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'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Figuras y tablas -
Figure 1

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

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'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figuras y tablas -
Figure 2

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

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Study flow diagram.
Figuras y tablas -
Figure 3

Study flow diagram.

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Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 1 Mental state: specific. 1a. Negative symptoms: clinically important change.
Figuras y tablas -
Analysis 1.1

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 1 Mental state: specific. 1a. Negative symptoms: clinically important change.

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Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 2 Mental state: specific. 1b. Negative symptoms: average endpoint score (various scales).
Figuras y tablas -
Analysis 1.2

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 2 Mental state: specific. 1b. Negative symptoms: average endpoint score (various scales).

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Study

Mirtazapine

Placebo

Berk 2001

PANSS negative at endpoint, high = poor

mean = 13.9

SD = 22.076

N = 15

PANSS negative at endpoint, high = poor

mean = 23.9

SD = 21.689

N = 15

Caforio 2013

PANSS negative at endpoint, high = poor

mean = 15.2

SD = 5.3

N = 9

PANSS negative at endpoint, high = poor

mean = 18.8

SD = 8.6

N = 11

Figuras y tablas -
Analysis 1.3

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 3 Mental sate: specific. 1c. Negative symptoms: average endpoint score (PANSS negative, high = poor) ‐skewed data.

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Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 4 Mental state: specific. 2a. Positive symptoms: average endpoint score (PANSS, high = poor).
Figuras y tablas -
Analysis 1.4

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 4 Mental state: specific. 2a. Positive symptoms: average endpoint score (PANSS, high = poor).

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Study

Mirtazapine

Placebo

Abbasi 2010

PANSS (at endpoint)

Mean = 11.875

SD = 5.625

N = 19

PANSS (at endpoint)

Mean = 13.75

SD = 3.75

N = 19

Berk 2001

PANSS (at endpoint)

Mean = 9.6

SD = 20.5268

N = 15

PANSS (at endpoint)

Mean = 8.2

SD = 7.7459

N = 15

Berk 2009

PANSS (at endpoint)

Mean = 18.47

SD = 6.44

N = 16

PANSS (at endpoint)

Mean = 14.44

SD = 5.65

N = 17

Caforio 2013

PANSS (at endpoint)

Mean = 10.05

SD = 1.86

N = 9

PANSS (at endpoint)

Mean = 12.8

SD = 3.73

N = 11

Terevnikov 2013

PANSS (at endpoint)

Mean = 18.1

SD = 7.2086

N = 20

PANSS (at endpoint)

Mean = 18.42

SD = 6.0226

N = 19

Zoccali 2004

SAPS (at endpoint)

Mean = 6.6

SD = 2.2

N = 10

SAPS (at endpoint)

Mean = 8.5

SD = 4.3

N = 10

Figuras y tablas -
Analysis 1.5

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 5 Mental state: specific. 2b. Positive symptoms: average endpoint score (various scales) ‐ skewed data.

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Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 6 Mental state: overall. 3a. Clinically important change (at least 20% change PANSS).
Figuras y tablas -
Analysis 1.6

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 6 Mental state: overall. 3a. Clinically important change (at least 20% change PANSS).

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Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 7 Mental state: overall. 3b. Average endpoint score (various scales).
Figuras y tablas -
Analysis 1.7

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 7 Mental state: overall. 3b. Average endpoint score (various scales).

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Study

Mirtazapine

Placebo

Berk 2001

PANSS (at endpoint)

Mean = 46.7

SD = 67.003

N = 15

PANSS (at endpoint)

Mean = 58.9

SD = 48.412

N = 15

Poyurovsky 2006

BPRS (change data, positive is reduction in score and improvement in overall mental state)

Mean = 0.3

SD = 6.3

N = 30

BPRS (change data, positive is reduction in score and improvement in overall mental state)

Mean = 0.07

SD = 6.44

N = 30

Figuras y tablas -
Analysis 1.8

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 8 Mental state: overall. 3c. Average change score (various scales) ‐ skewed data.

