NeuRA Basal ganglia March 2017

Transcription

1 Introduction The basal ganglia are a group of sub-cortical nuclei thought to be involved in motor control and learning. The nuclei comprising the basal ganglia include the caudate, putamen, globus pallidus, the subthalamic nucleus and the substantia nigra. The caudate and putamen together form the striatum, while the globus pallidus (including the ventral pallidum) and the putamen together form the lenticular nucleus. The striatum is the principal input centre, receiving afferents primarily from the cortex, but also the substantia nigra, thalamus, and external globus pallidus. There are two primary pathways from the striatum through the basal ganglia ( direct and indirect pathways) which incorporate different components of the basal ganglia circuitry, and play different roles in controlling and planning movements and cognition. Schizophrenia has been associated with altered structure and function of the basal ganglia. Understanding of brain alterations in people with schizophrenia may provide insight into changes in brain development associated with illness onset or progression. Reviews contained in this technical summary reflect structural imaging investigations (MRI), functional imaging investigations (fmri, PET, SPECT) as well as metabolic imaging (MRS) of basal ganglia function in schizophrenia. Method We have included only systematic reviews (systematic literature search, detailed methodology with inclusion/exclusion criteria) published in full text, in English, from the year 2000 that report results separately for people with a diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder or first episode schizophrenia. Reviews were identified by searching the databases MEDLINE, EMBASE, CINAHL, Current Contents, PsycINFO and the Cochrane library. Hand searching reference lists of identified reviews was also conducted. When multiple copies of reviews were found, only the most recent version was included. Reviews with pooled data are prioritised for inclusion. Review reporting assessment was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, which describes a preferred way to present a meta-analysis 1. Reviews rated as having less than 50% of items checked have been excluded from the library. The PRISMA flow diagram is a suggested way of providing information about studies included and excluded with reasons for exclusion. Where no flow diagram has been presented by individual reviews, but identified studies have been described in the text, reviews have been checked for this item. Note that early reviews may have been guided by less stringent reporting checklists than the PRISMA, and that some reviews may have been limited by journal guidelines. Evidence was graded using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group approach where high quality evidence such as that gained from randomised controlled trials (RCTs) may be downgraded to moderate or low if review and study quality is limited, if there is inconsistency in results, indirect comparisons, imprecise or sparse data and high probability of reporting bias. It may also be downgraded if risks associated with the intervention or other matter under review are high. Conversely, low quality evidence such as that gained from observational studies may be upgraded if effect sizes are large, there is a dose dependent response or if results are reasonably consistent, precise and direct with low associated risks (see end of table for an explanation of these terms) 2. The resulting table represents an objective summary of the available evidence, although the conclusions Page 1

2 are solely the opinion of staff of NeuRA (Neuroscience Research Australia). Results Moderate to low quality evidence suggests no differences in D2/D3 receptor availability in the substantia nigra of unmedicated people with schizophrenia compared to controls. We found seventeen systematic reviews that met our inclusion criteria Structural changes: MRI and DTI High quality evidence suggests increased grey matter in the caudate, bilateral putamen, and globus pallidus in people with schizophrenia compared to healthy controls. Moderate to low quality evidence suggests increased volume in these regions in children with schizophrenia. Moderate quality evidence suggests bilateral caudate nucleus grey matter is significantly reduced in first episode psychosis patients (particularly medication naïve patients) compared to chronic schizophrenia, people at high risk, and healthy controls. High quality evidence suggests a small effect of greater reductions over time in the left caudate in people with schizophrenia compared to healthy controls. Functional changes: fmri, PET, MRS and SPECT Moderate quality evidence suggests people with schizophrenia show reduced activity in the bilateral claustrum and the right putamen during executive function tasks. Moderate to low quality evidence suggests no functional abnormality in the basal ganglia during cognitive control, memory (long-term and working memory) and language processing. Moderate to low quality evidence suggests dopamine receptor occupancy in the striatum of people with schizophrenia varies according to treatment with first or second generation antipsychotics. Page 2

