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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], 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. Szeszko PR, et al. (2012). Schizophr Bull 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 PatientsControls tdfp MeanSDMeanSD 3rd Ventricle1058.8266.4924.5208.01.9420.1 4th Ventricle2027.3841.01788.3770.51.0420.3 5th Ventricle17.518.715.720.00.3420.8 Brain Stem20692.12931.219603.32647.41.3420.2 CC Anterior867.0100.9804.5144.81.6420.1 CC Central447.0111.9432.0109.40.4420.7 CC Mid Anterior472.8105.6496.3128.5-0.7420.5 CC Mid Posterior407.794.1414.789.5-0.3420.8 CC Posterior886.6155.9782.9158.32.2420.0 Cortex Volume453059.143233.8435618.948807.61.2420.2 Cortical White Matter Volume485657.156560.4459356.152848.51.6420.1 CSF1343.4279.41195.7211.72.0420.1 Left Accumbens area629.1145.6586.2128.91.0420.3 Left Amygdala1500.1196.21429.3228.11.1420.3 Left Caudate4165.1633.53572.1585.53.2420.0 Left Cerebellum Cortex49316.79966.446250.811355.90.9420.3 Left Cerebellum White Matter12918.81836.813252.32706.7-0.5420.6 Left choroid plexus1711.4240.51612.1437.30.9420.4 Left Cortex Volume226035.322695.0217192.424224.61.2420.2 Left Cortical White Matter Volume242189.729088.3228834.226638.41.6420.1 Left Hippocampus3911.9452.93932.7496.4-0.1420.9 Left Inferior Lateral Ventricle419.9269.9276.2146.02.2420.0 Left Lateral Ventricle6584.43582.05513.12673.01.1420.3 Left Pallidum1905.3334.31737.1297.11.8420.1 Left Putamen6387.81038.46048.91010.01.1420.3 Left Thalamus7928.1973.27378.4734.62.1420.0 Left Ventral DC6048.91010.04309.5551.41.5420.1 Left vessel102.457.988.251.50.9420.4 non WM hypointensities31.933.829.719.70.3420.8 Optic Chiasm211.7108.9160.688.31.7420.1 Right Accumbens area601.3141.7573.0127.20.7420.5 Right Amygdala1585.0241.31548.5310.00.4420.7 Right Caudate4154.8603.33638.3567.82.9420.0 Right Cerebellum Cortex51220.39518.947386.310786.61.2420.2 Right Cerebellum White Matter13067.32245.213493.22258.5-0.6420.5 Right choroid plexus1792.8297.11583.1498.91.7420.1 Right Cortex Volume227023.820623.6218426.524709.21.2420.2 Right Cortical White Matter Volume243467.427575.9230521.926337.01.6420.1 Right Hippocampus4058.5392.84018.1444.90.3420.8 Right Inferior Lateral Ventricle284.2130.5213.6132.11.8420.1 Right Lateral Ventricle6430.43189.05219.52502.51.4420.2 Right Pallidum1732.7294.21589.9278.51.7420.1 Right Putamen6330.11054.15768.2906.01.9420.1 Right Thalamus8041.11116.87532.4952.71.6420.1 Right Ventral DC4392.8480.74210.3650.51.0420.3 Right vessel76.146.470.047.60.4420.7 Sub Cortical Gray Volume183098.824177.9171113.328876.01.5420.1 Supra Tentorial Volume 1052115. 0 89552.4999185.0105328.21.8420.1 Total Gray Volume636157.952617.3606732.273273.91.5420.1 WM hypointensities1631.91005.51766.51184.3-0.4420.7 Left bankssts thickness2. Left caudal anterior cingulate thickness Left caudal middle frontal thickness2. Left cuneus thickness1. Left entorhinal thickness3. Left frontalpole thickness2. Left fusiform thickness2. Left inferior parietal thickness2. Left inferior temporal thickness2. Left insula thickness2. Left isthmus cingulate thickness2. Left lateral occipital thickness2. Left lateral orbitofrontal thickness2. Left lingual thickness1. Left medial orbitofrontal thickness2. Left middle temporal thickness2. Left paracentral thickness2. Left parahippocampal thickness2. Left pars opercularis thickness2. Left pars orbitalis thickness2. Left pars triangularis thickness2. 420.9 Left pericalcarine thickness1. Left post-central thickness2. Left posterior cingulate thickness2. Left pre-central thickness2. Left precuneus thickness2. Left rostral anterior cingulate thickness Left rostral middle frontal thickness2. Left superior frontal thickness2. Left superior parietal thickness2. Left superior temporal thickness2. Left supramarginal thickness2. Left temporal pole thickness3. Left transverse temporal thickness2. Right bankssts thickness2. Right caudal anterior cingulate thickness Right caudal middle frontal thickness2. Right cuneus thickness1. Right entorhinal thickness3. Right frontal pole thickness2. Right fusiform thickness2. Right inferior parietal thickness2. Right inferior temporal thickness2. Right insula thickness2. Right isthmus cingulate thickness2. Right lateral occipital thickness2. Right lateral orbitofrontal thickness2. Right lingual thickness1. Right medial orbitofrontal thickness2. Right middle temporal thickness2. Right para-central thickness2. Right para hippocampal cortical thickness Right pars opercularis thickness2. Right pars orbitalis thickness2. Right pars triangularis thickness2. Right pericalcarine thickness1. Right post-central thickness2. Right posterior cingulate thickness2. 420.9 Right pre-central thickness2. Right pre-cuneus thickness2. Right rostralanteriorcingulate thickness Right rostral middle frontal thickness2. Right superior frontal thickness2. Right superior parietal thickness2. Right superior temporal thickness2. Right supramarginal thickness2. Right temporal pole thickness3. Right transverse temporal thickness2. 117 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 3 4202702761462.22342.032 L thalamus in mm 3 792897373787352.12642.039 L caudate in mm 3 416563435725863.22742.002 R caudate in mm 3 415560336385682.92542.006 R parahippocampal cortical thickness in mm 2.4700.2452.3100.2422.16742.036 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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