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Evidence on aggressive initial dosing of mood stabilizers and antipsychotics is changing the way acute bipolar mania is treated. To help you apply this information, we searched the literature and meeting abstracts for aggressive strategies tested to date. This article discusses how to:
- identify patients who may benefit from loading or aggressive initial dosing
- calculate mood stabilizer dosages
- dose each atypical antipsychotic
- manage potential antipsychotic side effects during maintenance therapy.
PATIENT SELECTION
Rapidly achieving therapeutic blood levels relieves patient suffering faster than standard titration. It quickly calms the hyperactivity, impulsivity, tension, hostility, and uncooperativeness that distress patients and increase the risk of harm to themselves and others.
The challenge of using higher dosages is to minimize side effects. Loading is not a one-size-fits-all approach, as antimanic drugs’ unique pharmacokinetic and pharmacotherapeutic properties influence how each agent is used.
An interesting body of literature advocates using mood stabilizers plus antipsychotics to treat mania, suggesting greater efficacy than with either agent alone.16 This strategy raises important questions, such as:
- Can two drugs be loaded simultaneously?
- Can patients taking mood stabilizers be treated with antipsychotic loading, and can those taking antipsychotics receive loading dosages of mood stabilizers?
- Would “double loading” improve bipolar mania treatment?
Answers to these questions are needed because of increased demands on clinicians to control hospital costs by rapidly and effectively treating patients with bipolar mania.
Loading doses cannot be standardized but are calculated by multiplying target steady-state plasma concentration by volume of distribution. We suggest aggressive initial schedules for divalproex sodium and atypical antipsychotics in this article with the understanding that practitioners will adjust them based on each patient’s tolerance and response.
Hospitalization. Patients with acute bipolar mania should be supervised closely in the hospital during loading or aggressive initial dosing. Monitor for cardiovascular changes, neurologic disturbances, sensorium changes, and response.
Precautions. Not all patients are candidates for aggressive initial dosing. Contraindications include age <18 or >65 years, pregnancy, breast-feeding, medical illness, and known sensitivity to the medication being given.
Higher-than-usual dosing increases the risk of excessive drug concentrations in sensitive individuals—such as those with a history of sensitivity to lower dosages of similar medications—and toxic levels of drugs with long half-lives can persist. When in doubt, consider giving a smaller amount of the loading dose early in the day, followed later by a larger amount.
DRUG SELECTION
Loading and aggressive initial dosing strategies for bipolar mania were first advanced for divalproex sodium.1 Investigators then examined loading strategies for lithium and carbamazepine, as well as the antipsychotics olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole, which are known to have antimanic properties.
Olanzapine, quetiapine, and risperidone are FDA-approved for short-term treatment of acute manic episodes associated with bipolar I disorder, and similar indications were being considered for aripiprazole and ziprasidone as this article went to press. We discuss evidence on loading and aggressive initial dosing strategies for each agent.
No studies have compared one loading strategy with another. Thus, when we choose drugs for loading, we consider what each patient needs, available formulations, tolerability, and efficacy for long-term stabilization and maintenance treatment.
LITHIUM
Lithium loading targets the therapeutic range (<1.4 mEq/L), without crossing the toxic threshold (>1.5 mEq/L). Lithium loading has shown antimanic effects, although using >30 mg/kg/d causes severe nausea and vomiting.
Moscovich et al2 reported a case series of 9 adults with acute mania who received lithium loading dosages of 4,050 mg/d. Patients tolerated lithium well at plasma drug levels of approximately 1.2 to 1.4 mEq/L. Their manic symptoms declined significantly within 4 to 5 days, as measured by Clinical Global Impression (CGI) severity of illness, Biegel-Murphy Mania State Rating Scale, and Brief Psychiatric Rating Scale scores.
Table 1
How to calculate divalproex loading for acute bipolar mania*
| Days 1 and 2 |
| Patient weight in pounds x 15 = dosage (mg/d) (Example: 150 lbs x 15 = 1,750 mg/d) |
| Days 3 to 10 |
| Patient weight in pounds x 10 = dosage (mg/d) (Example: 150 lbs. x 10 = 1,500 mg/d) |
| To avoid splitting tablets, make dosage divisible by 125 (round up for young adults, round down for older adults). Divide into bid or tid doses for improved tolerability. |
| Days 4 and 7 |
| Draw blood to monitor valproic acid levels and for other values such as liver function studies. |
| * For use with oral divalproex sodium (delayed-release or extended-release formulations). Do not use valproic acid preparations, as loading is unlikely to be well tolerated. |
| Source: Reference 5 |
Kook et al3 attempted a 30-mg/kg loading dose of slow-release lithium carbonate in 38 patients to evaluate the safety of achieving a therapeutic level in 12 hours. No patient experienced adverse effects during loading or in the 12 hours after loading was completed.