3 Chan RCK, Di X, McAlonan GM, Gong Q Brain Anatomical Abnormalities in High-Risk Individuals, First-Episode, andchronic Schizophrenia: An Activation Likelihood Estimation Metaanalysis of IllnessProgression Schizophrenia Bulletin 2011; 37(1) Grey matter volume in people with first episode schizophrenia vs. healthy controls. Moderate quality evidence (large sample size, direct, unable to assess consistency or precision) suggests people with first episode schizophrenia have grey matter reductions in the right caudate nucleus compared to healthy controls, and compared to high risk individuals. volume Meta-analysis was performed using Anatomical Likelihood Estimate (ALE) analysis on Voxel-Based Morphometry MRI studies. FWHM 10mm, FDR corrected at p < studies, N = 1082 Right caudate: Talairach coordinates (10, 10, 12), cluster 224mm 3, ALE Between group comparisons: subtraction analysis between high risk individuals and first episode schizophrenia Greater grey matter reduction in first episode group; Right caudate: Talairach coordinates (10, 8, 14), cluster 224mm 3, ALE Left caudate: Talairach coordinates (-12, 6, 12), cluster 192mm 3, ALE No measure of consistency is reported. Ellison-Wright I, Glahn DC, Laird AR, Thelen SM, Bullmore E Page 3

4 The anatomy of first-episode and chronic schizophrenia: an anatomical likelihood estimation meta-analysis American Journal of Psychiatry, (8): Grey matter volume in first episode schizophrenia vs. chronic schizophrenia vs. healthy controls. Moderate quality evidence (large sample size, direct, unable to assess consistency or precision) suggests reductions in bilateral caudate head grey matter, which are absent in chronic schizophrenia. Increased grey matter was reported in the putamen. volume N = 1556, 27 studies First episode reductions Left caudate head: Talairach coordinates (-12, 6, 12), cluster 528mm 3, ALE 0.01, p = Right caudate head: Talairach coordinates (10, 10, 12), cluster 1392mm 3, ALE 0.012, p < First episode increases Left putamen: Talairach coordinates (-22, 0, 12), cluster 1592mm 3, ALE 0.008, p < No measure of consistency is reported. Ellison-Wright I, Bullmore E Anatomy of bipolar disorder and schizophrenia: A meta-analysis. Schizophrenia Research 2010; 117: 1-12 Grey matter volume in people with schizophrenia vs. healthy Page 4

5 controls. Moderate quality evidence (large sample sizes, direct, unable to assess consistency or precision) suggests grey matter increases were reported in the right globus pallidus and left caudate head in people with schizophrenia. volume Meta-analysis was performed using Activation Likelihood Estimate (ALE) analysis on Voxel-Based Morphometry MRI studies. FWHM 7mm, FDR corrected at p < studies, N = 4189 Regions of increased grey matter; Right globus pallidus: Talairach coordinates (16, 0, 4), Sum of ranks = 71.6, p = Left caudate head: Talairach coordinates (-6, 8, 4), Sum of ranks = 67.8, p = No measure of consistency is reported. Fusar-Poli P, Perez J, Broome M, Borgwardt S, Placentino A, Caverzasi E, Cortesi M, Veggiotti P, Politi P, Barale F, McGuire P Neurofunctional correlates of vulnerability to psychosis: A systematic review and meta-analysis Neuroscience & Biobehavioral Reviews 2007; 31(4): Functional activation in individuals at high risk of developing schizophrenia vs. healthy controls. Low quality evidence (one small observational study per outcome) is unclear as to the direction of the changes in functional activity in the striatum during cognitive tasks in individuals at high risk of developing schizophrenia. Page 5

