Risperidone versus other antipsychotics for people with severe mental illness and co‐occurring substance misuse

Henk S Temmingh; Taryn Williams; Nandi Siegfried; Dan J Stein

doi:10.1002/14651858.CD011057.pub2

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Figure 1

Risperidone

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Figure 2

Logic framework model with potential causal pathways: risperidone treatment in persons with dual diagnosis.

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Figure 3

PRISMA flow diagram of study selection from 2016 and 2017 searches

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Figure 4

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 5

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 RISPERIDONE versus CLOZAPINE ‐ all data short term (up to 6 months), Outcome 1 Mental state: 1. General: average endpoint scores (PANSS subscale, lower=better).

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Analysis 1.2

Comparison 1 RISPERIDONE versus CLOZAPINE ‐ all data short term (up to 6 months), Outcome 2 Mental state: 2. General: any change in general symptoms:.

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Analysis 1.3

Comparison 1 RISPERIDONE versus CLOZAPINE ‐ all data short term (up to 6 months), Outcome 3 Mental state: 3. Specific: positive, negative symptoms ‐ average endpoint scores (PANSS subscales, lower = better):.

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Analysis 1.4

Comparison 1 RISPERIDONE versus CLOZAPINE ‐ all data short term (up to 6 months), Outcome 4 Mental state: 4. Specific: anxiety symptoms.

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Analysis 1.5

Comparison 1 RISPERIDONE versus CLOZAPINE ‐ all data short term (up to 6 months), Outcome 5 Substance use.

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Analysis 1.6

Comparison 1 RISPERIDONE versus CLOZAPINE ‐ all data short term (up to 6 months), Outcome 6 Subjective Well‐being: average endpoint scores (Subjective Well‐being under Neuroleptics scale, SWN scale, higher=better).

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Analysis 1.7

Comparison 1 RISPERIDONE versus CLOZAPINE ‐ all data short term (up to 6 months), Outcome 7 Craving for substances.

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Analysis 1.8

Comparison 1 RISPERIDONE versus CLOZAPINE ‐ all data short term (up to 6 months), Outcome 8 Adherence to antipsychotic medication: discontinued medication.

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Analysis 1.9

Comparison 1 RISPERIDONE versus CLOZAPINE ‐ all data short term (up to 6 months), Outcome 9 Adverse effects. 1. Movement disorders.

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Analysis 1.10

Comparison 1 RISPERIDONE versus CLOZAPINE ‐ all data short term (up to 6 months), Outcome 10 Adverse effects: 2. Non‐movement disorder related side‐effects.

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Analysis 1.11

Comparison 1 RISPERIDONE versus CLOZAPINE ‐ all data short term (up to 6 months), Outcome 11 Leaving the study early.

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Analysis 2.1

Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 1 Mental state: 1. Specific: Depression‐ change scores (HAM‐D, higher = better), short term (up to 6 months).

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Analysis 2.2

Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 2 Mental state: 2. Specific: Positive symptoms, total score‐ average endpoint scores (SADS‐C‐PD scale, lower=better), short term (up to 6 months).

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Study	Intervention	Outcome (symptom subscore)	Mean	SD	N
Sevy 2011	Risperidone	Delusions	2.6	1.7	16
Sevy 2011	Olanzapine		2.7	1.6	21
Sevy 2011	Risperidone	Hallucinations	1.8	1.2	16
Sevy 2011	Olanzapine		2	1.6	21
Sevy 2011	Risperidone	Thought disorder	3.6	0.8	16
Sevy 2011	Olanzapine		4.5	2.6	21

Analysis 2.3

Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 3 Mental state: 3. Specific: Positive symptom subscales‐ average endpoint scores (SADS‐C‐PD subscores, lower=better), short term (up to 6 months)‐ skewed data.

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Analysis 2.4

Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 4 Mental state: 4. Specific: Negative symptoms, subscales‐ average endpoint scores (SANS subscales, lower=better), short term (up to 6 months).

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Analysis 2.5

Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 5 Substance use: 1. Reduction of cannabis use‐change data (number of joints smoked/week, LOCF data, higher =better)‐ short term data (up to 6 months).

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Analysis 2.6

Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 6 Substance use: 2. Discontinued substance use, short term (up to 6 months).

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Analysis 2.7

Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 7 Craving for substances: 1. Obsessive Compulsive Drug Use Scale‐ average endpoint score (OCDUS, lower=better)‐short term (up to 6 months).

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Analysis 2.8

Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 8 Craving for substances: 2. Desires for Drug Questionnaire‐ average endpoint scores (DDQ, LOCF data, lower=better), short term (up to 6 months).

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Analysis 2.9

Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 9 Adverse effects.

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Analysis 2.10

Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 10 Leaving study early: 1. Various reasons.

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Analysis 2.11

Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 11 Leaving study early: 2. Weeks in the study‐ average endpoint data (high=good), short term (up to 6 months).