Patients who develop a manic episode while taking lithium pose a therapeutic dilemma. If they stop taking lithium—especially abruptly—manic symptoms can return in as few as 2 days. For these patients, consider increasing the usual dosage by 50% to 100% on the first day of mania treatment,4 then continue a dosage that maintains efficacy and achieves a therapeutic blood level.
To avoid GI upset, avoid any single dose of >1,500 mg; if a greater dosage is needed, divide it for improved tolerance. Obtain lithium blood levels at baseline, after 4 days, and thereafter as clinically relevant to monitor for drug interactions that may affect serum levels.
Side effects—GI irritation, tremor, muscle weakness, thirst, polyuria—are common in the first week, and weight gain may occur after prolonged treatment.
DIVALPROEX
In a study by Keck et al1 of 19 adults with acute bipolar mania, aggressive initial dosing of divalproex sodium, 20 mg/kg/d, was well-tolerated and shortened hospitalization. Side effects including sedation and nausea occurred at a rate similar to that seen with more-gradual titration.
To calculate the initial dose, the authors used a conversion factor of 20 mg/kg/d or added a zero to the patient’s weight in pounds. This amount was given in single or divided doses the first day, then continued for 4 to 7 days. Blood levels were measured on day 4, and all 15 patients who completed the study achieved serum valproate levels >50 mcg/mL.
In a double-blind study by Hirschfeld et al,5 59 adults with Young Mania Rating Scale (YMRS) scores >14 were randomly assigned to receive divalproex oral loading; divalproex nonloading (250 mg tid on days 1 and 2, followed by standard titration on days 3 to 10); or lithium carbonate (300 mg tid, followed by standard titration on days 3 to 10).
Divalproex loading—30 mg/kg/d on days 1 and 2, followed by 20 mg/kg on days 3 to 10— yielded valproate levels >50 mcg/mL in 84% of patients by day 3. Rapid loading appeared to increase antimanic efficacy, as measured by YMRS endpoint scores, without increasing adverse effects. For Table 1, we converted this study’s metric values to patient weight in pounds.
Side effects. Divalproex can inhibit metabolism of other drugs (including anticonvulsants such as lamotrigine) and increase their blood levels. Side effects such as sedation, alopecia, abdominal pain, diarrhea, and tremor may require observation and treatment. Pancreatitis, hepatitis, and allergic reactions are rare but may require discontinuation.
Recommendation. Aggressive initial dosing and loading for patients with acute mania has been reported with enteric-coated delayed-release and extended-release6 divalproex sodium tablets. With identical dosages, the extended-release form produces 11% lower serum levels than the delayed-release form.7
Aggressive dosing of oral valproic acid preparations is not recommended and is likely to be poorly tolerated.8 A pilot study evaluating IV valproate loading in acute mania found no changes in mania in the 2 hours that followed loading.9
CARBAMAZEPINE
Carbamazepine is used off-label to treat mania and mixed phases of bipolar disorder.4,9,10 Excessive absorption rates are associated with dizziness, ataxia, and nausea. Side effects may occur when the plasma level is therapeutic for epilepsy (4 to 12 mcg/mL).11
In mania, the relationship between carbamazepine levels and clinical response is not always clear. Lerer et al12 found a correlation between acute mania response and a serum level of 8.8 mcg/mL (range 4.7 to 14.0 mcg/mL).
Patients with acute mania may require 600 to 1,600 mg/d. Carbamazepine is available in immediate-release and controlled-release preparations. Because generic preparations might not be bio-equivalent,13 use the same formulation throughout treatment to maintain consistent serum levels.
Enzymatic auto-induction—in which carbamazepine gradually increases the activity of its metabolic enzyme—is likely to occur at 3 to 5 weeks of administration, often after hospital discharge. An aggressive initial rescue adjustment can be used if a patient develops mania after having been stabilized on carbamazepine for >6 weeks. Because these patients are past the point of auto-induction, a target blood level of 8.8 mcg/mL can be used and the dosage adjusted proportionally.
For example, if mania recurs in a patient who is stabilized on carbamazepine, 400 mg/d (plasma level 4.5 mcg/mL), carbamazepine can be loaded up to 800 mg/d. Measure the plasma level within 4 days; the target level would be 9.0 mcg/mL (2 times 4.5 mcg/mL), which closely approximates steady state and sets up a ratio to reach the target level of 8.8 mcg/mL.
Side effects include ataxia, diplopia, and dizziness. Complete blood counts, liver function studies, plasma levels, and serum chemistries require regular monitoring.
Recommendation. Carbamazepine is not recommended for oral loading in patients who have never taken it or for those with hyponatremia, hepatic dysfunction, or history of intolerance or agranulocytosis.
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 |
|---|---|---|---|
| Aripiprazole24,25 | 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 |
| Olanzapine14,15 | 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 |
| Quetiapine19,21 | 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 |
| Risperidone16,18 | 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 |
| Ziprasidone22,23 | 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.
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.