6 functional activation 1 observational study, N = 32 Large effect size suggests reduced activation of striatum (d = 1.34) in non-psychotic relatives of schizophrenia patients compared to controls for working memory guided saccades. No measure of consistency is reported. Glahn DC, Laird AR, Ellison-Wright I, Thelen SM, Robinson JL, Lancaster JL, Bullmore E, Fox PT Meta-analysis of gray matter anomalies in schizophrenia: application of anatomic likelihood estimation and network analysis Biological Psychiatry 2008; 64(9): Grey matter density in people with schizophrenia vs. healthy controls. Moderate quality evidence (large sample sizes, direct, unable to assess consistency or precision) suggests schizophrenia is associated with significant increases in grey matter density in the putamen and caudate head in people with schizophrenia. volume Meta-analysis was performed using ALE analysis on Voxel-Based Morphometry MRI studies. FWHM 12mm, FDR corrected at p < studies, N = 2457 Regions were much smaller and more discrete; Left putamen: Talairach coordinates (-38, 0, 16), Voxel cluster size 1248mm 3, p < 0.01 Right putamen: Talairach coordinates (28, 6, 2), Voxel cluster size 464mm 3, p < 0.01 Right head of caudate: Talairach coordinates (8, 0, 4), Voxel cluster size 424mm 3, p < 0.01 Page 6

7 No measure of consistency is reported. Kambeitz J, Abi-Dargham A, Kapur S, Howes OD Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: Systematic review and meta-analysis of imaging studies British Journal of Psychiatry 2014; 204(6): Cortical and extrastriatal D2/D3 receptor availability (measured by PET or SPECT) in unmedicated people with schizophrenia vs. controls. Moderate to low quality evidence (medium-sized samples, inconsistent, imprecise, direct) suggests no differences in D2/D3 receptor availability in the substantia nigra. D2/D3 receptor availability Binding potential relative to the non-displaceable compartment Substantia nigra No significant differences between groups in D 2/D 3 receptor availability; 5 studies, N = 143, d = 0.04, 95%CI to 0.99, p = 0.90, I 2 = 85% Excluding one study of drug-naïve patients did not substantially change the effect (d = -0.04). Meta-regression showed no effect of publication year, gender, or age in any analysis. There was no evidence of publication bias. Some inconsistency. Some imprecision. Page 7

8 Lahuis B, Kemner C, Van Engeland H Magnetic resonance imaging studies on autism and childhood-onset schizophrenia in children and adolescents a review Acta Neuropsychiatrica 2003; 15(3): Brain volume in childhood-onset schizophrenia (COS) vs. healthy controls. Moderate to low quality evidence suggests child-onset schizophrenia patients exhibit increased volume in the basal ganglia. volume 12 studies, N unclear Increased volume was observed in the caudate, putamen, and globus pallidus. No measure of consistency is reported. Leung M, Cheung C, Yu K, Yip B, Sham P, Li Q, Chua S, McAlonan G Gray Matter in First-Episode Schizophrenia Before and After Antipsychotic Drug Treatment. Anatomical Likelihood Estimation Metaanalyses With Sample Size Weighting Schizophrenia Bulletin 2011; 37(1): Grey matter changes in people with first-episode schizophrenia (treated and medication naïve) vs. healthy controls. Moderate quality evidence (large sample sizes, indirect, unable to Page 8

9 assess consistency or precision) suggests greater reduction in the bilateral caudate in treatment naïve first episode schizophrenia patients compared to healthy controls and treated patients. volume Meta-analysis was performed using Anatomical Likelihood Estimate (ALE) analysis on Voxel-Based Morphometry MRI studies. FWHM 8mm, FDR corrected at p < studies, N = 327 Treatment naïve first-episode psychosis Right caudate: Talairach coordinates (10, 10, 12), cluster 1936mm 3, ALE Left caudate: Talairach coordinates (0, 12, 4), cluster 1936mm 3, ALE Regions where grey matter reductions were larger in magnitude in treatment naïve patients than in treated patients; Right caudate: Talairach coordinates (10, 10, 12), cluster 1992mm 3, ALE Left caudate: Talairach coordinates (0, 12, 4), cluster 360mm 3, ALE Left caudate: Talairach coordinates (-12, 6, 0), cluster 264mm 3, ALE No measure of consistency is reported. for within group comparison, indirect for between group comparison MacDonald AW, Thermenos HW, Barch DM, Seidman LJ Imaging genetic liability to schizophrenia: systematic review of FMRI studies of patients' nonpsychotic relatives Schizophrenia Bulletin 2009; 35(6): Functional activation in first-degree relatives of people with schizophrenia vs. healthy controls. Page 9

