Clotiapine for acute psychotic illnesses

Michael Berk; John Rathbone; Simone L Mandriota‐Carpenter

doi:10.1002/14651858.CD002304.pub2

Clotiapina para las enfermedades psicóticas agudas

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Referencias

Referencias de los estudios incluidos en esta revisión

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estudios excluidos
estudios a la espera de valoración
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Itoh H, Okamoto M, Miura S, Suzuki Y, Takemasa K, Shigeta M, Mochizuki N, Yagi G, Asaka H. A comparison between the clinical effectiveness of a dibenzothiazepine derivative and a phenothiazine derivative in schizophrenia. A controlled double‐blind study using clothiapine (W‐130) and perphenazine. Seishin Igaku 1969;11:465‐75.

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Itoh H, Okamoto T, Miura S, Suzuki Y, Takemasa K, Shigeta M, Mochizuki M, Yagi G, Asaka H. Comparison of a dibenzothiazepine derivative (clothiapine = w‐130) and a phenothiazine derivative (perphenazine) in schizophrenic patients using double‐blind technique [[data not available]]. Seishin Igaku 1969;11(6):465‐75. [MEDLINE: 72027147; PMID 4939829]

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Perales CJA, Garcia MA, Infantes PV, Valle EDG. Comparative study between clothiapine and trifluoperazine in acute episodes of paranoid schizophrenia [Estudio comparativo de la clotiapina y de la trifluoperazina en episodios agudos de esquizofrenia paranoide]. Acta Psiquiatrica y Psicologica de America Latina 1974;20(3):207‐13.

Subramaney U, Brook S, Berk M. A prospective randomised double blind controlled study of the efficacy of lorazepam versus Clothiapine in the control of acutely behaviourally disturbed patients. 10th European College of Neuropsychopharmacology Congress; 1997 Sep 13‐17; Vienna, Austria. 1997. [MEDLINE: 72027147; PMID 4939829]

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Subramaney U, Brook S, Berk M. A prospective randomised double‐blind controlled study of the efficacy of lorazepam versus clothiapine in the control of acutely behaviourally disturbed patients. South African Medical Journal 1998;88(3):307‐10.

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Uys H, Berk M. A controlled double blind study of zuclopenthixol acetate compared to clothiapine in acute psychosis including mania and exacerbation of chronic psychosis. Proceedings of XXth Collegium Internationale Neuro‐psychopharmacologicum, Melbourne, Australia. June 1996.

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Uys H, Berk M. A controlled double blind study of zuclopenthixol acetate compared to clothiapine in acute psychosis including mania and exacerbation of chronic psychosis. Unpublished Report1996. [MEDLINE: 72027147; PMID 4939829]

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Referencias de los estudios excluidos de esta revisión

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Bellomo LE. Clinical study with clothiapine in psychotic patients [Experiencia clínica con clotiapina en enfermos psicoticos]. La Semana Medica 1973;143:887‐90.

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Kaneko J, Tanimukai H, Kudo Y. A double‐blind, controlled study of the effects of clothiapine and chlorpromazine on schizophrenia [(Original Japanese)]. Clinical Psychiatry 1969;11:721‐8.

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Savoldi F, Arrigo A, Mille T, Tartara A. Clinical study of a new neuroleptic (Wander HF 2159) [Studio clinico di una nuova sostanza neurolettica (Wander HF 2159)]. La Riunione Nazionale della Societa Italiana di Neuropsicofarmacologia. 1967:7‐12.

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Referencias de los estudios en espera de evaluación

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Ayuso‐Gutierrez JL, Alvarez‐Egocheaga L. Therapeutic evaluation of Clothiapine in various psychopathological patterns [Valoracion terapeutica de la Clotiapina en diversos cuadros psicopatologicos]. Actas Luso Esp. Neurol. Psiquiatr. Cienc. Afines 1973;1(4):565‐70.

Belmaker R. Clotiapine for schizophrenia. Stanley Foundation Research Programs2009.

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Nahunek K, Svestka J, Ceskova E. On the question of differences between therapeutic responses after particular neuroleptics in comparison to perphenazine in schizophrenics [Kotazce rozdilnosti terapeutickych odpovedi po jednotlivych neurolepticich ve srovnani s perphenazinem u schizofrennich nemocnych]. Ceskoslovenska Psychiatrie 1981;77(1):25‐30. [MEDLINE: 81234669; PsycINFO 68‐01789; PMID 6113897]

Schliefer T, Bersudsky Y, Geller V, Belmaker RH. Clotiapine in schizophrenia: a controlled study. Proceedings of the 16th European College of Neuropsychopharmacology Congress; 2003 Sep 20‐24; Prague, Czech Republic. 2003.