1. Keck PE, Jr, McElroy SL, Tugrul KC, et al. Valproate oral loading in the treatment of acute mania. J Clin Psychiatry. 1993;54:305-8.
2. Moscovich DG, Shapira B, Lerer B, et al. Rapid lithiumization in acute manic patients. Hum Psychopharmacol. 1992;7:343-5.
3. Kook KA, Stimmel GL, Wilkins JN, et al. Accuracy and safety of a priori lithium loading. J Clin Psychiatry. 1985;46:49-51.
4. Carroll BT, Thalassinos A, Fawver JD. Loading strategies in acute mania. CNS Spectrums. 2001;6:919-30.
5. Hirschfeld RMA, Allen MH, McEvoy J, et al. Safety and tolerability of oral loading divalproex sodium in acutely manic bipolar patients. J Clin Psychiatry. 1999;60:815-18.
6. Miller BP, et al. Oral loading of extended-release divalproex in acute mania (presentation). New Orleans: American Psychiatric Association annual meeting, 2001.
7. Thibault M, Blume WT, Saint-Hilaire JM, et al. Divalproex extended-release versus the original divalproex tablet: results of a randomized, crossover study of well-controlled epileptic patients with primary generalized seizures. Epilepsy Res. 2002;50:243-9.
8. Hirschfeld RMA, Baker JD, Wozniak P, et al. The safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex, lithium, olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder. J Clin Psychiatry. 2003;64:841-6.
9. Phrolov K, Applebaum J, Levine J, et al. Single-dose intravenous valproate in acute mania. J Clin Psychiatry. 2004;65:68-70.
10. Keck PE, Jr, McElroy SL, Bennet TA. Pharmacologic loading in the treatment of acute mania. Bipolar Disord. 2000;2:42-6.
11. Dunn RT, Frye MS, Tim KA, et al. The efficacy and use of anticonvulsants in mood disorders. Clin Neuropharmacol. 1998;21:215-35.
12. Lerer B, Moore N, Meyendor E, et al. Carbamazepine versus lithium in mania a double-blind study. J Clin Psychiatry. 1987;48:89-93.
13. Brown B. The use of generic mood stabilizers: carbamazepine (monograph). J Clin Psychiatry. 1997;15(4):11-17.
14. Karagianis JL, Dawe IC, Thakur A, et al. Rapid tranquilization with olanzapine in acute psychosis: a case series. J Clin Psychiatry. 2001;62(suppl 2):12-16.
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.
20. Sachs G, Mullen JA, Devine NA, Sweitzer DE. Quetiapine versus placebo as adjunct to mood stabilizer for the treatment of acute mania (abstract). Bipolar Disord. 2002;4(suppl 1):133.-
21. Smith MA, McCoy R, Hamer J, Brecher M. Optimal titration for quetiapine (poster presentation): Boca Raton, FL: National Clinical Drug Evaluation Unit annual meeting, 2002.
22. Keck PE, Jr, Versiani M, Potkin S, et al. Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry. 2003;160:741-8.
23. Holtzheimer PE, Neumaier JF. Treatment of acute mania. CNS Spectrums. 2003;8(12):917-28.
24. Keck PE, Jr, Marcus R, Tourkodimitris S, et al. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry. 2003;160(9):1651-8.
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.
Evidence on aggressive initial dosing of mood stabilizers and antipsychotics is changing the way acute bipolar mania is treated. To help you apply this information, we searched the literature and meeting abstracts for aggressive strategies tested to date. This article discusses how to:
- identify patients who may benefit from loading or aggressive initial dosing
- calculate mood stabilizer dosages
- dose each atypical antipsychotic
- manage potential antipsychotic side effects during maintenance therapy.
PATIENT SELECTION
Rapidly achieving therapeutic blood levels relieves patient suffering faster than standard titration. It quickly calms the hyperactivity, impulsivity, tension, hostility, and uncooperativeness that distress patients and increase the risk of harm to themselves and others.
The challenge of using higher dosages is to minimize side effects. Loading is not a one-size-fits-all approach, as antimanic drugs’ unique pharmacokinetic and pharmacotherapeutic properties influence how each agent is used.
An interesting body of literature advocates using mood stabilizers plus antipsychotics to treat mania, suggesting greater efficacy than with either agent alone.16 This strategy raises important questions, such as:
- Can two drugs be loaded simultaneously?
- Can patients taking mood stabilizers be treated with antipsychotic loading, and can those taking antipsychotics receive loading dosages of mood stabilizers?
- Would “double loading” improve bipolar mania treatment?
Answers to these questions are needed because of increased demands on clinicians to control hospital costs by rapidly and effectively treating patients with bipolar mania.
Loading doses cannot be standardized but are calculated by multiplying target steady-state plasma concentration by volume of distribution. We suggest aggressive initial schedules for divalproex sodium and atypical antipsychotics in this article with the understanding that practitioners will adjust them based on each patient’s tolerance and response.