10 Moderate to low quality evidence (large sample size, direct, unable to assess precision or consistency) suggests no differences in functional activity during cognitive control tasks, memory tasks (long term and working) and language processing. Cognitive control tasks 7 studies investigated functional activity during cognitive control tasks, N = studies investigated the basal ganglia, 2/6 showed reduced activity compared to controls Working memory tasks 4 studies (5 independent samples) investigated functional activity during working memory tasks, N = studies investigated the basal ganglia, 1/2 showed increased activity compared to controls Long term memory tasks 3 studies investigated functional activity during episodic long term memory tasks, N = studies investigated the basal ganglia, 3/3 showed no group differences 1 study investigated functional activity during procedural long term memory tasks, N = 27 Reduced activity in relatives was shown in basal ganglia Language processing studies 4 studies investigated functional activity during language processing tasks, N = 164 4/4 showed no task-related response in the basal ganglia No measure of consistency is reported. Minzenberg MJ, Laird AR, Thelen S, Carter CS, Glahn DC Page 10

11 Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia Archives of General Psychiatry 2009; 66(8): Functional activation in individuals with schizophrenia vs. healthy controls: ALE analysis Note The claustrum is considered by some sources to be a part of the basal ganglia. Moderate quality evidence (large sample size, direct, unable to assess precision or consistency) suggests patients with schizophrenia show reduced activity in the bilateral claustrum and the right putamen during executive function tasks Activation following executive function tasks: where controls have > activity than patients with schizophrenia Meta-analysis results reported for 41 studies of either fmri or PET during executive function tasks. 41 studies, N = 1217 ALE analysis FWHM 12mm, False Discovery Rate (FDR) corrected model Significantly reduced activity in schizophrenia patients compared to controls Right claustrum: Talairach centre of mass (26, 22, 2), cluster volume 1766mm 3 Left claustrum: Talairach centre of mass (-28, 24, 0), cluster volume 880mm 3 Right putamen: Talairach centre of mass (20, -4, 14), cluster volume 448mm 3 No measure of consistency is reported. Navari S, Dazzan P Do antipsychotic drugs affect brain structure? A systematic and critical review of MRI findings. Page 11

12 Psychological Medicine 2009; 39(11): Brain volume in medicated, drug free and drug naïve schizophrenia patients and healthy controls: cross-sectional studies. Low quality evidence (sample sizes unclear, indirect, unable to assess consistency or precision) is unclear of the effect of antipsychotic medications on brain structure. Volumetry in drug free and drug naïve schizophrenia 1 study, N unclear Drug free patients showed increased putamen volume and reduced caudate nucleus volume compared to drug naïve patients and to controls. Volumetry in schizophrenia medicated in the short term ( 12 weeks) 1 study, N unclear Patients medicated with typical antipsychotics showed reduced basal ganglia volume compared to drug free patients. Volumetry in schizophrenia medicated in the long term (>12 weeks) 2 studies, N unclear One study reported no difference in basal ganglia and thalamic volume, another reported reduced basal ganglia and thalamic volume in patients treated with typical antipsychotics 2 No measure of consistency reported, results appear inconsistent for long term medication. Indirect comparisons of medicated and unmedicated schizophrenia patients. Brain volume in medicated, drug free and drug naïve schizophrenia patients and healthy controls: longitudinal studies. Low quality evidence is unclear as the effect of antipsychotics on brain structure over time. Page 12

