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Brain-morphological changes associated with acute antipsychotic treatment in first-episode schizophrenia Laila Asmal 1, Bonginkosi Chiliza 1, Stéfan du.

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Presentation on theme: "Brain-morphological changes associated with acute antipsychotic treatment in first-episode schizophrenia Laila Asmal 1, Bonginkosi Chiliza 1, Stéfan du."— Presentation transcript:

1 Brain-morphological changes associated with acute antipsychotic treatment in first-episode schizophrenia Laila Asmal 1, Bonginkosi Chiliza 1, Stéfan du Plessis 1, Jonathan Carr 2, Anneke Goosen 1, Martin Kidd 3, Matthijs Vink 4, Rene Kahn 4, Robin Emsley 1 From the Department of Psychiatry, 1 Department of Neurology, 2 Centre for Statistical Consultation, Stellenbosch University, South Africa, 3 Department 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 1.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 progression 4 Related to antipsychotic medication 5,6,7 Non-specific, due to –substance abuse –poor adherence –effects of co-morbid conditions 8 4. Lieberman J, et al. (2001). Biol.Psychiatry 49[6], ; 5. Smieskova R, et al. (2009). Curr.Pharm.Des 15[22], ; 6. Ho BC, et al. (2011). Arch.Gen.Psychiatry 68[2], ; 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], ; 10. Szeszko PR, et al. (2012). Schizophr Bull 38[3],

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 PatientsControls tdfp MeanSDMeanSD 3rd Ventricle th Ventricle th Ventricle Brain Stem CC Anterior CC Central CC Mid Anterior CC Mid Posterior CC Posterior Cortex Volume Cortical White Matter Volume CSF Left Accumbens area Left Amygdala Left Caudate Left Cerebellum Cortex Left Cerebellum White Matter Left choroid plexus Left Cortex Volume Left Cortical White Matter Volume Left Hippocampus Left Inferior Lateral Ventricle Left Lateral Ventricle Left Pallidum Left Putamen Left Thalamus Left Ventral DC Left vessel non WM hypointensities Optic Chiasm Right Accumbens area Right Amygdala Right Caudate Right Cerebellum Cortex Right Cerebellum White Matter Right choroid plexus Right Cortex Volume Right Cortical White Matter Volume Right Hippocampus Right Inferior Lateral Ventricle Right Lateral Ventricle Right Pallidum Right Putamen Right Thalamus Right Ventral DC Right vessel Sub Cortical Gray Volume Supra Tentorial Volume Total Gray Volume WM hypointensities Left bankssts thickness Left caudal anterior cingulate thickness Left caudal middle frontal thickness Left cuneus thickness Left entorhinal thickness Left frontalpole thickness Left fusiform thickness Left inferior parietal thickness Left inferior temporal thickness Left insula thickness Left isthmus cingulate thickness Left lateral occipital thickness Left lateral orbitofrontal thickness Left lingual thickness Left medial orbitofrontal thickness Left middle temporal thickness Left paracentral thickness Left parahippocampal thickness Left pars opercularis thickness Left pars orbitalis thickness Left pars triangularis thickness Left pericalcarine thickness Left post-central thickness Left posterior cingulate thickness Left pre-central thickness Left precuneus thickness Left rostral anterior cingulate thickness Left rostral middle frontal thickness Left superior frontal thickness Left superior parietal thickness Left superior temporal thickness Left supramarginal thickness Left temporal pole thickness Left transverse temporal thickness Right bankssts thickness Right caudal anterior cingulate thickness Right caudal middle frontal thickness Right cuneus thickness Right entorhinal thickness Right frontal pole thickness Right fusiform thickness Right inferior parietal thickness Right inferior temporal thickness Right insula thickness Right isthmus cingulate thickness Right lateral occipital thickness Right lateral orbitofrontal thickness Right lingual thickness Right medial orbitofrontal thickness Right middle temporal thickness Right para-central thickness Right para hippocampal cortical thickness Right pars opercularis thickness Right pars orbitalis thickness Right pars triangularis thickness Right pericalcarine thickness Right post-central thickness Right posterior cingulate thickness Right pre-central thickness Right pre-cuneus thickness Right rostralanteriorcingulate thickness Right rostral middle frontal thickness Right superior frontal thickness Right superior parietal thickness Right superior temporal thickness Right supramarginal thickness Right temporal pole thickness Right transverse temporal thickness ROIs Asegmentation volumes ventricles global grey and white matter volumes structures eg. basal ganglia, thalamus L hemisphere cortical thickness R hemisphere cortical thickness Global and regional measures

13 PatientsControls tdfp MeanSDMeanSD L inferior lateral ventricle in mm L thalamus in mm L caudate in mm R caudate in mm R parahippocampal cortical thickness in mm Baseline MRI differences patients vs. controls




17 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. Brain changes associated with treatment response:

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!

20 Moving towards personalised medicine …

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