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Brain volume in first-episode schizophrenia

Systematic review and meta-analysis of magnetic resonance imaging studies

Published online by Cambridge University Press:  02 January 2018

R. Grant Steen*
Affiliation:
Department of Psychiatry, University of North Carolina at Chapel Hill, North Carolina, USA
Courtney Mull
Affiliation:
Department of Psychiatry, University of North Carolina at Chapel Hill, North Carolina, USA
Robert Mcclure
Affiliation:
Department of Psychiatry, University of North Carolina at Chapel Hill, North Carolina, USA
Robert M. Hamer
Affiliation:
Department of Psychiatry, University of North Carolina at Chapel Hill, North Carolina, USA
Jeffrey A. Lieberman
Affiliation:
Department of Psychiatry, University of North Carolina at Chapel Hill, North Carolina, USA
*
Dr R. Grant Steen, Department of Psychiatry, University of North Carolina at Chapel Hill, Campus Box 7160, Chapel Hill, North Carolina 27599-7160, USA. Tel: +1 919 966 8382; e-mail: Grant_Steen@med.unc.edu
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Abstract

Background

Studies of people with schizophrenia assessed using magnetic resonance imaging (MRI) usually include patients with first-episode and chronic disease, yet brain abnormalities may be limited to those with chronic schizophrenia.

Aims

To determine whether patients with a first episode of schizophrenia have characteristic brain abnormalities.

Method

Systematic review and meta-analysis of 66 papers comparing brain volume in patients with a first psychotic episode with volume in healthy controls.

Results

Atotal of 52 cross-sectional studies included 1424 patients with a first psychotic episode; 16 longitudinal studies included 465 such patients. Meta-analysis suggests that whole brain and hippocampal volume are reduced (both P < 0.0001) and that ventricular volume is increased (P < 0.0001) in these patients relative to healthy controls.

Conclusions

Average volumetric changes are close to the limit of detection by MRI methods. It remains to be determined whether schizophrenia is a neurodegenerative process that begins at about the time of symptom onset, or whether it is better characterised as a neurodevelopmental process that produces abnormal brain volumes at an early age.

Type
Review Article
Copyright
Copyright © Royal College of Psychiatrists, 2006 

Schizophrenia is a disabling illness that affects over 2 million people in the USA alone, but its aetiology remains poorly understood (Reference HarrisonHarrison, 1999; Reference Siever and DavisSiever & Davis, 2004). In past years the disorder was studied by examining pathological brain tissue samples, often derived from patients who had died after a prolonged period of illness. In recent years, with the advent of brain imaging methods such as magnetic resonance imaging (MRI), it has become possible to study patients during their first episode of psychosis, before disease effects are obscured by the confounding influences typical of cases of chronic schizophrenia. This may make it possible to test hypotheses as to which brain volumetric changes are primary to the development of schizophrenia (Reference Shenton, Dickey and FruminShenton et al, 2001). Our goal in the study reported here is to provide an update of two excellent earlier reviews (Reference Wright, Rabe-Hesketh and WoodruffWright et al, 2000; Reference Shenton, Dickey and FruminShenton et al, 2001), but with a focus specifically on patients with first-episode schizophrenia.

METHOD

Study selection criteria

Relevant studies of patients with first-episode schizophrenia were identified in multiple searches as late as November 2004. The primary search used PubMed and the keywords SCHIZOPHRENIA and FIRST-EPISODE and MAGNETIC RESONANCE IMAGING and VOLUME, in all possible combinations. This search was repeated, substituting the keyword DRUG NAIVE for FIRST-EPISODE, and using the same search words again in all possible combinations. A secondary search was then undertaken, using each primary reference as a source. The bibliography of each source was searched for additional references that were missed by the PubMed search. In addition, the bibliographies of eight key review articles were searched (Reference Wright, Rabe-Hesketh and WoodruffWright et al, 2000; Reference Konick and FriedmanKonick & Friedman, 2001; Reference Okubo, Tomoyuki and OdaOkubo et al, 2001; Reference Shenton, Dickey and FruminShenton et al, 2001; Reference Kasai, Iwanami and YamasueKasai et al, 2002; Reference TorreyTorrey, 2002; Reference Davidson and HeinrichsDavidson & Heinrichs, 2003; Reference Antonova, Sharma and MorrisAntonova et al, 2004) for papers relating specifically to patients with first-episode disorder. Finally, current journals were reviewed to find references too new to have been reviewed. The primary search found 75 relevant references, whereas the secondary searches found an additional 16 references.

Studies were included in our analysis if brain MRI volumetric data were reported for both a population of patients with schizophrenia at first episode and a population of healthy controls evaluated concurrently. We excluded seven studies that did not report exclusively on patients with first-episode illness, and five studies that did not report concurrent data from healthy controls. Studies were also excluded if data from patients with first-episode psychosis were not separated from a larger population of patients with psychosis of some other type, or if results included patients with childhood-onset schizophrenia. We specifically excluded children younger than age 13 years from our analysis because there are rapid changes in brain volume among healthy children up to about age 9 years (Reference Pfefferbaum, Mathalon and SullivanPfefferbaum et al, 1994; Reference Giedd, Blumenthal and JeffriesGiedd et al, 1999), and the young age of patients with childhood-onset illness would make it difficult to control adequately for the effects of normal brain growth. Studies were also excluded if data were reported in a format that did not enable us to calculate patient brain volume as a percentage of the control group volume. Thus, we excluded studies that used voxel-based morphometry, since our calculations are based on volume rather than on number of pixels. We also excluded studies that reported results from a non-volumetric analysis of the data, or from a non-quantitative analysis of the data.

Of the total of 91 articles that were originally identified, 26 were excluded for any of the above reasons. A total of 65 articles were evaluated (Table 1), including 52 cross-sectional and 16 longitudinal studies. Data from all 52 eligible cross-sectional studies were entered into a spreadsheet that tabulated study details, including a brief description of the study, demography of the study populations, patient medications and the statistical analyses used. For patients, additional data were entered summarising the percentage difference in structure volume relative to controls, and whether or not this difference was statistically significant according to the analysis presented in the original reference.

