Supplementary information: Study characteristics and quality ratings

Study Design Region of Setting Participant diagnoses Total Duration Blinding of Pharmaceutical Relapse definition1 Reliability2 of Clinical Relapse rates
origin sample size (months) assessments industry funding relapse relevance3 of (by intervention
reported (yes/no) reported (yes/no) definition relapse group)
definition
Shawver, Gorham, Placebo controlled USA Inpatients Schizophrenia spectrum 120 6 Yes NR NR Poor Poor Placebo = 7/40
Leskin, Good & withdrawal vs disorder Maintenance = 4/80
Kabnick (1959) maintenance
Gross, Hitchman, Placebo controlled USA Outpatients Schizophrenia spectrum 90 7 Yes No NR Poor Poor Placebo = 41/56
Reeves, Lawrence & withdrawal vs disorder Maintenance = 3/34
Newell (1960) maintenance

Blackburn & Allen Placebo controlled USA Inpatient Schizophrenia spectrum 53 4 NR NR  1 standard error increase on Patient Good Poor Placebo = 13/28
(1961) withdrawal vs disorder Adjustment Record Maintenance = 3/25
placebo controlled  Move to closed ward (increased care)
drug holiday vs  Restarting medication
maintenance
Schiele, Vestre & Placebo controlled USA Inpatient Schizophrenia spectrum 80 9.5 Both NR Change in clinical condition (team Poor Poor Placebo = 12/20
Stein (1961) withdrawal vs disorder assessment) Maintenance = 2/60
maintenance
Olson & Peterson Placebo controlled USA Inpatient Schizophrenia spectrum 90 6 Yes NR Increase in ward behaviour ratings Poor Poor Drug Holiday
(1962) drug holiday vs disorder (placebo/open) =
open drug holiday 30/60
vs maintenance Maintenance = 0/30
Freeman & Alson Placebo controlled USA Inpatient Schizophrenia spectrum 94 6 NR NR Complete change in type of medication or Poor Poor Placebo = 13/46
(1962) withdrawal vs disorder treatment Maintenance = 6/48
maintenance
Troshinsky, Aaronson Placebo controlled USA Outpatient Schizophrenia spectrum 43 10 Yes No NR Poor Poor Placebo/no
& Stone (1962) withdrawal vs no disorder treatment = 12/19
treatment vs Maintenance = 1/24
maintenance
Whittaker & Hoy Placebo controlled UK Inpatient Schizophrenia spectrum 39 2.5 Yes No Resumption of antipsychotics Good Poor Placebo/no
(1963) withdrawal vs no disorder treatment = 10/26
treatment vs Maintenance = 1/13
maintenance
Caffey, Diamond, Placebo controlled USA Inpatient Schizophrenia spectrum 348 4 NR NR Resumption of antipsychotics Good Poor Placebo
Frank, Grasberger, withdrawal vs disorder (reduction/withdraw
Herman, Klett & placebo controlled al) = 90/260
Rothstein (1964) dose reduction vs Maintenance = 4/88
maintenance
Melynk, Worthington Placebo controlled Canada Inpatient Schizophrenia spectrum 40 1.5 Yes NR Return of relapse symptoms Poor Poor Placebo =
& Laverty (1966) withdrawal vs disorder 10/20Maintenance =
maintenance 0/20
Keskiner, Holden & Placebo controlled USA Outpatient Schizophrenia spectrum 24 3 Yes No Reinstatement of antipsychotics Good Poor Placebo = 8/11
Itil (1968) withdrawal vs disorder Maintenance = 3/13
maintenance
Prien, Cole & Belkin Placebo controlled USA Inpatient Schizophrenia spectrum 630 6 Yes No Resumption of antipsychotics Good Poor Placebo = 84/210
(1968) withdrawal vs disorder Maintenance =
maintenance 40/420
Morton (1968) Placebo controlled UK Inpatient Schizophrenia spectrum 40 6 NR NR Material from two scales (unspecified) Poor Poor Placebo = 14/20
withdrawal vs disorder plus general clinical impressions Maintenance = 5/20
maintenance
Prien, Levine & Cole Placebo controlled USA Inpatient Schizophrenia spectrum 341 6 Yes No NR Poor Poor Placebo =
(1969) withdrawal vs disorder 50/11Maintenance =
maintenance 1
35/230
Baro, Brugmans, Placebo controlled Belgium Inpatient Schizophrenia spectrum 26 2.5 NR NR ‘Indisputable’ signs of relapse as judged Poor Poor Placebo = 13/13
Dom & Van Lommel withdrawal vs disorder by two psychiatrists Maintenance = 0/13
Study Design Region of Setting Participant diagnoses Total Duration Blinding of Pharmaceutical Relapse definition1 Reliability2 of Clinical Relapse rates
