Psychotropic Drug Use among Icelandic Children: A Nationwide Population-Based Study

Introduction

P sychotropic drug use of children in Westernized countries is a subject of continuous debate. Although research in pediatric psychopharmacology has expanded during the past decade, utilization studies have typically rested on limited data sources (Vitiello 2007). Thus, the evidence base for prevalence of use and treatment safety, as well as long-term risks and effectiveness of many psychotropic agents (on and off-label use), for children remains fragmented.

Recent drug use studies have revealed pronounced variability in the use of psychotropics between pediatric populations, both across and within countries (Vitiello 2007). Use rates within the United States have been reported to be the highest, whereas figures from Europe are generally lower but rising. Many of these findings rest on information from self-reported surveys, insurance or reimbursement data, or community and localized pharmacy-dispensing data. These data sources are often restricted to specific social or regional groups or, in the case of self-reports, the memory retrieval of individuals, which may hamper solid conclusions (Zito et al. 1997; Olfson et al. 2002; Zito et al. 2003; Faber et al. 2005; Fegert et al. 2006; Zuvekas et al. 2006; Asheim et al. 2007; Castle et al. 2007; Clavenna et al. 2007; Zito et al. 2007).

With the establishment of the nationwide Medicines Registry in 2003, Iceland has a good opportunity to conduct population-based drug use research. The database contains individual-level information on all dispensed prescription drugs. The Registry enables us to follow an entire nation over an extended period of time for the use of various psychotropic drug groups. A recent study from this data source reported a substantial rise in pediatric use of methylphenidate (MPH), i.e., from 0.2 to 25.1 per 1000 children between 1989 and 2006, indicating a use rate equal to accounts from the United States (Olfson et al. 2002; Zuvekas et al. 2006; Castle et al. 2007; Scheffler et al. 2007; Zoega et al. 2007).

In the present study, we seek to answer whether use of other psychotropic drugs is also widespread among Icelandic children. More specifically we wanted to determine annual prevalence and incidence of psychotropic drug use in Icelandic children between 2003 and 2007 with regard to sex and age of the child, medical specialty of the prescriber, as well as unlicensed and off-label use of these drugs.

Methods

This is a population-based drug use study on pediatric psychotropic drug use in Iceland from January 1, 2003, to December 31, 2007.

Results

Discussion

In this nationwide population-based study, with complete registration of drug dispensing, we found a markedly high prevalence of psychotropic drug use in children (48.7 per 1000 in 2007) and a generally increasing prevalence of stimulants and antipsychotic drug use between 2003 and 2007. The use of antidepressants was decreased in the Icelandic pediatric population during the study period, but remains still markedly higher than reported use in other European countries.

Pediatric psychotropic use in Iceland, both overall and for specific subgroups, is considerably higher than what has been reported from other European countries, and thus closer to previously published use rates for children in the United States (Schirm et al. 2001; Olfson et al. 2002; Martin and Leslie 2003; Zito et al. 2003; Clavenna et al. 2007; Danish Medicines Agency 2008; Norwegian Institute of Public Health 2008; Sevilla-Dedieu and Kovess-Masfety 2008).

The extensive use (28.4 per 1000 children in 2007) of stimulants and atomoxetine, mainly used to treat attention-deficit/hyperactivity disorder (ADHD), is in accordance with use patterns previously described by the authors (Zoega et al. 2007). In 2003–2004, stimulant use in Iceland was at least two-fold that found for French, Dutch, and Norwegian children but slightly below the U.S. prevalence of 29 per 1000 children in 2002 (Faber et al. 2005; Zuvekas et al. 2006; Asheim et al. 2007; Sevilla-Dedieu and Kovess-Masfety 2008).

Even more pronounced is the difference in antidepressant use between children in Iceland and other European countries. In 2003–2004 approximately, 28 per 1000 Icelandic children received antidepressant treatment, as opposed to 2.3 per 1000 children reported in Italy, 3.7 per 1000 in Germany, 4.0 per 1000 in France, and the U.S prevalence of 18 per 1000 children in 2002 (Fegert et al. 2006; Vitiello et al. 2006; Clavenna et al. 2007; Sevilla-Dedieu and Kovess-Masfety 2008). Despite the steady decline in use among Icelandic children since 2004—a trend also apparent in other countries—the differences between Iceland and other European countries remain notable.

Given the reported side-effect profile of tricyclic antidepressants for children (Hazell et al. 1995; Hazell et al. 2002; Whittington et al. 2004), we find it disturbing that amitriptyline was the second most used psychotropic drug among Icelandic children in 2007 (Table 2). That year, around 10 per 1000 children in Iceland received this tricyclic, whereas pediatric use in Denmark and Norway was barely observable (Danish Medicines Agency 2008; Norwegian Institute of Public Health 2008). Amitriptyline use in Iceland warrants careful attention and further scrutiny of the reasons for its frequent prescribing.

We found a relatively high prevalence (10.6 per 1000 children in 2007) for antipsychotic use among children in Iceland and a significant rise in antipsychotic prevalence between 2003 and 2007. European prevalence estimates are many times lower than observed in this study for Icelandic children. Publicly available data from Nordic prescription registers show that the 2007 prevalence in Norway and Denmark was well below 1.0 per 1000 among 0- to 10-year-old children, 3.7 per 1000 among 10- to 19-year-old Norwegians, and 3.0 per 1000 among 10- to 14-year-old Danes (Danish Medicines Agency 2008; Norwegian Institute of Public Health 2008). Also, earlier prevalence ratios for antipsychotic use are markedly lower in Italy (in 2004), 0.53 per 1000 children; in France (in 2003), 1.0 per 1000; and in the Netherlands (in 1999), 3.4 per 1000 (Schirm et al. 2001; Clavenna et al. 2007; Sevilla-Dedieu and Kovess-Masfety 2008).