Table 1 Summary of cross-sectional and longitudinal studies included in review

Study Sample size Patient age Mean (years) Male %
Patient group n Control group n
Cross-sectional studies
    Bachmann et al (Reference Bachmann, Pantel and Flender2003) 31 12 26.4 45
    Barr et al (Reference Barr, Ashtari and Bilder1997) 32 42 26.3 59
    Bilder et al (Reference Bilder, Wu and Bogerts1994) 70 51 26.1 56
    Bogerts et al (Reference Bogerts, Ashtari and Degreef1990) 35 25 25 63
    Cahn et al (Reference Cahn, Hulshoff Pol and Bongers2002a ) 20 20 27.6 80
    Chua et al (Reference Chua, Lam and Tai2003) 19 29 31.6 90
    Corson et al (Reference Corson, Nopoulos and Andreasen1999) 36 41 26.9 69
    Crespo-Facorro et al (Reference Crespo -Facorro, Kim and Andreasen2000) 25 25 25.4 NR
    Degreef et al (Reference Degreef, Ashtari and Bogerts1992) 40 25 24.1 63
    DeLisi et al (Reference DeLisi, Hoff and Schwartz1991) 30 20 27.3 77
    DeLisi et al (Reference DeLisi, Stritzke and Riordan1992) 50 33 26.2 64
    DeLisi et al (Reference DeLisi, Hoff and Neale1994) 85 40 26.9 59
    Ettinger et al (Reference Ettinger, Chitnis and Kumari2001) 38 29 24.2 74
    Fannon et al (Reference Fannon, Tennakoon and O'Ceallaigh2000a ) 21 25 24 71
    Fannon et al (Reference Fannon, Chitnis and Deku2000b ) 37 25 24.3 70
    Gilbert et al (Reference Gilbert, Rosenberg and Harenski2001) 16 25 26.6 69
    Gunduz et al (Reference Gunduz, Wu and Ashtari2002) 51 28 24.5 73
    Hirayasu et al (Reference Hirayasu, Sheton and Salisbury1998) 17 18 26.7 82
    Hirayasu et al (Reference Hirayasu, Shenton and Salisbury1999) 17 20 27.2 82
    Hirayasu et al (Reference Hirayasu, McCarley and Salisbury2000b ) 20 22 27.3 80
    Hirayasu et al (Reference Hirayasu, Tanaka and Shenton2001) 17 17 22.8 88
    Hoff et al (Reference Hoff, Neal and Kushner1994) 62 35 26.5 63
    James et al (Reference James, Crow and Renowden1999) 29 20 16.8 69
    Joyal et al (Reference Joyal, Laakso and Tiihonen2002) 18 22 28 61
    Joyal et al (Reference Joyal, Laakso and Tiihonen2003) 18 22 28 61
    Kasai et al (Reference Kasai, Shenton and Salisbury2003a ) 27 29 25.2 85
    Keshavan et al (Reference Keshavan, Rosenberg and Sweeney1998a ) 16 17 27.2 69
    Keshavan et al (Reference Keshavan, Rosenberg and Sweeney1998b ) 17 17 25.4 71
    Laakso et al (Reference Laakso, Tiihonen and Syvalahti2001) 18 22 28 61
    Lang et al (Reference Lang, Kopala and Vandorpe2001) 30 23 22.9 70
    Lawrie et al (Reference Lawrie, Whalley and Kestelman1999) 20 30 20.7 75
    Lee et al (Reference Lee, Shenton and Salisbury2002) 22 24 26 77
    Lim et al (Reference Lim, Tew and Kushner1996) 22 51 25.2 68
    Matsumoto et al (Reference Matsumoto, Simmons and Williams2001a ) 40 40 15.5 50
    McCarley et al (Reference McCarley, Salisbury and Hirayasu2002) 15 18 27.6 80
    Niemann et al (Reference Niemann, Hammers and Coenen2000) 20 20 27.4 100
    Nopoulos et al (Reference Nopoulos, Torres and Flaum1995) 24 24 23.3 50
    Razi et al (Reference Razi, Greene and Sakuma1999) 13 31 23.4 54
    Salokangas et al (Reference Salokangas, Cannon and Van Erp2002) 11 19 36.6 27
    Smith et al (Reference Smith, Lang and Kopala2003) 33 19 22.8 79
    Sumich et al (Reference Sumich, Chitnis and Fannon2002) 25 16 24 100
    Szeszko et al (Reference Szeszko, Bilder and Lenez1999) 19 26 26 53
    Szeszko et al (Reference Szeszko, Gunning-Dixon and Ashtari2003a ) 69 49 27.1 54
    Szeszko et al (Reference Szeszko, Goldberg and Gunduz-Bruce2003b ) 46 34 25 67
    Velakoulis et al (Reference Velakoulis, Pantelis and McGorry1999) 16 42 20.8 88
    Whitworth et al (Reference Whitworth, Honeder and Kremser1998) 41 32 24.5 100
    Zipursky et al (Reference Zipursky, Lambe and Kapur1998a ) 46 61 26.2 54
    Total 1424 1315
    Mean (s.d.) 30.3 (16.5) 28.0 (10.7) 25.5 (3.2) 67.4
Studies reporting new data supplementing cross-sectional studies above
    Hirayasu et al (Reference Hirayasu, Shenton and Salisbury2000a ) describes data from Hirayasu et al (Reference Hirayasu, Sheton and Salisbury1998)
    Copolov et al (Reference Copolov, Velakoulis and McGorry2000) describes data from Velakoulis et al (Reference Velakoulis, Pantelis and McGorry1999)
    Zipursky et al (Reference Zipursky, Zhang-Wong and Lambe1998b ) describes data from Zipursky et al (Reference Zipursky, Lambe and Kapur1998a )
    Lieberman et al (Reference Lieberman, Alvir and Woerner1992) describes data from Bogerts et al (Reference Bogerts, Ashtari and Degreef1990), Degreef et al (Reference Degreef, Ashtari and Bogerts1992)
    Matsumoto et al (Reference Matsumoto, Simmons and Williams2001b ) describes data from Matsumoto et al (Reference Matsumoto, Simmons and Williams2001a )
Longitudinal studies
    Cahn et al (Reference Cahn, Hulshoff Pol and Lems2002b ) 34 36 26.2 85
    Chakos et al (Reference Chakos, Lieberman and Bilder1994) 29 10 25.2 59
    Degreef et al (Reference Degreef, Ashtari and Wu1991) 13 8 25.1 77
    DeLisi et al (Reference DeLisi, Stritzke and Riordan1992) 24 6 NR NR
    DeLisi et al (Reference DeLisi, Tew and Xie1995) 20 5 27.3 75
    DeLisi et al (Reference DeLisi, Sakuma and Tew1997) 50 20 27.4 64
    Gur et al (Reference Gur, Cowell and Turetsky1998) 20 17 27.8 55
    Ho et al (Reference Ho, Andreasen and Nopoulos2003) 73 23 24.5 73
    Kasai et al (Reference Kasai, Shenton and Salisbury2003b ) 13 22 27.3 77
    Keshavan et al (Reference Keshavan, Rosenberg and Sweeney1998b ) 11 12 24.1 55
    Lang et al (Reference Lang, Kopala and Vandorpe2001) 30 23 22.9 NR
    Lieberman et al (Reference Lieberman, Chakos and Wu2001) 107 20 26 52
    Puri et al (Reference Puri, Hutton and Saeed2001) 24 12 28.5 NR
    Wood et al (Reference Wood, Velakoulis and Smith2001) 17 26 NR NR
    Total 465 240
    Mean (s.d.) 33.2 (26.9) 17.1 (8.8) 26.0 (1.7) 67.2
Studies reporting new data supplementing longitudinal studies above
    DeLisi et al (Reference DeLisi, Sakuma and Ge1998) describes data from DeLisi et al (Reference DeLisi, Sakuma and Tew1997)
    Kasai et al (Reference Kasai, Shenton and Salisbury2003c ) describes data from Kasai et al (Reference Kasai, Shenton and Salisbury2003b )

The data entry process was then repeated for all eligible longitudinal studies. If a longitudinal study reported baseline data in a format that could be analysed as a cross-sectional study, this study was entered into both the cross-sectional and the longitudinal databases. The final database contained approximately 29 084 cells.

Data analysis

We sorted the cross-sectional database by brain structure, to determine where brain volumetric changes had been sought. Brain volume changes in the first-episode group were summarised, with respect to controls, on a structure-by-structure basis (further information available from the author upon request). We then conducted a meta-analysis of all cross-sectional studies that measured whole-brain volume in the first-episode group relative to controls (Table 2). For each component study in the meta-analysis, we abstracted information about sample properties (size, mean and standard deviation) from the original paper and fitted a blocked analysis of variance model (with study as the blocking factor) to examine group differences. We additionally fitted models with the group×treatment interaction, to assess heterogeneity; interactions were non-significant in all cases, so we used the models without the interaction terms. We did similar meta-analyses of cross-sectional studies that measured differences in hippocampal volume (Table 3) and ventricular volume (Table 4). Finally, we summarised all studies that reported longitudinal volumetric changes significant at P≤0.01 (further information available from the author upon request), to address the issue of which longitudinal changes are most robust by statistical criteria.

