Evidence-Based Reviews

Acute bipolar mania: Aggressive initial dosing provides faster symptom relief

Current Psychiatry. 2004 September;3(9):25-38

References

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17. Hirschfeld RMA, Keck PE, Jr, Karcher K, et al. Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2004;161:1057-65.

18. Khanna S, Vieta E, Lyons B, et al. Risperidone monotherapy in acute bipolar mania (abstract P219). Pittsburgh: Fifth International Conference on Bipolar Disorder, 2003.

19. Jones MW, Huizar K, et al. Quetiapine monotherapy for acute mania associated with bipolar disorder (poster presentation). San Francisco: American Psychiatric Association annual meeting, 2003.

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25. Sachs G, Sanchez R, Marcus R, et al. Aripiprazole vs placebo with an acute manic or mixed episode. New York: American Psychiatric Association annual meeting, 2004.

26. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes. Diabetes Care. 2004;27:596-601.

QUETIAPINE

Quetiapine has shown antimanic efficacy as monotherapy and as adjunctive therapy to mood stabilizers.^19,20 The effective dosage was a mean 600 mg/d (range 400 to 800 mg/d) in monotherapy and adjunctive treatment. These studies achieved 400 mg/d within the first 4 days (100 mg on day 1, 200 mg on day 2, 300 mg on day 3, and 400 mg on day 4).

These data combined with revised prescribing information suggest aggressive initial dose escalation of quetiapine within the first 4 days for selected patients. A titration study in patients with schizophrenia used a more-rapid escalation rate of 400 mg within 2 days.²¹ Dizziness, orthostatic hypotension, and sedation were not more frequent in this high-dose group than in the two lower-dose titration groups. In our experience, 200 to 400 mg can be given the first day of treatment.

ZIPRASIDONE

In a randomized, double-blind, controlled trial, Keck et al²² assigned 210 patients with a manic or mixed bipolar episode to 3 weeks of ziprasidone, 40 to 80 mg bid, or placebo. Ziprasidone produced rapid, sustained improvement in manic symptoms on all primary and most secondary efficacy measures, such as the YMRS and CGI.

Significant improvements seen within 2 days were maintained. Ziprasidone was well tolerated and was associated with a low EPS rate; neither weight gain nor clinically significant changes in vital signs were seen.

IM ziprasidone, which is approved for use in schizophrenia, may also have efficacy in bipolar mania.²³ The recommended dose of 20 mg IM is equivalent to 120 to 160 mg orally, so a single injection may reach the target antimanic dosage.

Recommendation. Ziprasidone could be an option for aggressive initial dosing for a patient who has previously received ziprasidone IM and is not at risk for QTc prolongation.

ARIPIPRAZOLE

In a randomized controlled trial, Keck et al²⁴ assigned 262 patients with acute bipolar mania or mixed states to aripiprazole, 30 mg/d, or placebo for 3 weeks. By day 4, manic symptoms were improved significantly more in patients receiving aripiprazole, and discontinuation rates were similar.

Similarly, in a randomized, controlled multi-center study, Sachs et al²⁵ used 30 mg/d in 272 patients with bipolar mania or mixed states. Compared with placebo, aripiprazole produced significant improvement by day 4, with similar discontinuation rates.

Recommendation. Aggressive initial dosing of aripiprazole could be useful for a patient who does not require an IM or rapidly dissolvable medication.

Table 4

Suggested response to metabolic changes during bipolar maintenance therapy

Metabolic change	Therapeutic action
≥5% increase in total body weight	Consider weight-reduction strategies or medication adjustment
Fasting glucose: ≥126 mg/mL ≥300 mg/mL or ≤60 mg/mL	Consider evaluation for diabetes mellitus Seek immediate consultation
Total cholesterol ≥200 mg/dL or triglycerides ≥165 mg/dL	Consider lipid-lowering with dietary and/or medication changes
Source: Adapted from reference 26.

MAINTENANCE THERAPY

Ideally, if a medication stabilizes a patient’s acute bipolar mania, that medication is continued for further stabilization and maintenance. Aggressive initial dosing befits this approach because it establishes a therapeutic blood level and usually reveals any side effects within days. Moreover, patients often prefer to continue the medication that provided relief when they felt most distressed.

Weight gain. Long-term use of atypical antipsychotics may be associated with weight gain, dyslipidemia, and the development of metabolic syndromes and diabetes mellitus. Weight gain risk may be further elevated in patients taking both antipsychotics and lithium or valproic acid.²⁶ When atypical antipsychotics are used for bipolar maintenance therapy, the American Diabetes Association and American Psychiatric Association recommend close monitoring (Tables 3 and 4).

Abnormal movements. Though tardive dyskinesia risk is very low with atypical antipsychotics, we recommend screening during the first year of treatment. The development of diabetes mellitus may precipitate or worsen abnormal movements.

Related resources

American Diabetes Association. www.diabetes.org
American Obesity Association. www.obesity.org
Expert Consensus Treatment Guidelines for Bipolar Disorder: A Guide for Patients and Families. Task Force for the APA Practice Guideline for the Treatment of Patients with Bipolar Disorder. www.psychguides.com/pfg3.php

Drug brand names

Aripiprazole • Abilify
Carbamazepine • Tegretol
Divalproex sodium • Depakote
Haloperidol • Haldol
Olanzapine • Zyprexa
Quetiapine • Seroquel
Risperidone • Risperdal
Valproic acid • Depakene
Ziprasidone • Geodon

Disclosures

Dr. Carroll is a consultant to Abbott Laboratories, Bristol-Myers Squibb Co., AstraZeneca Pharmaceuticals, Eli Lilly and Co., Janssen Pharmaceutica, and Pfizer Inc.

Dr. Fawver is a consultant to Eli Lilly and Co. and Pfizer Inc.

Dr. Thalassinos is a consultant for AstraZeneca Pharamaceuticals, Eli Lilly and Co., and Pfizer Inc.

Acknowledgment

The authors thank Donald R. Schmitt, PharmD, Christopher Thomas, PharmD, and Tina Fore, Library Service, Chillicothe VA Medical Center, for their help in identifying articles used in this review.