origin sample size (months) assessments industry funding relapse relevance3 of (by intervention
reported (yes/no) reported (yes/no) definition relapse group)
definition
(1970) maintenance
Leff & Wing (1971) Placebo controlled UK Outpatient Schizophrenia spectrum 35 12 Yes NR Clinician concerned and wanting to break Poor Poor Placebo = 12/15
withdrawal vs disorder blind Maintenance = 7/20
maintenance
Hershon, Kennedy & Placebo controlled UK Inpatient Schizophrenia spectrum 62 4 Yes NR Reinstatement of antipsychotics Good Poor Placebo = 9/32
McGuire withdrawal vs disorder Maintenance = 2/30
(1972) maintenance
Hogarty & Goldberg Placebo controlled USA Outpatient Schizophrenia spectrum 374 24 Yes No  Hospitalisation Good Good Placebo = 117/182
(1973) withdrawal vs disorder  Hospitalisation considered immanent Maintenance =
maintenance 58/192
Prien, Gillis & Caffey Placebo controlled USA Inpatient Schizophrenia spectrum 374 4 NR NR Restarting antipsychotics Good Poor Placebo =
(1973) dose reduction vs disorder 21/30Maintenance =
maintenance 11/73
Hirsch, Gaind, Rohde, Placebo controlled UK Outpatient Schizophrenia spectrum 74 9 Yes NR Restarting antipsychotics Good Poor Placebo = 25/38
Stevens & Wing withdrawal vs disorder Maintenance = 3/36
(1973) maintenance
Ota & Kurland (1973) Placebo controlled USA Inpatient Schizophrenia spectrum 44 3 Yes Yes NR Poor Poor Placebo = 4/12
withdrawal vs disorder Maintenance = 1/32
maintenance
Clark, Huber, Hill, Placebo controlled USA Outpatient Schizophrenia spectrum 35 6 NR Yes Therapeutic failure (not defined further) Poor Poor Placebo = 5/9
Wood & Costiloe withdrawal vs disorder Maintenance = 4/26
(1975) maintenance
Elie, Gagnon, Placebo controlled Canada Inpatient Schizophrenia spectrum 12 0.4 No NR NR Poor Poor Placebo = 1/6
Gauthier & Jequier withdrawal vs disorder Maintenance = 0/6
(1975) maintenance
Kurland, Ota & Placebo controlled USA Inpatient Schizophrenia spectrum 35 3 Yes Yes ‘Significant psychiatric decompensation’ Poor Poor Relapses not reporter
Slotnick (1975) withdrawal vs disorder by group
maintenance
Andrews, Hall & Placebo controlled UK Inpatient Schizophrenia spectrum 32 10.5 NR No Antipsychotic medication Good Poor Placebo = 6/17
Snaith (1976) withdrawal vs disorder Maintenance = 1/13
maintenance
Rifkin, Quitkin & Placebo controlled USA Outpatient Schizophrenia spectrum 73 12 Yes No Significant clinical deterioration with Poor Good Placebo = 15/22
Klein (1977) withdrawal vs disorder potential for or actual marked impact on Maintenance = 5/51
maintenance functioning
Dotti, Bersani, Open withdrawal Italy Outpatient Schizophrenia spectrum 20 9 NR NR Additional antipsychotic medication Good Poor Open withdrawal =
Rubino & Eliseo vs maintenance disorder 3/10
(1979) Maintenance = 1/10
Kane, Rifkin, Quitkin, Placebo controlled USA Outpatient Schizophrenia spectrum 17 6 Yes NR Symptoms suggestive of ‘immanent Poor Poor Placebo = 7/8
Nayak, Saraf, Ramos- withdrawal vs disorder psychotic relapse’ but not restricted to Maintenance = 2/9
Lorenzi, Klein & maintenance psychotic symptoms
Sachar (1979)
Levine, Schooler, Placebo controlled USA Outpatient Schizophrenia spectrum 67 3.75 Yes No  Hospitalisation Poor Poor Placebo
Severe, Escobar, withdrawal vs disorder  Need for increased medication (withdrawal/drug
Gelenberg, & Mandel placebo controlled  Need for increased support holiday) = 23/50
et al. (1980) drug holiday vs Maintenance = 4/17
maintenance
McCreadie, Dingwall, Open dose Scotland Mixed inpatient Schizophrenia spectrum 34 9 Yes No Worsening of symptoms leading to Poor Poor Open reduction =
Wiles & Heykants reduction vs and outpatient disorder withdrawal from trial 3/16
(1980) maintenance Maintenance = 3/18
Blackburn & Allen Placebo controlled USA Inpatient Schizophrenia spectrum 53 4 No NR  Change of 1 standard error on Patient Good Poor Placebo
(1981) withdrawal vs disorder Adjustment Report scale (withdrawal/drug