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Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 9 Mental state: specific. 4a. Depressive symptoms: average endpoint score (HAM‐D, high = poor).
Figuras y tablas -
Analysis 1.9

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 9 Mental state: specific. 4a. Depressive symptoms: average endpoint score (HAM‐D, high = poor).

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Study

Mirtazapine

Placebo

Berk 2001

HAMD (at endpoint)

Mean = 3.05

SD = 10.0697

N = 15

HAMD (at endpoint)

Mean = 4.5

SD = 7.7459

N = 15

Berk 2009

CDSS (at endpoint)

Mean = 3.94

SD = 3.73

N = 16

CDSS (at endpoint)

Mean = 3.35

SD = 3.35

N = 17

Caforio 2013

CDSS (at endpoint)

No significant difference detected between groups. P = 0.26

CDSS (at endpoint)

No significant difference detected between groups. P = 0.26

Poyurovsky 2006

HAMD (change data, positive is reduction in HAMD and improvement in symptoms)

Mean = 0.6

SD = 3.87

N = 30

HAMD (change data, positive is reduction in HAMD and improvement in symptoms)

Mean = 0.4

SD = 3.5

N = 30

Terevnikov 2013

CDSS (at endpoint)

Mean = 2.4

SD = 7.7607

N = 20

CDSS (at endpoint)

Mean = 3.32

SD = 6.7771

N = 20

Figuras y tablas -
Analysis 1.10

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 10 Mental state: specific. 4b. Depressive symptoms: average change score (various scales) ‐ skewed data.

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Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 11 Leaving the study early for any reason.
Figuras y tablas -
Analysis 1.11

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 11 Leaving the study early for any reason.

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Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 12 Global state: 1. Average endpoint score (CGI severity, high = poor).
Figuras y tablas -
Analysis 1.12

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 12 Global state: 1. Average endpoint score (CGI severity, high = poor).

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Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 13 Global state: 2a. Average change score (PGI, high = poor).
Figuras y tablas -
Analysis 1.13

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 13 Global state: 2a. Average change score (PGI, high = poor).

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Study

Mirtazapine

Placebo

Berk 2001

CGI severity

Mean = 2.31

SD = 2.09

N = 15

F = 12.7, P = 0.001, df = 1

CGI severity

Mean = 3.61

SD = 2.09

N = 15

F = 12.7, P = 0.001, df = 1

Berk 2001

CGI improvement

Mean = 1.41

SD = 1.81

N = 15

F = 14.62, df = 1, P < 0.001

CGI improvement

Mean = 2.52

SD = 1.81

N = 15

F = 14.62, df = 1, P < 0.001

Terevnikov 2013

Terevnikov 2013

CGI improvement (change data ‐ positive is reduction in score and improvement in CGI)

Mean change = 0.80

SD = 0.62

N = 20

CGI improvement (change data ‐ positive is reduction in score and improvement in CGI)

Mean change = 0.05

SD = 0.52

N = 19

Figuras y tablas -
Analysis 1.14

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 14 Global state: 2b. Average change date (various scales) ‐ skewed data.

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Study

Mirtazapine

Placebo

Other data tables

Berk 2009

Some improvement from baseline to week 6 was observed in both treatment arms for all measures of cognition.

Digit span: no significant differences between groups at endpoint.

Word learning: no significant differences between groups at endpoint.

Trail making: significantly worse than in placebo group at endpoint.

Verbal fluency: significantly worse than in placebo group at endpoint.

No further details were provided.

Some improvement from baseline to week 6 was observed in both treatment arms for all measures of cognition.

Digit span: no significant differences between groups at endpoint.

Word learning: no significant differences between groups at endpoint.

Trail making: significantly worse than in placebo group at endpoint.

Verbal fluency: significantly worse than in placebo group at endpoint.

No further details were provided.

Caforio 2013

No statistically significant difference was found between the two treatment groups for measures of working memory tested.

