Selective noradrenaline reuptake inhibitors for schizophrenia

Paul R L Matthews; Jamie Horder; Michael Pearce

doi:10.1002/14651858.CD010219.pub2

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Figure 1

Study flow diagram.

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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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Figure 3

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 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 1 Primary outcome ‐ A. Mental state: Specific ‐ clinically significant response or improvement in negative symptoms (SANS, high=worse) ‐ short term (12 weeks).

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Analysis 1.2

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 2 Primary outcome ‐ B. Clinical global response: Clinically significant response or improvement in global status (CGI‐S, high=worse) ‐ short term (4 weeks).

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Analysis 1.3

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 3 Mental state: 1. General ‐ clinically significant response or improvement in general/overall symptoms as defined in each study ‐ short term (2‐12 weeks).

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Analysis 1.4

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 4 Mental state: 2a. General: Average general/overall symptoms score (various scales, high=worse) ‐ short term (2 ‐ 12 weeks).

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Analysis 1.5

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 5 Mental state: 2b. General: Average general/overall symptoms score (various scales, high=worse) ‐ medium term (13 ‐ 26 weeks).

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Analysis 1.6

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 6 Mental state: 3a. Specific: Average symptoms score (various scales, high=worse) ‐ short term (2 ‐ 12 weeks).

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Analysis 1.7

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 7 Mental state: 3b. Specific: Average symptoms score (various scales, high=worse) ‐ medium term (13 ‐ 26 weeks).

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Study	NRI	NRI mean	NRI SD	NRI N	Placebo mean	Placebo SD	Placebo N
general ‐ overall symptoms (BPRS total)
Kelly 2009	Atomoxetine	30.2	8.2	11	36	11.6	12
general ‐ overall symptoms (PANSS general)
Friedman 2008	Atomoxetine	26.7	4.4	10	32	8	10
Hinkelmann 2013	Reboxetine	28.7	9.4	19	28.4	10.1	16
Schutz 2001	Reboxetine	29.6	8.92	12	30.4	7.44	11
general ‐ overall symptoms (PANSS total)
Schutz 2001	Reboxetine	67.67	20.66	12	70.67	14.96	11
specific ‐ mood (BPRS anxiety/depression)
Kelly 2009	Atomoxetine	6.4	1.9	11	8.3	3.6	12
specific ‐ mood (HRSD)
Hinkelmann 2013	Reboxetine	8.3	6.1	19	6.5	5.6	16
Poyurovsky 2003	Reboxetine	4.6	3.5	10	4.6	3.5	10
Poyurovsky 2007	Reboxetine	4.53	2	16	3	2	17
Schutz 2001	Reboxetine	6.93	4.95	12	6.93	3.17	11
specific ‐ negative symptoms (SANS)
Poyurovsky 2003	Reboxetine	18.9	13.4	10	23.2	18.8	10
specific ‐ negative symptoms (PANSS negative)
Friedman 2008	Atomoxetine	15.2	4.8	10	15.5	5.9	10
Hinkelmann 2013	Reboxetine	21.5	8.6	19	19.1	5.5	16
Schutz 2001	Reboxetine	25.13	9.53	12	23.27	7.21	11
specific ‐ positive symptoms (BPRS positive)
Kelly 2009	Atomoxetine	9.8	4.9	11	10.3	5.5	12
specific ‐ positive symptoms (PANSS positive)
Friedman 2008	Atomoxetine	13.2	4.5	10	14.6	4.5	10
Hinkelmann 2013	Reboxetine	10.6	4.6	19	8.6	2.4	16
Li 2008	Reboxetine	9.02	2.64	57	8.72	3.21	57
Schutz 2001	Reboxetine	14.1	5.68	12	15.8	7.29	11
Zhao 2013	Reboxetine	9.1	3.4	54	9.1	3.1	53
specific ‐ positive symptoms (SAPS)
Poyurovsky 2003	Reboxetine	4.8	3.9	10	11.8	12.2	10
Poyurovsky 2007	Reboxetine	3.21	3.2	31	2.66	2.4	28

Analysis 1.8

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 8 Mental state: 4a. General and specific: Average score (various scales, high=worse) ‐ skewed results ‐ short term (2 ‐ 12 weeks).

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Study	NRI	NRI mean	NRI SD	NRI N	Placebo mean	Placebo SD	Placebo N
general ‐ overall symptoms (BPRS total)
Ball 2011	Atomoxetine	30.8	5.8	14	31	8.9	12
general ‐ overall symptoms (PANSS general)
Usall 2014	Reboxetine	28.83	8.1	24	30.09	7.93	23
general ‐ overall symptoms (PANSS total)
Usall 2014	Reboxetine	59.96	17.89	24	62.04	19.9	23
Yu 2012	Reboxetine	24.24	3.54	33	26.86	1.66	32
specific ‐ negative symptoms (PANSS negative)
Usall 2014	Reboxetine	19.67	8.41	24	22.65	5.54	23
specific ‐ negative symptoms (SANS)
Usall 2014	Reboxetine	46.75	26.12	24	54.61	19.13	23
specific ‐ positive symptoms (PANSS positive)
Usall 2014	Reboxetine	11.46	4.14	24	12	5.68	23
Zhao 2013	Reboxetine	9	3.2	54	9.3	3.4	53

Analysis 1.9

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 9 Mental state: 4b. General and specific: Average score (various scales, high=worse) ‐ skewed results ‐ medium term (13 ‐ 26 weeks).

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Analysis 1.10

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 10 Cognitive functioning: 1. General ‐ average composite cognitive functioning score (SMD).

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Analysis 1.11

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 11 Cognitive functioning: 2. Specific ‐ average individual scores (SMD) ‐ short term (2 ‐ 12 weeks).

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Analysis 1.12

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 12 Quality of life: Average quality of life score (GQOLI‐74, high=better) ‐ short term (2 ‐ 12 weeks).

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Analysis 1.13

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 13 Clinical global response: 1a. Average clinical global status score (CGI‐S, high=worse) ‐ short term (2 ‐ 12 weeks).

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Study	NRI	NRI mean	NRI SD	NRI N	Placebo mean	Placebo SD	Placebo N
CGI‐I
Schutz 2001	Reboxetine	3.4	1.35	12	3.07	1.22	11
CGI‐S
Hinkelmann 2013	Reboxetine	4.2	1.5	19	3.6	1.3	16
Poyurovsky 2003	Reboxetine	3.1	1.3	10	3	1.1	10

Analysis 1.14

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 14 Clinical global response: 1b. Average clinical global status score (various scales, high=worse) ‐ short term (2 ‐ 12 weeks) ‐ skewed results.