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Study	Intervention	Mean (number of weeks)	SD	N
Smelson 2006	Risperidone	207	142.9	76
Smelson 2006	Olanzapine	267.9	127.4	85

Analysis 2.12

Comparison 2 RISPERIDONE versus OLANZAPINE, Outcome 12 Leaving study early: 3. Weeks in study‐ average endpoint data (high=good), short term (up to 6 months)‐ skewed data.

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Analysis 3.1

Comparison 3 RISPERIDONE versus PERPHENAZINE, Outcome 1 Leaving the study early: all cause discontinuation, long term (>12 months).

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Analysis 4.1

Comparison 4 RISPERIDONE versus QUETIAPINE, Outcome 1 Leaving the study early: all cause discontinuation, long term (>12 months).

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Analysis 5.1

Comparison 5 RISPERIDONE versus ZIPRASIDONE, Outcome 1 Leaving the study early: all cause discontinuation, long term (>12 months).

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Table 4. Suggested design for future trial

Methods	Allocation: centralised sequence generation with table of random numbers or computer‐generated code, stratified by severity of illness, sequence concealed till interventions assigned. Blinding: could be optional, depending on choice of outcome. Duration: 12 months.
Participants	Diagnosis: schizophrenia and co‐occurring ongoing substance misuse (clinical criteria). N = 300*. Age: adults. Sex: men and women. Setting: any.
Interventions	1. Risperidone: clinically indicated dose. N = 150. 2. Olanzapine: clinically indicated dose. N = 150.
Outcomes	Global state: CGI‐I and CGI‐S. Substance use: pragmatic binary/continuous measure. Well‐being: pragmatic binary/continuous measure. Craving: pragmatic binary/continuous measure. Service outcomes: re‐hospitalisation, days in hospital, time attending psychiatric outpatient clinic. Quality of life: important change. Adverse effects: including mortality, weight change and extrapyramidal symptoms. Satisfaction with care: patients/carers. Leaving the study early. Economic data. Other routine data, such as incidents with the police,
Notes	* size of study to detect a 10% difference in improvement with 80% certainty. For all outcomes there should be binary cut‐off points of clinically important improvement, defined before the study starts.

Table 4. Suggested design for future trial

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Summary of findings for the main comparison. RISPERIDONE versus CLOZAPINE ‐ all data short term for people with severe mental illness and co‐occurring substance misuse

RISPERIDONE versus CLOZAPINE ‐ all data short term (up to 6 months) for people with severe mental illness and co‐occurring substance misuse
Patient or population: for people with serious mental illness and co‐occurring substance misuse Setting: Intervention: Risperidone Comparison: Clozapine
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with Clozapine	Risk with Risperidone
Mental state: positive symptoms ‒average endpoint score (PANSS positive subscale, lower = better)		The mean positive symptoms (PANSS positive subscale, lower = better) in the intervention group was 0.9 higher (2.21 lower to 4.01 higher)	‐	36 (1 RCT)	⊕⊝⊝⊝ very low^{1 2}	No trial reported "improvement in symptoms of severe mental illness" ‒ this continuous measure is the nearest proxy for this.
Substance use: improvement ‒ (at least 20% reduction in use, TLFB scale)	Study population		RR 1.00 (0.30 to 3.35)	14 (1 RCT)	⊕⊝⊝⊝ very low^{3 4}
	429 per 1000	429 per 1000 (129 to 1000)
	Moderate
	429 per 1000	429 per 1000 (129 to 1000)
Subjective well‐being: Subjective well‐being under neuroleptics scale ‒ average endpoint scores (SWN scale, higher = better)		The mean subjective well‐being under neuroleptics scale score (SWN scale, higher = better) in the intervention group was 6 lower (14.82 lower to 2.82 higher)	‐	36 (1 RCT)	⊕⊝⊝⊝ very low^{1 2}
Craving for substances: Marijuana Craving Questionnaire ‒ average endpoint scores (MCQ, lower = better)		The mean craving for substances score on the Marijuana Craving Questionairre (MCQ, lower = better) in the intervention group was 7 higher (2.37 higher to 11.63 higher)	‐	28 (1 RCT)	⊕⊝⊝⊝ very low^{1 2}
Adherence to antipsychotic medication: discontinued medication	Study population		RR 4.05 (0.21 to 78.76)	36 (1 RCT)	⊕⊝⊝⊝ very low^{1 2}
	0 per 1000	0 per 1,000 (0 to 0)
	Moderate
	0 per 1,000	0 per 1,000 (0 to 0)
Adverse effects. 1. Movement disorders ‐ any extrapyramidal	Study population		RR 2.71 (0.30 to 24.08)	50 (2 RCTs)	⊕⊝⊝⊝ very low^{5 6}	Many adverse effects reported ‒ none designated 'clinically important' (extrapyramidal used as proxy).
	0 per 1000	0 per 1000 (0 to 0)
	Moderate
	0 per 1000	0 per 1000 (0 to 0)
Leaving the study early ‒ any reason	Study population		RR 0.49 (0.10 to 2.51)	45 (2 RCTs)	⊕⊝⊝⊝ very low^{5 6}
	318 per 1000	156 per 1000 (32 to 799)
	Moderate
	386 per 1000	189 per 1000 (39 to 968)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹ High risk of performance bias and detection bias ² Sample size is very small, optimal information size (OIS) not met to detect 25% difference ³ Performance bias, attrition bias, selective outcome reporting ⁴ Sample size is very small (n = 14) ⁵ High risk of performance bias, detection bias, attrition bias and selective outcomes reporting ⁶ Total sample size is very small (n<300), total event rate is very low and optimum information size (OIS) is not met

