Brugger et al.

1

Supplemental Information

Figure S1. Forest plot (random effects meta-analysis) of frontal cortex NAA levels in patients with chronic schizophrenia compared to controls. ........................................................................................ 2

Figure S2. Forest plot (random effects meta-analysis) of frontal cortex NAA levels in patients with first episode psychosis compared to controls. ....................................................................................... 3

Figure S3. Forest plot (random effects meta-analysis) of frontal cortex NAA levels in individuals at high risk of psychosis compared to controls. .......................................................................................... 4

Figure S4. Forest plot (random effects meta-analysis) of temporal cortex NAA levels in patients with chronic schizophrenia compared to controls. ........................................................................................ 5

Figure S5. Forest plot (random effects meta-analysis) of temporal cortex NAA levels in patients with first episode psychosis compared to controls. ....................................................................................... 6

Figure S6. Forest plot (random effects meta-analysis) of temporal cortex NAA levels in individuals at high risk of psychosis compared to controls. .......................................................................................... 7

Figure S7. Forest plot (random effects meta-analysis) of thalamic NAA levels in patients with chronic schizophrenia compared to controls. ..................................................................................................... 8

Figure S8. Forest plot (random effects meta-analysis) of thalamic NAA levels in patients with first episode psychosis compared to controls. ............................................................................................... 9

Figure S9. Funnel plot of studies of NAA levels in frontal cortex in patients with chronic schizophrenia ........................................................................................................................................ 10

Figure S10. Funnel plot of studies of NAA levels in frontal cortex in patients with first episode schizophrenia ........................................................................................................................................ 11

Figure S11. Funnel plot of studies of NAA levels in frontal cortex in individuals at risk of schizophrenia ........................................................................................................................................ 12

Figure S12. Funnel plot of studies of NAA levels in temporal cortex in patients with chronic schizophrenia ........................................................................................................................................ 13

Figure S13. Funnel plot of studies of NAA levels in temporal cortex in patients with first episode schizophrenia ........................................................................................................................................ 14

Figure S14. Funnel plot of studies of NAA levels in thalamus in patients with first episode and chronic schizophrenia ........................................................................................................................... 15

Figure S15. Funnel plot of studies of NAA levels in basal ganglia in patients with first episode and chronic schizophrenia ........................................................................................................................... 16

Table S1. Measures of heterogeneity and estimates of publication bias (*p < 0.05) for individuals at risk of psychosis (At risk), patients with first-episode schizophrenia (FES), chronic schizophrenia (Chronic), and for both patient groups combined (All pts).. ................................................................ 17

Table S2. 1H-MRS acquisition parameters for all included studies. ..................................................... 18

Table S3. Meta-regression of potential modifiers of NAA levels by region and illness phase (* corrected p < 0.05). ............................................................................................................................... 21

Please see main text for all references.

Brugger et al.

2

Figure S1. Forest plot (random effects meta-analysis) of frontal cortex NAA levels in patients with

chronic schizophrenia compared to controls.

Brugger et al.

3

Figure S2. Forest plot (random effects meta-analysis) of frontal cortex NAA levels in patients with first episode psychosis compared to controls.

Brugger et al.

4

Figure S3. Forest plot (random effects meta-analysis) of frontal cortex NAA levels in individuals at high risk of psychosis compared to controls.

Brugger et al.

5

Figure S4. Forest plot (random effects meta-analysis) of temporal cortex NAA levels in patients with chronic schizophrenia compared to controls.

Brugger et al.

6

Figure S5. Forest plot (random effects meta-analysis) of temporal cortex NAA levels in patients with first episode psychosis compared to controls.

Brugger et al.

7

Figure S6. Forest plot (random effects meta-analysis) of temporal cortex NAA levels in individuals at high risk of psychosis compared to controls.

Brugger et al.

8

Figure S7. Forest plot (random effects meta-analysis) of thalamic NAA levels in patients with chronic schizophrenia compared to controls.

Brugger et al.

9

Figure S8. Forest plot (random effects meta-analysis) of thalamic NAA levels in patients with first episode psychosis compared to controls.

Brugger et al.

10

Figure S9. Funnel plot of studies of NAA levels in frontal cortex in patients with chronic schizophrenia.

Brugger et al.