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Analysis 1.15

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 15 Leaving the study early: 1a. Short term (2 ‐ 12 weeks).

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Analysis 1.16

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 16 Leaving the study early: 1b. Medium term (13 ‐ 26 weeks).

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Analysis 1.17

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 17 Adverse effects: 1. General ‐ short term (binary, 2 ‐ 12 weeks).

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Analysis 1.18

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 18 Adverse effects: 2a.i. Specific ‐ short term (binary, 2 ‐ 12 weeks).

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Analysis 1.19

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 19 Adverse effects: 2a.ii. Specific ‐ extrapyramidal ‐ average change score (continuous, various scales, high=worse) ‐ short term (2 ‐ 12 weeks).

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Study	NRI	NRI mean	NRI SD	NRI N	Placebo mean	Placebo SD	Placebo N
AIMS
Kelly 2009	Atomoxetine	1.33	1.88	12	0.93	1.94	11
SAS
Kelly 2009	Atomoxetine	0.4	0.5	11	1.9	2.6	15
Schutz 2001	Reboxetine	2.5	3.4	11	2.3	2.9	15

Analysis 1.20

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 20 Adverse effects: 2a.iii. Specific ‐ extrapyramidal ‐ average change score (continuous, various scales, high=worse) ‐ short term (2 ‐ 12 weeks) ‐ skewed results.

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Analysis 1.21

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 21 Adverse effects: 2b.i. Specific ‐ medium term (binary, 13 ‐ 26 weeks).

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Analysis 1.22

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 22 Adverse effects: 2a.iv. Specific ‐ metabolic ‐ average weight gain (continuous, increase in kg).

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Analysis 1.23

Comparison 1 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO, Outcome 23 Social or general functioning: Average social functioning score (various subscales) ‐ short‐term (2 ‐ 12 weeks).

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Analysis 2.1

Comparison 2 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus ACTIVE CONTROL, Outcome 1 Mental state: 1a. General: Average general/overall symptoms score (PANSS general, high=worse) ‐ short term (2 ‐ 12 weeks).

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Analysis 2.2

Comparison 2 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus ACTIVE CONTROL, Outcome 2 Mental state: 1b. General: Average general/overall symptoms score (various scales, high=worse) ‐ medium term (13 ‐ 26 weeks).

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Analysis 2.3

Comparison 2 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus ACTIVE CONTROL, Outcome 3 Mental state: 2a. Specific: Average symptoms score (various scales, high=worse) ‐ short term (2 ‐ 12 weeks).

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Analysis 2.4

Comparison 2 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus ACTIVE CONTROL, Outcome 4 Mental state: 2b. Specific: Average symptoms score (various scales, high=worse) ‐ medium term (13 ‐ 26 weeks).

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Study	NRI	NRI mean	NRI SD	NRI N	Active control	Control mean	Control SD	Control N
general ‐ overall symptoms (PANSS general)
Hinkelmann 2013	Reboxetine	28.7	9.4	19	Citalopram	26.5	6.2	16
specific ‐ mood (HRSD)
Hinkelmann 2013	Reboxetine	8.3	6.1	19	Citalopram	9.6	5.8	16
specific ‐ negative symptoms (PANSS negative)
Hinkelmann 2013	Reboxetine	21.5	8.6	19	Citalopram	19.1	8.8	16
specific ‐ positive symptoms (PANSS positive)
Hinkelmann 2013	Reboxetine	10.6	4.6	19	Citalopram	11.1	4.8	16

Analysis 2.5

Comparison 2 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus ACTIVE CONTROL, Outcome 5 Mental state: 3a. General and specific: Average score (various scales, high=worse) ‐ skewed results ‐ short term (2 ‐ 12 weeks).

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Study	NRI	NRI mean	NRI SD	NRI N	Active control	Control mean	Control SD	Control N
general ‐ overall symptoms (PANSS general)
Usall 2014	Reboxetine	28.83	8.1	24	Citalopram	28.88	5.32	17
general ‐ overall symptoms (PANSS total)
Usall 2014	Reboxetine	59.96	17.89	24	Citalopram	59.41	11.72	17
specific ‐ negative symptoms (PANSS negative)
Usall 2014	Reboxetine	19.67	8.41	24	Citalopram	19.82	4.99	17
specific ‐ negative symptoms (SANS)
Usall 2014	Reboxetine	46.75	26.12	24	Citalopram	46.63	15.84	17
specific ‐ positive symptoms (PANSS positive)
Usall 2014	Reboxetine	11.46	4.14	24	Citalopram	10.71	3.58	17

Analysis 2.6

Comparison 2 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus ACTIVE CONTROL, Outcome 6 Mental state: 3b. General and specific: Average score (various scales, high=worse) ‐ skewed results ‐ medium term (13 ‐ 26 weeks).

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Analysis 2.7

Comparison 2 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus ACTIVE CONTROL, Outcome 7 Clinical global response: Average clinical global status score (CGI‐S, high=worse) ‐ short term (2 ‐ 12 weeks).

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Analysis 2.8

Comparison 2 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus ACTIVE CONTROL, Outcome 8 Leaving the study early: 1a. Short term (2 ‐ 12 weeks).

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Analysis 2.9

Comparison 2 SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus ACTIVE CONTROL, Outcome 9 Leaving the study early: 1b. Medium term (13 ‐ 26 weeks).

