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. 2018 Oct 19;2018(10):CD007852. doi: 10.1002/14651858.CD007852.pub2

Reboxetine versus other antidepressive agents for depression

Rachel Churchill 1,✉, Deborah M Caldwell 2, Hugh McGuire 3, Corrado Barbui 4, Andrea Cipriani 5, Toshi A Furukawa 6, Norio Watanabe 6, Glyn Lewis 7
PMCID: PMC6517264

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

1) To determine the efficacy of reboxetine in comparison with other antidepressive agents in alleviating the acute symptoms of depression. 2) To investigate acceptability of treatment with reboxetine in comparison with other antidepressive agents. 3) To investigate the adverse effects of reboxetine in comparison with other antidepressive agents.

Background

Description of the condition

Compared with other medical diagnoses, depression is very common. Lifetime prevalence estimates for major depression in the community range from 15 to 17% (APA 1994), 12‐month prevalence from 6 to 7% (Kessler 2003). The prevalence of major depression in the medical outpatient is 5 to 13% (Coyne 1994). Major depression is the third leading cause of burden among all diseases of the humankind after lower respiratory infections and HIV/AIDS in the year 2002, accounting for 4.5% of the total human suffering. Moreover, it is expected to show a rising trend during the next 20 years (WHO 2006). This condition is associated with a marked personal, social and economic morbidity, loss of functioning and productivity, and creates significant demands on service providers in terms of workload (NICE 2004). In the USA, the economic burden of depression has been estimated just over $83 billion in 2000, of which $26 were direct treatment costs, $5 billion were suicide‐related costs, and $52 billion were workplace costs (Greenberg 2003). They also suspect that these figures are still underestimates of the true economic burden of the disease, such as burden on family members and caregivers, cost of lost productivity while at work, and cost associated with those who remain untreated (Greenberg 2005).

Description of the intervention

Although pharmacological and psychological interventions are both effective for major depression, in primary and secondary care settings antidepressant (AD) drugs remain the mainstay of treatment (APA 2000; Ellis 2004; NICE 2004). Amongst ADs many different agents are available, including tricyclics (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin‐noradrenaline reuptake inhibitors (SNRIs: venlafaxine, duloxetine, milnacipran), and other newer agents (mirtazapine, mirtazapine, bupropion).

In many Wwestern countries, during the last 20 years, ADs consumption has dramatically risen, mainly because of the increasing consumption of SSRIs and newer ADs, which have progressively become the most commonly prescribed ADs (Ciuna 2004; Guaiana 2005). SSRIs are generally better tolerated than TCAs (Barbui 2000), and there is evidence of similar efficacy (Anderson 2000; Geddes 2000; Williams 2000). However, head‐to‐head comparison provided contrasting findings. Amitriptyline, for example, may have the edge over SSRIs in terms of efficacy (Guaiana 2003), and individual SSRIs and SNRIs may differ in terms of efficacy and tolerability (Cipriani 2005; Smith 2002).

How the intervention might work

Given that the most recent available evidence refers to the SSRIs as an homogeneous group (Arroll 2005; Geddes 2000; Hansen 2005), it is still unclear how each of SSRIs or newer agents compares with other ADs in terms of effects and side‐effects. A group of researchers therefore agreed to join forces under the rubric of the Multiple meta‐Analyses of New Generation Antidepressants (MANGA) Study to systematically review all available evidence for each specific newer antidepressant. We have up to now completed an individual review for fluoxetine (Cipriani 2005) and have published protocols for sertraline, milnacipran and fluvoxamine.

Reboxetine was the first a selective noradrenaline re‐uptake inhibitor (Dencker 2000). Its recommend dosage in the UK is 4 mg twice daily increased if necessary after 3‐4 weeks to 10 mg daily in divided doses with a maximum of 12 mg daily (BNF 2006). It is not recommended for used in children under 18 years and the elderly (BNF 2006). In placebo‐controlled studies its most frequent side ‐effects are dry mouth (27% versus 16%), constipation (17% versus 8%), increased sweating (14% versus 7%) and insomnia (14% versus 5%) (Tanum 2000). It has been licensed worldwide in over 50 countries, including Italy, Germany and the United Kingdom,.however in 2001, the US Food and Drug Administration declined Pharmacia's license application for the American market although no reason was provided.

