Pharmacopsychiatry 2020; 53(01): 5-13
DOI: 10.1055/a-0914-3260
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Adjunctive Reboxetine for Schizophrenia: Meta-analysis of Randomized Double-blind, Placebo-controlled Trials

Wei Zheng*
1   The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
,
Xian-Bin Li*
2   The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital & the Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China
,
Zhan-Ming Shi*
3   Chongqing Jiangbei Mental Health Center, Chongqing, China
,
Xin-Hu Yang
1   The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
,
Dong-Bin Cai
4   Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, China
,
Chee H. Ng
5   Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia
,
Gabor S. Ungvari
6   The University of Notre Dame Australia, Fremantle, Australia
7   Division of Psychiatry, School of Medicine, University of Western Australia, Perth, Australia
,
Wei-Jian Liu
1   The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
,
Yu-Jie Wu
1   The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
,
Yuan-Yuan Wang
8   Faculty of Health and Life Sciences, De Montfort University, Leicester, United Kingdom
,
Yu-Ping Ning
1   The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou, China
,
Yu-Tao Xiang
9   Unit of Psychiatry, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macao SAR, China
› Author Affiliations
Role of the Funding Source The study was supported by the University of Macau (SRG2014–00019-FHS; MYRG2015–00230-FHS; MYRG2016–00005-FHS), the National Natural Science Foundation of China (81601169), the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX201807, XLMX201807), Capital’s Funds for Health Improvement and Research (2018-2-2123), and the Major Science and Technology Award of the Science and Technology Department of Guangdong Province (2016B010108003).
Further Information

Publication History

received 02 April 2018
revised 25 April 2019

accepted 29 April 2019

Publication Date:
17 June 2019 (online)

Abstract

Background Results of previous studies on the safety and efficacy of adjunctive reboxetine for schizophrenia have been inconsistent.

Aim The aim of this study was to examine the efficacy and tolerability of reboxetine as an adjunct medication to antipsychotic treatment in a meta-analysis of randomized controlled trials (RCTs).

Methods Two independent investigators extracted data for a random effects meta-analysis and assessed the quality of studies using risk of bias and the Jadad scale. Weighted and standardized mean differences (WMDs/SMDs) and risk ratio (RR)±95% confidence intervals (CIs) were calculated.

Results Nine RCTs (n=630) with double-blind design were identified. Reboxetine outperformed placebo in improving negative (9 RCTs, n=602, SMD: −0.47 [95% CI: −0.87, −0.07], p=0.02; I2=82%), but not the overall, positive, and general psychopathology scores. The significant therapeutic effect on negative symptoms disappeared in the sensitivity analysis after removing an outlying study and in 50% (6/12) of the subgroup analyses. Reboxetine outperformed placebo in reducing weight (3 RCTs, n=186, WMD: −3.83 kg, p=0.04; I2=92%) and body mass index (WMD: −2.23 kg/m2, p=0.04; I2=95%). Reboxetine caused dry mouth but was associated with less weight gain overall and weight gain of ≥7% of the initial weight. All-cause discontinuation and other adverse events were similar between reboxetine and placebo.

Conclusion Adjunctive reboxetine could be useful for attenuating antipsychotic-induced weight gain, but it was not effective in treating psychopathology including negative symptoms in schizophrenia.

* These authors contributed equally to the paper.