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Table 12. Included and excluded studies and relevant Cochrane Reviews

Study tag	Specific patient characteristics	Intervention	Control	Relevant Cochrane Reviews
Barnes 2009	Negative symptoms	Citalopram	Placebo	Rummel‐Kluge 2006
Hou 2007	Negative symptoms	Citalopram	Placebo	Rummel‐Kluge 2006
Mueller 2005		Celecoxib	Placebo	Akhondzadeh 2011
Salokangas 1997		Citalopram	Placebo	‐
Shafti 2004		Clomipramine	Placebo	‐
		Citalopram	Placebo	‐
		Fluoxetine	Placebo	‐
		Nortiptyline	Placebo	‐
		Fluvoxamine	Placebo	‐
		Maprotiline	Placebo	‐
Hinkelmann 2013	Negative symptoms	Reboxetine	Placebo	Rummel‐Kluge 2006
Li 2008	Negative symptoms	Reboxetine	Placebo	Rummel‐Kluge 2006
Shafti 2015	Negative symptoms	Reboxetine	Placebo	Rummel‐Kluge 2006
Usall 2014	Negative symptoms	Reboxetine	Placebo	Rummel‐Kluge 2006
Yu 2012	Negative symptoms	Reboxetine	Control	Rummel‐Kluge 2006
Zhao 2013	Negative symptoms	Reboxetine	Placebo	Rummel‐Kluge 2006

Table 12. Included and excluded studies and relevant Cochrane Reviews

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Table 13. Suggested design for a future NRI trial

Methods	Allocation: randomised (with sequence generation and allocation concealment clearly described) Blinding: double blind (participants, clinicians, and outcome assessors) and blinding tested Duration: at least 3 months Design: parallel group Setting: inpatient and outpatient
Participants	Diagnosis: people with schizophrenia (duration > 6m) and prominent negative symptoms (e.g. PANSS negative > 30) N=300 Age: Any, but with recruitment focused on those aged 18‐65yrs Sex: Men and women
Interventions	1. Reboxetine (8‐12mg daily) in combination with any antipsychotic treatment including clozapine 2. Placebo in combination with any antipsychotic treatment including clozapine
Outcomes	Mental state: significant improvement in negative symptoms defined as 20% reduction in the PANSS negative scale*, average scores on the PANSS negative scale, significant improvement and average scores on the PANSS total, general, and positive scales and the HRSD Cognitive functioning: significant improvement in a clinical scale of cognitive functioning such as the Schizophrenia Cognition Rating Scale (SCoRS) total score, average scores on neurocognitive testing such as the MATRICS Consensus Cognitive Battery (MCCB) overall composite T‐score and individual domain scores Quality of life: significant improvement in a quality of life scale, average scores on a quality of life scale Clinical global response: significant improvment in clinical global status defined as CGI‐I scores of 1 or 2, average scores on the CGI‐S Service utilisation Adverse effects: leaving the study early (for any reason), serious adverse effects, average weight gain Satisfaction with treatment Social or general functioning
Notes	* recommended primary outcome, other outcomes listed are suggestions rather than an exhaustive list

Table 13. Suggested design for a future NRI trial

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Summary of findings for the main comparison. Noradrenaline reuptake inhibitors versus placebo

Selective noradrenaline reuptake inhibitor (NRI) versus placebo in schizophrenia
Patient or population: adults with schizophrenia Setting: inpatient and outpatient Intervention: NRI Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Quality of the evidence (GRADE)	Comments
	Risk with placebo	Risk with NRI
Mental state: significant response or improvement in negative symptoms (PANSS negative subscale, high = worse) ‐ short term (12 weeks)	Study population		RR 3.17 (1.52 to 6.58)	50 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1 2 3 4 5}	Additional information from average negative symptoms score was equivocal
	240 per 1000	761 per 1000 (365 to 1000)
Mental state: specific ‐ average positive symptoms score (PANSS positive subscale, high = worse) ‐ short term (2 to 12 weeks)	‐	The mean PANSS positive score in the intervention group was 0.16 less (0.96 less to 0.63 more)	‐	294 (5 RCTs)	⊕⊕⊝⊝ LOW ^{1, 6}	No data reported for our prespecified outcome: significant response or improvement in positive symptoms SAPS and BPRS positive subscale outcomes showed similar results
Clinical global response: significant response or improvement in global status (CGI‐S, high = worse) ‐ short term (4 weeks)	Study population		RR 0.99 (0.45 to 2.20)	28 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{3 4 5 7 9}	Additional information from average clinical global status score found a similar lack of effect
	467 per 1000	462 per 1000 (210 to 1000)
Cognitive functioning: significant response or improvement in cognitive functioning	no data reported for this outcome
Cognitive functioning: average compostive endpoint score (SMD, low = favours NRI) ‐ short term (2 to 12 weeks)		The mean composite cognitive functioning SMD in the intervention group was 0.04 standard deviations more (0.28 less to 0.36 more)	‐	180 (4 RCTs)	⊕⊕⊝⊝ LOW ^{7 8}
Quality of life: Average endpoint score (GQOLI‐74, high = better) ‐ short term (2 to 12 weeks)	‐	The mean GQOLI‐74 score in the intervention group was 9.36 more (7.89 more to 10.83 more)	‐	114 (1 RCT)	⊕⊝⊝⊝ VERY LOW ^{1, 2, 4, 5, 6}	No data reported for our prespecified outcome of significant response or improvement in quality of life
Adverse effects: Nausea ‐ short term (2 to 12 weeks)	Study population		RR 0.49 (0.10 to 2.41)	176 (3 RCTs)	⊕⊕⊝⊝ LOW ^5,7
	148 per 1000	72 per 1000 (15 to 356)
*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; SMD: Standardised mean difference
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 Imprecision: 'Serious' ‐ Small sample size ‐ Downgraded by 1 level ² Risk of bias: 'Serious' ‐ Methods of random sequence generation and allocation concealment are poorly described ‐ Downgraded by 1 level ³ Risk of bias: 'Serious' ‐ Evidence of selective reporting bias ‐ Downgraded by 1 level ⁴ Inconsistency: 'No' ‐ Only 1 study ‐ Not downgraded ⁵ Publication bias: 'Strongly suspected' ‐ Evidence of significant relevant unpublished or unusable results ‐ Downgraded by 1 level ⁶ Indirectness: 'Serious' ‐ Outcome of interest was not reported so a related outcome was substituted as a surrogate ‐ Downgraded by 1 level ⁷ Imprecision: 'Serious' ‐ Small sample size, confidence intervals include clinically significant benefits or harms ‐ Downgraded by 1 level ⁸ Risk of bias: 'Serious' ‐ Includes studies with high risk of attrition, reporting, and other sources of bias ‐ Downgraded by 1 level ⁹ Indirectness: 'Serious' ‐ Participants recruited specifically with depressive symptoms so unrepresentative of most patients with schizophrenia ‐ Downgraded by 1 level

Summary of findings for the main comparison. Noradrenaline reuptake inhibitors versus placebo

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Table 1. Mental state: 1.2 General ‐ Average general/overall symptoms score (PANSS general, negative MD favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

