Drop-out rates in placebo-controlled trials of antidepressant drugs: A systematic review and meta-analysis based on clinical study reports.

OBJECTIVE: To study the drop-out rates in trials of selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs and SNRIs). METHODS: This study is a systematic review and meta-analysis of trials. The main outcome measure: Overall drop-out rate. Secondary outcomes were drop-outs due to adverse events and lack of effect. We obtained clinical study reports (CSRs) of five antidepressant drugs from the European Medicines Agency and the UK's Medicines and Healthcare products Regulatory Agency. The eligibility criteria for selecting studies: double-blind randomised, placebo-controlled trials for any indication. DATA EXTRACTION AND ANALYSIS: The primary outcome was extracted by two researchers independently and meta-analysed using the Mantel-Haenszel method (fixed effect model). The secondary outcomes were extracted by one researcher and checked by another. Sensitivity analyses were performed using Peto's odds ratio and beta binomial methods, due to presence of null events, and by excluding unreliable trials. RESULTS: We included 71 CSRs (67,319 pages) with information on 73 trials (11,057 patients on SSRI or SNRI drugs, and 7,369 on placebo). There were minor discrepancies within the CSRs when a modified intention to treat principle was used and patients lost to follow up early in the trial were not accounted for. Significantly more patients dropped out on active drug than on placebo, risk ratio 1.08 (95% CI 1.03 to 1.13), with no difference between adults and children/ adolescents, RR = 1.08 (1.03 to 1.13) and 1.07 (0.95 to 1.21), respectively. When three trials with a prior single-blind phase on active drug were removed, the difference was a risk ratio of 1.12 (1.07 to 1.18), whereas the result was the same after removal of three trials with fraudulent data or other issues with data validity, risk ratio 1.08 (1.03 to 1.13). There were more drop-outs due to adverse events on active drug than on placebo, risk ratio 2.63 (2.33 to 2.96). There were fewer drop-outs due to lack of effect, risk ratio 0.47 (0.43 to 0.53). However, this result is biased; when more people drop out due to adverse effects, fewer can drop out because of lack of effect. CONCLUSIONS: By using CSRs, we were able to demonstrate for the first time that more patients dropped out on active drug than on placebo. As it can be argued that the drop-out rate reflects the patients' overall assessment of the balance between benefits and harms, our review adds to the growing concern that SSRIs and SNRIs might not have the desired effect. Our review also highlights the importance of using CSRs for undertaking reviews of drugs.

The Pharmacokinetics of Enalapril in Relation to CES1 Genotype in Healthy Danish Volunteers.

This study investigated the influence of variations in the carboxylesterase 1 gene (CES1) on the pharmacokinetics of enalapril. Forty-three healthy, Danish, Caucasian volunteers representing different pre-defined genotypes each received 10 mg of enalapril. At specified time-points, plasma concentrations of enalapril and the active metabolite enalaprilat were measured. The volunteers were divided into six different groups according to their genetic profile of CES1: group 1 (control group, n = 16) with two CES1 copies without non-synonymous SNPs in the exons; group 2 (n = 5) with four copies of CES1; group 3 (n = 6) harbouring the G143E polymorphism; group 4 (n = 2) with three CES1 copies and increased transcriptional activity of the duplication (CES1A2); group 5 (n = 4) harbouring the CES1A1c variant; and group 6 (n = 10) with three CES1 copies and the common promoter with low transcriptional activity of the duplication. The median AUC of enalaprilat in the control group was not significantly different from any of the other five groups (297 ng/ml x h in the control group versus 310, 282, 294, 344 and 306 ng/ml x h in groups 2-6, respectively). The terminal half-life of enalaprilat was significantly longer in group 6 compared with the control group (26.7 hr versus 12.7 hr, respectively). However, this was not considered clinically relevant. In conclusion, none of the selected variations of CES1 had a clinically relevant impact on the metabolism of enalapril.

Considering benefits and harms of duloxetine for treatment of stress urinary incontinence: a meta-analysis of clinical study reports.

