Morphological brain changes in schizophrenia

1. Brain-morphological changes associated with acute antipsychotic treatment in first-episode schizophrenia Laila Asmal1, Bonginkosi Chiliza1, Stéfan du Plessis1, Jonathan Carr2, Anneke Goosen1, Martin Kidd3, Matthijs Vink4, Rene Kahn4,Robin Emsley1 From the Department of Psychiatry,1 Department of Neurology,2Centre for Statistical Consultation, Stellenbosch University, South Africa,3Department of Psychiatry, University Medical Centre Utrecht, The Netherlands.4

2. Morphological brain changes in schizophrenia • Global and regional structural brain abnormalities.1 • Present at the first episode and even in the prodrome • consistent with a neuro-developmental origin • BUT … • Longitudinal studies indicate that progressive changes also occur.2 • Mostly in the early years of illness, and only in a subset.3 Haijma SV, et al. Schizophr Bull. (in press); 2. Olabi B, et al. (2011). Biol.Psychiatry 70[1], 88-96; 3. Andreasen NC, et al. (2013) Am.J Psychiatry (in press);) .

3. There is debate as to the causes of the progressive changes • Illness progression4 • Related to antipsychotic medication5,6,7 • Non-specific, due to • substance abuse • poor adherence • effects of co-morbid conditions8 4. Lieberman J, et al. (2001). Biol.Psychiatry 49[6], 487-499; 5. Smieskova R, et al. (2009). Curr.Pharm.Des 15[22], 2535-2549; 6. Ho BC, et al. (2011). Arch.Gen.Psychiatry 68[2], 128-137; 7. Dorph-Petersen R,et al. Neuropsychopharmacology (2005)30, 1649–1661; 8. Zipursky RB, et al. Schizophr Bull (in press

4. Brain changes and treatment response • Baseline symptoms predict brain changes during the course of treatment.9 • Baseline brain abnormalities in turn predict treatment response.10 • But the chronological relationships require elucidation. • May provide clues as to the neurobiological underpinnings of treatment response and adverse antipsychotic effects. 9. Collin G, et al. (2012). Schizophr Res 138[2-3], 171-176; 10. SzeszkoPR, et al. (2012). SchizophrBull 38[3], 569-578.

5. Our study • Aim: To further investigate the effects of acute antipsychotic treatment on global and regional brain structure using cortical/subcortical reconstruction

6. Methodological considerations • Treatment naïve patients with a first-episode of schizophrenia: • to avoid the influences of disease chronicity and previous treatment. • Long-acting injectable antipsychotics: • to avoid the confounding effect of covert non-adherence. • We also took care to exclude patients with substance abuse and comorbid pathology.

7. Methods and Materials • Single-site, double-blinded RCT over 13 weeks comparing long-acting risperidone injection and flupenthixol decanoate in antipsychotic-naive patients with a first-episode of schizophrenia. • Treatment: • Flexible doses starting at 25mg risperidone long-acting injection or 10mg flupenthixol decanoate 2-weekly • No treatment group effects were demonstrated in any of the MRI ROIs so treatment groups were pooled for all of the subsequent analyses.

8. Participants Inclusion: • Male or female; in- or outpatients; aged 16 to 45 yrs; • DSM-IV schizophreniform, schizophrenia or schizoaffective disorder • No previous exposure to antipsychotic medication • Right handedness Exclusion: • Substance abuse in the previous 6 months, significant general medical condition, mental retardation (IQ<70). Healthy controls: Matched by age, sex, ethnicity and educational status

9. Structural brain imaging • High-resolution T1-weighted data on a 3T Siemens Allegra MRI scanner • Scans were processed and analyzed using Freesurfer stable release version 5.1. • Analyses: modified ITT, MMRM

11. What can we do with FreeSurfer? • measure volume of cortical or subcortical structures • compute thickness of the cortical sheet • study differences of populations (diseased, control)

12. Global and regional measures • 117 ROIs • Asegmentation volumes • ventricles • global grey and white matter volumes • structures eg. basal ganglia, thalamus • L hemisphere cortical thickness • R hemisphere cortical thickness

13. Baseline MRI differences patients vs. controls

17. Brain changes associated with treatment response: • Improvements were associated with greater reductions in GM. • CGI-S and QoL significantly correlated with reductions in total GM volume • General psychopathology and PANSS total score improvements were associated with reductions in left entorhinal cortical thickness. • However, improvements in negative (and depressive) symptoms associated with lesser GM reductions • Notably, there were no significant correlations between changes in insight, positive symptoms or SOFAS and brain changes.

18. Brain changes associated with antipsychotic adverse effects • ESRS total and parkinsonism scores associated with greater total GM volumes. • Weight was associated with ventral diencephalon bilaterally and HDL with left ventral diencephalon. • triglycerides associated with subcortical and total GM volume • No significant correlations between changes in prolactin, glucose, LDL and cholesterol levels and brain changes.

19. Conclusions • Further evidence of acute brain plasticity in response to antipsychotic treatment • Some brain changes occurred in association with treatment response and others with emergent adverse-effects. • No differential effects between RLAI and FD • Generally, changes occurred bilaterally, with volume reductions for cortical and subcortical structures, and volume increases for ventricular measures • i.e. shrinkage!

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