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios excluidos
estudios a la espera de clasificación

Itoh 1969

Methods	Allocation: randomised, matched pairs, table of random numbers. Blinding: double. Duration: 60 days (preceded by 1 week washout).
Participants	Diagnosis: schizophrenia. History: 4 in 'state of intense excitement' ‐ possible to extract data on only these people. N = 80 (4 included). Sex: 62 M, 18 F. Age: mean ˜34 years. Setting: hospital. Exclusion criteria: not mentioned.
Interventions	1. Clotiapine: dose 45 to 90 mg/day orally by day 7, as needed thereafter, range 90‐290 mg/day. N = 2. 2. Perphenazine: dose 12‐24 mg/day orally by day 7, as needed thereafter, range 24‐64 mg/day. N = 2. Antiparkinsonian drugs and hypnotics permitted. No mention of non‐pharmacological interventions.
Outcomes	General improvement: overall clinical response. Unable to use ‐ Mental state: (BPRS ‐ data not extractable for 'acute' participants only). Adverse effects: (data not extractable for 'acute' participants only). Leaving the study early: (data not extractable for 'acute' participants only).
Notes	Trial sponsored by drug company.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

Jacobsson 1974

Methods	Allocation: randomised, pre‐established code. Blinding: double. Duration: one month (preceded by 'a few days' washout).
Participants	Diagnosis: 'psychotic syndromes of a schizophrenic type'. History: acute, first episode or relapse. N = 49. Sex: 23 M, 26 F. Age: range 18‐60 years. Setting: hospital. Exclusion criteria: neurological or somatic disorders, substance misuse as principal reason for hospital admission; history of spontaneous remission shortly after admission.
Interventions	1. Clotiapine: dose 40‐240 mg/day orally. N = 23. 2. Chlorpromazine: dose 100‐600 mg/day orally. N =2 6. Antiparkinsonian drugs and hypnotics permitted. No mention of non‐pharmacological interventions.
Outcomes	General improvement: overall clinical response. Adverse effects: needing antiparkinsonian treatment. Leaving study early. Unable to use ‐ Behaviour: (Wing Rating Scale for Ward Behaviour ‐ no SD, inexact p values). Mental state: (Authors' modification of the 'Martens & Jonsson' Symptom Scale ‐ no SD, inexact p values). Adverse effects: (Scale for Rating of Side‐Effects ‐ no SD, inexact p values).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Perales 1974

Methods	Allocation: randomised, table of random numbers. Blinding: double (but likely that oral doses of drugs caused unblinding). Duration: 45 days.
Participants	Diagnosis: paranoid schizophrenia. History: acute. N = 30. Sex: 26 M, 4 F. Age: range 19‐43 years. Setting: hospital. Exclusion criteria: other psychiatric diagnosis.
Interventions	1. Clotiapine: dose 40‐160 mg/day IM from day 1‐5, then 40‐160 mg/day orally until the end of trial. N =1 5. 2. Trifluoperazine: dose 2‐8 mg/day IM from day one to day five, then 10‐40 mg/day orally until the end of trial. N = 15. Antiparkinsonian drugs were permitted. No mention of non‐pharmacological interventions.
Outcomes	Global improvement: (degree of improvement on categorical scale). Adverse effects: (list of adverse effects). Leaving study early. Unable to use ‐ Mental state: (BPRS ‐ no SD, inexact p values). Adverse effects: (Bordelau's Extrapyramidal Symptoms Scale, use of antiparkinsonian drugs ‐ no SD).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Subramaney 1998

Methods	Allocation: randomised ‐ by toss of a coin. Blinding: double. Duration: one week.
Participants	Diagnosis: organic (psycho‐active substance) hallucinations, organic delusional disorder, schizophrenia, bipolar disorder (DSM III). History: acutely behaviourally disturbed with aggressive, disorganised behaviour. N = 60. Sex: 46 M, 14 F. Age: range 18‐45 years. Setting: hospital. Exclusion criteria: physical illness, pregnancy, abnormal routine blood tests.
Interventions	1. Clotiapine: maximum dose 40 mg IM 6 hourly + haloperidol 10 mg/day orally. N = 30. 2. Lorazepam: maximum dose 4 mg IM 6 hourly + haloperidol 10 mg/day orally. N = 30. No mention of antiparkinsonian drugs or non‐pharmacological interventions.
Outcomes	Mental state: (BPRS). Leaving study early. Unable to use ‐ Behaviour: Overt Aggression Scale (skewed data presented). Adverse effects: Simpson‐Angus Scale (skewed data presented).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Uys 1996

