University of Groningen Evidence-b(i)ased psychiatry de Vries, Ymkje Anna

Evidence-b(i)ased psychiatry

de Vries, Ymkje Anna

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Publication date: 2018

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):

de Vries, Y. A. (2018). Evidence-b(i)ased psychiatry. University of Groningen.

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2

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AM //BiBQM- 2+? `iB+H2Ƕb +QM+HmbBQM rb +HbbB}2/ b TQbBiBp2 Q` MQi@TQbBiBp2 UBM+Hm/BM; [m2biBQM#H2 M/ M2;iBp2V #b2/ QM i?2 b2Mi2M+2 BM i?2 #bi`+i `2TQ`iBM; i?2 mi?Q`bǶ Qp2`HH +QM+HmbBQM `2;`/BM; bim/v Qmi+QK2X *QM+HmbBQMb r2`2 +HbbB}2/ BM/2T2M/2MiHv #v _ M/ SC- r?Q rb #HBM/2/ iQ i?2 `2bmHib Q7 i?2 6. `2pB2rX

aiiBbiB+H MHvbBb

HH biiBbiB+H MHvb2b r2`2 T2`7Q`K2/ mbBM; ahh RRXyX h?2 #BMQKBH T`Q##BHBiv i2bi rb mb2/ iQ bb2bb r?2i?2` i?2 T`QTQ`iBQM Q7 TQbBiBp2 +QM+HmbBQMb BM DQm`MH `iB+H2b rb bB;MB}+MiHv /Bz2`2Mi 7`QK i?2 T`QTQ`iBQM Q7 TQbBiBp2 i`BHb ++Q`/BM; iQ i?2 6.X AM //BiBQM- r2 2tKBM2/ r?2i?2` MQi@TQbBiBp2 i`BHb U++Q`/BM; iQ i?2 6.V r2`2 KQ`2 HBF2Hv iQ #2 mMTm#HBb?2/- Q` Tm#HBb?2/ BM  TQbBiBp2 KMM2`- +QKT`2/ rBi? TQbBiBp2 i`BHb mbBM; 6Bb?2`Ƕb 2t+i i2biX h?2 T`2b2M+2 Q7 bim/v Tm#HB+iBQM #Bb Ui`BH `2bmHib MQi Tm#HBb?2/V-Qmi+QK2 `2TQ`iBM; #Bb U+?M;2b BM MHvbBb Q` T`BK`v 2M/TQBMi z2+iBM; bB;MB}+M+2 Q7 }M/BM;bV- M/ bTBM U#bi`+i +QM+HmbBQM MQi +QMbBbi2Mi rBi? Tm#HBb?2/ `2bmHib QM T`BK`v 2M/TQBMiV rb HbQ +QKT`2/ 7Q` TQbBiBp2 M/ MQi@TQbBiBp2 i`BHbX

q2 +QM/m+i2/ irQ K2i@MHvb2b, QM2 mbBM; /i 7`QK i?2 6. `2pB2rb M/ MQi?2` QM2 mbBM; i?2 +Q``2bTQM/BM; Tm#HBb?2/ /i (RN- Ry9)X >2/;2bǶ ; rb mb2/ b i?2 K2bm`2 Q7 2z2+i bBx2 M/ rb +H+mHi2/ mbBM; i?2 7QHHQrBM; 2[miBQM BM r?B+? t `2T`2b2Mib i?2 i biiBbiB+ M/ n1 M/ n2 `2 i?2 MmK#2`b Q7 bm#D2+ib BM i?2 /`m; M/ TH+2#Q

;`QmTb-`2bT2+iBp2Hv, g= t ×  1 n1 + 1 n2

h?2 pHm2b 7Q` ; r2`2 /Dmbi2/ mbBM; >2/;2bǶ +Q``2+iBQM 7Q` bKHH bKTH2 bBx2 (RN- Ry9)X h?2 i biiBbiB+ rb +H+mHi2/ 7`QK i?2 T`2+Bb2 T pHm2 M/ i?2 i`BH bKTH2 bBx2 mbBM; JB+`QbQ7i 1t+2HǶb hALo 7mM+iBQM- KmHiBTHvBM; i #v @R r?2M i?2 bim/v /`m; rb BM72`BQ` iQ TH+2#QX A7  T`2+Bb2 T pHm2 rb MQi pBH#H2 #2+mb2 Bi rb `2TQ`i2/ b  `M;2 U2X;X TIyXy8V- i?2 i biiBbiB+ rb +H+mHi2/ 7`QK Qi?2` bmKK`v biiBbiB+b- MK2Hv biM@ /`/ /2pBiBQMb- biM/`/ 2``Q`b- M/ N8W +QM}/2M+2 BMi2`pHb `QmM/ i?2 K2M /Bz2`2M+2X q?2M i?2 /i r2`2 T`2b2Mi2/ b /B+?QiQKBx2/ biiBbiB+b- >2/;2bǶ ; rb +H+mHi2/ 7`QK χ2 (Rkk)X A7 MQM2 Q7 i?2b2 /i r2`2 pBH#H2- M/ 6. M/ DQm`MH /i r2`2 Qi?2`rBb2 +QM;`m2Mi- /i r2`2 BKTmi2/ rBi? /i 2ti`+i2/ 7`QK i?2 Qi?2` bQm`+2X

//BiBQMHHv-ke

7Q` irQ DQm`MH `iB+H2b >2/;2bǶ ; rb +H+mHi2/ 7`QK i?2 6 biiBbiB+ UMHvbBb Q7 p`BM+2V (Rk9)X 6BMHHv- T pHm2b M/ Qi?2` 2{++v /i r2`2 MQi `2TQ`i2/ 7Q` k M2;iBp2 6. i`BHb i?i r2`2- BM QM2 +b2- MQi Tm#HBb?2/ M/- BM i?2 Qi?2` +b2- Tm#HBb?2/ b TQbBiBp2X h?2b2 T pHm2b r2`2 BKTmi2/ rBi? T4yXjNe- r?B+? rb /2`Bp2/ 7`QK Re MQMbB;MB}+Mi #mi T`2+Bb2 S pHm2b- ++Q`/BM; iQ i?2 K2i?Q/ T`2pBQmbHv /2b+`B#2/ #v hm`M2` 2i HX (RN)X 6Q` 2+? KmHiBTH2@/Qb2 bim/v- r2 +QKTmi2/  bBM;H2 bim/v@H2p2H 2z2+i bBx2 mbBM;  }t2/ 2z2+ib KQ/2H iQ TQQH i?2 pHm2b 7`QK i?i i`BHǶb KmHiBTH2 i`2iK2Mi `KbX q?2M +H+m@ HiBM; i?2 biM/`/ 2``Q`- 2+? i`BHǶb b?`2/ TH+2#Q M rb +QmMi2/ QM+2- `i?2` i?M `2/mM/MiHv- 7Q` 2+? /Qb2 ;`QmT iQ pQB/  bTm`BQmbHv HQr biM/`/ 2``Q`X  HBKBiiBQM Q7 i?Bb K2i?Q/ Bb i?i Bi QMHv T`iBHHv //`2bb2b 2``Q` /m2 iQ +Q``2HiBQM #2ir22M i?2 +QKT`BbQMb (Ryk)X *H+mHiBQMb Q7 HH 2z2+i bBx2b r2`2 T2`7Q`K2/ BM/2T2M/2MiHv #v _ M/ uoX

h?2 `M/QK 2z2+ib TQQHBM; K2i?Q/ rb mb2/ iQ ;2M2`i2 bmKK`v 2biBKi2b Q7 >2/;2bǶ ;X Ak <sub>M/ +QM}/2M+2 BMi2`pHb `QmM/ A</sub>k <sub>r2`2 +H+mHi2/ iQ bb2bb ?2i2`Q;2M2Biv (Rk8)X</sub>

Ak _{`2~2+ib i?2 T`QTQ`iBQM Q7 iQiH p`BM+2 2tTHBM2/ #v ?2i2`Q;2M2BivX}

J2i@`2;`2bbBQM-mbBM; i?2 `2bi`B+i2/ KtBKmK HBF2HB?QQ/ K2i?Q/- rb +QM/m+i2/ iQ 2tKBM2 i?2 BKT+i Q7 Tm#HB+iBQM biimb QM i?2 2z2+i 2biBKi2bX AM //BiBQM- T`2@bT2+B}2/ bm#;`QmT MHvb2b r2`2 T2`7Q`K2/ 7Q` 2+? MtB2iv /BbQ`/2`X