11

Figure S10. Funnel plot of studies of NAA levels in frontal cortex in patients with first episode schizophrenia.

Brugger et al.

12

Figure S11. Funnel plot of studies of NAA levels in frontal cortex in individuals at risk of schizophrenia.

Brugger et al.

13

Figure S12. Funnel plot of studies of NAA levels in temporal cortex in patients with chronic schizophrenia.

Brugger et al.

14

Figure S13. Funnel plot of studies of NAA levels in temporal cortex in patients with first episode schizophrenia.

Brugger et al.

15

Figure S14. Funnel plot of studies of NAA levels in thalamus in patients with first episode and chronic schizophrenia.

Brugger et al.

16

Figure S15. Funnel plot of studies of NAA levels in basal ganglia in patients with first episode and chronic schizophrenia.

Brugger et al.

17

Table S1. Measures of heterogeneity (Cochran Q and I2), and estimates of publication bias (*p < 0.05) for individuals at risk of psychosis (At risk), patients with first-episode schizophrenia (FES), chronic schizophrenia (Chronic), and for both patient groups combined (All pts).

Region Phase Q df Q P Value I2 (%) Publication bias t(df)

Frontal At risk 50.71 16 < 0.0001 68.4 -0.868(15) FES 60.76 31 0.0011 49 -0.531(30) Chronic 209.76 70 < 0.0001 66.6 -1.836(69)* All pts 271.26 103 < 0.0001 62 -1.709(102)* Temporal At risk 7.08 4 0.132 43.5 -0.558(3) FES 48.11 18 0.0001 62.6 -0.381(17) Chronic 110.73 34 < 0.0001 69.3 0.075(33) All pts 159.39 53 < 0.0001 66.7 0.051(52) Thalamus At risk 1.83 2 0.3998 0 0.446(1) FES 9.05 7 0.2491 22.7 -0.789(6) Chronic 25.67 19 0.1398 26 0.801(18) All pts 34.89 27 0.1418 22.6 0.405(26) Basal Ganglia FES 10.56 8 0.2281 24.2 1.089(7) Chronic 13.58 16 0.6301 0 0.858(15) All pts 24.18 25 0.509 0 1.305(24) Cerebellum All pts 7.72 5 0.1725 35.2 1.011(1) Occipital All pts 10.21 10 0.4223 2 1.939(4) Parietal All pts 2.83 9 0.9707 0 -0.560(4)

Brugger et al.

18

Table S2. 1H-MRS acquisition parameters for all included studies.

Study name Field strength Acquisition method Echo time (ms) Referencing method Ando et al. 2002 1.5 PRESS 40 ratio to Cr Auer et al. 2001 1.5 PRESS 35 water-scaled Aydin et al. 2007 1.5 STEAM 30, 38, 48, 65, 84, 135, and 300 water-scaled, multiple TE Aydin et al. 2008 1.5 STEAM 30, 38, 48, 65, 84, 135, and 300 water-scaled, multiple TE Bartha et al. 1997 1.5 STEAM 20 water-scaled Bartha et al. 1999 1.5 STEAM 20 water-scaled Başoğlu et al. 2006 1.5 PRESS 135 ratio to Cr Bertolino et al. 1996 1.5 MRSI 272 ratio to Cr Bertolino et al. 1998 1.5 MRSI 272 ratio to Cr Bertolino et al. 2000 1.5 MRSI 272 ratio to Cr Bertolino et al. 2000a 1.5 MRSI 272 ratio to Cr Bertolino et al. 2003 1.5 MRSI 272 ratio to Cr Block et al. 2000 1.5 PRESS 272 ratio to Cr Bluml et al. 1999 1.5 STEAM 30 water-scaled Buckley et al. 1994 1.5 STEAM 68 ratio to total spectrum metabolites Bustillo et al. 2001 1.5 STEAM, PRESS 30, 40 water-scaled Bustillo et al. 2002 1.5 PRESS 40 water-scaled Bustillo et al. 2002a 1.5 NOT STATED 40 water-scaled Bustillo et al. 2007 1.5 PRESS 40 water-scaled Callicott et al. 1998 1.5 MRSI 272 ratio to Cr Cecil et al. 1999 1.5 STEAM, PRESS 21, 16-21 ratio to Cr Choe et al. 1994 1.5 NOT STATED 30 ratio to Cr Choe et al. 1996 1.5 STEAM 20 ratio to Cr Deicken et al. 1997 1.5 PRESS 135 water-scaled Deicken et al. 1998 1.5 PRESS 135 ratio to Cr Deicken et al. 2001 1.5 MRSI 135 water-scaled Delamillieure et al. 2000 1.5 STEAM 30 ratio to Cr Delamillieure et al. 2000a 1.5 STEAM 30 ratio to Cr Delamillieure et al. 2002 1.5 STEAM 30 ratio to Cr Ende et al. 2000 1.5 PRESS, MRSI 135 coil reference voltage Ende et al. 2001 1.5 MRSI 135 coil reference voltage Ende et al. 2003 1.5 PRESS 135 coil reference voltage Ende et al. 2005 1.5 PRESS 135 not stated Fannon et al. 2003 1.5 PRESS 35 ratio to Cr Fujimoto et al. 1996 2 NOT STATED 135 ratio to Cr Fukuzako et al. 1995 2 STEAM 135 ratio to Cr

