Dr. Fukutaki is head of the psychiatric team at the Infectious Disease Clinic in the Department of Behavioral Health Services at the Denver Health Medical Center in Colorado, and clinical instructor in the Department of Psychiatry at the University of Colorado School of Medicine, also in Denver.

Dr. Allen is director of inpatient psychiatry in the Department of Behavioral Health Services at the Colorado Psychiatric Hospital in Denver and assistant professor of psychiatry in the Department of Psychiatry at the University of Colorado School of Medicine.

Acknowledgments: The authors report no financial, academic, or other support of this work.


 

Abstract

For both clinical and economic reasons, accelerated strategies for the control of manic symptoms are desirable. Today, significant improvement is expected within 3–4 days of treatment initiation. This article reviews the use of various classes of medications with this time frame in mind. Evidence is presented for methods of rapid loading of mood stabilizers and combinations of mood stabilizers and antipsychotics.

 

Introduction

Rapid stabilization of the acutely manic patient has become a more urgent task in both outpatient and acute care settings. Currier and Allen1 found that patients with bipolar disorder accounted for 13.2% of presentations to 51 psychiatric emergency services, suggesting that this diagnosis is disproportionately represented in emergency rooms compared to the general population. The economics of health care have shortened the length of psychiatric hospital stays and reduced the number of available psychiatric beds in hospitals, fostering a more aggressive approach to the treatment of mania.2 Classically, onset of therapeutic effects at 1 week has been the standard, but this is now outside the average length of stay in most settings. Treatments that produce substantial benefit in 3–4 days are required.

Treatment can be thought of as occurring in several phases with somewhat different priorities. The initial focus in acute care of the manic patient is on controlling behavior that may place the patient and others at risk. At this point in the treatment, route of administration for uncooperative patients and speed of onset for critical target symptoms are the drivers. In the next phase, rapid resolution of core manic symptoms that require continued hospitalization and impair functioning in the community take precedence. Finally, in the continuation and maintenance phase, evidence of prophylaxis and side-effect burden become the central considerations.

A number of medications have been shown to be useful in treating mania. However, many of these (lithium, topiramate, lamotrigine, carbamazepine) require gradual titration to avoid side effects, thus delaying the onset of therapeutic action. The safety and tolerability of orally-loading divalproex sodium has been demonstrated.3-7 Typical and atypical antipsychotics appear to be useful in stabilizing mania, in some cases at the initial dosage.5,8-19 Benzodiazepines (BZDs) have also been shown to have therapeutic effects in the treatment of mania and can be delivered intramuscularly with a minimal side-effect burden.20 Electroconvulsive therapy (ECT) is an effective treatment for acute mania21 but may be difficult to arrange in emergency circumstances. Unless maintenance ECT is available, medication therapy will still be needed for continuation and maintenance.

Given the severity of manic behavioral symptoms and the complexity of the longitudinal course of bipolar disorder, it is perhaps the exception when patients can be treated efficiently with a single agent. This article will review the acute management of mania from the standpoint of the most rapid and complete resolution of serious symptoms with the best tolerability and most seamless transition to continuation and maintenance.

 

Behavioral Emergency

A recently published expert consensus guideline for the management of behavioral emergencies found that emergency psychiatrists give very similar ratings to intramuscular (IM) BZDs alone or in combination with a high-potency conventional antipsychotic as the treatment of choice for the agitated manic patient. If the patient is cooperative enough to take oral medication, combining a BZD with an atypical is also considered first line. Typical strategies include lorazepam 2 mg IM or PO alone, or combined with haloperidol 5 mg IM or risperidone 2 mg PO.22 There is little evidence that parenteral combinations are superior to lorazepam alone in equivalent total doses.23 If oral medication is possible and repeated use is anticipated, clonazepam may be a good choice. The drug also has the advantage of longer half-life and less frequent administration.24

 

Acute Phase

Mood Stabilizer Monotherapy

Orally-loading divalproex sodium at 20–30 mg/kg/day for the first 2 days (divided into two doses separated by at least 4 hours) and continuing at 20 mg/kg/day thereafter, has been shown to be safe, tolerated, and effective in reducing mania.3-7 In one study,3 84% of the patients loaded with 30 mg/kg/day of divalproex sodium for the first 2 days and then treated with 20 mg/kg/day achieved therapeutic levels by day 3 with a mean of 83.8 mg/mL. Only 30% of the titrated divalproex patients had valproate serum levels above 50 mg/mL at day 3 of the study, and no lithium-treated patient had reached 0.8 mEq/L. No increase in the frequency or types of adverse events was noted between this group and the groups receiving titrated doses of divalproex sodium or lithium.