1‐Back accuracy (% correct) (at endpoint)

Mean = 69

SD = 21.9

N = 14

P = 0.1

2‐Back accuracy (% correct) (at endpoint)

Mean = 53.8

SD = 14.1

N = 14

P = 0.8

1‐Back reaction time (ms) (at endpoint)

Mean = 906

SD = 144.4

N = 14

P = 0.4

2‐Back reaction time (ms) (at endpoint)

Mean = 933.6

SD = 193.5

N = 14

P = 0.1

No statistically significant difference was found between the two treatment groups for measures of working memory tested.

1‐Back accuracy (% correct) (at endpoint)

Mean = 79.1

SD = 25.2

N = 14

P = 0.1

2‐Back accuracy (% correct) (at endpoint)

Mean = 57.7

SD = 24.9

N = 14

P = 0.8

1‐Back reaction time (ms) (at endpoint)

Mean = 616.8

SD = 389

N = 14

P = 0.4

2‐Back reaction time (ms) (at endpoint)

Mean = 643.2

SD = 348

N = 14

P = 0.1

Terevnikov 2013

The following data are presented as change from baseline at endpoint. Negative changes for points, and positive changes for time or for number of mistakes means improvement.

WAIS‐R Block design (points)

Mean = ‐4.94

SD = 4.61

N = 19

P = 0.021

Wechsler Memory Scale Digit Symbol (points)

Mean = ‐1.17

SD = 5.59

N = 19

P = 0.437

Wechsler Memory Scale digit span forward (points)

Mean = ‐0.21

SD = 1.18

N = 19

P = 0.421

Wechsler Memory Scale digit span backward (points)

Mean = ‐0.5

SD = 1.29

N = 19

P = 0.206

Wechsler Memory Scale digit span total (points)

Mean = ‐0.79

SD = 1.99

N = 19

P = 0.233

Wechsler Memory Scale logical memory (points)

Mean = ‐1.84 (2.73)

SD = 2.73

N = 19

P = 0.044

Wechsler Memory Scale logical memory delayed (points)

Mean = ‐1.50

SD = 1.79

N = 19

P = 0.044

Wechsler Memory Scale verbal paired associations (points)

Mean = ‐1.61

SD = 2.73

N = 19

P = 0.091

Wechsler Memory Scale verbal paired associations delayed (points)

Mean = ‐1.11

SD = 1.71

N = 19

P = 0.091

Wechsler Memory Scale visual reproduction (points)

Mean = ‐0.78

SD = 1.66

N = 19

P = 0.206

Wechsler Memory Scale visual reproduction delayed (points)

Mean = ‐1.29

SD = 2.08

N = 19

P = 0.065

Stroop dots (time)

Mean = 15.17

SD = 23.47

N = 19

P = 0.044

Stroop dots (number of mistakes)

Mean = 0.28

SD = 2.11

N = 19

P = 0.421

Stroop coloured words (time)

Mean = 16.00

SD = 34.20

N = 19

P = 0.164

Stroop coloured words (number of mistakes)

Mean = 0.89

SD = 1.91

N = 19

P = 0.208

Trail making test Part A (time)

Mean = 17.44

SD = 15.98

N = 19

P = 0.018

Trail making test Part A (number of mistakes)

Mean = 0

SD = 0.34

N = 19

P = 0.659

Trail making test Part B (time)

Mean = 21.76

SD = 37.33

N = 19

P = 0.053

Trail making test Part B (number of mistakes)

Mean = 0.18

SD = 1.63

N = 19

P = 0.421

Word fluency letter words

Mean = ‐1.16

SD = 2.61

N = 19

P = 0.199

Word fluency semantic

Mean = ‐0.95

SD = 2.97

N = 19

P = 0.313

The following data are presented as change from baseline at endpoint. Negative changes for points, and positive changes for time or for number of mistakes means improvement.