Table 2 Whole-brain volume in cross-sectional studies

Reference Whole-brain volume, cm3 Patient volume1 % Covariates P
Patient group Control group
Mean (s.d.) n Mean (s.d.) n
Cahn et al (Reference Cahn, Hulshoff Pol and Bongers2002a ) 1281.6 (118.7) 20 1353.9 (139) 20 94.7 1 NS
Lee et al (Reference Lee, Shenton and Salisbury2002) 1499.2 (120.2) 22 1555.2 (149.9) 24 96.4 2 NS
Hirayasu et al (Reference Hirayasu, Tanaka and Shenton2001) 1513 (117) 17 1469 (154) 17 103.0 1 NS
Fannon et al (Reference Fannon, Tennakoon and O'Ceallaigh2000a ) 991.1 (76.0) 21 1075.8 (113.0) 25 92.1 3 <0.02
Fannon et al (Reference Fannon, Chitnis and Deku2000b ) 1015.3 (98.5) 37 1075.8 (113.0) 25 94.4 3 <0.05
James et al (Reference James, Crow and Renowden1999) 1383 (163) 29 1405 (170) 20 98.4 2 NS
Hirayasu et al (Reference Hirayasu, Shenton and Salisbury1999) 1510 (101) 17 1533 (166) 20 98.5 2 NS
Szeszko et al (Reference Szeszko, Bilder and Lenez1999): Men 1347 (105) 10 1368 (97) 16 98.5 3 NS
Szeszko et al (Reference Szeszko, Bilder and Lenez1999): Women 1173 (81) 9 1231 (111) 10 95.3 3 NS
Velakoulis et al (Reference Velakoulis, Pantelis and McGorry1999) 1341.8 (134.9) 16 1372.1 (144.4) 140 97.8 5 NS
Lawrie et al (Reference Lawrie, Whalley and Kestelman1999) 1356 (178) 20 1334 (149) 30 101.6 1 NS
Keshavan et al (Reference Keshavan, Rosenberg and Sweeney1998b ) 1470.0 (183.0) 17 1578.9 (160.3) 17 93.1 1 <0.05
Whitworth et al (Reference Whitworth, Honeder and Kremser1998) 1210.2 (119.2) 41 1246.7 (84.2) 32 97.1 2 NS
Zipursky et al (Reference Zipursky, Lambe and Kapur1998a ) 1087 (114) 46 1108 (132) 61 98.1 2 NS
Nopoulos et al (Reference Nopoulos, Torres and Flaum1995) 1240 (139) 24 1270 (133) 24 97.6 2 NS
DeLisi et al (Reference DeLisi, Hoff and Schwartz1991) 1199.8 (139.3) 30 1204.7 (138.3) 20 99.6 4 NS
Kasai et al (Reference Kasai, Shenton and Salisbury2003a ) 1469 (114) 27 1510 (162) 29 97.3 2 NS
Szeszko et al (Reference Szeszko, Goldberg and Gunduz-Bruce2003b ) 1459 (168) 46 1476 (128) 34 98.8 4 NS
Chua et al (Reference Chua, Lam and Tai2003) 1392.1 (156.9) 19 1408.7 (98.4) 29 98.8 1 NS
Matsumoto et al (Reference Matsumoto, Simmons and Williams2001a ) 1254.0 (117.2) 40 1320.0 (123.4) 40 95.0 1 0.002
Keshavan et al (Reference Keshavan, Rosenberg and Sweeney1998a ) 1477.0 (185.3) 16 1576.6 (173.0) 17 93.7 0 NS
Meta-analysis 1318.1 524 1354.7 650 97.3 <0.0001

Table 3 Hippocampal volume in cross-sectional studies

Reference1 Hippocampal volume, mm3 Patient volume2 % P
Patient group Control group
Mean (s.d.) n Mean (s.d.) n
Left
    Smith et al (Reference Smith, Lang and Kopala2003): Men 3.01 (0.42) 26 3.13 (0.36) 10 96.2 NS
    Smith et al (Reference Smith, Lang and Kopala2003): Women 2.68 (0.18) 7 2.92 (0.31) 9 91.8 NS
    Sumich et al (Reference Sumich, Chitnis and Fannon2002) 2.70 (0.30) 25 3.08 (0.25) 16 87.7 0.007
    Laakso et al (Reference Laakso, Tiihonen and Syvalahti2001) 1.21 (0.24) 18 1.23 (0.18) 22 98.4 NS
    Niemann et al (Reference Niemann, Hammers and Coenen2000) 1.85 (0.32) 20 1.88 (0.25) 20 98.4 NS
    James et al (Reference James, Crow and Renowden1999) 2.35 (0.47) 29 2.52 (0.51) 20 93.3 NS
    Velakoulis et al (Reference Velakoulis, Pantelis and McGorry1999) 2.71 (0.52) 16 3.05 (0.37) 42 88.9 0.02
    Whitworth et al (Reference Whitworth, Honeder and Kremser1998) 2.45 (0.38) 41 2.82 (0.51) 32 86.9 <0.01
    Barr et al (Reference Barr, Ashtari and Bilder1997) 2.42 (0.47) 32 2.55 (0.44) 42 94.9 <0.001
    Szeszko et al (Reference Szeszko, Goldberg and Gunduz-Bruce2003b ) 3.31 (0.41) 46 3.56 (0.43) 34 93.0 <0.01
    Matsumoto et al (Reference Matsumoto, Simmons and Williams2001a ) 2.45 (0.49) 40 2.69 (0.50) 40 91.1 NS
    Meta-analysis 2.46 300 2.68 287 91.8 >0.0001
Right
    Smith et al (Reference Smith, Lang and Kopala2003): Men 3.00 (0.47) 26 3.19 (0.36) 10 94.0 NS
    Smith et al (Reference Smith, Lang and Kopala2003): Women 2.86 (0.39) 7 3.01 (0.33) 9 95.0 NS
    Sumich et al (Reference Sumich, Chitnis and Fannon2002) 2.74 (0.38) 25 3.17 (0.29) 16 86.4 0.02
    Laakso et al (Reference Laakso, Tiihonen and Syvalahti2001) 1.22 (0.23) 18 1.27 (0.19) 22 96.1 NS
    Niemann et al (Reference Niemann, Hammers and Coenen2000) 2.01 (0.27) 20 2.10 (0.34) 20 95.7 NS
    James et al (Reference James, Crow and Renowden1999) 2.40 (0.45) 29 2.44 (0.43) 20 98.4 NS
    Velakoulis et al (Reference Velakoulis, Pantelis and McGorry1999) 2.94 (0.39) 16 3.22 (0.40) 42 91.3 NS
    Whitworth et al (Reference Whitworth, Honeder and Kremser1998) 2.42 (0.35) 41 2.75 (0.66) 32 88.0 <0.01
    Barr et al (Reference Barr, Ashtari and Bilder1997) 2.21 (0.40) 32 2.71 (0.47) 42 81.5 NS
    Szeszko et al (Reference Szeszko, Goldberg and Gunduz-Bruce2003b ) 3.41 (0.43) 46 3.61 (0.43) 34 94.5 NS
    Matsumoto et al (Reference Matsumoto, Simmons and Williams2001a ) 2.70 (0.42) 40 2.80 (0.51) 40 96.4 NS
    Meta-analysis 2.53 300 2.76 287 91.7 <0.0001

