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.
‘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.
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.