Table 1.

Studies of ENIGMA SZ, BD, MDD, and 22q11DS Disorder Working Groups

Working Group	Study (author, year)	Cohort	N	Age Range (Years)	Imaging Modality	Main Findings
SZ	van Erp et al. 201651	15	SZ:2028 HC:2540	SZ:23–42 HC:22–43	sMRI(FreeSurfer subcortical volume)	SZ had smaller hippocampus (Cohen’s d = −0.46), amygdala (d = −0.31), thalamus (d = −0.31), accumbens (d = −0.25) and intracranial volumes (d = −0.12), as well as larger pallidum (d = 0.21) and lateral ventricle volumes (d = 0.37).
	Kelly et al. 201773	29	SZ:1963 HC:2359	SZ:18–77 HC:18–86	DTI (FA, RD, MD and AD)	SZ had a widespread, significant reduction in FA. Effect size was the greatest for the entire WM skeleton (d = 0.42), anterior corona radiata (d = 0.40) and corpus callosum (d = 0.39). This study shows robust and widespread WM changes in schizophrenia.
	Walton et al. 201765	17	SZ:1987	SZ:28–43	sMRI(FreeSurfer superior temporal gyrus thickness)	Severity of positive symptoms was negatively associated with superior temporal gyrus thickness of both hemispheres(ßstd = −0.052; P = 0.021; right: ßstd= −0.073; P = 0.001), controlling for age, sex, and site.
	Walton et al 201866	17	SZ:1985	SZ:28–43	sMRI(FreeSurfer medial orbitofrontal cortex thickness)	Severity of negative symptoms was negatively associated with medial orbitofrontal cortex thickness(βstd = −0.075; p = 0.019), controlling for age, sex, and site
	van Erp et al. 201864	39	SZ:4474 HC:5098	SZ:11–78 HC:10–87	sMRI(FreeSurfer cortical thickness and surface area)	SZ had a widespread reduction in cortical thickness (left/right hemisphere:Cohen’s d = −0.530/−0.516) and surface area(left/right hemisphere:Cohen’s d = −0.251/−0.254) with the greatest effect sizes for both in frontal and temporal lobe regions.
	Holleran et al. 2020105	11	SZ:760 HC:957	NA	DTI(gFA, LA-gFA)	gFA explained a significant amount of cognitive variation and similar effect sizes were observed in both patients (effect size = 0.20) and healthy participant groups (effect size = 0.32). Comparable patterns of association were also observed between LA-gFA and cognition. However, this association was unrelated to diagnosis.
BD	Hibar et al. 201655	20	BD: 1710 HC: 2594	NA	sMRI(FreeSurfer subcortical volume and intracranial volume)	BD had a significant volume reduction for mean hippocampus (Cohen’s d = −0.232) and thalamus(d = −0.148) and enlarged lateral ventricles (d = −0.260). No significant differences in volume between bipolar subtypes with greater magnitude differences for BDI with controls. Lithium treatment related to larger thalamic volumes.
	Hibar et al 2018.67	28	BD:2447 ( adult BD: 1837) HC:4056 ( HC: 2582)	NA	sMRI (FreeSurfer cortical thickness and surface area))	BD had a thinner cortex in frontal, temporal, parietal regions in both hemispheres with greatest effect sizes for left pars opercularis(cohen d = −0.293), left fusiform gyrus(cohen d = −0.288) and left rostral middle frontal cortex (cohen d = −0.276). A longer duration of illness was associated with a decrease in cortical thickness in the frontal, medial parietal and occipital regions. Lithium intake was associated with increased cortical thickness and had the largest effects in the left paracentral gyrus and the left and right superior parietal gyrus.
	Favre et al. 201947	26	BD:1482 HC:1551	18–65 for both groups	DTI (FA)	BD had a significantly lower FA in 29 regions with greatest effect for the corpus callosum (R2 = 0.041, Pcorr < 0.001) and cingulum (right: R2 = 0.041, left: R2 = 0.040, Pcorr < 0.001). Lithium medication, later onset and shorter disease duration were related to higher FA.
	Nunes et al. 2020106	13	BD:853 HC:2167	NA	sMRI (regional cortical thickness, surface area, subcortical volumes)	Applying machine learning to structural MRI data for differentiating bipolar disorders, accuracies ranged from 45.23% to 81.07% according to sites. Aggregate subject-level analyses showed the highest accuracy(65.23%).There was a substantive agreement between the best performing sites and regions that helped identify BD participants in aggregated datasets (Cohen’s Kappa = 0.83)
	Haukvik et al. 202056	23	BD:1472 HC:3226	NA	sMRI(FreeSurfer hippocampal subfield segmentation algorithm)	BD had smaller hippocampus (Cohen’s d = −0.20), cornu ammonis (CA)1 (d = −0.18), CA2/3(d = −0.11), CA4 (d = −0.19), molecular layer (d = −0.21), granule cell layer of dentate gyrus (d = −0.21), hippocampal tail (d = −0.10), subiculum (d = −0.15), presubiculum(d = −0.18), and hippocampal amygdala transition area (d = −0.17). Lithium use was associated with larger volumes whereas antipsychotic or antiepileptic medication use was associated with smaller subfield volumes.
