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

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);) .

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 handednessExclusion:• 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)

 Patients Controls

t df pMean SD Mean SD

3rd Ventricle 1058.8 266.4 924.5 208.0 1.9 42 0.14th Ventricle 2027.3 841.0 1788.3 770.5 1.0 42 0.35th Ventricle 17.5 18.7 15.7 20.0 0.3 42 0.8

Brain Stem 20692.1 2931.2 19603.3 2647.4 1.3 42 0.2

CC Anterior 867.0 100.9 804.5 144.8 1.6 42 0.1CC Central 447.0 111.9 432.0 109.4 0.4 42 0.7CC Mid Anterior 472.8 105.6 496.3 128.5 -0.7 42 0.5CC Mid Posterior 407.7 94.1 414.7 89.5 -0.3 42 0.8CC Posterior 886.6 155.9 782.9 158.3 2.2 42 0.0

Cortex Volume 453059.1 43233.8 435618.9 48807.6 1.2 42 0.2

Cortical White Matter Volume 485657.1 56560.4 459356.1 52848.5 1.6 42 0.1

CSF 1343.4 279.4 1195.7 211.7 2.0 42 0.1Left Accumbens area 629.1 145.6 586.2 128.9 1.0 42 0.3Left Amygdala 1500.1 196.2 1429.3 228.1 1.1 42 0.3Left Caudate 4165.1 633.5 3572.1 585.5 3.2 42 0.0

Left Cerebellum Cortex 49316.7 9966.4 46250.8 11355.9 0.9 42 0.3

Left Cerebellum White Matter 12918.8 1836.8 13252.3 2706.7 -0.5 42 0.6

Left choroid plexus 1711.4 240.5 1612.1 437.3 0.9 42 0.4

Left Cortex Volume 226035.3 22695.0 217192.4 24224.6 1.2 42 0.2

Left Cortical White Matter Volume 242189.7 29088.3 228834.2 26638.4 1.6 42 0.1

Left Hippocampus 3911.9 452.9 3932.7 496.4 -0.1 42 0.9Left Inferior Lateral Ventricle 419.9 269.9 276.2 146.0 2.2 42 0.0

Left Lateral Ventricle 6584.4 3582.0 5513.1 2673.0 1.1 42 0.3

Left Pallidum 1905.3 334.3 1737.1 297.1 1.8 42 0.1

Left Putamen 6387.8 1038.4 6048.9 1010.0 1.1 42 0.3

Left Thalamus 7928.1 973.2 7378.4 734.6 2.1 42 0.0

Left Ventral DC 6048.9 1010.0 4309.5 551.4 1.5 42 0.1

Left vessel 102.4 57.9 88.2 51.5 0.9 42 0.4non WM hypointensities 31.9 33.8 29.7 19.7 0.3 42 0.8Optic Chiasm 211.7 108.9 160.6 88.3 1.7 42 0.1Right Accumbens area 601.3 141.7 573.0 127.2 0.7 42 0.5Right Amygdala 1585.0 241.3 1548.5 310.0 0.4 42 0.7Right Caudate 4154.8 603.3 3638.3 567.8 2.9 42 0.0

Right Cerebellum Cortex 51220.3 9518.9 47386.3 10786.6 1.2 42 0.2

Right Cerebellum White Matter 13067.3 2245.2 13493.2 2258.5 -0.6 42 0.5

Right choroid plexus 1792.8 297.1 1583.1 498.9 1.7 42 0.1

Right Cortex Volume 227023.8 20623.6 218426.5 24709.2 1.2 42 0.2

Right Cortical White Matter Volume 243467.4 27575.9 230521.9 26337.0 1.6 42 0.1

Right Hippocampus 4058.5 392.8 4018.1 444.9 0.3 42 0.8

Right Inferior Lateral Ventricle 284.2 130.5 213.6 132.1 1.8 42 0.1

Right Lateral Ventricle 6430.4 3189.0 5219.5 2502.5 1.4 42 0.2

Right Pallidum 1732.7 294.2 1589.9 278.5 1.7 42 0.1

Right Putamen 6330.1 1054.1 5768.2 906.0 1.9 42 0.1

Right Thalamus 8041.1 1116.8 7532.4 952.7 1.6 42 0.1

Right Ventral DC 4392.8 480.7 4210.3 650.5 1.0 42 0.3Right vessel 76.1 46.4 70.0 47.6 0.4 42 0.7