Subgroup or sensitivity analysis (see text for details)	Number of trials	N	Mean difference	95% Confidence interval	I²
Overall outcome	5	294	‐2.17	‐3.93 to ‐0.40*	44%
Reboxetine	4	279	‐2.20	‐4.15 to ‐0.25*	55%
Clozapine‐only studies; excluding skewed change‐scores	2	221	‐2.80	‐4.87 to ‐0.72*	75%
Excluding studies without clozapine; negative symptoms	3	256	‐2.40	‐4.48 to ‐0.31*	65%
Excluding studies with imputed SD	3	236	‐2.66	‐4.50 to ‐0.82*	55%
Fixed‐effect model	5	294	‐2.73	‐3.71 to ‐1.74*	44%
Low risk of randomisation bias	2	58	0.89	‐3.60 to 5.37	0%
* Statistically significant at p<0.05

Table 1. Mental state: 1.2 General ‐ Average general/overall symptoms score (PANSS general, negative MD favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

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Table 2. Mental state: 1.2 General ‐ Average general/overall symptoms score (PANSS total, negative MD favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

Subgroup or sensitivity analysis (see text for details)	Number of trials	N	Mean difference	95% Confidence interval	I²
Overall outcome	4	309	‐2.84	‐5.28 to ‐0.40*	72%
Clozapine‐only studies	2	220	‐4.25	‐5.89 to ‐2.62*	0%
Excluding outlier; excluding high risk of bias	3	244	‐4.20	‐5.82 to ‐2.58*	0%
Negative symptoms; excluding imputed SD	3	186	‐2.94	‐5.54 to ‐0.34*	81%
Fixed‐effect model	4	309	‐2.12	‐3.12 to ‐1.11*	72%
* Statistically significant at p<0.05

Table 2. Mental state: 1.2 General ‐ Average general/overall symptoms score (PANSS total, negative MD favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

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Table 3. Mental state: 1.2 General ‐ Average general/overall symptoms score (PANSS total, negative MD favours NRI) ‐ medium‐term (13‐26wks) ‐ Exploration of heterogeneity

Subgroup or sensitivity analysis (see text for details)	Number of trials	N	Mean difference	95% Confidence interval	I²
Overall outcome	3	219	‐3.67	‐10.07 to 2.72	94%
Excluding outlier; excluding clozapine study	2	112	‐1.07	‐2.59 to 0.46	0%
Fixed‐effect model	3	219	‐3.63	‐4.87 to ‐2.39*	94%
* Statistically significant at p<0.05

Table 3. Mental state: 1.2 General ‐ Average general/overall symptoms score (PANSS total, negative MD favours NRI) ‐ medium‐term (13‐26wks) ‐ Exploration of heterogeneity

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Table 4. Mental state: 1.5 Specific ‐ Average negative symptoms score (PANSS negative, negative MD favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

Subgroup or sensitivity analysis (see text for details)	Number of trials	N	Mean difference	95% Confidence interval	I²
Overall outcome	6	359	‐0.99	‐2.53 to 0.56	71%
Reboxetine	5	341	‐1.20	‐2.80 to 0.40	74%
Clozapine‐only studies	2	221	‐1.60	‐3.96 to 0.76	84%
Excluding studies without clozapine	3	256	‐0.75	‐3.25 to 1.75	81%
Negative symptoms	4	321	‐1.47	‐3.04 to 0.09	77%
Excluding imputed SD	4	301	‐1.68	‐3.04 to ‐0.32*	70%
Excluding skewed change scores	3	286	‐1.92	‐3.28 to ‐0.55*	75%
Fixed‐effect model	6	259	‐1.82	‐2.46 to ‐1.18*	71%
Low risk of randomisation bias	2	58	3.55	‐0.43 to 7.54	0%
Excluding high risk of bias	5	294	‐0.12	‐2.31 to 2.07	71%
* Statistically significant at p<0.05

Table 4. Mental state: 1.5 Specific ‐ Average negative symptoms score (PANSS negative, negative MD favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

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Table 5. Mental state: 1.4 Specific ‐ Average positive symptoms score (PANSS positive, negative MD favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

Subgroup or sensitivity analysis (see text for details)	Number of trials	N	Mean difference	95% Confidence interval	I²
Overall outcome	5	294	‐0.16	‐0.96 to 0.63	0%
Reboxetine	4	279	‐0.24	‐1.05 to 0.57	0%
Clozapine‐only studies	2	221	‐0.15	‐1.02 to 0.72	0%
Excluding studies without clozapine; negative symptoms	3	256	‐0.22	‐1.04 to 0.60	0%
Fixed‐effect model	5	294	‐0.16	‐0.96 to 0.63	0%
Low risk of randomisation bias	2	58	‐0.76	‐2.93 to 1.40	0%

Table 5. Mental state: 1.4 Specific ‐ Average positive symptoms score (PANSS positive, negative MD favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

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Table 6. Cognitive functioning: 2.3 Average composite cognitive functioning score (SMD, negative favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

Subgroup or sensitivity analysis (see text for details)	Number of trials	N	Mean difference	95% Confidence interval	I²
Overall outcome	4	180	0.04	‐0.28 to 0.36	8%
Atomoxetine	3	147	‐0.07	‐0.55 to 0.41	33%
Fixed‐effect model	4	180	0.06	‐0.24 to 0.35	8%
Low risk of randomisation bias	2	55	‐0.18	‐1.06 to 0.69	61%
Excluding high risk of other bias	2	48	0.14	‐0.42 to 0.71	0%
Excluding high risk of attrition and reporting bias	3	70	‐0.12	‐0.66 to 0.43	22%

Table 6. Cognitive functioning: 2.3 Average composite cognitive functioning score (SMD, negative favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

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Table 7. Cognitive functioning: 2.9 Average speed of processing score (SMD, negative favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

Subgroup or sensitivity analysis (see text for details)	Number of trials	N	Mean difference	95% Confidence interval	I²
Overall outcome	4	177	0.08	‐0.21 to 0.38	0%
Atomoxetine	3	144	0.04	‐0.29 to 0.37	0%
Fixed‐effect model	4	177	0.08	‐0.21 to 0.38	0%
Low risk of randomisation bias	2	53	0.13	‐0.41 to 0.68	0%
Excluding high risk of attrition and other bias	2	48	0.23	‐0.34 to 0.80	0%
Excluding high risk of reporting bias	3	68	0.13	‐0.34 to 0.61	0%

Table 7. Cognitive functioning: 2.9 Average speed of processing score (SMD, negative favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

