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Objective:To provide an overview of the safety and tolerability of newer agents used to treat bipolar disorder (BPD) and provide clinicians with management strategies for drug-related toxicity and adverse effects.Data Sources:MEDLINE was searched through July 2005 for BPD treatment, adverse effects, tolerability, safety, emerging agents, atypical antipsychotics, new antiepileptic drugs (AEDs), risperidone, quetiapine, clozapine, ziprasidone, aripiprazole, lamotrigine, topiramate, gabapentin, oxcarbazepine, and olanzapine.Study Selection and Data Extraction:Results from randomized controlled trials, open-label studies, and reviews are described.Data Synthesis:Emerging agents recently approved for BPD include atypical antipsychotics and new AEDs. Safety and tolerability are as Important as efficacy because poor adherence in BPD worsens outcome; metabolic and other comorbidities pose specific challenges; and manic patients often require combination therapy, which increases adverse effects. Most atypical antipsychotics cause fewer extrapyramidal symptoms than conventional antipsychotics, but may cause more weight gain and metabolic complications. The newer AEDs generally cause less weight gain than the older agents, and some even promote weight loss. Several newer AEDs used in BPD also offer the advantages of fewer drug interactions and less need for therapeutic drug monitoring compared with older AEDs.Conclusions:Pending the results of ongoing controlled studies, several emerging agents may be useful additions to the therapeutic arsenal for BPD.

Objective: To evaluate and summarize the data on erythropoietin (EPO) use to prevent anemia in intensive care unit (ICU) patients. Data Sources: A literature search was performed using MEDLINE (1966–December 2003) using the key words erythropoietin, intensive care unit, anemia, and critically ill. Data Synthesis: Attempts to decrease the complications associated with anemia in ICU patients have recently focused on EPO use. Two comprehensive studies found that EPO significantly reduced the cumulative number of blood transfusions as compared to that of placebo. The assessing outcomes found no difference between the groups with respect to mortality rates, ventilation days, or length of stay. Conclusions: Available trials demonstrate reduced blood transfusions in ICU patients when EPO is administered. However, this result has not carried over as a defined clinical benefit. EPO use should be reserved for patients with longer hospital stays who are at risk for frequent blood transfusions as a comprehensive blood conservation strategy in the ICU.

Biomedical Communications and Informatics Reviews Section Editor Peter D. Anderson, PharmD, BCPP, DABFE, FASCP Clinical Pharmacist MedManagement, Inc. Massachusetts and Massachusetts Eye and Ear Infirmary Adjunct Associate Professor of Pharmacy University of Rhode Island Clinical Assistant Professor Northeastern University, School of Pharmacy Boston, Massachusetts E-mail: PAnder7291@aol.com Founding Editor James T. O’Donnell, PharmD, MS, ABCP, CNS, FACN Assistant Professor of Pharmacology Rush Medical College

OBJECTIVE: To report a case of extrapyramidal reaction associated with a dosage increase of clozapine. CASE SUMMARY: A 44-year-old white man with a 20-year history of chronic paranoid schizophrenia was admitted to an inpatient psychiatric facility. His prior medications restarted on admission were clozapine 650 mg at bedtime, haloperidol 10 mg at bedtime, clonazepam 2 mg/d, and aspirin 325 mg/d. Two days after admission (hospital day 3), clozapine and clonazepam were discontinued, and he was prescribed haloperidol 5 mg every morning and 10 mg every evening. Stabilization occurred over the following 24 days, with progressively lower dosages of haloperidol and increasing dosages of clozapine. Haloperidol was discontinued on day 24. On day 47, the patient was agitated and making bizarre statements; thus, the morning dose of clozapine was increased by 50 mg (total 450 mg/d). On day 48 at 2200, a dystonic reaction was diagnosed; he received intramuscular diphenhydramine 50 mg, which caused the reaction to subside. At the time of the adverse reaction, he was prescribed clozapine 450 mg/d, vitamin E 400 IU three times daily, aspirin 325 mg/d, and acetaminophen, milk of magnesia, and Maalox as needed. DISCUSSION: Although the risk of extrapyramidal symptoms (EPS) is significantly lower with clozapine than with conventional agents, elevated clozapine blood concentrations have been reported to cause EPS; other reports have cited severe dystonias and dyskinesias on abrupt clozapine withdrawal. Considering the medications prescribed at the time and the discontinuation of haloperidol 24 days before the event, clozapine was the most likely cause of the extrapyramidal reaction. CONCLUSIONS: Regardless of anticipated safety associated with novel antipsychotics such as clozapine, reports of dystonic reactions must be taken into account and patients monitored appropriately.

OBJECTIVE: To evaluate whether initiating lithium with predictive dosing compared with empiric dosing improves outcome in patients with manic symptoms. DESIGN: The study was a randomized, single-blind design and used the Modified Slattery predictive method. SETTING AND PARTICIPANTS: Eighteen inpatients at an urban psychiatric hospital with a Mania Rating Scale (MRS) score greater than or equal to 24 were enrolled. OUTCOME MEASURES: The study endpoint was defined as an MRS rating less than or equal to 14 or discharge from the hospital. Assessments (MRS, Brief Psychiatric Rating Scale, Clinical Global Impression, Systematic Assessment for Treatment of Emergent Events Scale, quality of life measures) were completed at baseline, on days 3 or 4 and 7 or 8, and weekly thereafter. RESULTS: The predictive group achieved a therapeutic concentration significantly sooner than did the empiric group (p=0.004); however, the mean serum lithium concentration at discharge did not differ between the groups. The predictive group was taking significantly higher dosages of antipsychotics in chlorpromazine equivalents on day 3 or 4 (p=0.05). Significantly fewer gastrointestinal/genitourinary adverse effects on day 3 or 4 were reported by patients in the predictive group (p=0.04). No difference was found between groups with any rating scale or other pharmacokinetic or medication item. Even though the difference did not meet statistical significance, the predictive group's length of stay in the acute unit was three days shorter than that of the empiric group, which may represent significant cost savings. CONCLUSIONS: The preliminary data do not suggest that patient outcome is improved by using Modified Slattery predictive dosing; however, the suggestion of a shorter length of stay in a restrictive unit merits further evaluation.