_2bmHib

6. `2pB2rb

q2 MHvx2/ N b2+QM/@;2M2`iBQM MiB/2T`2bbMib 7Q` /i `2Hi2/ iQ i?2 8 MtB2iv /BbQ`@ /2`bX qBi?BM i?Qb2 98 TQbbB#H2 /`m;@BM/B+iBQM +QK#BMiBQMb- kR `2 6.@TT`Qp2/X P7 i?Qb2- r2 r2`2 #H2 iQ /QrMHQ/ N 6. TT`QpH T+F;2b i?`Qm;? i?2 6. r2#bBi2c 7Q` i?2 `2KBMBM; Rk- r2 K/2 `2[m2bib iQ i?2 6. 6`22/QK Q7 AM7Q`KiBQM P{+2X P7 i?2b2-i?2 6. 6`22/QK Q7 AM7Q`KiBQM P{+2 7mH}HH2/ RR `2[m2bib ě i?2b2-i?2 6. BM7Q`K2/ mb i?i i?2 /`m; TT`QpH T+F;2 7Q` ~mQt2iBM2 7Q` TMB+ /BbQ`/2` rQmH/ MQi #2 pBH#H2 7Q` i H2bi R3 KQMi?bX h?Bb H27i ky TT`QpH T+F;2b BM i?Bb bim/vX h?2b2 /`m; TT`QpH T+F@ ;2b- r?B+? r2`2 Bbbm2/ #2ir22M RNN9 M/ kyy3- `2pB2r2/ i?2 `2bmHib Q7 8d `M/QKBx2/-TH+2#Q@+QMi`QHH2/ b?Q`i@i2`K i`BHbX

CQm`MH `iB+H2b

6Q` i?2 8d #Qp2@K2MiBQM2/ 6.@`2;Bbi2`2/ i`BHb- r2 B/2MiB}2/ 8k i`BHb Tm#HBb?2/ BM 93 Tm#HB+iBQMbX h?`22 Q7 i?2b2 `iB+H2b r2`2 2t+Hm/2/ 7`QK 7m`i?2` MHvb2bX b  `2bmHi- j //BiBQMH i`BHb r2`2 Dm/;2/ iQ #2 MQi 7mHHv Tm#HBb?2/X hrQ `iB+H2b TQQH2/ i`BHb r?B+? r2`2 MQi B/2MiB+H BM /2bB;M (Rke- Rkd) M/ MQi?2` TQQH2/@i`BHb `iB+H2 7BH2/ iQ T`2b2Mi

2

2M/TQBMi rb +H2`Hv 2KT?bBx2/- r2 2ti`+i2/ i?2 /`m;@TH+2#Q +QKT`BbQM `2TQ`i2/ }`bi BM i?2 i2ti Q7 i?2 `2bmHib b2+iBQM Q` BM i?2 i#H2 Q` };m`2 }`bi +Bi2/ BM i?2 i2ti (Ry9)X A7 KmHiBTH2 2M/TQBMib r2`2 B/2MiB}2/ b T`BK`v BM  bBM;H2 bim/v- `2bmHib r2`2 2ti`+i2/ 7Q` i?2 2M/TQBMi `2pB2r2/ b T`BK`v #v i?2 6.X .i 2ti`+iBQM M/ 2Mi`v rb /QM2 BM/2T2M/2MiHv #v _ M/ _a rBi? /Bb+`2TM+B2b `2bQHp2/ i?`Qm;? +QMb2Mbmb U_- _a-uoVX

AM //BiBQM- 2+? `iB+H2Ƕb +QM+HmbBQM rb +HbbB}2/ b TQbBiBp2 Q` MQi@TQbBiBp2 UBM+Hm/BM; [m2biBQM#H2 M/ M2;iBp2V #b2/ QM i?2 b2Mi2M+2 BM i?2 #bi`+i `2TQ`iBM; i?2 mi?Q`bǶ Qp2`HH +QM+HmbBQM `2;`/BM; bim/v Qmi+QK2X *QM+HmbBQMb r2`2 +HbbB}2/ BM/2T2M/2MiHv #v _ M/ SC- r?Q rb #HBM/2/ iQ i?2 `2bmHib Q7 i?2 6. `2pB2rX

aiiBbiB+H MHvbBb

HH biiBbiB+H MHvb2b r2`2 T2`7Q`K2/ mbBM; ahh RRXyX h?2 #BMQKBH T`Q##BHBiv i2bi rb mb2/ iQ bb2bb r?2i?2` i?2 T`QTQ`iBQM Q7 TQbBiBp2 +QM+HmbBQMb BM DQm`MH `iB+H2b rb bB;MB}+MiHv /Bz2`2Mi 7`QK i?2 T`QTQ`iBQM Q7 TQbBiBp2 i`BHb ++Q`/BM; iQ i?2 6.X AM //BiBQM- r2 2tKBM2/ r?2i?2` MQi@TQbBiBp2 i`BHb U++Q`/BM; iQ i?2 6.V r2`2 KQ`2 HBF2Hv iQ #2 mMTm#HBb?2/- Q` Tm#HBb?2/ BM  TQbBiBp2 KMM2`- +QKT`2/ rBi? TQbBiBp2 i`BHb mbBM; 6Bb?2`Ƕb 2t+i i2biX h?2 T`2b2M+2 Q7 bim/v Tm#HB+iBQM #Bb Ui`BH `2bmHib MQi Tm#HBb?2/V-Qmi+QK2 `2TQ`iBM; #Bb U+?M;2b BM MHvbBb Q` T`BK`v 2M/TQBMi z2+iBM; bB;MB}+M+2 Q7 }M/BM;bV- M/ bTBM U#bi`+i +QM+HmbBQM MQi +QMbBbi2Mi rBi? Tm#HBb?2/ `2bmHib QM T`BK`v 2M/TQBMiV rb HbQ +QKT`2/ 7Q` TQbBiBp2 M/ MQi@TQbBiBp2 i`BHbX

q2 +QM/m+i2/ irQ K2i@MHvb2b, QM2 mbBM; /i 7`QK i?2 6. `2pB2rb M/ MQi?2` QM2 mbBM; i?2 +Q``2bTQM/BM; Tm#HBb?2/ /i (RN- Ry9)X >2/;2bǶ ; rb mb2/ b i?2 K2bm`2 Q7 2z2+i bBx2 M/ rb +H+mHi2/ mbBM; i?2 7QHHQrBM; 2[miBQM BM r?B+? t `2T`2b2Mib i?2 i biiBbiB+ M/ n1 M/ n2 `2 i?2 MmK#2`b Q7 bm#D2+ib BM i?2 /`m; M/ TH+2#Q

;`QmTb-`2bT2+iBp2Hv, g= t ×  1 n1 + 1 n2

h?2 pHm2b 7Q` ; r2`2 /Dmbi2/ mbBM; >2/;2bǶ +Q``2+iBQM 7Q` bKHH bKTH2 bBx2 (RN- Ry9)X h?2 i biiBbiB+ rb +H+mHi2/ 7`QK i?2 T`2+Bb2 T pHm2 M/ i?2 i`BH bKTH2 bBx2 mbBM; JB+`QbQ7i 1t+2HǶb hALo 7mM+iBQM- KmHiBTHvBM; i #v @R r?2M i?2 bim/v /`m; rb BM72`BQ` iQ TH+2#QX A7  T`2+Bb2 T pHm2 rb MQi pBH#H2 #2+mb2 Bi rb `2TQ`i2/ b  `M;2 U2X;X TIyXy8V- i?2 i biiBbiB+ rb +H+mHi2/ 7`QK Qi?2` bmKK`v biiBbiB+b- MK2Hv biM@ /`/ /2pBiBQMb- biM/`/ 2``Q`b- M/ N8W +QM}/2M+2 BMi2`pHb `QmM/ i?2 K2M /Bz2`2M+2X q?2M i?2 /i r2`2 T`2b2Mi2/ b /B+?QiQKBx2/ biiBbiB+b- >2/;2bǶ ; rb +H+mHi2/ 7`QK χ2 (Rkk)X A7 MQM2 Q7 i?2b2 /i r2`2 pBH#H2- M/ 6. M/ DQm`MH /i r2`2 Qi?2`rBb2 +QM;`m2Mi- /i r2`2 BKTmi2/ rBi? /i 2ti`+i2/ 7`QK i?2 Qi?2` bQm`+2X

