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In the past 20 years, there has been much progress toward linking medical practice to evidence (1). The medical evidence base is now international and available to clinicians around the world. International differences in antidepressant (AD) medication prescribing practices are therefore of considerable epidemiologic significance. They may highlight departures from evidence-based practice. Ideally, international monitoring of practice patterns should be carried out to identify these differences. To date, this has not occurred, although epidemiologic surveys of prescribing practices carried out in different countries have highlighted heterogeneity in dosages used by clinicians treating mood disorders (2–4). It may also be possible to identify international differences as they appear in published clinical trials of AD medications. An ongoing Cochrane review concerned with the antidepressant fluoxetine includes published randomized controlled trials (RCTs) comparing fluoxetine with other antidepressants (5) and offers an opportunity for international comparisons. MethodsInclusion Criteria We included only studies randomly allocating patients with major depression to fluoxetine vs any other AD agent. We excluded crossover studies and trials of depression patients with a concomitant medical illness. Search Strategy We located RCTs by searching the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR) and the Cochrane Central Register of Controlled Trials (CENTRAL). We used the following terms: fluoxetin* or adofen or docutrix or erocap or fluctin or fluctine or fluoxeren or fontex or ladosage or lorien or lovan or mutan or prozac or prozyn or reneuron or sanzur or saurat or zactin. We searched Medline and Embase with no year limits, using the search terms fluoxetine and randomized controlled trial or random allocation or double-blind method. Non-English language articles were included and reference lists of relevant papers and previous systematic reviews were hand searched for published reports and citations of unpublished research. Data Extraction For each trial, we extracted the following information: year of publication; country wherein the study was carried out; setting; and minimum, maximum, and mean fluoxetine and comparator AD dosage. Studies carried out in psychiatric hospitals or in psychiatric wards of general hospitals and studies that recruited inpatients in these facilities and followed them up on an outpatient basis were considered RCTs in inpatients. Studies carried out in psychiatric outpatient settings (either public or private) or among general practice patients or in any other outpatient services were considered RCTs in outpatients. Finally, for each trial we recorded whether fluoxetine was the experimental drug studied in comparison with older AD agents or whether it was the reference drug studied in comparison with newer AD agents. Data Presentation and Analysis We converted fluoxetine and comparator AD dosages in mgs into multiples of the defined daily dosage (DDD) for each drug by dividing the prescribed daily dosage (PDD) by the DDD (PDD / DDD). This measure is the international unit of drug use approved by the World Health Organisation for drug use studies (6). The DDD is a theoretical unit of measurement defined as the assumed daily average maintenance dosage for a drug used for its main indication in adults. (A list of all medication DDDs is available at www.whocc.no/atcddd). The DDD of fluoxetine is 20 mg. A ratio of 1 indicates that the dosage prescribed is equal to the DDD of that drug; a ratio greater than 1 indicates a dosage higher than the standard dosage; a ratio lower than 1 means a low dosage (7). We used Fisher’s exact test to compare fluoxetine unweighted and weighted mean and maximum dosages in different countries. Fluoxetine mean dosages were weighted with weights based on the square root of each study’s sample size. Fluoxetine and comparator AD multiples of the DDD are reported with the 95%CI. We derived this from the standard error of the mean; it is a very useful measure of dispersion of a distribution. The use of CIs is strongly supported in reporting trials and metaanalyses. Previous studies have shown that RCTs carried out in outpatient settings tend to enrol patients with less severe forms of depression and to use lower dosages; higher dosages tend to be used when fluoxetine is the experimental rather than the comparator drug (8,9). The year of publication may also be associated with fluoxetine dosage. We therefore carried out a subgroup analysis to investigate the role of publication year, setting, and fluoxetine as the experimental