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Table 8. Cognitive functioning: 2.13 Average verbal learning/memory score (SMD, negative favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

Subgroup or sensitivity analysis (see text for details)	Number of trials	N	Mean difference	95% Confidence interval	I²
Overall outcome	4	181	0.01	‐0.31 to 0.32	7%
Atomoxetine	3	148	‐0.08	‐0.40 to 0.25	0%
Fixed‐effect model	4	181	0.01	‐0.28 to 0.30	7%
Low risk of randomisation bias	2	55	‐0.06	‐1.04 to 0.93	69%
Excluding high risk of other bias	2	48	0.26	‐0.31 to 0.83	0%
Excluding high risk of attrition and reporting bias	3	70	‐0.04	‐0.66 to 0.58	38%

Table 8. Cognitive functioning: 2.13 Average verbal learning/memory score (SMD, negative favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

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Table 9. Clinical global response: 4.1 Average clinical global status score (CGI‐S, negative MD favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

Subgroup or sensitivity analysis (see text for details)	Number of trials	N	Mean difference	95% Confidence interval	I²
Overall outcome	5	160	‐0.03	‐0.35 to 0.28	7%
Reboxetine; excluding high risk of bias	4	137	0.10	‐0.23 to 0.42	0%
Excluding imputed SD; excluding skewed change scores	3	105	‐0.15	‐0.60 to 0.29	37%
Fixed‐effect model	5	160	‐0.03	‐0.32 to 0.27	7%

Table 9. Clinical global response: 4.1 Average clinical global status score (CGI‐S, negative MD favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

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Table 10. Adverse effects: 6.2.1 All cause withdrawals (lower RR favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

Subgroup or sensitivity analysis (see text for details)	Number of trials	N	Relative risk	95% Confidence interval	I²
Overall outcome	8	401	0.94	0.63 to 1.39	0%
Atomoxetine	3	173	0.89	0.49 to 1.59	0%
Reboxetine	5	200	0.95	0.54 to 1.70	0%
Fixed‐effect model	8	401	0.95	0.64 to 1.41	0%
Low risk of bias in randomisation	5	182	0.92	0.54 to 1.56	0%
Excluding high risk of other bias	7	248	1.03	0.62 to 1.70	0%
Excluding high risk of reporting bias	7	252	0.97	0.58 to 1.60	0%
Excluding high risk of attrition bias	8	369	0.96	0.63 to 1.45	0%

Table 10. Adverse effects: 6.2.1 All cause withdrawals (lower RR favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

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Table 11. Adverse effects: 6.2.2 Withdrawal due to adverse events (lower RR favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

Subgroup or sensitivity analysis (see text for details)	Number of trials	N	Relative risk	95% Confidence interval	I²
Overall outcome	4	178	2.08	0.70 to 6.21	0%
Atomoxetine	3	153	1.88	0.58 to 6.08	0%
Fixed‐effect model	4	178	2.18	0.79 to 6.02	0%
Low risk of bias in randomisation	2	53	1.15	0.15 to 8.60	18%
Excluding high risk of other bias	2	45	4.48	0.56 to 35.52	0%
Excluding high risk of reporting bias	3	73	1.66	0.36 to 7.72	0%

Table 11. Adverse effects: 6.2.2 Withdrawal due to adverse events (lower RR favours NRI) ‐ short‐term (2‐12wks) ‐ Subgroup and sensitivity analysis

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Comparison 1. SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Primary outcome ‐ A. Mental state: Specific ‐ clinically significant response or improvement in negative symptoms (SANS, high=worse) ‐ short term (12 weeks) Show forest plot	1	50	Risk Ratio (M‐H, Random, 95% CI)	3.17 [1.52, 6.58]

2 Primary outcome ‐ B. Clinical global response: Clinically significant response or improvement in global status (CGI‐S, high=worse) ‐ short term (4 weeks) Show forest plot	1	28	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.45, 2.20]

3 Mental state: 1. General ‐ clinically significant response or improvement in general/overall symptoms as defined in each study ‐ short term (2‐12 weeks) Show forest plot	2	58	Risk Ratio (M‐H, Random, 95% CI)	1.15 [0.64, 2.09]

4 Mental state: 2a. General: Average general/overall symptoms score (various scales, high=worse) ‐ short term (2 ‐ 12 weeks) Show forest plot	7		Mean Difference (IV, Random, 95% CI)	Subtotals only

4.1 BPRS total	1	23	Mean Difference (IV, Random, 95% CI)	1.5 [‐6.64, 9.64]
4.2 PANSS general	5	294	Mean Difference (IV, Random, 95% CI)	‐2.17 [‐3.93, ‐0.40]
4.3 PANSS total	4	308	Mean Difference (IV, Random, 95% CI)	‐2.84 [‐5.28, ‐0.40]
5 Mental state: 2b. General: Average general/overall symptoms score (various scales, high=worse) ‐ medium term (13 ‐ 26 weeks) Show forest plot	4		Mean Difference (IV, Random, 95% CI)	Subtotals only

5.1 BPRS total	1	26	Mean Difference (IV, Random, 95% CI)	‐1.4 [‐7.08, 4.28]
5.2 PANSS general	2	154	Mean Difference (IV, Random, 95% CI)	‐2.90 [‐7.57, 1.77]
5.3 PANSS total	3	219	Mean Difference (IV, Random, 95% CI)	‐3.67 [‐10.07, 2.72]
6 Mental state: 3a. Specific: Average symptoms score (various scales, high=worse) ‐ short term (2 ‐ 12 weeks) Show forest plot	10		Mean Difference (IV, Random, 95% CI)	Subtotals only

6.1 mood (BPRS)	1	23	Mean Difference (IV, Random, 95% CI)	0.2 [‐2.60, 3.00]
6.2 mood (HRSD)	3	114	Mean Difference (IV, Random, 95% CI)	‐2.37 [‐4.29, ‐0.45]
6.3 negative (PANSS negative)	6	359	Mean Difference (IV, Random, 95% CI)	‐0.99 [‐2.53, 0.56]
6.4 negative (SANS)	3	129	Mean Difference (IV, Random, 95% CI)	‐2.47 [‐6.22, 1.28]
6.5 negative (SANS ‐ modified)	1	23	Mean Difference (IV, Random, 95% CI)	‐5.70 [‐18.01, 6.61]
6.6 positive (BPRS)	1	23	Mean Difference (IV, Random, 95% CI)	1.60 [‐2.59, 5.79]
6.7 positive (PANSS positive)	5	294	Mean Difference (IV, Random, 95% CI)	‐0.16 [‐0.96, 0.63]
6.8 positive (SAPS)	3	129	Mean Difference (IV, Random, 95% CI)	0.73 [‐1.29, 2.74]
7 Mental state: 3b. Specific: Average symptoms score (various scales, high=worse) ‐ medium term (13 ‐ 26 weeks) Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