BACKGROUND: The European Medicines Agency makes clinical study reports publicly available and publishes reasons for not approving applications for marketing authorization. Duloxetine has been approved in Europe for the treatment of stress urinary incontinence in women. The reported adverse effects of duloxetine include mental health problems and suicidality. We obtained clinical study reports from the European Medicines Agency concerning use of this drug for stress urinary incontinence. METHODS: We performed a meta-analysis of 4 randomized placebo-controlled trials of duloxetine (involving a total of 1913 patients) submitted to the European Medicines Agency for marketing approval for the indication of stress urinary incontinence in women. We used data from the clinical study reports (totalling 6870 pages and including individual patient data) to assess benefits (including frequency of incontinence and changes in quality-of-life scores, such as Patient Global Impression of Improvement rating) and harms (both general harms, including discontinuation because of adverse events, and harms related to suicidality, violent behaviour and their potential precursors, such as akathisia and activation [stimulating effects such as insomnia, anxiety and agitation]). RESULTS: Duloxetine was significantly better than placebo in terms of percentage change in weekly incontinence episodes (mean difference -13.56%, 95% confidence interval [CI] -21.59% to -5.53%) and change in Incontinence Quality of Life total score (mean difference 3.24, 95% CI 2.00 to 4.48). However, the effect sizes were small, and a sensitivity analysis (with removal of one trial) showed that the number needed to treat for a Patient Global Impression of Improvement rating of "much better or very much better" was 8 (95% CI 6 to 13). The numbers needed to harm were 7 (95% CI 6 to 8) for discontinuing because of an adverse event and 7 (95% CI 6 to 9) for experiencing an activation event. No suicidality, violence or akathisia events were noted. INTERPRETATION: Although duloxetine is effective for stress urinary incontinence in women, the rates of associated harm were high when individual patient data were analyzed, and the harms outweighed the benefits.

The impact of CES1 genotypes on the pharmacokinetics of methylphenidate in healthy Danish subjects.

AIMS: This study investigated the influence of CES1 variations, including the single nucleotide polymorphism (SNP) rs71647871 (G143E) and variation in copy number, on the pharmacokinetics of a single oral dose of 10 mg methylphenidate. METHODS: CES1 genotype was obtained from 200 healthy Danish Caucasian volunteers. Based on the genotype, 44 (19 males and 25 females) were invited to participate in an open, prospective trial involving six predefined genotypes: three groups with two, three and four CES1 copies, respectively; a group of carriers of the CES1 143E allele; a group of individuals homozygous for CES1A1c (CES1VAR); and a group having three CES1 copies, in which the duplication, CES1A2, had increased transcriptional activity. Plasma concentrations of methylphenidate and its primary metabolites were determined at scheduled time points. RESULTS: Median AUC of d-methylphenidate was significantly larger in the group carrying the 143E allele (53.3 ng ml-1  h-1 , range 38.6-93.9) than in the control group (21.4 ng ml-1  h-1 , range 15.7-34.9) (P < 0.0001). Median AUC of d-methylphenidate was significantly larger in the group with four CES1 copies (34.5 ng ml-1  h-1 , range 21.3-62.8) than in the control group (P = 0.01) and the group with three CES1 copies (23.8 ng ml-1  h-1 , range 15.3-32.0, P = 0.03). There was no difference between the groups with two and three copies of CES1. CONCLUSIONS: The 143E allele resulted in an increased AUC, suggesting a significantly decreased CES1 enzyme activity. Surprisingly, this was also the case in subjects with homozygous duplication of CES1, perhaps reflecting an undiscovered mutation affecting the activity of the enzyme.

Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports.

OBJECTIVE: To study serious harms associated with selective serotonin and serotonin-norepinephrine reuptake inhibitors.Design Systematic review and meta-analysis. MAIN OUTCOME MEASURES: Mortality and suicidality. Secondary outcomes were aggressive behaviour and akathisia. DATA SOURCES: Clinical study reports for duloxetine, fluoxetine, paroxetine, sertraline, and venlafaxine obtained from the European and UK drug regulators, and summary trial reports for duloxetine and fluoxetine from Eli Lilly's website. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Double blind placebo controlled trials that contained any patient narratives or individual patient listings of harms. DATA EXTRACTION AND ANALYSIS: Two researchers extracted data independently; the outcomes were meta-analysed by Peto's exact method (fixed effect model). RESULTS: We included 70 trials (64,381 pages of clinical study reports) with 18,526 patients. These trials had limitations in the study design and discrepancies in reporting, which may have led to serious under-reporting of harms. For example, some outcomes appeared only in individual patient listings in appendices, which we had for only 32 trials, and we did not have case report forms for any of the trials. Differences in mortality (all deaths were in adults, odds ratio 1.28, 95% confidence interval 0.40 to 4.06), suicidality (1.21, 0.84 to 1.74), and akathisia (2.04, 0.93 to 4.48) were not significant, whereas patients taking antidepressants displayed more aggressive behaviour (1.93, 1.26 to 2.95). For adults, the odds ratios were 0.81 (0.51 to 1.28) for suicidality, 1.09 (0.55 to 2.14) for aggression, and 2.00 (0.79 to 5.04) for akathisia. The corresponding values for children and adolescents were 2.39 (1.31 to 4.33), 2.79 (1.62 to 4.81), and 2.15 (0.48 to 9.65). In the summary trial reports on Eli Lilly's website, almost all deaths were noted, but all suicidal ideation events were missing, and the information on the remaining outcomes was incomplete. CONCLUSIONS: Because of the shortcomings identified and having only partial access to appendices with no access to case report forms, the harms could not be estimated accurately. In adults there was no significant increase in all four outcomes, but in children and adolescents the risk of suicidality and aggression doubled. To elucidate the harms reliably, access to anonymised individual patient data is needed.