Methods	Allocation: randomised ‐ by toss of a coin. Blinding: double. Duration: one week.
Participants	Diagnosis: schizophrenia, acute paranoid reaction, other and unspecific reactive psychosis, unspecified psychosis, bipolar mood disorder‐manic phase (ICD 9). History: acute restless or aggresive behaviour. N = 42. Sex: 42 M. Age: range 18‐65 years. Setting: hospital. Exclusion criteria: oral neuroleptics within the last six hours or depot neuroleptics within the last two weeks, clinically relevant medical or neurological disease, known organic brain disorder, pregnancy or inadequate contraception, abnormal laboratory values or history of drug abuse.
Interventions	1. Clotiapine: dose 40 mg IM initially, then 80‐160 mg/day, in divided doses, orally or IM. N = 21. 2. Zuclopenthixol acetate: dose 150 mg IM initially, repeated once after 72 hours. N = 21. Antiparkinsonian drugs, lithium and benzodiazepines permitted. No mention of non‐pharmacological interventions.
Outcomes	Adverse effects: (needing anticholinergic medication, frequent side‐effects, pain at site of injection). Leaving the study early. Unable to use ‐ General improvement: (CGI ‐ no data). Sedation: (Likert Scale ‐ no data). Mental state: (BPRS, Bech Rafaelsen Mania Rating Scale ‐ no SD). Adverse effects: (UKU ‐no usable data).
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Unclear risk	B ‐ Unclear

Diagnostic Manuals
DSM ‐ Diagnosic and Statistical Manual of Mental Disorders (American Psychiatric Association)
ICD ‐ International Classification of Diseases

General
IM ‐ intramuscular
Ht ‐ Haematocrit
Hb ‐ Haemoglobin
PRSS ‐ Psychiatric Rating Scale for Schizophrenia
RBC ‐ Red Blood Cell
WBC ‐ Wight Blood Cell
ESR ‐ Erithrocyte Sedimentation Rate
IV ‐ Intravenous injection
M ‐ Male
F ‐ Female
SD ‐ Standard Deviation

Scales
BPRS ‐ Brief Psychiatric Rating Scale
CGI ‐ Clinical Global Impression
UKU ‐ Udvalg for Kliniske ndersogelser

Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Bellomo 1973	Allocation: not randomised.
Bellomo 1975	Allocation: not randomised.
Bente 1966	Allocation: not randomised.
Block 1974	Allocation: randomised. Participants: chronic alcoholics, suffering from 'anxiety, tension, irritability or depression', but 'not blunted so severely that they could not be expected to cooperate'. Clearly not acute psychosis.
Caldas 1971	Allocation: not randomised.
Cante 1971	Allocation: not described. Participants: people with schizophrenia. Interventions: each group given same drug (clotiapine HF 2159).
Carra 1974	Allocation: not randomised.
Delay 1965	Allocation: not randomised.
Etienne 1976	Allocation: not randomised.
Gazzaniga 1972	Allocation: not randomised.
Gehring 1972	Allocation: not randomised.
Giordano 1973	Allocation: not randomised.
Kammerer 1967	Allocation: randomised. Participants: 'psychotic' or 'prepsychotic' inpatients suffering from schizophrenia, bipolar disorder mostly melancholia, brief psychotic episodes, chronic delirium, 'prepsychotic states', depression associated with alcohol misuse. Not all participants were 'acutely' ill. Interventions: clotiapine versus 'standard medication'. Outcomes: impossible to extract data for relevant participants ‐ authors could not be located.
Kaneko 1969	Allocation: by 'the double‐blind technique', matched pairs according to sex, age and clinical condition ‐ no mention of randomisation. Participants: people suffering from schizophrenia, some in a 'severe excited state' but could not be certain how many participants were in this condition, so data was not extractable for only these people.
Martin 1968	Allocation: not randomised.
Martins 1969	Allocation: not randomised.
Matsushita 1968	Allocation: not randomised.
Ohkuma 1970	Allocation: not randomised.
Oules 1973	Allocation: not randomised.
Rapidis 1975	Allocation: not randomised.
Rodova 1971	Allocation: randomised. Participants: people with schizophrenia, most not in an 'acute' phase. Interventions: clotiapine versus perphenazine. Outcomes: no usable data; authors contacted and Professor Svestka kindly replied; initial randomisation confirmed but data not available for just acutely ill people before the first crossover.
Rosier 1974	Allocation: not randomised.
Savoldi 1967	Allocation: not randomised.
Toerien 1973	Allocation: not randomised.
Traldi 1969	Allocation: not randomised.
Van Wyk 1971	Allocation: randomised. Participants: people with schizophrenia or 'toxic' psychosis (alcohol or drug abuse), acutely ill. Interventions: clotiapine versus chlorpromazine or thioridazine. Outcomes: attrition rate over 50%, no data on these participants and impossible to find out the exact number of dropouts; precise percentage of people cured and discharged from hospital before the end of the trial in each study group was presented. For two groups, these exact percentages amount to fractional numbers when applied to the number of participants in each group. We therefore supposed some data might be missing or have been modified.
Watanabe 1969	Allocation: not randomised.
Zapletalek 1971	Allocation: not randomised.

