Impact of Regulatory Safety Warnings on the Use of Antidepressants among Children and Adolescents in Finland

Abstract

Objective:

The aim of this study was to analyze changes in the prevalence and incidence of antidepressant use among children and adolescents in Finland post October, 2003.

Method:

The sample comprised all children and adolescents in Finland aged ≤19.0 years (n = 27,676) who collected one or more reimbursed prescriptions for an antidepressant in noninstitutional and nonhospital settings between January, 1998, and December, 2005. Time-series models were used to compare antidepressant use 60 months before and 24 months after the health advisory issued by the Food and Drug Administration (FDA) in October, 2003.

Results:

The annual prevalence (users/1,000 youths) of antidepressant use increased from 5.24 in 2002 to 5.93 in 2005. There was an increase in the monthly incidence (users = 1,000 youths) of selective serotonin reuptake inhibitors (SSRIs) use (+0.02498), fluoxetine use (+0.00691), and sertraline use (+0.00727) post October, 2003. When considering preadvisory trends in antidepressant use, only fluoxetine use was higher than the predicted post October 2003, use (<0.001). The use of all other SSRIs was significantly lower than predicted.

Conclusions:

In contrast to many other countries, the use of antidepressants continued to increase among children and adolescents in Finland post October, 2003. While the rate of fluoxetine use increased, there was a decline in the rate at which all other SSRIs were used.

Introduction

A ntidepressant medications are widely prescribed to children and adolescents (Bonati and Clavenna 2005; Sevilla-Dedieu and Kovess-Masfety 2008; Autti-Rämö et al. 2009). This is despite limited published data supporting their safety and efficacy in this population (Moreno et al. 2007). Recent controversy has centered on the possible association between use of selective serotonin reuptake inhibitors (SSRIs) and suicidal ideation and suicidal behavior among children and adolescents. Evidence for the efficacy of SSRIs in treating depressive disorder among children and adolescents is strongest for fluoxetine (Usala et al. 2008). Only fluoxetine is licensed for the treatment of depression among children and adolescents by the United States Food and Drug Administration (FDA). In Finland, since 2009 fluoxetine has been licensed to treat moderate to severe depression when used in addition to psychotherapy in children aged over eight years if the depression has not responded to between four to six psychotherapy meetings. Sertraline is licensed for the treatment of obsessive-compulsive disorder (OCD) among adolescents aged 13–17 years.

Safety concerns regarding the use of antidepressant medications among children and adolescents present a dilemma for clinicians. Major depressive disorder (MDD) has a point prevalence of 1–2% among children aged 6–12 years, and 2–5% among adolescents aged 13–18 years (Ryan 2005). Untreated depression is a risk factor for suicide, and suicide is the third leading cause of death among children and adolescents aged 10–19 years in the United States (Anderson and Smith 2005). Despite the widespread use of antidepressant medications among children and adolescents, fewer than half of children and adolescents with MDD receive treatment before 18 years of age (Ryan 2005).

Government and regulatory agencies have a duty to inform clinicians about the best available evidence on which to base their treatment decisions. In June, 2003, the United Kingdom Medicine and Healthcare Products Regulatory Agency (MHRA) warned against the use of paroxetine in children and adolescents aged less than 18 years of age. In September, 2003, the United Kingdom Committee on Safety of Medicines (CSM) issued a recommendation against the use of venlafaxine and all SSRIs except fluoxetine for treatment of MDD. In October, 2003, the FDA issued a health advisory drawing attention to suicide and suicide attempts among children and adolescents taking antidepressants. In September, 2004, the FDA issued a requirement that all antidepressants carry a “black box warning” alerting clinicians and consumers to the potential increased risk of suicide or suicidal thinking among children and adolescents taking antidepressants for any indication. In December, 2004, the European Medicines Agency (EMEA) recommended against the use of SSRIs among children and adolescents, and in April, 2005, recommended that SSRIs only be used among children and adolescents for their approved indications (fluoxetine for depression; fluoxetine, sertraline, and fluvoxamine for OCD). In Finland, the National Agency for Medicines (NAM) echoed the EMEA warning in February, 2004, and recommended a written warning be added to the Summary of Product Characteristics (SPC) in April, 2005. There were no changes to the product specifications in Finland prior to April, 2005, because depression was not accepted as an indication for SSRI use among children and adolescents at the time.

A series of previous studies have revealed significant reductions in the use of antidepressants among children and adolescents following the series of safety warnings and health advisories in Australia, Canada, Ireland, Norway, The Netherlands, United Kingdom, and United States (Bennett et al. 2005; Murray et al. 2005; Bramness et al. 2007; Dean et al. 2007; Gibbons et al. 2007; Kurdyak et al. 2007; Kurian et al. 2007; Libby et al. 2007; Nemeroff et al. 2007; Volkers et al. 2007). The objective of this study was to analyze and describe changes in the prevalence and incidence of antidepressant use in Finland following the health advisory issued by the FDA in October, 2003.

