Fluoxetine versus other types of pharmacotherapy for depression

Andrea Cipriani; Paulo Brambilla; Toshi A Furukawa; John Geddes; Manuela Gregis; Matthew Hotopf; Lara Malvini; Corrado Barbui

doi:10.1002/14651858.CD004185.pub2

. Author manuscript; available in PMC: 2014 Sep 15.

Published in final edited form as: Cochrane Database Syst Rev. 2005 Oct 19;(4):CD004185. doi: 10.1002/14651858.CD004185.pub2

Fluoxetine versus other types of pharmacotherapy for depression

Andrea Cipriani ¹, Paulo Brambilla ², Toshi A Furukawa ³, John Geddes ⁴, Manuela Gregis ¹, Matthew Hotopf ⁵, Lara Malvini ¹, Corrado Barbui ¹

PMCID: PMC4163961 EMSID: EMS58582 PMID: 16235353

Abstract

Background

Depression is common in primary care and it is associated with marked personal, social and economic morbidity, and creates significant demands on service providers in terms of workload. Treatment is predominantly pharmaceutical or psychological. Fluoxetine, the first of a group of antidepressant (AD) agents known as selective serotonin reuptake inhibitors (SSRIs), has been studied in many randomised controlled trials (RCTs) in comparison with tricyclic (TCA), heterocyclic and related ADs, and other SSRIs. These comparative studies provided contrasting findings. In addition, systematic reviews of RCTs have always considered the SSRIs as a group, and evidence applicable to this group of drugs might not be applicable to fluoxetine alone. The present systematic review assessed the efficacy and tolerability profile of fluoxetine in comparison with TCAs, SSRIs and newer agents.

Objectives

To determine the efficacy of fluoxetine, compared with other ADs, in alleviating the acute symptoms of depression, and to review its acceptability.

Search methods

Relevant studies were located by searching the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR), the Cochrane Central Register of Controlled Trials (CENTRAL), Medline (1966-2004) and Embase (1974-2004). Non-English language articles were included.

Selection criteria

Only RCTs were included. For trials which have a crossover design only results from the first randomisation period were considered.

Data were independently extracted by two reviewers using a standard form. Responders to treatment were calculated on an intention-to-treat basis: drop-outs were always included in this analysis. When data on drop-outs were carried forward and included in the efficacy evaluation, they were analysed according to the primary studies; when dropouts were excluded from any assessment in the primary studies, they were considered as treatment failures. Scores from continuous outcomes were analysed including patients with a final assessment or with the last observation carried forward. Tolerability data were analysed by calculating the proportion of patients who failed to complete the study and who experienced adverse reactions out of the total number of randomised patients. The primary analyses used a fixed effects approach, and presented Peto Odds Ratio (Peto OR) and Standardised Mean Difference (SMD).

Main results

On a dichotomous outcome fluoxetine was less effective than dothiepin (Peto OR: 2.09, 95% CI 1.08 to 4.05), sertraline (Peto OR: 1.40, 95% CI 1.11 to 1.76), mirtazapine (Peto OR: 1.64, 95% CI 1.01 to 2.65) and venlafaxine (Peto OR: 1.40, 95% CI 1.15 to 1.70). On a continuous outcome, fluoxetine was more effective than ABT-200 (Standardised Mean Difference (SMD) random effects: - 1.85, 95% CI - 2.25 to - 1.45) and milnacipran (SMD random effects: - 0.38, 95% CI - 0.71 to - 0.06); conversely, it was less effective than venlafaxine (SMD random effect: 0.11, 95% CI 0.00 to 0.23), however these figures were of borderline statistical significance.

Fluoxetine was better tolerated than TCAs considered as a group (Peto OR: 0.78, 95% CI 0.68 to 0.89), and was better tolerated in comparison with individual ADs, in particular than amitriptyline (Peto OR: 0.64, 95% CI 0.47 to 0.85) and imipramine (Peto OR: 0.79, 95% CI 0.63 to 0.99), and among newer ADs than ABT-200 (Peto OR: 0.21, 95% CI 0.10 to 0.41), pramipexole (Peto OR: 0.20, 95% CI 0.08 to 0.47) and reboxetine (Peto OR: 0.61, 95% CI 0.40 to 0.94).

Authors’ conclusions

There are statistically significant differences in terms of efficacy and tolerability between fluoxetine and certain ADs, but the clinical meaning of these differences is uncertain, and no definitive implications for clinical practice can be drawn. From a clinical point of view the analysis of antidepressants’ safety profile (adverse effect and suicide risk) remains of crucial importance and more reliable data about these outcomes are needed. Waiting for more robust evidence, treatment decisions should be based on considerations of clinical history, drug toxicity, patient acceptability, and cost. We need for large, pragmatic trials, enrolling heterogeneous populations of patients with depression to generate clinically relevant information on the benefits and harms of competitive pharmacological options. A meta-analysis of individual patient data from the randomised trials is clearly necessary.

Medical Subject Headings (MeSH): Antidepressive Agents [therapeutic use]; Antidepressive Agents, Second-Generation [*therapeutic use]; Antidepressive Agents, Tricyclic [therapeutic use]; Depression [*drug therapy]; Fluoxetine [*therapeutic use]; Randomized Controlled Trials as Topic; Serotonin Uptake Inhibitors [*therapeutic use]

MeSH check words: Humans

BACKGROUND

Depression is a relevant problem in primary care; it is associated with marked personal, social and economic morbidity, and creates significant demands on service providers in terms of workload. Treatment is predominantly pharmaceutical or psychological. Fluoxetine is the first of a group of antidepressant (AD) agents known as selective serotonin reuptake inhibitors (SSRIs). It was first used more than ten years ago, and soon after its introduction it became the most prescribed agent for depression in many countries. Fluoxetine became a culturally fashionable treatment, acquired popularity in the lay news and media, and sociologists described it as a ‘socio-psychopharmaceutical’ phenomenon, the ‘Prozac boom’ (Slingsby 2002).

The phenomenal success of fluoxetine raised some concern because results from randomised clinical trials (RCTs) did not clearly indicate substantial benefits over conventional agents. There are many published RCTs of fluoxetine in comparison with tricyclic (TCA), heterocyclic and related ADs, as well as head-to-head comparisons between fluoxetine and other SSRIs. However, contrasting findings emerged. Bech and colleagues (Bech 2000), who systematically reviewed published and unpublished RCTs comparing fluoxetine with TCA, found a trend in favour of fluoxetine in studies conducted in the USA, and a trend favouring TCA in studies conducted outside the USA. Anderson (Anderson 2000), who pooled efficacy and tolerability data from 102 RCTs comparing SSRIs and TCAs, showed no overall difference in efficacy between SSRIs and TCAs. However, the SSRIs were better tolerated, with significantly low rates of treatment discontinuation. According to this analysis, a physician need to treat 26 patients with one of the SSRIs to see the advantage over TCAs in one subject. This advantage was similar for each individual SSRI except for fluvoxamine which did not differ from TCAs. Freemantle and Mason provided similar findings, suggesting that SSRIs are associated with an absolute reduction in dropouts of about 4% (Freemantle 2000), and Geddes and colleagues, who conducted a Cochrane review, concluded that there are no clinically significant differences in effectiveness between SSRIs and TCAs, and treatment decisions need to be based on considerations of relative patient acceptability, toxicity and cost (Geddes 2000). Head-to-head comparisons of new drugs have been recently summarised by Anderson (Anderson 2001). This review showed superior efficacy of serotonin and noradrenaline reuptake inhibitors (SNRIs) over SSRIs and, in terms of side-effects, better tolerability of sertraline than other SSRIs, and greater frequency of agitation on fluoxetine than other SSRIs (Anderson 2001). Another systematic review of head-to-head comparisons showed no difference in efficacy between individual SSRIs, and highlighted some differences in terms of tolerability: fluoxetine was associated with more agitation, weight loss and dermatological reactions than the other SSRIs (Edwards 1999). No increased risk of suicidal acts or ideation in fluoxetine treated subjects was shown. In older people Katona and Livingstone (Katona 2002), who systematically reviewed available experimental studies in late life depression, showed significant superiority for paroxetine over fluoxetine. Although these studies provided important information on the efficacy and tolerability profile of fluoxetine over control ADs, conclusive data are still lacking, and debate persists on the proper place of fluoxetine in the pharmacological treatment of depression (Freemantle 2000).