placebo controlled  Transfer to closed ward holiday) = 13/28
drug holiday vs  Resumption of antipsychotic Maintenance = 3/25
maintenance medication
Shenoy, Sadler, Placebo controlled USA Outpatient Schizophrenia spectrum 31 1.2 NR NR NR Poor Poor No relapses reported
Study Design Region of Setting Participant diagnoses Total Duration Blinding of Pharmaceutical Relapse definition1 Reliability2 of Clinical Relapse rates
origin sample size (months) assessments industry funding relapse relevance3 of (by intervention
reported (yes/no) reported (yes/no) definition relapse group)
definition
Goldberg, Hamer & withdrawal vs disorder in either group
Ross (1981) maintenance
Cheung (1981) Benzodiazepine Hong Kong Outpatient Schizophrenia spectrum 28 18 Yes NR  Recurrence of ‘schizophrenic Poor Poor Benzodiazepine
substitution vs disorder symptoms’ substitution = 8/13
maintenance  Need for antipsychotic medication Maintenance = 2/15
 Need for electroconvulsive therapy
Wistedt (1981) Placebo controlled Sweden Outpatient Schizophrenia spectrum 38 6 Yes NR  Increase in at least 6 scores on the Poor Poor Placebo = 10/16
withdrawal vs disorder Comprehensive Psychiatric rating Maintenance = 6/22
maintenance scale
 Occurrence of psychotic behaviour

Odejide & Placebo controlled Nigeria Outpatient Schizophrenia spectrum 68 12 Yes NR  Hospitalisation (for schizophrenia) Poor Poor Placebo = 5/35
Aderounmu (1982) withdrawal vs disorder  ‘Major treatment change’ Maintenance = 5/33
maintenance
McCreadie, Mackie, Placebo controlled Scotland Inpatient Schizophrenia spectrum 28 10 Yes No Reappearance of symptoms leading to Poor Poor Placebo = 3/13
Morrison & Kidd dose reduction vs disorder withdrawal from the trial Maintenance = 3/15
(1982) maintenance
Kane, Rifkin, Quitkin, Placebo controlled USA Outpatient Mixed psychosis 28 12 NR No Substantial deterioration with potential Poor Poor Placebo = 7/17
Nayak & Ramos- withdrawal vs (including affective for ‘marked social impairment’ Maintenance = 0/11
Lorenzi (1982) maintenance psychoses)
Nishikawa, Tsuda, Placebo controlled Japan Outpatient Schizophrenia spectrum 55 36 NR NR ‘Symptoms’ of relapse, including Poor Poor Placebo/substitution
Tanaka, Koga & withdrawal vs disorder insomnia and nervousness = 13/13
Uchida (1982) benzodiazepine Maintenance = 35/74
substitution vs
imiprimaine
substitution vs
maintenance
placebo controlled
drug holiday vs
maintenance
Zissis, Psaras & Placebo controlled Greece Inpatient Schizophrenia spectrum 30 4 Yes NR  ‘Treatment failure’ defined as Good Poor Placebo = 12/16
Lyketsos (1982) withdrawal vs disorder additional treatment of >40mg oral Maintenance = 0/16
maintenance haloperidol
 ‘Treatment failure’ defined as >3ml of
double blind medication (depot
Haldol or placebo)
Gardos, Cole, Rapkin, Placebo controlled USA Outpatient Schizophrenia spectrum 36 6 Yes No NR Poor Poor Placebo = 3/27
LaBrie, Baquelod, withdrawal vs disorder Maintenance = 1/9
Moore, Sovner & maintenance
Doyle (1984)
Nishikawa, Tsuda, Placebo controlled Japan Outpatient Schizophrenia spectrum 87 12 NR NR ‘Symptoms’ of relapse, including Poor Poor Placebo = 13/13
Tanaka, Hoaki & withdrawal vs disorder insomnia and nervousness Maintenance = 35/74
Koga (1984) maintenance
Crow, MacMillan, Placebo controlled UK Outpatient First episode psychosis 120 24 Yes NR  Hospitalisation Good Poor Placebo = 41/66
Johnson & Johnstone withdrawal vs  Hospitalisation considered necessary Maintenance = 25/54
(1986) maintenance but not possible
 Resumption of antipsychotics
Spohn, Coyne, Placebo controlled USA Inpatient Schizophrenia spectrum 100 3.5 Yes No ‘First signs of symptom exacerbation’ Poor Poor Placebo = 44/64
Larson, Mittleman, withdrawal vs disorder Maintenance = 5/36
Spray & Hayes (1986) maintenance
Carpenter, Heinrichs Open withdrawal USA Outpatient Schizophrenia spectrum 41 24 NR No Hospitalisation Good Good Open
& Hanlon (1987) plus intermittent disorder withdrawal/intermitt