Method

Ethical considerations

The study protocol was approved by the Faculty of Pharmacy, University of Helsinki. Ethics approval was not required because only deidentified patient data were used and persons were not contacted.

Sample and data sources

The sample comprised all children and adolescents aged ≤19.0 years (n = 27,676) who collected one or more reimbursed prescriptions for an antidepressant medication in Finland between January, 1998, and December, 2005. Data were extracted from the prescription register of the Social Insurance Institution of Finland (Kela). The Kela prescription register contains reimbursement data for all 5.3 million Finnish residents. All Finnish residents are eligible to receive full or partial reimbursements for antidepressant medications. Persons residing in a public hospital or institutional care are not eligible for reimbursement and, thus, their medication purchases are not included in the Kela register. Information including each patient's birth date, gender, dispensing date of each prescription and number of dispensed packages was extracted from the Kela register.

All medications were classified according to the Anatomical Therapeutic Chemical (ATC) classification system (WHO Collaborating Centre for Drug Statistics Methodology 2006). Antidepressant medications were categorized as N06AA nonselective monoamine reuptake inhibitors (clomipramine, doxepin, imipramine, nortriptyline, amitriptyline, trimipramine), N06AB SSRIs (escitalopram, citalopram, fluoxetine, sertraline, paroxetine, fluvoxamine), N06AG monoamine oxidaze A inhibitors (moclobemide), or N06AX other antidepressants (trazodone, duloxetine, reboxetine, venlafaxine, milnacipran, mianserin, mirtazapine).

Measures

The annual prevalence and annual and monthly incidence of antidepressant use were calculated for each antidepressant. The annual prevalence was defined as the number of children and adolescents who were dispensed one or more reimbursed prescriptions for an antidepressant medication during a calendar year (reported as users/1,000 youths). The annual prevalence was calculated for 1998–2005. The annual and monthly incidences were defined as the total number of new users of reimbursed antidepressant medications during a calendar year and calendar month, respectively (reported as users/1,000 youths). A child or adolescent was considered a new user if there was no previous record of their having been dispensed an antidepressant in the Kela register between January, 1998, and December, 2005. In Finland up to a 3-month supply of medications can be reimbursed in one transaction. Accordingly, monthly incidences were not considered prior to September, 1998, to provide an 8-month drug-free period for determination of new users. A child or adolescent was considered to have ceased taking an antidepressant when there was no record of them having been dispensed an antidepressant for 6 months. To be able to apply this definition, adolescents who got their last prescription at age 19 were excluded from the dataset (and the dataset was limited to June, 2005) when calculating the percentage of children and adolescents who received only one antidepressant prescription. All other calculations were performed for children and adolescents aged ≤19.0 years. All prevalence and incidence calculations were performed using annual age-specific population statistics obtained from Statistics Finland.

Statistical analyses

Segmented, interrupted time-series analysis was used to assess the impact of the FDA health advisory issued in October, 2003. This health advisory was selected because previous studies have shown it had the strongest impact on physicians' prescribing practices in other countries (Gibbons et al. 2007; Libby et al. 2007; Nemeroff et al. 2007). Regression models were used to forecast the postwarning monthly incidences of all antidepressant, SSRI, fluoxetine, citalopram, paroxetine, sertraline, and fluvoxamine use. The forecasts were performed using best-fit models based on the corresponding prewarning monthly incidences. The observed and forecasted monthly incidences of all antidepressant, SSRI, fluoxetine, citalopram, paroxetine, sertraline, and fluvoxamine use were tabulated. Monthly incidences of antidepressant use in the pre- and postwarning periods, as well as postwarning observed and forecasted monthly incidences, were compared using t-tests. Observed monthly incidences of antidepressant use in the postwarning period were further compared with the incidences of antidepressant use in September, 2003, by using one sample t-tests. All statistical analyses were performed using the Statistical Package for the Social Sciences Version 16.0 (SPSS Inc., Chicago, IL).

Results

A total of 27,676 children and adolescents (aged ≤19.0 years) were dispensed 147,635 prescriptions for antidepressant medications in noninstitutional and nonhospital settings in Finland between January, 1998, and December, 2005. In all, 65% of children and adolescents were female (n = 18,020). The mean age of initial antidepressant dispensing was 16.9 years for females (range 0–19) and 16.1 years for males (range 0–19). The mean number of all antidepressant prescriptions reimbursed per child or adolescent during the study period was 5.3 (range 1–93). A total of 31% of children and adolescents received only one antidepressant prescription.