Another study5 compared oral loading of divalproex sodium 20 mg/kg/day with haloperidol 0.2 mg/kg/day, using lorazepam up to 4 mg/day to control agitation. The greatest rate of improvement for both drug regimens occurred over the first 3 days of treatment. Divalproex sodium was as effective as haloperidol in reducing mania and psychosis during the 6-day study, and produced fewer side effects. In a recent consensus guideline for the management of behavioral emergencies, approximately half the panel of emergency psychiatrists endorsed the 30 mg/kg strategy and half endorsed the 20 mg/kg strategy.25

Therapeutic efficacy with intravenous loading of valproate has also been reported.26,27 One report26 states parenteral valproate loading was effective in reducing manic symptoms in an 81-year-old woman in 2 days. Valproate 125 mg was infused in 100 cc of 5% dextrose in water over an hour, every 6 hours, for two doses. The dosage was then increased to 200 mg every 6 hours. The patient received nine doses of valproate before stabilizing, at which time her serum valproate level was 53 mg/mL. No side effects were noted. Grunze and colleagues27 treated seven bipolar patients, five of whom were in manic or mixed states, with parenteral valproate. They noted reduction in mania occurred without side effects in four of the five manic or mixed-state patients, one of whom had been nonresponsive to oral valproate loading.

In addition to its quick action, divalproex has a number of other advantages in the acute setting. Swann and colleagues28 correlated the number of previous affective episodes in 154 manic patients to therapeutic response to lithium and divalproex sodium. They found that divalproex was more effective than lithium in stabilizing manic patients with more than 10 prior affective episodes, and that response to lithium resembled that of placebo in this group of patients. Several other factors, such as substance use, may limit the usefulness of lithium in acute settings.

 

Typical Antipsychotics

Typical antipsychotics have been shown to be effective in the treatment of mania.5,10,11,16 Chou and colleagues16 examined the effect of haloperidol 5–25 mg/day, with and without lithium, in a double-blind, placebo-controlled study of 63 acutely psychotic bipolar manic inpatients. They found that low-dose haloperidol was insufficient as monotherapy in reducing mania, but when combined with lithium was as effective as high-dose haloperidol at clinical outcome. Studies by Chou16 and Rifkin29 suggest haloperidol 10 mg/day is effective as monotherapy. However, the risks of extrapyramidal side effects, sedation, dysphoria, and tardive dyskinesia with typical antipsychotics impact tolerability and safety in the long-term.

 

Atypical Antipsychotics

Evidence is emerging in support of the therapeutic benefits of atypical antipsychotics in the treatment of mania.8,9,12-15,18,19,30 Two double-blind, placebo-controlled studies8,12 have shown olanzapine to be superior to placebo in reducing mania. Tohen and colleagues8 found this difference appeared 1 week after randomization. More weight gain and somnolence were noted with olanzapine than with placebo. Sanger and colleagues19 continued one of the studies12 into a 49-week open-label trial of olanzapine at a mean modal dose of 13.9 mg/day and found that 88.3% of patients experienced a remission of manic symptoms, while 25.5% subsequently relapsed. Forty-one percent of patients were maintained on olanzapine monotherapy. Somnolence, depression, and weight gain were the most common side effects noted.