Supplementary information

 
  • References

  • 1 Tiihonen J, Halonen P, Wahlbeck K. et al. Topiramate add-on in treatment-resistant schizophrenia: A randomized, double-blind, placebo-controlled, crossover trial. J Clin Psychiatry 2005; 66: 1012-1015
  • 2 Kane JM, Correll CU. Past and present progress in the pharmacologic treatment of schizophrenia. J Clin Psychiatry 2010; 71: 1115-1124
  • 3 Carbon M, Correll CU. Clinical predictors of therapeutic response to antipsychotics in schizophrenia. Dialogues Clin Neurosci 2014; 16: 505-524
  • 4 Muscatello MR, Bruno A, De Fazio P. et al. Augmentation strategies in partial responder and/or treatment-resistant schizophrenia patients treated with clozapine. Expert Opin Pharmacother 2014; 15: 2329-2345
  • 5 Wolff-Menzler C, Hasan A, Malchow B. et al. Combination therapy in the treatment of schizophrenia. Pharmacopsychiatry 2010; 43: 122-129
  • 6 Nelson JC. Combined treatment strategies in psychiatry. J Clin Psychiatry 1993; 54 Suppl 42-49
  • 7 Veerman SRT, Schulte PFJ, de Haan L. Treatment for negative symptoms in schizophrenia: A comprehensive review. Drugs 2017; 77: 1423-1459
  • 8 Hartmann-Riemer MN, Hager OM, Kirschner M. et al. The association of neurocognitive impairment with diminished expression and apathy in schizophrenia. Schizophr Res 2015; 169: 427-432
  • 9 Cohen AS, Saperstein AM, Gold JM. et al. Neuropsychology of the deficit syndrome: New data and meta-analysis of findings to date. Schizophr Bull 2007; 33: 1201-1212
  • 10 Singh SP, Singh V, Kar N. et al. Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: Meta-analysis. Br J Psychiatry 2010; 197: 174-179
  • 11 Correll CU, Sikich L, Reeves G. et al. Metformin for antipsychotic-related weight gain and metabolic abnormalities: When, for whom, and for how long?. Am J Psychiatry 2013; 170: 947-952
  • 12 Maayan L, Vakhrusheva J, Correll CU. Effectiveness of medications used to attenuate antipsychotic-related weight gain and metabolic abnormalities: A systematic review and meta-analysis. Neuropsychopharmacology 2010; 35: 1520-1530
  • 13 Zheng W, Li XB, Tang YL. et al. Metformin for weight gain and metabolic abnormalities associated with antipsychotic treatment: meta-analysis of randomized placebo-controlled trials. J Clin Psychopharmacol 2015; 35: 499-509
  • 14 Wu RR, Zhang FY, Gao KM. et al. Metformin treatment of antipsychotic-induced dyslipidemia: An analysis of two randomized, placebo-controlled trials. Mol Psychiatry 2016; 21: 1537-1544
  • 15 Liu Z, Zheng W, Gao S. et al. Metformin for treatment of clozapine-induced weight gain in adult patients with schizophrenia: A meta-analysis. Shanghai Arch Psychiatry 2015; 27: 331-340
  • 16 Wu RR, Zhao JP, Jin H. et al. Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: A randomized controlled trial. JAMA 2008; 299: 185-193
  • 17 Mizuno Y, Suzuki T, Nakagawa A. et al. Pharmacological strategies to counteract antipsychotic-induced weight gain and metabolic adverse effects in schizophrenia: A systematic review and meta-analysis. Schizophr Bull 2014; 40: 1385-1403
  • 18 Poyurovsky M, Isaacs I, Fuchs C. et al. Attenuation of olanzapine-induced weight gain with reboxetine in patients with schizophrenia: A double-blind, placebo-controlled study. Am J Psychiatry 2003; 160: 297-302
  • 19 Czobor P, Volavka J, Sheitman B. et al. Antipsychotic-induced weight gain and therapeutic response: A differential association. J Clin Psychopharmacol 2002; 22: 244-251
  • 20 Correll CU, Ng-Mak DS, Stafkey-Mailey D. et al. Cardiometabolic comorbidities, readmission, and costs in schizophrenia and bipolar disorder: A real-world analysis. Ann Gen Psychiatry 2017; 16: 9
  • 21 Correll CU, Solmi M, Veronese N. et al. Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: A large-scale meta-analysis of 3 211 768 patients and 113,383,368 controls. World Psychiatry 2017; 16: 163-180
  • 22 Poyurovsky M, Fuchs C, Pashinian A. et al. Attenuating effect of reboxetine on appetite and weight gain in olanzapine-treated schizophrenia patients: A double-blind placebo-controlled study. Psychopharmacology (Berl) 2007; 192: 441-448
  • 23 Eyding D, Lelgemann M, Grouven U. et al. Reboxetine for acute treatment of major depression: Systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials. BMJ (Clinical research ed) 2010; 341: c4737
  • 24 Cipriani A, Furukawa TA, Salanti G. et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: A systematic review and network meta-analysis. Lancet 2018; 391: 1357-1366
  • 25 Li XP, Wang ZM, Zhao SX. et al. Effect of reboxetine combined with clozapine on negative symptoms quality of life of the patients with schizophrenia. China Journal of Health Psychology 2008; 16: 133-135