Summary of findings for the main comparison. RISPERIDONE versus CLOZAPINE ‐ all data short term for people with severe mental illness and co‐occurring substance misuse

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Summary of findings 2. RISPERIDONE versus OLANZAPINE ‒ short‐ and long‐term data for people with severe mental illness and co‐occurring substance misuse

RISPERIDONE versus OLANZAPINE‐ all data short term (up to 6 months) for people with severe mental illness and co‐occurring substance misuse
Patient or population: people with serious mental illness and co‐occurring substance misuse Setting: In and outpatients, United States Intervention: Risperidone Comparison: Olanzapine
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with Olanzapine	Risk with Risperidone
Mental state: 2. Specific‐ Positive symptoms, total score‐ average endpoint scores (SADS‐C‐PD scale, lower = better)		The mean positive symptoms total score at endpoint (SADS‐C‐PD scale, lower = better) in the intervention group was 1.5 lower (3.82 lower to 0.82 higher)	‐	37 (1 RCT)	⊕⊝⊝⊝ very low^{1 2}
Substance use: 1. Reduction of cannabis use‐change data (number of joints smoked/week)		The reduction of cannabis joints smoked (number of joints smoked/week‐short term data, up to 6 months) in the intervention group was 0.4 higher (4.72 lower to 5.52 higher)	‐	41 (1 RCT)	⊕⊝⊝⊝ very low^{3 4}
Subjective well‐being			‐	‐	‐	No trial reported on this important outcome for participants with a co‐occurring substance use disorder
Craving for substances: 2. Drug Desires Questionnaire‐ average endpoint scores (DDQ, lower = better)		The mean endpoint. Drug Desires Questionnaire‐ endpoint scores (DDQ, lower = better), short term, up to 6 months‐in the intervention group was5 higher (4.86 lower to 14.86 higher)	‐	41 (1 RCT)	⊕⊝⊝⊝ very low^{2 3}
Adherence to antipsychotic medication: number of missed doses, average endpoint data, short term (up to 6 months)	‐		‐	‐	‐	no useable data available for this outcome
Adverse effects: Parkinsonism ‐ average endpoint score (SAS, high = worse)		The mean adverse effects: ‐ Parkinsonism‐ average endpoint score (SAS, high = worse)‐ short‐term‐ up to 6 months in the intervention group was 0.08 lower (1.21 lower to 1.05 higher)	‐	16 (1 RCT)	⊕⊝⊝⊝ very low^{2 5}
Leaving study early: any reason	Study population		RR 0.68 (0.34 to 1.35)	77 (2 RCTs)	⊕⊝⊝⊝ very low^{4 6}
	357 per 1000	243 per 1000 (121 to 482)
	Moderate
	411 per 1000	279 per 1000 (140 to 554)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
¹ High risk for performance bias, allocation concealment, unknown risk for attrition and slective reporting ² Very low sample size, optimal information size (OIS) not met ³ High risk of attrition bias, study sponsored by pharmaceutical industry ⁴ Very low sample size, optimal information criterion not met, CI crosses both appreciable harm and benefit ⁵ High attrition risk, high other risk of funding by pharmaceutical industry, all other risk items unclear risk of bias ⁶ High risk of performance, attrition and funding bias. Several domains with unclear risk of bias

Summary of findings 2. RISPERIDONE versus OLANZAPINE ‒ short‐ and long‐term data for people with severe mental illness and co‐occurring substance misuse

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Summary of findings 3. RISPERIDONE versus PERHENAZINE ‒ long‐term data for people with severe mental illness and co‐occurring substance misuse

RISPERIDONE versus PERPHENAZINE‐long term data (>12 months) for people with severe mental illness and co‐occurring substance misuse
Patient or population: people with severe mental illness and co‐occurring substance misuse Setting: Outpatients, United States Intervention: RISPERIDONE Comparison: PERPHENAZINE
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with PERPHENAZINE	Risk with RISPERIDONE
Leaving the study early: any reason	Study population		RR 1.05 (0.92 to 1.20)	281 (1 RCT)	⊕⊕⊝⊝ low^{1 2}
	750 per 1000	788 per 1000 (690 to 900)
	Moderate
	750 per 1000	788 per 1000 (690 to 900)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹ High risk of attrition bias, but this does not affect this particular outcomes ² Optimal information size criterion is met but the estimate includes no effect with both appreciable harm and benefit

