Antidepressant prescribing in Irish children: secular trends and international comparison in the context of a safety warning

Depression is common in young people and contributes to a variety of negative outcomes such as poor academic attainment, difficulty in peer and family relations, and increased risk of suicide [1]. Major depressive disorder has a lifetime prevalence of 20.7 % in adults [1, 2]; and affects up to 10 % of children [3]. Common symptoms of depression in childhood include low mood, loss of interest in once enjoyed activities, psychosomatic symptoms and in severe cases thoughts of suicide [1]. Depression in childhood, if left untreated, is likely to continue into adulthood and over time becomes increasingly difficult to treat [4]. Childhood depression can last for several months, is recurrent and is twice as likely to be observed in teenage girls as teenage boys [5]. A higher rate of depression in teenage girls has been associated with hormonal changes related to puberty rather than age related development [5].

Anti-depressants are often used to treat depression, anxiety and other disorders in children and adolescents [6]. The late 1990’s saw a steady increase in the use of anti-depressants in children, fuelled primarily by the rise in popularity of selective serotonin reuptake inhibitors (SSRIs) [7‐9]. This rise was influenced by two factors; early studies showing their effectiveness in treating adult depression and drug trials that showed the ineffectiveness of tryciclic anti-depressants in the treatment of childhood depression [3]. Further support for their use in childhood depression and anxiety came from early randomised controlled trials (RCT) which showed high levels of SSRI efficacy in comparison to placebo [7, 10, 11]. However, reviews of SSRI safety and efficacy in the treatment of childhood depression later revealed they were more harmful than what had been originally reported [12, 13].

In 2003, the Food and Drug Administration (FDA) requested that GlaxoSmithKline (GSK) provide the results of all drug trials that had examined the efficacy of SSRIs in the treatment of Major Depressive Disorder (MDD) in children. This request followed the airing of a documentary which highlighted the side effects of Seroxat (paroxetine) and the suppression of data reporting these side effects by the pharmaceutical industry. In May 2003, the GSK report revealed an association with paroxetine and suicidal behaviour in children. Following this, and other reports the FDA published an advisory paper highlighting the increased risk of suicidal behaviour in children being treated with SSRIs. Later that year, the Medicines and Health Regulatory Agency (MHRA) issued a recommendation to withdraw the use of all SSRIs in children with MDD, except for fluoxetine [12], a move which was endorsed by the Irish Medical Board (IMB). In late 2004, the FDA required that manufacturers add a black box warning to all SSRIs including the risk of suicidal behaviours [13]. The SSRIs paroxetine, sertraline and citralopram were contraindicated in children for the treatment of depression following these warnings. Since 2004 these warnings have been extended, the FDA increased the age bracket from 18 to 24 in 2007 and the IMB adapted the SSRI warning up to the age of 25 in 2008 (see Table 1) [14].

Increased rates in psychotropic drug prescribing in children have been reported in recent times [15‐19], and anti-depressants are often the most frequently prescribed [15‐17]. While studies have shown that prevalence of anti-depressants declined immediately following the introduction of the FDA boxed warnings [6, 20], there is evidence to suggest that this decline was not sustained and that the prevalence of paediatric anti-depressant prescribing is on the rise [21]. Furthermore, there is wide variability across countries in the use of anti-depressant medication for children. For example, in 2000 in the US, the prevalence was 15 times greater than that of Germany, and the rate in Germany was 9 times greater than that in Denmark [9]. These differences are thought to be due to several factors; including differences in diagnostic criteria, treatment guidelines, drug regulations and healthcare systems [9].

The aims of the current study are (i) to examine whether the introduction of the IMB warnings was associated with a reduction in overall and specific prevalence of anti-depressants in Irish children, and (ii) to establish whether the effect of this warning was maintained. Age and gender trends were also considered, and additionally, the prevalence of anti-depressants in children in Ireland was compared to international studies.

The study observed that SSRI prescription rates reduced significantly following the introduction of the IMB warning. It showed that paroxetine rates reduced from 2002 onwards, which may indicate the influence of media coverage on Irish prescribing. Results show that adolescent girls are more likely to receive a prescription of anti-depressants than adolescent boys and the overall prevalence of anti-depressants in 0–15 year olds in Ireland lies close to the median value in comparison to international studies.

