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Modulatory effects of ketamine, risperidone and lamotrigine on resting brain perfusion in healthy human subjects

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Abstract

Rationale

Resting brain perfusion, measured using the MRI-based arterial spin labelling (ASL) technique, is sensitive to detect central effects of single, clinically effective, doses of pharmacological compounds. However, pharmacological interaction experiments, such as the modulation of one drug response in the presence of another, have not been widely investigated using a task-free ASL approach.

Objectives

We assessed the effects of three psychoactive compounds (ketamine, risperidone and lamotrigine), and their interaction, on resting brain perfusion in healthy human volunteers.

Methods

A multivariate Gaussian process classification (GPC) and more conventional univariate analyses were applied. The four pre-infusion conditions for each subject comprised risperidone, lamotrigine and two placebo sessions. The two placebo conditions enabled us to evaluate the classification performance in a test-retest setting, in addition to its performance in distinguishing the active oral drugs from placebo (direct effect on brain perfusion). The post ketamine- or saline-infusion scans allowed the effect of ketamine, and its interaction with risperidone and lamotrigine, on brain perfusion to be characterised.

Results

The pseudo-continuous ASL measurements of perfusion were sensitive to the effects of ketamine infusion and risperidone. The GPC captured consistent changes in perfusion across the group and contextualised the univariate changes with a larger pattern of regions contributing to accurate discrimination of ketamine from placebo.

Conclusions

The findings argue against perfusion changes confounding in the previously described evoked BOLD response to ketamine and emphasise the blockade of the NMDA receptor over neuronal glutamate release in determining the perfusion changes induced by ketamine.

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Acknowledgments

NEWMEDS—the work leading to these results, has received funding from the Innovative Medicines Initiative Joint Undertaking (IMI) under Grant Agreement No. 115008. We thank Dr. David Alsop for facilitating the ASL pulse sequence used in this study.

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Authors and Affiliations

  1. Tailored Therapeutics - Neuroscience, Eli Lilly and Company, Indianapolis, IN, 46285, USA

    Sergey Shcherbinin & Adam J. Schwarz

  2. Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King’s College, London, UK

    Orla Doyle, Fernando O. Zelaya, Sara de Simoni & Mitul A. Mehta

Authors
  1. Sergey Shcherbinin
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  2. Orla Doyle
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  3. Fernando O. Zelaya
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  4. Sara de Simoni
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  5. Mitul A. Mehta
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  6. Adam J. Schwarz
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Corresponding author

Correspondence to Adam J. Schwarz.

Additional information

Mitul A Mehta and Adam J. Schwarz are joint last authors.

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Shcherbinin, S., Doyle, O., Zelaya, F.O. et al. Modulatory effects of ketamine, risperidone and lamotrigine on resting brain perfusion in healthy human subjects. Psychopharmacology 232, 4191–4204 (2015). https://doi.org/10.1007/s00213-015-4021-z

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  • DOI: https://doi.org/10.1007/s00213-015-4021-z

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