treatment vs ent treatment =
maintenance 11/21
Maintenance = 9/20
Channabasavanna & Placebo controlled India Outpatient Schizophrenia spectrum 28 4 Yes NR Additional haloperidol Good Poor Placebo = 12/14
Study Design Region of Setting Participant diagnoses Total Duration Blinding of Pharmaceutical Relapse definition1 Reliability2 of Clinical Relapse rates
origin sample size (months) assessments industry funding relapse relevance3 of (by intervention
reported (yes/no) reported (yes/no) definition relapse group)
definition
Michael (1987) withdrawal vs disorder Maintenance = 1/14
maintenance
Gitlin, Midha, Placebo controlled Canada, USA NR Schizophrenia spectrum 12 12 Yes No NR Poor Poor No relapses reported
Fogelson & withdrawal cross disorder
Nuechterlein (1988) over design
McCreadie, Wiles, Placebo controlled Scotland Outpatient Schizophrenia spectrum 15 12 NR Yes Hospitalisation Good Good Placebo = 4/7
Grant, Crockett, withdrawal vs disorder Maintenance = 0/8
Mahmood, maintenance
Livingstone, Watt,
Green, Kershaw,
Todd, Scott, Loudon,
Dyer, Philip &
Batchelor (1989)
Carpenter, Hanlon, Open withdrawal USA Outpatient Schizophrenia spectrum 116 24 Yes No Hospitalisation Good Good Open
Heinrichs, plus intermittent disorder withdrawal/intermitt
Summerfelt, treatment vs ent treatment =
Kirkpatrick, Levine & maintenance 30/57
Buchanan (1990) Maintenance = 21/59
Jolley, Hirsch, Placebo controlled UK Outpatient Schizophrenia spectrum 49 24 Yes No Psychotic symptoms as measured by Poor Poor Placebo/intermittent
Morrison, McRink & withdrawal plus disorder Manchester scale (scale criteria not treatment = 12/24
Wilson (1990) intermittent specified) Maintenance = 3/25
treatment vs
maintenance
Herz, Glazer, Placebo controlled USA Outpatient Schizophrenia spectrum 101 24 NR No  PAS psychotic symptoms increase to Poor Poor Placebo/intermittent
Mostert, Sheard, withdrawal plus disorder moderate or severe for 2 days plus treatment = 15/50
Szymanski, Hafez, intermittent GAS <30 for 2 days Maintenance = 8/51
Mirza & Vana (1991) treatment vs  Clinician consensus
maintenance
Eklund & Forsman Placebo controlled Sweden Mixed inpatient Schizophrenia spectrum 41 15.75 Yes Yes NR Poor Poor Placebo = 16/23
(1991) withdrawal vs and outpatient disorder Maintenance = 2/18
maintenance
Ruskin & Nyman Placebo controlled USA Outpatient Schizophrenia spectrum 23 6 Yes No Clinical judgement of psychotic or Poor Poor Placebo = 5/10
(1991) withdrawal vs disorder prodromal symptoms Maintenance = 1/8
maintenance
Sampath, Shah, Krska Placebo controlled UK Inpatient Schizophrenia spectrum 24 12 No No Increase 25% BPRS total plus worsening Poor Poor Placebo = 9/12
& Soni (1992) withdrawal vs disorder of ward behaviour Maintenance = 4/12
maintenance
Pietzcker, Gaebel, Open withdrawal Germany Outpatient Schizophrenia spectrum 364 24 NR NR Increase of ≥ 10 points on BPRS psychosis Good Good Open
Kopcke, Linden, plus intermittent disorder factor plus ≥ 20 point increase on GAS withdrawal/intermitt
Muller-Spahn & treatment vs plus ≥ 6 on CGI-S (usually requiring ent treatment =
Tegeler (1993) maintenance hospitalisation) 134/242
Maintenance =
28/122

Schooler, Keith, Placebo controlled USA Mixed inpatient Schizophrenia spectrum 313 24 Yes NR Increase of 2 points on BPRS psychotic Good Poor Relapse rates not
Severe, Matthews, dose reduction vs and outpatient disorder items for >1 week reporter by group
Bellack, Glick, placebo controlled
Hargreaves, Kane, withdrawal plus
Ninan, Frances, intermittent
Jacobs, Lieberman, treatment vs
Mance, Simpson & maintenance
Woerner (1997)
Cooper, Butler, Placebo controlled Europe Mixed inpatient Schizophrenia spectrum 119 6 Yes Yes  Increase CGI-S ≥2 plus increase of at Good Poor Placebo = 21/58
Tweed & Welch withdrawal vs and outpatient disorder least 2 BPRS positive symptoms ≥2 at Maintenance = 4/61
(2000) maintenance 2 assessments over 3 days
 Hospitalisation plus increase CGI-S ≥2