//BiBQMHHv-ke

7Q` irQ DQm`MH `iB+H2b >2/;2bǶ ; rb +H+mHi2/ 7`QK i?2 6 biiBbiB+ UMHvbBb Q7 p`BM+2V (Rk9)X 6BMHHv- T pHm2b M/ Qi?2` 2{++v /i r2`2 MQi `2TQ`i2/ 7Q` k M2;iBp2 6. i`BHb i?i r2`2- BM QM2 +b2- MQi Tm#HBb?2/ M/- BM i?2 Qi?2` +b2- Tm#HBb?2/ b TQbBiBp2X h?2b2 T pHm2b r2`2 BKTmi2/ rBi? T4yXjNe- r?B+? rb /2`Bp2/ 7`QK Re MQMbB;MB}+Mi #mi T`2+Bb2 S pHm2b- ++Q`/BM; iQ i?2 K2i?Q/ T`2pBQmbHv /2b+`B#2/ #v hm`M2` 2i HX (RN)X 6Q` 2+? KmHiBTH2@/Qb2 bim/v- r2 +QKTmi2/  bBM;H2 bim/v@H2p2H 2z2+i bBx2 mbBM;  }t2/ 2z2+ib KQ/2H iQ TQQH i?2 pHm2b 7`QK i?i i`BHǶb KmHiBTH2 i`2iK2Mi `KbX q?2M +H+m@ HiBM; i?2 biM/`/ 2``Q`- 2+? i`BHǶb b?`2/ TH+2#Q M rb +QmMi2/ QM+2- `i?2` i?M `2/mM/MiHv- 7Q` 2+? /Qb2 ;`QmT iQ pQB/  bTm`BQmbHv HQr biM/`/ 2``Q`X  HBKBiiBQM Q7 i?Bb K2i?Q/ Bb i?i Bi QMHv T`iBHHv //`2bb2b 2``Q` /m2 iQ +Q``2HiBQM #2ir22M i?2 +QKT`BbQMb (Ryk)X *H+mHiBQMb Q7 HH 2z2+i bBx2b r2`2 T2`7Q`K2/ BM/2T2M/2MiHv #v _ M/ uoX

h?2 `M/QK 2z2+ib TQQHBM; K2i?Q/ rb mb2/ iQ ;2M2`i2 bmKK`v 2biBKi2b Q7 >2/;2bǶ ;X Ak <sub>M/ +QM}/2M+2 BMi2`pHb `QmM/ A</sub>k <sub>r2`2 +H+mHi2/ iQ bb2bb ?2i2`Q;2M2Biv (Rk8)X</sub>

Ak _{`2~2+ib i?2 T`QTQ`iBQM Q7 iQiH p`BM+2 2tTHBM2/ #v ?2i2`Q;2M2BivX}

J2i@`2;`2bbBQM-mbBM; i?2 `2bi`B+i2/ KtBKmK HBF2HB?QQ/ K2i?Q/- rb +QM/m+i2/ iQ 2tKBM2 i?2 BKT+i Q7 Tm#HB+iBQM biimb QM i?2 2z2+i 2biBKi2bX AM //BiBQM- T`2@bT2+B}2/ bm#;`QmT MHvb2b r2`2 T2`7Q`K2/ 7Q` 2+? MtB2iv /BbQ`/2`X

_2bmHib

6. `2pB2rb

q2 MHvx2/ N b2+QM/@;2M2`iBQM MiB/2T`2bbMib 7Q` /i `2Hi2/ iQ i?2 8 MtB2iv /BbQ`@ /2`bX qBi?BM i?Qb2 98 TQbbB#H2 /`m;@BM/B+iBQM +QK#BMiBQMb- kR `2 6.@TT`Qp2/X P7 i?Qb2- r2 r2`2 #H2 iQ /QrMHQ/ N 6. TT`QpH T+F;2b i?`Qm;? i?2 6. r2#bBi2c 7Q` i?2 `2KBMBM; Rk- r2 K/2 `2[m2bib iQ i?2 6. 6`22/QK Q7 AM7Q`KiBQM P{+2X P7 i?2b2-i?2 6. 6`22/QK Q7 AM7Q`KiBQM P{+2 7mH}HH2/ RR `2[m2bib ě i?2b2-i?2 6. BM7Q`K2/ mb i?i i?2 /`m; TT`QpH T+F;2 7Q` ~mQt2iBM2 7Q` TMB+ /BbQ`/2` rQmH/ MQi #2 pBH#H2 7Q` i H2bi R3 KQMi?bX h?Bb H27i ky TT`QpH T+F;2b BM i?Bb bim/vX h?2b2 /`m; TT`QpH T+F@ ;2b- r?B+? r2`2 Bbbm2/ #2ir22M RNN9 M/ kyy3- `2pB2r2/ i?2 `2bmHib Q7 8d `M/QKBx2/-TH+2#Q@+QMi`QHH2/ b?Q`i@i2`K i`BHbX

CQm`MH `iB+H2b

6Q` i?2 8d #Qp2@K2MiBQM2/ 6.@`2;Bbi2`2/ i`BHb- r2 B/2MiB}2/ 8k i`BHb Tm#HBb?2/ BM 93 Tm#HB+iBQMbX h?`22 Q7 i?2b2 `iB+H2b r2`2 2t+Hm/2/ 7`QK 7m`i?2` MHvb2bX b  `2bmHi- j //BiBQMH i`BHb r2`2 Dm/;2/ iQ #2 MQi 7mHHv Tm#HBb?2/X hrQ `iB+H2b TQQH2/ i`BHb r?B+? r2`2 MQi B/2MiB+H BM /2bB;M (Rke- Rkd) M/ MQi?2` TQQH2/@i`BHb `iB+H2 7BH2/ iQ T`2b2Mi

b2T`i2 `2bmHib 7Q` i?2 BM+Hm/2/ i`BHb (Rk3) M/ BM+Hm/2/  i`BH i?i rb T`2pBQmbHv Tm#HBb?2/ b  biM/@HQM2 Tm#HB+iBQM (RkN)X 0 10 20 30 40

Positive trials Not−positive trials

Number of trials

Published in agreement with FDA Published in disagreement with FDA Unpublished

6B;m`2 kXR, Sm#HB+iBQM biimb Q7 TQbBiBp2 M/ MQi@TQbBiBp2 6. i`BHb

h`BH Qmi+QK2 p2`bmb Tm#HBb?2/ `2bmHib

h?2 T`QTQ`iBQM Q7 TQbBiBp2 }M/BM;b rb dkW U9Rf8dV ++Q`/BM; iQ i?2 6. p2`bmb NeW U9jf98V ++Q`/BM; iQ i?2 Tm#HBb?2/ HBi2`im`2X h?Bb /Bz2`2M+2 rb biiBbiB+HHv bB;MB}+Mi U#BMQKBH i2bi TIyXyyRVX

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aim/v Tm#HB+iBQM #Bb

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Positive trials Not−positive trials

Number of trials

Published in agreement with FDA Published in disagreement with FDA Unpublished

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PM2 Q7 i?2 j #Qp2@K2MiBQM2/ Tm#HB+iBQMb Ui`BH Rky- T`Qt2iBM2 7Q` S.V T`2b2Mi2/ QMHv Q#b2`p2/@+b2b MHvb2b 7Q` i?2 T`BK`v Qmi+QK2 (RjN)c ++Q`/BM; iQ i?2 6.- i?2 T`BK`v MHvbBb BMpQHp2/ Hbi@Q#b2`piBQM@+``B2/@7Q`r`/ UGP*6V MHvb2b- i?2 `2bmHib Q7 r?B+? r2`2 MQi biiBbiB+HHv bB;MB}+MiX

AM i?2 `iB+H2 T`2b2MiBM; `2bmHib Q7 i`BH 8kN- /i 7`QK bm#D2+ib rBi? S. r?Q r2`2 `M@ /QKBx2/ iQ /Bz2`2Mi /Qb;2b Q7 b2`i`HBM2 r2`2 TQQH2/ M/ +QKT`2/ iQ i?2 TH+2#Q ;`QmT-vB2H/BM;  bB;MB}+Mi `2bmHi (RkN)c i?2 6. `2pB2r b?Qr2/ i?i i?2 T`BK`v `2bmHib 7Q` 2+? Q7 i?2 BM/BpB/mH /Qb;2 ;`QmTb r2`2 MQMbB;MB}+MiX

jy

6BMHHv- QM2 `iB+H2 T`2b2MiBM; i?2 `2bmHib Q7 i`BH N8@yyj- r?B+? +QKT`2/ i?2 2z2+i Q7 b2`i`HBM2 UrBi? M/ rBi?Qmi 2tTQbm`2 i?2`TvV iQ TH+2#Q UrBi? M/ rBi?Qmi 2tTQbm`2 i?2`TvV BM TiB2Mib rBi? a.- +QK#BM2/ b+Q`2b QM i?`22 2M/TQBMib U/BbQ`/2`@bT2+B}+ *HBMB+H :HQ#H AKT`2bbBQM a+H2 (b2p2`Biv M/ BKT`Qp2K2Mi) M/ aQ+BH S?Q#B a+H2V BM `2bTQMb2 p2`bmb MQM@`2bTQMb2 +i2;Q`B2b (R8d)c i?2 6. `2pB2r b?Qr2/ i?i i?2 T`BK`v 2M/TQBMi rb i?2 b2p2`Biv iQiH b+Q`2 Q7 i?2 /BbQ`/2`@bT2+B}+ *HBMB+H :HQ#H AKT`2bbBQM a+H2 M/ i?i i?Bb rb MQMbB;MB}+MiX

aTBM

aTBM rb T`2b2Mi BM M //BiBQMH j Qmi Q7 Re URNWV Q7 i?2 MQi@TQbBiBp2 i`BHb M/ MQi T`2b2Mi 7Q` TQbBiBp2 i`BHb U6Bb?2`Ƕb 2t+i i2bi T4yXykV Uh#H2 kXRVX 1+? Q7 i?2b2 j `iB+H2b (Ree- RdR- R93) `2TQ`i2/ i?i i?2 T`BK`v 2M/TQBMi rb MQMbB;MB}+Mi BM i?2 `2bmHib b2+iBQM #mi- BM i?2 #bi`+i- +QM+Hm/2/ i?i i?2 i`BH rb TQbBiBp2X h?2 6. +HbbB}2/ i?2b2 i`BHb b [m2biBQM#H2 Ui`BH kjdfk93, b2`i`HBM2 7Q` P*.V Q` M2;iBp2 Ui`BH 1ydN, ~mQt2iBM2 7Q` P*. M/ i`BH jNR, p2MH7tBM2 1_ 7Q` S.VX *QM+HmbBQMb QM bim/v /`m; 2{++v 7Q` i?2b2 i`BHb- ++Q`/BM; iQ i?2 6. M/ i?2 mi?Q`b Q7 i?2 DQm`MH `iB+H2b- `2 BM+Hm/2/ BM h#H2 kXj BM i?2 TT2M/BtX

