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,2 Centre for Statistical Consultation, Stellenbosch University, South Africa,3 Department of Psychiatry, University Medical Centre Utrecht, The Netherlands.4

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);) .

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

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.

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

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.

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.

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

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

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)

Global and regional measures   Patients Controls t df p Mean SD 3rd Ventricle 1058.8 266.4 924.5 208.0 1.9 42 0.1 4th Ventricle 2027.3 841.0 1788.3 770.5 1.0 0.3 5th Ventricle 17.5 18.7 15.7 20.0 0.8 Brain Stem 20692.1 2931.2 19603.3 2647.4 1.3 0.2 CC Anterior 867.0 100.9 804.5 144.8 1.6 CC Central 447.0 111.9 432.0 109.4 0.4 0.7 CC Mid Anterior 472.8 105.6 496.3 128.5 -0.7 0.5 CC Mid Posterior 407.7 94.1 414.7 89.5 -0.3 CC Posterior 886.6 155.9 782.9 158.3 2.2 0.0 Cortex Volume 453059.1 43233.8 435618.9 48807.6 1.2 Cortical White Matter Volume 485657.1 56560.4 459356.1 52848.5 CSF 1343.4 279.4 1195.7 211.7 2.0 Left Accumbens area 629.1 145.6 586.2 128.9 Left Amygdala 1500.1 196.2 1429.3 228.1 1.1 Left Caudate 4165.1 633.5 3572.1 585.5 3.2 Left Cerebellum Cortex 49316.7 9966.4 46250.8 11355.9 0.9 Left Cerebellum White Matter 12918.8 1836.8 13252.3 2706.7 -0.5 0.6 Left choroid plexus 1711.4 240.5 1612.1 437.3 Left Cortex Volume 226035.3 22695.0 217192.4 24224.6 Left Cortical White Matter Volume 242189.7 29088.3 228834.2 26638.4 Left Hippocampus 3911.9 452.9 3932.7 496.4 -0.1 Left Inferior Lateral Ventricle 419.9 269.9 276.2 146.0 Left Lateral Ventricle 6584.4 3582.0 5513.1 2673.0 Left Pallidum 1905.3 334.3 1737.1 297.1 1.8 Left Putamen 6387.8 1038.4 6048.9 1010.0 Left Thalamus 7928.1 973.2 7378.4 734.6 2.1 Left Ventral DC 4309.5 551.4 1.5 Left vessel 102.4 57.9 88.2 51.5 non WM hypointensities 31.9 33.8 29.7 19.7 Optic Chiasm 108.9 160.6 88.3 1.7 Right Accumbens area 601.3 141.7 573.0 127.2 Right Amygdala 1585.0 241.3 1548.5 310.0 Right Caudate 4154.8 603.3 3638.3 567.8 2.9 Right Cerebellum Cortex 51220.3 9518.9 47386.3 10786.6 Right Cerebellum White Matter 13067.3 2245.2 13493.2 2258.5 -0.6 Right choroid plexus 1792.8 1583.1 498.9 Right Cortex Volume 227023.8 20623.6 218426.5 24709.2 Right Cortical White Matter Volume 243467.4 27575.9 230521.9 26337.0 Right Hippocampus 4058.5 392.8 4018.1 444.9 Right Inferior Lateral Ventricle 284.2 130.5 213.6 132.1 Right Lateral Ventricle 6430.4 3189.0 5219.5 2502.5 1.4 Right Pallidum 1732.7 294.2 1589.9 278.5 Right Putamen 6330.1 1054.1 5768.2 906.0 Right Thalamus 8041.1 1116.8 7532.4 952.7 Right Ventral DC 4392.8 480.7 4210.3 650.5 Right vessel 76.1 46.4 70.0 47.6 Sub Cortical Gray Volume 183098.8 24177.9 171113.3 28876.0 Supra Tentorial Volume 1052115.0 89552.4 999185.0 105328.2 Total Gray Volume 636157.9 52617.3 606732.2 73273.9 WM hypointensities 1631.9 1005.5 1766.5 1184.3 -0.4 Left bankssts thickness 2.3 2.4 -1.7 Left caudal anterior cingulate thickness 2.6 2.7 Left caudal middle frontal thickness -1.4 Left cuneus thickness Left entorhinal thickness 3.1 Left frontalpole thickness 2.8 Left fusiform thickness 2.5 Left inferior parietal thickness -2.0 Left inferior temporal thickness Left insula thickness Left isthmus cingulate thickness Left lateral occipital thickness -2.9 Left lateral orbitofrontal thickness Left lingual thickness -2.1 Left medial orbitofrontal thickness Left middle temporal thickness Left paracentral thickness Left parahippocampal thickness Left pars opercularis thickness Left pars orbitalis thickness -0.2 Left pars triangularis thickness Left pericalcarine thickness -1.3 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 -0.9 Left superior parietal thickness -1.6 Left superior temporal thickness Left supramarginal thickness Left temporal pole thickness 3.5 3.4 Left transverse temporal thickness Right bankssts thickness Right caudal anterior cingulate thickness Right caudal middle frontal thickness Right cuneus thickness Right entorhinal thickness 3.0 Right frontal pole thickness -0.8 Right fusiform thickness Right inferior parietal thickness Right inferior temporal thickness Right insula thickness Right isthmus cingulate thickness Right lateral occipital thickness -2.2 Right lateral orbitofrontal thickness Right lingual thickness Right medial orbitofrontal thickness Right middle temporal thickness Right para-central thickness -1.1 Right para hippocampal cortical thickness Right pars opercularis thickness Right pars orbitalis thickness Right pars triangularis thickness Right pericalcarine thickness -3.4 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 -1.5 Right superior parietal thickness Right superior temporal thickness -1.0 Right supramarginal thickness Right temporal pole thickness Right transverse temporal thickness 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

Baseline MRI differences patients vs. controls df p Mean SD L inferior lateral ventricle in mm3 420 270 276 146 2.223 42 .032 L thalamus in mm3 7928 973 7378 735 2.126 .039 L caudate in mm3 4165 634 3572 586 3.227 .002 R caudate in mm3 4155 603 3638 568 2.925 .006 R parahippocampal cortical thickness in mm 2.470 0.245 2.310 0.242 2.167 .036

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.

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.

Conclusions i.e. shrinkage! 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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