rather than comparator drug as possible confounders of international dosage comparisons. ResultsCharacteristics of Included Studies A total of 131 articles reported results from 132 clinical trials comparing fluoxetine with another AD (10–140). Most studies were carried out in the US or in Europe. There were 34 studies conducted exclusively in the US and 1 study that was conducted jointly in the US and Canada. There were 74 European studies. Of these, 12 were conducted in the UK, 9 in Belgium, 7 in Germany, 13 in France, and 11 in Italy. An additional 12 studies derived from other single European countries; the remaining 10 were international collaborations. Of the final 23 studies, 12 were North American but non-US studies: 8 were conducted in Canada and 4 in Mexico. There were 4 South American Studies, 1 each from New Zealand and Australia, 2 African studies, and 1 conducted in Israel. Three studies were international collaborations between Europe and Australia or South America. In North America, most (30/32) clinical trials reporting dosage information were outpatient trials. In Europe, approximately one-half (37/66) the trials reporting this information were outpatient trials, the remainder being inpatient (n = 11) or mixed (n = 18) trials. In 35/74 studies conducted in Europe and in 15/34 studies conducted in North America, fluoxetine was the experimental drug. In the remaining trials, fluoxetine was the control agent. Fluoxetine minimum dosage was reported in 130 trials. The minimum dosage did not vary greatly across these international regions: 111 (85.4%) adopted a 20-mg daily minimum dosage. The mean and maximum dosages, however, presented much more variability. Fluoxetine Mean Dosage Information on fluoxetine mean dosage was available in 74 studies. In this group of studies, the average mean dosage was 38.5 mg daily. Lower dosages were generally observed in the European studies, compared with the US studies (Table 1). Weighting these averages by the square root of sample size had no effect on these estimates (Table 1). Comparison of the DDD ratio of the mean fluoxetine dosage used in each group of countries confirmed that higher dosages were used in US studies (Table 1).
Fluoxetine Maximum Dosage Information on fluoxetine maximum dosage was available in 130 studies. The European and US patterns were found to differ markedly (Table 2), with the modal maximum being 20 mg daily in Europe and 80 mg daily in the US. The pattern in Canada and Mexico (where the modal maximum was 60 mg daily) appeared to be intermediary between these 2 extremes, but the small number of trials precluded a definitive interpretation. Again, comparison of the DDD ratio of the maximum fluoxetine dosage in each group of countries confirmed that higher dosages were used in US studies (Table 2).
Comparator AD Mean and Maximum Dosage Comparison of the mean and maximum dosage of comparator ADs used in each group of countries, expressed as DDD ratios, showed that higher mean and maximum dosages were used in US studies (Table 3).
Subgroup Analysis Fluoxetine maximum dosage could not be stratified by setting because only a few US trials were not outpatient trials. However, after restriction of the comparison to outpatient trials, the European–US maximum dosage difference remained significant: in Europe, 53/74 outpatient trials (71.6%) employed a maximum fluoxetine dosage of 20 to 40 mg daily; in the US, 10/34 outpatient trials (29.4%) employed a maximum fluoxetine dosage of 20 to 40 mg daily (Fisher’s exact P < 0.001). In addition, the fluoxetine maximum dosage was stratified according to whether fluoxetine was used as the experimental or the control agent. Where fluoxetine was the experimental drug, 25/39 European trials (64.1%) employed a maximum fluoxetine dosage of 20 to 40 mg daily, whereas 1/19 US trials (5.3%) employed a maximum fluoxetine dosage of 20 to 40 mg daily (Fisher’s exact P < 0.001). Where fluoxetine was the control drug, 28/35 European trials (80%) employed a maximum fluoxetine dosage of 20 to 40 mg daily, whereas 9/15 US trials (60%) employed a maximum fluoxetine dosage of 20 to 40 mg daily (Fisher’s exact P = 0.17). Earlier studies tended to use higher mean fluoxetine dosages. Overall, the mean fluoxetine dosage for studies published prior to 1994 was 49.6 mg daily, compared with 28.6 mg daily in subsequent studies. Within each time period, however, differences between the US and European studies continued to be evident. In European studies conducted after 1994, the mean fluoxetine dosage was 24.7 mg daily (95%CI, 21.5 to 27.9), compared with 36.8 mg daily in the US studies (95%CI, 30.5 to 43.1). We observed a similar pattern