7.1 negative (PANSS negative)	3	219	Mean Difference (IV, Random, 95% CI)	‐3.25 [‐4.04, ‐2.47]
7.2 negative (SANS)	1	47	Mean Difference (IV, Random, 95% CI)	‐7.12 [‐19.39, 5.15]
7.3 positive (PANSS positive)	2	154	Mean Difference (IV, Random, 95% CI)	‐0.14 [‐1.30, 1.02]
8 Mental state: 4a. General and specific: Average score (various scales, high=worse) ‐ skewed results ‐ short term (2 ‐ 12 weeks) Show forest plot			Other data	No numeric data

8.1 general ‐ overall symptoms (BPRS total)			Other data	No numeric data
8.2 general ‐ overall symptoms (PANSS general)			Other data	No numeric data
8.3 general ‐ overall symptoms (PANSS total)			Other data	No numeric data
8.4 specific ‐ mood (BPRS anxiety/depression)			Other data	No numeric data
8.5 specific ‐ mood (HRSD)			Other data	No numeric data
8.6 specific ‐ negative symptoms (SANS)			Other data	No numeric data
8.7 specific ‐ negative symptoms (PANSS negative)			Other data	No numeric data
8.8 specific ‐ positive symptoms (BPRS positive)			Other data	No numeric data
8.9 specific ‐ positive symptoms (PANSS positive)			Other data	No numeric data
8.10 specific ‐ positive symptoms (SAPS)			Other data	No numeric data
9 Mental state: 4b. General and specific: Average score (various scales, high=worse) ‐ skewed results ‐ medium term (13 ‐ 26 weeks) Show forest plot			Other data	No numeric data

9.1 general ‐ overall symptoms (BPRS total)			Other data	No numeric data
9.2 general ‐ overall symptoms (PANSS general)			Other data	No numeric data
9.3 general ‐ overall symptoms (PANSS total)			Other data	No numeric data
9.4 specific ‐ negative symptoms (PANSS negative)			Other data	No numeric data
9.5 specific ‐ negative symptoms (SANS)			Other data	No numeric data
9.6 specific ‐ positive symptoms (PANSS positive)			Other data	No numeric data
10 Cognitive functioning: 1. General ‐ average composite cognitive functioning score (SMD) Show forest plot	5		Std. Mean Difference (Random, 95% CI)	Subtotals only

10.1 short term (2 ‐ 12 weeks)	4	180	Std. Mean Difference (Random, 95% CI)	0.04 [‐0.28, 0.36]
10.2 medium term (13 ‐ 26 weeks)	1	26	Std. Mean Difference (Random, 95% CI)	‐0.66 [‐1.46, 0.13]
11 Cognitive functioning: 2. Specific ‐ average individual scores (SMD) ‐ short term (2 ‐ 12 weeks) Show forest plot	4		Std. Mean Difference (Random, 95% CI)	Subtotals only

11.1 working memory	2	53	Std. Mean Difference (Random, 95% CI)	‐0.11 [‐0.89, 0.67]
11.2 reasoning/problem solving	3	158	Std. Mean Difference (Random, 95% CI)	0.03 [‐0.28, 0.34]
11.3 speed of processing	4	177	Std. Mean Difference (Random, 95% CI)	0.08 [‐0.21, 0.38]
11.4 attention	3	161	Std. Mean Difference (Random, 95% CI)	‐0.01 [‐0.51, 0.48]
11.5 verbal learning/memory	4	181	Std. Mean Difference (Random, 95% CI)	0.01 [‐0.31, 0.32]
11.6 visual learning/memory	1	22	Std. Mean Difference (Random, 95% CI)	‐0.44 [‐1.29, 0.41]
12 Quality of life: Average quality of life score (GQOLI‐74, high=better) ‐ short term (2 ‐ 12 weeks) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

12.1 general ‐ total	1	114	Mean Difference (IV, Random, 95% CI)	9.36 [7.89, 10.83]
12.2 specific ‐ well being ‐ material	1	114	Mean Difference (IV, Random, 95% CI)	0.21 [‐2.34, 2.76]
12.3 specific ‐ well being ‐ physical	1	114	Mean Difference (IV, Random, 95% CI)	0.68 [‐1.35, 2.71]
12.4 specific ‐ well being ‐ psychological	1	114	Mean Difference (IV, Random, 95% CI)	10.0 [8.01, 11.99]
12.5 specific ‐ well being ‐ social	1	114	Mean Difference (IV, Random, 95% CI)	10.02 [8.03, 12.01]
13 Clinical global response: 1a. Average clinical global status score (CGI‐S, high=worse) ‐ short term (2 ‐ 12 weeks) Show forest plot	5	160	Mean Difference (IV, Random, 95% CI)	‐0.03 [‐0.35, 0.28]

14 Clinical global response: 1b. Average clinical global status score (various scales, high=worse) ‐ short term (2 ‐ 12 weeks) ‐ skewed results Show forest plot			Other data	No numeric data

14.1 CGI‐I			Other data	No numeric data
14.2 CGI‐S			Other data	No numeric data
15 Leaving the study early: 1a. Short term (2 ‐ 12 weeks) Show forest plot	9		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

15.1 any reason	9	401	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.63, 1.39]
15.2 due to adverse effects	4	178	Risk Ratio (M‐H, Random, 95% CI)	2.08 [0.70, 6.21]
15.3 due to psychiatric symptoms	3	183	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.44, 2.13]
16 Leaving the study early: 1b. Medium term (13 ‐ 26 weeks) Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

16.1 any reason	3	169	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.52, 1.62]
16.2 due to adverse effects	1	33	Risk Ratio (M‐H, Random, 95% CI)	1.47 [0.31, 6.95]
16.3 due to psychiatric symptoms	1	49	Risk Ratio (M‐H, Random, 95% CI)	4.44 [0.22, 88.04]
17 Adverse effects: 1. General ‐ short term (binary, 2 ‐ 12 weeks) Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