J2i@MHvbBb

h?2 TQQH2/ 2z2+i bBx2 #b2/ QM i?2 6. /i rb yXjj UN8W *A, yXkN @ yXj3c TIyXyyRVX >2i2`Q;2M2Biv rb KQ/2`i2 UAk_{4jNWc N8W *A, R8W @ 8eWVX 6Q` i`BHb Tm#HBb?2/ BM}

;`22K2Mi rBi? i?2 6. `2pB2r `2bmHib- i?2 TQQH2/ 2z2+i bBx2 U>2/;2bǶ ;4yXj3c N8W *A, yXj9@yX9kc TIyXyyRV rb H`;2` i?M i?2 TQQH2/ 2z2+i bBx2 Q7 i`BHb i?i r2`2 MQi Tm#HBb?2/ Q` Tm#HBb?2/ BM /Bb;`22K2Mi rBi? i?2 6. +QM+HmbBQM U;4yXRdc N8W *A, yXyN @ yXkec TIyXyyRVX J2i@`2;`2bbBQM b?Qr2/ i?Bb /Bz2`2M+2 iQ #2 biiBbiB+HHv bB;MB}+Mi U;4yXkRc N8W *A, yXRk @ yXjyc i49XeRc TIyXyyRVX

h?2 TQQH2/ 2z2+i bBx2 #b2/ QM i?2 Tm#HBb?2/ HBi2`im`2 rb yXj3 UN8W *A, yXjj @ yX9kc TIyXyyRVX >2i2`Q;2M2Biv rb HQr UAk<sub>4jyWc N8W *A, yW @ 8RWVX h?Bb 2z2+i bBx2 `2T`2@</sub>

b2Mi2/  R8W BM+`2b2 BM 2z2+i bBx2 +QKT`2/ rBi? i?2 pHm2 #b2/ QM i?2 6. /iX h?Bb /Bz2`2M+2 rb MQi biiBbiB+HHv bB;MB}+Mi #v K2i@`2;`2bbBQM U;4yXy9c N8W *A, @yXyk @ yXRyc i4RXjec T4yXR3VX

1z2+i bBx2b #b2/ QM /i 7`QK i?2 6. `2pB2rb r2`2 yXjk 7Q` :.- yXk3 7Q` S.- yXkd 7Q` Sha.- M/ yXjN 7Q` #Qi? P*. M/ a.X 6Q` HH /BbQ`/2`b i?2 TQQH2/ 2z2+i bBx2b Q7 i`BHb Tm#HBb?2/ BM ;`22K2Mi rBi? i?2 6. `2pB2r `2bmHib r2`2 H`;2` i?M i?2 TQQH2/ 2z2+i bBx2b Q7 i`BHb i?i r2`2 MQi Tm#HBb?2/ Q` Tm#HBb?2/ BM /Bb;`22K2Mi rBi? i?2 6. +QM+HmbBQM Uh#H2 kXkVX b  `2bmHi 7Q`2bi THQib 7Q` HH /BbQ`/2`b b?Qr2/ 72r2` MQMbB;MB}+Mi i`BHb ++Q`/BM; iQ i?2 Tm#HBb?2/ HBi2`im`2 i?M ++Q`/BM; iQ i?2 6.- 2bT2+BHHv 7Q` S.

h#H2 kXk, J2i@MHvbBb

6.

Sm#HBb?2/ LQi Tm#HBb?2/

hQiH BM ;`22K2Mi BM ;`22K2Mi CQm`MH Pp2`2biBKi2

.BbQ`/2` >2/;2bǶ ;_{UN8W *AV} >2/;2bǶ ;_{UN8W *AV} >2/;2bǶ ;_{UN8W *AV} >2/;2bǶ ;_{UN8W *AV} W T

:. yXjk yXj9 yXRR yXj9 _{eW yXe8}

UyXk8@yXjNV UyXk3@yX9RV U@yXyN@yXjRV UyXkd@yX9RV

S. yXk3 yXjj yXRj yXj8 _{k8W yXj3}

UyXky@yXjeV UyXk8@yX9RV U@yXyk@yXkNV UyXk9@yX9eV

a. yXjN yX9j yXyN yX9k _{3W yX8e}

UyXjy@yX9NV UyXj8@yX8yV U@yXRR@yXkNV UyXj8@yX9NV

Sha. yXkd yXjj yXRj yXjk _{RNW yXde}

UyXRR@yX99V UyXR9@yX8jV U@yXRk@yXj3V UyXR9@yX8yV

P*. yXjN yX99 yXjy yX98 _{R8W yX9k}

UyXjy@yX9NV UyXjj@yX89V UyXRR@yX93V UyXj8@yX8eV

Pp2`HH yXjj yXj3 yXRd yXj3 _{R8W yXR3}

UyXkN@yXj3V UyXj9@yX9kV UyXyN@yXkeV UyXjj@yX9kV

6., 6QQ/ M/ .`m; /KBMBbi`iBQMc :., ;2M2`HBx2/ MtB2iv /BbQ`/2`c P*., Q#b2bbBp2 +QK@ TmHbBp2 /BbQ`/2`c S., TMB+ /BbQ`/2`c Sha., TQbii`mKiB+ bi`2bb /BbQ`/2`c a., bQ+BH MtB2iv /BbQ`/2`X

M/ P*. U6B;m`2b kXk M/ kXj (b22 6B;m`2b kX9- kX8- M/ kXe BM i?2 TT2M/Bt 7Q` :.-a.- M/ Sha.)VX

1z2+i bBx2b #b2/ QM i?2 HBi2`im`2 r2`2 H`;2` 7Q` HH /BbQ`/2`b b +QKT`2/ rBi? 27@ 72+i bBx2b #b2/ QM i?2 6. `2pB2rb- rBi? i?2 bKHH2bi BM+`2b2b 7Q` :. U;4yXj9- eW BM+`2b2V M/ a. U;4yX9k- 3W BM+`2b2V M/ H`;2` BM+`2b2b 7Q` P*. U;4yX98- R8W BM+`2b2V- Sha. U;4yXjk- RNW BM+`2b2V M/ S. U;4yXj8- k8W BM+`2b2VX >Qr2p2`- i?2 /Bz2`2M+2b BM 2z2+i 2biBKi2b #b2/ QM i?2 DQm`MH `iB+H2b M/ i?2 6. `2pB2rb r2`2 MQi biiBbiB+HHv bB;MB}+Mi 7Q` Mv Q7 i?2 BM/BpB/mH /BbQ`/2`b Uh#H2 kXkVX

.Bb+mbbBQM

h?Bb bim/v b?Qr2/ i?2 T`2b2M+2 Q7 `2TQ`iBM; #Bb BM `M/QKBx2/ +QMi`QHH2/ i`BHb QM i?2 2{++v Q7 b2+QM/@;2M2`iBQM MiB/2T`2bbMib 7Q` MtB2iv /BbQ`/2`bX h`BHb i?i i?2 6. Dm/;2/ iQ #2 TQbBiBp2 r2`2 Qp2` 8 iBK2b KQ`2 HBF2Hv iQ #2 Tm#HBb?2/ BM ;`22K2Mi rBi? i?2 6. MHvbBb i?M MQi@TQbBiBp2 i`BHbX b  `2bmHi- NeW U9jf98V Q7 i?2 DQm`MH `iB+H2b r2`2 7`K2/ TQbBiBp2Hv- r?BH2 dkW U9Rf8dV Q7 i?2 i`BHb r2`2 /22K2/ TQbBiBp2 #v i?2 6.X HH 2tKBM2/ `2TQ`iBM; #Bb2b r2`2 T`2b2Mi KQM; i?2 BM+Hm/2/ i`BHb- MK2Hv bim/v Tm#HB+iBQM #Bb- Qmi+QK2 `2TQ`iBM; #Bb- M/ bTBMX

jk 0.38 (0.05 − 0.71) 0.84 (0.42 − 1.25) 0.44 (0.08 − 0.81) 0.46 (0.06 − 0.85) 0.37 (0.12 − 0.62) 0.40 (0.15 − 0.66) −0.10 (−0.43 − 0.23) 0.37 (0.12 − 0.62) 0.15 (−0.09 − 0.40) 0.19 (−0.05 − 0.43) 0.20 (0.06 − 0.34) 0.49 (0.18 − 0.79) 0.34 (0.03 − 0.65) 0.23 (−0.06 − 0.53) 0.39 (0.09 − 0.69) 0.25 (−0.10 − 0.59) 0.55 (0.20 − 0.89) 0.18 (−0.19 − 0.55) 0.48 (0.29 − 0.68) 0.45 (0.25 − 0.64) 0.42 (0.23 − 0.62) 0.40 (0.21 − 0.60) 0.22 (−0.01 − 0.44) 0.18 (−0.04 − 0.41) 0.05 (−0.16 − 0.27) 0.05 (−0.16 − 0.27) 0.28 (0.20 − 0.36) 0.35 (0.24 − 0.46) 120 Ballenger, 1998 108 Oehrberg, 1995 187 Lecrubier, 1997 223 494 495 497 Sheehan, 2005 629 Pohl, 1998 630 Pollack, 1998 529 Londborg, 1998 514 398 Pollack, 2007a 399 Pollack, 2007b 353 Liebowitz, 2009 391 Bradwejn, 2005 FDA subtotal Journal subtotal