Summary of findings 3. RISPERIDONE versus PERHENAZINE ‒ long‐term data for people with severe mental illness and co‐occurring substance misuse

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Summary of findings 4. RISPERIDONE versus QUETIAPINE ‒ short‐ and long‐term data for people with severe mental illness and co‐occurring substance misuse

RISPERIDONE versus QUETIAPINE‐ short and long term data (up to 6months and > 12 months) for people with severe mental illness and co‐occurring substance misuse
Patient or population: people with severe mental illness and co‐occurring substance misuse Setting: Outpatients, United States Intervention: RISPERIDONE Comparison: QUETIAPINE
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with QUETIAPINE	Risk with RISPERIDONE
Leaving the study early: 1. any reason, long term (>12 months)	Study population		RR 0.96 (0.86 to 1.07)	294 (1 RCT)	⊕⊕⊝⊝ low^{3 4}
	825 per 1000	792 per 1000 (709 to 883)
	Moderate
	825 per 1000	792 per 1000 (709 to 883)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹ Risk of bias unclear across all groups and with high risk of funding bias ² Sample size meets optimal information threshold/ required sample size to detect 25% difference from control group in in PANSS score; at alpha of 0.05 and power of 80%. ³ Outcome not affected by risk of attrition bias ⁴ Optimal information criterion not met, estimate includes both appreciable harm and benefit

Summary of findings 4. RISPERIDONE versus QUETIAPINE ‒ short‐ and long‐term data for people with severe mental illness and co‐occurring substance misuse

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Summary of findings 5. RISPERIDONE versus ZIPRASIDONE ‒ long‐term data (> 12 months) for people with severe mental illness and co‐occurring substance misuse

RISPERIDONE versus ZIPRASIDONE‐ all data long term data (>12 months) for people with severe mental illness and co‐occurring substance misuse
Patient or population: people with severe mental illness and co‐occurring substance misuse Setting: Outpatients, United States Intervention: RISPERIDONE Comparison: ZIPRASIDONE
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with ZIPRASIDONE	Risk with RISPERIDONE
Leaving the study early: any reason	Study population		RR 0.96 (0.85 to 1.10)	240 (1 RCT)	⊕⊕⊝⊝ low^{1 2}
	819 per 1000	787 per 1000 (696 to 901)
	Moderate
	819 per 1000	787 per 1000 (696 to 901)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio; OR: Odds ratio;
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to that of the estimate of the effect Moderate quality: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different Low quality: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect Very low quality: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect
¹ Risk of attrition bias high but this does not affect this outcome ² Optimal information size criterion met but estimate includes both appreciable harm and benefit. Total sample size small

Summary of findings 5. RISPERIDONE versus ZIPRASIDONE ‒ long‐term data (> 12 months) for people with severe mental illness and co‐occurring substance misuse

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Table 1. Assessment of risk of bias

Sequence generation	Low: investigators described a random component in the sequence generation process such as the use of random number table, coin tossing, cards or envelope shuffling etc. High: investigators described a non‐random component in the sequence generation process such as the use of odd or even date of birth, algorithm based on the day/date of birth, hospital or clinic record number. Unclear: insufficient information to permit judgment of the sequence generation process.
Allocation concealment	Low: participants and the investigators enrolling participants cannot foresee assignment, e.g. central allocation; or sequentially numbered, opaque, sealed envelopes. High: participants and investigators enrolling participants can foresee upcoming assignment, e.g. an open random allocation schedule (e.g. a list of random numbers); or envelopes were unsealed or nonopaque or not sequentially numbered. Unclear: insufficient information to permit judgment of the allocation concealment or the method not described.
Blinding of participants and personnel	Low: blinding of the participants, key study personnel, and unlikely that the blinding could have been broken, or lack of blinding unlikely to introduce bias. No blinding in the situation where non‐blinding is not likely to introduce bias. High: no blinding, incomplete blinding and the outcome is likely to be influenced by lack of blinding. Blinding of participants and key study personnel attempted but likely that blinding could have been broken and the outcome is likely to be influenced by lack of blinding. Unclear: insufficient information to permit judgment of 'low risk' or 'high risk', or otherwise the study did not address this outcome.
Blinding of outcome assessment	Low: no blinding of the outcome assessment but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding, or blinding of outcome assessment ensured and unlikely that blinding could have been broken. High: no blinding of outcome assessment and outcome measurement is likely to be influenced by lack of blinding, or blinding of outcome assessment but likely that blinding could have been broken and outcome measurement is likely to be influenced by lack of blinding. Unclear: insufficient information to permit judgement of 'low risk' or 'high risk', or the study did not address this outcome.
Incomplete outcome data	Low: no missing outcome data, reasons for missing outcome data unlikely to be related to true outcome, or missing outcome data balanced in number across groups. High: reason for missing outcome data likely to be related to true outcome, with either imbalance in number across groups or reasons for missing data. Unclear: insufficient reporting of attrition or exclusions.
Selective reporting	Low: a protocol is available which clearly states the primary outcome as the same as in the final trial report. High: the primary outcome differs between the protocol and final trial report. Unclear: no trial protocol is available or there is insufficient reporting to determine if selective reporting is present.
Other forms of bias	Low: there is no evidence of bias from other sources. High: there is potential bias present from other sources (e.g. fraudulent activity, extreme baseline imbalance or bias related to specific study design). Unclear: insufficient information to permit judgment of adequacy or otherwise of other forms of bias.

