Meta-analyses were based on original data from the US IND database, on a virtual total of 87 studies of 9,084 potential patients using the drug.
Main results and study characteristics are summarized in table .
Study characteristics and main results
The paper evaluating efficacy and safety of fluoxetine for the short-term treatment of major depression[31
], calculated the odds ratio analysis and the percentage of responders (based on HDRS-17 improvement and CGI outcome) compared with placebo and TCAs. All performed analysis showed a statistically significant benefit compared with placebo. No statistically significant differences were observed in the comparison with TCAs in terms of efficacy.
In terms of discontinuations, significantly more dropouts because of lack of efficacy were observed in the placebo treated group. No significant difference was observed in the comparison with TCAs.
Significantly more TCA treated patients discontinued the studies than fluoxetine treated patients (on an average of about 2 times more); more fluoxetine treated patients discontinued for the same reason.
Overall, significantly fewer patients on fluoxetine discontinued treatment due to any adverse event compared (as compared with TCAs), while a not-significant difference in discontinuation rate for any reason was found vs placebo.
Minor differences in the Fluoxetine group, regarding the discontinuation rate for any reason, were not found to be statistically significant, as compared to the placebo group.
The Beasley meta-analysis is on the safety of fluoxetine compared with TCAs or placebo[28
], substantially confirmed these results in terms of safety. It also adds some interesting information about types of ADE and better points out the role of fluoxetine's dosage. Considering only events with an incidence above 5%, it was observed in the TCA higher group, an incidence of cholinergic ADEs (dry mouth, constipation, abnormal vision), sedation (somnolence), dizziness and peresthesia, than in patients using fluoxetine at dosages from 20 to 80 mg/die. Fluoxetine treated patients showed a higher incidence of nausea, insomnia, diarrhea, anorexia and rhinitis.
The same type of effects were substantially observed in the comparison with placebo, but some of these (nervousness, tremor, dizziness, dyspepsia) were not found to be statistically higher than in placebo treated patients, when only 20 mg/die dose was used.
The results of the analysis of discontinuations was consistent with the one reported in the Bech study[31
]. Furthermore, the drop out ratio due to adverse events of patients using 20 mg/die of fluoxetine, was similar to the ratio observed in the placebo-treated group.
These results, in terms of safety, are substantially confirmed by the Beasley study[29
] where only a 20 mg/die dosage was compared with placebo. Furthermore, these fluoxetine treated patients demonstrated significantly greater remission and response rates, mean changes on HAMD-17 total score, anxiety/somatization, retardation and cognitive disturbance factor score, than placebo treated patients (p < 0,01).
All these results confirm the hypothesis that fluoxetine at 20 mg/die, the most commonly used effective dose in the treatment of major depression, has an improved safety and tolerability profile compared with higher doses of fluoxetine.
The results of the Tollefson[34
] study assess that the probability of achieving a clinical response, defined as HAMD-21 score reduction from baseline of at least 50%, was similar for both fluoxetine and placebo at the end of week 1. However, by week 2 and after, the probability of response was greater for fluoxetine than placebo. These results challenged the current belief that a 3 to 4 week delay in the onset of antidepressant action is to be expected.
A recent Cochrane group overview on the use of antidepressants in the treatment of bulimia nervosa, including randomized placebo-controlled studies published until 2000, found that the use of drugs decreased the relative risk of binge episodes. The only SSRI included in the analysis was fluoxetine (60 mg/die).
No statistically significant differential effect could be demonstrated regarding efficacy among TCAs, SSRIs, MAOIs and other classes of antidepressants.
The results of this meta-analysis show that patients treated with antidepressants were more likely to prematurely interrupt the treatment due to an adverse event. Patients treated with TCAs dropped out for any reason more frequently than patients treated with placebo. The opposite was found with fluoxetine.
The authors conclude, "fluoxetine is the most systematically studied antidepressant agent. Even if it is not superior to other drugs in terms of efficacy, its better tolerability may justify its use as a first line antidepressant in bulimia nervosa. A daily dose of 60 mg is more effective that the antidepressant doses of 20 mg. Eight weeks seems to be an appropriate period to obtain a relevant clinical improvement. If only a partial response is noted, an alternative therapeutic approach is indicated"[27
In an analysis of the results from one fluoxetine and two clomipramine studies, Jenije et al. found both treatments to be effective with fluoxetine having fewer side effects. In this study all three treatments (clomipramine, fluoxetine and behavior therapy) were significantly effective for OCD symptoms, anxiety and depression. Only behavior therapy was not significantly effective for depressed mood.
The authors conclude: "There are still not enough appropriate treatment studies available to determine statistically the superiority of any treatment"[26
Up to 4% of the elderly experience major depression and as many as 44% experience depressive symptoms[27
]. At least three published, population-based studies associate depression in the elderly patient with greater than expected mortality[32
The mean improvement in baseline-to-endpoint HAMD-17 scores was significantly greater in fluoxetine (-7.9 ± 7.5) vs placebo-treated patients (-6.3 ± 7.1) (p < 0.01).
In the global population the anxious and nonanxious subgroups, the analysis of psychomotor agitation, psychotic anxiety or somatic anxiety, shows a consistent, but not statistically significant, trend in the improvement rate in fluoxetine treated patients as compared to the placebo group.
The only adverse event most frequently reported by fluoxetine treated patients wisthin the anxious subgroup was nervousness (p=0.03). No statistically significant differences were reported between fluoxetine and placebo-treated patients within the nonanxious subgroup.
The percentage of fluoxetine treated patients that discontinued studies due to an adverse event (11.5%) was not statistically different from placebo treated patients (9.6%) (p=0.39)[33
Suicidal ideation, assessed using the item 3 of HAMD scale which systematically rates suicidality, was evaluated using data as belonging to clinical studies comparing fluoxetine with TCAs and placebo. These were considered as emergencies (any change from 0 or 1 to 3 or 4 in the item during the double blind period) and as "worsening" any increase from baseline. The pooled incidence of suicidal acts was 0.3% for fluoxetine, 0.2% for placebo and 0.4% for TCAs; fluoxetine did not differ statistically from any comparator group. Suicidal ideation emerged slightly below the significance rate, less often than with placebo (0.9% vs 2.6%: p=0.094) and numerically less often than TCAs (1.7% vs 3.4%; p=0.102). The pooled incidence of substantial suicidal ideation emergencies was 1.2% for fluoxetine, 2.6% for placebo and 3.6% for TCAs; the incidence was significantly lower with fluoxetine than with placebo (p=0.042) and TCAs (p=0.001). The pooled incidence of "worsening", as the pooled incidence of improvement of suicidal ideation, did not differ between groups except with the incidence of improvement with fluoxetine (72.2%); which was statistically superior than with placebo (54.8%; p < 0.001) [30
All meta-analyses previously reviewed did not include or did not evaluate the safety of fluoxetine in pregnant women. An ad-hoc meta-analysis on data belonging to different sources, examined the increased risk for major malformations following the use of fluoxetine during the first trimester of pregnancy. The pooled relative risk and 95% confidence interval for major malformations does not suggest an association between the use of fluoxetine during the first trimester of pregnancy and the increased risk of major malformations. The authors conclude that the use of fluoxetine during the first trimester of pregnancy is not associated with measurable teratogenic effects in humans[26