Table 4 Ventricular volume in cross-sectional studies

Reference1 Ventricular volume, mm3 Volume2 % P
Patient group Control group
Mean (s.d.) n Mean (s.d.) n
Left lateral ventricle
    Fannon et al (Reference Fannon, Tennakoon and O'Ceallaigh2000a ) 5.10 (3.00) 14 4.50 (1.90) 25 113.3 NS
    Fannon et al (Reference Fannon, Chitnis and Deku2000b ) 6.20 (3.20) 37 4.50 (1.90) 25 137.8 <0.05
    James et al (Reference James, Crow and Renowden1999) 9.66 (4.00) 29 6.16 (2.30) 20 156.8 <0.001
    Lawrie et al (Reference Lawrie, Whalley and Kestelman1999) 3.90 (2.50) 20 3.80 (2.80) 30 102.6 NS
    Whitworth et al (Reference Whitworth, Honeder and Kremser1998) 4.96 (2.97) 41 2.81 (1.49) 32 176.5 <0.001
    Barr et al (Reference Barr, Ashtari and Bilder1997) 9.16 (4.22) 32 6.98 (2.90) 42 131.2 <0.02
    DeLisi et al (Reference DeLisi, Hoff and Schwartz1991) 6.84 (2.10) 30 5.54 (1.80) 20 123.5 <0.04
    Chua et al (Reference Chua, Lam and Tai2003) 6.00 (1.50) 19 5.00 (2.00) 29 120.0 0.02
    Degreef et al (Reference Degreef, Ashtari and Bogerts1992) 8.91 (3.96) 40 6.70 (2.14) 25 133.0 NS
    Meta-analysis 6.86 262 5.13 248 133.7 <0.0001
Right lateral ventricle
    Fannon et al (Reference Fannon, Tennakoon and O'Ceallaigh2000a ) 4.60 (2.10) 14 4.70 (1.90) 25 97.9 NS
    Fannon et al (Reference Fannon, Chitnis and Deku2000b ) 5.80 (2.90) 37 4.70 (1.90) 25 123.4 NS
    James et al (Reference James, Crow and Renowden1999) 8.12 (3.32) 29 5.89 (2.28) 20 137.9 <0.02
    Lawrie et al (Reference Lawrie, Whalley and Kestelman1999) 3.70 (2.60) 20 3.50 (2.00) 30 105.7 NS
    Whitworth et al (Reference Whitworth, Honeder and Kremser1998) 4.99 (2.95) 41 3.11 (1.65) 32 160.5 <0.01
    Barr et al (Reference Barr, Ashtari and Bilder1997) 8.22 (4.22) 32 6.52 (2.69) 42 126.1 <0.02
    DeLisi et al (Reference DeLisi, Hoff and Schwartz1991) 6.75 (2.90) 30 5.60 (1.70) 20 120.5 NS
    Chua et al (Reference Chua, Lam and Tai2003) 5.10 (1.70) 19 4.40 (1.70) 29 115.9 NS
    Degreef et al (Reference Degreef, Ashtari and Bogerts1992) 8.15 (3.05) 40 6.75 (2.10) 25 121.0 NS
    Meta-analysis 6.26 262 5.02 248 124.7 <0.0001
Third ventricle
    Cahn et al (Reference Cahn, Hulshoff Pol and Bongers2002a ) 0.85 (0.32) 20 0.62 (0.36) 20 137.1 0.05
    Fannon et al (Reference Fannon, Tennakoon and O'Ceallaigh2000a ) 0.77 (0.20) 14 0.68 (0.21) 25 113.2 NS
    Fannon et al (Reference Fannon, Chitnis and Deku2000b ) 0.90 (0.40) 37 0.70 (0.20) 25 128.6 <0.05
    James et al (Reference James, Crow and Renowden1999) 2.08 (0.66) 29 1.60 (0.35) 20 130.0 0.006
    Lawrie et al (Reference Lawrie, Whalley and Kestelman1999) 0.60 (0.40) 20 0.40 (0.20) 30 150.0 0.02
    Lim et al (Reference Lim, Tew and Kushner1996) 0.34 (0.12) 22 0.27 (0.13) 51 125.9 <0.05
    DeLisi et al (Reference DeLisi, Hoff and Schwartz1991) 0.99 (0.40) 22 0.91 (0.20) 13 108.8 NS
    Degreef et al (Reference Degreef, Ashtari and Bogerts1992) 1.33 (0.38) 40 1.12 (0.32) 25 118.8 <0.03
    Meta-analysis 0.99 204 0.79 209 125.3 <0.0001

RESULTS

The primary PubMed search was able to find 75 of the 91 papers evaluated in this study, or 82% of the relevant references. This suggests that PubMed, although an effective tool, cannot be relied upon to find all relevant references.

A total of 52 studies were included in the cross-sectional analysis (Table 1), these studies involving 1424 patients with first-episode schizophrenia (30.3 patients per study, s.d.=16.5) and 1315 healthy controls (28.0 controls per study, s.d.=10.7). A total of 16 studies were included in the longitudinal analysis, these studies involving 465 patients (33.2 patients per study, s.d.=26.9) and 240 healthy controls (17.1 controls per study, s.d.=8.8). The average age of patients across all studies was 26 years. Even after excluding studies that comprised only male patients (reasoning that a study with a sample composed only of men must have made an effort to exclude women), roughly two-thirds of patients were men, suggesting that males are more common among young patients with first episodes of schizophrenia.

Relatively few brain structures have been evaluated in multiple studies (further information available from the author upon request); of 14 comparisons that showed a significant volumetric decrease in grey matter of patients’ brains, only 6 comparisons were replicated more than three times. Most volumetric studies were small, even when the focus was a structure in which measurement error could be substantial. The total number of patients evaluated per structure, averaged across all 14 central grey matter structures, was 97.6 (s.d.=82.5), but it was only 65.5 (s.d.=47.6) if amygdala, hippocampus and the amygdala– hippocampal complex were excluded. Most volumetric changes that are significant relate to grey matter, and more findings relate to central than to peripheral (cortical) grey matter. Virtually all significant volumetric differences from normal in grey matter are patient deficits in volume, compared with controls.

Cross-sectional studies that measured whole-brain volume deficits in patients with first-episode schizophrenia are summarised in Table 2. For this particular comparison there have been 21 studies, with a large number of participants (patients, n=524; controls, n=650), but only 4 studies found significance. Meta-analysis showed that the average patient brain volume was 2.7% smaller than the average control brain volume (P<0.0001). Group (patient v. control) and study differences together account for 57% of the variation in brain volume, but group differences alone were able to account for less than 1% of the variation in brain volume (P<0.0001). Thus, there was a significant variation in brain volume between studies (P<0.0001), although there was no significant study heterogeneity.

There was variation in the number (and type) of covariates used in the various studies of brain volume, suggesting that it may be problematic to pool studies in a single meta-analysis. Nevertheless, the number of statistical covariates used in analysis did not seem to be related to the level of statistical significance obtained. The 4 studies that found significance had an average of 2.0 covariates, whereas the 17 non-significant studies had an average of 2.2 covariates.

Cross-sectional studies that measured hippocampal volume deficits in patients with first-episode schizophrenia are summarised in Table 3. There have been 10 separate studies of the hippocampus, with total participant numbers of 300 patients and 287 controls. Meta-analysis shows that the volume deficit in patient hippocampus is about 8% on both right and left sides (P<0.0001). This deficit is somewhat larger than the 4% volume deficit reported in a meta-analysis of hippocampal volume in patients with chronic schizophrenia (Reference Nelson, Saykin and FlashmanNelson et al, 1998). Group and study differences together accounted for 64% of the variation in hippocampal volume, but group differences alone were able to account for only 2% of this variation (P<0.0001). Study-related variation in hippocampal volume was significant (P<0.0001), without significant study heterogeneity.

Cross-sectional studies that measured the lateral or third ventricles in patients with first-episode schizophrenia are also summarised (Table 4). There have been 11 studies of ventricular volume, with total participant numbers of 204 patients and 209 controls. Meta-analysis shows that the lateral ventricle volume surplus in patients is about 34% on the left side and 25% on the right side (both P<0.0001). Group and study differences together account for 31% of the variation in ventricular volume on the left side and 26% on the right side (both P<0.0001), with group differences accounting for 6% or less of the variation in ventricular volume (both P<0.0001). For third ventricle measurements, group and study differences together accounted for 68% of the variation in third ventricle volume (P<0.0001), with group differences accounting for 4% of the variation in ventricular volume. Study-related variation in ventricular volume was significant (all P<0.0001), without significant study heterogeneity.

We summarised robustly significant (P≤0.01) findings from longitudinal studies of brain volume change in patients (further information available from the author upon request). This compilation demonstrates that longitudinal studies are generally of recent vintage; of eight studies recorded, five were published within the past 5 years. Several longitudinal changes in the volume of the brain were robustly significant after diagnosis, including a significant decrease in volume of the whole brain after diagnosis. No significant longitudinal change was identified in white matter or cerebellum, so longitudinal changes in whole-brain volume may be limited to the grey matter.

DISCUSSION

Our synthesis of brain volumetric studies suggests that a great deal more work is needed. There are relatively few studies that specifically relate to patients with first episodes of schizophrenia (see Table 1); the existing studies have a rather small sample size and studies that reported a high degree of significance tended to have a smaller sample size than normal. Most significant volumetric findings are not well replicated, and few findings are robustly significant, in either cross-sectional or longitudinal studies. Studies of patients with first episodes tend to be smaller than the average of 33 patients per study reported in a systematic review of 180 studies of patients with (mostly) chronic schizophrenia (Reference Shenton, Dickey and FruminShenton et al, 2001). Thus, the total number of first-episode cases that have been evaluated overall is small, given the complexity of the illness.

Whole-brain volume deficits

Whole-brain volume differences between first-episode cases and controls are apparently quite subtle (Reference Harrison, Freemantle and GeddesHarrison et al, 2003). Cross-sectional studies that measured whole-brain volume reported an average volume deficit in the first-episode group of less than 3% (see Table 2), despite a large sample size. This finding agrees well with a study of brain weight at autopsy, in which 540 older patients with chronic schizophrenia were compared with 794 controls (Reference Harrison, Freemantle and GeddesHarrison et al, 2003). This study found that the brain weight of patients with chronic disorder was 2% less than that of healthy controls (P=0.04), but that disease-related differences were far less significant than brain weight differences attributable to either age or gender (both P<0.0001). No correlation was found between brain weight and the duration of psychosis, which may mean that brain atrophy is not progressive after diagnosis (Reference Harrison, Freemantle and GeddesHarrison et al, 2003).