A major problem with some of these systematic reviews is that they analysed the SSRIs as a group, and evidence applicable to this group of drugs might not be entirely applicable to fluoxetine alone. In fact, pharmacological considerations suggest the SSRIs are an heterogeneous class. These agents exert a selective and potent inhibition of serotonin reuptake, which is thought to be relevant for their antidepressant action, but the potency of this serotonin inhibition is different between individual compounds. Similarly, there are differences in their secondary pharmacological actions, such as blockade of norepinephrine and dopamine reuptake, serotonin 2C agonist action, muscarinic cholinergic antagonist action, interaction with the sigma receptor, inhibition of the enzyme nitric oxide synthetase and inhibition of the cytochrome P450 enzymes (Wong 1995). These pharmacological properties highlight the relevance of studying individual SSRIs in comparison with the rest. The Bech and colleagues meta-analysis (Bech 2000), which included RCTs comparing fluoxetine and TCAs, considered only RCTs from the fluoxetine manufacturer’s (Eli Lilly) database, and did not include head-to-head comparisons with other SSRIs or studies comparing fluoxetine with newer agents. The present systematic review assessed the evidence for the efficacy and tolerability of fluoxetine in comparison with TCAs, SSRIs and newer agents.

OBJECTIVES

(1) To determine the efficacy of fluoxetine compared to control agents in alleviating the acute symptoms of depression.

(2) To review acceptability of treatment with fluoxetine compared with control agents.

(3) To investigate the adverse effects of fluoxetine treatment.

(4) To determine overall suicide rates on fluoxetine treatment.

(5) To determine whether fluoxetine dose and RCT quality are associated with treatment outcome.

METHODS

Criteria for considering studies for this review

Types of studies

Only randomised controlled trials were included. For trials which have a crossover design only results from the first randomisation period were considered.

Types of participants

Study participants were of either sex and any age with a primary diagnosis of depression. Studies adopting any criteria to define patients suffering from depression were included. Most recent studies used DSM-IV or ICD 10 criteria. Older studies used ICD9, DSM III / DSM III R or other diagnostic systems. In addition, a concurrent diagnosis of another psychiatric disorder was not considered an exclusion criteria. AD trials in depressive patients with a concomitant medical illness were excluded.

Types of interventions

Included trials compared fluoxetine with tricyclic/heterocyclic ADs or with one of the SSRIs (fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram) or newer agents. Clinical trials comparing fluoxetine with herbal products (i.e. Hypericum) were included as well.

Types of outcome measures

Efficacy was evaluated using the following outcome measures:

Number of patients who responded to treatment showing a reduction of at least 50% at the HDRS out of the total number of randomised patients (intention-to-treat analysis);
Group mean scores at the end of the trial on Hamilton Depression Scale (HDRS), or Montgomery-Asberg Depression Scale (MADRS), or any depression scale.

Tolerability was evaluated using the following outcome measures:

Number of patients who dropped out during the trial as a proportion of the total number of randomised patients - Total drop out rate
Number of patients who dropped out during the trial as a proportion of the total number of randomised patients - Due to inefficacy
Number of patients who dropped out during the trial as a proportion of the total number of randomised patients - Due to side effects

Search methods for identification of studies

1. Relevant studies were located by searching the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR) and the Cochrane Central Register of Controlled Trials (CENTRAL). The following terms were used: FLUOXETIN* OR adofen or docutrix or erocap or uctin or uctine or uoxeren or fontex or ladose or lorien or lovan or mutan or prozac or prozyn or reneuron or sanzur or saurat or zactin.

2. Medline (1966-2004) and Embase (1974-2004) were searched using the search term \fluoxetine“ and \randomised controlled trial” or \random allocation“ or \double-blind method”. Non-English language articles were included.

3. Reference lists of relevant papers and previous systematic reviews were handsearched for published reports and citations of unpublished research.

Data collection and analysis

Duplicate studies

Considerable care was taken to exclude duplicate publications.

Data extraction

Data were independently extracted by two reviewers (AC and PB) using a standard form.

Study quality

The main quality criteria noted was reporting of the concealment of random allocation, which has been found to be related to study effect (Schulz 1995). Studies were given a quality rating ranging from C (poorest quality) to A (best quality). C = inadequately concealed (e.g. via alternation or reference to an open random number table). B = no adequate details about how the randomisation procedure was carried out were given a rating of B. A= trials that were reported to have taken adequate measures to conceal allocation (e.g. serially numbered, opaque, sealed envelopes; numbered or coded bottles or containers).

Dichotomous outcomes

The number of patients undergoing the randomisation procedure, the number of patients who failed to complete the study - because of side effects, inefficacy and any cause - were recorded. The number of patients showing a reduction of at least 50% at the HDRS was extracted.

Continuous outcomes

The mean scores at endpoint, the standard deviation (SD) or standard error (SE) of these values, and the number of patients included in these analyses, were extracted. Data were extracted from the HDRS or MADRS or any depression scale. When only the SE was reported, it was converted into SD according to Altman (Altman 1996).

Statistical analysis

Responders to treatment were calculated on an intention-to-treat (ITT) basis: drop-outs were always included in this analysis. When data on drop-outs were carried forward and included in the efficacy evaluation (Last Observation Carried Forward, LOCF), they were analysed according to the primary studies; when dropouts were excluded from any assessment in the primary studies, they were considered as drug failures. Scores from continuous outcomes were analysed including patients with a final assessment or with a LOCF to the final assessment. Tolerability data were analysed by calculating the proportion of patients who failed to complete the study and who experienced adverse reactions out of the total number of randomised patients. The primary analysis used a fixed effect approach, the Peto Odds Ratio (Peto OR). In addition, a random effects estimate, which takes accounts of any additional between-study variation, was calculated using a moment estimator of the between-study variance (DerSimonian 1986) as a sensitivity check on the fixed effect estimate. A standardised weighed mean difference (SMD) was used for continuous outcomes. This measure provided the effect size of the intervention in units of standard deviations. Scores from different outcome scales can be summarized in an overall SMD. Heterogeneity of treatment effect between studies was formally tested using the Chi Square statistic. Sub-group analyses were performed to assess the possibility of differences in the efficacy and tolerability of fluoxetine according to control AD class, study quality and fluoxetine dose. Stratification by each control agent was performed to ascertain whether there are treatment differences between fluoxetine and AD drugs belonging to the same pharmacological class.

RESULTS

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

The original searches yielded 883 studies: after reading abstracts, 364 papers were considered potentially relevant for this review. Of these, 219 were excluded because of multiple publications or not randomised trials. The remaining 145 were retrieved for more detailed evaluation and 132 RCTs meeting the inclusion criteria were included.

During the period that the review was being undertaken, the CCDAN Controlled Trials Register (CCDANCTR) was considerably updated and the indexing improved. To ensure that no important studies had been missed following the original searches, another search of the new CCDANCTR-Studies register was undertaken just prior to publication. These additional searches yielded 125 new references that the authors had not yet assessed. The authors reviewed this list and identified which studies might be included. Of these 125 references, 37 were poster presentations, 15 were excluded on the basis of the design, 14 were excluded on the basis of the diagnosis, eight were excluded due to the comparison used, seven either had no data or reported secondary analyses of existing data, and 25 were additional publications of trials already included. Of the remaining 19 references, on the basis of the information available, the authors deemed eight to be likely to meet the inclusion criteria and were uncertain about another 11 references. These references have been placed in the Awaiting Assessment section and, if they meet the inclusion criteria, will be included in a review update to be published in Issue 1, 2006.