The most frequently reimbursed antidepressants between January, 1998, and December, 2005, were citalopram (n = 41,959), fluoxetine (n = 28,106), and paroxetine (n = 20,668). Escitalopram was frequently reimbursed from 2003 onward (n = 8,870). The mean number of different types of antidepressant medications reimbursed per child or adolescent was 1.33 (range 1–9), with 76% of children and adolescents dispensed only one type of antidepressant medication. Of 7,912 children and adolescents who were new users of antidepressants during the study period and who received six or more antidepressant prescriptions, 34% received two or more different types of antidepressant medications within the first six dispensings.

The overall annual prevalence and incidence of antidepressant use increased between 1998 and 2005. The annual prevalence increased from 2.23 users/1,000 youths in 1998, to 5.24 users/1,000 youths in 2002 and 5.93 users/1,000 youths in 2005. The annual incidence of antidepressant use increased from 2.01 new users/1,000 youths in 1999, to 3.02 new users/1,000 youths in 2002 and 3.12 new users/1,000 youths in 2005. There was a significant increase in the monthly incidence (users/1,000 youths) of SSRI use (+0.02498), fluoxetine use (+0.00691), and sertraline use (+0.00727) post October 2003 (Table 1). When considering preadvisory trends in antidepressant use, only the incidence of fluoxetine use was higher than the predicted post October, 2003, incidence (p < 0.001). Use of all other SSRIs was significantly lower than predicted.

Table 1.

Monthly Incidence of Antidepressant Use Pre (October, 1998, to September, 2003) and Post (October, 2003, to September, 2005) the United States Food and Drug Administration Health Advisory

Treatment characteristics	Monthly incidence (SD) prewarning period (prescriptions/1,000 youths)	Monthly incidence (SD) postwarning period (prescriptions/1,000 youths)	Observed change in monthly incidence (prescriptions/1,000 youths)	Independent samples t-test ^a	One-sample t-test ^b	Forecasted monthly incidence (SD) postwarning period ^c (prescriptions/1,000 youths)	Paired-samples t-test ^d
All AD drugs	0.2205 (0.0532)	0.2550 (0.0606)	0.03449	t(82) = −2.580, p = 0.012	t(23) = 0.808, p = 0.427	0.2702 (0.0357)	t(23) = −2.275, p = 0.033
All SSRI	0.1839 (0.0463)	0.2089 (0.0502)	0.02498	t(82) = −2.182, p = 0.032	t(23) = 0.576, p = 0.570	0.2290 (0.0299)	t(23) = −3.467, p = 0.002
Fluoxetine	0.0450 (0.0124)	0.0519 (0.0164)	0.00691	t(34) = −1.855, p = 0.0.072	t(23) = 5.333, p < 0.001	0.0350 (0.0090)	t(23) = 5.182, p < 0.001
Citalopram	0.0735 (0.0178)	0.0527 (0.0200)	−0.02080	t(82) = 4.672, p < 0.001	t(23) = −7.407, p = 0.427	0.0928 (0.0109)	t(23) = −11.978, p < 0.001
Paroxetine	0.0317 (0.0183)	0.0170 (0.0094)	−0.01465	t(77) = 4.809, p < 0.001	t(23) = −13.520, p < 0.001	0.0346 (0.0108)	t(23) = −12.908, p < 0.001
Sertraline	0.0252 (0.0089)	0.0325 (0.0087)	0.00727	t(82) = −3.400, p = 0.001	t(23) = −3.082, p = 0.005	0.0425 (0.0048)	t(23) = −6.092, p < 0.001
Fluvoxamine	0.0085 (0.0038)	0.0041 (0.0021)	−0.00444	t(73) = 6.835, p < 0.001	t(23) = −4.488, p < 0.001	0.0067 (0.0029)	t(23) = −4.256 p < 0.001

Independent-samples t-test comparing mean incidence rates in pre- and post-warning period.

One sample t-test comparing mean incidence rates in post-warning period with incidence rates for September, 2003.

Forecast performed by using best-fit model based on prewarning utilization data.

Statistics of paired-samples t-test comparing observed and forecasted mean incidence rates for postwarning period.

Abbreviations: SD = Standard deviation; AD = antidepressants.

Discussion

In contrast to drug use trends observed in other countries, the overall use of antidepressants and SSRIs continued to increase in Finland in the 24 months following the health advisory issued by the FDA in October, 2003. There was an increase in the use of fluoxetine and an absolute reduction in the use of paroxetine, citalopram, and fluvoxamine. When comparing observed and forecasted monthly incidences, all SSRIs except fluoxetine were used to a lower extent than predicted.