	McWhinney et al. 202157	17	BD:1134 HC: 1601	NA	sMRI(Free surfer subcortical volume, lateral ventricles volume)	BD had higher body mass index(BMI), larger lateral ventricular volume, and smaller volumes of amygdala, hippocampus, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. 18.4 % of the total association between BD and ventricular volume was related to the higher body mass index (BMI) in BD (Z = 2.73, p = 0.006). Other subcortical areas were robustly associated with BD even after controlling BMI, and there was no interaction between BD and BMI in relation to subcortical brain volume.
MDD	Schmaal et al. 201658	15	MDD:1728 HC:7199	NA	sMRI (FreeSurfer subcortical volume)	MDD had a reduced hippocampal volume(Cohen’s d = −0.14, % difference = −1.24). This effect is largely attributed to recurrent depression(Cohen’s d = −0.17, % difference = −1.44) not first onset MDD. Earlier onset age was associated with smaller hippocampal (Cohen’s d = −0.20, % difference = −1.85) and amygdala volume (Cohen’s d = −0.11, % difference = −1.23) and larger lateral ventricle volume (Cohen’s d = 0.12, % difference = 5.11).
	Schmaal et al. 201768	20	MDD:2148 HC:7957	NA	sMRI(FreeSurfer cortical thickness and surface area)	MDD had a reduced cortical volume in the orbitofrontal cortex, anterior and posterior cingulate, insula and temporal lobes (Cohen’s d effect sizes: −0.10 to −0.14). Patients with the first episode and adult onset showed more pronounced cortical thinning in these areas. There was no difference in cortical thickness between adolescent patients and controls. The total surface area of the left and right hemispheres was smaller in adolescent major depressive disorder.
	Frodl et al. 201746	9	MDD:958 HC:2078	NA	sMRI(FreeSurfer subcortical gray matter volume,lateral ventricles, and total intracranial volume)	Significant interactions between childhood adversity, MDD diagnosis, gender, and site were apparent. The caudate volume is lower in females, independent of MDD, which was associated with increased exposure to adversity in childhood(right caudate: F=10.7, p< 0.001, Bonferroni correction: pcorr<0.007; left caudate F=13.4, p<0.001, pcorr <0.005). All subcategories of childhood adversity were negatively associated with the caudate volume, in females, especially emotional and physical negligence (regardless of age, ICV, imaging site, MDD diagnosis).
	Renteria et al. 201759		MDD with suicide :451 MDD no suicide:650 HC:1996	NA	sMRI (FreeSurfer subcortical gray matter volume, lateral ventricles, and total intracranial volume)	MDD with suicidal symptoms had a reduced intracranial volume (P = 4.12 × 10−3) or a 2.87% volume reduction (Cohen’s d = −0.284) compared to controls.
	van Velzen et al 2018.74	20	MDD:1305 HC:1602	12–88 for both groups	DTI (FA, RD)	MDD had a widespread lower FA in 16 out of 25 WM tracts of interest (Cohen’s d: 0.12 to 0.26). The most contributing regions were corona radiata and corpus callosum regions. Depressive patients also had a widespread higher RD (Cohen’s d: 0.12 to 0.18). These effects are largely explained by recurrent depression and adult onset depression.
	Tozzi et al 202049	12	MDD:1284 HC:2588	13–89 for both groups	sMRI (FreeSurfer cortical thickness and surface area)	Childhood maltreatment was inversely related to cortical thickness in the banks of the superior temporal sulcus (Wald χ2 = 14.583, p FDR = 0.033, B = −0.001) and supramarginal gyrus (Wald χ2= 8.889, p FDR = 0.049, B = −0.001). A significant negative effect on the surface area of the middle temporal lobe was also reported (Wald χ2 = 12.368, p FDR = 0.015, B = −1.504). Individuals with a history of both childhood neglect and abuse were associated with reduced cortical thickness in the inferior parietal lobe (Wald χ2 = 15.273, p FDR = 0.023), middle temporal lobe (Wald χ2 = 15.273, p FDR = 0.023) and precuneus (Wald χ2 = 15.325, p FDR = 0.023).
	Han et al. 2020107	19	MDD:2675 HC:4314	18–75 for both groups	sMRI(FreeSurfer cortical thickness, surface area, lateral ventricles and total intracranial volume)	MDD had a higher brain-predicted age difference (brain PAD) of +1.08 (SE 0.22) years (Cohen’s d = 0.14, 95% CI 0.08–0.20).
	de Kovel et al. 2019 108	31(Cortical regions), 32(Subcortical regions)	Cortical regions-MDD:2256 HC:3504 Subcortical regions-MDD: 2540 HC:4230	NA	sMRI(FreeSurfer subcortical volumes, cortical thickness and surface area)	No significant effects of MDD diagnosis were found for any of the cortical thickness, cortical surface, or subcortical volume asymmetry index (AI) after correction for multiple testing. The strongest effect of diagnosis involved a Cohen’s d value of 0.085 for the superior temporal gyrus thickness AI, which was not significant after adjustment for multiple testing.
