APPENDIX 12: STUDY CHARACTERISTICS OF INCLUDED STUDIES Number of Interventions/ Adjunctive Treatment APDs Failed Sample Author, Year Country Sponsor Comparators Duration Prior to Size (Mean Dose) Allowed (Weeks) Study

Grant from Stanley Medical research Institute, RIS+CLZ Benzodiazepines Janssen 515.6±138.7 mg/d CLZ for anxiety and/or AKDEDE et al. Pharmaceutica, and 42 Turkey for 6 weeks ≥3 30 (2005) THE Ritter 5.1±1.3 mg/day RIS EPS allowed if Foundation, the PLC+CLZ necessary William K. 414.3±96.9 mg/d CLZ Warren Medical Research Foundation ANIL YAGCIOGLU et 45 See Akdede 2006 al. (2005) AMI400+CLZ 400mg/d AMI and 300 Occasional mg/d CLZ intake of 49 Sanofi- AMI600+CLZ benzodiazepines, ASSION et al. (2008) Germany 6 weeks ≥1 16 Synthelabo 600 mg/d AMI and sedatives, or 300mg/d CLZ PLC+CLZ allowed 300 mg/d CLZ

60 France and Novartis Phama RIS (H): median 9 mg/d AZORIN et al. (2001) Not reported 12 weeks ≥1 273 Canada S.A. CLZ: median: 600 mg/d Lorazepam or Janssen oxazepam for BONDOLFI et al. France and RIS (H): 6.4 mg/d 66 Research sleep induction 8 weeks ≥2 86 (1998) Switzerland CLZ: 291.2 mg/d Foundation or daytime sedation;

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Number of Interventions/ Adjunctive Treatment APDs Failed Sample Author, Year Country Sponsor Comparators Medications Duration Prior to Size (Mean Dose) Allowed (Weeks) Study

biperiden and for EPS Supported by grants from Brain Research center, funded by the ARI+CLZ Antidepressants, Ministry of 15.5±7.1 mg/d ARI and 38 CHANG et al. (2008) Korea Science and 400 mg/d CLZ 8 weeks ≥3 62 and Technology; PLC+CLZ benzodiazepine Republic of 400mg/d CLZ Korea and Otsuka Pharmaceutical CITROME et al. 58 59 See Volavka 2002 (2001) Diazepam allowed for sedation; Janssen 68 RIS (H): 12 mg/d CLAUS et al. (1992) Belgium Research 12 weeks Not reported 44 Hal: 10 mg/d allowed for EPS; Foundation for acute dystonia OLZ+PLC: 25 mg/d Benztropine Supported by CPZ+Benz: mesylate NIMH grants. Eli CONLEY et al. 1200 mg/d ( 65 USA Lilly provided 6 weeks ≥3 84 (1998) chlorpromazine and 4 group), or investigational mg/d benztropine placebo drugs mesylate (

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Number of Interventions/ Adjunctive Treatment APDs Failed Sample Author, Year Country Sponsor Comparators Medications Duration Prior to Size (Mean Dose) Allowed (Weeks) Study

group). Lorazepam (up to 8 mg/day) for agitation or anxiety. No other centrally acting medications. NIMH and lorazepam or 8 weeks CONLEY et al. Intervention OLZ (H): 50 mg/d 76 USA benztropine (pre- ≥2 13 (2003) Research Center CLZ: 450 mg/d mesylate crossover) grants CZOBOR et al. 58 71 See Volavka 2002 (2002) Benzodiazepines and anticholinergics, ARI+CLZ sleep aids for 11.1 mg/d ARI and insomnia, anti- 383.8±158.2 mg/d CLZ depressants and FLEISCHHACKER et Bristol-Meyers 54 Austria PLC+CLZ mood stabilizers 16 weeks Not reported 207 al. (2010) Squibb 12.0 mg/day PLC and at a stable dose 362.6.8±158.7 mg/d if the patient CLZ taking prior to study entry. Propranolol for akathisia. RIS+CLZ Stanley Medical 4 mg/d RIS and 456 FREUDENREICH et stable 41 USA Research mg/d CLZ 6 weeks ≥2 24 al. (2007) psychotropics Institute PLC+CLZ 456 mg/d CLZ

158 Systematic Review of Combination and High-Dose AAPs for Schizophrenia

Number of Interventions/ Adjunctive Treatment APDs Failed Sample Author, Year Country Sponsor Comparators Medications Duration Prior to Size (Mean Dose) Allowed (Weeks) Study