Brugger et al.

19

Fukuzako et al. 1999 2 STEAM 60 ratio to Cr Fukuzako et al. 2000 2 STEAM 60 ratio to Cr Galińska et al. 2009 1.5 PRESS 35 ratio to Cr Giménez et al. 2003 1.5 PRESS 35 ratio to Cho Hagino et al. 2002 1.5 PRESS 270 ratio to Cr Heimberg et al. 1998 1.5 STEAM 30 ratio to Cr Jakary et al. 2005 1.5 MRSI 135 water-scaled Jessen et al. 2006 1.5 PRESS 272 ratio to Cr Kegeles et al. 2000 1.5 STEAM 20 ratio to Cr Keshavan et al. 1997 1.5 STEAM 20 ratio to Cr Lim et al. 1998 1.5 MRSI 144 ratio to Cr Lutkenhoff et al. 2008 3 PRESS 30 water-scaled Maier et al. 1996 1.5 STEAM 10 water-scaled, T1 and T2 effects Martínez-Granados et al. 2008 1.5 PRESS 272 ratio to Cr Miyaoka et al. 2005 1.5 PRESS 30 ratio to Cr Molina et al. 2006 1.5 PRESS 136 ratio to Cr Nasrallah et al. 1994 1.5 STEAM 50 ratio to root mean square signal noise Ohara et al. 2000 1.5 PRESS 40 ratio to Cr Ohrmann et al. 2005 1.5 NOT STATED water-scaled Ohrmann et al. 2007 1.5 STEAM 20 water-scaled Ohrmann et al. 2008 1.5 PRESS 32 water-scaled Olbrich et al. 2008 2 PRESS 30 water-scaled Omori et al. 2000 1.5 PRESS 136 ratio to Cr O'Neill et al. 2004 1.5 MRSI 272 water-scaled Öngür et al. 2008 4 PRESS 30-500 water-scaled Pae et al. 2004 1.5 STEAM 20 ratio to Cr Purdon et al. 2008 3 STEAM 20 ratio to Cr Rowland et al. 2009 3 PRESS 35 water-scaled Sanches et al. 2008 1.5 PRESS 135 ratio to Cho + Cr Sarramea Crespo et al. 2008 1.5 PRESS 35 ratio to Cr Scherk et al. 2008 1.5 NOT STATED 30 ratio to Cr Sharma et al. 1992 1.5 STEAM 28.5 ratio to Cr Shimizu et al. 2007 1.5 PRESS 144 ratio to Cr Shioiri et al. 1996 1.5 STEAM 135 ratio to Cr Sigmundsson et al. 2003 1.5 PRESS 136 water-scaled Stanley et al. 2007 1.5 STEAM 20 water-scaled Steel et al. 2001 2 PRESS 145 corrected for coil-loading Stone et al. 2009 3 PRESS 30 water-scaled

Brugger et al.