13 Volumetry in drug free and drug naïve schizophrenia N unclear, varying follow up (range 4 weeks to 2 years) One study showed drug naïve patients on a course of atypical antipsychotics with increased caudate volume identical to controls, another study also showed increased caudate and accumbens volume with atypical antipsychotics. One study showed increased striatal volume in drug naïve patients following antipsychotic treatment (type unspecified). Volumetry in schizophrenia medicated in the short term ( 12 weeks) 3 studies, N unclear, varying follow up Three studies reported increased basal ganglia volume following typical medication, a further two studies reported reduced basal ganglia volume over the treatment period with mostly atypical medication. Volumetry in schizophrenia medicated in the long term (>12 weeks) 3 studies, N unclear, varying follow up Three studies considered the effect of switching from long term typical medication to atypical medication and reported reduced basal ganglia volume, particularly the caudate. Authors propose this effect could represent normalization of volumes previously increased by typical medication. No measure of consistency is provided, results appear inconsistent. Indirect comparisons of medicated and unmedicated schizophrenia patients. Olabi B, Ellison-Wright I, McIntosh AM, Wood SJ, Bullmore E, Lawrie SM Are There Progressive Brain Changes in Schizophrenia? A Meta-Analysis of Structural Magnetic Resonance Imaging Studies Biological Psychiatry 2011; 70(1): Progressive changes in grey matter volume in people with schizophrenia vs. healthy controls. Page 13

14 High quality evidence (large sample sizes, consistent, precise, direct) suggests significantly greater reductions over time in the left caudate in people with schizophrenia. Grey matter volume Progressive changes in grey matter volume reported across longitudinal MRI scans over 1-10 years. 31 studies, N = 1867 Significant, small effect of greater reductions over time in schizophrenia compared to controls; Left Caudate: N = 253, 3 studies, d = , 95%CI to -0.07, p = 0.013, I 2 = 0% No differences between groups; Right Caudate: N = 253, 3 studies, d = , 95%CI to 0.23, p = 0.470, I 2 = 41.6% Consistent Precise Smieskova R, Fusar-Poli P, Allen P, Bendfeldt K, Stieglitz RD, Drewe J, Radue E W, McGuire PK, Riecher-Rossler A, Borgwardt SJ The Effects of Antipsychotics on the Brain: What Have We Learnt from Structural Imaging of Schizophrenia? - A Systematic Review Current Pharmaceutical Design 2009; 15(22): Grey matter volume changes in cross-sectional and longitudinal assessments in treated and untreated people with schizophrenia compared to healthy controls. Moderate to low quality evidence (unclear sample size, direct, unable to assess consistency or precision) is largely unclear as to the role of medication in mediating structural alterations in people with schizophrenia. Atypical antipsychotic medications appear broadly to be associated with less structural alterations than typical medications. Page 14

15 Changes reported in cross-sectional MRI studies One study reported treatment with typical antipsychotics was associated with increased basal ganglia volume in first episode psychosis patients. Changes reported in longitudinal whole-brain studies 13 studies used VBM methodology to assess structural changes following administration of antipsychotics. increases were reported only for treatment with typical antipsychotics, not for atypical. Patients treated with haloperidol (typical) showed significant increases in caudate nucleus compared to patients treated with olanzapine (atypical). In chronic patients treated with atypical antipsychotics, increased basal ganglia density was reported. In early onset patients, atypical treatment was associated with increased caudate volume compared to healthy controls. Compared to antipsychotic naïve patients, treated patients (mixed typical and atypical) had increased caudate. Changes reported in longitudinal region-of-interest studies 7 studies used region of interest analysis to assess structural changes of the basal ganglia following administration of antipsychotics. They reported no significant differences in volume in patients treated with atypical medication, though small increases were reported with typical. No measure of consistency is reported, results appear inconsistent. Steen RG, Hamer RM, Lieberman JA Measurement of brain metabolites by 1 H magnetic resonance spectroscopy in patients with schizophrenia: a systematic review and meta-analysis Page 15

16 Neuropsychopharmacology 2005; 30(11): Metabolic N-acetylaspartate amino acid (NAA) activity (measured by 1 H-MRS) in grey matter regions in people with schizophrenia vs. healthy controls. Low quality evidence (sample size unclear, direct inconsistent, unable to assess precision) is unclear of NAA levels in the striatum of people with schizophrenia compared to controls. NAA levels in grey matter regions 6 studies consider NAA, N unclear Patient average 98.5% of control levels Lenticular nucleus (putamen + globus pallidus) 2 studies consider NAA, N unclear Patient average 104.5% of control levels Caudate nucleus 3 studies consider NAA, N unclear Patient average 100.3% of control levels Putamen 7 studies consider NAA, N unclear Patient average 100.6% of control levels Striatum (caudate+putamen) 1 study considers NAA, N unclear Patient average 112.6% of control levels Inconsistent - significant heterogeneity reported, p < Stone JM, Davis JM, Leucht S, Pilowsky LS Cortical dopamine D2/D3 receptors are a common site of action for antipsychotic drugs--an original patient data meta-analysis of the SPECT Page 16

