Paul R L Matthews, Jamie Horder, Michael Pearce

Schizophrenia is frequently a chronic and disabling illness with a heterogeneous range of symptoms. The positive symptoms usually respond to antipsychotics but the cognitive and negative symptoms of schizophrenia are difficult to treat with conventional antipsychotics and significantly impact on quality of life and social outcomes. Selective noradrenaline reuptake inhibitors (NRIs) increase prefrontal dopamine and noradrenaline levels without significantly affecting subcortical dopamine levels, making them an attractive candidate for treating cognitive and negative symptoms. To investigate the effects of selective noradrenaline reuptake inhibitors (NRIs), compared with a placebo or control treatment, for people with schizophrenia. We searched the Cochrane Schizophrenia Group's Trials Register (up to 7 February 2017) which is based on regular searches of MEDLINE, Embase, CINAHL, BIOSIS, AMED, PubMed, PsycINFO, and registries of clinical trials. There are no language, date, document type, or publication status limitation for inclusion of records into the register. We inspected references of all included studies for further relevant studies. We included randomised controlled trials (RCTs) comparing NRIs with either a control treatment or placebo for people with schizophrenia or related disorders (such as schizoaffective disorder) by any means of diagnosis. We included trials that met our selection criteria and provided useable information. We independently inspected all citations from searches, identified relevant abstracts, and independently extracted data from all included studies. For binary data we calculated risk ratio (RR), for continuous data we calculated mean difference (MD), and for cognitive outcomes we derived standardised mean difference (SMD) effect sizes, all with 95% confidence intervals (CI) and using a random-effects model. We assessed risk of bias for the included studies and used the GRADE approach to produce a 'Summary of findings' table which included our prespecified main outcomes of interest. Searching identified 113 records. We obtained the full text of 48 of these records for closer inspection. Sixteen trials, randomising a total of 919 participants are included. The majority of trials included adults with schizophrenia or similar illness who were inpatients, and while they were poorly characterised, most appeared to include patients with a chronic presentation. The intervention NRI in nine of the 16 trials was reboxetine, with atomoxetine and viloxazine used in the remaining trials. 14 trials compared NRIs with placebo. Only two trials provided data to compare NRIs against an active control and both compared reboxetine to citalopram but at 4 weeks and 24 weeks respectively so they could not be combined in a meta-analysis.One trial was described as 'open' and we considered it to be at high risk of bias for randomisation and blinding, three trials were at high risk of bias for attrition, six for reporting, and two for other sources of bias. Our main outcomes of interest were significant response or improvement in positive/negative mental state, global state and cognitive functioning, average cognitive functioning scores, significant response or improvement in quality of life and incidence of nausea. All data for main outcomes were short term.NRIs versus placeboMental state results showed significantly greater rates of improvement in negative symptoms scores (1 RCT, n = 50; RR 3.17, 95% CI 1.52 to 6.58; very low quality evidence) with NRIs on the PANSS negative. No data were reported for significant response or improvement in positive symptoms, but average endpoint PANSS positive scores were available and showed no difference between NRIs and placebo (5 RCTs, n = 294; MD -0.16, 95% CI -0.96 to 0.63; low-quality evidence). Improvement in clinical global status was similar between groups (1 RCT, n = 28; RR 0.99, 95% CI 0.45 to 2.20; very low quality evidence). Significant response or improvement in cognitive functioning data were not reported. Average composite cognitive scores showed no difference between NRIs and placebo (4 RCTs, n = 180; SMD 0.04, 95% CI -0.28 to 0.36; low-quality evidence). Significant response or improvement in quality of life data were not reported, however average endpoint scores from the GQOLI-74 were reported. Those receiving NRIs had better quality of life scores compared to placebo (1 RCT, n = 114; MD 9.36, 95% CI 7.89 to 10.83; very low quality evidence). All-cause withdrawals did not differ between the treatment groups (8 RCTs, n = 401, RR 0.94 95% CI 0.63 to 1.39; moderate-quality evidence). Rates of nausea were not greater with NRIs (3 RCTs, n = 176; RR 0.49, 95% CI 0.10 to 2.41; low-quality evidence). Our results provide tentative very low quality evidence that compared to placebo, NRIs (specifically reboxetine) may have a benefit on the negative symptoms of schizophrenia. Limited evidence also suggests that NRIs have no effect on the positive symptoms of schizophrenia or cognitive functioning. NRIs appear generally well tolerated with no real differences in adverse effects such as nausea noted between NRIs and placebo. However, these results are based on short-term follow-up and are poor quality - there is need for more good-quality evidence. A large RCT of reboxetine over a longer period of time, focusing specifically on negative and cognitive symptoms as well as more detailed and comprehensive reporting of outcomes, including adverse events, is required.