Why it is important to do this review

Only limited evidence has been established regarding the efficacy and tolerability of reboxetine in comparison with other antidepressants, to date. Unsystematic reviews of both published and unpublished data showed that reboxetine was as effective as the SSRI fluoxetine and the TCAs imipramine and desipramine (Stahl 2002; Versiani 2000). Therefore, there is a good reason to conduct a comprehensive systematic quantitative review using currently best‐available evidence on comparative efficacy and adverse effects of reboxetine against other antidepressants.

Objectives

1) To determine the efficacy of reboxetine in comparison with other antidepressive agents in alleviating the acute symptoms of depression. 2) To investigate acceptability of treatment with reboxetine in comparison with other antidepressive agents. 3) To investigate the adverse effects of reboxetine in comparison with other antidepressive agents.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials using a parallel group design will be included. Quasi‐randomised trials, such as those allocating by using alternate days of the week, will be excluded. For trials which have a crossover design only results from the first randomisation period will be considered.

Types of participants

Patients aged 18 years or older, of both sexes, with a primary diagnosis of depression.

Studies adopting any standardised criteria to define patients suffering from unipolar major depression will be included. Most recent studies are likely to have used DSM‐IV (APA 1994) or ICD‐10 (WHO 1992) criteria. Older studies may have used ICD‐9 (WHO 1978), DSM‐II (APA 1980)I / DSM‐ III‐R (APA 1987) or other diagnostic systems. ICD‐9 does not comprise a set of operationalised criteria, because it has only names diseases and does not specify diagnostic criteria, so studies using ICD‐9 will be excluded. On the other hand, studies using Feighner criteria (Feighner 1972) or Research Diagnostic Criteria (Spitzer 1977) will be included. We will include the following subtypes: 'Chronic, with catatonic features, with melancholic features, with atypical features, with postpartum onset, with seasonal pattern, but we will exclude 'with psychotic features.'

Studies in which less than 20% of the participants may be suffering from bipolar depression will be included, but the validity of this decision will be examined in a sensitivity analysis.

A concurrent secondary diagnosis of another psychiatric disorder will not be considered as an exclusion criterion. However, a concurrent primary diagnosis of Axis I or II disorders will be an exclusion criterion. AD trials for depressive patients with a serious concomitant medical illness will also be excluded.

Types of interventions

Experimental intervention Reboxetine (as monotherapy). No restrictions on dose, frequency, intensity and duration will be applied.

Comparator interventions All other antidepressive agents in the treatment of acute depression, including:

1) conventional tricyclic ADs (TCAs) 2) heterocyclic antidepressants (e.g. maprotiline) 3) SSRIs (fluoxetine, fluvoxamine, citalopram, paroxetine, sertraline) 4) newer antidepressants (SNRIs such as venlafaxine, duloxetine, milnacipran; MAOIs or newer agents such as mirtazapine, bupropion, reboxetine; and non‐conventional ADs, such as herbal products ‐ e.g. hypericum).

No restrictions on dose, frequency, intensity and duration will be applied.

Other types of psychopharmacological agent such as anxiolytics, anticonvulsants, antipsychotics or mood‐stabilizers were excluded. Trials in which escitalopram was used as an augmentation strategy were also excluded

Trials in which reboxetine is compared to another type of psychopharmacological agent ie anxiolytics, antic‐convulsants, anti‐psychotics or mood‐stabilizers will be excluded. Trials in which reboxetine is used as an augmentation strategy will also be excluded.

Types of outcome measures

Primary outcomes

1) Number of patients who responded to treatment showing a reduction of at least 50% on the Hamilton Rating Scale of Depression (HAM‐D) (Hamilton 1960) or the Montgomery‐Asberg Depression RAting Scale (MADRS) (Montgomery 1979), or any other depression scale, depending on the study authors' definition) or "much or very much improved" (score 1 or 2) on CGI‐Improvement (Guy 1970) out of the total number of randomised patients. Where both are provided, we prefer the former criteria for judging response.

When studies report response rates at various time points of the trial, we have decided a priori to subdivide the treatment indices as follows. 1) early response rates: between 1 and 4 weeks, the time point closest to 2 weeks will be given preference. 2) acute phase treatment response rates: between 6 and 12 weeks, the time point given in the original study as the study endpoint is given preference. 3) follow‐up response rates: between 4 and 6 months, the time point closest to 24 weeks will be given preference. The acute phase treatment response rates, i.e. between 6 and 12 weeks, will be our primary outcome of interest.