WAIS‐R Block design (points)

Mean = ‐1.18

SD = 2.90

N = 19

P = 0.313

Wechsler Memory Scale Digit Symbol (points)

Mean = ‐1.53

SD = 5.62

N = 19

P = 0.347

Wechsler Memory Scale digit span forward (points)

Mean = ‐0.11

SD = 0.58

N = 19

P = 0.438

Wechsler Memory Scale digit span backward (points)

Mean = 0.12

SD = 1.02

N = 19

P = 0.528

Wechsler Memory Scale digit span total (points)

Mean = 0.0

SD = 0.97

N = 19

P = 0.659

Wechsler Memory Scale logical memory (points)

Mean = ‐2.28

SD = 2.40

N = 19

P = 0.039

Wechsler Memory Scale logical memory delayed (points)

Mean = ‐1.00

SD = 2.14

N = 19

P = 0.200

Wechsler Memory Scale verbal paired associations (points)

Mean = ‐1.1

SD = 3.77

N = 19

P = 0.4960

Wechsler Memory Scale verbal paired associations delayed (points)

Mean = ‐0.55

SD = 2.17

N = 19

P = 0.437

Wechsler Memory Scale visual reproduction (points)

Mean = 0.01

SD = 2.14

N = 19

P = 0.559

Wechsler Memory Scale visual reproduction delayed (points)

Mean = ‐1.50

SD = 2.96

N = 19

P = 0.0720

Stroop dots (time)

Mean = ‐0.22

SD = 35.93

N = 19

P = 0.525

Stroop dots (number of mistakes)

Mean = 0.06

SD = 1.51

N = 19

P = 0.559

Stroop coloured words (time)

Mean = 16.18

SD = 68.05

N = 19

P = 0.421

Stroop coloured words (number of mistakes)

Mean = ‐0.06

SD = 4.41

N = 19

P = 0.497

Trail making test Part A (time)

Mean = 14.29

SD = 40.41

N = 19

P = 0.421

Trail making test Part A (number of mistakes)

Mean = ‐0.12

SD = 0.48

N = 19

P = 0.421

Trail making test Part B (time)

Mean = ‐13.44

SD = 75.53

N = 19

P = 0.659

Trail making test Part B (number of mistakes)

Mean = 0.07

SD = 1.58

N = 19

P = 0.4210.540

Word fluency letter words (points)

Mean = ‐0.22

SD = 2.60

N = 19

P = 0.659

Word fluency semantic (points)

Mean = ‐0.78

SD = 3.04

N = 19

P = 0.421

Figuras y tablas -
Analysis 1.15

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 15 Cognitive functioning: other data.

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Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 16 Adverse events: 1a. General (participants with at least one adverse event).
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Analysis 1.16

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 16 Adverse events: 1a. General (participants with at least one adverse event).

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Study

Number of events (mirtazapine)

Number of participants (mirtazapine)

Number of events (placebo)

Number of participants (placebo)

Abbasi 2010

33

19

20

19

Berk 2001

14

15

14

15

Berk 2009

0

16

1

17

Caforio 2013

3

14

0

14

Cho 2011

4

11

1

9

Poyurovsky 2003

5

13

1

13

Poyurovsky 2006

29

30

14

30

Terevnikov 2013

12

20

10

19

Zoccali 2004

5

10

0

Figuras y tablas -
Analysis 1.17

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 17 Adverse events: 1b. General (total number of adverse events) ‐ count data.

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Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 18 Adverse effects: 2a. Extrapyramidal: clinically important change akathisia.
Figuras y tablas -
Analysis 1.18

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 18 Adverse effects: 2a. Extrapyramidal: clinically important change akathisia.

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Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 19 Adverse effects: 2b. Extrapyramidal ‐ full resolution of akathisia.
Figuras y tablas -
Analysis 1.19

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 19 Adverse effects: 2b. Extrapyramidal ‐ full resolution of akathisia.

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Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 20 Adverse effects: 2c. Extrapyramidal ‐ specific effects.
Figuras y tablas -
Analysis 1.20

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 20 Adverse effects: 2c. Extrapyramidal ‐ specific effects.

