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,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
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], ; 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. 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
2931.2
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
1.2
Cortical White Matter Volume
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
9966.4
0.9
Left Cerebellum White Matter
1836.8
2706.7
-0.5
0.6
Left choroid plexus
1711.4
240.5
1612.1
437.3
Left Cortex Volume
Left Cortical White Matter Volume
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
9518.9
Right Cerebellum White Matter
2245.2
2258.5
-0.6
Right choroid plexus
1792.8
1583.1
498.9
Right Cortex Volume
Right Cortical White Matter Volume
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
Supra Tentorial Volume
Total Gray Volume
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

13. Baseline MRI differences patients vs. controlsdf 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

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 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!

20. Moving towards personalised medicine …