Resistant Schizophrenia: Brain Imaging Provides Insight

Megan Brooks

March 17, 2016

A comprehensive review of brain imaging studies provides support for the two main hypotheses regarding the neurobiology of treatment-resistant schizophrenia, namely, "whether treatment- resistant schizophrenia is best understood as a more severe form of responsive schizophrenia or whether it has a fundamentally different pathophysiology," Robert McCutcheon, MBBS, MRCPsych, told Medscape Medical News.

"Our review shows some support for both of these hypotheses. On some measures, such as gray matter reductions, resistant patients do appear to show more severe abnormalities compared to responsive patients. On other measures examining neurochemical functioning, however, it seems that there can be quite different processes operating in responsive and resistant patients," Dr McCutcheon explained.

The findings were published online March 3 in Lancet Psychiatry.

Similarities and Differences

About 30% of patients with schizophrenia fail to respond adequately to antipsychotics, and there is often a major delay in identifying resistant patients and offering them the optimal treatment with clozapine (multiple brands). "This is an area where there is a great need for both improved treatments and earlier identification of resistance. Neuroimaging research has the potential to aid in both of these endeavors," Dr McCutcheon told Medscape Medical News.

He and two colleagues reviewed 61 relevant neuroimaging studies that examined patients with treatment-resistant schizophrenia or that longitudinally assessed the effects of clozapine treatment.

They report that structural studies "uniformly" show gray matter reductions in patients with treatment-resistant schizophrenia, particularly in frontal and temporal regions, compared with healthy control individuals. Patients with treatment-resistant schizophrenia, in comparison with healthy control persons, also show decreased metabolism and perfusion in frontal areas; enlargement of the posterior corpus callosum; disruption of white matter tracts, particularly in the corpus callosum; and increased perfusion in the basal ganglia.

When comparing resistant patients to responsive patients, "the most replicated finding was a greater reduction in grey matter in resistant patients, predominantly in frontal areas," the investigators note. Studies that employed fMRI and EEG also suggest a continuum of pathology, they say; neurobiological differences between healthy control persons and patients with schizophrenia who respond to antipsychotic medications are even more pronounced in treatment-resistant patients.

In terms of neurochemistry studies, two positron emission tomography (PET) studies suggest that patients with treatment-resistant schizophrenia might have different dopaminergic functioning compared with responsive patients.

"Apart from neuroimaging, other evidence also supports both continuum and categorical hypotheses," the reviewers note. For example, results from one study suggest a "potential genetic framework on which categorically different schizophrenia subtypes could be placed, and categorical differences in dopaminergic and glutamatergic function might be able to account for differences in treatment response. Conversely, other studies provide support for the continuum hypothesis, showing that patients with increased exposure to both environmental and genetic risk factors are more likely to be treatment resistant."

As for response to clozapine, the evidence points to reduced prefrontal atrophy in responders compared with nonresponders and suggests that clozapine leads to a reduction in the volume of the caudate nucleus.

Ready for Prime Time?

Taken together, the available evidence supports the hypothesis that "some of the neurobiological changes seen in treatment-resistant schizophrenia lie along a continuum with treatment- responsive schizophrenia, whereas other differences are categorical in nature and have potential to be used as biomarkers," the authors conclude.

Is neuroimaging ready for prime time in resistant schizophrenia? "MRI or EEG may be indicated in some cases of resistant schizophrenia to rule out organic causes," said Dr McCutcheon. "The use of PET, however, remains primarily restricted to research settings. No neuroimaging technique is currently used clinically to guide treatment choices in standard clinical practice."

Going forward, Dr McCutcheon said what the field needs are "well-controlled, adequately powered, ideally prospective studies from illness onset to definitively determine the key aspects of the neurobiology underlying treatment resistance and to identify reliable biomarkers."

"This is a clear and rigorous review," Mario Quarantelli, MD, senior researcher, Biostructure and Bioimaging Institute, National Research Council, Naples, Italy, told Medscape Medical News. However, "great heterogeneity in the criteria to define treatment resistance limits the comparability of results from different groups," he noted.

Dr Quarantelli agreed with the researchers' conclusions that "...for neuroimaging findings to be clinically translatable, future studies need to focus on a priori hypotheses and be adequately powered.

"I don't see a clinical role for neuroimaging in this specific field in the near future apart from ruling out additional brain pathologies, which in some cases may influence response to therapy," he added.

The study was funded by Medical Research Council UK Maudsley Charity, the Wellcome Trust, the UK National Institute for Health Research Biomedical Research Centre at South London, the Maudsley National Health Service Foundation Trust, and King's College London. Dr McCutcheon and one coauthor report no relevant financial relationships. One coauthor reports receiving investigator-initiated research funding from and/or participating in advisory or speaker meetings organized by AstraZeneca, Autifony, BMS, Eli Lilly, Jannsen, Lundbeck, Lyden-Delta, Otsuka, Servier, Sunovion, and Roche.

Lancet Psychiatry. Published online March 3, 2016. Abstract

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