A multi-centre, randomised, double-blind, placebo-controlled clinical trial of methylphenidate in the initial treatment of acute mania (MEMAP study)
Introduction
Treatment response of patients with acute mania with antipsychotic agents, benzodiazepines or lithium often requires high dosages and occurs with a delay of several days (Goikolea et al., 2013, Grande et al., 2016). Recently the ‘vigilance regulation model of mania’ has been proposed which suggests that stimulant medications could be a treatment option similar to their beneficial effects in ADHD (Hegerl et al., 2009, Hegerl and Hensch, 2014). This model is based on a variety of clinical as well as preclinical findings which suggest that an unstable regulation of vigilance (vigilance=“brain arousal") is an important pathogenetic factor not only in ADHD but also in mania. Manic symptoms are interpreted as an autoregulatory attempt of the organism to stabilize vigilance by creating a stimulating environment (Hegerl and Hensch, 2014). Indeed, our research group and others have found unstable vigilance regulation with rapid transitions to EEG drowsiness patterns and sleep stages in mania (Van Sweden, 1986, Ulrich, 1994, Small et al., 1999, Schönknecht et al., 2010). Furthermore, destabilizing vigilance (e.g. by sleep deficits or therapeutic sleep deprivation) can trigger mania in vulnerable subjects (Wu and Bunney, 1990, Plante and Winkelman, 2008; for further references see Hegerl and Hensch, 2014); in contrast, stabilizing vigilance (e.g. by prolonged sleep) could be shown to have antimanic effects (e.g., Frank et al., 2005). In line with this concept antimanic effects of stimulant medications have been reported in several case reports and case series (e.g., Beckmann and Heinemann, 1976; Garvey et al., 1987; Schönknecht et al., 2010; for review see Hegerl et al., 2009 as well as Hegerl and Hensch, 2014). A pilot study (Bschor et al., 2001) even demonstrated reduction of manic symptoms already two hours after onset of treatment with methylphenidate in a patient with acute mania and unstable vigilance regulation (for further arguments for antimanic effects of stimulant medications see Hegerl and Hensch, 2014).
In view of this background, the MEMAP study (Kluge et al., 2013), a RCT was designed to assess the efficacy and safety of short-term treatment with methylphenidate in patients with acute mania.
The primary aim of the RCT was to test the hypothesis that a 2.5 day treatment with methylphenidate immediate release given twice daily has better antimanic effects measured with the Young Mania Rating Scale (YMRS, primary outcome) (Young et al., 1978) than placebo. It was further analysed whether instability of vigilance at baseline predicts response to methylphenidate.
Section snippets
Study design overview
Details of the study design have been published elsewhere (Kluge et al., 2013). In short, the MEMAP study is an exploratory, randomized, double-blind, placebo-controlled, international multi-center phase IIIb RCT. It has been designed to assess the efficacy and safety of the stimulant medication drug methylphenidate (Medikinet®) in the initial 2.5 day treatment of acute mania in patients suffering from bipolar affective disorders. The primary comparison in this RCT was between methylphenidate
Participant disposition and patient characteristics
Participant disposition is illustrated in Fig. 1.
The interim analysis was performed after 42 patients had been accrued. Of these patients, all were analyzable for efficacy. Overall, there were no significant between-group differences in demographic and clinical characteristics of patients at baseline (see Table 1). Group differences regarding comedication were more pronounced (see Table S1). However, patients from the methylphenidate group and patients in the group getting a placebo did not
Discussion
The hypothesis that acute short-term treatment with methylphenidate has antimanic effects in patients with bipolar affective disorder was not confirmed. Also concerning secondary outcomes such as cognitive performance (SCIP (Purdon, 2005)), global functioning (CGI-BP (Spearing et al., 1997)) and severity of agitation (PANSS-EC (Montoya et al., 2011)) no group differences were found.
It was hypothesized that there might be a causal relationship between the instability of vigilance regulation and
Role of funding source
The work was supported by a grant of the Spanish ‘Ministerio de Sanidad, Politica Social e Igualdad’ (Ministry of Health, Social Politics and Equality), EC10-110, EC10-297, EC10-333 and EC10-064, and by the Instituto de Salud Carlos III of Spain (CIBERSAM), grant 11INT2 which had been provided after a peer review process. The funding source had no rule in the study design, in the collection, analysis and interpretation of data, in the writing of the manuscript and in the decision to submit the
Conflicts of interest
Professor Hegerl has served as an advisory board member for Eli Lilly, Lundbeck, Otsuka, Takeda, and Servier, as a consultant for Nycomed, and as a speaker for Bristol-Myers Squibb, Medice Arzneimittel, Novartis, and Roche Pharma. Dr. Dr. Bauer has received grant support from the Stanley Medical Research Institute, NARSAD and the European Commission (FP7). Moreover, he was/is consultant for AstraZeneca, Eli Lilly, Servier, Lundbeck, Bristol-Myers Squibb and Otsuka. He has received Speaker
Contributors
UH, EV and MK designed the study and wrote the protocol. UH and RM drafted the manuscript and completed a first version of the article. RM undertook the statistical analyses. Acquisition and analyses of EEG data were performed by CS and JD. In addition, CS acquired and analyzed actigraphic data. AGA, IZ and MK played an important role in the acquisition of clinical data. All authors contributed to interpretations of the results of the MEMAP trial, revised the manuscript and approved the final
Acknowledgements
The work was supported by a grant of the Spanish ‘Ministerio de Sanidad, Politica Social e Igualdad’ (Ministry of Health, Social Politics and Equality), EC10-110, EC10-297, EC10-333 and EC10-064, and by the Instituto de Salud Carlos III of Spain (CIBERSAM), grant 11INT2 which had been provided after a peer review process. The funding source had no rule in the study design, in the collection, analysis and interpretation of data, in the writing of the manuscript and in the decision to submit the
References (23)
- et al.
Faster onset of antimanic action with haloperidol compared to second-generation antipsychotics: a meta-analysis of randomized clinical trials in acute mania
Eur. Neuropsychopharmacol.
(2013) - et al.
Bipolar disorder
Lancet
(2016) - et al.
The vigilance regulation model of affective disorders and ADHD
Neurosci. Biobehav. Rev.
(2014) - et al.
Clinical and quantitative EEG studies of mania
J. Affect. Disord.
(1999) - et al.
Modification of the Clinical Global Impressions (CGI) Scale for use in bipolar illness (BP): the CGI-BP
Psychiatr. Res.
(1997) Disturbed vigilance in mania
Biol. Psychiatry
(1986)- et al.
Evaluation of experiments with adaptive interim analyses
Biometrics
(1994) - et al.
D-Amphetamine in manic syndrome
Arzneim.-Forsch./Drug Res.
(1976) - et al.
Decreased level of EEG-vigilance in acute mania as a possible predictor for a rapid effect of methylphenidate: a case study
Clin. Electroencephalogr.
(2001) - Dilling, H., Mombour, W., Schmidt, M.H., 2006 International Classification of Mental Disorders. ICD-10 Chapter V (F)....
The International College of Neuropsychopharmacology (CINP) treatment guidelines for bipolar disorder in adults (CINP-BD-2017), Part 4: unmet needs in the treatment of bipolar disorder and recommendations for future research
Int. J. Neuropsychopharmacol.
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