Secondary outcomes

1) Number of patients who achieved remission, showing =<7 on 17‐item HAM‐D or showing <=10 (Zimmerman 2004) (or any other similar value on depression scale, depending on the study authors' definition. The cutoff point is set a priori at 7 for the 17‐item HAM‐D and at 8 for all the other longer versions of HAM‐D) or "not ill or borderline mentally ill" (score 1 or 2) on CGI‐Severity out of the total number of randomised patients. Where both are provided, we prefer the former criteria for judging remission.

2) Group mean scores at the end of the trial on Hamilton Depression Scale (HAM‐D) (Hamilton 1960), or Montgomery‐Asberg Depression Scale (MADRS) (Hamilton 1960), or any other depression scale.

3) Social adjustment, social functioning including the Global Assessment of Function (GAF) (Luborsky 1962) scores

4) Health‐related quality of life : We will limit ourselves to SF‐12 or SF‐36 (Ware 1993), HoNOS (Wing 1994) and WHO‐QOL (WHOQOL Group 1998).

5) Costs to health care services

6) Acceptability will be evaluated using the following outcome measures: a) Number of patients who dropped out during the trial as a proportion of the total number of randomised patients ‐ Total drop out rate b) Number of patients who dropped out during the trial as a proportion of the total number of randomised patients ‐ Due to inefficacy c) Number of patients who dropped out during the trial as a proportion of the total number of randomised patients ‐ Due to side effects

7) Tolerability will be evaluated using the following outcome measures: 1. Total number of patients experiencing at least some side effects 2. Total number of patients experiencing the following specific side effects will be sought for: a) sleepiness/drowsiness b) insomnia c) dry mouth d) constipation e) urination problem f) hypotention g) agitation/anxiety h) suicide wishes/gestures/attempts i) completed suicide j) vomiting/nausea k) diarrhoea

In order not to miss any relatively rare or unexpected yet important side effects, in the data extraction phase, we will collect all side effects data reported in the literature and will discuss ways to summarise them post hoc.

Search methods for identification of studies

Electronic searches

CCDANCTR‐Studies will be searched using the following search strategy: Diagnosis = Depress* or Dysthymi* or "Adjustment Disorder*" or "Mood Disorder*" or "Affective Disorder" or "Affective Symptoms" and Intervention = Reboxetine

CCDANCTR‐References will be searched using the following search strategy: Keyword = Depress* or Dysthymi* or "Adjustment Disorder*" or "Mood Disorder*" or "Affective Disorder" or "Affective Symptoms" and Free‐Text = Reboxetine

Searching other resources

1) Handsearches Trial databases of the following drug‐approving agencies ‐ (the Food and Drug Administration (FDA) in the USA, the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK, the European Medicines Agency (EMEA) in the EU, the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, the Therapeutic Goods Administration (TGA)) in Australia) and ongoing trial registers (clinicaltrials.gov in the USA, ISRCTN and National Research Register in the UK, Nederlands Trial Register in the Netherlands, EUDRACT in the EU, UMIN‐CTR in Japan and the Australian Clinical Trials Registry in Australia) will be hand‐searched for published, unpublished and ongoing controlled trials. Appropriate journals and conference proceedings relating to reboxetine treatment for depression have already been hand‐searched and incorporated into the CCDANCTR databases.

2) Personal communication Pharmaceutical companies and experts in this field will be asked if they know of any study which meets the inclusion criteria of this review.

3) Reference checking Reference lists of the included studies, previous systematic reviews and major textbooks of affective disorder written in English will be checked for published reports and citations of unpublished research. The reference of all included studies will be checked via Science Citation Index) for articles which have cited the included study.

Data collection and analysis

Selection of studies

Studies relating to reboxetine generated by the electronic search of CCDANCTR‐Studies will be scanned by one review author (HMG). Those studies which meet the following rough inclusion criteria will constitute the preliminary list and their full texts will be retrieved. The rough inclusion criteria are: 1) randomised trial 2) comparing reboxetine against any other antidepressant 3) in patients with depression, regardless of the diagnostic criteria used.

Studies relating to reboxetine generated by the search strategies of CCDANCTR‐References and the other complementary searches will be checked by HMG and another independent reviewer to see if they meet the rough inclusion criteria, firstly based on the title and abstracts. All the studies rated as possible candidates by either of the two reviewers will be added to the preliminary list and their full texts will be retrieved. All the full text articles in this preliminary list will then be assessed by two independent reviewers to see if they meet the strict inclusion criteria. If the raters disagree the final rating will be made by consensus with the involvement (if necessary) of another member of the review group. Non‐congruence in selection of trials will be reported as percentage disagreement. Considerable care will be taken to exclude duplicate publications.