Study Design Region of Setting Participant diagnoses Total Duration Blinding of Pharmaceutical Relapse definition1 Reliability2 of Clinical Relapse rates
origin sample size (months) assessments industry funding relapse relevance3 of (by intervention
reported (yes/no) reported (yes/no) definition relapse group)
definition
plus increase of at least 2 BPRS
positive symptoms ≥2 at 1 assessment
 CGI-S ≥ 6 (severely ill) for 24 hours if
outpatient
 Requiring special observation for
suicide or aggression if inpatient
Wiedemann, Open withdrawal Germany NR Schizophrenia spectrum 52 18 NR No Rating of severe on any BPRS psychosis Good Poor Open
Hahlweg, Muller, plus intermittent disorder item (≥6) withdrawal/intermitt
Feinstein, Hank & treatment vs ent treatment = 8/24
Dose (2001) maintenance Maintenance = 1/27
Arato, O’Connor, Placebo controlled Europe Inpatient Schizophrenia spectrum 278 12 NR Yes  PANSS P7 or G8 ≥6 for 2 days Poor Poor Placebo = 43/71
Meltzer, et al. (2002) withdrawal vs disorder  CGI >6 for 2 days Maintenance =
maintenance  Need for additional treatment (not 71/207
specified what)
Beasley, Sutton, Placebo controlled Croatia, Poland, Outpatient Schizophrenia spectrum 326 12 Yes Yes  Any BPRS positive item >4 plus Good Poor Placebo = 28/102
Hamilton, Walker, withdrawal vs Romania, disorder increase of 2 points at endpoint Maintenance = 9/224
Dossenbach, Taylor, maintenance Russia,USA,  BPRS positive subscale increase >4
Alaka, Bykowski & Yugoslavia  Hospitalisation due to positive
Tollefson (2003) psychotic symptoms
 Suicide or serious suicide attempt
Pigott, Carson, Saha, Placebo controlled USA, Czech Mixed inpatient Schizophrenia spectrum 297 6.5 NR Yes  Increase in total PANSS ≥ 20% Good Poor Placebo = 85/149
Torbeyns, Stock & withdrawal vs republic, and outpatient disorder  Increase in PANSS items hostility or Maintenance =
Ingenito (2003) maintenance Poland, Russia, uncooperativeness ≥ 5 for 2 days 50/148
Ukraine  CGI-I ≥ 5
Peuskens, Trivedi, Placebo controlled India & Eastern NR Schizophrenia spectrum 197 9 Yes Yes  Increase total PANSS ≥ 30 Good Poor Placebo = 50/103
Malyarov, Brecher, withdrawal vs Europe disorder  CGI-I ≥ 6 Maintenance = 11/94
Svensson, Miller, maintenance  Hospitalisation
Persson & Meulien  Additional antipsychotics
(2007)
Wunderink, Open flexible The NR First episode psychosis 128 24 Yes Yes  Admission plus one PANSS positive Good Poor Reduction/withdrawa
Nienhuis, Sytema, reduction and Netherlands item ≥5 l = 28/65
Sloof, Knegtering & withdrawal vs  Increased appointments plus one Maintenance = 13/63
Wiersma (2007) maintenance PANSS positive item ≥5
 Increased drug dose plus one PANSS
positive item ≥5
Kramer, Simpson, Placebo controlled USA, Turkey, NR Schizophrenia spectrum 205 10 NR Yes  Increase PANSS total ≥ 25% if baseline Poor Poor Placebo = 52/101
Maciulis, Kushner, withdrawal vs India, Romania, disorder >40; increase of 10 points if baseline Maintenance =
Vijapurkar, Lim & maintenance Latvia, <40 for 2 consecutive days 23/104
Eerdekens (2007) Lithuania  Increase in PANSS items (items not
specified in paper) to ≥5 if score ≤3 at
baseline; or ≥6 if ≥4 at baseline for 2
days
 Increase in CGI-S to ≥4 for those with
scores ≤3 at baseline or ≥5 if scored 4
or more at baseline for 2 consecutive
days
 Deliberate self-harm
 Suicidal or homicidal ideation
 Aggression
Chen, Hui, Lam, Chiu, Placebo controlled Hong Kong Outpatient First episode psychosis 178 12 Yes Yes Increase in P1, P2, P3, P6, or G9 to Good Poor Placebo = 56/89
Law, Chung, Tso, withdrawal vs between 3 and 5, plus increase in CGI-S ≥ Maintenance = 27/89
Pang, Chan, Wong, maintenance 3 (mild) (authors say ‘liberal’ definition)
Mo, Chan, Yao, Hung
& Honer (2010)
Hough, Gopal, Placebo controlled International NR Schizophrenia spectrum 408 10 Yes Yes  Increase PANSS total ≥ 25% if baseline Poor Poor Placebo = 97/203
Vijapurkar, Lim, withdrawal vs disorder Maintenance =