Trial Hedges' g (95% CI)

0.0 0.5 1.0

Hedges' g

6B;m`2 kXk, 6Q`2bi THQi 7Q` S.X *B`+H2b BM/B+i2 6. 2z2+i bBx2b- r?BH2 i`BM;H2b BM/B+i2

i?2 Ki+?BM; DQm`MH 2z2+i bBx2b U7Q` Tm#HBb?2/ i`BHbVX

AM  T`2pBQmb bim/v i?i 2tKBM2/ `2TQ`iBM; #Bb BM i`BHb QM b2+QM/@;2M2`iBQM MiB/2@ T`2bbMib 7Q` KDQ` /2T`2bbBp2 /BbQ`/2` (RN)- i?2 Qp2`HH 2z2+i bBx2 #b2/ QM i?2 6. /i rb yXjR- [mBi2 +QKT`#H2 iQ i?2 2z2+i bBx2 Q7 yXjj 7QmM/ BM i?Bb bim/vX 7i2` +QM/m+i@ BM; irQ K2i@MHvb2b- QM2 #b2/ QM /i 7`QK i?2 6. `2pB2rb M/ i?2 Qi?2` #b2/ QM /i 7`QK i?2 +Q``2bTQM/BM; DQm`MH `iB+H2b- r2 7QmM/ i?i `2TQ`iBM; #Bb BM~i2/ i?2

2

h#H2 kXk, J2i@MHvbBb

6.

Sm#HBb?2/ LQi Tm#HBb?2/

hQiH BM ;`22K2Mi BM ;`22K2Mi CQm`MH Pp2`2biBKi2

.BbQ`/2` >2/;2bǶ ;_{UN8W *AV} >2/;2bǶ ;_{UN8W *AV} >2/;2bǶ ;_{UN8W *AV} >2/;2bǶ ;_{UN8W *AV} W T

:. yXjk yXj9 yXRR yXj9 _{eW yXe8}

UyXk8@yXjNV UyXk3@yX9RV U@yXyN@yXjRV UyXkd@yX9RV

S. yXk3 yXjj yXRj yXj8 _{k8W yXj3}

UyXky@yXjeV UyXk8@yX9RV U@yXyk@yXkNV UyXk9@yX9eV

a. yXjN yX9j yXyN yX9k _{3W yX8e}

UyXjy@yX9NV UyXj8@yX8yV U@yXRR@yXkNV UyXj8@yX9NV

Sha. yXkd yXjj yXRj yXjk _{RNW yXde}

UyXRR@yX99V UyXR9@yX8jV U@yXRk@yXj3V UyXR9@yX8yV

P*. yXjN yX99 yXjy yX98 _{R8W yX9k}

UyXjy@yX9NV UyXjj@yX89V UyXRR@yX93V UyXj8@yX8eV

Pp2`HH yXjj yXj3 yXRd yXj3 _{R8W yXR3}

UyXkN@yXj3V UyXj9@yX9kV UyXyN@yXkeV UyXjj@yX9kV

6., 6QQ/ M/ .`m; /KBMBbi`iBQMc :., ;2M2`HBx2/ MtB2iv /BbQ`/2`c P*., Q#b2bbBp2 +QK@ TmHbBp2 /BbQ`/2`c S., TMB+ /BbQ`/2`c Sha., TQbii`mKiB+ bi`2bb /BbQ`/2`c a., bQ+BH MtB2iv /BbQ`/2`X

M/ P*. U6B;m`2b kXk M/ kXj (b22 6B;m`2b kX9- kX8- M/ kXe BM i?2 TT2M/Bt 7Q` :.-a.- M/ Sha.)VX

1z2+i bBx2b #b2/ QM i?2 HBi2`im`2 r2`2 H`;2` 7Q` HH /BbQ`/2`b b +QKT`2/ rBi? 27@ 72+i bBx2b #b2/ QM i?2 6. `2pB2rb- rBi? i?2 bKHH2bi BM+`2b2b 7Q` :. U;4yXj9- eW BM+`2b2V M/ a. U;4yX9k- 3W BM+`2b2V M/ H`;2` BM+`2b2b 7Q` P*. U;4yX98- R8W BM+`2b2V- Sha. U;4yXjk- RNW BM+`2b2V M/ S. U;4yXj8- k8W BM+`2b2VX >Qr2p2`- i?2 /Bz2`2M+2b BM 2z2+i 2biBKi2b #b2/ QM i?2 DQm`MH `iB+H2b M/ i?2 6. `2pB2rb r2`2 MQi biiBbiB+HHv bB;MB}+Mi 7Q` Mv Q7 i?2 BM/BpB/mH /BbQ`/2`b Uh#H2 kXkVX

.Bb+mbbBQM

h?Bb bim/v b?Qr2/ i?2 T`2b2M+2 Q7 `2TQ`iBM; #Bb BM `M/QKBx2/ +QMi`QHH2/ i`BHb QM i?2 2{++v Q7 b2+QM/@;2M2`iBQM MiB/2T`2bbMib 7Q` MtB2iv /BbQ`/2`bX h`BHb i?i i?2 6. Dm/;2/ iQ #2 TQbBiBp2 r2`2 Qp2` 8 iBK2b KQ`2 HBF2Hv iQ #2 Tm#HBb?2/ BM ;`22K2Mi rBi? i?2 6. MHvbBb i?M MQi@TQbBiBp2 i`BHbX b  `2bmHi- NeW U9jf98V Q7 i?2 DQm`MH `iB+H2b r2`2 7`K2/ TQbBiBp2Hv- r?BH2 dkW U9Rf8dV Q7 i?2 i`BHb r2`2 /22K2/ TQbBiBp2 #v i?2 6.X HH 2tKBM2/ `2TQ`iBM; #Bb2b r2`2 T`2b2Mi KQM; i?2 BM+Hm/2/ i`BHb- MK2Hv bim/v Tm#HB+iBQM #Bb- Qmi+QK2 `2TQ`iBM; #Bb- M/ bTBMX

jk 0.38 (0.05 − 0.71) 0.84 (0.42 − 1.25) 0.44 (0.08 − 0.81) 0.46 (0.06 − 0.85) 0.37 (0.12 − 0.62) 0.40 (0.15 − 0.66) −0.10 (−0.43 − 0.23) 0.37 (0.12 − 0.62) 0.15 (−0.09 − 0.40) 0.19 (−0.05 − 0.43) 0.20 (0.06 − 0.34) 0.49 (0.18 − 0.79) 0.34 (0.03 − 0.65) 0.23 (−0.06 − 0.53) 0.39 (0.09 − 0.69) 0.25 (−0.10 − 0.59) 0.55 (0.20 − 0.89) 0.18 (−0.19 − 0.55) 0.48 (0.29 − 0.68) 0.45 (0.25 − 0.64) 0.42 (0.23 − 0.62) 0.40 (0.21 − 0.60) 0.22 (−0.01 − 0.44) 0.18 (−0.04 − 0.41) 0.05 (−0.16 − 0.27) 0.05 (−0.16 − 0.27) 0.28 (0.20 − 0.36) 0.35 (0.24 − 0.46) 120 Ballenger, 1998 108 Oehrberg, 1995 187 Lecrubier, 1997 223 494 495 497 Sheehan, 2005 629 Pohl, 1998 630 Pollack, 1998 529 Londborg, 1998 514 398 Pollack, 2007a 399 Pollack, 2007b 353 Liebowitz, 2009 391 Bradwejn, 2005 FDA subtotal Journal subtotal

Trial Hedges' g (95% CI)