Data extraction and management

One reviewer will first extract data concerning participant characteristics (age, sex, depression diagnosis, comorbidity, depression severity, antidepressant treatment history for the index episode, study setting), intervention details (intended dosage range, mean daily dosage actually prescribed, co‐intervention if any, reboxetine as investigational drug or as comparator drug, sponsorship) and outcome measures of interest from the included studies. The results will be compared with those in the completed reviews of individual antidepressants in the Cochrane Library. If there are any discrepancies, a second reviewer will intervene and the agreed‐upon results will be used in the review as well as fed back to the authors of the completed reviews.

Assessment of risk of bias in included studies

The Cochrane risk‐of‐bias tool as recommended in RevMan 5.0.0 will be used. This instrument consists of six items. Two of the items assess the strength of the randomisation process in preventing selection bias in the assignment of participants to interventions: adequacy of sequence generation and allocation concealment. The third item (blinding) assesses the influence of performance bias on the study results. The fourth item assesses the likelihood of incomplete outcome data, which raise the possibility of bias in effect estimates. The fifth item assesses selective reporting, the tendency to preferentially report statistically significant outcomes. It requires a comparison of published data with trial protocols, when such are available. The final item refers to other sources of bias that are relevant in certain circumstances, for example, in relation to trial design (methodologic issues such as those related to crossover designs and early trial termination) or setting.

Two review authors (RC, DC) will assess risk of bias in each trial independently, in accordance with the Cochrane Handbook (Higgins 2008). Where inadequate details of allocation concealment and other characteristics of trials are provided, the trial authors will be contacted in order to obtain further information. If the raters disagree, the final rating will be made by consensus with the involvement (if necessary) of another member of the review group. The ratings will also be compared with those in the completed reviews of individual antidepressants in the Cochrane Library. If there are any discrepancies, they will be fed back to the authors of the completed reviews.

Measures of treatment effect

For dichotomous or event‐like data, odds ratios (OR) will be calculated with 95% confidence intervals. Continuous data will be analyzed using weighted mean differences (with 95% confidence intervals) or standardized mean differences (where different measurement scales are used).

Unit of analysis issues

For trials with a crossover design, only results from the first randomisation period will be considered. If the trial is a three (or more)‐armed trial involving a placebo arm, the data will be extracted from the placebo arm as well.

Dealing with missing data

Dichotomous outcomes Responders and remitters to treatment will be calculated on an intention‐to‐treat (ITT) basis: drop‐outs will always be included in this analysis. Where participants have withdrawn from the trial before the endpoint, it will be assumed they would have experienced the negative outcome by the end of the trial (e.g. failure to respond to treatment). The validity of this decision will be examined in sensitivity analyses by applying worst and best case scenarios (Cf Funnel plot analyses and Sensitivity analyses). When dichotomous outcomes are not reported but baseline mean and endpoint mean and standard deviation (SD) of the HAM‐D (or any other depression scale) are provided, we will calculate the number of responding and remitted patients according to a validated imputation method (Furukawa 2005). We will examine the validity of this imputation in the sensitivity analyses.

Continuous outcomes We will apply a loose ITT analysis, whereby all the patients with at least one post‐baseline measurement are represented by their last observations carried forward with due consideration of the potential bias and uncertainty introduced.

Where standard deviations are not recorded, authors will be asked to supply the data. When only the SE or t‐statistics or p values are reported, the SDs will be calculated according to Altman (Altman 1996). In the absence of data from trial authors the mean standard deviation from other studies will be used (Furukawa 2006).

Assessment of heterogeneity

The I2 statistic will be used to assess heterogeneity between studies, using a range of 50% to 90% as a guideline for indicating substantial heterogeneity. However, in using this guideline we will take into account the direction and magnitude of treatment effects and also the strength of evidence against the null hypothesis of homogeneity using the P‐value from the χ2 test.

Assessment of reporting biases

Funnel plot analysis will be performed to check for existence of small study effects including publication bias.

Data synthesis

Dichotomous outcomes Data will be entered into RevMan 5.0 software by two reviewers (double data entry). The primary analysis will use a random effects model as some clinical diversity across the studies is considered inevitable (Higgins 2005 ‐ handbook) and empirical work on summary effect measures has suggested a random effects model using the odds ratio has the highest generalisability across baseline risks (Furukawa 2002). The robustness of this decision will be routinely examined by running a fixed effect model (using OR) and a random effects model (using risk ratio as summary measure) and reporting material differences between the models.