Table 1. Assessment of risk of bias

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Table 2. Scales, diagnostic instruments and other outcome measures used in included studies

*Diagnostic tools*	Abbreviation	Source of scale/ instrument	Study using instrument	Results reported or usable data for re‐analysis/ quantitative synthesis or qualitative results/data only
Structured Clinical Interview for DSM Disorders	SCID‐I	First 1994	Akerele 2007; Sevy 2011; Swartz 2008; van Nimwegen 2008	Not an outcome measure
Mental state scales
Brief Psychiatric Rating Scale	BPRS	Lukoff 1986	Noordsy 2010	No results or usable data reported or obtained
Clinical Global Impression scale	CGI	Guy 1976	Akerele 2007; Noordsy 2010	No results or usable data reported or obtained
Hamilton Depression Rating Scale	HAM‐D	Hamilton 1960	Akerele 2007	Results reported; usable data for quantitative synthesis
Positive and Negative Syndrome Scale	PANSS	Kay 1986	Akerele 2007;Greenspan 2005; Machielsen 2014; Swartz 2008	Results reported; usable data for quantitative synthesis
Schedule for Affective Disorders and Schizophrenia ‒ Change Version with Psychosis and Disorganization items	SADS‐C‐PD	Endicott 1978	Sevy 2011	Results reported; usable data for quantitative synthesis
Schedule for the Assessment of Negative Symptoms	SANS	Andreasen 1982	Noordsy 2010	No results or usable data reported or obtained
*Substance use scales*
Addiction Severity Index	ASI	McLellan 1980; McLellan 1992	Akerele 2007	No results or usable data reported or obtained
Composite International Diagnostic Interview	CIDI	Robins 1988	Machielsen 2014	Not an outcome measure
Substance Use Questionnaire	SUQ	Sevy 2011, Locally derived instrument/ non‐validated	Sevy 2011	Results reported, used together with urine testing; usable data for quantitative synthesis
Time‐Line Follow‐Back	TLFB	Sobell 1992	Noordsy 2010	Results reported in dichotomised format for quantitative synthesis
Quantitative Substance Use Inventory		Locally derived instrument/ non‐validated	Akerele 2007	Non‐validated scale
Subjective‐Wellbeing Scales
Subjective Well‐being Under Neuroleptics Scale	SWN	de Haan 2002; Naber 1995	Machielsen 2014; van Nimwegen 2008	Results reported; usable data for quantitative synthesis
Craving for substances measures
Cocaine Craving Report		Weddington 1990	Akerele 2007	No usable data for quantitative synthesis
Desires for Drug Questionnaire	DDQ	Franken 2002	van Nimwegen 2008	Results reported; usable data for quantitative synthesis
Marijuana Craving Report		Weddington 1990	Akerele 2007	No usable data for quantitative synthesis
Marijuana Craving Questionnaire	MCQ	Heishman 2009	Machielsen 2014	Results reported; usable data for quantitative synthesis
Obsessive Compulsive Drug Use Scale	OCDUS	Dekker 2012	Machielsen 2014;van Nimwegen 2008	Results reported; usable data for quantitative synthesis
*Adverse effect scales*
Abnormal Involuntary Movement Scale	AIMS	National Institute of Mental Health 1988	Akerele 2007	No results or usable data reported or obtained
Barnes Akathisia Rating Scale	BARS	Barnes 1989	Brunette 2011	No results or usable data reported or obtained
Simpson Angus Scale	SAS	Simpson 1970	Akerele 2007	Results reported; usable data for quantitative synthesis
*Other measures (categorical or time to event)*
Urine assay for cannabis and cocaine use (proportion of treatment group positive per week)			Akerele 2007	No usable data for quantitative synthesis
Number of participants with improvement in substance use (categorised as improved or not‐improved versus unchanged)			Noordsy 2010	Results reported; usable data for quantitative synthesis (dichotomised)
Days of self‐reported drug use in past week			Akerele 2007	No usable data for quantitative synthesis
Weeks in treatment			Akerele 2007; Smelson 2006	Results reported; usable data for quantitative synthesis
Number of participants not completing the study			Akerele 2007; Machielsen 2014; Noordsy 2010; Sevy 2011; Swartz 2008	Results reported, usable data for quantitative synthesis
Compliance with medication (missed doses)			Akerele 2007	No usable data for quantitative synthesis

Table 2. Scales, diagnostic instruments and other outcome measures used in included studies