Sub Cortical Gray Volume 183098.8 24177.9 171113.3 28876.0 1.5 42 0.1

Supra Tentorial Volume 1052115.0 89552.4 999185.0 105328.2 1.8 42 0.1

Total Gray Volume 636157.9 52617.3 606732.2 73273.9 1.5 42 0.1

WM hypointensities 1631.9 1005.5 1766.5 1184.3 -0.4 42 0.7

Left bankssts thickness 2.3 0.2 2.4 0.2 -1.7 42 0.1Left caudal anterior cingulate thickness 2.6 0.3 2.7 0.3 -0.5 42 0.6

Left caudal middle frontal thickness 2.6 0.1 2.6 0.1 -1.4 42 0.2

Left cuneus thickness 1.8 0.1 1.8 0.2 0.0 42 1.0Left entorhinal thickness 3.1 0.4 2.9 0.4 1.7 42 0.1Left frontalpole thickness 2.9 0.4 2.8 0.3 1.1 42 0.3Left fusiform thickness 2.5 0.1 2.5 0.2 -0.4 42 0.7

Left inferior parietal thickness 2.4 0.1 2.5 0.1 -2.0 42 0.1

Left inferior temporal thickness 2.6 0.1 2.6 0.2 0.4 42 0.7

Left insula thickness 2.9 0.2 2.9 0.2 -0.1 42 0.9

Left isthmus cingulate thickness 2.6 0.2 2.6 0.2 0.0 42 1.0

Left lateral occipital thickness 2.0 0.1 2.2 0.2 -2.9 42 0.0

Left lateral orbitofrontal thickness 2.7 0.2 2.6 0.2 1.1 42 0.3

Left lingual thickness 1.9 0.1 1.9 0.1 -2.1 42 0.0

Left medial orbitofrontal thickness 2.6 0.2 2.6 0.2 0.5 42 0.7

Left middle temporal thickness 2.7 0.2 2.8 0.2 -0.5 42 0.6

Left paracentral thickness 2.4 0.2 2.4 0.2 -0.5 42 0.6

Left parahippocampal thickness 2.5 0.3 2.4 0.3 1.0 42 0.3

Left pars opercularis thickness 2.6 0.2 2.6 0.1 0.3 42 0.7

Left pars orbitalis thickness 2.7 0.3 2.7 0.3 -0.2 42 0.9

Left pars triangularis thickness 2.5 0.2 2.5 0.2 0.2 42 0.9

Left pericalcarine thickness 1.5 0.1 1.6 0.1 -1.3 42 0.2Left post-central thickness 2.1 0.1 2.0 0.1 0.5 42 0.6

Left posterior cingulate thickness 2.7 0.2 2.7 0.1 0.7 42 0.5

Left pre-central thickness 2.5 0.2 2.5 0.1 0.5 42 0.6Left precuneus thickness 2.4 0.1 2.4 0.1 -0.3 42 0.8Left rostral anterior cingulate thickness 2.8 0.3 2.8 0.3 0.6 42 0.6

Left rostral middle frontal thickness 2.4 0.1 2.4 0.1 -0.6 42 0.5

Left superior frontal thickness 2.8 0.2 2.9 0.2 -0.9 42 0.4

Left superior parietal thickness 2.2 0.1 2.2 0.1 -1.6 42 0.1

Left superior temporal thickness 2.6 0.1 2.6 0.2 -0.6 42 0.5

Left supramarginal thickness 2.5 0.2 2.5 0.2 -1.4 42 0.2

Left temporal pole thickness 3.5 0.4 3.4 0.5 1.1 42 0.3

Left transverse temporal thickness 2.2 0.3 2.1 0.2 0.5 42 0.6

Right bankssts thickness 2.4 0.2 2.5 0.2 -0.9 42 0.4Right caudal anterior cingulate thickness 2.6 0.3 2.5 0.3 1.5 42 0.1