Hospitalization. Patients with acute bipolar mania should be supervised closely in the hospital during loading or aggressive initial dosing. Monitor for cardiovascular changes, neurologic disturbances, sensorium changes, and response.
Precautions. Not all patients are candidates for aggressive initial dosing. Contraindications include age <18 or >65 years, pregnancy, breast-feeding, medical illness, and known sensitivity to the medication being given.
Higher-than-usual dosing increases the risk of excessive drug concentrations in sensitive individuals—such as those with a history of sensitivity to lower dosages of similar medications—and toxic levels of drugs with long half-lives can persist. When in doubt, consider giving a smaller amount of the loading dose early in the day, followed later by a larger amount.
DRUG SELECTION
Loading and aggressive initial dosing strategies for bipolar mania were first advanced for divalproex sodium.1 Investigators then examined loading strategies for lithium and carbamazepine, as well as the antipsychotics olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole, which are known to have antimanic properties.
Olanzapine, quetiapine, and risperidone are FDA-approved for short-term treatment of acute manic episodes associated with bipolar I disorder, and similar indications were being considered for aripiprazole and ziprasidone as this article went to press. We discuss evidence on loading and aggressive initial dosing strategies for each agent.
No studies have compared one loading strategy with another. Thus, when we choose drugs for loading, we consider what each patient needs, available formulations, tolerability, and efficacy for long-term stabilization and maintenance treatment.
LITHIUM
Lithium loading targets the therapeutic range (<1.4 mEq/L), without crossing the toxic threshold (>1.5 mEq/L). Lithium loading has shown antimanic effects, although using >30 mg/kg/d causes severe nausea and vomiting.
Moscovich et al2 reported a case series of 9 adults with acute mania who received lithium loading dosages of 4,050 mg/d. Patients tolerated lithium well at plasma drug levels of approximately 1.2 to 1.4 mEq/L. Their manic symptoms declined significantly within 4 to 5 days, as measured by Clinical Global Impression (CGI) severity of illness, Biegel-Murphy Mania State Rating Scale, and Brief Psychiatric Rating Scale scores.
Table 1
How to calculate divalproex loading for acute bipolar mania*
| Days 1 and 2 |
| Patient weight in pounds x 15 = dosage (mg/d) (Example: 150 lbs x 15 = 1,750 mg/d) |
| Days 3 to 10 |
| Patient weight in pounds x 10 = dosage (mg/d) (Example: 150 lbs. x 10 = 1,500 mg/d) |
| To avoid splitting tablets, make dosage divisible by 125 (round up for young adults, round down for older adults). Divide into bid or tid doses for improved tolerability. |
| Days 4 and 7 |
| Draw blood to monitor valproic acid levels and for other values such as liver function studies. |
| * For use with oral divalproex sodium (delayed-release or extended-release formulations). Do not use valproic acid preparations, as loading is unlikely to be well tolerated. |
| Source: Reference 5 |
Kook et al3 attempted a 30-mg/kg loading dose of slow-release lithium carbonate in 38 patients to evaluate the safety of achieving a therapeutic level in 12 hours. No patient experienced adverse effects during loading or in the 12 hours after loading was completed.
Patients who develop a manic episode while taking lithium pose a therapeutic dilemma. If they stop taking lithium—especially abruptly—manic symptoms can return in as few as 2 days. For these patients, consider increasing the usual dosage by 50% to 100% on the first day of mania treatment,4 then continue a dosage that maintains efficacy and achieves a therapeutic blood level.
To avoid GI upset, avoid any single dose of >1,500 mg; if a greater dosage is needed, divide it for improved tolerance. Obtain lithium blood levels at baseline, after 4 days, and thereafter as clinically relevant to monitor for drug interactions that may affect serum levels.
Side effects—GI irritation, tremor, muscle weakness, thirst, polyuria—are common in the first week, and weight gain may occur after prolonged treatment.
DIVALPROEX
In a study by Keck et al1 of 19 adults with acute bipolar mania, aggressive initial dosing of divalproex sodium, 20 mg/kg/d, was well-tolerated and shortened hospitalization. Side effects including sedation and nausea occurred at a rate similar to that seen with more-gradual titration.
To calculate the initial dose, the authors used a conversion factor of 20 mg/kg/d or added a zero to the patient’s weight in pounds. This amount was given in single or divided doses the first day, then continued for 4 to 7 days. Blood levels were measured on day 4, and all 15 patients who completed the study achieved serum valproate levels >50 mcg/mL.
In a double-blind study by Hirschfeld et al,5 59 adults with Young Mania Rating Scale (YMRS) scores >14 were randomly assigned to receive divalproex oral loading; divalproex nonloading (250 mg tid on days 1 and 2, followed by standard titration on days 3 to 10); or lithium carbonate (300 mg tid, followed by standard titration on days 3 to 10).