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Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 21 Adverse effects: 2d. Extrapyramidal: average change score (various scales).
Figuras y tablas -
Analysis 1.21

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 21 Adverse effects: 2d. Extrapyramidal: average change score (various scales).

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Study

Mirtazapine

Placebo

Abbasi 2010

Mean ESRS scores for placebo group were higher throughout the trial, but the difference was not statistically significant: F = 2.05, df = 1, P = 0.16.

Mean ESRS scores for placebo group were higher throughout the trial, but the difference was not statistically significant: F = 2.05, df = 1, P = 0.16.

Berk 2001

SAS measured at endpoint with no statistical significance found between groups (specifics not reported).

SAS measured at endpoint with no statistical significance found between groups (specifics not reported).

Poyurovsky 2003

SAS (endpoint)

Mean = 4.9

SD = 2.4

N = 10

BAS (endpoint)

Mean = 2.90

SD = 1.60

N = 10

SAS (endpoint)

Mean = 6

SD = 5.5

N = 10

BAS (endpoint)

Mean = 6.5

SD = 1.55

N = 10

Terevnikov 2013

SAS (endpoint)

Mean = 10.00

SD = 7.60

N = 20

SAS (endpoint)

Mean = 9.58

SD = 5.77

N = 19

Figuras y tablas -
Analysis 1.22

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 22 Adverse effects: 2e. Extrapyramidal: average endpoint score (various scales) ‐ skewed or unusable data.

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Study

Mirtazapine

Placebo

Abbasi 2010

Biperiden dose (mg)

Mean = 104.04

SD = 109.215

N = 20

Biperiden dose (mg)

Mean = 125.09

SD = 88.28

N = 20

Abbasi 2010

Cumulative biperiden dose (mg) = 2568

N = 20

Cumulative biperiden dose (mg) = 3108

N = 20

Abbasi 2010

Days of biperiden treatment

Mean = 16.38

SD = 17.54

N = 20

Days of biperiden treatment

Mean = 21.22

SD = 12.48

N = 20

Figuras y tablas -
Analysis 1.23

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 23 Adverse effects: 2f. Extrapyramidal: treatment details ‐ skewed data.

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Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 24 Adverse events: 3. Other specific effects.
Figuras y tablas -
Analysis 1.24

Comparison 1 Mirtazapine adjunct versus placebo adjunct ‐ short term, Outcome 24 Adverse events: 3. Other specific effects.

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Table 1. Suggested design of future study

Methods

Participants

Interventions

Outcomes

General

Allocation: random (with adequate description of sequence generation and allocation concealment)

Blinding: double (described and tested)

Duration: 6 months

Setting: multiple centres, inpatient and outpatient units

Diagnosis: schizophrenia (DSM‐V / ICD ‐ 10)

Age: adults

Size: N > 300

Sex: both

Stage of illness: any

Antipsychotic: any

Exclusions: current major depressive episode or antidepressant drug use

1. mirtazapine 30 mg plus regular antipsychotic

2. placebo plus regular antipsychotic

Primary outcome: quality of life

Other outcomes: family/caretaker satisfaction, service utilisation, employment, leaving the study early, mental state (PANSS including subscales), global impression (CGI), adverse events.

Prospectively registered and free from industry funding.

CGI: Clinical Global Impression

DSM‐V: American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders ‐ 5th edition

ICD ‐ 10: International Statistical Classification of Diseases and Related Health Problems 10th Revision

mg: milligram

N: number

PANSS: Positive and Negative Syndrome Scale
Figuras y tablas -
Table 1. Suggested design of future study
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Summary of findings for the main comparison. Mirtazapine adjunct versus placebo adjunct

Mirtazapine versus placebo

Patient or population: schizophrenia
Setting: inpatient
Intervention: mirtazapine plus standard care
Comparison: placebo plus standard care

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with placebo

Risk with mirtazapine

Mental state: specific negative symptoms ‐ clinically important change (no important response)

Study population

RR 0.81
(0.57 to 1.14)

20
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1, 2 ,3

Clinically important change was defined as a reduction of 20% or greater on SANS.

