Relative Efficacy of Different Agents There are relatively few head to head comparisons of antimanic

agents and the results can be summarized as follows: • Olanzapine and valproate have been compared in two

double blind studies, which yielded equivalent efficacy in one study and a modest superiority of olanzapine in the other. Tolerability favored valproate in both studies.

• Valproate and carbamazepine may have greater efficacy than lithium in patients with mixed mania, rapid cycling, or high levels of comorbidity.

• Quetiapine has performed comparably to lithium in controlled trials. • Risperidone, quetiapine, and aripiprazole have all performed similarly to haloperidol in active comparator trials.

Acute mania is often a clinic emergency and is generally treated in an inpatient setting. Rapid mood stabilization and the reduction of agitation take priority over concerns about medication side effects. Polypharmacy is the rule in this setting, with atypical antipsychotic agents frequently added to lithium or an anticonvulsant. In support of this approach, recent studies have demonstrated improved antimanic response with the addition to lithium or valproate of olanzapine, risperidone, or quetiapine. Generally, these combinations are quite safe, but

MOOD STABILIZERS 93 caution should be used if combining lithium with older antipsy-

chotics as it may increase the risk of extrapyramidal effects and possibly, of neurotoxicity. In addition, the combination of thioridazine and lithium is contraindicated due to an increased risk of ventricular arrhythmias.

The American Psychiatric Association guidelines for bipolar disorder have recommend lithium or valproate plus an atypical antipsychotic as the first-line therapy for acute mania. Less severely ill patients may be treated with a single antimanic agent (lithium, valproate, or an atypical antipsychotic; this recommendation was published prior to the FDA approval of extended release carbamazepine). The Expert Consensus Guideline Series published in 2004 provides similar first-line recommendations but also lists lithium alone as a first-line treatment for euphoric mania or for non-rapid cycling hypomania. Valproate is preferred to lithium if either psychosis or rapid cycling is present. Short-term adjunctive treatment with a benzodiazepine is endorsed as an augmentation for agitation and anxiety, and for providing needed sedation. If an antidepressant appears to be linked to switching or cycle acceleration in a manic patient, it should be tapered and discontinued. Bear in mind, however, that manic episodes are often followed by a period of severe depression, and also that abrupt antidepressant discontin- uation may increase the risk of a sudden manic shift. The options for treatment of acute mania are listed in Table 3-3.

ANXIOLYTICS Among current anxiolytic agents, benzodiazepines are usually selected as adjuncts to treat acute mania because of their safety and efficacy. Although some have claimed specific antimanic efficacy for clonazepam or other benzodiazepines, most psychiatrists are more impressed with their benefits as adjunctive sedatives than with more specific antimanic activity. Lorazepam is often the benzodiazepine selected for this indication because it yields predictable blood levels when administered intramuscularly. Benzodiazepines have a wide margin of safety and can be safely administered in even very high doses, suppressing potentially dangerous excitement and allowing patients much needed sleep. When used together with an antipsychotic agent, benzodiazepines counteract the

94 HANDBOOK OF PSYCHIATRIC DRUGS

Treatments for Acute Mania TREATMENT

ADVANTAGES DISADVANTAGES Lithium

Efficacy: 70–80% Side effects: sedation, weight gain, tremor hair loss, polyuria Low therapeutic index

Valproate Comparable efficacy to Li Side effects: sedation, May be better in mixed

weight gain, tremor, states

hair loss Carbamazepine

Comparable efficacy to Li Side effects: neurologic May be better in mixed

(ataxia, vertigo, states

diplopia) Atypical

Comparable efficacy to Li Side effects, differ by Antipsychotics

individual agent. Risk of tardive dyskinesia

Typical Comparable efficacy to Li May worsen bipolar Antipsychotics

Rapid onset of action depression. Greater risk of tardive dyskinesia

Electroconvulsive More difficult to Therapy

patients unable to take administer. Long-term medication

effectiveness unclear Anxiolytics

Good as adjunctive Probably not specifically sedatives, wide margin

antimanic. Potential of safety

abuse and dependence

antipsychotic agent’s tendency to provoke extrapyramidal reactions and seizures. For lorazepam, 1 to 2 mg can be administered by mouth or intramuscularly as frequently as hourly.

Relative Efficacy of Different Agents There are relatively few head to head comparisons of antimanic