It is critically important to determine when whole-brain volume deficits in patients with schizophrenia first become significant, as this could have bearing on the aetiology of the disorder (Reference HarrisonHarrison, 1999). If whole-brain volume becomes abnormal early in childhood, this would suggest a neurodevelopmental aetiology; alternatively, if whole-brain volume becomes abnormal shortly before the onset of symptoms – or even after symptoms have developed – this would suggest a neurodegenerative aetiology. Population-based data suggest that head size is abnormal at birth among those who later develop schizophrenia, compared with controls (Reference Ward, Friedman and WiseWard et al, 1996; Reference HarrisonHarrison, 1999). Research in the offspring of people with schizophrenia, in people at high genetic risk of this disorder or in patients in its prodromal phase might help to address this aetiological question.

When does volumetric change occur?

Some brain structures in people with first-episode schizophrenia appear to show a volumetric deficit that is significant at diagnosis and that is also progressive over the later course of illness. For example, the lateral ventricles are significantly larger than normal at diagnosis (Table 4) and ventricular volume tends to increase significantly in longitudinal studies. Volumetric deficits at diagnosis are seen in the hippocampus (Table 3), in cortical grey matter, in Heschl's gyrus, in the planum temporale and in temporal grey matter, and all of these structures also show continued volumetric loss over time (further information available from the author upon request).

Some brain tissues appear to show a volumetric deficit at diagnosis, but the deficit may not progress over time. For example, there are volumetric deficits in the thalamus at diagnosis, according to four studies, but no longitudinal change has yet been described. Similarly, volume deficits in the insula are significant at diagnosis, according to two studies, but no longitudinal change has been described. This may mean that volumetric changes in the thalamus and insula are indeed not progressive, or it may mean that there are simply too few longitudinal studies to identify a progressive volume loss that is actually present in these structures.

Imaging difficulties

There are a great many difficulties in measuring brain volumes of patients with schizophrenia by MRI. A major problem is that the volumetric loss in patients is no more than 4% per year (further information available upon request), which may be close to the limit of detection by MRI, given the precision of volumetric methods (Reference Howard, Roberts and Garcia-FinanaHoward et al, 2003; Reference MacFall, Payne and KrishnanMacFall et al, 2004). A longitudinal study of a volume phantom found that changes of up to 5% could be introduced by changes in scanner hardware or software (Reference MacFall, Payne and KrishnanMacFall et al, 2004). Such ‘machine drift’ can have an impact on volume measurement, as shown by a study of intracranial content in 113 healthy elderly participants (Reference MacFall, Payne and KrishnanMacFall et al, 2004). Although the intracranial content cannot change after the cranial sutures close (Reference Pfefferbaum, Mathalon and SullivanPfefferbaum et al, 1994; Reference Giedd, Blumenthal and JeffriesGiedd et al, 1999), error in its measurement averaged ±1.5% (Reference MacFall, Payne and KrishnanMacFall et al, 2004). This error could be corrected but, in the absence of correction, would confound any longitudinal measurement of brain volume (Reference MacFall, Payne and KrishnanMacFall et al, 2004). In studies that control for intracranial volume, imprecision or inaccuracy may not have a major impact, but poor precision or low accuracy in even a subset of volumetric studies would lead to a lack of consensus among the various studies.

Imprecision or inaccuracy in the measurement of brain volume can arise in many ways. Perhaps the most likely source of error is voxel misclassification during brain segmentation (Reference Wang and DoddrellWang & Doddrell, 2002). Voxels classified as one tissue type could, with a relatively minor change in tissue T 1 or T 2, be classified as another tissue type (Reference Steen, Ogg and ReddickSteen et al, 1997). A second major issue is the familiar partial volume problem; since several tissues can occur in a volume much smaller than a typical imaging voxel, this would introduce error into the volume estimate of any tissue type (Reference Tofts, Barker and FilippiTofts et al, 1997; Reference Ballester, Zisserman and BradyBallester et al, 2000; Reference Wang and DoddrellWang & Doddrell, 2002), and could potentially change the proportional allocation of tissue to tissue type. A third problem is the inconspicuousness of tissue edges; this type of error is really another type of partial volume error that would primarily affect the estimate of grey matter volume, since this often has poorly defined edges with cerebrospinal fluid. Error in the measurement of grey matter volume would change the estimate of total brain volume, so controlling for brain volume would not necessarily eliminate ‘machine drift’ in a longitudinal study. A fourth issue is head tilt, or angulation of the imaging slab over the brain, since different volumes of brain may be interrogated in different imaging examinations. This problem can only be overcome by striving for full brain coverage during an examination. Finally, non-systematic non-systematic errors (mistakes) can be made during the complex analytic process that is required for MRI volumetry (Reference Haller, Banerjee and ChristensenHaller et al, 1997). In short, because error can be substantial and because brain volumetric changes from normal in patients with first-episode schizophrenia appear to be quite small, some of the differences reported between patients and controls (Tables 2, 3, 4) are probably artefactual.

Clinical difficulties

A great many clinical difficulties complicate a volumetric search for the causes of schizophrenia. An enormous problem is that patients are typically treated with antipsychotic medications as soon as possible after diagnosis. Different patients may receive different medications at different dosages, and such treatment heterogeneity is almost impossible to eliminate. This makes it essential to determine whether there are acute effects of medication on total brain volume (Reference DeLisi, Hoff and SchwartzDeLisi et al, 1991; Reference Chakos, Lieberman and BilderChakos et al, 1994; Reference Gur, Cowell and TuretskyGur et al, 1998). If brain volumetric changes in response to medication are rapid, then the length of time between first medication and imaging evaluation could be a major confounder. Antipsychotic medication has been postulated to have an effect on basal ganglia volume in as little as 6 months (Reference Chakos, Lieberman and BilderChakos et al, 1994), and it is possible that brain volumetric change in response to medication occurs even more rapidly. A further difficulty inherent to studying first-episode cases is that some patients may have been symptomatic, but undiagnosed, for a long time. If progressive brain volume changes are rapid in the period surrounding diagnosis, then the duration of undiagnosed illness would be a serious confounder. However, since no consistent relationship has been found between duration of illness and brain volume loss (Reference Harrison, Freemantle and GeddesHarrison et al, 2003), this may be less likely.

Recruiting patients with schizophrenia can be time-consuming, difficult and expensive, since many are unable or unwilling to comply with study requirements. Another problem is that brain structure may be weakly correlated with brain function, so that substantial variation in brain volume could be found in the absence of any variation in brain function (Reference UttalUttal, 2001). These two problems together probably account for why so many studies of brain volume appear to be underpowered (Table 2). Many studies lack a sample size sufficient to test hypotheses that relate to what may be an inherently weak relationship, especially given the limitations of the methods (Reference Haller, Banerjee and ChristensenHaller et al, 1997; Reference Howard, Roberts and Garcia-FinanaHoward et al, 2003; Reference MacFall, Payne and KrishnanMacFall et al, 2004). To complicate the picture further, there may be genetic heterogeneity within the diagnosis, such that patients in a single study might actually have different diseases that converge in causing psychotic symptoms.

Concluding remarks

The most robust volumetric findings in patients with schizophrenia are those of grey matter volume loss (Table 3) and ventricular volume increase (Table 4), and these findings are probably linked. In monozygotic twins discordant for schizophrenia, there is a correlation between reduced left temporal grey matter volume and increased volume of cerebrospinal fluid in the left temporal horn, suggesting that loss of grey matter leads to an increase in ventricular volume (Reference Suddath, Casanova and GoldbergSuddath et al, 1989). Many more longitudinal studies of brain volume change in patients with first psychotic episodes are needed to determine which tissues are prone to the atrophy that manifests as ventricular volume increase.