1000 per 1000

810 per 1000
(570 to 1000)

Mental state: overall mental state ‐ clinically important change*

Study population

RR 0.69
(0.51 to 0.92)

77
(2 RCTs)

⊕⊝⊝⊝
VERY LOW 6, 8,9

* Mental state: clinically important change positive symptoms data not available.

Improvement in overall mental state was defined by

Abbasi 2010 as improvement in PANSS total of >50%. Terevnikov 2013: defined as improvement of PANSS total by > 20%.

816 per 1000

563 per 1000
(416 to 751

Leaving the study early for any reason

Study population

RR 1.03
(0.64 to 1.66)

310
(9 RCTs)

⊕⊕⊕⊝
MODERATE 4

162 per 1000

167 per 1000
(104 to 269)

Global state: average endpoint score (CGI severity, high = poor)*

The mean global state: average score at endpoint (CGI severity) was 4

MD 0.10 lower
(0.68 lower to 0.48 higher)

‐

39
(1 RCT)

⊕⊝⊝⊝
VERY LOW 1,3,5

Data for clinically important change not reported.

Quality of life: clinically important change

‐

‐

‐

‐

‐

No study reported data for this important outcome

Service utilisation: number of days in hospital

‐

‐

‐

‐

‐

No study reported data for this important outcome

Adverse effects: extrapyramidal ‐ clinically important change akathisia

Study population

RR 0.33
(0.20 to 0.52)

86
(2 RCTs)

⊕⊕⊝⊝
LOW 6,7

Both studies defined important change as reduction of BAS by at least 2

Adverse events ‐ incidence of serious adverse events: data on variability was not available, preventing meta‐analysis of these count data.

930 per 1000

307 per 1000
(186 to 484)

*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).

BAS: Barnes Akathisa Scale; BPRS: Brief Psychiatric Rating Scale; CGI: Clinical Global Impression; CI: Confidence interval; HAM‐D: Hamilton Depression Rating Scale; MD: Mean difference; RR: Risk ratio; RCT: Randomised controlled trial; SANS: Scale for the Assessment of Negative Symptoms.

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: serious (downgraded by 1). This study did not describe blinding of outcome assessors, only analysed data from study completers (per protocol analysis)

2 Risk of bias: serious (downgraded by 1).This study recorded depressive symptoms with HAM‐D at baseline, and used the depressive subscale of BPRS at follow‐up.

3 Imprecision (downgraded by 1). Although the CI around the estimate of effect is relatively tight, the sample size was smaller than the optimal information size (one small study only N < 200).

4 Risk of bias: serious (downgraded by 1). Several studies have unclear risk of bias, particularly regarding random sequence generation and blinding, as well as failure to describe allocation concealment. This bias is likely to lower confidence in the estimate of the effect.

5 Indirectness: serious (downgraded by 1). Not clinically meaningful binary data

6 Imprecision: serious (downgraded by 1). Although the CI around the estimate of effect is relatively tight, the sample size was smaller than the optimal information size (two small studies N < 200)

7Risk of bias: serious (downgraded by 1). One of the included studies did not report intention‐to‐treat data and had a high risk of bias.

8 There was a moderate‐high degree of heterogeneity for this outcome I2 = 75%

9 The two studies had different cutoffs for clinical significance. Abbasi 2010: defined as improvement in PANSS total of >50%. Terevnikov 2013: defined as improvement of PANSS total by > 20%.