Of the 132 included studies, 113 contributed usable data for the tolerability analysis and 114 for the efficacy analysis. The majority of the studies (69 RCTs) recruited less than 100 participants, and almost all (130 RCTs) were reported to be double-blind. The mean length of follow-up was 8 weeks (SD 5.1). Twelve trials enrolled in-patients, 24 both in- and out-patients, while the remaining studies were conducted in out-patients facilities. The majority of studies (74%) enrolled patients suffering from DSM-III-R, DSM-IV or ICD 10 criteria for major depression. Elderly subjects (over 65 years old) were included in 58 studies. There were 58 studies comparing fluoxetine with TCAs, 9 studies with heterocyclics, 22 with SSRIs and 44 studies comparing fluoxetine with other newer ADs. Comparator ADs were amitriptyline (20), clomipramine (5), desipramine (3), dothiepin (6), doxepin (4), imipramine (14), lofepramine (1), nomifensine (1), nortriptyline (3) and trimipramine (1) among TCAs; maprotiline (6) and mianserin (3) among heterocyclics; citalopram (2), fluvoxamine (1), paroxetine (8), sertraline (9) and both paroxetine and sertraline (2) among SSRIs; amineptine (2), ABT-200 (1), amisulpride (1), buproprion (1), duloxetine (1), hypericum (3), milnacipran (2), mirtazepine (2), moclobemide (7), nefazodone (3), phenelzine (1), pramipexole (1), reboxetine (2), tianeptine (4), trazodone (3) and venlafaxine (10) among other newer ADs.

The great majority of studies (123) used the HDRS as primary or secondary outcome measure, while a minority of studies used the MADRS and Clinical Global Impression scale (CGI). Around an half of included trials (73) reported the total number of patients experiencing any side effects, while the remaining studies reported the number of patients experiencing individual side effects only. Only 27 studies adopted interview-based scales to detect side effects.

Risk of bias in included studies

Description of concealment of allocation was rated as B in all studies.

Effects of interventions

Peto ORs lower than one, and negative SMDs (falling to the left of the midline) indicate a difference in favour of fluoxetine. Funnel plots did not suggest evidence of publication bias.

Comparative efficacy

Analysis of efficacy was based upon 4494 patients treated with fluoxetine and 4817 with an alternative AD.

TCAs

Defining as response the number of patients showing a reduction of at least 50% at the HDRS, we found no statistically significant difference in terms of efficacy between fluoxetine and TCAs as a class (Peto OR: 0.95, 95% CI 0.80 to 1.14). In head-to-head comparisons, only dothiepin was found to be significantly more effective than fluoxetine (Peto OR: 2.09, 95% CI 1.08 to 4.05). Similarly, no statistically significant differences between fluoxetine and TCAs, and between fluoxetine and individual comparator ADs were found on continuous outcome (overall SMD random effects: 0.07, 95% CI - 0.06 to 0.20).

Heterocyclics

Defining as response the number of patients showing a reduction of at least 50% at the HDRS, we found no statistically significant difference in terms of efficacy between fluoxetine and mianserin and an advantage in terms of efficacy, although not statistically significant, in favour of maprotiline over fluoxetine (Peto OR: 1.92, 95% CI 0.92 to 3.98). However, considering continuous outcome, no statistically significant difference between fluoxetine and any heterocyclic AD was found.

SSRIs

There was a statistically significant difference in terms of efficacy in favour of sertraline over fluoxetine, both on a dichotomous (Peto OR: 1.40, 95% CI 1.11 to 1.76) and continuous outcome (SMD random effect: 0.22, 95% CI 0.00 to 0.44). Paroxetine had an advantage in terms of efficacy, although this was not statistically significant, on a dichotomous outcome only (Peto OR: 1.25, 95% CI 0.96 to 1.63).

Newer ADs

Venlafaxine was significantly more effective than fluoxetine, both on a dichotomous (Peto OR: 1.40, 95% CI 1.15 to 1.70) and continuous outcome (SMD random effect: 0.11, 95% CI 0.00 to 0.23). Mirtazepine was significantly more effective than fluoxetine only on a dichotomous outcome (Peto OR: 1.64, 95% CI 1.01 to 2.65). For dichotomous outcome, a non-statistically significant advantage favouring hypericum (Peto OR: 1.34, 95% CI 0.93 to 1.94) and moclobemide (Peto OR: 1.27, 95% CI 0.94 to 1.71) over fluoxetine was found. Conversely, a non-statistically significant advantage favouring fluoxetine over amineptine (Peto OR: 0.38, 95% CI 0.14 to 1.04) was found. A statistically significant difference in favour of fluoxetine over ABT-200 (SMD random effects: - 1.85, 95% CI - 2.25 to - 1.45) and milnacipran (SMD random effects: - 0.38, 95% CI - 0.71 to - 0.06) was found on a continuous outcome.

Comparative tolerability

Analysis of safety was based upon 7034 patients treated with fluoxetine and 7357 with an alternative AD.

TCAs

In terms of patients who dropped out during the trial for any cause, fluoxetine was better tolerated than TCAs (Peto OR: 0.78, 95% CI 0.68 to 0.89). In particular, fluoxetine was better tolerated than amitriptyline (Peto OR: 0.64, 95% CI 0.47 to 0.85) and imipramine (Peto OR: 0.79, 95% CI 0.63 to 0.99). An advantage in terms of tolerability, although not statistically significant, was found in favour of fluoxetine over lofepramine (Peto OR: 0.51, 95% CI 0.25 to 1.03) and nortriptyline (Peto OR: 0.68, 95% CI 0.45 to 1.03); by contrast, dothiepin was better tolerated than fluoxetine (Peto OR: 1.44, 95% CI 0.98 to 2.12).

In terms of patients who dropped out during the trial due to inefficacy, TCAs as a group (Peto OR: 1.28, 95% CI 0.96 to 1.69) and imipramine specifically (Peto OR: 1.34, 95% CI 0.94 to 1.93) had an advantage over fluoxetine, although this was not statistically significant.

The analysis of dropouts due to side effects revealed that amitripty-line (Peto OR: 0.40, 95% CI 0.27 to 0.61), clomipramine (Peto OR: 0.34, 95% CI 0.15 to 0.78), desipramine (Peto OR: 0.25, 95% CI 0.07 to 0.92), imipramine (Peto OR: 0.44, 95% CI 0.33 to 0.58) and overall TCAs (Peto OR: 0.54, 95% CI 0.45 to 0.64) were significantly less effective than fluoxetine. Only dothiepin showed a different pattern (Peto OR: 1.58, 95% CI 0.90 to 2.78).

Heterocyclics

Considering the total number of patients who dropped out during the trial no statistically significant difference was found between fluoxetine and each heterocyclic AD. Only an advantage in terms of dropouts due to any reason was found favouring maprotiline over fluoxetine (Peto OR: 1.75, 95% CI 0.93 to 3.30).

SSRIs

In terms of patients who dropped out during the trial for any reason, no statistically significant difference was found between fluoxetine and each SSRIs, with the exception of possible advantage of sertraline over fluoxetine (Peto OR: 1.23, 95% CI 0.98 to 1.55). Although not statistically significant, a tendency in favour of fluoxetine over citalopram was found in terms of number of dropouts due to side effects (Peto OR: 0.57, 95% CI 0.30 to 1.09).

Newer ADs

ABT-200 and pramipexole were less well tolerated than fluoxetine in terms of failure to complete the trial for any reason (Peto OR: 0.21, 95% CI 0.10 to 0.41 and Peto OR: 0.20, 95% CI 0.08 to 0.47, respectively) and in terms of dropouts due to side effects (Peto OR: 0.14, 95% CI 0.06 to 0.31 and Peto OR: 0.19, 95% CI 0.07 to 0.51, respectively). Fluoxetine was less well tolerated than reboxetine in terms of total dropouts (Peto OR: 0.61, 95% CI 0.40 to 0.94). Furthermore a not significant advantage in terms of dropouts due to side effects was found in favours of fluoxetine over venlafaxine (Peto OR: 0.76, 95% CI 0.57 to 1.03).

Adverse effects

Of the 132 included RCTs, 71 (54%) reported the total number of patients experiencing any side effects, while the remaining studies reported the number of patients experiencing individual side effects only. Only a minority of included studies (20%) adopted interview-based scales to detect side effects. Analysis of full side-effect profile of fluoxetine in comparison with other antidepressants has been published elsewhere (Brambilla 2004). Data from this review showed higher occurrence of activating and gastrointestinal side effects with fluoxetine than TCAs and increased rates of cholinergic adverse events with TCAs. Agitation and insomnia were significantly increased in fluoxetine-treated depressed patients compared to TCA-ones. Robust evidence suggesting differences between fluoxetine and other SSRIs was not found. The only significant differences were sweating, more common in fluoxetine-than paroxetine-treated patients, and nausea, more common in fluoxetine- than fluvoxamine-treated patients. As a class, the SSRIs induced less weight loss than fluoxetine. Dry mouth, dizziness, sweating and nausea were significantly decreased in fluoxetine-treated depressed patients compared with some new antidepressants-ones (venlafaxine, reboxetine, phenelzine, nefazodone), but not with others (amisulpride, hypericum and tianeptine).

