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01 April 2021

Cognitive flexibility potential new target in treatment resistant schizophrenia

Researchers at King’s College London have found that an important brain mechanism that allows us to switch between thinking about two or more ideas may help treat patients with schizophrenia who do not respond well to current treatments.

Top of a girls head lying down in an MRI machine

Schizophrenia effects approximately 1% of the population and roughly one third of patients do not get better with treatment at a high cost to the patient and their family as well as healthcare services.

Researchers used sophisticated brain imaging techniques to look at cognitive flexibility, which is a person’s ability to flexibly update their thinking depending on new information, in 34 control, 21 treatment-responsive and 20 treatment-resistant participants recruited from the South London and Maudsley NHS Foundation Trust. Brain connectivity and levels of glutamate, a key neurotransmitter in the brain, were compared and related to the participant’s behaviour and clinical symptoms, such as hallucinations.

A new subtype of schizophrenia

During a task set by the researchers while undergoing fMRI scanning, patients with treatment resistance showed an absence of the cognitive flexibility mechanism compared to treatment-responsive patients. This suggests an alternative mechanism impacting learning and decision making that is uniquely impaired in treatment resistance.

This significantly altered cognitive flexibility suggests treatment resistance represents a subtype of schizophrenia with a distinct underlying neurobiological mechanism.

Researchers suggest that a personalised antipsychotic treatment that targets the cognitive flexibility brain mechanism may offer a new long-term treatment target.

For the first time, we show a fundamental problem in cognitive flexibility in patients with schizophrenia that fail to respond to treatment. While this is a small study, the findings are important as they present a clear target for long-term treatment in these patients.

Dr Charlotte Horne, lead author and Postdoctoral research associate at Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London

She added, “Our research also helps us move towards treatment strategies that work for each person, meaning that in future, each patient with schizophrenia has the best chance of recovery.”

We propose a core non-dopaminergic impairment that impacts cognitive control networks in treatment-resistant schizophrenia.

Author Sukhwinder Shergill, Professor of Psychiatry & Systems Neuroscience at IoPPN and Consultant Psychiatrist at South London and Maudsley NHS Foundation Trust

He continued, “This impairment disrupted learning and could be underpinned by abnormal glutamate function. These findings inform the focus of future treatment strategies (e.g. glutamatergic targets and giving clozapine earlier) in resistant patients.”

Cognitive control network connectivity differentially disrupted in treatment resistant schizophrenia was published 30th March in Neuroimage: Clinical and was funded by the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre, the European Research Council and the Wellcome/EPSRC Centre for Medical Engineering.


To find out more or to arrange interviews, please contact the Communications team at NIHR Maudsley BRC:

  • Alex Booth, Communications and Engagement Manager, NIHR Maudsley Biomedical Research Centre, Tel 020 7848 0495
  • Serena Rianjongdee, Communications and Engagement Officer, NIHR Maudsley Biomedical Research Centre, Tel 020 7848 2137

In this story

Charlotte Horne

Postdoctoral research associate

Sukhwinder Shergill

Professor of Psychiatry & Systems Neuroscience