0.0 0.5 1.0

Hedges' g

6B;m`2 kXk, 6Q`2bi THQi 7Q` S.X *B`+H2b BM/B+i2 6. 2z2+i bBx2b- r?BH2 i`BM;H2b BM/B+i2

i?2 Ki+?BM; DQm`MH 2z2+i bBx2b U7Q` Tm#HBb?2/ i`BHbVX

AM  T`2pBQmb bim/v i?i 2tKBM2/ `2TQ`iBM; #Bb BM i`BHb QM b2+QM/@;2M2`iBQM MiB/2@ T`2bbMib 7Q` KDQ` /2T`2bbBp2 /BbQ`/2` (RN)- i?2 Qp2`HH 2z2+i bBx2 #b2/ QM i?2 6. /i rb yXjR- [mBi2 +QKT`#H2 iQ i?2 2z2+i bBx2 Q7 yXjj 7QmM/ BM i?Bb bim/vX 7i2` +QM/m+i@ BM; irQ K2i@MHvb2b- QM2 #b2/ QM /i 7`QK i?2 6. `2pB2rb M/ i?2 Qi?2` #b2/ QM /i 7`QK i?2 +Q``2bTQM/BM; DQm`MH `iB+H2b- r2 7QmM/ i?i `2TQ`iBM; #Bb BM~i2/ i?2

0.59 (0.26 − 0.93) 0.86 (0.49 − 1.23) 0.76 (0.51 − 1.00) 0.25 (−0.06 − 0.55) 0.25 (−0.05 − 0.56) 0.60 (0.28 − 0.92) 0.40 (0.08 − 0.72) 0.40 (0.08 − 0.72) 0.44 (0.18 − 0.70) 0.43 (0.17 − 0.69) 0.43 (0.17 − 0.69) 0.61 (0.31 − 0.90) 0.14 (−0.18 − 0.45) 0.30 (0.06 − 0.54) 0.38 (0.14 − 0.63) 0.42 (0.00 − 0.85) 0.42 (0.00 − 0.85) 0.35 (0.10 − 0.60) 0.35 (0.10 − 0.60) 0.42 (0.11 − 0.73) 0.42 (0.11 − 0.73) 0.13 (−0.17 − 0.43) 0.39 (0.30 − 0.49) 0.45 (0.35 − 0.56) HCEP−1 HCEP−2 Tollefson, 1994 E079 Montgomery, 1993 5529 5534 Goodman, 1996 3103 Hollander, 2003a 116 Hollander, 2003b 118 136 Zohar, 1996 237/248 Chouinard, 1990 371/372 Greist, 1995 546 Kronig, 1999 495 FDA subtotal Journal subtotal

Trial Hedges' g (95% CI)

0.0 0.5 1.0

Hedges' g

6B;m`2 kXj, 6Q`2bi THQi 7Q` P*.X *B`+H2b BM/B+i2 6. 2z2+i bBx2b- r?BH2 i`BM;H2b

BM/B+i2 i?2 Ki+?BM; DQm`MH 2z2+i bBx2b U7Q` Tm#HBb?2/ i`BHbVX

TT`2Mi 2z2+i bBx2 #v R8WX h?Bb BM+`2b2 rb MQi biiBbiB+HHv bB;MB}+Mi- BM +QMi`bi iQ i?2 H`;2` BM~iBQM 7+iQ` UjkWV 7QmM/ 2`HB2` rBi? KDQ` /2T`2bbBp2 /BbQ`/2` (RN)X 6Q` i?2 BM/BpB/mH MtB2iv /BbQ`/2`b- i?2 BM~iBQM 7+iQ`b `M;2/ 7`QK eW U:.V iQ k8W US.V- BM/B+iBM; i?2 BKTQ`iM+2 Q7 mbBM; mM#Bb2/ /i BM K2i@MHvb2b QM i?2 2{++v Q7 b2+QM/@;2M2`iBQM MiB/2T`2bbMib 7Q` MtB2iv /BbQ`/2`bX

AM i?2 KBM MHvb2b r2 +QK#BM2/ }p2 /BbQ`/2`b +HbbB}2/ b MtB2iv /BbQ`/2`b BM .aJ@ j9

Aoc ?Qr2p2`- BM .aJ@o- P*. Bb MQr +HbbB}2/ mM/2` Q#b2bbBp2@+QKTmHbBp2 M/ `2Hi2/ /BbQ`/2`b- r?BH2 Sha. Bb mM/2` i`mK@ M/ bi`2bbQ`@`2Hi2/ /BbQ`/2`bX h?2`27Q`2- rBi? i?2 `2+2Mi +?M;2 BM itQMQKv- Qm` ;`QmTBM; Q7 i?2b2 /BbQ`/2`b +QmH/ #2 pB2r2/ b  HBKBiiBQM- Hi?Qm;? 2{++v Q7 i?2 /`m;b rb +QKT`#H2 +`Qbb /BbQ`/2`bX

 +H2`2` HBKBiiBQM Q7 i?2 +m``2Mi bim/v Bb i?i i?2 i`BHb 7Q` i?2 BM/BpB/mH MtB2iv /BbQ`@ /2`b r2`2 72r BM MmK#2`- /2+`2bBM; i?2 TQr2` Q7 i?2 bm#;`QmT MHvb2bX M //BiBQMH HBKBiiBQM Bb i?i r2 /B/ MQi 2tKBM2 #Bb2/ `2TQ`iBM; Q7 ?`K Qmi+QK2b- r?B+? };m`2b BMiQ i?2 Qp2`HH `BbF@#2M2}i `iBQ Q7  /`m;- #mi bm+? M 2tKBMiBQM rQmH/ ?p2 #22M #2vQM/ i?2 b+QT2 Q7 i?2 +m``2Mi bim/vX

*2`iBM /i pBH#H2 QMHv BM TQQH2/@i`BHb Tm#HB+iBQMb r2`2 +HbbB}2/ b mMTm#HBb?2/-r?B+? +QmH/ HbQ #2 pB2r2/ b  HBKBiiBQMX >Qr2p2`-  bim/v Q7 MiB/2T`2bbMi i`BHb bm#KBii2/ iQ i?2 ar2/Bb? /`m; `2;mHiQ`v mi?Q`Biv b?Qr2/ i?i TQbBiBp2 i`BHb r2`2 KQ`2 HBF2Hv iQ #2 Tm#HBb?2/ b biM/@HQM2 Tm#HB+iBQMb- r?BH2 M2;iBp2 i`BHb i2M/2/ iQ #2 `2TQ`i2/ QMHv rBi?BM TQQH2/@i`BHb Tm#HB+iBQMb (kd)X SQQH2/ MHvb2b Kv MQi 7QHHQr i?2 T`2/2i2`KBM2/ MHvbBb THM M/ TQr2` +H+mHiBQM M/ +M i?2`27Q`2 vB2H/ /Bz2`2Mi +QM+HmbBQMb i?M i?2 Q`B;BMH i`BHbX SQQH2/ MHvb2b `2 HbQ bbQ+Bi2/ rBi? dzbHKB bHB+BM;Ǵ UTm#HBb?BM; bBKBH` `2bmHib 7`QK QM2 bim/v BM KmHiBTH2 Tm#HB+iBQMbV (Rd9)X h?2`2@ 7Q`2- Hi?Qm;? i?2b2 Tm#HB+iBQMb Kv T`QpB/2 M2r BM7Q`KiBQM- 2bT2+BHHv QM bm#;`QmTb M/ b2+QM/`v 2M/TQBMib- i?2v `2 bmb+2TiB#H2 iQ #Bb (Rd8)X h?Bb #Bb +M #2 `2/m+2/ #v }`bi Tm#HBb?BM; i?2 Q`B;BMH i`BH `2bmHibX 6mim`2 `2b2`+? +QmH/ bb2bb i?2 #Bb i?i Bb BMi`Q/m+2/ #v TQQH2/@i`BHb Tm#HB+iBQMbX

6BMHHv- r2 /B/ MQi +QMi+i /`m; bTQMbQ`b iQ bF r?2i?2` bT2+B}+ i`BHb r2`2 Tm#HBb?2/ BM i?2 b+B2MiB}+ HBi2`im`2- bQ i?2`2 Bb  bKHH +?M+2 i?i i`BHb +QmH/ ?p2 #22M KBb+HbbB}2/ b mMTm#HBb?2/X >Qr2p2`- +QMbB/2`BM; i?2 2ti2MbBp2 HBi2`im`2 b2`+? K2i?Q/b- Bi b22Kb mMHBF2Hv i?i bm+? i`BH Tm#HB+iBQMb rQmH/ #2 /Bb+Qp2`#H2 #v i?2 ivTB+H ?2Hi? +`2 T`Q72bbBQMHX

 bi`2M;i? Q7 i?Bb bim/v Bb i?i- 7Q` ky Q7 i?2 kR 6.@TT`Qp2/ /`m;@BM/B+iBQM +QK#B@ MiBQMb- r2 r2`2 #H2 iQ BM+Hm/2 /i 7`QK HH T`2K`F2iBM; `M/QKBx2/ +QMi`QHH2/ i`BHb-i?2`2#v HHQrBM;  `2HB#H2 bb2bbK2Mi Q7 /Bz2`2Mi `2TQ`iBM; #Bb2b 7Q` i?2b2 i`BHbX >Qr@ 2p2`- Bi Bb BKTQ`iMi iQ MQi2 i?i r2 +QmH/ MQi BM+Hm/2 /i 7`QK `2D2+i2/ /`m;@BM/B+iBQM TTHB+iBQMb #2+mb2 i?2 6. /Q2b MQi `2H2b2 i?2b2 `2pB2rb (Ry8)X Ai Bb HBF2Hv i?i i?2 KQmMi Q7 `2TQ`iBM; #Bb i?i rb 7QmM/ rQmH/ BM+`2b2 B7 i?2b2 i`BHb r2`2 iQ #2 2tKBM2/ b r2HHX