Study Design Region of Setting Participant diagnoses Total Duration Blinding of Pharmaceutical Relapse definition1 Reliability2 of Clinical Relapse rates
origin sample size (months) assessments industry funding relapse relevance3 of (by intervention
reported (yes/no) reported (yes/no) definition relapse group)
definition
Morozova & maintenance >40; increase of 10 points if 36/205
Eerdekens (2010) baseline<40
 Increase in PANSS (P1, P2, P3, P6, P7,
P8) ≥5 if score≤3 at baseline; or ≥6 if
≥4 at baseline
 Deliberate self-harm
 Clinically significant suicidal or
homicidal ideation
 Aggression
Wang, Xiang, Cai, Open dose China Mixed inpatient Schizophrenia spectrum 404 19 NR Yes  Increase in psychiatric care plus Poor Poor Open reduction =
Weng, Bo, Zhao, Liu, reduction vs and outpatient disorder increase in ≥25% PANSS total if 49/271
Wang, Weng, Zhang, maintenance baseline > 40 or 10 points if < 40 Maintenance =
Chen, Tang &  CGI-I ≥6 10/133
Ungvari (2010)  Hospitalisation
 Deliberate self-harm
 Clinically significant homicidal or
suicidal ideation
 Violence resulting in damage to
another person or property

Gaebel, Riesbeck, Placebo controlled Germany Outpatient First episode psychosis 44 12 NR No Increase PANSS positive > 10 plus CGI-I ≥ Good Good Placebo/intermittent
Wolwer, Klimke, withdrawal plus 6 plus decrease in GAF by > 20 between 2 treatment = 4/21
Eickhoff, von intermittent visits (2 weeks apart) Maintenance = 0/23
Wilmsdorff, Lemke, treatment vs
Heuser, Maier, Huff, maintenance
Schmitt, Sauer,
Riedel, Klingberg,
Kopcke, Ohmann &
Moller (2011)
Remington, Seeman, Placebo controlled Canada Outpatient Schizophrenia spectrum 35 6 NR No Increase of ≥ 20% in BPRS total score Good Poor Placebo = 4/17
Feingold, Mann, dose reduction vs disorder Maintenance = 3/18
Shammi & Kapur maintenance
(2011)
Boonstra, Burger, Open flexible The Outpatient First episode psychosis 20 24 No Yes  Any PANSS positive ≥ 4 plus increase Good Poor Open
Grobbee & Kahn reduction and Netherlands of 20% PANSS total reduction/withdrawal
(2011) withdrawal vs  Hospitalisation = 4/11
maintenance Maintenance = 1/9
Kane, Mackle, Snow- Placebo controlled USA, Russia, Outpatient Schizophrenia spectrum 386 6.5 Yes Yes  Increase in PANSS total ≥ 20% if total Poor Poor Placebo = 90/192
Adami, Zhao, Szegedi withdrawal vs India, Latvia, disorder score ≥ 50 or ≥ 10 point increase if Maintenance =
& Panagides (2011) maintenance Croatia, baseline score < 50 plus CGI-S ≥ 4 for ≥ 24/194
Ukraine 2 days within a week
 PANSS item score ≥ 5 on P7 and G8
plus CGI-S≥4 for 2 days within a week
 PANSS item score ≥ 5 on two items of
P2, P3 and G9 plus CGI-S ≥ 4 for ≥ 2
days within a week
 Hospitalisation (or increased level of
hospitalisation for those in hospital)
 Increased psychiatric care
 Arrest or imprisonment
 Additional antipsychotic
 Addition of other medication
 Electroconvulsive therapy
 Other relevant measure
Kane, Sanchez, Perry, Placebo controlled USA, Mexico, Outpatient Schizophrenia spectrum 403 12 Yes Yes  Clinical worsening as defined by CGI-I Good Poor Placebo = 53/134
Jin, Johnson, Forbes, withdrawal vs Argentia, disorder ≥ 5 and an increase on any of 4 Maintenance =
Study Design Region of Setting Participant diagnoses Total Duration Blinding of Pharmaceutical Relapse definition1 Reliability2 of Clinical Relapse rates
origin sample size (months) assessments industry funding relapse relevance3 of (by intervention
reported (yes/no) reported (yes/no) definition relapse group)
definition
McQuade, Carson & maintenance Bulgaria, individual PANSS items (conceptual 27/269
Fleischhacker (2012) Romania, disorganization, hallucinatory
Serbia, behaviour, suspiciousness or unusual
Slovakia, thought content) ≥ 4 with an absolute
Russia, India, increase of equal or greater than 2 on
Taiwan, that specific item since randomisation
Malaysia, the or an increase ≥ 4 on the combined
Philipines score of these items since
randomisation
 Risk of suicide as defined by CGI-SS
score of 4 (severely suicidal) or 5