Continuous outcomes Continuous outcomes will be analysed using a random effects model. A sensitivity analysis using a fixed effect model will be done routinely to investigate the effect of choice of method on the estimates. Material differences between the models will be reported

Skewed data and non‐quantitative data will be presented descriptively. An outcome will be considered skewed when the mean is smaller than twice the SD.

Subgroup analysis and investigation of heterogeneity

Subgroup analyses should be performed and interpreted with caution because multiple analyses will lead to false positive conclusions (Oxman 1992). However, we will perform the following subgroup analyses, where possible, for the following a priori reasons.

1) Reboxetine dosing (fixed low dosage, fixed standard dosage, fixed high dosage; flexible low dosage, flexible standard dosage, flexible high dosage), because there is evidence to suspect that low dosage antidepressant may be associated with better outcomes both in terms of effectiveness and side effects than standard or high dosage antidepressants (Bollini 1999; Furukawa 2003) and also because fixed versus flexible dosing schedule may affect estimates of treatment effectiveness (Khan 2003); 2) Comparator dosing (low effective range, medium to high effective range), as it is easy to imagine that there are greater chances of completing the study on the experimental drug than on the comparator drug that is increased to the maximum dosage; 3) Depression severity (Severe major depression, moderate/mild major depression); 4) Treatment settings (psychiatric inpatients, psychiatric outpatients, primary care); 5) Elderly patients (>=65 years of age), separately from other adult patients.

Sensitivity analysis

The following sensitivity analyses are planned a priori. By limiting the studies to be included to those with higher quality, we will examine if the results changed and we meant to check for the robustness of the observed findings, as follows: 1) Excluding trials with unclear concealment of random allocation and/or unclear double blinding 2) Excluding trials whose drop out rate is greater than 20% 3) Performing the worst case scenario ITT (all the patients in the experimental group experience the negative outcome and all those allocated to the comparison group experience the positive outcome) and the best case scenario ITT (all the patients in the experimental group experience the positive outcome and all those allocated to the comparison group experience the negative outcome) 4) Excluding trials for which the response rates had to be calculated based on the imputation method (Furukawa 2005) and those for which the SD had to be borrowed from other trials (Furukawa 2006). 5) Examination of "wish bias" by comparing reboxetine as investigational drug vs reboxetine as comparator, as there is evidence to suspect that a new antidepressant might perform worse when used as a comparator than when used as an experimental agent (Barbui 2004) 6) Excluding studies funded by the pharmaceutical company marketing reboxetine. This sensitivity analysis is particularly important in view of the recent repeated findings that funding strongly affects outcomes of research studies (Als‐Nielsen 2003; Bhandari 2004; Lexchin 2003; Montgomery 2004; Perlis 2005; Procyshyn 2004) and because industry sponsorship and authorship of clinical trials are increasing over 20 years (Buchkowsky 2004).

If subgroups within any of the subgroup or sensitivity analyses turned out to be significantly different in effectiveness from one another, we will run meta‐regression for exploratory analyses of additive or multiplicative influences of the variables in question. Our routine application of random effects and fixed effect models as well as our secondary outcomes of remission rates and continuous severity measures may be considered additional forms of sensitivity analyses.

Acknowledgements

The authors would like to thank Vivien Hunot, Julian Higgins and Georgia Salanti for their helpful comments and feedback on the MANGA protocols.

What's new

Date Event Description
19 October 2018 Amended Protocol for a Cochrane Review withdrawn from publication.
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History

Protocol first published: Issue 2, 2009

Date Event Description
21 April 2010 Amended Republishing with updated contact details and minor amendments to references
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Contributions of authors

All co‐authors contributed to the development and drafting of the protocol.

Sources of support

Internal sources

  • University of Bristol, UK.

External sources

  • Department of Health, UK.

Declarations of interest

AC, CB, HM, RC, DC, GL: none declared

TAF has received several research grants and fees for speaking from some pharmaceutical companies, which market or plan to market antidepressants (escitalopram, fluvoxamine, mirtazapine, paroxetine, sertraline) and antipsychotics (aripiprazole, olanzapine, perospirone).

NW has received speaking fees from GlaxoSmithKline for evidence‐based medicine

Notes

The planned review outlined in this protocol has not been successfully converted into a full Cochrane Review within established timelines and for this reason has been withdrawn by the Common Mental Disorders CRG from the CDSR.

Withdrawn from publication for reasons stated in the review

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