the first line of treatment for all phases of bipolar disorder. If this fails, the next step often includes either a combination of these mood stabilizers or lamotrigine if depression is the dominant phase of the illness. When clinically indicated, atypical antipsychotics can be used instead of a second mood stabilizer. Patients with bipolar disorder receive, on average, 3 or more medications, including mood stabilizers, atypical antipsychotics, and, sometimes, antidepressants for breakthrough depression.15

AV 2. Managing Complex Medication Regimens in Bipolar Disorder (01:52)

Combination therapy can improve treatment response and possibly allow for lower dosing of medications, which may reduce adverse events. However, combining medications can cause additive side effect and tolerability issues (AV 2). For example, weight gain is likely to be more common in patients taking multiple drugs and should be closely monitored because, in addition to contributing to physical morbidity, obesity is correlated with a greater number of lifetime depressive and manic episodes, a shorter time to recurrence (particularly of depressive episodes) during maintenance treatment, and greater treatment resistance within depressive episodes.16 Other problems with combination therapy include drug-drug interactions, suboptimal dosing of both agents, decreased adherence, and increased cost for the patient. Therefore, when choosing medications, physicians should balance treatment benefit and risk. Patients should be followed closely so that side effects, tolerability issues, and breakthrough symptoms can be addressed to enhance treatment adherence and improve patient outcomes.

For Clinical Use


  • Continue the treatment regimen that stabilized the mood episode for each patient with bipolar disorder
  • Be aware of each medication’s possible side effects, particularly weight gain
  • Systematically monitor patients for tolerability issues


Drug Names

aripiprazole (Abilify), carbamazepine (Carbatrol, Equetro, and others), divalproex (Depakote and others), lamotrigine (Lamictal and others), lithium (Lithobid and others), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal and others), ziprasidone (Geodon)


FDA = Food and Drug Administration
EPS = extrapyramidal symptoms
GI = gastrointestinal

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