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Table 3. Excluded randomised and quasi randomised studies and their relevant comparisons

Study tag	Participants			Comparison	Relevant review
Study tag	Primary problem	Co‐morbidity	Note (reasons for exclusion)	Comparison	Relevant review
Blin 1996	schizophrenia	Excludes participants with alcohol or drug abuse in past year	Excludes comorbidity	risperidone, haloperidol, methotrimeprazine	‐
Gaebel 2010	schizophrenia, schizoaffective disorder	Excludes participants with alcohol or drug abuse in past year	Excludes comorbidity	risperidone, olanzapine, conventional antipsychotics vs. risperidone long‐acting injectable (RLAI),or quetiapine	‐
Green 2001	schizophrenia	cannabis use disorder	Excluded as this was a study protocol, authors contacted for unpublished data, no response	risperidone vs. clozapine	‐
Harvey 2007	bipolar type I disorder	No measure of substance use	Excludes comorbidity	risperidone, quetiapine	‐
Ikuta 2014	schizophrenia, schizophreniform, psychosis not otherwise specified	No measure of substance use	Excludes comorbidity	risperidone, aripirazole	‐
Kerfoot 2011	schizophrenia	Co‐occurring substance use in subgroup of 44.9%	No comparison of study medication, mainly a prognostic study of the impact of substance use	risperidone, quetiapine, perphenazine, olanzapine, ziprasidone	‐
Liemburg 2011	schizophrenia	No measure of substance use	Excludes comorbidity	risperidone, aripiprazole	‐
Liu 2008	mental disorders due to alcohol use	substance induced mental disorders	Exclusion criterion	risperidone, olanzapine	Suggested review: risperidone versus other antipsychotics for substance induced psychosis
NCT00063349	schizophrenia	Co‐occurring cannabis use disorder	Study protocol, authors contacted for unpublished data no response	risperidone, clozapine
NCT00130923	schizophrenia, schizoaffective disorder	Co‐occurring alcohol use disorder (abuse or dependence)	Comparison of same medication (risperidone) in different preparations (oral vs depot)	oral risperidone, depot risperidone	‐
NCT00169026	schizophrenia, schizoaffective disorder	Co‐occurring alcohol and substance use disorder	Study protocol, study terminated, authors contacted for unpublished data no response	clozapine, conventional antipsychotics, atypical antipsychotics	‐
NCT00498550	schizophrenia, schizoaffective disorder	Co‐occurring cannabis use disorder	Study protocol, authors contacted no data provided	clozapine, conventional antipsychotics, atypical antipsychotics	‐
Nejtek 2008	bipolar I and II disorder, recent manic or mixed episode with or without psychosis	co‐occurring cocaine or methamphetamine use disorder	Only 8.3% of total sample had psychotic features and 15.9% had bipolar type II disorder.	risperidone, quetiapine	Suggested review: Risperidone versus other antipsychotics in bipolar disorder with co‐occurring substance use disorders
Perlis 2006	bipolar I disorder with mania or mixed states	Excludes participants with recent substance use	Excludes comorbidity. Excludes bipolar disorder with psychotic features.	risperidone or olanzapine	‐
Rezayat 2014	bipolar disorder, acute mania	Excludes participants with drug or alcohol use in past 3 months	Excludes comorbidity	aripiprazole, risperidone	‐
Rubio 2006a	schizophrenia	Co‐occurring substance use disorders	Quasi‐randomisation	risperidone long‐acting depot, zuclopenthixol long‐acting depot	‐
Rubio 2006b	schizophrenia	Co‐occurring substance use disorders	Quasi‐randomisation	risperidone (oral), zuclopenthixol (oral), zuclopenthixol long acting depot	‐
Sachs 2002	bipolar with current manic or mixed episode	Study excludes participants with drug or alcohol in past 1 months	Excludes comorbidity	mood stabiliser augmentation with risperidone, haloperidol or placebo	‐
Sajatovic 2002	psychotic disorders: schizoaffective disorder, bipolar I disorder, major depressive disorder, delusional disorder, Alzheimer's dementia, schizophreniform disorder, vascular dementia, and substance abuse dementia	No subgroups with substance use reported	Excludes comorbidity. Authors contacted for unpublished data, no response.	risperidone, quetiapine	‐
Smulevich 2005	bipolar I disorder	Excludes participants with recent substance use	Excludes comorbidity	haloperidol, risperidone, placebo	‐
van Nimwegen 2008a	schizophrenia, schizophreniform, schizoaffective disorder	No measure of substance use	Excludes comorbidity	haloperidol, risperidone, placebo	‐
Yatham 2007	bipolar I and II	Excludes participants with drug or alcohol use in past 3 months.	Excludes comorbidity	continuation of oral risperidone, olanzapine, quetiapine or switch to long‐acting injectable LAI risperidone	‐
Zhangyue 2005	schizophrenia or schizophrenia‐like illnesses	Excludes participants with alcohol or substance dependence	Quasi‐randomisation.Excludes comorbidity.	aripiprazole versus risperidone	‐