  • 26 Sun J, Liu Y, Wang HX. et al. Effect of Reboxetine combined with Haloperidol in the treatment of first-episode schizophrenia on cognition function. China Practical Medical 2011; 06: 4-6
  • 27 Zhao SX, Li ZS, Gen HS. et al. Double-blind, placebo-controlled study of adjunctive reboxetine for metabolic syndrome induced by clozapine in patients with schizophrenia. Hebei Medical Journal 2013; v 35: 3226-3228
  • 28 Shafti SS, Jafarabad MS, Azizi R. Tackling negative symptoms in male patients with schizophrenia using a norepinephrine reuptake inhibitor. Available at
  • 29 Usall J, Lopez-Carrilero R, Iniesta R. et al. Double-blind, placebo-controlled study of the efficacy of reboxetine and citalopram as adjuncts to atypical antipsychotics for negative symptoms of schizophrenia. J Clin Psychiatry 2014; 75: 608-615
  • 30 Hinkelmann K, Yassouridis A, Kellner M. et al. No effects of antidepressants on negative symptoms in schizophrenia. J Clin Psychopharmacol 2013; 33: 686-690
  • 31 Matthews PRL, Horder J, Pearce M. Selective noradrenaline reuptake inhibitors for schizophrenia. Cochrane Database Syst Rev 2018; 1: CD010219
  • 32 Helfer B, Samara MT, Huhn M. et al. Efficacy and safety of antidepressants added to antipsychotics for schizophrenia: A systematic review and meta-analysis. Am J Psychiatry 2016; 173: 876-886
  • 33 Kishi T, Mukai T, Matsuda Y. et al. Efficacy and safety of noradrenalin reuptake inhibitor augmentation therapy for schizophrenia: A meta-analysis of double-blind randomized placebo-controlled trials. J Psychiatr Res 2013; 47: 1557-1563
  • 34 Choi YJ. Efficacy of adjunctive treatments added to olanzapine or clozapine for weight control in patients with schizophrenia: A systematic review and meta-analysis. Scientific World Journal 2015; 2015: 970730
  • 35 Yu JN, Chai M. [Treatment of negative symptoms of schizophrenia: A controlled study]. Jilin Medical Journal. 2012; 33: 4988-4989
  • 36 Leucht S, Komossa K, Rummel-Kluge C. et al. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry 2009; 166: 152-163
  • 37 Amrami-Weizman A, Maayan R, Gil-Ad I. et al. The effect of reboxetine co-administration with olanzapine on metabolic and endocrine profile in schizophrenia patients. Psychopharmacology 2013; 230: 23-27
  • 38 Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261-276
  • 39 Overall JE, Gorham DR. The Brief Psychiatric Rating-Scale. Psychol Rep 1962; 10: 799-812
  • 40 Andreasen NC. Scale for the Assessment of Negative Symptoms (SANS). IA: University of Iowa; Iowa City: 1983
  • 41 Andreasen NC. Scale for the Assessment of Positive Symptoms (SAPS). IA: University of Iowa; Iowa City: 1984
  • 42 Moher D, Liberati A, Tetzlaff J. et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Ann Intern Med 2009; 151: 264-269
  • 43 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177-188
  • 44 Egger M, Davey Smith G, Schneider M. et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629-634
  • 45 Higgins J, Higgins J. Cochrane Handbook for Systematic Reviews of Interventions. Hoboken: John Wiley & Sons; 2008
  • 46 Balshem H, Helfand M, Schunemann HJ. et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011; 64: 401-406
  • 47 Atkins D, Best D, Briss PA. et al. Grading quality of evidence and strength of recommendations. BMJ 2004; 328: 1490
  • 48 Zheng W, Cai DB, Zhang QE. et al. Adjunctive ondansetron for schizophrenia: A systematic review and meta-analysis of randomized controlled trials. J Psychiatr Res 2019; 113: 27-33
  • 49 Jadad AR, Moore RA, Carroll D. et al. Assessing the quality of reports of randomized clinical trials: Is blinding necessary?. Control Clin Trials 1996; 17: 1-12
  • 50 Linde K, Clausius N, Ramirez G. et al. Are the clinical effects of homeopathy placebo effects? A meta-analysis of placebo-controlled trials. Lancet 1997; 350: 834-843
  • 51 Schutz G, Berk M. Reboxetine add on therapy to haloperidol in the treatment of schizophrenia: A preliminary double-blind randomized placebo-controlled study. Int Clin Psychopharmacol 2001; 16: 275-278
  • 52 Sterne JA, Sutton AJ, Ioannidis JP. et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ (Clinical research ed.) 2011; : 343-d4002
  • 53 Mayer AF, Schroeder C, Heusser K. et al. Influences of norepinephrine transporter function on the distribution of sympathetic activity in humans. Hypertension 2006; 48: 120-126
  • 54 Poyurovsky M, Fuchs C, Pashinian A. et al. Reducing antipsychotic-induced weight gain in schizophrenia: A double-blind placebo-controlled study of reboxetine-betahistine combination. Psychopharmacology (Berl) 2013; 226: 615-622
  • 55 Ascher-Svanum H, Stensland M, Zhao Z. et al. Acute weight gain, gender, and therapeutic response to antipsychotics in the treatment of patients with schizophrenia. BMC Psychiatry 2005; 5: 3