Suicide

In terms of suicide rate, no differences emerged between fluoxetine and control AD. Suicide is a rare event, and this might have reduced the power of highlighting significant differences. However, although this topic is an important issue and still under debate (Cipriani 2005), only 4 studies reported completed suicide as an outcome, and only 16 studies mentioned the occurrence of any deliberate self harm during trial duration.

Fluoxetine dose

Data about dose were extensively analysed elsewhere (Barbui 2004). To determine whether fluoxetine dose was associated with treatment outcome, a metaregression analysis was carried out Having adjusted for possible confounders, fluoxetine dose (continuous outcome) was not associated with a statistically significant advantage for fluoxetine RCTs.

DISCUSSION

This systematic review detected differences between fluoxetine and some comparator AD. On a dichotomous outcome, fluoxetine was less effective than dothiepin, sertraline, mirtazapine, venlafaxine. On continuous outcome fluoxetine was more effective than ABT-200 and milnacipran, and less effective than sertraline and venlafaxine. However, it is uncertain how these differences translate into clinically meaningful measures. Despite the large number of comparative trials included in this systematic review, the total number of randomised patients was under 15,000. Studies were short - usually 8 weeks or less - and the mean size of each trial was around 110 participants, indicating that they were generally underpowered for demonstrating clinically meaningful differences.

Continuous outcome measures were more often employed in trials comparing fluoxetine with TCAs than in trials comparing fluoxetine with other SSRIs or newer ADs, where measures were frequently dichotomised to calculate the proportion of participants who experienced an arbitrary percentage reduction in symptoms, usually a 50% reduction in the total Hamilton score. Apart from being arbitrary and of uncertain clinical relevance, this approach sacrifices statistical power. Given that small differences are expected between ADs, ideally more powerful method of analysis should have been employed, in order to increase the likelihood of detecting such differences. Comparing scores on continuous outcome measures, however, has the disadvantage of providing findings difficult to be translated into clinically sound figures, such as absolute differences and NNTs. Another approach, sometimes used in AD trials, is to calculate the proportion of patients with a score below a predefined cut-off (for example less than 7 at the Hamilton) and to consider these patients as ‘recovered’ (Frank 1991). This approach may be more useful because it is based on a clinical definition of recovery. In the present systematic review, differences in results obtained using dichotomous and continuous outcome measures should be interpreted bearing in mind these considerations. In addition, in studies reporting mean scores but failing to report the corresponding SDs we averaged the mean SD values reported in other studies belonging to the same group (Furukawa 2005).

In this systematic review each individual AD was compared with fluoxetine. Fluoxetine was chosen as the reference SSRI because it has been a market leader since its introduction almost 20 years ago, and also because it has frequently been used both as a new drug, compared with reference TCAs in early clinical trials, and as a reference compound, compared with other SSRIs and newer ADs in recent studies. This might have somewhat influenced the overall comparisons, since recent data showed that fluoxetine dose was higher in trials where the aim was to demonstrate its efficacy in comparison with older ADs, and lower in trials where the aim was to demonstrate a new drug’s efficacy against fluoxetine. This difference affected fluoxetine response rate and dropouts, which were higher in trials where fluoxetine was used as the experimental compound (Barbui 2004). From a clinical point of view the analysis of antidepressants’ safety profile (adverse effect and suicide risk) remains of crucial importance. Considering how difficult it is to determine significant differences in terms of effectiveness, nowadays the choice of antidepressants is mainly based on knowledge about associated side effects. More reliable data is required about the adverse effects associated with different drugs. To further address this, trial authors and the pharmaceutical industry will be asked to provide raw data (published and unpublished) of randomized trials. Taking into account of any new information, an update of this review is scheduled by April 2006 to better inform clinical practice.

A limitation of this analysis is that studies with different designs were pooled together. By making multiple comparisons we might have committed type 1 error - that is reporting a spurious association. Pooling together trials with different designs might have limited the external validity of findings (Zimmermann 2002). We run a post hoc sensitivity analysis excluding studies with a follow up duration less than 6 weeks or longer than 16 weeks. We found that results didn’t differ materially. In terms of failure to complete for any reason, the comparison between fluoxetine and imipramine became not statistically significant (Peto OR 0.81, 95% CI 0.64 to 1.02). By contrast, a slightly more favourable profile favouring TCAs over fluoxetine was found in terms of dropouts due to inefficacy (Peto OR 1.37, 95% CI 1.03 to 1.83). Another limitation is that publication bias cannot be completely excluded, even though funnel plots did not show any evidence of publication bias. Funnel plots work on the assumption that researchers are less likely to leave unpublished the results of large trials, than they are with small trials. For the meta-analyses of TCAs and SSRIs the funnel plots have generally been symmetrical, suggesting publication bias is absent. However, recent evidence showing non-publication of large industry sponsored trials on children and adolescents with major depression suggests that publication bias may remain a very serious limitation to the entire literature comparing SSRIs and TCAs (Parker 2003; Hotopf 2005). If important information are concealed, the funnel plot (and other formal statistical tests which work on the same principle) will not be able to detect publication bias under these circumstance.

AUTHORS’ CONCLUSIONS

Implications for practice

The main finding of the present study is that there are statistically significant differences in terms of efficacy and tolerability between fluoxetine and certain ADs, but the clinical meaning of these differences is uncertain, and no definitive implications for clinical practice can be drawn. The better efficacy profile of sertraline and venlafaxine (and possibly other ADs) over fluoxetine seemed clinically meaningful, but this needs further investigation. It is possible that differences would emerge in controlled trials of longer duration. Waiting for more robust evidence, treatment decisions are to be based on considerations of drug toxicity, patient acceptability, and cost.

Implications for research

Trials comparing two or more active treatments need to be much larger and of better quality than the studies that we identified for this review. More clinically meaningful outcome measures in trials of antidepressants, such as ability to work or admission to hospital, are needed. For a comprehensive analysis of the different antidepressants’ safety profile, more reliable data is needed. Regarding available evidence, a meta-analysis of individual patient data from the randomised trials is clearly necessary but has not been done. An analytical approach with head-to-head comparison might in addition be seen as a methodological contribution in the evaluation of treatment effectiveness.

PLAIN LANGUAGE SUMMARY.

Fluoxetine compared with other antidepressants for depression

The efficacy and tolerability of fluoxetine was compared to other antidepressants (tricyclics, heterocyclics and newer antidepressants) for the acute treatment of depressive illness. One hundred thirty-two randomised controlled trials were identified. Pooling the results from the trials, statistically significant differences in efficacy and in tolerability were found between fluoxetine and some antidepressants. However, it is difficult to draw clear clinically meaningful conclusions and more reliable data about antidepressants’ safety profile are needed. Without more robust evidence, the researchers suggest that treatment decisions are to be based on considerations of drug toxicity, patient acceptability, and cost.

ACKNOWLEDGEMENTS

We would like to thank the CCDAN Editorial Team for their support, information and advice.

SOURCES OF SUPPORT

Internal sources

Department of Medicine and Public Health, Section of Psychiatry and Clinical Psychology, University of Verona, Italy.
Department of Psychiatry, University of Oxford, UK.