20

Szulc et al. 2007 1.5 PRESS 35 ratio to Cr Tanaka et al. 2006 1.5 PRESS 30 water-scaled Tang et al. 2007 3 PRESS 30 not stated Tayoshi et al. 2009 3 STEAM 18 water-scaled Tebartz van Elst et al. 2005 2 PRESS 30 water-scaled Théberge et al. 2002 4 STEAM 20 water-scaled Théberge et al. 2003 4 STEAM 20 water-scaled Thomas et al. 1998 1.5 STEAM 18 ratio to Cr Tibbo et al. 2000 3 PRESS 120 ratio to Cr Tibbo et al. 2004 3 STEAM 20 ratio to Cr Tunc-Skarka et al. 2009 3 PRESS 30, 80, 200, 300 and 420 water-scaled Venkatraman et al. 2006 4 PRESS 30 not stated Weber-Fahr et al. 2002 1.5 PRESS 135 water-scaled Wobrock et al. 2008 1.5 PRESS 30 ratio to Cr Wood et al. 2003 1.5 PRESS 135 ratio to Cr Wood et al. 2007 3 PRESS 30 water-scaled Wood et al. 2008 3 PRESS 30 water-scaled Yamasue et al. 2002 1.5 PRESS 35 ratio to Cr Yamasue et al. 2003 1.5 PRESS 35 water-scaled Yasukawa et al. 2005 1.5 PRESS 30 ratio to Cr Yoo et al. 2009 1.5 PRESS 140 water-scaled Yurgelun-Todd et al. 1996 1.5 NOT STATED 20 ratio to Cr Zabala et al. 2007 1.5 PRESS 136 water-scaled

Brugger et al.

21

Table S3. Meta-regression of potential modifiers of NAA levels by region and illness phase (* corrected p < 0.05).

Region Phase Modifier Intercept Co-efficient P-value Adjusted P-value (BH)

frontal at risk Age 0.15594274 -0.004742847 0.7762049 0.94382294 frontal at risk MRS Echo Time 0.51220596 -0.00384089 0.03602375 0.23579182 frontal at risk Laterality -0.05506215 0.036691689 0.9166049 0.97334418 frontal at risk Acquisition Method 0.1793679 -0.098146924 0.76250587 0.94382294 frontal at risk Outcome measure 0.94031382 -0.520708848 0.2283028 0.58807389 frontal at risk Overall symptoms (PANSS) -2.36539285 0.066803631 0.2286954 0.58807389 frontal at risk Risk Type 0.10458268 -0.042101595 0.9197183 0.97334418 frontal at risk Subregion -0.05370892 0.055419276 0.909369 0.97334418 frontal chr Age -1.7632313 0.03651777 0.08287126 0.42597558 frontal chr Duration of Illness -0.7463544 0.01468232 0.5529304 0.93189774 frontal chr Treatment duration -1.6719801 0.01580522 0.79812365 0.94382294 frontal chr MRS Echo Time -0.2230628 -0.001747431 0.07917078 0.42597558 frontal chr Laterality -0.1047981 -0.19483579 0.16715378 0.58807389 frontal chr Acquisition Method -0.4200045 0.010843384 0.93278817 0.97334418 frontal chr Outcome measure -0.4400897 0.05840435 0.69803589 0.94382294 frontal chr Age of onset -5.4310586 0.22006038 0.02190158 0.19711422 frontal chr Overall symptoms (PANSS) -1.4340833 0.01272291 0.25812727 0.6408677 frontal chr Negative Symptoms (PANSS) -2.3833574 0.07170166 0.29834232 0.69343154 frontal chr Positive Symptoms (PANSS) -0.3139109 -0.00888872 0.79962777 0.94382294 frontal chr Subregion -0.8942017 0.25729741 0.22675257 0.58807389 frontal fep Age -0.210795475 -0.011316664 0.595379114 0.93189774 frontal fep Duration of Illness -0.764989979 0.120380304 0.428409998 0.8336627 frontal fep Treatment duration -0.326142376 -0.656463833 0.000180649 * 0.01269461 frontal fep MRS Echo Time -0.520614655 0.001339599 0.349670553 0.750032 frontal fep Laterality -0.698965874 0.165446209 0.362752978 0.750032 frontal fep Acquisition Method -0.444230802 0.015111663 0.928922431 0.97334418 frontal fep Outcome measure 0.007872518 -0.341911865 0.147016322 0.58806529

Brugger et al.