The increase in incidence and annual prevalence of antidepressant use in Finland between 1998 and 2002 was consistent with the trend observed in other countries (Sourander et al. 2002; Zito et al. 2002; Delate et al. 2004; Murray et al. 2004; Ma et al. 2005). Unlike in Finland, however, the incidence of antidepressant use declined in Australia, Canada, Ireland, The Netherlands, United Kingdom, and United States following the series of safety warnings and health advisories issued between 2003 and 2005 (Murray et al. 2005; Dean et al. 2007; Gibbons et al. 2007; Kurdyak et al. 2007; Kurian et al. 2007; Nemeroff et al. 2007; Volkers et al. 2007). The international differences in antidepressant use may be attributable to differences in prescribing guidelines, drug regulations, health service delivery, cultural beliefs, and the reimbursement of specific drugs (Vitiello 2008). SSRIs were the most common class of antidepressants prescribed to children and adolescents in Finland. This was similar to the pattern in the United States, Canada, and Australia, but different from the pattern in Germany, where use of St. John's Wort and tricyclic antidepressants is common (Fegert et al. 2006; Zito et al. 2006). Fluoxetine was the most prescribed antidepressant to children and adolescents in Finland in 2005. This was consistent with fluoxetine having proven most efficacious in clinical trials (Usala et al. 2008) and being the only SSRI licensed for depression in children and adolescents by the FDA. Fluoxetine is also recommended as the medication treatment of choice for child and adolescent depression in the Finnish Current Care Guidelines for depression (Käypä hoito 2007).

The combined prescribing of citalopram and escitalopram in Finland in 2005 exceeded that of fluoxetine. This is despite research suggesting that escitalopram may not be any more efficacious than placebo for child and adolescent depression (Wagner et al. 2006). Only one out of two studies of citalopram found the medication to be superior to placebo (Wagner et al. 2004). A possible reason may be that citalopram and escitalopram are the most prescribed antidepressants to adults in Finland (National Agency for Medicines & The Social Insurance Institution of Finland 2006). The familiarity with citalopram and escitalopram gained through adult use may translate into high usage among children and adolescents.

In Finland, the male adult population suicide rate, and to a lesser extent the female adult population suicide rate, began to fall around the time of increased sales of antidepressant medications (Reseland et al. 2006). The decline in prescribing of SSRIs to children and adolescents in the United States and The Netherlands corresponded to an increase in the number of completed youth suicides (Gibbons et al. 2007). While the results of these ecological studies should be interpreted cautiously, as causality cannot be determined, they highlight the urgent need for further research into the relationship between depression, antidepressant medication, and youth suicide. Additional quantitative and qualitative studies are also needed to determine how clinicians in Finland have embraced the recommendations regarding the regular monitoring of children and adolescents prescribed antidepressants. A recent study conducted in the United States found that adherence to FDA guidelines for follow-up of children and adolescents prescribed antidepressants was low (Bhatia et al. 2008).

Strengths and limitations

Our study employed a comprehensive national prescription register used to calculate the prevalence and incidence of antidepressant use. The register included details of all prescriptions for antidepressant medications reimbursed for community-dwelling children and adolescents in Finland. However, the register does not include comprehensive information on patient diagnoses. It is likely that some children and adolescents included in our study were prescribed antidepressants for indications other than depression, including anxiety, nocturnal enuresis, neuropathic pain, and OCD. We analyzed changes in the prevalence and incidence of dispensing of antidepressants rather than the prescribing of antidepressants. As with previous pharmacoepidemiological studies, our data do not prove a causal association between the safety warnings and changes in antidepressant use. It is possible that antidepressant use was also impacted by other factors. These factors may have included the introduction of mandatory generic substitution by pharmacists in April, 2003 (Aalto-Setälä et al. 2007). We do not know whether specific children or adolescents were dispensed antidepressants prior to 1998. Previous research has suggested the incidence of antidepressant prescribing may have been influenced by the length of the medication-free period used to define a new user (Gardarsdottir et al. 2006). Like several previous studies, we included adolescents aged up to and including 19 years (Fegert et al. 2006; Zito et al. 2006; Zito et al. 2008). These factors should be considered when comparing the prevalence and incidence of antidepressant use in our study to data reported from other countries.

Conclusions

In contrast to other countries, the overall incidence of antidepressant use among children and adolescents in Finland continued to increase following the FDA health advisory issued in October, 2003. While the rate of fluoxetine use increased, the rate of all other SSRI use decreased and/or was lower than predicted. Further research is needed to determine whether Finnish clinicians have embraced recommendations regarding the regular monitoring of children and adolescents who were prescribed antidepressants.

Footnotes

Disclosures

At the time of conducting the study Ms. Svala was a researcher at the Faculty of Pharmacy, University of Helsinki. Ms. Svala is a now an employee of Orion Corporation, Orion Pharma. Drs. Foulon, Chen, Saastamoinen, and Bell and Ms Koskinen have no conflicts of interest or financial ties to disclose.

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