Outcome measures

Primary outcome measure
The primary outcome measure is the severity of manic symptoms as assessed by the Young Mania Rating Scale (YMRS) [41]. The YMRS is a clinician-administered mania rating scale. It has 11 items and is based on the patient’s subjective report of his or her clinical condition, normally over the previous 48 hours. In this study, the period is usually since the last scoring; at baseline and day 9 the scoring refers to the last 24 hours. Additional information is based upon clinical observations made during the course of the clinical interview. The items being scored are elevated mood, increased motor activity-energy, sexual interest, sleep, irritability, speech (rate and amount), language-thought disorder, content, disruptive-aggressive behaviour, appearance, and insight. The purpose of each item is to rate the severity of that abnormality in the patient. A score of ≥ 12 indicates mania. The primary endpoint is after 2.5 days of treatment.

Secondary outcome measures
Secondary outcome variables comprise: 
• Clinical impression as assessed by the Clinical Global Impressions Scale Bipolar version (CGI–BP) [43]. This is a modified version of the Clinical Global Impressions Scale (CGI) specifically for use in assessing global illness severity and change in patients with bipolar disorder. It will be rated twice, before first and after last treatment.
• Severity of agitation as assessed by the Positive and Negative Syndrome scale - excited component (PANSS-EC) [42]. The PANSS–EC is an easy and fast to administer and easy to record scale for assessment of excitation and agitation including five items: poor impulse control, tension, hostility, uncooperativeness and excitement. It has been validated and is appropriate for repeated measures and will be scored up to 5 times per visit.
• EEG-vigilance as assessed by the ‘Vigilance Algorithm Leipzig’ (VIGALL) [44]. The VIGALL is an algorithm using topographic and spectral EEG-information for classifying different stages of wakefulness ranging from alertness over drowsiness to sleep. During stages A and B subjects are awake, during stage C asleep. Stages and sub-stages are defined as follows: stage A: high alpha power: (A1: high occipital alpha power, A2: high overall alpha power, A3: high frontal alpha power); stage B: alpha absent (B1: ‘flat’ desynchronised EEG, B2/3: high delta/theta power); stage C: K-complexes or sleep spindles. Resting EEGs will be conducted twice, before first and after last treatment.
• Total amount of movements over the study period as assessed by actigraphy.
• Cognitive performance as assessed by the “Screen for Cognitive Impairment in Psychiatry” (SCIP) [45]. The SCIP was designed for detecting cognitive deficits in several psychotic and affective disorders. It may be administered without the need for additional equipment (only pencil and paper) and requires nearly 15 min. Three alternative forms of the scale are available to facilitate repeated testing while minimising learning effects. The SCIP includes a Working Memory Test, a Verbal Learning Test-Immediate, a Verbal Fluency Test, a Verbal Learning Test-Delayed, and a Processing Speed Test. The SCIP will be performed three times, at baseline at day 1 and day 2.