IM ‐ intramuscular injection

Characteristics of studies awaiting assessment [ordered by study ID]

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estudios incluidos
estudios excluidos

Ayuso‐Gutierrez 1973

Methods
Participants
Interventions
Outcomes
Notes	To be assessed.

Belmaker 2009

Methods
Participants
Interventions
Outcomes
Notes	To be assessed.

Geller 2005

Methods
Participants
Interventions
Outcomes
Notes	To be assessed.

Nahunek 1981

Methods
Participants
Interventions
Outcomes
Notes	To be assessed.

Schliefer 2003

Methods
Participants
Interventions
Outcomes
Notes	To be assessed.

Data and analyses

Open in table viewer

Comparison 1. CLOTIAPINE versus STANDARD MEDICATION ‐ OTHER ANTIPSYCHOTICS

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 General clinical impression: No significant improvement Show forest plot	3	83	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.25, 2.66]
Open in figure viewer Analysis 1.1 Comparison 1 CLOTIAPINE versus STANDARD MEDICATION ‐ OTHER ANTIPSYCHOTICS, Outcome 1 General clinical impression: No significant improvement.
2 Hospital and service outcome: Not well enough to be discharged Show forest plot	1	49	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.93, 1.16]
Open in figure viewer Analysis 1.2 Comparison 1 CLOTIAPINE versus STANDARD MEDICATION ‐ OTHER ANTIPSYCHOTICS, Outcome 2 Hospital and service outcome: Not well enough to be discharged.
3 Leaving the study early Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.3 Comparison 1 CLOTIAPINE versus STANDARD MEDICATION ‐ OTHER ANTIPSYCHOTICS, Outcome 3 Leaving the study early.
3.1 any reason	3	121	Risk Ratio (M‐H, Random, 95% CI)	2.26 [0.40, 12.88]
3.2 adverse effects	3	121	Risk Ratio (M‐H, Random, 95% CI)	5.63 [0.28, 111.43]
4 Adverse effects: 1. Movement disorders ‐ use of antiparkinsonian medication Show forest plot	2	91	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.03, 4.10]
Open in figure viewer Analysis 1.4 Comparison 1 CLOTIAPINE versus STANDARD MEDICATION ‐ OTHER ANTIPSYCHOTICS, Outcome 4 Adverse effects: 1. Movement disorders ‐ use of antiparkinsonian medication.
5 Adverse effects: 2. Incidence of specific side‐effects Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
Open in figure viewer Analysis 1.5 Comparison 1 CLOTIAPINE versus STANDARD MEDICATION ‐ OTHER ANTIPSYCHOTICS, Outcome 5 Adverse effects: 2. Incidence of specific side‐effects.
5.1 dry mouth	1	42	Risk Ratio (M‐H, Random, 95% CI)	0.4 [0.09, 1.84]
5.2 headache	1	30	Risk Ratio (M‐H, Random, 95% CI)	1.83 [0.92, 3.66]
5.3 insomnia	1	30	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.82, 1.70]
5.4 pain at site of injection	1	42	Risk Ratio (M‐H, Random, 95% CI)	5.0 [0.25, 98.27]
5.5 palpitations	1	42	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.10, 2.44]
5.6 rash	1	49	Risk Ratio (M‐H, Random, 95% CI)	5.63 [0.28, 111.43]
5.7 seizure	1	42	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.13, 69.70]
5.8 sweating ‐ facial	1	30	Risk Ratio (M‐H, Random, 95% CI)	1.38 [0.78, 2.41]