This review confirms that grey matter deficits are present in patients with first-episode psychosis (Reference Hulshoff-Pol, Schnack and MandlHulshoff-Pol et al, 2001), whereas white matter changes have seldom been described (Reference Sanfilipo, Lafargue and RusinekSanfilipo et al, 2000; Reference Hulshoff-Pol, Brans and van HarenHulshoff-Pol et al, 2004). Yet it is still not known whether changes in grey matter volume at first episode are associated with disease progression itself or with the many correlates of disease, including antipsychotic medication, alcoholism, drug misuse, malnutrition or even social deprivation. Both alcoholism (Reference JoyceJoyce, 1996) and malnutrition (Reference Swayze, Anderson and ArndtSwayze et al, 1996) are associated with acutely reversible changes in brain volume. Such volumetric changes are postulated to result from changes in brain water content, secondary to systemic hydration or serum protein content (Reference JoyceJoyce, 1996; Reference Swayze, Anderson and ArndtSwayze et al, 1996). Similar hydration mechanisms could be important in schizophrenia, since many patients suffer from malnutrition, dehydration and exposure (Reference Shenton, Dickey and FruminShenton et al, 2001), so it is important to control for such environmental effects in studies.

It remains to be determined whether schizophrenia is a neurodegenerative process that begins at about the time of symptom onset and manifests as progressive volumetric loss thereafter, or whether it is better characterised as a neurodevelopmental process that results in abnormal brain volume beginning at an early age (Reference Maynard, Sikich and LiebermanMaynard et al, 2001).

Acknowledgements

R.G.S. is supported by the National Alliance for Research on Schizophrenia and Depression as a Hofmann Trust Investigator. Our research was also supported by MH61603 (J.A.L.), the University of North Carolina at Chapel Hill Schizophrenia Research Center, the National Institute of Mental Health Silvio Conte Center for the Neuroscience of Mental Disorders (MH164065) and the Foundation of Hope.

Footnotes

Declaration of interest

None.