Divalproex loading—30 mg/kg/d on days 1 and 2, followed by 20 mg/kg on days 3 to 10— yielded valproate levels >50 mcg/mL in 84% of patients by day 3. Rapid loading appeared to increase antimanic efficacy, as measured by YMRS endpoint scores, without increasing adverse effects. For Table 1, we converted this study’s metric values to patient weight in pounds.
Side effects. Divalproex can inhibit metabolism of other drugs (including anticonvulsants such as lamotrigine) and increase their blood levels. Side effects such as sedation, alopecia, abdominal pain, diarrhea, and tremor may require observation and treatment. Pancreatitis, hepatitis, and allergic reactions are rare but may require discontinuation.
Recommendation. Aggressive initial dosing and loading for patients with acute mania has been reported with enteric-coated delayed-release and extended-release6 divalproex sodium tablets. With identical dosages, the extended-release form produces 11% lower serum levels than the delayed-release form.7
Aggressive dosing of oral valproic acid preparations is not recommended and is likely to be poorly tolerated.8 A pilot study evaluating IV valproate loading in acute mania found no changes in mania in the 2 hours that followed loading.9
CARBAMAZEPINE
Carbamazepine is used off-label to treat mania and mixed phases of bipolar disorder.4,9,10 Excessive absorption rates are associated with dizziness, ataxia, and nausea. Side effects may occur when the plasma level is therapeutic for epilepsy (4 to 12 mcg/mL).11
In mania, the relationship between carbamazepine levels and clinical response is not always clear. Lerer et al12 found a correlation between acute mania response and a serum level of 8.8 mcg/mL (range 4.7 to 14.0 mcg/mL).
Patients with acute mania may require 600 to 1,600 mg/d. Carbamazepine is available in immediate-release and controlled-release preparations. Because generic preparations might not be bio-equivalent,13 use the same formulation throughout treatment to maintain consistent serum levels.
Enzymatic auto-induction—in which carbamazepine gradually increases the activity of its metabolic enzyme—is likely to occur at 3 to 5 weeks of administration, often after hospital discharge. An aggressive initial rescue adjustment can be used if a patient develops mania after having been stabilized on carbamazepine for >6 weeks. Because these patients are past the point of auto-induction, a target blood level of 8.8 mcg/mL can be used and the dosage adjusted proportionally.
For example, if mania recurs in a patient who is stabilized on carbamazepine, 400 mg/d (plasma level 4.5 mcg/mL), carbamazepine can be loaded up to 800 mg/d. Measure the plasma level within 4 days; the target level would be 9.0 mcg/mL (2 times 4.5 mcg/mL), which closely approximates steady state and sets up a ratio to reach the target level of 8.8 mcg/mL.
Side effects include ataxia, diplopia, and dizziness. Complete blood counts, liver function studies, plasma levels, and serum chemistries require regular monitoring.
Recommendation. Carbamazepine is not recommended for oral loading in patients who have never taken it or for those with hyponatremia, hepatic dysfunction, or history of intolerance or agranulocytosis.
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 |
|---|---|---|---|
| Aripiprazole24,25 | 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 |
| Olanzapine14,15 | 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 |
| Quetiapine19,21 | 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 |
| Risperidone16,18 | 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 |
| Ziprasidone22,23 | 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.
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.
Evidence on aggressive initial dosing of mood stabilizers and antipsychotics is changing the way acute bipolar mania is treated. To help you apply this information, we searched the literature and meeting abstracts for aggressive strategies tested to date. This article discusses how to:
- identify patients who may benefit from loading or aggressive initial dosing
- calculate mood stabilizer dosages
- dose each atypical antipsychotic
- manage potential antipsychotic side effects during maintenance therapy.
PATIENT SELECTION
Rapidly achieving therapeutic blood levels relieves patient suffering faster than standard titration. It quickly calms the hyperactivity, impulsivity, tension, hostility, and uncooperativeness that distress patients and increase the risk of harm to themselves and others.
The challenge of using higher dosages is to minimize side effects. Loading is not a one-size-fits-all approach, as antimanic drugs’ unique pharmacokinetic and pharmacotherapeutic properties influence how each agent is used.
An interesting body of literature advocates using mood stabilizers plus antipsychotics to treat mania, suggesting greater efficacy than with either agent alone.16 This strategy raises important questions, such as:
- Can two drugs be loaded simultaneously?
- Can patients taking mood stabilizers be treated with antipsychotic loading, and can those taking antipsychotics receive loading dosages of mood stabilizers?
- Would “double loading” improve bipolar mania treatment?
Answers to these questions are needed because of increased demands on clinicians to control hospital costs by rapidly and effectively treating patients with bipolar mania.
Loading doses cannot be standardized but are calculated by multiplying target steady-state plasma concentration by volume of distribution. We suggest aggressive initial schedules for divalproex sodium and atypical antipsychotics in this article with the understanding that practitioners will adjust them based on each patient’s tolerance and response.