External sources

No sources of support supplied

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Aguglia 1993

Methods	Eight-week double-blind, multicentre study.
Participants	Outpatients suffering from a major depressive episode according to DSM-III-R, with a baseline score on HDRS-17 of at least 18, recruited from nine separated psychiatric clinics. Age range: 18 years or more. Exclusion criteria: depression secondary to other conditions, concomitant illness of renal, cardiac or hepatic origin; hypersensitivity to other antidepressants, likelihood of poor compliance, risk of suicide, peptic ulcer history, an improvement of greater than 25% in the HDRS score during a pre-treatment placebo washout period
Interventions	Fluoxetine: 56 participants. Sertraline: 52 participants. Fluoxetine dose range: 20-60 mg/day. Sertraline dose range: 50-150 mg/day. Benzodiazepines were allowed for hypnotic use and as maintenance treatment for pre-existing anxiety
Outcomes	Hamilton Rating Scale for Depression (HDRS) and for Anxiety (HAM-A), Montgomery and Asberg Scale for Depression (MADRS), Zung Self-Rating Scale for Anxiety, Leeds Sleep Evaluation Questionnaire, Clinical Global Impression Scale, including severity (CGI-S) and improvement (CGI-I)
Notes	75% of the patients were women. Higher percentage of patients with a family history of psychiatric illness in the fluoxetine group. Higher percentage of patients with severe depression in the fluoxetine group (30.4%) than in the sertraline group (13.7%). Funding: unclear
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Six-week double-blind, randomised study.
Participants	Outpatients meeting DSM-IV diagnostic criteria for major depression, with a minimum baseline score of 20 on the HDRS-17. Age range: 19-54 years old. Exclusion criteria: any other psychiatric primary disease, current or past history of bipolar disorder, use of anxiolitic or MAOI or tryptophan, organic mental disorder, epilepsy, suicidal tendencies, any severe general disease, pregnancy, lactation
Interventions	Fluoxetine: 24 participants. Nortriptyline: 24 participants. Fluoxetine dose: 60 mg/day. Nortriptyline dose: 150 mg/day.
Outcomes	Primary outcome: Hamilton Rating Scale for Depression (HDRS-17)
Notes	Funding: unclear
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Twelve-week double-blind study
Participants	Outpatients suffering from a major depressive episode, recurrent depression or disthymia according to DSM-III-R, with a score of at least 25 on the HARD and on the FARD scales. Age range: 25-65 years. Exclusion criteria: not reported.
Interventions	Fluoxetine: 104 participants. Tianeptine: 102 participants. Fluoxetine dose: 20 mg/day. Tianeptine dose: 37.5 mg/day. Benzodiazepines were allowed only if severe anxiety or sleep disorders
Outcomes	HARD (humeur, angoisse, ralentissement, danger), FARD (Ferreri anxiety rating diagram), HSCL (Hopkins Symptom check-list)
Notes	Funding: by Academy
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Five-week double-blind randomised study
Participants	Inpatients fulfilling DSM-III criteria for major depressive episode and scoring at least 18 on HDRS-17. Age range: more than 65 years old. Exclusion criteria: not reported.
Interventions	Fluoxetine: 13 participants. Amitriptyline: 15 participants. Fluoxetine dose: 20 mg/day. Amitriptyline dose: 75 mg/day.
Outcomes	Hamilton Rating Scale for Depression (HDRS)
Notes	Elderly only. Funding: unclear
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Twelve-week double-blind randomised multicentre study
Participants	Outpatients meeting DSM-IV diagnostic criteria for major depression, with a minimum baseline score of 20 on the 21-item HDRS, recruited from three clinical sites. Age range: 18-65 years. Exclusion criteria: known sensitivity to venlafaxine or fluoxetine, a history of any clinically significant cardiac, hepatic or renal disease or abnormalities on a screening physical examination, ECG or laboratory tests, with any mental or neurologic disorder and breast-feeding women; used of any investigational drug, antipsychotic drug, electroconvulsive therapy or sumatriptan within 30 days of baseline, fluoxetine within 21 days and MAO-I within 14 days
Interventions	Fluoxetine: 47 participants. Venlafaxine: 40 participants. Fluoxetine dose range: 20-40 mg/day. Venlafaxine dose range: 75-150 mg/day.
Outcomes	Hamilton Rating Scale for Depression (HDRS-21), Montgomery and Asberg Scale for Depression (MADRS), Clinical Global Impression Scale
Notes	Patients in the fluoxetine group had more chronic histories of depression at baseline. Predominance of females in the whole study. Funding: by industry
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Eight-week double-blind, randomised multicentre study.
Participants	In- and outpatients meeting DSM-III-R diagnostic criteria for major depression, with a minimum baseline score of 22 on the 21-item HDRS, recruited from 33 clinical sites. Age range: 18-65 years. Exclusion criteria: history of unresponsiveness to antidepressant treament, association with endocrine disorders, substance abuse, drug hypersensitivity, chronic respiratory insufficiency, or gastro-intestinal, hepatic or renal disease, ECT within 6 months of baseline, high risk of suicide, pregnancy or absence of adequate contraception measures
Interventions	Fluoxetine: 127 participants. Reboxetine: 126 participants. Placebo: 128. Fluoxetine dose range: 20-40 mg/day. Reboxetine dose range: 8-10 mg/day. Chloral hydrate (0.5-1 g) was allowed as hypnotic.
Outcomes	Primary outcome: absolute change in the HDRS-21 total score. Secondary outcomes: GCI Severity, CGI Improvement, MADRS, SASS, PGI, Quality of Sleep questionnaire
Notes	Response: decrease of at least 50% in the HAM-D total score. Remission: total score less than 10. Funding: unclear
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Six-week double-blind, randomised multicentre study.
Participants	Outpatients fulfilling DSM-III-R criteria for major depressive episode, with a score of at least 25 on MADRS and of at least 4 on CGI-S. Age range: 19-68 years. Exclusion criteria: serious or uncontrolled medical illness, major anxiety, agitation, suicide risk, resistance during the current episode to at least two antidepressants, substance abuse or dependence, concomitant therapy with lithium, MAO-I, long-acting neuroleptic
Interventions	Fluoxetine: 93 participants. Milnacipram: 97 participants. Fluoxetine dose: 20 mg/day. Milnacipram dose: 100 mg/day.
Outcomes	Hamilton Rating Scale for Depression (HDRS-24), Montgomery and Asberg Scale for Depression (MADRS), Clinical Global Impression Scale
Notes	Funding: by industry
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Eight-week double-blind, randomised two-centre study.
Participants	Outpatients with a diagnosis of moderate to severe major depressive episode without psychotic features or bipolar disorder of the depressed type according to DSM-III-R, with a total score of least 18 points on HDRS-17 at baseline. Age range: over 18 years old. Exclusion criteria: concomitant organic mental disorder, psychoactive substance abuse disorder, schizophrenia or other psychotic disorder or any medical condition that controindicated treatment with antidepressants; pregnancy or lactating; women of childbearing popotential not practicing a reliable method of contraception
Interventions	Fluoxetine: 37 participants. Nefazodone: 37 participants. Fluoxetine dose range: 20-40 mg/day. Nefazodone: 400-500 mg/day. Concomitant psychotropic medication was prohibited, but occasionally use of benzodiazepines for severe anxiety or insomnia
Outcomes	Hamilton Rating Scale for Depression, Hamilton Rating Scale for Anxiety, Clinical Global Impression, Patient Global Assessment
Notes	One attempted suicide in the fluoxetine group. Funding: by industry
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Eight-week double-blind, randomised study.
Participants	Outpatients with a diagnosis of depressive episode less than 2 months duration, according to DSM-III criteria, with a minimum score of 25 on the MADRS. Age range: 18-65 yeras old. Exclusion criteria: absence of resistance to mianserin or fluoxetine, absence of associated psychotropic treatment, with the exception of prazepam (40 mg/day)
Interventions	Fluoxetine: 33 participants. Mianserin: 32 participants. Fluoxetine dose range: 20-40 mg/day. Mianserin dose range: 60-90 mg/day.
Outcomes	Hamilton Rating Scale for Depression, Hamilton Rating Scale for Anxiety, Montgomery and Asberg Scale for Depression (MADRS)
Notes	Funding: by industry
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Six-week double-blind, randomised, multicentre study.
Participants	In- and outpatients fulfilling DSM-III-R criteria for major depressive disorder, with a total score of at least 20 on HDRS-21. Age range: 18-60 years. Exclusion criteria: use of heterocyclics antidepressant drugs within 7 days or MAOI within 14 days of starting active treatment; patients with other significant medical disoders
Interventions	Fluoxetine: 28 participants. Desipramine: 30 participants. Fluoxetine dose range: 20-60 mg. Desipramine dose range: 150-250 mg/day.
Outcomes	Hamilton Rating Scale for Depression (HDRS-21), Clinical Global Impression, Patient self-rated Global Improvement
Notes	Funding: by industry
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Twenty-six-week double-blind, randomised, multicentre study.
Participants	Outpatients (primary care) fulfilling DSM-IV criteria for major depressive disorder, with a MADRS score of at least 20. Age range: 18-65 years. Exclusion criteria: Pregnancy, lactation, failure to use a safetable contraceptive method; concurrent major psychiatric disorders, such as anxiety disorder, dementia, somatoform disorders, agoraphobia, social phobia, any history of schizophrenia, psychosis or personality disorder; severe concurrent medical illness; alcohol or drug dependence; serious adverse reactions related to medicines; pprevious treatment with antidepressant for less than 3 week; major suicide risk
Interventions	Fluoxetine: 120 participants. Sertraline: 122 participants. Fluoxetine dose range: 20-60 mg/day. Sertraline dose range: 50-150 mg/day.