(attempted suicide) on part 1 or a
score of 6 (much worse) or 7 (very
much worse) on part 2
 Hospitalisation due to worsening
psychotic symptoms
 Violent behaviour resulting in clinically
significant self-injury, injury to
another person, or property damage
Wunderink, Nieboer, Open flexible The Outpatient First episode psychosis 103 84 NR Yes At least one ’relevant’ PANSS item > 3 for Poor Poor Open
Wiersma, Sytema & reduction and Netherlands one week assessed from clinical notes reduction/withdrawal
Nienhuis (2013) withdrawal vs = 32/52
maintenance Maintenance = 35/51
Takeuchi, Suzuki, Open fixed dose Japan Mixed inpatient Schizophrenia spectrum 61 7 No No ≥ 4 (moderate) on at least one of PANSS Good Poor Open reduction =
Remington, Bies, reduction vs and outpatient disorder positive items (P1, P2, P3 or P6) 1/31
Abe, Graff-Guerrero, maintenance Maintenance = 1/30
Watanabe, Mimura
& Uchida (2013)
Fu, Turkoz, Placebo controlled NR Mixed inpatient Schizophrenia spectrum 334 15 Yes Yes  Increase in PANSS total ≥ 25% if Poor Poor Placebo = 57/170
Simonson, Walling, withdrawal vs and outpatient disorder baseline >45, or increase 10 points if Maintenance =
Schooler, maintenance baseline <45 25/164
Lindenmayer, Canuso  Increase in one PANSS item (P1, P2,
& Alphs (2014) P3, P4, P6, P7, G8, G14) to ≥ 6 if
baseline < 4 or ≥ 5 if baseline was ≤3
 Increase in CGI-S SCA ≥2 points if
baseline 1-3 and ≥ 1 point if baseline
≥4
 Hospitalisation
 Increased visits to avert ‘immanent
hospitalisation’
 Increased medication to avert
‘immanent hospitalisation’
 Deliberate self-harm
 Homicidal or suicidal ideation
 Violence
Fleischhacker, Placebo controlled Austria, Outpatient Schizophrenia spectrum 663 9.5 NR Yes  CGI-I ≥5 plus increase in P2, P3, P6 or Good Poor Placebo = 29/131
Sanchez, Perry, Jin, dose reduction vs Belgium, disorder unusual thought content to > 4 Maintenance =
Peters-Strickland, maintenance Bulgaria, Chile, representing ≥2 point increase 43/532
Johnson, Baker, Croatia,  CGI-I ≥5 plus increase in total score on
Eramo, McQuade, Estonia, France, the 4 items of ≥ 4
Carson, Walling & Hungary, Italy,  CGI-SS 4 or 5 in Part 1 or 6 or 7 on
Kane (2014) South Korea, Part 2
Poland, South  Hospitalisation for psychotic
Africa, symptoms
Thailand, USA  Violence (resulting in clinically
relevant damage) to self, other or
Study Design Region of Setting Participant diagnoses Total Duration Blinding of Pharmaceutical Relapse definition1 Reliability2 of Clinical Relapse rates
origin sample size (months) assessments industry funding relapse relevance3 of (by intervention
reported (yes/no) reported (yes/no) definition relapse group)
definition
property
Rui, Wang, Liang, Liu, Placebo controlled China NR Schizophrenia spectrum 135 Variable Yes NR  25% increase PANSS total for those Poor Poor Placebo = 55/71
Wu, Wu, Nuamah & withdrawal vs disorder with baseline > 40 or 10 point Maintenance = 16/64
Gopal (2014) maintenance increase for those with baseline < 40
 Increase in one PANSS item (P1, P2,
P3, P6, P7, G8) to ≥ 6 if baseline < 4 or
≥ 5 if baseline was ≤3
 Hospitalisation
 Deliberate self-harm
 Homicidal or suicidal ideation
 Violence
Durgam, Earley, Li, Li, Placebo controlled USA, India, Outpatient Schizophrenia spectrum 200 24.25 Yes Yes  Increase ≥30% in PANSS total score Poor Poor Placebo/no
Lu, Laszlovszky, withdrawal vs no Romania, disorder for patients who scored ≥50 at treatment = 47/99
Fleischhaker & treatment vs Slovakia, randomization or a ≥10-point increase Maintenance =
Nasrallah (2016) maintenance Ukraine for patients who scored <50 at 25/101
randomization
 Score N 4 on any of the 7 PANSS items
assessed at randomization (delusions,
conceptual disorganization,
hallucinatory behavior,
suspiciousness/persecution, hostility,
uncooperativeness, poor impulse
control)
 CGI-S score increase ≥ 2 points from
randomization
 Deliberate self-harm
 Homicidal or suicidal ideation
 Aggression