Olfson et al. (2006) found that diagnosis of bipolar disorder increased greatly among American children between 1993 and 2002. They also demonstrated a sharp national increase (six-fold) in antipsychotic treatment. Similarly, Rani et al. (2008) found a doubling of antipsychotic prevalence between 1992 and 2005 among U.K. children in primary care. In 2007, three antipsychotics —risperidone, aripiprazole, and quetiapine—were among the 10 most used psychotropic drugs for both boys and girls in Iceland (Table 2). Risperidone's summary product characteristics (SPC) indications include severe behavioral disorders and autism in young children (older than age 5) and acute and chronic schizophrenic psychoses among youths older than 15. Neither aripiprazole nor quetiapine are, on the other hand, licensed for use under age 18 (Iceland Medicines Control Agency 2008). Potential metabolic complications, such as weight gain and insulin sensitivity, coupled with the lack of research on the long-term effects of pediatric use of antipsychotics, warrant a further justification for the extensive use of these drugs in Iceland.

We detected a time trend toward reduced incidence of psychotropic drug use between 2004 and 2007, along with a tendency toward increasing prevalence. This may reflect a leveling off in the rising use of these drugs among children in Iceland, longer drug treatment duration, or a combination of both. The overall decreasing incidence was primarily driven by significantly fewer children initiating antidepressant treatment. The fall in antidepressant incidence, 11.9 per 1000 children to 8.0 between 2004 and 2007, is in accordance with recent trends reported from other countries (Murray et al. 2005; Bramness et al. 2007; Dean et al. 2007; Gibbons et al. 2007; Nemeroff et al. 2007; Volkers et al. 2007; Olfson et al. 2008). Reasons for this decline may be traced to public health warnings, issued by European and U.S. regulators in 2003 and 2004, media campaigns against the use in treatment of childhood depression, and uncertainty regarding long-term effects of use U.S. Food and Drug Administration 2003; Directorate of Health Iceland 2004; Jureidini et al. 2004; Ramchandani 2004; Vitiello et al. 2004; Whittington et al. 2004). A few recent studies have examined a proposed association between the decline of antidepressant use and increased risk of suicide among youths (Bridge et al. 2007; Gibbons et al. 2007; Olfson et al. 2008; Simon 2008; Wheeler et al. 2008), but results still remain inconclusive.

The decrease of new antidepressant users among Icelandic children is, furthermore, likely to be a function of drug substitution when treating ADHD, from tricyclic antidepressants to both long-acting MPH and atomoxetine. Baldursson et al. (2000) showed that tricyclic antidepressants (amitriptyline) were the most common drug choice in 1998–1999 for Icelandic physicians treating children referred to the National University Hospital outpatient ADHD clinic. Since that time, however, pediatric use of long-acting MPH and atomoxetine, marketed in Iceland in 2002 and 2006, respectively, has risen markedly (Zoega et al. 2007; Iceland Social Insurance 2008).

We excluded the drug hydroxyzine (N05BB01) from all analyses of this study. Although classified as an anxiolytic (N05B) in the WHO ATC classification system (World Health Organization 2008), the drug also has a main indication for allergic reactions (Iceland Medicines Control Agency 2008) and is primarily used as such for children in Iceland. The exclusion of hydroxyzine may be debated because our data did not include information on the diagnosis for which the drug was prescribed.

Given the still fragmented research base for safety and efficacy of childhood psychotropic drug use, it is not surprising to see that one fourth of all psychotropic drug prescriptions to children in Iceland in 2007 were either off-label (age inappropriate) or unlicensed. This concurs with previous studies from other countries showing similar proportions of pediatric prescriptions to be off-label (Ufer et al. 2003; Volkers et al. 2007; Sevilla-Dedieu and Kovess-Masfety 2008). To minimize clinical risk for children with mental health problems, it is essential that physicians initiating and maintaining treatment be equipped with proper education and up-to-date knowledge on pharmaceutical safety. Our results show that pediatricians most often initiated psychotropic treatment for children in Iceland between 2004 and 2007. This concurs with the fact that child and adolescent psychiatrists are 10 times fewer than pediatricians in Iceland. We did not attempt to determine which medical specialties were most likely to maintain psychotropic drug treatment for children in this study.

The rationale for the demonstrated extensiveness of psychotropic use among Icelandic children remains unclear. Assuming that prevalence of mental health disorders is not considerably higher in Iceland than elsewhere in Europe (Gudmundsson et al. 2007; Polanczyk et al. 2007), the first possible explanation may lie in the registration of drug dispensing data in Iceland, i.e., that it better captures actual use than elsewhere. This is, however, not a probable cause when comparing use between the Nordic countries, where registration of drug-dispensing rests on very similar nationwide databases. A central and well-financed health-care system, which includes unrestrained access to specialist and generous public co-payment of drugs, is a possible underlying factor for the widespread use. Additionally, because drug use is a direct function of prescribing habits, part of the explanation may lie in the education of Icelandic medical specialists, many of whom seek training and continuing education in the United States, where relatively high psychotropic use rates are also found. Further research is needed to assess the determinants of pediatric use of psychotropics in Iceland and the quality and outcomes of treatment.

Conclusion

In comparison to reported use in other European countries, this nationwide study provides evidence for strikingly high psychotropic drug use among children in Iceland. Further scrutiny is needed to assess the rationale behind the widespread use of various psychotropics, especially subtypes of tricyclic antidepressants and antipsychotics, with known adverse side effects.