Background : Ketamine a NMDA non-competitive antagonist has been used as a model of psychosis for many years; more recently some preliminary clinical data have suggested a rapid and long lasting antidepressant effect of a single dose of ketamine. In rodents, ketamine has been shown to increase gamma frequency EEG power (Lazarewicz et al., 2010) and produce nystagmus. Since gamma-band EEG may be affected by nystagmus [1]-Greenberg S et al 2008), it appears important to assess whether ketamine-induced gamma EEG response is due to pure neural activity or is contaminated by oculomotor activity, before considering this latter EEG parameter as a pharmacodynamic biomarker of NMDA blockade . In addition, since ketamine and several other NMDA antagonists produce mydriasis in mice [2], pupil size wasconsidered as a second , potentially useful, pharmacodynamic biomarker for ketamine.

Study design: This was a randomised, double-blind, crossover study of ketamine (0.5 mg/kg iv) versus saline infusion for 1 hour on 15 young healthy male volunteers. Parameters were measured before  0.25, 1, 3  and 8 hours post infusion.

Methods :Quantified EEG (qEEG) in eyes closed and eyes opened conditions (3 min for each condition) was recorded with 28 scalp electrodes and 4 additional electrodes to monitor eye movements. Low  and high pass filters were set to 70 Hz and  0.3 Hz  and a notch filter to 50 Hz..

Spontaneous nystagmus and saccades were measured with an Electronystagmography by two independent raters. Saccades were characterized by their average speed,  Peak Saccadic Velocity,  mean amplitude, latency and asymmetry. Static measurements of pupil size was measured on both eyes at the same time with a computerized infrared pupillometer after 10 min adaptation to the light condition.

Clinical scale relevant for psychiatric disorders (CADSS) and subjective ratings were also used.

Results : Ketamine significantly increased resting gamma EEG power from 1 to 3 hours post infusion over almost the entire scalp. These effects were observed in the whole gamma band (32.5-64 Hz) and in the two conditions but were more pronounced with eyes closed.

Ketamine did not induce spontaneous nystagmus and 98.4% of recordings  were free of any nystagmus. The kappa coefficient between raters was 0.6626. The optokinetic parameters were unaffected by ketamine except mean Amplitude which was significantly reduced  but at time 0.25h only (p<0.001).

There was a trend (p=0.728) for ketamine to produce  a short-lasting mydriatic response  of low magnitude. Pupil size correlated with  absolute energy in the Gamma-1 and Gamma-2 qEEG band.

Ketamine produced a dissociated state detected on all items of the CADSS and a drop in subjective alertness at 1h post dosing.

Conclusions :Gamma EEG response to ketamine was  related to a direct cortical effect and not  due to a saccade-mediated artefact. Overall it can be concluded that the ketamine-induced small gamma-band qEEG effects stem from cerebral sources.