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White matter microstructure in schizophrenia: effects of disorder, duration and medication

  • Richard Kanaan (a1), Gareth Barker (a1), Michael Brammer (a1), Vincent Giampietro (a1), Sukhwinder Shergill (a1), James Woolley (a1), Marco Picchioni (a1), Timothea Toulopoulou (a1) and Philip McGuire (a1)...

Abstract

Background

Diffusion tensor magnetic resonance imaging studies in schizophrenia to date have been largely inconsistent. This may reflect variation in methodology, and the use of small samples with differing illness duration and medication exposure.

Aims

To determine the extent and location of white matter microstructural changes in schizophrenia, using optimised diffusion tensor imaging in a large patient sample, and to consider the effects of illness duration and medication exposure.

Method

Scans from 76 patients with schizophrenia and 76 matched controls were used to compare fractional anisotropy, a measure of white matter microstructural integrity, between the groups.

Results

We found widespread clusters of reduced fractional anisotropy in patients, affecting most major white matter tracts. These reductions did not correlate with illness duration, and there was no difference between age-matched chronically and briefly medicated patients.

Conclusions

The finding of widespread fractional anisotropy reductions in our larger sample of patients with schizophrenia may explain some of the inconsistent findings of previous, smaller studies.

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Copyright

This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial licence (http://creativecommons.org/licenses/by-nc/4.0/), which permits noncommercial re-use, distribution, and reproduction in any medium, provided the original work is unaltered and is properly cited. The written permission of Cambridge University Press must be obtained for commercial re-use or in order to create a derivative work.

Corresponding author

Correspondence: Dr Richard Kanaan, Institute of Psychiatry, Department of Psychological Medicine, PO 62, Denmark Hill, London SE5 9RJ, UK. Email: r.kanaan@iop.kcl.ac.uk

Footnotes

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Declaration of interest

None.

Funding detailed in Acknowledgements.

Footnotes

References

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White matter microstructure in schizophrenia: effects of disorder, duration and medication

  • Richard Kanaan (a1), Gareth Barker (a1), Michael Brammer (a1), Vincent Giampietro (a1), Sukhwinder Shergill (a1), James Woolley (a1), Marco Picchioni (a1), Timothea Toulopoulou (a1) and Philip McGuire (a1)...

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White matter microstructure in schizophrenia: effects of disorder, duration and medication

  • Richard Kanaan (a1), Gareth Barker (a1), Michael Brammer (a1), Vincent Giampietro (a1), Sukhwinder Shergill (a1), James Woolley (a1), Marco Picchioni (a1), Timothea Toulopoulou (a1) and Philip McGuire (a1)...
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Reply to Chua & McAlanon

Richard A Kanaan, Clinical lecturer
03 June 2009

We are grateful for the comments of Chua and McAlonan (2009) on our recent paper (Kanaan et al., 2009). We agree that the process of establishing a definitive extent of white matter disruption in schizophrenia, and its relationship with illness duration and antipsychotic medication, is likely to be a lengthy one – larger studies such as ours notwithstanding. But we would like to clarify our reasoning with respect to their comments, and the methodological alternatives they suggest.

Firstly, we suspect that a ‘core pathology’ for white matter abnormalities in schizophrenia may be rather more elusive than the reconciliation we attempted. Though the recent meta-analysis by Ellison- Wright and Bullmore (2009) has found areas of most common difference in the 15 studies they examined, it should be noted that only a fraction of the studies they looked at shared these differences – and the history of DTI in schizophrenia is full of such conflicts (Kanaan et al., 2005). Though there may indeed be areas of greater difference, therefore, the evidence is against any difference that is common to all.

Secondly, with regard to distinguishing the effects of duration of illness and antipsychotic medication, drug-naïve cohorts clearly offer enormous potential as the authors acknowledge. Such cohorts are difficultto obtain in the developed world however, and the alternative approach they suggest – of ANOVA with co-variation -has similar difficulties since duration of treatment and illness will be so strongly correlated in most samples. And we note that the studies they cite as demonstrating the effectiveness of this approach either did not co-vary for medication exposure (Szeszko et al., 2005), or did not use DTI (Chua et al., 2009).

