Noradrenaline reuptake inhibitors and schizophrenia


Schizophrenia is a chronic illness characterised by a range of symptoms including positive and negative symptoms. Examples of positive symptoms include hallucinations, delusions, and bizarre and inappropriate behaviour.

Negative symptoms include affective flattening, lack of speech, lack of motivation and inability to feel pleasure with any activity. In addition to these symptoms, patients also experience significant cognitive deficits and attention disorders. All these symptoms have a great impact on the person’s quality of life.2,3

Positive symptoms respond well to antipsychotics. However, the negative symptoms are usually hard to treat. Selective noradrenaline reuptake inhibitors (NRIs) such as atomoxetine and reboxetine are associated with improvement of the negative symptoms. Atomoxetine is used to treat attention deficit hyperactivity disorder (ADHD) symptoms and reboxetine is indicated to treat major depressive disorders. The most common side effects of both of these medications include loss of appetite, nausea, agitation, insomnia, dizziness, constipation, fatigue, dry mouth, sedation, sweating and palpitations. Reboxetine is associated with postural hypotension and atomoxetine with hypertension.4,5

NRIs increase prefrontal dopamine without significantly affecting subcortical dopamine levels, which makes them less likely to be abused and more suitable for managing the negative symptoms of schizophrenia. It is believed that positive symptoms are associated with excess subcortical dopamine, while deficits in the prefrontal dopamine contribute to negative symptoms.6 The aim of this review is to scope the literature on the effectiveness of NRIs for the management of negative symptoms of schizophrenia.

Characteristics of studies

Randomised controlled trials (RCTs) comparing NRIs with either a control treatment or placebo for people with schizophrenia or related disorders such as schizoaffective disorder. Participants were over the age of 18 years and were diagnosed by any means.

Quality of the research

Studies included in the report had a low or unclear risk of bias. Overall, the quality of the evidence ranged from low to very low depending on the measures reported in the studies. The main sources of bias were selective reporting and incomplete outcome of data.


  • The following databases were searched: the Cochrane Schizophrenia Group’s Trials Register, MEDLINE, Embase, CINAHL, BIOSIS, AMED, PubMed, PsycINFO and registries of clinical trials. All references of included studies were checked for potential relevant studies.
  • The primary outcome measures were mental state, cognitive functioning, quality of life and clinical global response.
  • The secondary outcome measures were service utilisation, leaving the study early, satisfaction with the treatment, social or general functioning and economic outcomes.
  • A total of 16 studies with a total of 919 participants were included. The majority of the studies included inpatients with schizophrenia or similar illness with a chronic presentation.
  • Reboxetine was included in nine out of the 16 trials included. The remaining trials included atomoxetine and viloxazine. A total of 14 trials compared NRIs with placebo. Only two trials provided data to compare NRIs against an active control.
  • Mental state results showed significant increased 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. There was no effect on the positive symptoms.
  • The 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).
  • There was no significant response or improvement in cognitive functioning data.
  • There was no difference in the average composite cognitive scores between NRIs and placebo (4 RCTs, n = 180; SMD 0.04, 95% CI −0.28 to 0.36; low-quality evidence).
  • There was no significant response or improvement in quality of life data reported; however, scores from the GQOLI-74 were reported. Those receiving NRIs had higher 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 were not different between the treatment groups (8 RCTs, n = 401, RR 0.94 95% CI 0.63 to 1.39; moderate-quality evidence).
  • The incidence of adverse events such as nausea was not greater with NRIs (3 RCTs, n = 176; RR 0.49, 95% CI 0.10 to 2.41; low-quality evidence). However, weight loss was observed with reboxetine.
  • There were no results reported on the other secondary outcome measures.


There is evidence to support the benefit of NRIs on the negative symptoms of schizophrenia. NRIs had no effect on the positive symptoms and were shown to be well tolerated. Quality of life scores were also better on the intervention medications. These results are based on a small number of studies with low quality data.

Implications for practice

NRIs could be used for the management of negative symptoms of schizophrenia; however, larger studies are needed to confirm their beneficial effect on cognitive impairment.

DR HANAN KHALIL is the Director of the Centre for Chronic Disease Management, a collaborating centre of the Joanna Briggs Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, and a reviewer for the consumer group of the Cochrane Collaboration. She is also Editor in Chief of the International Journal of Evidenced Based HealthCare.

The purpose of this evidence summary is to present the best available evidence regarding the effectiveness of Noradrenaline reuptake inhibitors (NRIs) for the treatment of negative symptoms of schizophrenia. For the full review, please refer to Matthews PRL, Horder J, Pearce M. Selective noradrenaline reuptake inhibitors for schizophrenia. Cochrane Database of Systematic Reviews 2018, Issue 1. Art. No.: CD010219. DOI: 10.1002/14651858.CD010219. pub2.1


  1. Matthews PRL, Horder J, Pearce M. Selective noradrenaline reuptake inhibitors for schizophrenia. Cochrane Database of Systematic Reviews 2018, Issue 1. Art. No.: CD010219. DOI: 10.1002/14651858.CD010219.pub2
  2. Barnes TR, Schizophrenia Consensus Group of British Association for Psychopharmacology. Evidence based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. Journal of Psychopharmacology 2011;25(5):567–620.
  3. Makinen J, Miettunen J, Isohanni M, Koponen H. Negative symptoms in schizophrenia: a review. Nordic Journal of Psychiatry 2008;62(5):334–41.
  4. Chamberlain SR, Del Campo N, Dowson J, et al. Atomoxetine improved response inhibition in adults with attention deficit/ hyperactivity disorder. Biological Psychiatry 2007;62(9):977–84.
  5. Li X, Wang Z, Zhao S. Effect of reboxetine combined with clozapine on negative symptoms and quality of life of the patients with schizophrenia. Chinese Journal of Health Psychology 2008;16(2):133–5.
  6. Kishi T, Mukai T, Matsuda Y, Moriwaki M, Iwata N. Efficacy and safety of noradrenalin reuptake inhibitor augmentation therapy for schizophrenia: a meta-analysis of double-blind randomized placebo-controlled trials. Journal of Psychiatric Research 2013;47(11):1557–63.