17 and PET in vivo receptor imaging literature Schizophrenia Bulletin 2009; 35(4): Dopamine D2/D3 receptor occupancy in the striatum and temporal cortex of schizophrenia patients compared to healthy controls following first and second generation antipsychotic administration. Indirectly compared to efficacy measurements of antipsychotics in separate patient groups. Moderate to low quality evidence (direct, small to moderate sample size, unable to assess precision and consistency) suggests dopamine receptor occupancy may be different depending on first or second generation antipsychotic treatment. Low quality evidence (indirect, unable to assess sample size, precision and consistency) is unclear about the relationship between receptor occupancy and drug effectiveness, side effects or measurement type. Single ligands had significantly higher occupancy than dual ligands. Significant difference in occupancy rates between first and second generation antipsychotics was reported, when controlling for ligand type and modelling method. D2/D3 receptor occupancy Fifteen studies were pooled to estimate the dopamine receptor occupancy. Striatal occupancy following first generation antipsychotic administration: N = 28, 74% ± 12% Striatal occupancy following second generation antipsychotic administration: N = 115, 49% ± 21% t = 8.8, p < 4x10-13 Ratio of striatal/temporal occupancy for first generation antipsychotics: 96 ± 24% Ratio of striatal/temporal occupancy for second generation antipsychotics: 74 ± 35% t = 3.7, p < Subgroup analysis 1: correlation to clinical efficacy Indirect comparison using dose-response curve calculated from separate efficacy studies into first and second generation antipsychotics. Occupancy correlated with drug effectiveness for striatal D2/D3: r = 0.76, p = Subgroup analysis 2: correlation to extrapyramidal side effects Page 17

18 Indirect comparison using dose-response curve calculated from separate efficacy studies into first and second generation antipsychotics. Dose was correlated linearly with occupancy in the striatum, r = 0.59, p = EPSE are known to increase with dose and so are likely to be associated more with striatal dopamine. Subgroup analysis 3: controlling for assessment method; Simplified Reference Tissue Modelling vs. Ratio modelling No significant difference was found in the occupancy estimates of both methods in the striatum. The association of measurement method and drug type (typical vs. atypical) was zero for both regions. Subgroup analysis 4: single vs. dual ligands In the striatum, single ligand binding had an 18% lower (95%CI 10 to 25%) occupancy estimate than dual ligands. F = 22, p = Subgroup analysis 5: ANCOVA with ligand type and modelling method covariates In the striatum, occupancy was estimated at 74%, 95%CI 66 to 82% for first generation antipsychotics. For second generation antipsychotics, occupancy was estimated at 47%, 95%CI 44 to 54% This is a significant difference of 27%, 95%CI 18 to 36% between the two classes of antipsychotics F = 37, p = No measure of consistency is reported. CIs not reported for all outcomes, precise for subgroup analyses 4 and 5. Taylor H, Ricciardi A, Dazzan P A review of caudate nucleus volume in first episode psychosis Clinical Neuropsychiatry 2007; 4(5-6): Cross-sectional comparison of caudate nucleus volume in antipsychotic naive first episode psychosis patients vs. healthy controls. Page 18

19 Moderate to low quality evidence (direct, unable to fully assess precision or consistency data appears inconsistent) suggests bilateral caudate nucleus is significantly reduced in drug naive first episode psychosis patients compared to healthy controls. Bilateral caudate nucleus volume 7 studies, N = of 7 studies reported consistently reduced volume in bilateral caudate nucleus in patients. 3 of 7 studies reported no significant difference in caudate nucleus volume, although 2 of the 3 had methodological limitations. 2 No measure of consistency is reported. Cross-sectional comparison of medicated first episode psychosis patients (maximum 12 week treatment with first or second generation antipsychotics) compared to healthy controls. Moderate quality evidence (large sample size, direct, unable to fully assess precision or consistency data appears consistent) suggests no significant difference in bilateral caudate volume in medicated first episode psychosis patients compared to healthy controls. Bilateral caudate nucleus volume 4 studies, N = of 4 studies reported no significant difference in bilateral caudate nucleus volume. 3 No measure of consistency is reported. Longitudinal comparison of medicated first episode psychosis patients compared to healthy controls, measured at several varying time points. Moderate quality evidence (large sample size, direct, unable to fully assess precision or consistency data appears consistent) Page 19