in studies conducted prior to 1994, where the mean European dosage was 45.2 mg daily (95%CI, 35.2 to 55.2) and the mean US dosage was 57.8 mg daily (95%CI, 47.5 to 68.2). However, the CIs associated with the latter set of estimates did not provide statistical confirmation of dosage differences. DiscussionFluoxetine clinical trials conducted in the US used higher dosages, compared with trials conducted in Europe. Comparisons with other world regions were difficult because of the small number of clinical trials conducted in places other than the US and Europe. This study has limitations. First, we excluded a relevant proportion of RCTs not reporting dosage information from the analysis. In many cases, trial reports failed to specify either the mean dosage of fluoxetine and the comparator AD employed or the proportion of subjects receiving a specified dosage regimen. In some cases, the maximum fluoxetine dosage was reported—a measure probably reflecting the trial design more than the investigators’ prescribing behaviour. The systematic exclusion of studies lacking data on dosages may have determined selection bias, since it could be hypothesized that the studies not reporting dosage information were those adopting particularly high or low dosage regimens. Obviously, only a proper reporting of all dosage information in clinical trials of AD drugs would have overcome this limitation; however, studies not reporting dosage information were equally distributed across the world regions, and their exclusion did not likely hamper the international comparison. A second limitation is that the small number of included studies did not allow proper stratification by confounders. Since RCTs carried out in outpatient settings tend both to enrol patients with less severe forms of depression and to use lower dosages (141), it was relevant to show that, after restriction of the comparison to outpatient trials, the European–US difference in maximum dosage remained significant. However, the same analysis was not possible in inpatient settings because only a small number of inpatient trials had dosage information. Similarly, previous data showed that higher dosages tend to be used when fluoxetine is an experimental rather than a comparator drug (8), and after we restricted comparison to trials where fluoxetine was the experimental drug, the European–US maximum dosage difference remained significant. However, when we conducted the same analysis after restricting the comparison to trials where fluoxetine was the control drug, we failed to find statistically significant differences, which possibly reflects the small number of studies included in this analysis. Finally, we did not analyze the relation between dosage and outcome or side effects. Although this would have added some interesting insights to our results, it was not preplanned in the protocol of this systematic review. We therefore decided to avoid a post hoc analysis that might generate unreliable and ambiguous data. Clinical trial data can be expected to reflect local clinical practice patterns, since most clinical trial protocols allow some flexibility for dosage, and the practice patterns of participating clinicians are likely to be reflected in the dosages that they use in the trial. Obviously, clinicians who participate in clinical trials do not necessarily represent all clinicians prescribing a drug, nor does the manner of practice in a clinical trial necessarily reflect daily practice. The differences reported here may therefore be only indirect evidence of different practice styles. However, effects in the opposite direction are also plausible. These differences may reflect a different style of practice in the US, or they may be contributing to the perpetuation of different styles of practice. 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Author(s)Manuscript received November 2003, revised, and accepted April 2004. 1. Associate Professor, Departments of Community Health Sciences and Psychiatry, University of Calgary, Calgary, Alberta. 2. Postdoctoral Fellow, Department of Medicine and Public Health, Section of Psychiatry, University of Verona, Verona, Italy. 3. Assistant Professor, Department of Pathology and Experimental and Clinical Medicine, Section of Psychiatry, University of Udine, Udine, Italy. 4. Assistant Professor, Department of Medicine and Public Health, Section of Psychiatry, University of Verona, Verona, Italy. Address for correspondence: Dr C Barbui, Department of Medicine and Public Health, Section of Psychiatry, University of Verona, Ospedale Policlinico 37134 Verona, Italy. e-mail: corrado.barbui@univr.it
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