Hospitalization. Patients with acute bipolar mania should be supervised closely in the hospital during loading or aggressive initial dosing. Monitor for cardiovascular changes, neurologic disturbances, sensorium changes, and response.
Precautions. Not all patients are candidates for aggressive initial dosing. Contraindications include age <18 or >65 years, pregnancy, breast-feeding, medical illness, and known sensitivity to the medication being given.
Higher-than-usual dosing increases the risk of excessive drug concentrations in sensitive individuals—such as those with a history of sensitivity to lower dosages of similar medications—and toxic levels of drugs with long half-lives can persist. When in doubt, consider giving a smaller amount of the loading dose early in the day, followed later by a larger amount.
DRUG SELECTION
Loading and aggressive initial dosing strategies for bipolar mania were first advanced for divalproex sodium.1 Investigators then examined loading strategies for lithium and carbamazepine, as well as the antipsychotics olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole, which are known to have antimanic properties.
Olanzapine, quetiapine, and risperidone are FDA-approved for short-term treatment of acute manic episodes associated with bipolar I disorder, and similar indications were being considered for aripiprazole and ziprasidone as this article went to press. We discuss evidence on loading and aggressive initial dosing strategies for each agent.
No studies have compared one loading strategy with another. Thus, when we choose drugs for loading, we consider what each patient needs, available formulations, tolerability, and efficacy for long-term stabilization and maintenance treatment.
LITHIUM
Lithium loading targets the therapeutic range (<1.4 mEq/L), without crossing the toxic threshold (>1.5 mEq/L). Lithium loading has shown antimanic effects, although using >30 mg/kg/d causes severe nausea and vomiting.
Moscovich et al2 reported a case series of 9 adults with acute mania who received lithium loading dosages of 4,050 mg/d. Patients tolerated lithium well at plasma drug levels of approximately 1.2 to 1.4 mEq/L. Their manic symptoms declined significantly within 4 to 5 days, as measured by Clinical Global Impression (CGI) severity of illness, Biegel-Murphy Mania State Rating Scale, and Brief Psychiatric Rating Scale scores.
Table 1
How to calculate divalproex loading for acute bipolar mania*
| Days 1 and 2 |
| Patient weight in pounds x 15 = dosage (mg/d) (Example: 150 lbs x 15 = 1,750 mg/d) |
| Days 3 to 10 |
| Patient weight in pounds x 10 = dosage (mg/d) (Example: 150 lbs. x 10 = 1,500 mg/d) |
| To avoid splitting tablets, make dosage divisible by 125 (round up for young adults, round down for older adults). Divide into bid or tid doses for improved tolerability. |
| Days 4 and 7 |
| Draw blood to monitor valproic acid levels and for other values such as liver function studies. |
| * For use with oral divalproex sodium (delayed-release or extended-release formulations). Do not use valproic acid preparations, as loading is unlikely to be well tolerated. |
| Source: Reference 5 |
Kook et al3 attempted a 30-mg/kg loading dose of slow-release lithium carbonate in 38 patients to evaluate the safety of achieving a therapeutic level in 12 hours. No patient experienced adverse effects during loading or in the 12 hours after loading was completed.
Patients who develop a manic episode while taking lithium pose a therapeutic dilemma. If they stop taking lithium—especially abruptly—manic symptoms can return in as few as 2 days. For these patients, consider increasing the usual dosage by 50% to 100% on the first day of mania treatment,4 then continue a dosage that maintains efficacy and achieves a therapeutic blood level.
To avoid GI upset, avoid any single dose of >1,500 mg; if a greater dosage is needed, divide it for improved tolerance. Obtain lithium blood levels at baseline, after 4 days, and thereafter as clinically relevant to monitor for drug interactions that may affect serum levels.
Side effects—GI irritation, tremor, muscle weakness, thirst, polyuria—are common in the first week, and weight gain may occur after prolonged treatment.
DIVALPROEX
In a study by Keck et al1 of 19 adults with acute bipolar mania, aggressive initial dosing of divalproex sodium, 20 mg/kg/d, was well-tolerated and shortened hospitalization. Side effects including sedation and nausea occurred at a rate similar to that seen with more-gradual titration.
To calculate the initial dose, the authors used a conversion factor of 20 mg/kg/d or added a zero to the patient’s weight in pounds. This amount was given in single or divided doses the first day, then continued for 4 to 7 days. Blood levels were measured on day 4, and all 15 patients who completed the study achieved serum valproate levels >50 mcg/mL.
In a double-blind study by Hirschfeld et al,5 59 adults with Young Mania Rating Scale (YMRS) scores >14 were randomly assigned to receive divalproex oral loading; divalproex nonloading (250 mg tid on days 1 and 2, followed by standard titration on days 3 to 10); or lithium carbonate (300 mg tid, followed by standard titration on days 3 to 10).
