Acute bipolar mania: Aggressive initial dosing provides faster symptom relief
Loading achieves rapid therapeutic blood levels but requires careful patient monitoring and drug titration.
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.
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.
‘Double loading’? No evidence yet supports this concept
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.
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 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.
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.
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 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 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
Suggested antipsychotic loading for acute bipolar mania and mixed states*
Aggressive initial dosing schedule
30 mg once daily with food
Nausea and vomiting may occur in first few days; adjust dosage based on tolerance and response
1 and 2
40 mg in single or divided dosage
Adjust dosage based on tolerance and response; oral or IM formulations may be used
100 mg upon admission and 100 mg at bedtime
Adjust dosage based on tolerance and response
3 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
20 mg IM in single dose (may repeat for severe agitation) or 40 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.