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The effect of ketamine on psychopathology and implications for understanding schizophrenia and its therapeutic use: a meta-analysis

Published online by Cambridge University Press:  18 June 2021

Katherine Beck*
Affiliation:
IoPPN King's College London
Guy Hindley
Affiliation:
IoPPN King's College London
Faith Borgan
Affiliation:
IoPPN King's College London
Cedric Ginestet
Affiliation:
IoPPN King's College London
Robert McCutcheon
Affiliation:
IoPPN King's College London
Stefan Brugger
Affiliation:
IoPPN King's College London
Naomi Driesen
Affiliation:
Yale University School, Dept. of Psychiatry and National Centre for PTSD, VA Connecticut
Mohini Ranganathan
Affiliation:
Yale University School, Dept. of Psychiatry and National Centre for PTSD, VA Connecticut
Deepak D'Souza
Affiliation:
Yale University School, Dept. of Psychiatry and National Centre for PTSD, VA Connecticut
Matthew Taylor
Affiliation:
University Department of Psychiatry, Warneford Hospital
John Krystal
Affiliation:
Yale University School, Dept. of Psychiatry and National Centre for PTSD, VA Connecticut
Oliver Howes
Affiliation:
IoPPN King's College London
*
*corresponding author.
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Abstract

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Aims

To conduct a meta-analysis of the effect of ketamine on psychopathology in healthy volunteers and patients with schizophrenia, and the experimental factors affecting this.

Background

Ketamine is increasingly used to treat depression and other psychiatric disorders but can induce schizophrenia-like symptoms. Despite this, the consistency and magnitude of symptoms induced by ketamine, or what factors influence the effects of ketamine on these remain unknown.

Method

MEDLINE, EMBASE and PsychINFO databases were searched for within-subject placebo controlled studies reporting symptoms using the Brief Psychiatric Rating Scale (BPRS) or Positive and Negative Syndrome Scale (PANSS) in response to an acute ketamine challenge in healthy participants or people with schizophrenia. Two independent investigators extracted study-level data for a random-effects meta-analysis. Total, positive and negative BPRS and PANSS scores were extracted. Sub-group analyses were conducted examining the effect of: blinding status, ketamine preparation, infusion method and time between ketamine and placebo condition. Standardized mean change scores were used as effect sizes for individual studies. Standardized mean changes between ketamine and placebo for total, positive and negative BPRS and PANSS were calculated.

Result

Of 7819 citations retrieved, 36 studies involving healthy participants were included. The overall sample included 725 healthy volunteers exposed to both the ketamine and placebo condition. Ketamine induced a significant increase in transient psychopathology in healthy participants, for total (Standardized mean change (SMC) = 1.50 (95% CI = 1.23 to 1.77), p < 0.0001), positive (SMC = 1.55 (95% CI = 1.29 to 1.81), p < 0.0001) and negative (SMC = 1.16, (95% CI = 0.96 to 1.35), p < 0.0001) symptom ratings, relative to the placebo condition. This effect was significantly greater for positive symptoms than negative symptoms (p = 0.004). Bolus followed by constant infusion increased ketamine's effect on positive symptoms relative to infusion alone (p = 0.006). Single-day study design increased ketamine's effect on total symptoms (p = 0.007), but age and gender did not moderate effects. There were insufficient studies for meta-analysis of studies in schizophrenia. Of these studies, two found a significant increase in symptoms with ketamine administration in total and positive symptoms. Only one study found an increase in negative symptom severity with ketamine.

Conclusion

These findings show that acute ketamine administration induces schizophrenia-like symptomatology with large effect sizes but there is a greater increase in positive than negative symptoms, and when a bolus is used. These findings suggest bolus doses should be avoided in its therapeutic use to minimize the risk of inducing transient positive psychotic symptoms.

Type
Research
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright
Copyright © The Author(s), 2021. Published by Cambridge University Press on behalf of the Royal College of Psychiatrists
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