Table 3. Excluded randomised and quasi randomised studies and their relevant comparisons

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Comparison 1. RISPERIDONE versus CLOZAPINE ‐ all data short term (up to 6 months)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mental state: 1. General: average endpoint scores (PANSS subscale, lower=better) Show forest plot	1	36	Mean Difference (IV, Fixed, 95% CI)	2.70 [‐2.14, 7.54]

2 Mental state: 2. General: any change in general symptoms: Show forest plot	1	14	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.01, 2.34]

3 Mental state: 3. Specific: positive, negative symptoms ‐ average endpoint scores (PANSS subscales, lower = better): Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

3.1 Mental state: Positive symptoms ‐ average endpoint score (PANSS positive subscale, lower=better)	1	36	Mean Difference (IV, Random, 95% CI)	0.90 [‐2.21, 4.01]
3.2 Mental state: Negative symptoms ‐ average endpoint score (PANSS negative subscale, lower=better)	1	36	Mean Difference (IV, Random, 95% CI)	4.0 [0.79, 7.21]
4 Mental state: 4. Specific: anxiety symptoms Show forest plot	1	14	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.14, 63.15]

5 Substance use Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5.1 Substance use: Improvement (at least 20% reduction in use, TLFB scale)	1	14	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.30, 3.35]
5.2 Substance use: Discontinued substance use	1	28	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.41, 3.12]
6 Subjective Well‐being: average endpoint scores (Subjective Well‐being under Neuroleptics scale, SWN scale, higher=better) Show forest plot	1	36	Mean Difference (IV, Random, 95% CI)	‐6.0 [‐14.82, 2.82]

7 Craving for substances Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

7.1 Craving for substances: 1. Specific: current craving‐ average endpoint scores (Marijuana Craving Questionairre, MCQ, lower=better)	1	28	Mean Difference (IV, Random, 95% CI)	7.00 [2.37, 11.63]
7.2 Craving for substances: 2. Specific: past week craving‐ average endpoint scores (Obsessive Compulsive Drug Use Scale, OCDUS, lower=better)	1	28	Mean Difference (IV, Random, 95% CI)	14.20 [4.45, 23.95]
8 Adherence to antipsychotic medication: discontinued medication Show forest plot	1	36	Risk Ratio (M‐H, Random, 95% CI)	4.05 [0.21, 78.76]

9 Adverse effects. 1. Movement disorders Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

9.1 any extrapyramidal side‐effects	2	50	Risk Ratio (M‐H, Random, 95% CI)	2.71 [0.30, 24.08]
9.2 akathisia	1	14	Risk Ratio (M‐H, Random, 95% CI)	2.0 [0.23, 17.34]
10 Adverse effects: 2. Non‐movement disorder related side‐effects Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

10.1 Cardiovascular: palpitations	1	14	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.14, 63.15]
10.2 Cardiovascular: hypotension	1	14	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.02, 7.02]
10.3 Central nervous system: headache	1	14	Risk Ratio (M‐H, Random, 95% CI)	0.2 [0.01, 3.54]
10.4 Central Nervous System: somnolence	1	14	Risk Ratio (M‐H, Random, 95% CI)	0.2 [0.03, 1.30]
10.5 Dermatological: acne	1	14	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.14, 63.15]
10.6 Endocrinological: decreased libido	1	14	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.02, 7.02]
10.7 Ear and labarynthine: ear canal blockage	1	14	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.14, 63.15]
10.8 Gastrointestinal: abdominal pain	1	14	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.14, 63.15]
10.9 Gasstrointesinal: elevated liver function tests	1	14	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.14, 63.15]
10.10 Gastrointestinal: hypersalivation	1	14	Risk Ratio (M‐H, Random, 95% CI)	0.11 [0.01, 1.74]
10.11 General adverse effects: fatigue	1	14	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.02, 7.02]
10.12 Injuries: sprain	1	14	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.02, 7.02]
10.13 Metabolic: increased appetite	1	14	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.02, 7.02]
10.14 Metabolic: weight gain	1	14	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.19, 5.24]
10.15 Musculosceletal: ankle pain	1	14	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.02, 7.02]
10.16 Musculosceletal: knee and foot pain	1	14	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.02, 7.02]
10.17 Musculosceletal: muscle twitch	1	14	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.14, 63.15]
10.18 Renal: urinary retention	1	14	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.02, 7.02]
10.19 Renal: urinary urgency	1	14	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.02, 7.02]
11 Leaving the study early Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

11.1 any reason	2	45	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.10, 2.51]
11.2 due to inefficacy	1	14	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Comparison 1. RISPERIDONE versus CLOZAPINE ‐ all data short term (up to 6 months)

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Comparison 2. RISPERIDONE versus OLANZAPINE