Divalproex loading—30 mg/kg/d on days 1 and 2, followed by 20 mg/kg on days 3 to 10— yielded valproate levels >50 mcg/mL in 84% of patients by day 3. Rapid loading appeared to increase antimanic efficacy, as measured by YMRS endpoint scores, without increasing adverse effects. For Table 1, we converted this study’s metric values to patient weight in pounds.
Side effects. Divalproex can inhibit metabolism of other drugs (including anticonvulsants such as lamotrigine) and increase their blood levels. Side effects such as sedation, alopecia, abdominal pain, diarrhea, and tremor may require observation and treatment. Pancreatitis, hepatitis, and allergic reactions are rare but may require discontinuation.
Recommendation. Aggressive initial dosing and loading for patients with acute mania has been reported with enteric-coated delayed-release and extended-release6 divalproex sodium tablets. With identical dosages, the extended-release form produces 11% lower serum levels than the delayed-release form.7
Aggressive dosing of oral valproic acid preparations is not recommended and is likely to be poorly tolerated.8 A pilot study evaluating IV valproate loading in acute mania found no changes in mania in the 2 hours that followed loading.9
CARBAMAZEPINE
Carbamazepine is used off-label to treat mania and mixed phases of bipolar disorder.4,9,10 Excessive absorption rates are associated with dizziness, ataxia, and nausea. Side effects may occur when the plasma level is therapeutic for epilepsy (4 to 12 mcg/mL).11
In mania, the relationship between carbamazepine levels and clinical response is not always clear. Lerer et al12 found a correlation between acute mania response and a serum level of 8.8 mcg/mL (range 4.7 to 14.0 mcg/mL).
Patients with acute mania may require 600 to 1,600 mg/d. Carbamazepine is available in immediate-release and controlled-release preparations. Because generic preparations might not be bio-equivalent,13 use the same formulation throughout treatment to maintain consistent serum levels.
Enzymatic auto-induction—in which carbamazepine gradually increases the activity of its metabolic enzyme—is likely to occur at 3 to 5 weeks of administration, often after hospital discharge. An aggressive initial rescue adjustment can be used if a patient develops mania after having been stabilized on carbamazepine for >6 weeks. Because these patients are past the point of auto-induction, a target blood level of 8.8 mcg/mL can be used and the dosage adjusted proportionally.
For example, if mania recurs in a patient who is stabilized on carbamazepine, 400 mg/d (plasma level 4.5 mcg/mL), carbamazepine can be loaded up to 800 mg/d. Measure the plasma level within 4 days; the target level would be 9.0 mcg/mL (2 times 4.5 mcg/mL), which closely approximates steady state and sets up a ratio to reach the target level of 8.8 mcg/mL.
Side effects include ataxia, diplopia, and dizziness. Complete blood counts, liver function studies, plasma levels, and serum chemistries require regular monitoring.
Recommendation. Carbamazepine is not recommended for oral loading in patients who have never taken it or for those with hyponatremia, hepatic dysfunction, or history of intolerance or agranulocytosis.
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 |
|---|---|---|---|
| Aripiprazole24,25 | 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 |
| Olanzapine14,15 | 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 |
| Quetiapine19,21 | 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 |
| Risperidone16,18 | 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 |
| Ziprasidone22,23 | 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.
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.
1. Keck PE, Jr, McElroy SL, Tugrul KC, et al. Valproate oral loading in the treatment of acute mania. J Clin Psychiatry. 1993;54:305-8.
2. Moscovich DG, Shapira B, Lerer B, et al. Rapid lithiumization in acute manic patients. Hum Psychopharmacol. 1992;7:343-5.
3. Kook KA, Stimmel GL, Wilkins JN, et al. Accuracy and safety of a priori lithium loading. J Clin Psychiatry. 1985;46:49-51.
4. Carroll BT, Thalassinos A, Fawver JD. Loading strategies in acute mania. CNS Spectrums. 2001;6:919-30.
5. Hirschfeld RMA, Allen MH, McEvoy J, et al. Safety and tolerability of oral loading divalproex sodium in acutely manic bipolar patients. J Clin Psychiatry. 1999;60:815-18.
6. Miller BP, et al. Oral loading of extended-release divalproex in acute mania (presentation). New Orleans: American Psychiatric Association annual meeting, 2001.
7. Thibault M, Blume WT, Saint-Hilaire JM, et al. Divalproex extended-release versus the original divalproex tablet: results of a randomized, crossover study of well-controlled epileptic patients with primary generalized seizures. Epilepsy Res. 2002;50:243-9.
8. Hirschfeld RMA, Baker JD, Wozniak P, et al. The safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex, lithium, olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder. J Clin Psychiatry. 2003;64:841-6.
9. Phrolov K, Applebaum J, Levine J, et al. Single-dose intravenous valproate in acute mania. J Clin Psychiatry. 2004;65:68-70.
