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Evidence-Based Reviews

Bipolar maintenance: Are atypical antipsychotics really ‘mood stabilizers’?

Atypical antipsychotics are being used more frequently for bipolar maintenance. Do we know enough about their long-term efficacy and safety?

Vol. 3, No. 4 / April 2004

Maintenance therapy with mood stabilizers is the most critical phase of bipolar disorder treatment but the stage with the least available evidence about medication risks and benefits. The FDA’s recent approval of olanzapine for bipolar maintenance raises the question of whether atypical antipsychotics are really mood stabilizers. This article attempts to answer that question by:

  • describing the “ideal” mood stabilizer
  • discussing atypicals’ advantages over conventional antipsychotics in bipolar patients
  • comparing efficacy data for the six available atypicals
  • recommending strategies to prevent and treat atypicals’ potentially serious side effects during long-term therapy.

What is a ‘mood stabilizer’?

Successful mood stabilizer maintenance therapy decreases the time patients are sick and disabled. Although somewhat dated after only 2 years, the most recent American Psychiatric Association (APA) practice guidelines1 support using mood stabilizers for patients with bipolar I and bipolar II disorders.

Table 1

Bipolar maintenance treatment goals

  • Prevent manic or depressive relapse
  • Reduce subthreshold symptoms
  • Reduce suicide risk
  • Reduce cycling frequency
  • Reduce mood instability
  • Improve functioning

Adapted from American Psychiatric Association practice guidelines for treating patients with bipolar disorder (reference 1)

The goals of maintenance therapy are listed in Table 1. The ideal mood stabilizer would work in maintenance and all bipolar phases and treatment stages—from treating acute depression, mania, hypomania, and mixed states to preventing abnormal mood elevations and depressions. It would not precipitate depression or mania, rapid cycling, or cycle acceleration.

In other words, the best “mood stabilizer” would work in all four treatment roles of bipolar disorder: treating highs and lows, and preventing highs and lows. No such mood stabilizer exists, although lithium may come closest to the ideal.2

Most U.S. psychiatrists use combination therapies for bipolar disorder, particularly when treating acute manic states. The most common combination is a “known” mood stabilizer—such as lithium or divalproex—plus an antipsychotic to quickly control mania.

After mania remits, clinicians often try to eliminate the antipsychotic in hopes of maintaining mood stability and euthymia with the mood stabilizer alone. This was especially true before atypical antipsychotics were approved, given the risk for tardive dyskinesia (TD) associated with long-term use of conventional antipsychotics.

Unfortunately, patients frequently relapse with this strategy, so psychiatrists may leave their bipolar patients on atypical antipsychotics during long-term maintenance. But how good are atypicals as mood stabilizers? Perhaps more importantly, how safe is long-term use of atypicals in bipolar patients?

Antipsychotics as mood stabilizers

The 2002 APA practice guidelines discuss efficacy data for using lithium, divalproex or valproate, lamotrigine, carbamazepine, and electroconvulsive therapy for bipolar maintenance treatment. Two sentences on antipsychotic drug use note:

  • one placebo-controlled study of a conventional antipsychotic showing no efficacy
  • some data supporting clozapine as a prophylactic bipolar treatment.1

A 1998 review of five open trials3 touched on conventional depot antipsychotics’ value in reducing manic or affective illness. However, the authors warned:

  • no controlled trials existed
  • maintenance antipsychotic treatment may be associated with increased risk for tardive movement disorders
  • conventional agents can exacerbate depressive symptoms in some patients.

Using conventional antipsychotics long-term in bipolar disorder is not advisable, with the possible exception of depot preparations in nonadhering patients with severe illness. Long-acting injectable atypicals—such as the recently approved IM risperidone—may displace any use of conventional antipsychotics in bipolar patients.

