PMC:3598541 / 24188-27505 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/3598541","sourcedb":"PMC","sourceid":"3598541","source_url":"http://www.ncbi.nlm.nih.gov/pmc/3598541","text":"Discussion\nBased upon previous reports on the benefit of psychostimulants in the treatment of mania and upon the ‘vigilance regulation model of mania’, we present here the study protocol of the ‘Methylphenidate in Mania project’ (MEMAP), a randomised double blind placebo-controlled trial to test the effectiveness of methylphenidate in the early treatment of mania.\nDuring study protocol development, the following considerations have been made:\nThe screening visit on day -2 or day -1 and first treatment on day 0 accommodates both the need for an early treatment and the ICH Guideline for Good Clinical Practice requirement to provide the subject “ample time and opportunity to inquire about details of the trial and to decide whether or not to participate in the trial” [48]. In addition, it allows checking routine laboratory values and plasma levels of concomitant medication prior to first study drug administration. Furthermore, an initial placebo effect through arrival on the ward will not be considered when baseline evaluations are performed one day after arrival and not on the day of arrival. Manic symptoms will be assessed throughout 2 h after study drug intake to make sure that changes are not related to grossly different plasma levels. In addition, manic symptoms will be always assessed in the morning (12.00 at baseline, 11.00 h all other evaluations) to minimize influences of circadian mood changes.\nThe maximum dose of 20 mg twice daily analogous to 0.29 mg/kg (daily total dose: 40 mg ≈ 0.58 mg/kg) is lower than in the majority of 26 studies listed in a recent systematic review on the safety of therapeutic methylphenidate in adults [49] which considers methylphenidate safe in the dose range from 20 to 90 mg/day. Overall, we therefore do not expect a significantly higher frequency of side effects.\nThe administration of methylphenidate in addition to pre-existing mood-stabilising medication is expected to be well tolerated as this has been shown for combination therapy with other psychotropic drugs [36,37].\nThe short duration in this study in which patients may not receive established antimanic medication of 4.5 days at maximum (screening + treatment period), being shorter than usual wash-out or placebo run in-periods of 7 days in other studies in the same indication [50,51], justifies the treatment with placebo in the half of the patients. That is particularly true since inpatients will be closely monitored by specialised psychiatry staff allowing an immediate intervention in case of a substantial worsening of mania.\nSince methylphenidate has been shown and is expected to act very rapidly [40], a treatment duration of 2.5 days has been considered sufficient.\nWhile the study may yield the results that methylphenidate is in principle efficacious in the treatment of mania, the short study duration does not allow drawing any conclusions about efficacy and safety in the longer term what is a limitation.\nIn conclusion, we propose here a randomised double blind placebo-controlled study to test the efficacy and safety of methylphenidate in the early treatment of mania based upon the ‘vigilance regulation model of mania’. A positive study outcome could substantially impact our understanding of the etiopathogenesis of mania and open new perspectives in its 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