Figuras y tablas -
Summary of findings for the main comparison. Mirtazapine adjunct versus placebo adjunct
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Comparison 1. Mirtazapine adjunct versus placebo adjunct ‐ short term

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mental state: specific. 1a. Negative symptoms: clinically important change Show forest plot

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

0.81 [0.57, 1.14]

1.1 No important response (reduction in SANS overall score from baseline of at least 20%)

1

20

Risk Ratio (M‐H, Fixed, 95% CI)

0.81 [0.57, 1.14]

2 Mental state: specific. 1b. Negative symptoms: average endpoint score (various scales) Show forest plot

5

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

2.1 PANSS negative (high = poor)

4

130

Mean Difference (IV, Fixed, 95% CI)

‐2.65 [‐4.45, ‐0.84]

2.2 SANS (high = poor)

2

40

Mean Difference (IV, Fixed, 95% CI)

‐15.04 [‐20.06, ‐10.01]

3 Mental sate: specific. 1c. Negative symptoms: average endpoint score (PANSS negative, high = poor) ‐skewed data Show forest plot

Other data

No numeric data

4 Mental state: specific. 2a. Positive symptoms: average endpoint score (PANSS, high = poor) Show forest plot

1

20

Mean Difference (IV, Fixed, 95% CI)

‐2.20 [‐5.29, 0.89]

5 Mental state: specific. 2b. Positive symptoms: average endpoint score (various scales) ‐ skewed data Show forest plot

Other data

No numeric data

6 Mental state: overall. 3a. Clinically important change (at least 20% change PANSS) Show forest plot

2

77

Risk Ratio (M‐H, Fixed, 95% CI)

0.69 [0.51, 0.92]

6.1 No response

2

77

Risk Ratio (M‐H, Fixed, 95% CI)

0.69 [0.51, 0.92]

7 Mental state: overall. 3b. Average endpoint score (various scales) Show forest plot

7

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

7.1 PANSS (high = poor)

6

170

Mean Difference (IV, Fixed, 95% CI)

‐3.84 [‐7.89, 0.21]

7.2 BPRS (high = poor)

1

20

Mean Difference (IV, Fixed, 95% CI)

‐19.30 [‐22.10, ‐16.50]

8 Mental state: overall. 3c. Average change score (various scales) ‐ skewed data Show forest plot

Other data

No numeric data

9 Mental state: specific. 4a. Depressive symptoms: average endpoint score (HAM‐D, high = poor) Show forest plot

2

53

Mean Difference (IV, Fixed, 95% CI)

1.51 [‐1.72, 4.74]

10 Mental state: specific. 4b. Depressive symptoms: average change score (various scales) ‐ skewed data Show forest plot

Other data

No numeric data

11 Leaving the study early for any reason Show forest plot

9

310

Risk Ratio (M‐H, Fixed, 95% CI)

1.03 [0.64, 1.66]

12 Global state: 1. Average endpoint score (CGI severity, high = poor) Show forest plot

1

39

Mean Difference (IV, Fixed, 95% CI)

‐0.10 [‐0.68, 0.48]

13 Global state: 2a. Average change score (PGI, high = poor) Show forest plot

1

39

Mean Difference (IV, Fixed, 95% CI)

‐0.54 [‐0.97, ‐0.11]

14 Global state: 2b. Average change date (various scales) ‐ skewed data Show forest plot

Other data

No numeric data

15 Cognitive functioning: other data Show forest plot

Other data

No numeric data

15.1 Other data tables

Other data

No numeric data

16 Adverse events: 1a. General (participants with at least one adverse event) Show forest plot

2

71

Risk Ratio (M‐H, Fixed, 95% CI)

0.96 [0.81, 1.12]

17 Adverse events: 1b. General (total number of adverse events) ‐ count data Show forest plot

Other data

No numeric data

18 Adverse effects: 2a. Extrapyramidal: clinically important change akathisia Show forest plot

2

86

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.20, 0.52]

18.1 No clinically important response (reduction of at least 2 on BAS)

2

86

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.20, 0.52]

19 Adverse effects: 2b. Extrapyramidal ‐ full resolution of akathisia Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

20 Adverse effects: 2c. Extrapyramidal ‐ specific effects Show forest plot

2

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

20.1 Parkinsonism

1

30

Risk Ratio (M‐H, Fixed, 95% CI)