References

Antonova, E., Sharma, T., Morris, R., et al (2004) The relationship between brain structure and neurocognition in schizophrenia: a selective review. Schizophrenia Research, 70, 117145.Google Scholar
Bachmann, S., Pantel, J., Flender, A., et al (2003) Corpus callosum in first-episode patients with schizophrenia – a magnetic resonance imaging study. Psychological Medicine, 33, 10191027.CrossRefGoogle ScholarPubMed
Ballester, M. A. G., Zisserman, A. & Brady, M. (2000) Segmentation and measurement of brain structures in MRI including confidence bounds. Medical Image Analysis, 4, 189200.CrossRefGoogle Scholar
Barr, W. B., Ashtari, M., Bilder, R. M., et al (1997) Brain morphometric comparison of first-episode schizophrenia and temporal lobe epilepsy. British Journal of Psychiatry, 170, 515519.CrossRefGoogle ScholarPubMed
Bilder, R. M., Wu, H., Bogerts, B., et al (1994) Absence of regional hemispheric volume asymmetries in first-episode schizophrenia. American Journal of Psychiatry, 151, 14371447.Google Scholar
Bogerts, B., Ashtari, M., Degreef, G., et al (1990) Reduced temporal limbic structure volumes on magnetic resonance images in first episode schizophrenia. Psychiatry Research, 35, 113.Google Scholar
Cahn, W., Hulshoff Pol, H. E., Bongers, M., et al (2002a) Brain morphology in antipsychotic-naïve schizophrenia: a study of multiple brain structures. British Journal of Psychiatry, 181 (suppl. 43), s66s72.CrossRefGoogle Scholar
Cahn, W., Hulshoff Pol, H. E., Lems, E. B., et al (2002b) Brain volume changes in first-episode schizophrenia: a 1-year follow-up study. Archives of General Psychiatry, 59, 10021010.Google Scholar
Chakos, M. H., Lieberman, J. A., Bilder, R. M., et al (1994) Increase in caudate nuclei volumes of first-episode schizophrenic patients taking antipsychotic drugs. American Journal of Psychiatry, 151, 14301436.Google ScholarPubMed
Chua, S. E., Lam, I. W., Tai, K. S., et al (2003) Brain morphological abnormality in schizophrenia is independent of country of origin. Acta Psychiatrica Scandinavica, 108, 269275.Google Scholar
Copolov, D., Velakoulis, D., McGorry, P., et al (2000) Neurobiological findings in early phase schizophrenia. Brain Research Reviews, 31, 157165.CrossRefGoogle ScholarPubMed
Corson, P. W., Nopoulos, P., Andreasen, N. C., et al (1999) Caudate size in first-episode neuroleptic-naive schizophrenic patients measured using an artificial neural network. Biological Psychiatry, 46, 712720.CrossRefGoogle ScholarPubMed
Crespo -Facorro, B., Kim, J., Andreasen, N. C., et al (2000) Insular cortex abnormalities in schizophrenia: a structural magnetic resonance imaging study of first-episode patients. Schizophrenia Research, 46, 3543.CrossRefGoogle ScholarPubMed
Davidson, L. L. & Heinrichs, R. W. (2003) Quantification of frontal and temporal lobe brain-imaging findings in schizophrenia: a meta-analysis. Neuroimaging, 122, 6987.Google Scholar
Degreef, G., Ashtari, M., Wu, H. W., et al (1991) Follow-up MRI study in first episode schizophrenia. Schizophrenia Research, 5, 204206.CrossRefGoogle ScholarPubMed
Degreef, G., Ashtari, M., Bogerts, B., et al (1992) Volumes of ventricular system subdivisions measured from magnetic resonance images in first-episode schizophrenic patients. Archives of General Psychiatry, 49, 531537.CrossRefGoogle ScholarPubMed
DeLisi, L. E., Hoff, A. L., Schwartz, J. E., et al (1991) Brain morphology in first-episode schizophrenic-like psychotic patients: a quantitative magnetic resonance imaging study. Biological Psychiatry, 29, 159175.CrossRefGoogle ScholarPubMed
DeLisi, L. E., Stritzke, P., Riordan, H., et al (1992) The timing of brain morphological changes in schizophrenia and their relationship to clinical outcome. Biological Psychiatry, 31, 241254.CrossRefGoogle ScholarPubMed
DeLisi, L. E., Hoff, A. L., Neale, C., et al (1994) Asymmetries in the superior temporal lobe in male and female first-episode schizophrenic patients: measures of the planum temporale and superior temporal gyrus by MRI. Schizophrenia Research, 12, 1928.CrossRefGoogle ScholarPubMed
DeLisi, L. E., Tew, W., Xie, S., et al (1995) A prospective follow-up study of brain morphology and cognition in first-episode schizophrenic patients: preliminary findings. Biological Psychiatry, 38, 349360.Google Scholar
DeLisi, L. E., Sakuma, M., Tew, W., et al (1997) Schizophrenia as a chronic active brain process: a study of progressive brain structural change subsequent to the onset of schizophrenia. Psychiatry Research, 74, 129140.CrossRefGoogle Scholar
DeLisi, L. E., Sakuma, M., Ge, S., et al (1998) Association of brain structural change with the heterogeneous course of schizophrenia from early childhood through five years subsequent to a first hospitalization. Psychiatry Research, 84, 7588.CrossRefGoogle ScholarPubMed
Ettinger, U., Chitnis, X. A., Kumari, V., et al (2001) Magnetic resonance imaging of the thalamus in first-episode psychosis. American Journal of Psychiatry, 158, 116118.CrossRefGoogle ScholarPubMed
Fannon, D., Tennakoon, L., O'Ceallaigh, S., et al (2000a) Third ventricle enlargement and developmental delay in first-episode psychosis: preliminary findings. British Journal of Psychiatry, 177, 354359.CrossRefGoogle ScholarPubMed
Fannon, D., Chitnis, X., Deku, V., et al (2000b) Features of structural brain abnormality detected in first-episode psychosis. American Journal of Psychiatry, 157, 18291834.CrossRefGoogle ScholarPubMed
Giedd, J. N., Blumenthal, J., Jeffries, N. O., et al (1999) Brain development during childhood and adolescence: a longitudinal MRI study. Nature Neuroscience, 2, 861863.Google Scholar
Gilbert, A. R., Rosenberg, D. R., Harenski, K., et al (2001) Thalamic volumes in patients with first-episode schizophrenia. American Journal of Psychiatry, 158, 618624.CrossRefGoogle ScholarPubMed
Gunduz, H., Wu, H., Ashtari, M., et al (2002) Basal ganglia volumes in first-episode schizophrenia and healthy comparison subjects. Biological Psychiatry, 51, 801808.CrossRefGoogle ScholarPubMed
Gur, R. E., Cowell, P., Turetsky, B. I., et al (1998) A follow-up magnetic resonance imaging study of schizophrenia. Relationship of neuroanatomical changes to clinical and neurobehavioral measures. Archives of General Psychiatry, 55, 145152.CrossRefGoogle ScholarPubMed
Haller, J. W., Banerjee, A., Christensen, G. E., et al (1997) Three-dimensional hippocampal MR morphometry with high-dimensional transformation of a neuroanatomic atlas. Radiology, 202, 504510.Google Scholar
Harrison, P. J. (1999) The neuropathology of schizophrenia: a critical review of the data and their interpretation. Brain, 122, 593624.Google Scholar
Harrison, P. J., Freemantle, N. & Geddes, J. R. (2003) Meta-analysis of brain weight in schizophrenia. Schizophrenia Research, 64, 2534.CrossRefGoogle ScholarPubMed
Hirayasu, Y., Sheton, M. E., Salisbury, D. F., et al (1998) Lower left temporal lobe MRI volumes in patients with first-episode schizophrenia compared with psychotic patients with first-episode affective disorder and normal subjects. American Journal of Psychiatry, 155, 13841391.CrossRefGoogle ScholarPubMed
Hirayasu, Y., Shenton, M. E., Salisbury, D. F., et al (1999) Subgenual cingulate cortex volume in first-episode psychosis. American Journal of Psychiatry, 156, 10911093.CrossRefGoogle ScholarPubMed
Hirayasu, Y., Shenton, M. E., Salisbury, D. F., et al (2000a) Hippocampal and superior temporal gyrus volume in first-episode schizophrenia. Archives of General Psychiatry, 57, 618619.CrossRefGoogle ScholarPubMed
Hirayasu, Y., McCarley, R. W., Salisbury, D. F., et al (2000b) Planum temporale and Heschl gyrus volume reduction in schizophrenia: a magnetic resonance imaging study of first-episode patients. Archives of General Psychiatry, 57, 692699.CrossRefGoogle ScholarPubMed
Hirayasu, Y., Tanaka, S., Shenton, M. E., et al (2001) Prefrontal gray matter volume reduction in first episode schizophrenia. Cerebral Cortex, 11, 374381.CrossRefGoogle ScholarPubMed
Ho, B. C., Andreasen, N. C., Nopoulos, P., et al (2003) Progressive structural brain abnormalities and their relationship to clinical outcome: a longitudinal magnetic resonance imaging study early in schizophrenia. Archives of General Psychiatry, 60, 585594.CrossRefGoogle ScholarPubMed
Hoff, A. L., Neal, C., Kushner, M., et al (1994) Gender differences in corpus callosum size in first-episode schizophrenics. Biological Psychiatry, 35, 913919.CrossRefGoogle ScholarPubMed
Howard, M. A., Roberts, N., Garcia-Finana, M., et al (2003) Volume estimation of pre-frontal cortical subfields using MRI and stereology. Brain Research. Brain Research Protocols, 10, 125138.CrossRefGoogle Scholar
Hulshoff-Pol, H. E., Schnack, H. G., Mandl, R. C., et al (2001) Focal gray matter density changes in schizophrenia. Archives of General Psychiatry, 58, 11181125.CrossRefGoogle ScholarPubMed
Hulshoff-Pol, H. E., Brans, R. G. H., van Haren, N. E. M., et al (2004) Gray and white matter volume abnormalities in monozygotic and same-gender dizygotic twins discordant for schizophrenia. Biological Psychiatry, 55, 126130.Google Scholar
James, A. C., Crow, T. J., Renowden, S., et al (1999) Is the course of brain development in schizophrenia delayed? Evidence from onsets in adolescence. Schizophrenia Research, 40, 110.CrossRefGoogle ScholarPubMed
Joyal, C. C., Laakso, M. P., Tiihonen, J., et al (2002) A volumetric MRI study of the entorhinal cortex in first episode neuroleptic-naive schizophrenia. Biological Psychiatry, 51, 10051007.CrossRefGoogle ScholarPubMed
Joyal, C. C., Laakso, M. P., Tiihonen, J., et al (2003) The amygdala and schizophrenia: a volumetric magnetic resonance imaging study in first-episode, neuroleptic-naive patients. Biological Psychiatry, 54, 13021304.Google Scholar
Joyce, E. M. (1996) Aetiology of alcoholic brain damage: alcoholic neurotoxicity or thiamine malnutrition? British Medical Bulletin, 50, 99114.CrossRefGoogle Scholar
Kasai, K., Iwanami, A., Yamasue, H., et al (2002) Neuroanatomy and neurophysiology in schizophrenia. Neuroscience Research, 43, 93110.Google Scholar
Kasai, K., Shenton, M. E., Salisbury, D. F., et al (2003a) Differences and similarities in insular and temporal pole MRI gray matter volume abnormalities in first-episode schizophrenia and affective psychosis. Archives of General Psychiatry, 60, 10691077.CrossRefGoogle ScholarPubMed