Open in table viewer

Comparison 2. CLOTIAPINE versus STANDARD MEDICATION ‐ BENZODIAZEPINES

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mental state: No significant improvement ‐ three days after beginning of treatment Show forest plot

1

60

Mean Difference (IV, Fixed, 95% CI)

‐3.36 [‐8.09, 1.37]

Analysis 2.1

Comparison 2 CLOTIAPINE versus STANDARD MEDICATION ‐ BENZODIAZEPINES, Outcome 1 Mental state: No significant improvement ‐ three days after beginning of treatment.

2 Leaving the study early Show forest plot

1

60

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.07, 15.26]

Analysis 2.2

Comparison 2 CLOTIAPINE versus STANDARD MEDICATION ‐ BENZODIAZEPINES, Outcome 2 Leaving the study early.

3 Behaviour: Aggression (Overt Aggression Scale, skewed data, high=poor) Show forest plot

Other data

No numeric data

Analysis 2.3


Study	Clotiapine N	Clotiapine mean (SD)	Lorazepam N	Lorazepam Mean (SD)
on admission
Subramaney 1998	30	6.43 (4.07)	30	5.87 (3.27)
by 24 hours
Subramaney 1998	30	1.33 (2.78)	30	1.83 (3.14)
by 72 hours
Subramaney 1998	30	1.30 (2.85)	30	1.17 (2.15)
by 1 week
Subramaney 1998	29	1.41(4.14)	29	1.03 (2.26)

Comparison 2 CLOTIAPINE versus STANDARD MEDICATION ‐ BENZODIAZEPINES, Outcome 3 Behaviour: Aggression (Overt Aggression Scale, skewed data, high=poor).

3.1 on admission

Other data

No numeric data

3.2 by 24 hours

Other data

No numeric data

3.3 by 72 hours

Other data

No numeric data

3.4 by 1 week

Other data

No numeric data

4 Adverse effects: Movement disorders (Simpson‐Angus Scale, skewed data, high=poor) Show forest plot

Other data

No numeric data

Analysis 2.4


Study	Clotiapine N	Clotiapine mean (SD)	Lorazepam N	Lorazepam mean (SD)
by 24 hours
Subramaney 1998	30	2.67 (2.43)	30	1.2 (1.81)
by 72 hours
Subramaney 1998	30	2.83 (2.15)	30	1.67 (2.47)
by 1 week
Subramaney 1998	30	2.07 (1.86)	30	1.37 (2.22)

Comparison 2 CLOTIAPINE versus STANDARD MEDICATION ‐ BENZODIAZEPINES, Outcome 4 Adverse effects: Movement disorders (Simpson‐Angus Scale, skewed data, high=poor).

4.1 by 24 hours

Other data

No numeric data

4.2 by 72 hours

Other data

No numeric data

4.3 by 1 week

Other data

No numeric data

Analysis 1.1

Comparison 1 CLOTIAPINE versus STANDARD MEDICATION ‐ OTHER ANTIPSYCHOTICS, Outcome 1 General clinical impression: No significant improvement.

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Analysis 1.2

Comparison 1 CLOTIAPINE versus STANDARD MEDICATION ‐ OTHER ANTIPSYCHOTICS, Outcome 2 Hospital and service outcome: Not well enough to be discharged.

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Analysis 1.3

Comparison 1 CLOTIAPINE versus STANDARD MEDICATION ‐ OTHER ANTIPSYCHOTICS, Outcome 3 Leaving the study early.

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Analysis 1.4

Comparison 1 CLOTIAPINE versus STANDARD MEDICATION ‐ OTHER ANTIPSYCHOTICS, Outcome 4 Adverse effects: 1. Movement disorders ‐ use of antiparkinsonian medication.

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Analysis 1.5

Comparison 1 CLOTIAPINE versus STANDARD MEDICATION ‐ OTHER ANTIPSYCHOTICS, Outcome 5 Adverse effects: 2. Incidence of specific side‐effects.