17.1 any	3	199	Risk Ratio (M‐H, Random, 95% CI)	3.49 [0.14, 90.29]
17.2 serious	3	271	Risk Ratio (M‐H, Random, 95% CI)	2.95 [0.47, 18.36]
18 Adverse effects: 2a.i. Specific ‐ short term (binary, 2 ‐ 12 weeks) Show forest plot	7		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

18.1 anticholinergic ‐ constipation	2	146	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.24, 2.29]
18.2 anticholinergic ‐ dry mouth	3	176	Risk Ratio (M‐H, Random, 95% CI)	3.46 [1.40, 8.53]
18.3 anticholinergic ‐ impotence	1	30	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.13, 68.26]
18.4 cardiovascular ‐ tachycardia	1	114	Risk Ratio (M‐H, Random, 95% CI)	3.33 [0.97, 11.48]
18.5 central nervious system ‐ anorexia	1	32	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.01, 2.56]
18.6 central nervous system ‐ dizziness	3	176	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.54, 4.31]
18.7 central nervous system ‐ fatigue	2	62	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.12, 8.60]
18.8 central nervous system ‐ headache	1	121	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.52, 2.90]
18.9 central nervous system ‐ insomnia	2	146	Risk Ratio (M‐H, Random, 95% CI)	4.79 [0.85, 26.84]
18.10 central nervous system ‐ sedation	2	58	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.28, 1.94]
18.11 extrapyramidal ‐ acute dystonia	1	30	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.07, 14.55]
18.12 extrapyramidal ‐ akathisia	3	88	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.25, 3.09]
18.13 extrapyramidal ‐ hypersalivation	1	30	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.01, 7.58]
18.14 extrapyramidal ‐ parkinsonism	1	30	Risk Ratio (M‐H, Random, 95% CI)	1.8 [0.79, 4.11]
18.15 extrapyramidal ‐ tremor	1	32	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.24, 4.23]
18.16 extrapyramidal ‐ stiffness	1	32	Risk Ratio (M‐H, Random, 95% CI)	0.2 [0.03, 1.53]
18.17 extrapyramidal ‐ use of antiparkinson medication	3	135	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.44, 1.45]
18.18 gastrointestinal ‐ abdominal pain	1	32	Risk Ratio (M‐H, Random, 95% CI)	1.5 [0.29, 7.81]
18.19 gastrointestinal ‐ nausea	3	176	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.10, 2.41]
18.20 gastrointestinal ‐ vomiting	1	32	Risk Ratio (M‐H, Random, 95% CI)	0.2 [0.01, 3.86]
18.21 gastrointestinal ‐ diarrhoea	1	32	Risk Ratio (M‐H, Random, 95% CI)	0.2 [0.01, 3.86]
18.22 immune system ‐ rash	1	30	Risk Ratio (M‐H, Random, 95% CI)	3.0 [0.13, 68.26]
18.23 immune system ‐ sore throat	1	32	Risk Ratio (M‐H, Random, 95% CI)	0.2 [0.01, 3.86]
18.24 metabolic ‐ weight loss	1	32	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.04, 2.87]
18.25 metabolic ‐ significant weight gain	2	85	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.20, 0.73]
19 Adverse effects: 2a.ii. Specific ‐ extrapyramidal ‐ average change score (continuous, various scales, high=worse) ‐ short term (2 ‐ 12 weeks) Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

19.1 AIMS	1	26	Mean Difference (IV, Random, 95% CI)	0.3 [‐2.34, 2.94]
19.2 BAS	1	59	Mean Difference (IV, Random, 95% CI)	‐0.18 [‐0.65, 0.29]
19.3 SAS	2	85	Mean Difference (IV, Random, 95% CI)	‐0.27 [‐1.79, 1.25]
20 Adverse effects: 2a.iii. Specific ‐ extrapyramidal ‐ average change score (continuous, various scales, high=worse) ‐ short term (2 ‐ 12 weeks) ‐ skewed results Show forest plot			Other data	No numeric data

20.1 AIMS			Other data	No numeric data
20.2 SAS			Other data	No numeric data
21 Adverse effects: 2b.i. Specific ‐ medium term (binary, 13 ‐ 26 weeks) Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

21.1 anticholinergic ‐ constipation	1	107	Risk Ratio (M‐H, Random, 95% CI)	4.58 [1.04, 20.23]
21.2 anticholinergic ‐ dry mouth	1	107	Risk Ratio (M‐H, Random, 95% CI)	1.53 [0.27, 8.78]
21.3 anticholinergic ‐ sweating	1	107	Risk Ratio (M‐H, Random, 95% CI)	13.24 [0.76, 229.32]
21.4 cardiovascular ‐ QT prolongation	1	37	Risk Ratio (M‐H, Random, 95% CI)	3.4 [0.42, 27.59]
21.5 cardiovascular ‐ tachycardia	1	107	Risk Ratio (M‐H, Random, 95% CI)	1.78 [0.55, 5.74]
21.6 central nervous system ‐ dizziness	1	107	Risk Ratio (M‐H, Random, 95% CI)	1.36 [0.32, 5.78]
21.7 central nervous system ‐ insomnia	1	107	Risk Ratio (M‐H, Random, 95% CI)	13.24 [0.76, 229.32]
21.8 extrapyramidal ‐ tremor	1	37	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.20, 0.89]
21.9 gastrointestinal ‐ nausea	1	107	Risk Ratio (M‐H, Random, 95% CI)	5.09 [0.62, 42.16]
22 Adverse effects: 2a.iv. Specific ‐ metabolic ‐ average weight gain (continuous, increase in kg) Show forest plot	4		Mean Difference (IV, Random, 95% CI)	Subtotals only

22.1 short term (2 ‐ 12 weeks)	3	186	Mean Difference (IV, Random, 95% CI)	‐2.17 [‐3.19, ‐1.15]
22.2 medium term (13 ‐ 26 weeks)	2	133	Mean Difference (IV, Random, 95% CI)	‐3.12 [‐10.67, 4.42]
23 Social or general functioning: Average social functioning score (various subscales) ‐ short‐term (2 ‐ 12 weeks) Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