Weiden, Manning, Placebo controlled India, Ukraine Outpatient Schizophrenia spectrum 303 6.5 Yes Yes  Increase PANSS total ≥ 30% from Poor Poor Placebo = 96/150
Wolfgang, Ryan, withdrawal vs disorder baseline Maintenance =
Mancione, Han, maintenance  CGI-I 6 or 7 27/153
Ahmed & Mayo  Hospitalisation (due to worsening
(2016) schizophrenia)
 Increase in antipsychotic medication
 Worsening suicidal behaviour
 Worsening homicidal or aggressive
behaviour
Tandon, Cucchiaro, Placebo controlled USA, Slovakia, NR Schizophrenia spectrum 285 7 Yes Yes  Increase ≥ 25% PANSS total plus CGI-S Poor Poor Placebo = 72/141
Philips, Hernandez, withdrawal vs Russia, Serbia, disorder increase of ≥ 1 point for 2 visits (no Maintenance =
Mao, Pikalov & maintenance France, South more than 10 d apart) 61/144
Loebel (2016) Africa, Italy  PANSS hostility or uncooperativeness
≥ 5 at one visit
 2 PANSS items (P1, P2, P3, unusual
thought content) ≥ 5
 Hospitalisation
 Additional medication
 Insufficient response reported as AE
 Deliberate self-harm
 Suicidal or homicidal ideation
 Violence, aggression
 Electroconvulsive therapy
Correll, Kohegyi, Placebo controlled India, Malaysia, NR Schizophrenia spectrum 146 12 Yes Yes  CGI-I≥5 plus increase in P2, P3, P6 or Poor Poor Placebo = 18/48
Zhao, Baker, withdrawal vs the Philippines, disorder unusual thought content to > 4 Maintenance = 19/98
McQuade, Salzman, maintenance Romania, representing ≥2 point increaser or
Sanchez, Nyilas & Russia, increase in total score on the 4 items
 Study Design Region of Setting Participant diagnoses Total Duration Blinding of Pharmaceutical Relapse definition1 Reliability2 of Clinical Relapse rates
origin sample size (months) assessments industry funding relapse relevance3 of (by intervention
reported (yes/no) reported (yes/no) definition relapse group)
definition
Carson (2017) Taiwan, USA of ≥ 4
 CGI-I 6 or 7
 Hospitalisation
 Suicidal behaviour
 Violence
Fleischhacker, Placebo controlled USA, Ukraine, Mixed inpatient Schizophrenia spectrum 202 12 Yes Yes  CGI-I≥5 plus increase in P2, P3, P6 or Good Poor Placebo = 40/105
Hobart, Ouyang, withdrawal vs Serbia, and outpatient disorder unusual thought content to > 4 Maintenance = 13/97
Forbes, Pfister, maintenance Malaysia, representing ≥2 point increase
McQuade, Carson, Romania,  CGI-I ≥5 plus increase in total score on
Sanchez, Nyilas & Colombia, the 4 items of ≥ 4
Weiller (2017) Turkey  Suicidal behaviour assessed by C-SSRS
 Violence (resulting in clinically
relevant damage) to self, other or
property

Zhou, Li, Li Cui & Placebo controlled China Mixed inpatient Schizophrenia spectrum 75 12 Yes Yes ≥ 4 (moderate) on at least one of PANSS Good Poor Placebo = 4/37
Ning (2018) withdrawal vs and outpatient disorder positive items (P1, P2, P3 or P6) Maintenance = 6/38
maintenance
1 each bullet point indicates an alternative definition

2 Definitions were rated as showing good reliability if they: used objective criteria like hospitalisation, resumption of antipsychotics, precisely specified rating scale changes or if they provided precise descriptions of other methods; face to face assessments were required for rating scale
assessments unless there was a convincing justification for the reliability of other methods. These requirements had to apply to all definitions or criteria.

3 Definitions were rated as showing good clinical relevance if they specified an increase in positive psychotic symptoms and a measure that indicated a level of severity or global or functional deterioration of at least a moderate degree for all cases of relapse. Trials defining relapse solely
as hospitalisation or ‘necessary’ hospitalisation were also included.

NR not reported; ECT electro convulsive therapy; PAS Problem Appraisal Scale; GAS Global Assessment Scale; BPRS Brief Psychiatric Rating Scale; PANSS Positive and Negative Syndrome Scale; CGI-I Clinical Global Impressions- Improvement; CGI-S Clinical Global Impressions- Severity;
GAF Global Assessment of Functioning