Hostility Events in Adult and Paediatric Placebo-Controlled Trials on Therapy and in Withdrawal Phase

In these trials, hostile events are found to excess in both adults and children on paroxetine compared with placebo, and are found across indications, and both on therapy and during withdrawal. The rates were highest in children with obsessive-compulsive disorder (OCD), where the odds ratio of a hostile event was 17 times greater (95% confidence interval [CI], 2.22–130.0).

In their submissions to the Committee on Safety of Medicines Expert Working Group, GlaxoSmithKline also reported that 11,491 patients entered trials comparing paroxetine with other antidepressants [5]. In this patient cohort, 44 hostile events occurred on paroxetine or other drugs, a rate of 0.38%. In the subset of trials comparing paroxetine with another SSRI, there were 16 hostile events in 2,418 patients (0.66%). These SSRI comparator trials may be confounded by indication; the SSRI comparator trials might, for instance, have included a higher proportion of patients with OCD.

Finally, in healthy volunteer studies, hostile events occurred in three of 271 (1.1%) volunteers taking paroxetine, compared with zero in 138 taking placebo [5]. Although not statistically significant, this finding is striking because hostile events are unusual in healthy volunteer trials, and this figure was higher than the rate reported in clinical populations above. GlaxoSmithKline ascribed these episodes to the fact that the volunteers were confined, although this applied to both paroxetine and placebo volunteers. One other healthy volunteer study has reported aggressive behaviour in one volunteer taking sertraline [8].

In data from sertraline paediatric trials submitted by Pfizer, aggression was the joint commonest cause for discontinuation from the two sertraline placebo-controlled trials in depressed children [9]. In these trials, eight of 189 patients randomised to sertraline discontinued for aggression, agitation, or hyperkinesis (a coding term for akathisia), compared with no dropouts for these reasons in 184 patients on placebo (95% CI, 1.72–infinity). When discontinuations for any manifestation of treatment-induced activation (suicidal ideation or attempts, aggression, agitation, hyperkinesis, or aggravated depression) were considered, there were 15 discontinuations on sertraline compared with two on placebo, a relative risk of 7.3 (95% CI, 1.70–31.5; p = 0.0015). The report of these studies does not include an analysis of these data [9]. In the only other placebo-controlled sertraline paediatric trial, undertaken in children and adolescents with OCD, there were ten dropouts out of 92 patients on sertraline, five of whom discontinued for behavioural activation, two for agitation, one for aggression, one for nervousness, and one for emotional lability. In comparison, there was one discontinuation for hyperkinesis out of a total of two dropouts from 95 patients on placebo [10].

Finally, in paediatric trials of venlafaxine (Wyeth), two percent of children dropped out because of hostility, more than double the rate of dropout on placebo [11].

By 2003, 121 cases of aggression on paroxetine had been reported to the Medicines and Healthcare Products Regulatory Agency (MHRA), and by January 2006 that number had risen to 211 [12]. It should be noted that such reporting systems estimate that physicians report between one and ten percent of adverse effects on treatment [13].