23.1 activity ‐ activities (inverted SLOF, high=worse)	1	15	Mean Difference (IV, Random, 95% CI)	0.0 [‐3.30, 3.30]
23.2 activity ‐ hospital activity (SSPI, high=worse)	1	114	Mean Difference (IV, Random, 95% CI)	‐0.03 [‐0.17, 0.11]
23.3 activity ‐ disease indoor activity (SSPI, high=worse)	1	114	Mean Difference (IV, Random, 95% CI)	‐0.14 [‐0.28, ‐0.00]
23.4 activity ‐ physical functioning (inverted SLOF, high=worse)	1	15	Mean Difference (IV, Random, 95% CI)	‐0.3 [‐1.12, 0.52]
23.5 personal care ‐ personal care skills (inverted SLOF, high=worse)	1	15	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐1.43, 1.03]
23.6 personal care ‐ self‐care (SSPI, high=worse)	1	114	Mean Difference (IV, Random, 95% CI)	‐0.03 [‐0.22, 0.16]
23.7 personal care ‐ social acceptability (inverted SLOF, high=worse)	1	15	Mean Difference (IV, Random, 95% CI)	0.1 [‐0.72, 0.92]
23.8 relationships ‐ family role (SSPI, high=worse)	1	114	Mean Difference (IV, Random, 95% CI)	‐0.09 [‐0.23, 0.05]
23.9 relationships ‐ interest and concern in the external environment (SSPI, high=worse)	1	114	Mean Difference (IV, Random, 95% CI)	‐0.19 [‐0.37, ‐0.01]
23.10 relationships ‐ interpersonal relationships (inverted SLOF, high=worse)	1	15	Mean Difference (IV, Random, 95% CI)	‐1.20 [‐5.41, 3.01]
23.11 relationships ‐ relationships and caring for others (SSPI, high=worse)	1	114	Mean Difference (IV, Random, 95% CI)	‐0.09 [‐0.24, 0.06]
23.12 relationships ‐ sexual role (SSPI, high=worse)	1	114	Mean Difference (IV, Random, 95% CI)	‐0.03 [‐0.21, 0.15]
23.13 relationships ‐ social withdrawal (SSPI, high=worse)	1	114	Mean Difference (IV, Random, 95% CI)	‐0.32 [‐0.49, ‐0.15]
23.14 work ‐ professional skills (SSPI, high=worse)	1	114	Mean Difference (IV, Random, 95% CI)	‐0.19 [‐0.34, ‐0.04]
23.15 work ‐ responsibility and planning (SSPI, high=worse)	1	114	Mean Difference (IV, Random, 95% CI)	‐0.03 [‐0.21, 0.15]
23.16 work ‐ work skills (inverted SLOF, high=worse)	1	15	Mean Difference (IV, Random, 95% CI)	‐3.0 [‐5.48, ‐0.52]

Comparison 1. SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus PLACEBO

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Comparison 2. SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus ACTIVE CONTROL

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mental state: 1a. General: Average general/overall symptoms score (PANSS general, high=worse) ‐ short term (2 ‐ 12 weeks) Show forest plot	1	35	Mean Difference (IV, Random, 95% CI)	2.90 [‐2.85, 8.65]

2 Mental state: 1b. General: Average general/overall symptoms score (various scales, high=worse) ‐ medium term (13 ‐ 26 weeks) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

2.1 PANSS total	1	41	Mean Difference (IV, Random, 95% CI)	1.62 [‐6.89, 10.13]
2.2 PANSS general	1	41	Mean Difference (IV, Random, 95% CI)	0.62 [‐2.00, 5.24]
3 Mental state: 2a. Specific: Average symptoms score (various scales, high=worse) ‐ short term (2 ‐ 12 weeks) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

3.1 mood (HRSD)	1	35	Mean Difference (IV, Fixed, 95% CI)	3.00 [‐1.24, 7.24]
3.2 negative (PANSS negative)	1	35	Mean Difference (IV, Fixed, 95% CI)	1.5 [‐4.34, 7.34]
3.3 positive (PANSS positive)	1	35	Mean Difference (IV, Fixed, 95% CI)	1.7 [‐1.52, 4.92]
4 Mental state: 2b. Specific: Average symptoms score (various scales, high=worse) ‐ medium term (13 ‐ 26 weeks) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

4.1 negative (PANSS negative)	1	41	Mean Difference (IV, Random, 95% CI)	0.26 [‐3.66, 4.18]
4.2 negative (SANS)	1	41	Mean Difference (IV, Random, 95% CI)	‐0.27 [‐12.69, 12.15]
4.3 positive (PANSS positive)	1	41	Mean Difference (IV, Random, 95% CI)	0.74 [‐1.86, 3.34]
5 Mental state: 3a. General and specific: Average score (various scales, high=worse) ‐ skewed results ‐ short term (2 ‐ 12 weeks) Show forest plot			Other data	No numeric data

5.1 general ‐ overall symptoms (PANSS general)			Other data	No numeric data
5.2 specific ‐ mood (HRSD)			Other data	No numeric data
5.3 specific ‐ negative symptoms (PANSS negative)			Other data	No numeric data
5.4 specific ‐ positive symptoms (PANSS positive)			Other data	No numeric data
6 Mental state: 3b. General and specific: Average score (various scales, high=worse) ‐ skewed results ‐ medium term (13 ‐ 26 weeks) Show forest plot			Other data	No numeric data

6.1 general ‐ overall symptoms (PANSS general)			Other data	No numeric data
6.2 general ‐ overall symptoms (PANSS total)			Other data	No numeric data
6.3 specific ‐ negative symptoms (PANSS negative)			Other data	No numeric data
6.4 specific ‐ negative symptoms (SANS)			Other data	No numeric data
6.5 specific ‐ positive symptoms (PANSS positive)			Other data	No numeric data
7 Clinical global response: Average clinical global status score (CGI‐S, high=worse) ‐ short term (2 ‐ 12 weeks) Show forest plot	1	35	Mean Difference (IV, Random, 95% CI)	0.0 [‐0.89, 0.89]

8 Leaving the study early: 1a. Short term (2 ‐ 12 weeks) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

8.1 any reason	1	35	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.17, 2.41]
9 Leaving the study early: 1b. Medium term (13 ‐ 26 weeks) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

9.1 any reason	1	57	Risk Ratio (M‐H, Random, 95% CI)	1.13 [0.48, 2.67]
9.2 due to psychiatric symptoms	1	49	Risk Ratio (M‐H, Random, 95% CI)	1.77 [0.17, 18.26]

Comparison 2. SELECTIVE NORADRENALINE REUPTAKE INHIBITORS versus ACTIVE CONTROL

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