20 suggests no significant difference in bilateral caudate volume over time in medicated first episode psychosis patients compared to healthy controls. Bilateral caudate nucleus volume 6 studies, N = of 6 studies reported no significant difference in overall bilateral caudate nucleus volume. No measure of consistency is reported. Wright IC, Rabe-Hesketh S, Woodruff PW, David AS, Murray RM, Bullmore ET Meta-analysis of regional brain volumes in schizophrenia American Journal of Psychiatry 2000; 157(1): Brain volume in people with schizophrenia vs. healthy controls. High quality evidence (large sample size, consistent, precise, direct) suggests increased right caudate, right putamen, and globus pallidus volume in people with schizophrenia compared to healthy controls. volume Left caudate No effect average volume of schizophrenia caudate 101% of control volume, 95%CI 97% to 106%; 10 studies, N = 565, d = 0.06, no CIs reported, p = 0.01 Right caudate Small effect size, average volume of schizophrenia caudate 99% of control volume, 95%CI 95% to 103%; 10 studies, N = 565, d = -0.06, no CIs reported, p = 0.02 Left putamen Page 20

21 No effect, average volume of schizophrenia putamen 104% of control volume, 95%CI 99% to 110%; 7 studies, N = 255, d = 0.21, no CIs reported, p = 0.14 Right putamen Small effect size average volume of schizophrenia putamen 104% of control volume, 95%CI 97% to 110%; 7 studies, N = 255, d = 0.24, no CIs reported, p < 0.01 Left globus pallidus Large effect size average volume of schizophrenia globus pallidus 118% of control volume, 95%CI 110% to 126%; 2 studies, N = 84, d = 1.06, no CIs reported, p = 0.03 Right globus pallidus Large effect size average volume of schizophrenia globus pallidus 121% of control volume, 95%CI 109% to 135%; 2 studies, N = 84, d = 1.34, no CIs reported, p = 0.03 Consistent Precise (95%CIs do not exceed 10% in either direction) for all except Globus pallidus. Explanation of acronyms Page 21

22 ALE = Activation Likelihood Estimate for Gaussian smoothed foci, CI = Confidence Interval, COS = child-onset schizophrenia, d = Cohen s d and g = Hedges g = standardized mean differences (see below for interpretation of effect sizes), FDR = False Discovery Rate correction for multiple comparisons, FWHM = full width at half maximum, applied as a smoothing kernel, fmri = Functional Magnetic Resonance Imaging, 1 H-MRS = Proton Magnetic Resonance Spectroscopy, MRI = magnetic resonance imaging, MNI = Montreal Neurological Institute system for stereotactic space, N = number of participants, NAA = N-acetylaspartate amino acid, p = statistical probability of obtaining that result (p < 0.05 generally regarded as significant), PET = Positron Emission Tomography Page 22