An overall reduction in the prevalence of SSRIs and all anti-depressants in children over the study period was seen. These reductions appear to be influenced by the IMB and MHRA regulatory recommendations of 2003. Higher rates of fluoxetine prescribing further supports this. The MHRA deemed fluoxetine an acceptable treatment of MDD in children, a stance which was adopted by the IMB. Interestingly, the prevalence of fluoxetine increases from 2002 to 2011. This suggests that while the prevalence of SSRIs decreased over time, the prevalence of fluoxetine, in Ireland, was not affected by the general black box warning placed on all SSRIs by the FDA.

In addition to an overall reduction in the prevalence of anti-depressants, the study observed a significant reduction in the prevalence of contra-indicated anti-depressants - paroxetine and citralopram and to some extent sertraline. This decrease, coupled with the increase of fluoxetine prescribing, suggests a possible link between the IMB warning and prescription practices. The decrease in citralopram began in 2003, the year the warning was issued. The decline in paroxetine use was more pronounced than the other SSRIs and began in 2002, prior to the IMB warnings [25].

Since 2005 the prevalence of SSRIs in children on the GMS has remained relatively stable (2.1/1000 population). While not significant, the prevalence increased in the latter part of the study period. This may indicate that concerns about the risks associated with SSRIs have dissipated in recent years. This may be due to contradictions that exist in recent literature regarding the safety and efficacy of SSRIs. For example, some studies report no increased risk of suicidality following SSRI prescriptions in childhood [26] and others suggest that a relationship exists between decreases in the prevalence of SSRIs and increases in suicide behaviour among young people [27]. Contrary to this view a recent review of published and unpublished SSRI research revealed significant increases in suicidal behaviour in children taking contraindicated SSRIs [12‐14, 28, 29].

Age and gender analysis revealed that before adolescence (<12 years of age), boys were more likely to be prescribed an anti-depressant than girls. This trend reversed after age 12 where significantly more girls received an anti-depressant prescription than boys. This finding is in line with previous research, whereby prepubescent boys show higher rates of anti-depressant prescriptions than prepubescent girls [11], and adolescent girls show higher rates of anti-depressant prescriptions than adolescent boys [11, 21, 24]. Research shows that girls aged 3–13 years are less likely than boys to be diagnosed with major depression and girls age 12–17 are more likely to meet the diagnostic criteria of major depression than boys [11]. Age trends reveal that older children (12–15 age groups) are more likely to be prescribed an anti-depressant than both younger age groups. This is consistent with previous research which shows that the rate of anti-depressant and overall psychotropic prescriptions increases with age [18, 27].

The prevalence of anti-depressants in the current study are similar in size and trend to those found in the UK primary care database which examined prevalence from 1995 to 2009 [11]. They found a reduction of SSRI rates following the FDA warning. However, of the contra-indicated SSRIs only paroxetine showed a significant decrease following 2003; citralopram and sertraline were not affected. This difference in contra-indicated prescription trends may be a consequence of methodological differences between our study and the UK study. Our study examined year on year prescription rates, whereas the UK study looked at 3 time periods (1995 – 2002, 2003–2005, and 2006–2009).

While the overall prevalence for the current study was similar to the UK, it was higher than Germany, the Netherlands and Denmark. Denmark showed the smallest overall prevalence and the Danish prescribing trends did not seem to be affected by the FDA warning. The rates in the US study were twice the rate of our study, which is in line with previous research findings [17]. The differences in prescription trends may be due to high levels of heterogeneity between the studies, cultural variation in prescription practices and differences in the availability of other treatments options [28].

After 2003, a significant decrease in the prevalence of SSRIs in children, particularly paroxetine and citralopram, was found. The prevalence of fluoxetine remained stable and increased from 2002 to 2011. The direction and timing of these trends suggest that medical practitioners followed the FDA and CSM advice, although the earlier reduction of paroxetine would suggest that the negative media attention had an influence on prevalence, though it is unknown whether this effect was patient or practitioner driven.