AMI+CLZ 437±104 mg/d AMI and 536–550 mg/d CLZ GENC et al. (2007)50 Turkey Not reported QUET+CLZ Not reported 8 weeks ≥1 56 596 125.25 mg/d QUET and 536–550 mg/d CLZ Lorazepam, propranolol, GREEN at al. 62 62 59 67 See KERN et al. (1999) chloral hydrate, See KERN et al. (1999) (1997) † analyzed benztropine or biperiden Lorazepam or RIS+CLZ chloral hydrate Stanley medical 2.94±0.2 mg/d RIS and for treatment of Multinational research 492 mg/d±192 mg/d agitation or other (Canada, institute. 44 CLZ symptoms, not HONER et al. (2006) China, 8 weeks Not reported 68 PLC+CLZ within 48 hours Germany, provided by 2.88±0.42 mg/d PLC of cognitive tests. UK) Jansen-Ortho, and 492 mg/d±131 Anticholinergics Canada mg/d CLZ for acute side effects. antidepressants, mood stabilizers or hypnotics if stable dose for 72 QUET (H): 1,144 mg/d HONER et al. (2011) Canada Astra Zeneca 30 days prior to 8 weeks ≥1 131 QUET: 799 mg/d entry. Flurazepam or zaleplon for sleep, lorazepam

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Number of Interventions/ Adjunctive Treatment APDs Failed Sample Author, Year Country Sponsor Comparators Medications Duration Prior to Size (Mean Dose) Allowed (Weeks) Study

for agitation. for treatment- emergent EPS Johnson & RIS+CLZ Johnson 4.43±1.5 mg/d RIS and JOSIASSEN et al. 46 USA Pharmaceutical ≥600 mg/d CLZ Not reported 12 weeks ≥3 40 (2005) Research & PLC+CLZ Development ≥600 mg/d CLZ Antidepressants (not or ); anticholinergics; mood stabilizers; anticonvulsants ARI + (RIS or QUET) (not Bristol-Meyers 10.3 mg/d ARI and 513 carbamazepine); Squibb, USA and mg/d QUET or and 36 benzodiazepines KANE et al. (2009) USA Otsuka 4.6 mg/d RIS 16 weeks ≥1 323 if pts receiving Pharmaceutical PLC + (RIS or QUET) stable dose for ≥ 4 Co Ltd, Japan 516 mg/d QUET or 4.8 weeks prior to mg/d RIS study entry. Benzodiazepine for manage treatment- emergent agitation or anxiety. KELLY et al. (2003)48 See Conley 200376 KELLY et al. (2006)43 See Conley 200376

160 Systematic Review of Combination and High-Dose AAPs for Schizophrenia

Number of Interventions/ Adjunctive Treatment APDs Failed Sample Author, Year Country Sponsor Comparators Medications Duration Prior to Size (Mean Dose) Allowed (Weeks) Study

64 62 56 KERN et al. (1998) † See KERN et al. (1999) analyzed NIMH UCLA Research Center Lorazepam, for the Study of propranolol, Schizophrenia, chloral hydrate, 62 RIS (H): 7mg/d 64 KERN et al. (1999) † USA Janssen benztropine or 8 weeks ≥2 classes Hal: 19 mg/d analyzed Research biperiden Foundation, (See GREEN at Department of al. (1997)67) Veterans Affairs Sulpiride+OLZ(H): up to 600 mg/d Sul and KOTLER et al. 22.4±4.37 mg/d OLZ 47 Israel Not reported None 8 weeks ≥1 17 (2004) OLZ(H): 22.4±4.37 mg/d OLZ (no placebo) Lithium, depakote, other mood stabilizers, OLZ (H): 26.2 ± 6.5 antidepressants, 40 mg/d KUMRA et al. (2008) USA Not reported stimulants, and 12 weeks ≥2 39 CLZ: 403.1 ± 201.8 naltrexone. 3 mg/d subjects could not be tapered off previous APD. RIS+CLZ KUWILSKY et al. 37 2.75±1.3 mg/d RIS and 37 37 55 See Zink 2009 See Zink 2009 52 weeks See Zink 2009 (2010) † 450.0±168.3 mg/d CLZ ZIP+CLZ

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Number of Interventions/ Adjunctive Treatment APDs Failed Sample Author, Year Country Sponsor Comparators Medications Duration Prior to Size (Mean Dose) Allowed (Weeks) Study