Atypical antipsychotics hold several advantages over conventional agents:

  • significantly reduced risk for TD and extrapyramidal symptoms (EPS)
  • lack of serum prolactin elevation (except with risperidone)
  • improved cognition
  • possible decreased suicidality, particularly with clozapine.4

Table 2

Tips for managing atypicals’ potentially serious side-effect risks

Weight gain/obesity




Evaluate comorbid conditions such as eating disorders or substance abuse
Take nutritional and exercise history

Check weight and waist circumference at baseline and every visit
Calculate body mass index at every visit
Prescribe healthy diet and exercise

Patient education, careful monitoring, and prevention are most-effective treatments
Drug therapy for persistent weight gain or early rapid gain (>7% in first 6 months). Agents of potential benefit include topiramate, sibutramine, metformin, zonisamide, and orlistat (see Table 3)

Glucose control/type 2 diabetes




Take history of glucose intolerance or diabetes
Ask about family history of diabetes, obesity, hypertension, heart disease

Check baseline weight and plasma glucose
Obtain fasting plasma glucose every 3 months for first year, then annually
Prescribe healthy diet and exercise

Primary prevention through careful monitoring is most effective
Discontinue atypical antipsychotic; use other mood stabilizer unless atypical is only effective drug for that patient
Oral hypoglycemics (metformin, others)





Take history of hyperlipidemia or cardiovascular disease
Ask about family history of hyperlipidemia

Check fasting lipid profile including triglycerides at baseline and every 3 months in first year
Prescribe healthy diet and exercise

Monitor diet, exercise, weight, lipids regularly
Change atypical antipsychotic or use other mood stabilizer (as described above)
Oral antilipemics (simvastatin, others)

Evidence for atypicals

Olanzapine is the only atypical FDA-approved for relapse prevention in bipolar disorder. This approval is supported by several studies, most notably two 1-year, double-blind trials:

  • Mean time to any mood relapse was 174 days in patients taking olanzapine, mean 12.5 mg/d (±5 mg), compared with 22 days in a placebo group (Eli Lilly and Co., data on file).
  • Manic relapse rate was 14.3% in patients treated with olanzapine, ~12 mg/d, compared with 28% in patients treated with lithium, ~1,100 mg/d (mean 0.76 mEq/L). The two treatments were similarly effective in preventing depressive relapse.5

As a mood stabilizer, olanzapine was as effective as divalproex in a 47-week randomized, double-blind study of 251 adults with bipolar I disorder.6 Patients treated with olanzapine improved more rapidly and had fewer manic symptoms than those treated with divalproex, but bipolar relapse rates were similar in both treatment groups.

Risperidone appears to have a role as a potential maintenance mood stabilizer in bipolar patients, although double-blind trials are lacking.

In a 6-month, open-label investigation, relapse rates were 16% for depression and 7% for mania in bipolar patients receiving risperidone (average 4 mg/d) combined with mood-stabilizing medications.7 These relapse rates are lower than those typically reported for mood-stabilizing monotherapy.

In another 6-month, open-label study, risperidone monotherapy (average 4 mg/d) was effective for treating mania and maintaining euthymia.8

IM risperidone is a useful option for bipolar patients chronically nonadherent with oral medications; it also substantially reduces the risk of neuroleptic side effects compared with older depot antipsychotics.

Quetiapine was recently approved as an antimanic agent and may possess mood-stabilizing properties. In a preliminary study of 10 patients with bipolar disorder, adding quetiapine (mean 200 mg/d) to existing mood stabilizer therapy for 12 weeks improved psychopathology, mania, and depression rating scale scores.9

More-recent unpublished data suggest dosing quetiapine to approximately 600 mg/d as monotherapy or an adjunct to treat acute mania, though controlled maintenance studies are lacking (AstraZeneca Pharmaceuticals, data on file).

Others. Some early evidence supports using ziprasidone and aripiprazole for bipolar mania:

  • Ziprasidone monotherapy, 40 to 80 mg bid, was significantly more effective than placebo in reducing acute mania symptoms in a 3-week, double-blind, randomized trial of 197 patients with bipolar I disorder.10
  • Aripiprazole monotherapy, 15 to 30 mg/d, had a significantly greater effect than placebo in a 3-week, double-blind, randomized trial of 262 patients in acute manic or mixed bipolar episodes. Response rates among patients with mania were 40% with aripiprazole and 19% with placebo.11

Both ziprasidone and aripiprazole were well-tolerated in these brief trials, although their efficacy as long-term mood-stabilizers in bipolar disorder is unclear.