Kasai, K., Shenton, M. E., Salisbury, D. F., et al (2003b) Progressive decrease of left Heschl gyrus and planum temporale gray matter volume in first-episode schizophrenia: a longitudinal magnetic resonance imaging study. Archives of General Psychiatry, 60, 766775.CrossRefGoogle ScholarPubMed
Kasai, K., Shenton, M. E., Salisbury, D. F., et al (2003c) Progressive decrease of left superior temporal gyrus graymatter volume in patients with first-episode schizophrenia. American Journal of Psychiatry, 160, 156164.CrossRefGoogle Scholar
Keshavan, M. S., Rosenberg, D., Sweeney, J. A., et al (1998a) Decreased caudate volume in neuroleptic-naive psychotic patients. American Journal of Psychiatry, 155, 774778.Google ScholarPubMed
Keshavan, M. S., Rosenberg, D., Sweeney, J. A., et al (1998b) Superior temporal gyrus and the course of early schizophrenia: progressive, static, or reversible? Journal of Psychiatric Research, 32, 161167.Google Scholar
Konick, L. C. & Friedman, L. (2001) Meta-analysis of thalamic size in schizophrenia. Biological Psychiatry, 49, 2838.CrossRefGoogle ScholarPubMed
Laakso, M. P., Tiihonen, J., Syvalahti, E., et al (2001) A morphometric MRI study of the hippocampus in first-episode, neuroleptic-naive schizophrenia. Schizophrenia Research, 50, 37.Google Scholar
Lang, D. J., Kopala, L. C., Vandorpe, R. A., et al (2001) An MRI study of basal ganglia volumes in first-episode schizophrenia patients treated with risperidone. American Journal of Psychiatry, 158, 625631.Google Scholar
Lawrie, S. M., Whalley, H., Kestelman, J. M., et al (1999) Magnetic resonance imaging of brain in people at high risk of developing schizophrenia. Lancet, 353, 3033.CrossRefGoogle ScholarPubMed
Lee, C. U., Shenton, M. E., Salisbury, D. F., et al (2002) Fusiform gyrus volume reduction in first-episode schizophrenia: a magnetic resonance imaging study. Archives of General Psychiatry, 59, 775781.CrossRefGoogle ScholarPubMed
Lieberman, J. A., Alvir, J. M., Woerner, M., et al (1992) Prospective study of psychobiology in first-episode schizophrenia at Hillside Hospital. Schizophrenia Bulletin, 18, 351371.Google Scholar
Lieberman, J., Chakos, M., Wu, H., et al (2001) Longitudinal study of brain morphology in first episode schizophrenia. Biological Psychiatry, 49, 487499.CrossRefGoogle ScholarPubMed
Lim, K. O., Tew, W., Kushner, M., et al (1996) Cortical gray matter volume deficit in patients with first-episode schizophrenia. American Journal of Psychiatry, 153, 15481553.Google Scholar
MacFall, J. R., Payne, M. E. & Krishnan, K. R. R. (2004) MR scanner geometry changes: phantom measurements compared to intracranial contents calculations. Proceedings of the International Society for Magnetic Resonance in Medicine, 11, 2182.Google Scholar
Matsumoto, H., Simmons, A., Williams, S., et al (2001a) Structural magnetic imaging of the hippocampus in early onset schizophrenia. Biological Psychiatry, 49, 824831.CrossRefGoogle ScholarPubMed
Matsumoto, H., Simmons, A., Williams, S., et al (2001b) Superior temporal gyrus abnormalities in early-onset schizophrenia: similarities and differences with adult-onset schizophrenia. American Journal of Psychiatry, 158, 12991304.CrossRefGoogle ScholarPubMed
Maynard, T. M., Sikich, L., Lieberman, J. A., et al (2001) Neural development, cell–cell signalling, and the ‘two-hit’ hypothesis of schizophrenia. Schizophrenia Bulletin, 27, 457476.CrossRefGoogle ScholarPubMed
McCarley, R. W., Salisbury, D. F., Hirayasu, Y., et al (2002) Association between smaller left posterior superior temporal gyrus volume on magnetic resonance imaging and smaller left temporal P300 amplitude in first-episode schizophrenia. Archives of General Psychiatry, 59, 321331.CrossRefGoogle ScholarPubMed
Nelson, M. D., Saykin, A. J., Flashman, L. A., et al (1998) Hippocampal volume reduction in schizophrenia as assessed by MRI: a meta-analytic study. Archives of General Psychiatry, 55, 433440.Google Scholar
Niemann, K., Hammers, A., Coenen, V. A., et al (2000) Evidence of a smaller left hippocampus and left temporal horn in both patients with first episode schizophrenia and normal control subjects. Psychiatry Research, 99, 93110.CrossRefGoogle ScholarPubMed
Nopoulos, P., Torres, I., Flaum, M., et al (1995) Brain morphology in first-episode schizophrenia. American Journal of Psychiatry, 152, 17211723.Google ScholarPubMed
Okubo, Y., Tomoyuki, S. & Oda, K. (2001) A review of MRI studies of progressive brain changes in schizophrenia. Journal of Medical and Dental Science, 48, 6167.Google ScholarPubMed
Pfefferbaum, A., Mathalon, D. H., Sullivan, E. V., et al (1994) A quantitative magnetic resonance imaging study of changes in brain morphology from infancy to late adulthood. Archives of Neurology, 51, 874887.Google Scholar
Puri, B. K., Hutton, S. B., Saeed, N., et al (2001) A serial longitudinal quantitative MRI study of cerebral changes in first-episode schizophrenia using image segmentation and subvoxel registration. Psychiatry Research, 106, 141150.CrossRefGoogle ScholarPubMed
Razi, K., Greene, K. P., Sakuma, M., et al (1999) Reduction of the parahippocampal gyrus and the hippocampus in patients with chronic schizophrenia. British Journal of Psychiatry, 174, 512519.CrossRefGoogle ScholarPubMed
Salokangas, R. K. R., Cannon, T., Van Erp, T., et al (2002) Structural magnetic resonance imaging in patients with first-episode schizophrenia, psychotic and severe non-psychotic depression and healthy controls: results of the Schizophrenia and Affective Psychoses (SAP) project. British Journal of Psychiatry, 181 (suppl.43), s5865.CrossRefGoogle Scholar
Sanfilipo, M., Lafargue, T., Rusinek, H., et al (2000) Volumetric measure of the frontal and temporal lobe regions in schizophrenia. Archives of General Psychiatry, 57, 471480.CrossRefGoogle ScholarPubMed
Shenton, M. E., Dickey, C. C., Frumin, M., et al (2001) A review of MRI findings in schizophrenia. Schizophrenia Research, 49, 152.Google Scholar
Siever, L. J. & Davis, K. L. (2004) The pathophysiology of schizophrenia disorders: perspectives from the spectrum. American Journal of Psychiatry, 161, 398413.Google Scholar
Smith, G. N., Lang, D. J., Kopala, L. C., et al (2003) Developmental abnormalities of the hippocampus in first-episode schizophrenia. Biological Psychiatry, 53, 555561.Google Scholar
Steen, R. G., Ogg, R., Reddick, W. E., et al (1997) Age-related changes in the pediatric brain: quantitative magnetic resonance imaging provides evidence of maturational changes during adolescence. American Journal of Neuroradiology, 18, 819828.Google Scholar
Suddath, R. L., Casanova, M. F., Goldberg, T. E., et al (1989) Temporal lobe pathology in schizophrenia: a quantitative magnetic resonance imaging study. American Journal of Psychiatry, 146, 464472.Google Scholar
Sumich, A., Chitnis, X. A., Fannon, D. G., et al (2002) Temporal lobe abnormalities in first-episode psychosis. American Journal of Psychiatry, 159, 12321235.Google Scholar
Swayze, V. W., Anderson, A., Arndt, S., et al (1996) Reversibility of brain tissue loss in anorexia nervosa assessed with a computerized Talairach 3-D proportional grid. Psychological Medicine, 26, 381390.Google Scholar
Szeszko, P. R., Bilder, R. M., Lenez, T., et al (1999) Investigation of frontal lobe subregions in first-episode schizophrenia. Psychiatry Research, 90, 115.CrossRefGoogle ScholarPubMed
Szeszko, P. R., Gunning-Dixon, F., Ashtari, M., et al (2003a) Reversed cerebellar asymmetry in men with first-episode schizophrenia. Biological Psychiatry, 53, 450459.CrossRefGoogle ScholarPubMed
Szeszko, P. R., Goldberg, E., Gunduz-Bruce, H., et al (2003b) Smaller anterior hippocampal formation volume in antipsychotic-naive patients with first-episode schizophrenia. American Journal of Psychiatry, 160, 21902197.Google Scholar
Tofts, P. S., Barker, G. J., Filippi, M., et al (1997) An oblique cylinder contrast-adjusted (OCCA) phantom to measure the accuracy of MRI brain lesion volume estimation schemes in multiple sclerosis. Magnetic Resonance Imaging, 15, 183192.Google Scholar
Torrey, E. F. (2002) Studies of individuals with schizophrenia never treated with antipsychotic medications: a review. Schizophrenia Research, 58, 101151.Google Scholar
Uttal, W. (2001) The New Phrenology: The Limits of Localizing Cognitive Processes in the Brain. Cambridge, MA: MIT Press.Google Scholar
Velakoulis, D., Pantelis, C., McGorry, P. D., et al (1999) Hippocampal volume in first-episode psychoses and chronic schizophrenia: a high-resolution magnetic resonance imaging study. Archives of General Psychiatry, 56, 133141.Google Scholar
Wang, D. & Doddrell, D. M. (2002) MR image-based measurement of rates of change in volumes of brain structures. Part 1: Method and validation. Magnetic Resonance Imaging, 20, 2740.Google Scholar
Ward, K. E., Friedman, L., Wise, A., et al (1996) Meta-analysis of brain and cranial size in schizophrenia. Schizophrenia Research, 22, 197213.Google Scholar
Whitworth, A. B., Honeder, M., Kremser, C., et al (1998) Hippocampal volume reduction in male schizophrenic patients. Schizophrenia Research, 31, 7381.CrossRefGoogle ScholarPubMed
Wood, S. J., Velakoulis, D., Smith, D. J., et al (2001) A longitudinal study of hippocampal volume in first episode psychosis and chronic schizophrenia. Schizophrenia Research, 52, 3746.Google Scholar
Wright, I. C., Rabe-Hesketh, S., Woodruff, P. W. R., et al (2000) Meta-analysis of regional brain volumes in schizophrenia. American Journal of Psychiatry, 157, 1625.CrossRefGoogle ScholarPubMed
Zipursky, R. B., Lambe, E. K., Kapur, S., et al (1998a) Cerebral gray matter volume deficits in first episode psychosis. Archives of General Psychiatry, 55, 540546.CrossRefGoogle ScholarPubMed
Zipursky, R. B., Zhang-Wong, J., Lambe, E. K., et al (1998b) MRI correlates of treatment response in first episode psychosis. Schizophrenia Research, 30, 8190.Google Scholar
Figure 0

Table 1 Summary of cross-sectional and longitudinal studies included in review

Figure 1

Table 2 Whole-brain volume in cross-sectional studies

Figure 2

Table 3 Hippocampal volume in cross-sectional studies

Figure 3

Table 4 Ventricular volume in cross-sectional studies

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