120±65.3 mg/d ZIP and 325.0±185.4 mg/d CLZ OLZ (H): 31.4±6.0 mg/d LINDENMAYER et al. 58 58 101 57 See Volavka, 2002 RIS (H): 11.6±3.7 mg/d See Volavka 2002 (2003) † analyzed CLZ: 477.2±157.2 mg/d Hal: 25.8±5.1 mg/d OLZ(H): mean modal McEVOY et al. NIMH, IVAX 23.4 mg/d Non-APD meds 70 USA 24 weeks ≥1 68 (2006) corporation CLZ: mean modal permitted 332.1 mg/d OLZ(H): 33.6±11.2 MELTZER et al. Eli Lilly and other 39 USA mg/d Anti-depressants 26 weeks ≥2 40 (2008) foundations CLZ: 564±243 ARI+CLZ: 4 to 15mg/d funded by ARI, CLZ dose not 74 Bristol-Myers MILLAR et al. (2008) Not reported reported Not reported 16 weeks ≥1 207 Squibb and PLC+CLZ: CLZ dose Otsuka not reported Hal+CLZ 4 mg/d Hal and MOSSAHEB et al. 73 Austria Not reported 450±70.7 mg/d CLZ Not reported 10 weeks ≥3 10 (2006) PLC+CLZ 500±81.7 mg/d CLZ RIS+CLZ: 4 mg/d RIS; RICHARDSON et al. Lilly CLZ dose not reported 75 USA Not reported 16 weeks ≥1 65 (2009) Pharmaceuticals PLC+CLZ: CLZ dose not reported ROSENHECK et al. Dept. Veterans CLZ(H): 628 mg/d benztropine 63 USA 52 weeks ≥2 245 (1999) Affairs Health Hal: 28.2 mg/d mesylate

162 Systematic Review of Combination and High-Dose AAPs for Schizophrenia

Number of Interventions/ Adjunctive Treatment APDs Failed Sample Author, Year Country Sponsor Comparators Medications Duration Prior to Size (Mean Dose) Allowed (Weeks) Study

Services R&D, Sandoz Pharm. Co. +OLZ(H) 17.42±6.07 mg/2 wks 52 FLU and 21.96±5.03 SHAFTI (2009) Iran Not reported None 12 weeks ≥1 28 mg/d OLZ PLC+OLZ(H): 21.96±5.03 mg/d OLZ SUL+CLZ 10 weeks ≥3 28 600 mg/d SUL and SHILOH et al. (1997)51 Israel Not reported 403.1±137.2 mg/d CLZ None PLC+CLZ 445.8±132.2 mg/d CLZ Benzodiazepine, 18 weeks ≥2 180 Multinational OLZ(H): 20.5 ± 2.8 chloral hydrate, TOLLEFSON et al. (Europe and mg/d 53 Eli Lilly biperiden or (2001) South CLZ: 303.6 ± 108.7 benztropine Africa) mg/d mesylate Benztropine, 14 weeks ≥1 167 lorazepam, analyzed OLZ (H): 30.4±6.6 hydrochloride, or NIMH grant; mg/d chloral hydrate VOLAVKA et al. pharmaceutical 58 USA RIS (H): 11.6±3.2 mg/d were allowed. No (2002) companies CLZ: 526.6±140.3 mg/d other mood provided drugs Hal: 25.7±5.7 mg/d stabilizers or antidepressants allowed

Systematic Review of Combination and High Dose AAPs for Schizophrenia 163

Number of Interventions/ Adjunctive Treatment APDs Failed Sample Author, Year Country Sponsor Comparators Medications Duration Prior to Size (Mean Dose) Allowed (Weeks) Study

VOLAVKA et al. 58 56 See Volavka 2002 2004 RIS+CLZ 16 weeks ≥1 69 4 mg/d RIS and CLZ level 680.1±446.6 WEINER et al. NIMH and U. of 69 USA ng/mL Not reported (2010) Maryland PLC+CLZ CLZ level 491.2±264.0 ng/mL Anticholinergics (benztropine or WIRSHING et al. 62 RIS (H): 7.5 ± 1.9 mg/d biperiden), 62 61 See Kern 1999 See Kern 1999 67 (1999) Hal: 19.4 ± 5.6 mg/d propranolol, lorazepam, temazepam RIS+CLZ 3.82 ± 1.8 mg/d RIS Valproic acid, Pfizer Pharma and 437.5±140.4 mg/d 37 antidepressants, ZINK et al. (2009) † Germany GmbH and other CLZ 6 weeks ≥2 24 benzodiazepine, author grants ZIP+CLZ clonazepam 134±34.4 mg/d ZIP and 370.8±150.0 mg/d CLZ † Several trials were reported in multiple publications; however, the number of patients included in analyses or the time point reported was different between publications.

164 Systematic Review of Combination and High-Dose AAPs for Schizophrenia