23 Explanation of technical terms * Bias has the potential to affect reviews of both RCT and observational studies. Forms of bias include; reporting bias selective reporting of results, publication bias - trials that are not formally published tend to show less effect than published trials, further if there are statistically significant differences between groups in a trial, these trial results tend to get published before those of trials without significant differences; language bias only including English language reports; funding bias - source of funding for the primary research with selective reporting of results within primary studies; outcome variable selection bias; database bias - including reports from some databases and not others; citation bias - preferential citation of authors. Trials can also be subject to bias when evaluators are not blind to treatment condition and selection bias of participants if trial samples are small 20. Different effect measures are reported by different reviews. ALE analysis (Anatomical Likelihood Estimate) refers to a voxel-based metaanalytic technique for structural imaging in which each point of statistically significant structural difference is spatially smoothed into Gaussian distribution space, and summed to create a statistical map estimating the likelihood of difference in each voxel, as determined by the entire set of included studies. Incorporated with the Genome Scan Meta-analysis (GSMA), the meta-analysis of coordinates from multiple studies can be weighted for sample size to create a random effect analysis. The ALE statistic (if reported) represents the probability of a group difference occurring at each voxel included in the analysis. Fractional similarity network analysis refers to a network analysis technique in which secondary networks are identified within the larger framework of activity, creating a matrix for regional co-activity. Weighted mean difference scores refer to mean differences between treatment and comparison groups after treatment (or occasionally pre to post treatment) and in a randomised trial there is an assumption that both groups are comparable on this measure prior to treatment. Standardised mean differences are divided by the pooled standard deviation (or the standard deviation of one group when groups are homogenous) which allows results from different scales to be combined and compared. Each study s mean difference is then given a weighting depending on the size of the sample and the variability in the data. 0.2 represents a small effect, 0.5 a medium effect, and 0.8 and over represents a large effect 20. Odds ratio (OR) or relative risk (RR) refers to the probability of a reduction (< 1) or an increase (> 1) in a particular outcome in a treatment group, or a group exposed to a risk factor, relative to the comparison group. For example, a RR of 0.75 translates to a reduction in risk of an outcome of 25% relative to those not receiving the treatment or not exposed to the risk factor. Conversely, a RR of 1.25 translates to an increased risk of 25% relative to those not receiving treatment or not having been exposed to a risk factor. A RR or OR of 1.00 means there is no difference between groups. A medium effect is considered if RR > 2 or < 0.5 and a large effect if RR > 5 or < lnor stands for logarithmic OR where a lnor of 0 shows no difference between groups. Hazard ratios Page 23

24 measure the effect of an explanatory variable on the hazard or risk of an event. Correlation coefficients (eg, r) indicate the strength of association or relationship between variables. They are an indication of prediction, but do not confirm causality due to possible and often unforseen confounding variables. An r of 0.10 represents a weak association, 0.25 a medium association and 0.40 and over represents a strong association. Unstandardised (b) regression coefficients indicate the average change in the dependent variable associated with a 1 unit change in the independent variable, statistically controlling for the other independent variables. Standardised regression coefficients represent the change being in units of standard deviations to allow comparison across different scales.reliability and validity refers to how accurate the instrument is. Sensitivity is the proportion of actual positives which are correctly identified (100% sensitivity = correct identification of all actual positives) and specificity is the proportion of negatives which are correctly identified (100% specificity = not identifying anyone as positive if they are truly not). Inconsistency refers to differing estimates of treatment effect across studies (i.e. heterogeneity or variability in results) that is not explained by subgroup analyses and therefore reduces confidence in the effect estimate. I² is the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance) - 0% to 40%: heterogeneity might not be important, 30% to 60%: may represent moderate heterogeneity, 50% to 90%: may represent substantial heterogeneity and 75% to 100%: considerable heterogeneity. I² can be calculated from Q (chi-square) for the test of heterogeneity with the following formula; Imprecision refers to wide confidence intervals indicating a lack of confidence in the effect estimate. Based on GRADE recommendations, a result for continuous data (standardised mean differences, not weighted mean differences) is considered imprecise if the upper or lower confidence limit crosses an effect size of 0.5 in either direction, and for binary and correlation data, an effect size of GRADE also recommends downgrading the evidence when sample size is smaller than 300 (for binary data) and 400 (for continuous data), although for some topics, this criteria should be relaxed 22. Indirectness of comparison occurs when a comparison of intervention A versus B is not available but A was compared with C and B was compared with C, which allows indirectcomparisons of the magnitude of effect of A versus B. Indirectness of population, comparator and or outcome can also occur when the available evidence regarding a particular population, intervention, comparator, or outcome is not available so is inferred from available evidence. These inferred treatment effect sizes are of lower quality than those gained from head-to-head comparisons of A and B. Page 24

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