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Analysis 2.1

Comparison 2 CLOTIAPINE versus STANDARD MEDICATION ‐ BENZODIAZEPINES, Outcome 1 Mental state: No significant improvement ‐ three days after beginning of treatment.

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Analysis 2.2

Comparison 2 CLOTIAPINE versus STANDARD MEDICATION ‐ BENZODIAZEPINES, Outcome 2 Leaving the study early.

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Study	Clotiapine N	Clotiapine mean (SD)	Lorazepam N	Lorazepam Mean (SD)
on admission
Subramaney 1998	30	6.43 (4.07)	30	5.87 (3.27)
by 24 hours
Subramaney 1998	30	1.33 (2.78)	30	1.83 (3.14)
by 72 hours
Subramaney 1998	30	1.30 (2.85)	30	1.17 (2.15)
by 1 week
Subramaney 1998	29	1.41(4.14)	29	1.03 (2.26)

Analysis 2.3

Comparison 2 CLOTIAPINE versus STANDARD MEDICATION ‐ BENZODIAZEPINES, Outcome 3 Behaviour: Aggression (Overt Aggression Scale, skewed data, high=poor).

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Study	Clotiapine N	Clotiapine mean (SD)	Lorazepam N	Lorazepam mean (SD)
by 24 hours
Subramaney 1998	30	2.67 (2.43)	30	1.2 (1.81)
by 72 hours
Subramaney 1998	30	2.83 (2.15)	30	1.67 (2.47)
by 1 week
Subramaney 1998	30	2.07 (1.86)	30	1.37 (2.22)

Analysis 2.4

Comparison 2 CLOTIAPINE versus STANDARD MEDICATION ‐ BENZODIAZEPINES, Outcome 4 Adverse effects: Movement disorders (Simpson‐Angus Scale, skewed data, high=poor).

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Table 1. Survey of Medical Directors of 20 Emergency rooms in the USA

Favoured drug regime	Number
haloperidol + lorazepam +/‐ benztropine	11
droperidol	4
benzodiazepine (unspecified) alone	3
droperidol + lorazepam + diphenhydramine	1
haloperidol + benztropine	1

Table 1. Survey of Medical Directors of 20 Emergency rooms in the USA

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Table 2. Drugs for rapid tranquillisation in London survey

Drug of choice	Mean dose (range)
diazepam*	27 (10‐80)
haloperidol	22 (10‐60)
chlorpromazine	162 (50‐400)
droperidol	14 (10‐20)
paraldehyde	U/K
amytal	U/K
lorazepam	U/K
nitrazepam**	U/K
* most frequent ** least frequent

Table 2. Drugs for rapid tranquillisation in London survey

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Table 3. Preferred medication for rapid tranquillisation in Rio de Janeiro

Drug of choice	Mean dose (range)	Frequency of use
haloperidol + promethazine	5 (2.5‐10) + 50 (25‐100)	61%
haloperidol + promethazine + diazepam	5 (2.5‐10) + 50 (25‐100) + 10	15%
diazepam	10	9%
haloperidol + promethazine + chlorpromazine	5 + 50 + 25	7%
chlorpromazine + diazepam + promethazine	25 + 10 + 50	1%
chlorpromazine + promethazine	25 + 50	1%
chlorpromazine	25	1%
diazepam + promethazine	10 + 50	1%
haloperidol + diazepam	5 + 10	1%
promethazine	50	1%

Table 3. Preferred medication for rapid tranquillisation in Rio de Janeiro

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Comparison 1. CLOTIAPINE versus STANDARD MEDICATION ‐ OTHER ANTIPSYCHOTICS

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 General clinical impression: No significant improvement Show forest plot	3	83	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.25, 2.66]

2 Hospital and service outcome: Not well enough to be discharged Show forest plot	1	49	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.93, 1.16]

3 Leaving the study early Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 any reason	3	121	Risk Ratio (M‐H, Random, 95% CI)	2.26 [0.40, 12.88]
3.2 adverse effects	3	121	Risk Ratio (M‐H, Random, 95% CI)	5.63 [0.28, 111.43]
4 Adverse effects: 1. Movement disorders ‐ use of antiparkinsonian medication Show forest plot	2	91	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.03, 4.10]