Outcomes	Montgomery and Asberg Scale for Depression and Clinical Global Impression
Notes	Response: decrease of at least 50% in the MADRS total score. Funding: by industry
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Five-week double-blind, randomised, study.
Participants	Outpatients fulfilling Research Diagnostic Criteria (RDC) criteria for major depressive disorder, with a score of at least 20 on HDRS, of 8 on Raskin. Age range: 23-69 years. Exclusion criteria: suicide risk, history of schizophrenia or other psychotic state likely to be aggravated by imipramine, organic brain disease, history of seizures; glaucoma, chronic urinary retention or serious cardiovascular disease; history of multiple adverse reaction to drugs, drug or alcohol abuse, pregnancy
Interventions	Fluoxetine: 20 participants. Imipramine: 20 participants. Fluoxetine dose range: 60-80 mg/day. Imipramine dose range: 125-300 mg/day.
Outcomes	Hamilton Rating Scale for Depression, Raskin and Covi; Patient Global Impressions, Clinical Global Impressions
Notes	Patients over 65 years old in the imipramine group only. Funding: by Academy
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Five-week, double-blind, randomised study.
Participants	Outpatients fulfilling DSM-III criteria for major depression, with a score of at least 20 on HDRS. Age range: not stated. Exclusion criteria: suicidal ideas, psychosis, seizure disorders, serious cardiac, renal or hepatic disease, alcoholism or drug abuse, use of antidepressant drug with the preceeding 14 days, concurrent medication potentially interacting
Interventions	Total sample: 30 (fluoxetine 18 and imipramine 12?) Fluoxetine dose range: 20-60 mg/day. imipramine dose range: 75-175 mg/day.
Outcomes	Hamilton Rating Scale for Depression, Clinical Global Impression
Notes	Funding: unclear
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Fifty-two-week double-blind, randomised, multicentre study.
Participants	Outpatients fulfilling ICD-10 criteria for major depression, with a Mini Mental State Examination score of at least 22, HDRS score of at least 18. Age range: over 65 years old. Exclusion criteria: concurrent major medical disorders, dementia, any history of schizophrenia, psychosis; alcohol or drug dependence; major suicide risk; use of long-acting neuroleptic drugs within 6 months or oral neuroleptics within 2 weeks before the study entry; ECT; daily use of benzodiazepines within 8 weeks or SSRI within 4 weeks, MAOI within 3 weeks, TCA within 1 week before the study entry
Interventions	Fluoxetine: 119 participants. Paroxetine: 123 participants. Fluoxetine dose range: 20-60 mg/day. Paroxetine dose range: 20-40 mg/day.
Outcomes	Hamilton Rating Scale for Depression (HDRS-21), Clinical Anxiety Scale, BSRT, BIMT, CLAS, CTT, WPW, MMSE and Clinical Global Impression
Notes	Depression response: total score less than 10 on the HDRS. Anxiety response: total score less than 8 on the CAS. Funding: by industry
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Five-week double-blind, randomised study.
Participants	Outpatients fulfilling Research Diagnostic Criteria (RDC) criteria for major depressive disorder, with a score of at least 21 on HDRS and of at least 8 on the Raskin scale. Age range: 21-70 years. Exclusion criteria: physical illness, schizophrenia, schizoaffective illness, chronic or acute organic brain syndrome, mental deficiency, alcoholism, epilepsy, drug addiction
Interventions	Fluoxetine: 23 participants. Amitriptyline: 28 participants. Fluoxetine dose range: 40-80 mg/day. Amitriptyline dose range: 100-300 mg/day. benzodiazepines were allowed for agitation and insomnia.
Outcomes	Primary outcome: Hamilton Rating Scale for Depression (HDRS-17), Clinical Global Impression, Efficacy Index-Side Effects rating. Secondary outcomes: HAM-D factors and Zung Depression Scale
Notes	One attempted suicide in the fluoxetine group. Funding: unclear
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Twelve-week double-blind, randomised, multicentre study.
Participants	Patients fulfilling DSM-III criteria for major depressive disorder, with a score of at least 20 on HDRS-21. Age range: not stated. Exclusion criteria: significant concurrent illness including renal, hepatic, cardiovascular or neurological disease, non-stabilised diabetes, other current Axis I psychiatric diagnosis; organic brain syndrome, past or present abuse of alcohol or drugs; pregnancy or lactating; ECT; continuous lithium therapy in preceeding 2 months, use of important psychotropic drug, current therapy with an anticoagulant or type 1 antiarrhytmic
Interventions	Fluoxetine: 101 participants. Paroxetine: 102 participants. Fluoxetine dose range: 20-80 mg/day. Paroxetine dose range: 20-50 mg/day. Chloral hydrate was allowed just during the first two weeks of the study
Outcomes	Primary outcome: Hamilton Rating Scale for Depression (HDRS-21), Clinical Global Impression. Secondary outcomes: HAM- anxiety and somatisation scores.
Notes	Response: decrease of at least 50% in the HAM-D total score and/or a total score less than 10. Two participants dropped out (1 in the fluoxetineand 1 in the paroxetine group) due to attempted suicide. Funding: by industry
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Eight-week double-blind, randomised, multicentre study.
Participants	Outpatients fulfilling DSM-III-R criteria for major depression, with a score of at least 20 on the HDRS-21 and depressive symptoms for at least 1 month before study entry. Age range: 18-60. Exclusion criteria: pregnancy, absence of methods of contraception, known sensitivity to fluoxetine or venlafaxine, history of significant cardiac, renal or hepatic disease, clinically significant abnormalities on a screening examination, ECG, laboratory tests, acute suicide tendency, seizures, history or presence of any psychotic disorder not associated with depression, drug or alcohol dependence within the past year, psychotherapy, use of fluoxetine, antipsychotic drugs, ECT, MAOI within the past 14 days, any other antidepressant, anxiolitics, sedative-hypnotic drugs (but zopiclone) within 7 days before baseline
Interventions	Fluoxetine: 186 participants. Venlafaxine: 196 participants. Fluoxetine dose range: 20-40. Venlafaxine dose range: 75-125.
Outcomes	Primary outcomes: Hamilton Rating Scale for Depression (HDRS-21), Montgomery and Asberg Scale for Depression (MADRS), CGI-Severity of Illness and Improvement
Notes	Response: decrease of at least 50% in the HAM-D or in the MADRS, or a CGI-I score of 1 or 2. Funding: by industry
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Six-week double-blind, randomised, two-site study.
Participants	Inpatients fulfilling DSM-III-R criteria for major depressive disorder without psychotic features, with a score of at least 18 on the HDRS-17. Age range: 18-70 years. Exclusion criteria: high suicide risk, other psychiatric diagnosis, somatic disease which could controindicate treatment with fluoxetine or maprotiline, history of hypersensitivity, severe allergies, multiple severe reactions to drugs, lactation, pregnancy or pregnancy wish, MAOI use within 2 weeks before starting the trial
Interventions	Fluoxetine: 30 participants. Maprotiline: 35 participants. Fluoxetine dose range: 40-80. Maprotiline dose range: 50-150. Only oxazepam was allowed as hypnotic or anxiolitic, if absolutely required
Outcomes	Hamilton Rating Scale for Depression (HDRS-17), Raskin Depression Scale, Covi Anxiety Scale, CGI Severity and Improvement,
Notes	Funding: by industry
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Ten-week double-blind, randomised, multicentre study.
Participants	In- and outpatients fulfilling DSM-III-R criteria for major depressive disorder, with a score of at least 16 on the HDRS-17. Age range: over 60 years old. Exclusion criteria: mental organic disorder, MMSE less than 24, high suicide risk, history of alcohol or drug abuse, severe physical illness, epilepsy, schizophrenia
Interventions	Fluoxetine: 32 participants. Amitriptyline: 33 participants. Fluoxetine dose: 20 mg/day. Amitriptyline dose range: 50-100 mg/day. Patients taking lorazepam 5 mg/day for at least 6 months before enrollment were allowed to continue; triazolam was allowed (0.25 mg/day) during the first 2 weeks for insomnia
Outcomes	Hamilton Rating Scale for Depression (HDRS-17), Montgomery and Asberg Scale for Depression (MADRS), Covi Anxiety Scale, CGI-Severity and Improvement, PGI, LSEQ
Notes	Response: decrease of at least 50% in the HAM-D total score or a total score less than 10. Funding: unclear
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Six-week double-blind, randomised, study.
Participants	Patients fulfilling DSM-III criteria for major depression, with a score of at least 18 on the HDRS-21. Age range: 18-65. Exclusion criteria: pregnancy, lactation, severe concomitant disease, schizophrenia, abuse of alcohol or drugs, severe risk of suicide, ECT in the previous 3 months, MAOI or oral neuroleptics in the previous 14 days, depot neuroleptics in the previous 4 weeks, patients receiving lithium
Interventions	Fluoxetine: 41 participants. Paroxetine: 37 participants. Fluoxetine dose range: 20-60 mg/day. Paroxetine dose range: 20-40 mg/day. Temazepam or other short-acting benzodiazepines were permitted as hypnotic
Outcomes	Hamilton Rating Scale for Depression (HDRS-21), Montgomery and Asberg Scale for Depression (MADRS), Hopkins Symptoms Check List, CGI-impression
Notes	Funding: by industry
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Nine-week double-blind study.
Participants	Outpatients fulfilling DSM-III-R criteria for major depression, with a score of at least 15 on the HDRS-21. Age range: 18-60 years. Exclusion criteria: not stated.
Interventions	Fluoxetine: 35 participants. Amitriptyline: 31 participants. Fluoxetine dose:20 mg/day. Amitriptyline dose: 150 mg/day.
Outcomes	Hamilton Rating Scale for Depression (HDRS-21), Clinical Global Impression
Notes	Response: decrease of at least 50% in the HAM-D total score. Funding: by industry.
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