	Ho et al. 202061	10	MDD:1781 HC: 2953	NA	sMRI (shape metrics (thickness and surface area) on the surface of seven bilateral subcortical structures: nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus)	Adolescent-onset MDD (≤21 years) had a reduced thickness and surface area of hippocampal ammonis cornea (CA) 1 and basolateral amygdala (Cohen’s d = −0.164 to −0.180). Patients with recurrent MDD had lower hippocampal CA1 and basolateral amygdala thickness and surface area (Cohen’s d = −0.173 to −0.184) compared to the first episode of MDD.
	Leerssen et al. 202072	15	MDD:1053 HC:2108 BD(clinical control):260	13–79	sMRI(cortical thickness, surface area and subcortical volumes)	MDD patients with more severe insomnia had a smaller surface area of the right insula( f2= 0.02, ΔR2 = 1.5%, pcorr= 0.031), left inferior frontal gyrus pars triangularis (f2 = 0.02, ΔR2 = 1.8%, pcorr = 0.018), the left frontal pole (f2 = 0.01, ΔR2 =0.6%, pcorr = 0.031), right superior parietal cortex (f2 = 0.02, ΔR2 = 1.6%, pcorrected = 0.026), right medial OFC (f2 = 0.02, ΔR2 = 1.3%, pcorr = 0.031), and the right supramarginal gyrus (f2 = 0.02, ΔR2 = 1.3%, pcorrected = 0.031). Associations were specific for insomnia severity and MDD diagnosis (not for overall depression severity, HC, BD)
	Opel et al. 202071	28	MDD:2901 HC:3519	NA	sMRI(total and regional cortical thickness and surface area and measures of subcortical and intracranial volumes)	Obesity was associated with lower cortical thickness (most pronounced in the temporo-frontal lobe, maximum Cohen ´s d (left fusiform gyrus) = −0.33), regionally specific cortical surface area alterations, and increased subcortical volume in the amygdala, the thalamus and the nucleus accumbens.
	Campos et al. 202160	18	MDD:6448 (of whom, attempted suicide:694) HC:12477	NA	sMRI(regional cortical thickness and surface area and measures of subcortical, lateral ventricular, and intracranial volumes)	Depressed suicidal attempters had smaller volumes in the left and right thalamus and right pallidum compared with both clinical (Cohen’s d = −0.13, −0.14, and −0.12, respectively) and healthy control. Attempeters also had smaller surface area in the left inferior parietal lobe after multiple correction when compared with clinical control(Cohen’s d = −0.12).
22q11DS	Sun et al. 201870	10	22q11DS:474 HC:315	NA	sMRI(FreeSurfer cortical thickness and surface area)	22q11DS had thicker cortical gray matter overall (left/right hemispheres: Cohen’s d = 0.61/0.65), but thinner temporal and cingulate cortex. 22q11DS had a smaller surface area (left/right hemispheres: d = −1.01/−1.02). These neuroanatomic patterns could differentiate 22q11DS with 93.8% accuracy. 22q11DS subjects with psychosis showed thinner cortex compared to those without psychosis and 22q11DS-psychosis and idiopathic schizophrenia showed significant convergence of affected brain regions, especially in the frontotemporal cortex. Results showed a strong effect of deletion size on local cortical surface area, most notably in the frontal and parietal lobes.
	Villalón-Reina et al. 201948	10	22q11DS:334 HC:260	6–52 for both groups	DTI(FA, MD, RD, AD)	22q11DS had widespread smaller MD, RD, AD, most prominent in areas with major cortico-cortical and cortico-thalamic fibers (Cohen’s d= −0.9 to −1.3). 22q11DS showed higher mean partial anisotropy (FA) in the corpus callosum and projection fibers (internal capsule and corona radiata) compared to controls, but lower FA than controls primarily in areas with associative fibers. Psychosis of 22q11DS was associated with a more substantial reduction in diffusion coefficient in multiple regions.
	Ching et al. 202063	11	22q11DS: 533 HC: 330	6–56 for both groups	sMRI(gross volume and subcortical shape morphometry)	22q11DS had a lower intracranial volume (ICV), thalamus, putamen, hippocampus, and amygdala volume and larger lateral ventricles, caudate nucleus, and nucleus accumbens (Cohen’s d=−0.90–0.93). Results showed widespread subcortical structure changes, affected by deletion size and psychotic illness. 22q11DS with psychosis demonstrated significant convergence with idiopathic schizophrenia, and other severe neuropsychiatric illnesses.

N, Number; SZ, Schizophrenia; BD, bipolar disorder; MDD, major depressive disorder; 22q11.2 Deletion Syndrome, 22q11DS; HC, Healthy Control; NA, not available; DTI, diffusion tensor imaging; FA, fractional anisotropy; RD, radial diffusivity; MD, mean diffusivity; AD, axial diffusivity; gFA, global fractional anisotropy component; LA-gFA, fractional anisotropy component for six long association tracts.