AM //BiBQM- Qm` 2biBKiBQM Q7 i?2 KQmMi Q7 `2TQ`iBM; #Bb T`2b2Mi KB;?i HbQ #2 BM@ ~m2M+2/ #v i?2 7+i i?i HH i`BHb r2`2 bTQMbQ`2/ #v T?`K+2miB+H BM/mbi`B2bX u2i `2TQ`iBM; #Bb Bb MQi `2bi`B+i2/ iQ T?`K+QHQ;B+H i`2iK2Mib bTQMbQ`2/ #v /`m; +QK@ TMB2b (Rde)X aBM+2 `2TQ`iBM; #Bb ?b #22M b?QrM 7Q` i?2 i`2iK2Mi Q7 /2T`2bbBQM rBi? Tbv+?Qi?2`Tv (Rdd)- Bi b?QmH/ #2 rQ`i?r?BH2 iQ bvbi2KiB+HHv bb2bb `2TQ`iBM; #Bb BM i`BHb mbBM; Tbv+?Qi?2`Tv 7Q` MtB2iv /BbQ`/2`b b r2HHX

2

0.59 (0.26 − 0.93) 0.86 (0.49 − 1.23) 0.76 (0.51 − 1.00) 0.25 (−0.06 − 0.55) 0.25 (−0.05 − 0.56) 0.60 (0.28 − 0.92) 0.40 (0.08 − 0.72) 0.40 (0.08 − 0.72) 0.44 (0.18 − 0.70) 0.43 (0.17 − 0.69) 0.43 (0.17 − 0.69) 0.61 (0.31 − 0.90) 0.14 (−0.18 − 0.45) 0.30 (0.06 − 0.54) 0.38 (0.14 − 0.63) 0.42 (0.00 − 0.85) 0.42 (0.00 − 0.85) 0.35 (0.10 − 0.60) 0.35 (0.10 − 0.60) 0.42 (0.11 − 0.73) 0.42 (0.11 − 0.73) 0.13 (−0.17 − 0.43) 0.39 (0.30 − 0.49) 0.45 (0.35 − 0.56) HCEP−1 HCEP−2 Tollefson, 1994 E079 Montgomery, 1993 5529 5534 Goodman, 1996 3103 Hollander, 2003a 116 Hollander, 2003b 118 136 Zohar, 1996 237/248 Chouinard, 1990 371/372 Greist, 1995 546 Kronig, 1999 495 FDA subtotal Journal subtotal

Trial Hedges' g (95% CI)

0.0 0.5 1.0

Hedges' g

6B;m`2 kXj, 6Q`2bi THQi 7Q` P*.X *B`+H2b BM/B+i2 6. 2z2+i bBx2b- r?BH2 i`BM;H2b

BM/B+i2 i?2 Ki+?BM; DQm`MH 2z2+i bBx2b U7Q` Tm#HBb?2/ i`BHbVX

TT`2Mi 2z2+i bBx2 #v R8WX h?Bb BM+`2b2 rb MQi biiBbiB+HHv bB;MB}+Mi- BM +QMi`bi iQ i?2 H`;2` BM~iBQM 7+iQ` UjkWV 7QmM/ 2`HB2` rBi? KDQ` /2T`2bbBp2 /BbQ`/2` (RN)X 6Q` i?2 BM/BpB/mH MtB2iv /BbQ`/2`b- i?2 BM~iBQM 7+iQ`b `M;2/ 7`QK eW U:.V iQ k8W US.V- BM/B+iBM; i?2 BKTQ`iM+2 Q7 mbBM; mM#Bb2/ /i BM K2i@MHvb2b QM i?2 2{++v Q7 b2+QM/@;2M2`iBQM MiB/2T`2bbMib 7Q` MtB2iv /BbQ`/2`bX

AM i?2 KBM MHvb2b r2 +QK#BM2/ }p2 /BbQ`/2`b +HbbB}2/ b MtB2iv /BbQ`/2`b BM .aJ@ j9

Aoc ?Qr2p2`- BM .aJ@o- P*. Bb MQr +HbbB}2/ mM/2` Q#b2bbBp2@+QKTmHbBp2 M/ `2Hi2/ /BbQ`/2`b- r?BH2 Sha. Bb mM/2` i`mK@ M/ bi`2bbQ`@`2Hi2/ /BbQ`/2`bX h?2`27Q`2- rBi? i?2 `2+2Mi +?M;2 BM itQMQKv- Qm` ;`QmTBM; Q7 i?2b2 /BbQ`/2`b +QmH/ #2 pB2r2/ b  HBKBiiBQM- Hi?Qm;? 2{++v Q7 i?2 /`m;b rb +QKT`#H2 +`Qbb /BbQ`/2`bX

 +H2`2` HBKBiiBQM Q7 i?2 +m``2Mi bim/v Bb i?i i?2 i`BHb 7Q` i?2 BM/BpB/mH MtB2iv /BbQ`@ /2`b r2`2 72r BM MmK#2`- /2+`2bBM; i?2 TQr2` Q7 i?2 bm#;`QmT MHvb2bX M //BiBQMH HBKBiiBQM Bb i?i r2 /B/ MQi 2tKBM2 #Bb2/ `2TQ`iBM; Q7 ?`K Qmi+QK2b- r?B+? };m`2b BMiQ i?2 Qp2`HH `BbF@#2M2}i `iBQ Q7  /`m;- #mi bm+? M 2tKBMiBQM rQmH/ ?p2 #22M #2vQM/ i?2 b+QT2 Q7 i?2 +m``2Mi bim/vX

*2`iBM /i pBH#H2 QMHv BM TQQH2/@i`BHb Tm#HB+iBQMb r2`2 +HbbB}2/ b mMTm#HBb?2/-r?B+? +QmH/ HbQ #2 pB2r2/ b  HBKBiiBQMX >Qr2p2`-  bim/v Q7 MiB/2T`2bbMi i`BHb bm#KBii2/ iQ i?2 ar2/Bb? /`m; `2;mHiQ`v mi?Q`Biv b?Qr2/ i?i TQbBiBp2 i`BHb r2`2 KQ`2 HBF2Hv iQ #2 Tm#HBb?2/ b biM/@HQM2 Tm#HB+iBQMb- r?BH2 M2;iBp2 i`BHb i2M/2/ iQ #2 `2TQ`i2/ QMHv rBi?BM TQQH2/@i`BHb Tm#HB+iBQMb (kd)X SQQH2/ MHvb2b Kv MQi 7QHHQr i?2 T`2/2i2`KBM2/ MHvbBb THM M/ TQr2` +H+mHiBQM M/ +M i?2`27Q`2 vB2H/ /Bz2`2Mi +QM+HmbBQMb i?M i?2 Q`B;BMH i`BHbX SQQH2/ MHvb2b `2 HbQ bbQ+Bi2/ rBi? dzbHKB bHB+BM;Ǵ UTm#HBb?BM; bBKBH` `2bmHib 7`QK QM2 bim/v BM KmHiBTH2 Tm#HB+iBQMbV (Rd9)X h?2`2@ 7Q`2- Hi?Qm;? i?2b2 Tm#HB+iBQMb Kv T`QpB/2 M2r BM7Q`KiBQM- 2bT2+BHHv QM bm#;`QmTb M/ b2+QM/`v 2M/TQBMib- i?2v `2 bmb+2TiB#H2 iQ #Bb (Rd8)X h?Bb #Bb +M #2 `2/m+2/ #v }`bi Tm#HBb?BM; i?2 Q`B;BMH i`BH `2bmHibX 6mim`2 `2b2`+? +QmH/ bb2bb i?2 #Bb i?i Bb BMi`Q/m+2/ #v TQQH2/@i`BHb Tm#HB+iBQMbX