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mental state: 1. Specific: Depression‐ change scores (HAM‐D, higher = better), short term (up to 6 months) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.1 short‐term (up to 6 months)	1	22	Mean Difference (IV, Random, 95% CI)	‐0.11 [‐0.78, 0.56]
2 Mental state: 2. Specific: Positive symptoms, total score‐ average endpoint scores (SADS‐C‐PD scale, lower=better), short term (up to 6 months) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

2.1 short term, up to 6 months)	1	37	Mean Difference (IV, Random, 95% CI)	‐1.5 [‐3.82, 0.82]
3 Mental state: 3. Specific: Positive symptom subscales‐ average endpoint scores (SADS‐C‐PD subscores, lower=better), short term (up to 6 months)‐ skewed data Show forest plot			Other data	No numeric data

4 Mental state: 4. Specific: Negative symptoms, subscales‐ average endpoint scores (SANS subscales, lower=better), short term (up to 6 months) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

4.1 Negative symptoms: Affective flattening	1	39	Mean Difference (IV, Random, 95% CI)	0.5 [‐0.17, 1.17]
4.2 Negative symptoms: alogia	1	39	Mean Difference (IV, Random, 95% CI)	0.40 [‐0.22, 1.02]
4.3 Negative symptoms: avolition‐apathy	1	39	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.73, 0.53]
4.4 Negative symptoms: asociality‐anhedonia	1	39	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.80, 0.60]
5 Substance use: 1. Reduction of cannabis use‐change data (number of joints smoked/week, LOCF data, higher =better)‐ short term data (up to 6 months) Show forest plot	1	41	Mean Difference (IV, Random, 95% CI)	0.40 [‐4.72, 5.52]

6 Substance use: 2. Discontinued substance use, short term (up to 6 months) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6.1 Substance use: 2. Stopped using cannabis (Urine testing and Substance Use Questionnaire)	1	37	Risk Ratio (M‐H, Random, 95% CI)	1.19 [0.68, 2.08]
6.2 Substance use: 2. Stopped using alcohol (Substance Use Questionnaire)	1	37	Risk Ratio (M‐H, Random, 95% CI)	1.31 [0.73, 2.36]
7 Craving for substances: 1. Obsessive Compulsive Drug Use Scale‐ average endpoint score (OCDUS, lower=better)‐short term (up to 6 months) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

7.1 short‐term (up to 6 months)	1	41	Mean Difference (IV, Random, 95% CI)	1.30 [‐3.51, 6.11]
8 Craving for substances: 2. Desires for Drug Questionnaire‐ average endpoint scores (DDQ, LOCF data, lower=better), short term (up to 6 months) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

8.1 Short‐term (up to 6 months)	1	41	Mean Difference (IV, Random, 95% CI)	5.0 [‐4.86, 14.86]
9 Adverse effects Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

9.1 Movement disorders: Parkinsonism‐ average endpoint score (SAS, high = worse)‐ short‐term (up to 6 months)	1	16	Mean Difference (IV, Random, 95% CI)	‐0.08 [‐1.21, 1.05]
9.2 Non‐movement disorder related side‐effects: Weight gain‐ average endpoint score (BMI, lower=better)‐ short term (up to 6 months)	1	37	Mean Difference (IV, Random, 95% CI)	‐1.0 [‐3.99, 1.99]
10 Leaving study early: 1. Various reasons Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

10.1 any reason, short term (up to 6 months)	2	77	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.34, 1.35]
10.2 any reason, long term (> 12 months)	1	299	Risk Ratio (M‐H, Random, 95% CI)	1.07 [0.94, 1.21]
10.3 readmission, short term (up to 6 months)	1	28	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.07, 14.45]
10.4 intolerable adverse effects, short term (up to 6 months)	1	28	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
10.5 participant loss of interest, short term (up to 6 months)	1	28	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.14, 1.33]
11 Leaving study early: 2. Weeks in the study‐ average endpoint data (high=good), short term (up to 6 months) Show forest plot	1	28	Mean Difference (IV, Random, 95% CI)	0.0 [‐3.35, 3.35]

12 Leaving study early: 3. Weeks in study‐ average endpoint data (high=good), short term (up to 6 months)‐ skewed data Show forest plot			Other data	No numeric data

Comparison 2. RISPERIDONE versus OLANZAPINE

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Comparison 3. RISPERIDONE versus PERPHENAZINE

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Leaving the study early: all cause discontinuation, long term (>12 months) Show forest plot	1	281	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.92, 1.20]

Comparison 3. RISPERIDONE versus PERPHENAZINE

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Comparison 4. RISPERIDONE versus QUETIAPINE

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Leaving the study early: all cause discontinuation, long term (>12 months) Show forest plot	1	294	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.86, 1.07]

Comparison 4. RISPERIDONE versus QUETIAPINE

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Comparison 5. RISPERIDONE versus ZIPRASIDONE

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Leaving the study early: all cause discontinuation, long term (>12 months) Show forest plot	1	240	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.85, 1.10]

Comparison 5. RISPERIDONE versus ZIPRASIDONE

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