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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15. Baker RW, Kinon BJ, Maguire GA, et al. Effectiveness of rapid initial dose escalation of up to 40 milligrams per day of oral olanzapine in acute agitation. J Clin Psychopharmacol. 2003;23(4):342-8.

16. Sachs GS, Grossman F, Ghaemi SN, et al. Combination of mood stabilizer with risperidone or haloperidol for the treatment of acute mania: a double-blind, placebo controlled comparison of efficacy and safety. Am J Psychiatry. 2002;159:1146-54.

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.

OLANZAPINE

Olanzapine has pharmacologic properties favorable for loading.⁴ The recommended dosage for acute mania is 15 mg/d with standard titration; Karagianis et al¹⁴ showed that initial loading doses of >20 mg/d resulted in good control of agitated patients with psychosis. Side effects were uncommon, with sedation occurring in 14% of patients in this case series. The loading dose reduced agitation more effectively than did dosages <20 mg/d given to similar patients.

A multicenter study of 148 acutely agitated inpatients with a variety of psychiatric disorders compared olanzapine rapid initial dose escalation with usual clinical practice.¹⁵ Mean aggressive dosages were 28.8 mg/d on day 1, 30.3 mg/d on day 2, and 16.1 mg/d on day 5. Usual-practice dosages were 10 mg/d, plus lorazepam, 0 to 4 mg/d for the first 2 days and 0 to 2 mg/d on days 3 to 4. Based on Positive and Negative Syndrome Scale excited component subscale scores, olanzapine loading controlled agitation more effectively than did usual practice, with similar side-effect rates.

IM olanzapine or the orally dissolving form are bioequivalent to the tablets and may be used for acute agitation associated with bipolar mania in certain clinical settings.¹⁴

Table 2

Suggested antipsychotic loading for acute bipolar mania and mixed states*

Drug	Day(s)	Aggressive initial dosing schedule	Comment
Aripiprazole^24,25	1 2 to 3 4+	30 mg once daily with food 30 mg/d with food Reduce dosage by 10 to 15 mg/d, based on tolerance and response	Nausea and vomiting may occur in first few days; adjust dosage based on tolerance and response
Olanzapine^14,15	1 and 2 3 and 4 5 to 10	40 mg in single or divided dosage 20 to 30 mg at bedtime 15 mg once daily (may reduce to 5, 7.5, or 10 mg/d)	Adjust dosage based on tolerance and response; oral or IM formulations may be used
Quetiapine^19,21	1 2 and 3 4 to 10	100 mg upon admission and 100 mg at bedtime 100 mg bid (or tid to qid) plus 100 to 200 mg at bedtime 200 mg bid plus 200 to 300 mg at bedtime; may adjust to 400 to 800 mg/d)	Adjust dosage based on tolerance and response
Risperidone^16,18	1 2 3 and 4	3 mg in single or divided dosage 4 mg in single or divided dosage 5 mg in single or divided dosage	Adjust dosage by 1 mg up or down, based on tolerance and response; use tablet, rapid-dissolving tablet, or liquid form, but not long-acting IM form
Ziprasidone^22,23	1 2	20 mg IM in single dose (may repeat for severe agitation) or 40 mg po bid with food 60 to 80 mg po bid with food	Adjust dosage based on tolerance and response
* For hospitalized or partially hospitalized patients, ages18. Not recommended for patients who are pregnant, breastfeeding, medically ill, age >65, or with known sensitivity to the antipsychotic being given.

RISPERIDONE

Sachs et al¹⁶ studied 156 inpatients who developed an acute manic or mixed episode while receiving lithium or divalproex. These patients were randomly assigned to begin adjunctive risperidone, 2 mg/d, haloperidol, or placebo. Dosing was flexible, increasing or decreasing by 1 mg/d. Risperidone’s mean modal dosage was 3.8 mg/d across 3 weeks, with mean exposure of 17 days. Risperidone plus a mood stabilizer was more effective than a mood stabilizer alone, and the combination provided rapid, well-tolerated control of manic symptoms.

In a double-blind trial, Hirschfeld et al¹⁷ randomly assigned 279 patients with acute bipolar mania to risperidone, 1 to 6 mg/d, or placebo for 3 weeks. As early as day 3, YMRS scores were reduced significantly more with risperidone than with placebo. Somnolence was the most common side effect, and mean modal dosage was 4.1 mg/d.

Table 3

Screening schedule for antipsychotic side effects during bipolar maintenance treatment

Baseline
Side effect	Recommended screening
Weight gain	Weight and body mass index (BMI) monthly for first 3 months; waist circumference
Hypertension	Blood pressure
Hyperglycemia	Fasting plasma glucose, with glycosylated hemoglobin (Hb A 1c ) if hyperglycemia is detected
Hyperlipidemia	Fasting lipid profile
Tardive dyskinesia	Abnormal Involuntary Movement Scale (AIMS) or other screen
Ophthalmic changes	Ophthalmologic examination for patients taking quetiapine and for all with diabetes mellitus
Follow-up schedules
3 months
Weight and BMI
Blood pressure
Fasting plasma glucose, with Hb A 1c if hyperglycemia is detected; Hb A 1c values may be used to measure interval changes in glucose tolerance
Fasting lipid profile
6 months
AIMS or other tardive dyskinesia screen
Ophthalmologic examination
Source: Adapted from reference 26.

In a multicenter, randomized, double-blind, placebo-controlled study of patients with acute bipolar mania, Khanna et al¹⁸ assigned patients to receive risperidone monotherapy (mean modal dosage 5.6 mg/d) or placebo for 3 weeks. Mania scores of patients receiving risperidone were significantly lower at weeks 1 and 2, compared with the placebo group. Risperidone was well-tolerated, with no unexpected adverse events.

Recommendation. Because of a risk of extrapyramidal symptoms (EPS) and orthostatic hypotension, initial risperidone loading dosages >4 mg on day 1 are not recommended.