Using clozapine raises concerns about potentially serious adverse events, although it remains the only agent with proven efficacy in treatment-refractory mania.12,13 Clozapine also appears to reduce hospitalization and affective relapse rates and improve symptoms and quality of life.14,15

Long-term safety

Compared with conventional antipsychotics, EPS are not a major concern with the atypical agents. Except for risperidone, atypicals’ effect on prolactin levels generally is not clinically meaningful. Atypicals appear to be “mood-friendly,” whereas conventional antipsychotics seem to contribute to dysphoria or cause depression in some patients.

Sedation or other annoying side effects such as dry mouth or dizziness can occur with any atypical. Other more-serious side effects may complicate antipsychotic treatment, as we are coming to understand from using atypicals for long-term schizophrenia management.

Table 3

Weight-loss medications for bipolar patients taking atypical antipsychotics



Side effects



500 to 1,000 mg bid


First-line in patients with comorbid type 2 diabetes


120 mg tid

GI distress
Change in bowel

For patients with BMI >27
Supplement fat-soluble vitamins


5 to 15 mg/d

Dry mouth

For patients with BMI 27 to 30
Risk of serotonin syndrome if given with serotonergic drugs


50 to 250 mg/d


Consider first-line for its potential additive mood-stabilizing effect
May help comorbid binge-eating or seizure disorders


100 to 600 mg/d


Consider first-line for its potential additive mood-stabilizing effect
May help comorbid binge-eating or seizure disorders

Movement disorders. Antipsychotics appear more likely to cause EPS in patients with mood disorders than with schizophrenia. In one study using conventional antipsychotics, bipolar patients were 4 to 5 times more likely than schizophrenia patients to experience acute dystonia.16

Although atypicals pose some small risk for acute EPS and TD, the risk is near placebo-level with clinically relevant and comparable dosages.17 Even so, it is important to educate patients to watch for emerging signs of TD during long-term treatment with any antipsychotic. EPS risk may be dose-dependent, particularly with risperidone.18

Weight gain and obesity. Patients with bipolar disorder are more likely to be overweight or obese (body mass index [BMI] > 30) than the general population,17,19 though the reasons are unknown. Studies suggest an obesity prevalence of 32% to 35% in bipolar patients, compared with 18% in the general population.20,21

All atypicals can cause weight gain, although olanzapine and clozapine are associated with the greatest mean weight gains. In three long-term trials (47 weeks to 18 months), bipolar patients who received olanzapine gained significantly more weight (mean 2 to 3 kg) than those receiving lithium or divalproex.19

Cases with much greater weight gain—even leading to clinical obesity—have been observed, particularly with olanzapine. Although evidence from registration trials and clinical experience show lesser weight gains with risperidone, quetiapine, ziprasidone, and aripiprazole, some of our patients do gain weight while taking these agents—either alone or in combination with lithium or divalproex.

Weight management. Because patients with bipolar disorder may be at increased risk for weight gain and obesity, weight management techniques may improve their health by:

  • decreasing morbidity and mortality tied to weight-related physical illnesses
  • enhancing psychological well-being.1

In addition to diet and exercise counseling, some bipolar patients taking long-term atypical antipsychotics may benefit from adjunctive weight-loss medications (Table 3). We generally use such medications for bipolar patients who:

  • persistently gain weight despite best dietary practices
  • gain substantial weight early in treatment with an atypical antipsychotic that is providing effective symptomatic relief.

Early weight gain—particularly gains of >7% within the first 6 weeks—might predict large weight gain over time.

Diabetes. In September 2003, the FDA requested a class-wide labeling change to warn about a possible link between atypical antipsychotics and diabetes. The FDA recommended blood sugar monitoring of patients taking atypicals, especially those with obesity risk factors or family history of diabetes.

Type 2 diabetes develops in some patients taking atypicals, whether or not they gain substantial weight.22 This suggests that weight gain associated with bipolar disorder and the use of atypical antipsychotics may be independent risk factors for diabetes—a clear concern when treating bipolar patients.

Evidence provides no clear answer as to which atypicals may increase diabetes risk. Cautious use and vigilant monitoring of blood glucose are therefore recommended for every patient taking an atypical for long-term therapy. Also watch for increases in triglycerides and cholesterol17 in patients taking atypicals as bipolar maintenance therapy.

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