10. Keck PE, Jr, McElroy SL, Bennet TA. Pharmacologic loading in the treatment of acute mania. Bipolar Disord. 2000;2:42-6.
11. Dunn RT, Frye MS, Tim KA, et al. The efficacy and use of anticonvulsants in mood disorders. Clin Neuropharmacol. 1998;21:215-35.
12. Lerer B, Moore N, Meyendor E, et al. Carbamazepine versus lithium in mania a double-blind study. J Clin Psychiatry. 1987;48:89-93.
13. Brown B. The use of generic mood stabilizers: carbamazepine (monograph). J Clin Psychiatry. 1997;15(4):11-17.
14. Karagianis JL, Dawe IC, Thakur A, et al. Rapid tranquilization with olanzapine in acute psychosis: a case series. J Clin Psychiatry. 2001;62(suppl 2):12-16.
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.
20. Sachs G, Mullen JA, Devine NA, Sweitzer DE. Quetiapine versus placebo as adjunct to mood stabilizer for the treatment of acute mania (abstract). Bipolar Disord. 2002;4(suppl 1):133.-
21. Smith MA, McCoy R, Hamer J, Brecher M. Optimal titration for quetiapine (poster presentation): Boca Raton, FL: National Clinical Drug Evaluation Unit annual meeting, 2002.
22. Keck PE, Jr, Versiani M, Potkin S, et al. Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry. 2003;160:741-8.
23. Holtzheimer PE, Neumaier JF. Treatment of acute mania. CNS Spectrums. 2003;8(12):917-28.
24. Keck PE, Jr, Marcus R, Tourkodimitris S, et al. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry. 2003;160(9):1651-8.
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.
1. Keck PE, Jr, McElroy SL, Tugrul KC, et al. Valproate oral loading in the treatment of acute mania. J Clin Psychiatry. 1993;54:305-8.
2. Moscovich DG, Shapira B, Lerer B, et al. Rapid lithiumization in acute manic patients. Hum Psychopharmacol. 1992;7:343-5.
3. Kook KA, Stimmel GL, Wilkins JN, et al. Accuracy and safety of a priori lithium loading. J Clin Psychiatry. 1985;46:49-51.
4. Carroll BT, Thalassinos A, Fawver JD. Loading strategies in acute mania. CNS Spectrums. 2001;6:919-30.
5. Hirschfeld RMA, Allen MH, McEvoy J, et al. Safety and tolerability of oral loading divalproex sodium in acutely manic bipolar patients. J Clin Psychiatry. 1999;60:815-18.
6. Miller BP, et al. Oral loading of extended-release divalproex in acute mania (presentation). New Orleans: American Psychiatric Association annual meeting, 2001.
7. Thibault M, Blume WT, Saint-Hilaire JM, et al. Divalproex extended-release versus the original divalproex tablet: results of a randomized, crossover study of well-controlled epileptic patients with primary generalized seizures. Epilepsy Res. 2002;50:243-9.
8. Hirschfeld RMA, Baker JD, Wozniak P, et al. The safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex, lithium, olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder. J Clin Psychiatry. 2003;64:841-6.
9. Phrolov K, Applebaum J, Levine J, et al. Single-dose intravenous valproate in acute mania. J Clin Psychiatry. 2004;65:68-70.
10. Keck PE, Jr, McElroy SL, Bennet TA. Pharmacologic loading in the treatment of acute mania. Bipolar Disord. 2000;2:42-6.
11. Dunn RT, Frye MS, Tim KA, et al. The efficacy and use of anticonvulsants in mood disorders. Clin Neuropharmacol. 1998;21:215-35.
12. Lerer B, Moore N, Meyendor E, et al. Carbamazepine versus lithium in mania a double-blind study. J Clin Psychiatry. 1987;48:89-93.
13. Brown B. The use of generic mood stabilizers: carbamazepine (monograph). J Clin Psychiatry. 1997;15(4):11-17.
14. Karagianis JL, Dawe IC, Thakur A, et al. Rapid tranquilization with olanzapine in acute psychosis: a case series. J Clin Psychiatry. 2001;62(suppl 2):12-16.
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.
20. Sachs G, Mullen JA, Devine NA, Sweitzer DE. Quetiapine versus placebo as adjunct to mood stabilizer for the treatment of acute mania (abstract). Bipolar Disord. 2002;4(suppl 1):133.-
21. Smith MA, McCoy R, Hamer J, Brecher M. Optimal titration for quetiapine (poster presentation): Boca Raton, FL: National Clinical Drug Evaluation Unit annual meeting, 2002.
22. Keck PE, Jr, Versiani M, Potkin S, et al. Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry. 2003;160:741-8.
23. Holtzheimer PE, Neumaier JF. Treatment of acute mania. CNS Spectrums. 2003;8(12):917-28.
24. Keck PE, Jr, Marcus R, Tourkodimitris S, et al. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry. 2003;160(9):1651-8.
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.