Starting dose and onset of action. The primary goal in treating bipolar mania is to stabilize the patient as rapidly and safely as possible. Medications with a rapid onset of action may lead to health care savings, shorter hospital stays, and decreased morbidity and mortality. The earliest day at which a medication effect separates from placebo is one indication of how quickly a medication works. However, it is important to note that early placebo-controlled studies used day 7 as the first postrandomization measurement day, while more recent studies used day 2. Tohen and colleagues15,16 conducted 2 placebo-controlled trials involving olanzapine. The starting dosages were 10 and 15 mg/d, respectively. Although olanzapine separated from placebo at the end of each study, the starting dosage of 15 mg/d had a faster onset of action, separating from placebo at day 7 versus day 21. The mean dose was similar in both studies.
Risperidone trials used day 3 as their first measurement date. Both studies gave an initial dosage of 3 mg/d. One study showed a separation from placebo on day 3,17 while another showed a separation on day 7.18 Quetiapine trials used a titration schedule to minimize adverse effects. The dosage was 100 mg/d on day 1, followed by an increase of 100 mg/d until day 4, and up to a maximum dosage of 600 mg/d on day 5. Separation from placebo occurred on day 4 and day 7.19,20 Ziprasidone studies used day 2 as the first measurement date. The starting dosage was 80 mg/d on day 1, and 160 mg/d by day 2. Both studies separated from placebo on day 2.21,22 Aripiprazole studies both started at a dosage of 30 mg/d and could be decreased to 15 mg/d on day 2 to minimize adverse effects. Both studies showed a separation from placebo on day 4.23,24
Concomitant medication and completion rates. The examination of concomitant medications is important because they may produce a confounding effect on efficacy measures. For example, hypnotics may help patients sleep better at night, thus reducing the YMRS score for sleep. Likewise, if higher doses of lorazepam are used to treat anxiety, manic symptoms and discontinuations because of side effects may be decreased. In reviewing placebo-controlled trials, there is no consensus on the maximum dose or duration of concomitant medications. Olanzapine studies allowed the use 4 mg/d of lorazepam from days 1 through 7 in one trial, and 2 mg/d from days 1 through 4 in a second trial.15,16 It is interesting to note that the higher dose of lorazepam was allowed in the trial with a lower starting olanzapine dosage of 10 mg/d.
Both risperidone studies allowed 8 mg/d of lorazepam from days 1 through 3, while a ziprasidone trial allowed 8 mg/d from days 1 through 7.17,18,22 Up to 6 mg/d of lorazepam from days 1 through 4 in the aripiprazole studies was allowed. Quetiapine studies also allowed 6 mg/d of lorazepam from days 1 through 4.19,20 Furthermore, in the quetiapine study by Bowden and colleagues,19 chloral hydrate at dosages of 2000 mg/d was allowed from days 1 through 7 and up to 1000 mg/d from days 8 through 84. In addition, zolpidem was allowed from days 1 through 84.
Drugs Mentioned in This Article
Carbamazepine (Carbatrol, Tegretol, others)
Chloral hydrate (Aquachloral)
Chlorpromazine (Largactil, Thorazine)
Divalproex (Epival, Depakote)
Lithium (Eskalith, Lithane, Lithobid)
Valproate/Valproic acid (Depakote, others)
Zolpidem tartrate (Ambien)
Calabrese JR, Vieta E, Shelton MD. Latest maintenance data on lamotrigine in bipolar disorder. Eur Neuropsychopharmacol. 2003;2:S57-S66.
Tohen M, Greil W, Calabrese JR, et al. Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month randomized, double blind, controlled clinical trial. Am J Psychiatry. 2005;162:1282-1290.
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