PERMALINK

Fluoxetine versus other types of pharmacotherapy for depression

Andrea Cipriani

Paulo Brambilla

Toshi A Furukawa

John Geddes

Manuela Gregis

Matthew Hotopf

Lara Malvini

Corrado Barbui

Abstract

Background

Objectives

Search methods

Selection criteria

Main results

Authors’ conclusions

BACKGROUND

OBJECTIVES

METHODS

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Search methods for identification of studies

Data collection and analysis

Duplicate studies

Data extraction

Study quality

Dichotomous outcomes

Continuous outcomes

Statistical analysis

RESULTS

Description of studies

Risk of bias in included studies

Effects of interventions

Comparative efficacy

TCAs

Heterocyclics

SSRIs

Newer ADs

Comparative tolerability

TCAs

Heterocyclics

SSRIs

Newer ADs

Adverse effects

Suicide

Fluoxetine dose

DISCUSSION

AUTHORS’ CONCLUSIONS

Implications for practice

Implications for research

PLAIN LANGUAGE SUMMARY.

Fluoxetine compared with other antidepressants for depression

ACKNOWLEDGEMENTS

CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

DATA AND ANALYSES

Comparison 1.

Comparison 2.

Comparison 3.

Comparison 4.

Comparison 5.

Comparison 6.

Comparison 7.

Comparison 8.

Analysis 1.1. Comparison 1 Fluoxetine vs TCAs, Outcome 1 Failure to respond - HDRS (−50%).

Analysis 1.2. Comparison 1 Fluoxetine vs TCAs, Outcome 2 End-point score on HDRS

Analysis 1.3. Comparison 1 Fluoxetine vs TCAs, Outcome 3 Failure to complete - Total

Analysis 1.4. Comparison 1 Fluoxetine vs TCAs, Outcome 4 Failure to complete - Inefficacy

Analysis 1.5. Comparison 1 Fluoxetine vs TCAs, Outcome 5 Failure to complete - Side Effects

Analysis 2.1. Comparison 2 Fluoxetine vs Heterocyclics, Outcome 1 Failure to respond - HDRS (−50%)

Analysis 2.2. Comparison 2 Fluoxetine vs Heterocyclics, Outcome 2 End-point score on HDRS

Analysis 2.3. Comparison 2 Fluoxetine vs Heterocyclics, Outcome 3 Failure to complete - Total

Analysis 2.4. Comparison 2 Fluoxetine vs Heterocyclics, Outcome 4 Failure to complete - Inefficacy

Analysis 2.5. Comparison 2 Fluoxetine vs Heterocyclics, Outcome 5 Failure to complete - Side Effects

Analysis 3.1. Comparison 3 Fluoxetine vs other SSRIs, Outcome 1 Failure to respond - HDRS (−50%)

