Presentation on theme: "Brain-morphological changes associated with acute antipsychotic treatment in first-episode schizophrenia Laila Asmal1, Bonginkosi Chiliza1, Stéfan du Plessis1,"— Presentation transcript:
1 Brain-morphological changes associated with acute antipsychotic treatment in first-episode schizophreniaLaila Asmal1, Bonginkosi Chiliza1, Stéfan du Plessis1, Jonathan Carr2, Anneke Goosen1, Martin Kidd3, Matthijs Vink4, Rene Kahn4, Robin Emsley1From 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.1Present at the first episode and even in the prodromeconsistent with a neuro-developmental originBUT …Longitudinal studies indicate that progressive changes also occur.2Mostly in the early years of illness, and only in a subset.3Haijma SV, et al. Schizophr Bull. (in press); 2. Olabi B, et al. (2011). Biol.Psychiatry 70, 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 progression4Related to antipsychotic medication5,6,7Non-specific, due tosubstance abusepoor adherenceeffects of co-morbid conditions84. Lieberman J, et al. (2001). Biol.Psychiatry 49, ; 5. Smieskova R, et al. (2009). Curr.Pharm.Des 15, ; 6. Ho BC, et al. (2011). Arch.Gen.Psychiatry 68, ; 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.9Baseline brain abnormalities in turn predict treatment response.10But 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,
5 Our studyAim: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 MaterialsSingle-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-weeklyNo 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 disorderNo previous exposure to antipsychotic medicationRight 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
9 Structural brain imaging High-resolution T1-weighted data on a 3T Siemens Allegra MRI scannerScans 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 structurescompute thickness of the cortical sheetstudy differences of populations (diseased, control)
12 Global and regional measures PatientsControlstdfpMeanSD3rd Ventricle1058.8266.4924.5208.01.9420.14th Ventricle2027.3841.01788.3770.51.00.35th Ventricle17.518.715.720.00.8Brain Stem2931.22622.214.171.124CC Anterior867.0100.9804.5144.81.6CC Central447.0111.9432.0126.96.36.199CC Mid Anterior472.8105.6496.3128.5-0.70.5CC Mid Posterior407.794.1414.789.5-0.3CC Posterior886.6155.9782.9188.8.131.52Cortex Volume1.2Cortical White Matter VolumeCSF1343.4279.41195.7211.72.0Left Accumbens area629.1145.6586.2128.9Left Amygdala1500.1196.21429.3228.11.1Left Caudate4165.1633.53572.1585.53.2Left Cerebellum Cortex9966.40.9Left Cerebellum White Matter1836.82706.7-0.50.6Left choroid plexus1711.4240.51612.1437.3Left Cortex VolumeLeft Cortical White Matter VolumeLeft Hippocampus3911.9452.93932.7496.4-0.1Left Inferior Lateral Ventricle419.9269.9276.2146.0Left Lateral Ventricle6584.43582.05513.12673.0Left Pallidum1905.3334.31737.1297.11.8Left Putamen6387.81038.46048.91010.0Left Thalamus7928.1973.27378.4734.62.1Left Ventral DC4309.5551.41.5Left vessel102.457.988.251.5non WM hypointensities31.933.829.719.7Optic Chiasm108.9160.688.31.7Right Accumbens area601.3141.7573.0127.2Right Amygdala1585.0241.31548.5310.0Right Caudate4154.8603.33638.3567.82.9Right Cerebellum Cortex9518.9Right Cerebellum White Matter2245.22258.5-0.6Right choroid plexus1792.81583.1498.9Right Cortex VolumeRight Cortical White Matter VolumeRight Hippocampus4058.5392.84018.1444.9Right Inferior Lateral Ventricle284.2130.5213.6132.1Right Lateral Ventricle6430.43189.05219.52502.51.4Right Pallidum1732.7294.21589.9278.5Right Putamen6330.11054.15768.2906.0Right Thalamus8041.11116.87532.4952.7Right Ventral DC4392.8480.74210.3650.5Right vessel76.146.470.047.6Sub Cortical Gray VolumeSupra Tentorial VolumeTotal Gray VolumeWM hypointensities1631.91005.51766.51184.3-0.4Left bankssts thickness2.32.4-1.7Left caudal anterior cingulate thickness2.62.7Left caudal middle frontal thickness-1.4Left cuneus thicknessLeft entorhinal thickness3.1Left frontalpole thickness2.8Left fusiform thickness2.5Left inferior parietal thickness-2.0Left inferior temporal thicknessLeft insula thicknessLeft isthmus cingulate thicknessLeft lateral occipital thickness-2.9Left lateral orbitofrontal thicknessLeft lingual thickness-2.1Left medial orbitofrontal thicknessLeft middle temporal thicknessLeft paracentral thicknessLeft parahippocampal thicknessLeft pars opercularis thicknessLeft pars orbitalis thickness-0.2Left pars triangularis thicknessLeft pericalcarine thickness-1.3Left post-central thicknessLeft posterior cingulate thicknessLeft pre-central thicknessLeft precuneus thicknessLeft rostral anterior cingulate thicknessLeft rostral middle frontal thicknessLeft superior frontal thickness-0.9Left superior parietal thickness-1.6Left superior temporal thicknessLeft supramarginal thicknessLeft temporal pole thickness3.53.4Left transverse temporal thicknessRight bankssts thicknessRight caudal anterior cingulate thicknessRight caudal middle frontal thicknessRight cuneus thicknessRight entorhinal thickness3.0Right frontal pole thickness-0.8Right fusiform thicknessRight inferior parietal thicknessRight inferior temporal thicknessRight insula thicknessRight isthmus cingulate thicknessRight lateral occipital thickness-2.2Right lateral orbitofrontal thicknessRight lingual thicknessRight medial orbitofrontal thicknessRight middle temporal thicknessRight para-central thickness-1.1Right para hippocampal cortical thicknessRight pars opercularis thicknessRight pars orbitalis thicknessRight pars triangularis thicknessRight pericalcarine thickness-3.4Right post-central thicknessRight posterior cingulate thicknessRight pre-central thicknessRight pre-cuneus thicknessRight rostralanteriorcingulate thicknessRight rostral middle frontal thicknessRight superior frontal thickness-1.5Right superior parietal thicknessRight superior temporal thickness-1.0Right supramarginal thicknessRight temporal pole thicknessRight transverse temporal thicknessGlobal and regional measures117 ROIsAsegmentation volumesventriclesglobal grey and white matter volumesstructures eg. basal ganglia, thalamusL hemisphere cortical thicknessR hemisphere cortical thickness
13 Baseline MRI differences patients vs. controls dfpMeanSDL inferior lateral ventricle in mm34202702761462.22342.032L thalamus in mm3792897373787352.126.039L caudate in mm3416563435725863.227.002R caudate in mm3415560336385682.925.006R parahippocampal cortical thickness in mm2.4700.2452.3100.2422.167.036
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 volumeGeneral 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 reductionsNotably, 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 volumeNo 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 treatmentSome brain changes occurred in association with treatment response and others with emergent adverse-effects.No differential effects between RLAI and FDGenerally, changes occurred bilaterally, with volume reductions for cortical and subcortical structures, and volume increases for ventricular measuresi.e. shrinkage!