0.6 [0.29, 1.23]

20.2 Akathisia

1

30

Risk Ratio (M‐H, Fixed, 95% CI)

0.14 [0.01, 2.55]

20.3 Dystonia

1

30

Risk Ratio (M‐H, Fixed, 95% CI)

0.33 [0.01, 7.58]

20.4 Additional anticholinergic drug use

1

30

Risk Ratio (M‐H, Fixed, 95% CI)

0.46 [0.24, 0.88]

20.5 Tremor

1

38

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.16, 6.38]

21 Adverse effects: 2d. Extrapyramidal: average change score (various scales) Show forest plot

1

Mean Difference (IV, Fixed, 95% CI)

Subtotals only

21.1 SAS, high = poor

1

60

Mean Difference (IV, Fixed, 95% CI)

‐0.27 [‐1.97, 1.43]

21.2 BAS , high = poor

1

60

Mean Difference (IV, Fixed, 95% CI)

‐0.03 [‐0.69, 0.63]

22 Adverse effects: 2e. Extrapyramidal: average endpoint score (various scales) ‐ skewed or unusable data Show forest plot

Other data

No numeric data

23 Adverse effects: 2f. Extrapyramidal: treatment details ‐ skewed data Show forest plot

Other data

No numeric data

24 Adverse events: 3. Other specific effects Show forest plot

8

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

24.1 Weight gain

4

127

Risk Ratio (M‐H, Fixed, 95% CI)

3.19 [1.17, 8.65]

24.2 Headache

4

157

Risk Ratio (M‐H, Fixed, 95% CI)

1.44 [0.54, 3.82]

24.3 Sedation/drowsiness

7

223

Risk Ratio (M‐H, Fixed, 95% CI)

1.64 [1.01, 2.68]

24.4 Increased appetite

2

77

Risk Ratio (M‐H, Fixed, 95% CI)

2.57 [0.66, 10.07]

24.5 Weakness

1

39

Risk Ratio (M‐H, Fixed, 95% CI)

2.86 [0.12, 66.11]

24.6 Hypersedimentaiton

1

39

Risk Ratio (M‐H, Fixed, 95% CI)

2.86 [0.12, 66.11]

24.7 Arrythmia/palpitations

1

60

Risk Ratio (M‐H, Fixed, 95% CI)

1.0 [0.15, 6.64]

24.8 Uterine myoma

1

39

Risk Ratio (M‐H, Fixed, 95% CI)

2.86 [0.12, 66.11]

24.9 Dizziness

3

137

Risk Ratio (M‐H, Fixed, 95% CI)

2.32 [0.83, 6.51]

24.10 Collapse

1

39

Risk Ratio (M‐H, Fixed, 95% CI)

0.32 [0.01, 7.35]

24.11 Acute Respiratory Distress Syndrome

1

39

Risk Ratio (M‐H, Fixed, 95% CI)

0.32 [0.01, 7.35]

24.12 Nausea

2

77

Risk Ratio (M‐H, Fixed, 95% CI)

1.55 [0.45, 5.41]

24.13 Agitation

2

77

Risk Ratio (M‐H, Fixed, 95% CI)

0.70 [0.15, 3.32]

24.14 Sleep disturbance

2

77

Risk Ratio (M‐H, Fixed, 95% CI)

0.20 [0.02, 1.61]

24.15 Dry mouth

2

98

Risk Ratio (M‐H, Fixed, 95% CI)

2.25 [0.74, 6.81]

24.16 Blurred vision

1

60

Risk Ratio (M‐H, Fixed, 95% CI)

1.33 [0.33, 5.45]

24.17 Conjunctivitis

1

39

Risk Ratio (M‐H, Fixed, 95% CI)

0.32 [0.01, 7.35]
Figuras y tablas -
Comparison 1. Mirtazapine adjunct versus placebo adjunct ‐ short term
Ir a la tabla de la revisión