5 Adverse effects: 2. Incidence of specific side‐effects Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 dry mouth	1	42	Risk Ratio (M‐H, Random, 95% CI)	0.4 [0.09, 1.84]
5.2 headache	1	30	Risk Ratio (M‐H, Random, 95% CI)	1.83 [0.92, 3.66]
5.3 insomnia	1	30	Risk Ratio (M‐H, Random, 95% CI)	1.18 [0.82, 1.70]
5.4 pain at site of injection	1	42	Risk Ratio (M‐H, Random, 95% CI)	5.0 [0.25, 98.27]
5.5 palpitations	1	42	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.10, 2.44]
5.6 rash	1	49	Risk Ratio (M‐H, Random, 95% CI)	5.63 [0.28, 111.43]
5.7 seizure	1	42	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.13, 69.70]
5.8 sweating ‐ facial	1	30	Risk Ratio (M‐H, Random, 95% CI)	1.38 [0.78, 2.41]

Comparison 1. CLOTIAPINE versus STANDARD MEDICATION ‐ OTHER ANTIPSYCHOTICS

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Comparison 2. CLOTIAPINE versus STANDARD MEDICATION ‐ BENZODIAZEPINES

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mental state: No significant improvement ‐ three days after beginning of treatment Show forest plot	1	60	Mean Difference (IV, Fixed, 95% CI)	‐3.36 [‐8.09, 1.37]

2 Leaving the study early Show forest plot	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.07, 15.26]

3 Behaviour: Aggression (Overt Aggression Scale, skewed data, high=poor) Show forest plot			Other data	No numeric data

3.1 on admission			Other data	No numeric data
3.2 by 24 hours			Other data	No numeric data
3.3 by 72 hours			Other data	No numeric data
3.4 by 1 week			Other data	No numeric data
4 Adverse effects: Movement disorders (Simpson‐Angus Scale, skewed data, high=poor) Show forest plot			Other data	No numeric data

4.1 by 24 hours			Other data	No numeric data
4.2 by 72 hours			Other data	No numeric data
4.3 by 1 week			Other data	No numeric data

Comparison 2. CLOTIAPINE versus STANDARD MEDICATION ‐ BENZODIAZEPINES

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Referencias

Referencias de los estudios incluidos en esta revisión

Itoh 1969 {published data only}

Jacobsson 1974 {published data only}

Perales 1974 {published data only}

Subramaney 1998 {published data only}

Uys 1996 {unpublished data only}

Referencias de los estudios excluidos de esta revisión

Bellomo 1973 {published data only}

Bellomo 1975 {published data only}

Bente 1966 {published data only}

Block 1974 {published data only}

Caldas 1971 {published data only}

Cante 1971 {published data only}

Carra 1974 {published data only}

Delay 1965 {published data only}

Etienne 1976 {published data only}

Gazzaniga 1972 {published data only}

Gehring 1972 {published data only}

Giordano 1973 {published data only}

Kammerer 1967 {published data only}

Kaneko 1969 {published data only}

Martin 1968 {published data only}

Martins 1969 {published data only}

Matsushita 1968 {published data only}

Ohkuma 1970 {published data only}

Oules 1973 {published data only}

Rapidis 1975 {published data only}

Rodova 1971 {published data only}

Rosier 1974 {published data only}

Savoldi 1967 {published data only}

Toerien 1973 {published data only}

Traldi 1969 {published data only}

Van Wyk 1971 {published data only}

Watanabe 1969 {published data only}

Zapletalek 1971 {published data only}

Referencias de los estudios en espera de evaluación

Ayuso‐Gutierrez 1973 {published data only}

Belmaker 2009 {published data only}

Geller 2005 {published data only}

Nahunek 1981 {published data only}

Schliefer 2003 {published data only}

Referencias adicionales

Altman 1996

Axelsson 1992

Binder 1999

Bland 1997

Chalmers 1983

Chouinard 1993

Clarke 2003

Cunnane 1994

Divine 1992

Donner 2002

Dorevitch 1999

Egger 1997

Fisher 1993

Greenberg 1992

Gulliford 1999

Higgins 2003

Hu 1991

Huf 2002a

Huf 2002b

Hughes 1999

Jadad 1996

Krakowski 1999

Lokshin 1998

Moher 2001

Moritz 1999

Overall 1962

Pilowsky 1992

Simpson 1970

Taylor 1985

Taylor 1998

Tiihonen 1997

TREC 2003

Ukoumunne 1999

Yudofsky 1986

Characteristics of studies