6BMHHv- r2 /B/ MQi +QMi+i /`m; bTQMbQ`b iQ bF r?2i?2` bT2+B}+ i`BHb r2`2 Tm#HBb?2/ BM i?2 b+B2MiB}+ HBi2`im`2- bQ i?2`2 Bb  bKHH +?M+2 i?i i`BHb +QmH/ ?p2 #22M KBb+HbbB}2/ b mMTm#HBb?2/X >Qr2p2`- +QMbB/2`BM; i?2 2ti2MbBp2 HBi2`im`2 b2`+? K2i?Q/b- Bi b22Kb mMHBF2Hv i?i bm+? i`BH Tm#HB+iBQMb rQmH/ #2 /Bb+Qp2`#H2 #v i?2 ivTB+H ?2Hi? +`2 T`Q72bbBQMHX

 bi`2M;i? Q7 i?Bb bim/v Bb i?i- 7Q` ky Q7 i?2 kR 6.@TT`Qp2/ /`m;@BM/B+iBQM +QK#B@ MiBQMb- r2 r2`2 #H2 iQ BM+Hm/2 /i 7`QK HH T`2K`F2iBM; `M/QKBx2/ +QMi`QHH2/ i`BHb-i?2`2#v HHQrBM;  `2HB#H2 bb2bbK2Mi Q7 /Bz2`2Mi `2TQ`iBM; #Bb2b 7Q` i?2b2 i`BHbX >Qr@ 2p2`- Bi Bb BKTQ`iMi iQ MQi2 i?i r2 +QmH/ MQi BM+Hm/2 /i 7`QK `2D2+i2/ /`m;@BM/B+iBQM TTHB+iBQMb #2+mb2 i?2 6. /Q2b MQi `2H2b2 i?2b2 `2pB2rb (Ry8)X Ai Bb HBF2Hv i?i i?2 KQmMi Q7 `2TQ`iBM; #Bb i?i rb 7QmM/ rQmH/ BM+`2b2 B7 i?2b2 i`BHb r2`2 iQ #2 2tKBM2/ b r2HHX

AM //BiBQM- Qm` 2biBKiBQM Q7 i?2 KQmMi Q7 `2TQ`iBM; #Bb T`2b2Mi KB;?i HbQ #2 BM@ ~m2M+2/ #v i?2 7+i i?i HH i`BHb r2`2 bTQMbQ`2/ #v T?`K+2miB+H BM/mbi`B2bX u2i `2TQ`iBM; #Bb Bb MQi `2bi`B+i2/ iQ T?`K+QHQ;B+H i`2iK2Mib bTQMbQ`2/ #v /`m; +QK@ TMB2b (Rde)X aBM+2 `2TQ`iBM; #Bb ?b #22M b?QrM 7Q` i?2 i`2iK2Mi Q7 /2T`2bbBQM rBi? Tbv+?Qi?2`Tv (Rdd)- Bi b?QmH/ #2 rQ`i?r?BH2 iQ bvbi2KiB+HHv bb2bb `2TQ`iBM; #Bb BM i`BHb mbBM; Tbv+?Qi?2`Tv 7Q` MtB2iv /BbQ`/2`b b r2HHX

aTBM +M `2bmHi 7`QK /Bz2`2Mi- BMi2MiBQMH Q` mMBMi2MiBQMH- bi`i2;B2b- 7Q` 2tKTH2 #v 7Q+mbBM; QM b2+QM/`v 2M/TQBMib 7Q` r?B+? bB;MB}+Mi `2bmHib r2`2 Q#iBM2/ (Rd3)X CQm`MH `iB+H2b 7Q` r?B+? bTBM rb B/2MiB}2/ HbQ Q7i2M `2TQ`i2/ dzK`;BMHHv bB;MB}+Mi `2bmHibǴ UT pHm2b #2ir22M yXy8 M/ yXRyV BM i?2 T`2b2Mi bim/vX A/2HHv- BMi2`T`2iiBQM Q7 i`BH `2bmHib b?QmH/ MQi #2 #b2/ bQH2Hv QM  T pHm2 BM/B+iBM; r?2i?2` `2bmHib `2 biiBbiB+HHv bB;MB}+Mi Q` MQi (9y)X AM //BiBQM iQ T`QpB/BM; T pHm2b- 7mim`2 `2b2`+? +QmH/ +QMbB/2` BM+Hm/BM; "v2b 7+iQ`b b  K2bm`2 Q7 i?2 bi`2M;i? Q7 i?2 2pB/2M+2X "v2b 7+iQ`b bi2K 7`QK "v2bBM biiBbiB+b M/ ?p2 i?2 /pMi;2 i?i i?2v +M 2tT`2bb i?2 bi`2M;i? Q7 i?2 2pB/2M+2 QM  +QMiBMmQmb b+H2 (RdN)X

_2TQ`iBM; #Bb bB;MB}+MiHv BM+`2b2/ i?2 MmK#2` Q7 TQbBiBp2 p2`bmb M2;iBp2 Tm#HB+iBQMb BM i?2 HBi2`im`2 BM i?2 T`2b2Mi bim/vX h?Bb HBF2Hv BKT+ib +HBMB+BMǶb T2`+2TiBQMb Q7 i?2 2{++v Q7 i?2b2 /`m;b- r?B+? +QmH/ `2bQM#Hv #2 2tT2+i2/ iQ z2+i T`2b+`BTiBQM #2?pBQ`X AM #Qi? 1m`QT2 M/ BM i?2 la- mb2 Q7 MiB/2T`2bbMib ?b #22M `BbBM; K`F2/Hv Qp2` i?2 Hbi irQ /2+/2b rBi? Km+? Q7 i?i mb2 TT2`BM; iQ #2 /`Bp2M #v MQM@bT2+BHBbib BM b2iiBM;b Q7 T`BK`v +`2 (R3y- R3R)X Hi?Qm;? Bi b?QmH/ #2 MQi2/ i?i i?2b2 bim/B2b +QmH/ MQi iF2 BMiQ ++QmMi BM/B+iBQMb 7Q` r?B+? i?2 /`m;b r2`2 T`2b+`B#2/-  `2HBbiB+ pB2r Q7 i?2 2{++v Q7 i?2b2 ;2Mib Bb BKTQ`iMi +`Qbb HH BM/B+iBQMbX _2bmHib Q7 i?2 +m``2Mi bim/v M/ Qi?2` bim/B2b +QKT`BM; Tm#HBb?2/ `2bmHib iQ /i 7`QK 6. `2pB2rb Q` Qi?2` `2;Bbi`B2b (RN- dd) +M T2`?Tb bbBbi +HBMB+BMb BM ;BMBM;  KQ`2 `2HBbiB+ pB2r Q7 i?2 2pB/2M+2 7Q` i?2 2{++v Q7 MiB/2T`2bbMib BM i?2 Ub?Q`i@i2`KV i`2iK2Mi Q7 z2+iBp2 /BbQ`/2`bX

h?Bb bim/v //b iQ i?2 ;`QrBM; #Q/v Q7 HBi2`im`2 2bi#HBb?BM; i?2 T2`pbBp2M2bb Q7 `2@ TQ`iBM; #Bb (j9- Rde- R3k)X Ai HbQ ?B;?HB;?ib i?2 M22/ iQ //`2bb i?Bb T`Q#H2K mbBM; p`BQmb K2bm`2b- b `2+2MiHv `2pB2r2/ (R3j)X PM2 bm;;2bi2/ TT`Q+?- r?B+? rQmH/ /@ /`2bb Qmi+QK2 `2TQ`iBM; #Bb M/ bTBM U#mi MQi bim/v Tm#HB+iBQM #BbV- rQmH/ `2[mB`2 T22` `2pB2r2`b iQ KF2 T`2HBKBM`v /2+BbBQMb #b2/ QM i?2 bi`2M;i? Q7 i?2 K2i?Q/b BM i?2 Q`B;BMH i`BH T`QiQ+QH (Rde) bQ i?i i?2B` /2+BbBQMb `2 MQi BM~m2M+2/ #v i?2 biiBbiB+H bB;MB}+M+2 Q7 bim/v `2bmHib (R39)X lb2 Q7 bim/v `2;Bbi`B2b- HBF2 *HBMB+Hh`BHbX;Qp- +M HbQ `2/m+2 `2TQ`iBM; #Bb BM i?2 b+B2MiB}+ HBi2`im`2 (Rde)- #mi i?Bb `2;Bbi`v /Q2b MQi v2i 7mM+@ iBQM QTiBKHHvX 6Q` 2tKTH2- 7Q` i?2 KDQ`Biv Q7 i`BHb bm#D2+i2/ iQ KM/iQ`v `2TQ`iBM; rBi?BM QM2 v2` 7QHHQrBM; i`BH +QKTH2iBQM- `2bmHib r2`2 MQi TQbi2/ rBi?BM i?Bb iBK27`K2 (R38)X

AM bmKK`v- Hi?Qm;? i?2 KDQ`Biv Q7 i`BHb QM i?2 2{++v Q7 6.@TT`Qp2/ b2+QM/@ ;2M2`iBQM MiB/2T`2bbMib 7Q` MtB2iv /BbQ`/2`b r2`2 TQbBiBp2- p`BQmb `2TQ`iBM; #Bb2b r2`2 T`2b2MiX h?2b2 `2TQ`iBM; #Bb2b H2/ iQ M Qp2`Hv TQbBiBp2 `2T`2b2MiiBQM Q7 bB;MB}+Mi }M/BM;b BM i?2 b+B2MiB}+ HBi2`im`2X

je

TT2M/Bt

h#H2 kXj, 6. +QM+HmbBQM pbX DQm`MH +QM+HmbBQM 7Q` `iB+H2b rBi? bTBM

.`m; .BbQ`/2` h`BH 6. GBi2`im`2

o2MH7tBM2

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