22

frontal fep Age of onset -4.360003782 0.175791899 0.001225912 * 0.02942189 frontal fep Overall symptoms (PANSS) -2.72586451 0.028745427 0.00448371 0.08070678 frontal fep Negative Symptoms (PANSS) -0.580129939 0.010419937 0.828736756 0.95180176 frontal fep Positive Symptoms (PANSS) -0.731428493 0.018513531 0.310012253 0.69752757 frontal fep Subregion -0.439881565 -0.004602918 0.986113996 0.98862848 temporal at risk Age -1.2622618 0.02416023 0.13835677 0.58598161 temporal at risk MRS Echo Time -0.08381048 -0.002329496 0.21833382 0.58807389 temporal at risk Outcome measure 0.6180435 -0.65117903 0.03493991 0.23579182 temporal chr Age -0.5334577 -0.001885899 0.948652843 0.97575721 temporal chr Duration of Illness -0.4245525 -0.012781917 0.752202192 0.94382294 temporal chr MRS Echo Time -0.4935516 -0.000970939 0.549800897 0.93189774 temporal chr Laterality -0.689393 0.052898356 0.725601216 0.94382294 temporal chr Acquisition Method -0.468789 -0.069396855 0.7336104 0.94382294 temporal chr Outcome measure -0.7492552 0.072901898 0.790358518 0.94382294 temporal chr Age of onset -1.9853644 0.071158368 0.614259232 0.93503805 temporal chr Overall symptoms (PANSS) 3.5703324 -0.050596849 0.020307215 0.19711422 temporal chr Negative Symptoms (PANSS) 3.1049593 -0.150365854 0.000352628 * 0.01269461 temporal chr Positive Symptoms (PANSS) 4.9573865 -0.359261152 0.030048148 0.23579182 temporal fep Age 1.3257 -0.0701 0.012185504 0.14622605 temporal fep Duration of Illness -0.7655 0.069 0.7656 0.94382294 temporal fep Treatment duration -0.6055 -1.3194 0.6651 0.94382294 temporal fep MRS Echo Time -0.2129231 -0.002921243 0.18786525 0.58807389 temporal fep Laterality -0.1936 -0.191 0.4753 0.87747692 temporal fep Acquisition Method -0.2771036 -0.081003859 0.78665532 0.94382294 temporal fep Outcome measure 0.7288 -0.7386 0.0064 0.09216 temporal fep Age of onset 7.7863 -0.3523 0.0936 0.42597558 temporal fep Overall symptoms (PANSS) -2.4124 0.025 0.0702 0.4212 thalamus chr Age -0.05150697 -0.007773174 0.7430407 0.94382294 thalamus chr Duration of Illness -0.40432254 -0.000353971 0.98862848 0.98862848 thalamus chr MRS Echo Time -0.15744525 -0.001472713 0.20304006 0.58807389

Brugger et al.

23

thalamus chr Laterality -0.35947383 0.025323496 0.83282654 0.95180176 thalamus chr Acquisition Method -0.09321198 -0.137588907 0.36459889 0.750032 thalamus chr Outcome measure -0.83835518 0.319923856 0.15858916 0.58807389 thalamus chr Age of onset 2.7494438 -0.13139156 0.09466124 0.42597558 thalamus chr Overall symptoms (PANSS) 0.4691245 -0.010963791 0.57803513 0.93189774 thalamus chr Negative symptoms (PANSS) 0.77277367 -0.052020921 0.38080845 0.7616169 thalamus chr Positive symptoms (PANSS) 1.03582788 -0.09822608 0.57727303 0.93189774 thalamus fep Age 0.05841769 -0.01958018 0.4640409 0.87747692 thalamus fep Duration of Illness -0.6967577 0.2291796 0.5622501 0.93189774 thalamus fep Treatment duration -0.3500399 -0.11638999 0.5852951 0.93189774 thalamus fep MRS Echo Time -0.38965678 -0.00022807 0.9083153 0.97334418 thalamus fep Laterality -0.04557282 -0.25551317 0.226024 0.58807389 thalamus fep Acquisition Method -0.58786447 0.115738342 0.6233587 0.93503805 thalamus fep Outcome measure 0.21275637 -0.41100799 0.2253015 0.58807389 thalamus fep Overall symptoms (PANSS) -1.46856672 0.01758715 0.2985608 0.69343154

chr, chronic; fep, first episode psychosis; PANSS, Positive and Negative Syndrome Scale.