Methods	Eight-week randomised, multicentre study.
Participants	Outpatients fulfilling DSM-III-R criteria for major depression, with a score of at least 20 on the HDRS-21. Age range: 18-55 years. Exclusion criteria: lactation, childbearing potential, previous treatment with venlafaxine or fluoxetine, history of clinically significant medical disease, abnormalities on ECG or laboratory tests, acute suicidal tendencies, history of seizure disorder, organic mental disorder, bipolar disorder, history of any psychotic disorder not associated with depression, current use of investigational drugs, antipsychotic drugs, ECT within the previous 30 days or MAOI or paroxetine within the previous 14 days, use of antidepressant or hypnotic drugs, but zopiclone (7.5 mg), history of drug or alcohol abuse
Interventions	Fluoxetine: 75 participants. Venlafaxine: 70 participants. Fluoxetine dose range: 20-40 mg/day. Venlafaxine dose range: 75-150 mg/day. Only zopiclone was allowed for insomnia.
Outcomes	Hamilton Rating Scale for Depression (HDRS-21), Montgomery and Asberg Scale for Depression (MADRS), Clinical Global Impression, SCL-61
Notes	Funding: by industry
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Eight-week randomised, double-blind, multicentre study.
Participants	Outpatients fulfilling DSM-III-R criteria for major depression, with a score of at least 20 on the HDRS-21. Age range: 18-83. Exclusion criteria: history of clinically significant disease, abnormalities on ECG or laboratory tests, acute suicidal tendencies, history of seizure disorder, organic mental disorder, bipolar disorder or personality disorder, history of any psychotic disorder not associated with depression, venlafaxine or fluoxetine hypersensitivity or use within 2 months of baseline, current use of investigational drugs, antipsychotic drugs, ECT or MAOI within the previous 14 days, use of antidepressant drug within 7 days, use of any anxiolitic that could not be withdrawn at baseline, drug or alcolhol abuse within 2 years of the start of the study
Interventions	Fluoxetine: 161 participants. Venlafaxine: 153 participants. Fluoxetine dose: 20 mg/day. Venlafaxine dose range: 75-150 mg/day.
Outcomes	Primary outcomes: Hamilton Rating Scale for Depression (HDRS-21), Montgomery and Asberg Scale for Depression (MADRS), CGI scales
Notes	Response: decrease of at least 50% in the HAM-D or MADRS total score, or a score of 1 or 2 on the CGI. Funding: by industry
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Six-week randomised, double-blind study.
Participants	Outpatients fulfilling DSM-III-R criteria for double depression (disthimia and major depression), with a score of at least 16 on the HDRS. Age range: 18-65 years. Exclusion criteria: suicidal tendencies, delusional depression, severe organic disease, alcoholism, drug abuse, ongoin ECT or structured psychotherapy
Interventions	Fluoxetine: 21 participants. Moclobemide: 21 participants. Fluoxetine dose: 20. Moclobemide dose: 300. Use of single benzodiazepines was allowed at discretion of the doctor
Outcomes	Primary outcomes: percentage of responders defined as decrease of at least 50% in the HDRS. Secondary outcomes: endpoint score on HDRS, percentage of end of treatment CGI very good and good responses
Notes	Funding: by industry
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Five-week randomised, double-blind, multicentre study.
Participants	Outpatients fulfilling DSM-III-R criteria for major depression (single episode or recurrent). Age range: 18-65 years. Exclusion criteria: concurrent diagnosis of bipolar disorder or schizophrenia, hyperactivity or agitation, presence of hyper thyroidism or a clinically unstable medical condition, history of narrow angle glaucoma, urinary retention, seizures or substance abuse, MAOI use within 14 days of baseline, pregnancy, lactation, potential childbearing, history of allergy to the study drugs
Interventions	Fluoxetine: 103 participants. Nortriptyline: 102 participants. Fluoxetine dose range: 20-40 nortriptyline dose range: 50-100.
Outcomes	Hamilton Rating Scale for Depression, Zung Depression Scale, CGI Impression
Notes	Funding: unclear
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Twelve-week randomised, double-blind, multicentre study.
Participants	Outpatients fulfilling DSM-III-R criteria for moderate to moderately severe major depression without a history of mania or hypomania, with a score of at least 18 on the HDRS-17, of at least 8 on the Raskin Depression Scale (and grater than Covi score). Mean age: 41.3 years. Exclusion criteria: schizophrenia, adjustment disorder, bipolar disorder, panic disorder, social phobia, obsessive complusive disorder, psychotic depression, atypical depression, serious concomitant medical illness, significant abnormal laboratory values, history of seizure disorder, high suicidal risk, recent history of alcohol or drug abuse, use other psychotropic drug within 14 days of baseline, ECT within 3 months of baseline, any investigational drug within 30 days of baseline, previous treatment with paroxetine, pregnancy, childbearing potential without contraceptive
Interventions	Fluoxetine: 54 participants. Paroxetine: 55 participants. Placebo: 19 participants. Fluoxetine dose range: 20-80 mg/day. Paroxetine dose range: 20-50 mg/day.
Outcomes	Hamilton Rating Scale for Depression (HDRS-21), Covi Anxiety Scale, Raskin Depression Scale
Notes	Response: decrease of at least 50% in the HDRS-21 total. score. Funding: by industry
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Ten- to sixteen-week randomised, double-blind, multicentre study
Participants	Outpatients fulfilling DSM-IV criteria for major depression or atypical major depression, with a baseline score of at least 16 on the first 17 items of the HDRS-28. Mean age: 40.3 in the fluoxetine group, 44.1 in the sertraline one, 41.4 in the paroxetine one. Exclusion criteria: pregnancy, lactation, suicide risk, serious medical illness, seizurfe disorders, presence of any of the following diagnosis: organic mental disorder, substance use disorder, schizophrenia, delusional disorder, psychotic disorders not elsewhere classified, biopolar disorder, antisocial personality disorder, mood congruent or modd incongruent features, history of multiple adverse drug reations, concomitant use of any antidepressants, anxiolitic or other psychotropic medication witin 7 days prior study entry, with the exception of chloral hydrate, hyper- or hypothyroidism, use of MAOI within 2 weeks of active therapy, lack of response to the treatment of a current major depressive episode by any SSRI
Interventions	Fluoxetine: 35 participants. Sertraline: 43 participants. Paroxetine: 30 participants. Fluoxetine dose range: 20-60 mg/day. Sertraline dose range: 50-200 mg/day. Paroxetine dose range: 20-60 mg/day.
Outcomes	Primary outcome: total score on the Hamilton Rating Scale for Depression (HDRS-17), Hamilton Anxiety/Somatisation Factor
Notes	Patients recruited had major depression and a high level of anxiety. Response: decrease of at least 50% in the HDRS-17 total. Remission: total score of maximum 7 on the HDRS-17 at the endpoint. Funding: by industry
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Ten-week randomised, double-blind, multicentre study.
Participants	Outpatients fulfilling DSM-IV criteria for major depression or atypical major depression, with a baseline score of at least 16 on the first 17 items of the HDRS-28. Age range: over 18 years old. Exclusion criteria: pregnancy, lactation, suicide risk, serious medical illness, seizure disorders, presence of any of the following diagnosis: organic mental disorder, substance use disorder, schizophrenia, delusional disorder, psychotic disorders not elsewhere classified, bipolar disorder, antisocial personality disorder, mood congruent or modd incongruent features, history of multiple adverse drug reations, concomitant use of any antidepressants, anxiolitic or other psychotropic medication witin 7 days prior study entry, with the exception of chloral hydrate, hyper- or hypothyroidism, use of MAOI within 2 weeks of active therapy, lack of response to the treatment of a current major depressive episode by any SSRI
Interventions	Fluoxetine: 92 participants. Sertraline: 96 participants. Paroxetine: 96 participants. Fluoxetine dose range: 20-60 mg/day. Sertraline dose range: 50-200 mg/day. Paroxetine dose range: 20-60 mg/day.
Outcomes	Primary outcome: total score on the Hamilton Rating Scale for Depression (HDRS-17). Secondary outcome: improvement on the CGI Severity scale and HAM-D sleep disturbance, A/S, R, cognitive disturbance (COG) factors
Notes	Response: decrease of at least 50% in the HDRS-17 total. Remission: total score of maximum 7 on the HDRS-17 at the endpoint. Funding: by industry
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Five-week randomised, double-blind study.
Participants	Outpatients fulfilling Research Diagnostic Criteria criteria for unipolar major depression, with a score of at least 20 on the HDRS and Raskin Depression Scale score of at least 8. Age range: 19-69 years. Exclusion criteria: serious illness or condition th<at controindicated the use of amitriptilyne or that could make patients unsuitable for study
Interventions	Fluoxetine: 22 participants. Amitriptyline: 22 participants. Fluoxetine dose range: 20-80 mg/day. Amitriptyline dose range: 75-300 mg/day. Only chloral hydrate (max 1 g) was allowed for sleep and one benzodizepine for agitation
Outcomes	Hamilton Rating Scale for Depression, Raskin Depression Scale, Covi Anxiety Scale, CGI
Notes	Funding: unclear
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Six-week randomised, double-blind two-centre study.
Participants	Outpatients fulfilling DSM-III-R criteria for non-psychotic major depressive episode, lasting between 4 weeks to 2 years, single or recurrent, which was not secondary to another pre-existing psychiatric or medical condition, with a score of at least 20 on the HDRS-21. Age range: over 18 years old. Exclusion criteria: seizures, current diagnosis or history of hepatic or renal disfunction, anorexia or bulimia, other unstable medical disorder, pregnancy, lactation, childbearing potential, alcohol or substance abuse within the past year, use of psychoactive drug within 1 week of baseline, previous treatment with buproprion or fluoxetine, high suicidal risk
Interventions	Fluoxetine: 62 participants. Bupropion: 61 participants. Fluoxetine dose range: 20-80 mg/day. Bupropion dose range: 225-450 mg/day.
Outcomes	Hamilton Rating Scale for Depression (HDRS-21), CGI Severity and Improvement, Hamilton Rating Scale for Anxiety
Notes	Funding: by industry
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear

Methods	Four-week randomised, double-blind, two-centre study.
Participants	Inpatients fulfilling DSM-III-R criteria for major depression, with a score of at least 18 on the HDRS-17. Age range: 18-65 years old. Exclusion criteria: seroious allergise, drug and alcohol abuse, resistance to a previous treatment with an antidepressant prescribed at an effective dosae during at leaast 3 weeks, and theraphy with MAOI in the last 14 days, or with fluoxetine in the last 5 weeks
Interventions	Fluoxetine: 34 participants. Moclobemide: 36 participants. Fluoxetine dose range: 20-40 mg/day. Moclobemide dose range: 300-600 mg/day. Chloral hydratwe and low dose of diazepam as hypnotic or/and anxiolitic were allowed
Outcomes	Hamilton Rating Scale for Depression (HDRS-17), CGI.
Notes	Response: decrease of at least 50% in the HDRS-17 total. Funding: unclear
*Risk of bias*
Item	Authors’ judgement	Description
Allocation concealment?	Unclear	B - Unclear