Yours sincerely

Dr Richard A A Kanaan, MRCPsych

Prof Gareth J Barker, PhD

Prof Philip K McGuire, FRCPsych

References

Chua SA, McAlanon G, Is there core DTI pathology in schizophrenia? A response to Kanaan et al 2009. 1st April 2009

Chua SE, Deng Y, Chen EY, Law CW, Chiu CP, Cheung C, et al. Early striatal hypertrophy in first-episode psychosis within 3 weeks of initiating antipsychotic drug treatment. Psychol Med 2009; 39: 793-800.

Ellison-Wright I, Bullmore E. Meta-analysis of diffusion tensor imaging studies in schizophrenia. Schizophr Res 2009; 108: 3-10.

Kanaan R, Barker G, Brammer M, Giampietro V, Shergill S, Woolley J, et al. White matter microstructure in schizophrenia: effects of disorder, duration and medication. Br J Psychiatry 2009; 194: 236-42.

Kanaan RA, Kim JS, Kaufmann WE, Pearlson GD, Barker GJ, McGuire PK. Diffusion tensor imaging in schizophrenia. Biol Psychiatry 2005; 58: 921- 9.

Szeszko PR, Ardekani BA, Ashtari M, Kumra S, Robinson DG, Sevy S, et al. White matter abnormalities in first-episode schizophrenia or schizoaffective disorder: a diffusion tensor imaging study. Am J Psychiatry 2005; 162: 602-5.
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Conflict of interest: None Declared

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Is there core DTI pathology in schizophrenia ? A response to Kanaan et al 2009

Dr Siew E Chua, Associate Professor
01 April 2009

Kanaan et al. (2009) reported widespread abnormalities in white matter in 76 patients with schizophrenia compared to 76 healthy controls. A secondary analysis of 45 of the patients showed mean extracted fractional anisotropy

scores to be unrelated to illness duration and duration of antipsychotic treatment. We wish to make two comments.

First, their main hypothesis that they would reconcile inconsistencies in the literature is a worthy, but elusive, goal. The problem of nosological heterogeneity “afflicts” not only the definition of schizophrenia, but also the interpretation of FA localization. FA score localities are commonly citedin terms of grey or white matter terminology. Given such heterogeneity, it would suffice to adopt the lesser goal of showing core pathology (in other

words, the Venn diagram intersection). Coreness of pathology alows for diversity, without having to reconcile everything.

Second, we note the secondary analysis was performed to dissect out the effects of the disorder, from that of illness duration and treatment. The authors achieved this by using FA scores extracted from the principal analysis, which were then used to compare chronically with briefly-medicated patients. Perhaps newly diagnosed, neuroleptic-naive patients help most to partition out these effects (Cheung et al 2007) but they are not essential. An alternative approach is voxel-based ANOVA covarying for illness duration and atypical antipsychotic duration/dosage since this can

help to maximizes anatomical coverage (particularly in the striatum where antipsychotic effects are detectable at even 2 (Szeszko et al, 2005) to 3 weeks of treatment (Chua et al, 2008)).

Yours sincerely

Dr Siew E Chua, MRCPsych

Dr Grainne M McAlonan, PhD

References

Cheung V, Cheung C, McAlonan GM, Deng Y, Wong JGWS et al (2007). A DTI study of structural dysconnectivity in never-medicated, first- Psychological Medicine, Oct 22, 1-9.

Chua SE, Deng Y, Chen EYH, Law CW, Chiu CPY, Cheung C et al (2008). Early striatal hypertrophy in first-episode psychosis within 3 weeks of initiating antipsychotic drug treatment. Psychological Medicine 1-8.

Kanaan R, Barker G, Brammer M, Giampietro V, Shergill S et al (2009).

White matter microstructure in schizophrenia: effects of disorder, duration and medication. British Journal of Psychiatry March 194 :236-242.

Szeszko PR, Ardekani BA, Ashtari M, Kumra S, Robinson DG, Sevy S et al (2005). White matter abnormalities in first-episode schizophrenia or schizoaffective disorder : a diffusion tensor imaging study. American Journal of Psychiatry 162, 602-605
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Conflict of interest: None Declared

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