Right caudal middle frontal thickness 2.6 0.1 2.6 0.2 0.3 42 0.8

Right cuneus thickness 1.8 0.1 1.9 0.1 -1.7 42 0.1Right entorhinal thickness 3.1 0.4 3.0 0.4 0.9 42 0.4Right frontal pole thickness 2.8 0.4 2.9 0.4 -0.8 42 0.4Right fusiform thickness 2.5 0.1 2.4 0.2 0.7 42 0.5

Right inferior parietal thickness 2.4 0.1 2.5 0.1 -1.7 42 0.1

Right inferior temporal thickness 2.6 0.2 2.6 0.2 -0.2 42 0.8

Right insula thickness 2.9 0.1 2.9 0.1 0.3 42 0.8

Right isthmus cingulate thickness 2.6 0.2 2.5 0.2 0.6 42 0.6

Right lateral occipital thickness 2.1 0.1 2.2 0.2 -2.2 42 0.0

Right lateral orbitofrontal thickness 2.6 0.1 2.6 0.2 0.7 42 0.5

Right lingual thickness 1.9 0.1 2.0 0.1 -2.1 42 0.0

Right medial orbitofrontal thickness 2.6 0.2 2.6 0.2 0.1 42 0.9

Right middle temporal thickness 2.8 0.2 2.8 0.2 0.6 42 0.6

Right para-central thickness 2.4 0.2 2.4 0.2 -1.1 42 0.3Right para hippocampal cortical thickness 2.5 0.2 2.3 0.2 2.2 42 0.0

Right pars opercularis thickness 2.7 0.2 2.7 0.2 0.4 42 0.7

Right pars orbitalis thickness 2.7 0.2 2.7 0.2 0.1 42 0.9

Right pars triangularis thickness 2.6 0.2 2.6 0.2 -0.2 42 0.9

Right pericalcarine thickness 1.5 0.1 1.6 0.1 -3.4 42 0.0

Right post-central thickness 2.0 0.1 2.0 0.1 0.0 42 1.0

Right posterior cingulate thickness 2.7 0.2 2.6 0.2 0.2 42 0.9

Right pre-central thickness 2.5 0.2 2.5 0.2 0.5 42 0.6Right pre-cuneus thickness 2.4 0.2 2.4 0.1 -0.2 42 0.8

Right rostralanteriorcingulate thickness 2.8 0.2 2.8 0.2 0.9 42 0.4

Right rostral middle frontal thickness 2.4 0.1 2.4 0.2 -0.5 42 0.7

Right superior frontal thickness 2.8 0.1 2.9 0.2 -1.5 42 0.1

Right superior parietal thickness 2.2 0.1 2.3 0.1 -2.2 42 0.0

Right superior temporal thickness 2.6 0.1 2.7 0.2 -1.0 42 0.3

Right supramarginal thickness 2.5 0.1 2.5 0.2 -0.2 42 0.9

Right temporal pole thickness 3.5 0.4 3.4 0.5 1.4 42 0.2

Right transverse temporal thickness 2.1 0.2 2.2 0.2 -0.5 42 0.6

• 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

Patients Controlst df p

Mean SD 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 42 .039

L caudate in mm3 4165 634 3572 586 3.227 42 .002

R caudate in mm3 4155 603 3638 568 2.925 42 .006

R parahippocampal cortical thickness in mm

2.470 0.245 2.310 0.242 2.167 42 .036

Baseline MRI differences patients vs. controls

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:

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

• 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!

Moving towards personalised medicine …