Zarate and colleagues9 suggest that quetiapine 300 mg/day is effective in reducing symptoms of mania. Dunayevich and colleagues17 treated seven hospital inpatients who had bipolar disorder, manic or mixed, with psychotic features using quetiapine, either as monotherapy (n=1) or as an adjunct to treatment with a mood stabilizer (either lithium, carbamazepine, valproate, and/or divalproex sodium) in a retrospective study. The patients were generally titrated from dosages of 50 mg BID/TID per day up to 200–500 mg/day within 3–8 days (mean dosage=421 mg/day). Two patients were considered “very much improved” by Clinical Global Impression-Change score, three were “much improved” (including the patient treated with quetiapine monotherapy), and two were “minimally improved.” The most common side effects were sedation and dizziness.

Ghaemi and colleagues15 published a small study suggesting risperidone at a dosage of 2.75±1.8 mg/day may be an effective treatment in patients with bipolar disorder. Segal and colleagues18 studied 45 inpatients diagnosed with mania in a randomized, double-blind trial of either 6 mg/day of risperidone (n=15), 10 mg/day of haloperidol (n=15), or 800–1,200 mg/day of lithium (n=15, lithium levels=0.6–1.2 mmol/L). At the end of the 28-day trial, all three groups showed significant improvement, with similar rates of improvement at days 7, 14, 21, and 28. The authors concluded that monotherapy with risperidone appears to be comparable to lithium and haloperidol in the treatment of mania.

Ziprasidone is a new novel antipsychotic that has recently been reported to be effective in mania.31 In keeping with the focus on rapid improvement, ziprasidone 80–160 mg/day separated from placebo at day 2 in this study. Keck and colleagues32 conducted a randomized, double-blind, placebo-controlled study of 34 hospitalized patients with schizoaffective disorder (bipolar type), and found that ziprasidone 160 mg/day was significantly better than placebo (P<.001) in reducing manic symptoms over the 6-week study period. The time required for ziprasidone to separate from placebo was not provided.

 

Drug Combinations

As suggested previously, medication combinations may offer advantages in terms of response time and may also reduce the side-effect burden to the extent that lower doses of component drugs may be utilized. One study relevant to the acute setting compared treatment with a mean of 3.83 mg/day of risperidone, 6.23 mg of haloperidol, or placebo in combination with either lithium or divalproex for 3 weeks. Over two thirds of subjects in each group received divalproex as their mood stabilizer.30 At weeks 1 and 2, the risperidone-mood stabilizer combination was associated with significantly greater improvement compared to a mood stabilizer alone and was numerically superior to the haloperidol combination at some points. Levels of psychosis in the three groups were similar and, as expected, did not affect outcome.

 

Continuation and Maintenance

Aggressive treatment is better tolerated in the acute phase. Moving into continuation and maintenance, side-effect burden and its impact on adherence becomes a major consideration. Sedation, movement disorders, and weight gain may reduce the long-term usefulness of some drugs. However, adjunctive medications should be tapered and discontinued cautiously only after the estimated end of a typical manic phase, based either on the individual’s history or a minimum of 12 weeks.

Bipolar patients may appear to have fairly stable mood but continue to complain of anxiety. This may be evidence of an incompletely stabilized mood disorder that might be better treated with an atypical antipsychotic, even in the absence of psychotic symptoms, than with a BZD. Atypical antipsychotics do not cause the habituation sometimes seen with BZDs and may have greater benefits in mood stability over time.

Longer-term considerations argue for maintenance treatment with a traditional mood stabilizer as the foundation, possibly in combination with an atypical antipsychotic rather than with an atypical antipsychotic alone. Only one open-label trial33 of atypical antipsychotic monotherapy maintenance has been published. In that study, which lacked a comparison drug and suffered a 39.8% drop-out rate, an average of 6.6 months of olanzapine monotherapy was associated with a 25% relapse rate.

 

Conclusion

Finding ways to stabilize the acutely manic patient is desirable from the standpoint of both patient care and cost-effectiveness. Bipolar disorder will often require multiple medications in any given phase and alterations between phases of different types. Treatment should always include a traditional mood stabilizer, if tolerated, with additional medications as required for each presentation. Current data suggest that oral loading with divalproex, augmented with an atypical antipsychotic and/or a BZD for agitation, may be the most rapid and best-tolerated strategy for the broadest spectrum of acutely manic patients.  PP

 

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