JAMR is part-time professor at the Utrecht University and vice-president of external scientific collaborations for GSK in Europe, and holds stock in GSK. GSK was a co-funder for this study as part of the Dutch government-led research consortium TI-Pharma-Escher programme. The department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, has received unrestricted research funding from the Netherlands Organisation for Health Research and Development (ZonMW), the Dutch Health Care Insurance Board (CVZ), the Royal Dutch Pharmacists Association (KNMP), the private-public funded Top Institute Pharma (
Analyzed the data: JFH SVB AKM TP. Contributed reagents/materials/analysis tools: JW VV SVB. Wrote the paper: JF AKM GT TP. Conceived and designed the study: JFH AKM GT JAMR SVB TP. Performed the analyses: JFH SVB. Statistical support: SVB.
In 2003–2004 and 2007–2008, the regulatory banning of SSRI use in pediatrics and young adults due to concerns regarding suicidality risk coincided with negative media coverage. SSRI use trends were analyzed from 2000–2010 in the Netherlands (NL) and the UK, and whether trend changes might be associated with media coverage of regulatory warnings.
Monthly SSRIs sales were presented as DDDs/1000 inhabitants/day. SSRI-use trends were studied using time-series segmented regression analyses. Timing of trend changes was compared with two periods of media coverage of warnings. Annual Dutch SSRI prescription data were analyzed by age group.
Trend changes in SSRI use largely corroborated with the periods of media coverage of warnings. British SSRI use declined from 3.9 to 0.7 DDDs/month (95%CI 3.3;4.5 & 0.5;0.9, respectively) before the first warning period (2003–2004). A small decrease of −0.6 DDDs/month (−1.2; −0.05) was observed in Dutch SSRI use shortly after 2003–2004. From 2007–2008, British SSRI use stabilized, whilst Dutch SSRI use diminished to −0.04 DDDs/month (−0.4;0.3). Stratified analyses showed a rapid decrease of −1.2 DDDs/month (−2.1; −1.7) in UK paroxetine use before 2003–2004, but only a minimal change in Dutch paroxetine use (−0.3 DDDs/month −0.8;0.2). Other SSRI use, especially (es)citalopram, increased during 2003–2004 in both countries. Significant reductions in Dutch paroxetine use were observed in pediatrics, adolescents, and young adults after 2003–2004.
Changes in SSRI use (NL & UK) were associated with the timing of the combined effect of media coverage and regulatory warnings. Our long-term assessment illustrates that changes in SSRI use were temporal, drug-specific and more pronounced in pediatrics and young adults. The twofold increase in SSRI use over one decade indicates that regulatory warnings and media coverage may come and go, but they do not have a significant impact on the overall upward trend of SSRI use as a class in both countries.
Health care providers and consumers alike seek health and medical information from the news media and act accordingly, changing their perceptions and behavior
In a previous study, we analyzed the long-term dynamics of ‘good’ and ‘bad’ news in scientific journals and Dutch and British newspapers in the context of the SSRIs and suicidality controversy
IMS Health provided monthly antidepressant sales data in the NL and the UK for time trends assessment on a national (aggregated) level. Antidepressant sales data in the NL were available from January 2000 to January 2006 for tricyclic antidepressants (TCAs) and other antidepressants (monoamine oxidase inhibitors (MAOIs), as well as serotonin-norepinephrine reuptake inhibitors (SNRIs, etc.). Sales data for SSRIs were available from January 2000 to July 2010. Antidepressant sales data in the UK were available from January 2000 to January 2010 for all antidepressants. Escitalopram entered the market in August 2004 in the NL and in June 2002 in the UK. The sales data provided by IMS Health consisted of wholesaler information from ambulatory care and hospitals that cover, on average, 90% of the total therapeutic drug sales in the NL and UK. IMS Health also provided monthly Dutch SSRIs prescription data stratified by specialty from January 2000 to January 2010. This dataset was used to ascertain changes in the prescribing habits of general practitioners (GPs), and specialists (psychiatrists, cardiologists, oncologists, etc.). The GIP-database (Dutch insurance data retrieved from ambulatory care; not hospitals) provided yearly aggregate SSRI prescription data stratified by age groups from 2000 to 2010. The GIP-database covers, on average, 83% of the insured population in the NL
Sales data were classified into three main groups: a) SSRIs, b) TCAs, and c) other antidepressants (other ADs). IMS Health’s sales data were delivered in standard counts, which is the volume unit used to describe sales per counting unit (i.e., tablet, capsule, etc.), together with the given concentration of the active compound. For each antidepressant, monthly use was converted into defined daily doses (DDD)/1000 inhabitants/day, using the standard counts sold, dosage strength, and monthly population estimates per country. The DDD is the international unit of drug utilization approved by WHO for drug utilization studies and is defined as the average maintenance dose of the studied drug when used for its major indication in adults
The age groups were defined as pediatrics (0–14 years old), adolescents (15–19 years old), young adults (20–24 years old), adults (25–64 years old), and elderly (65 years and older). However, the GIP data combined the use of antidepressants for 15 to 24-year-olds between 2000–2001 hindering a differentiation between adolescents and young adults. Therefore, the ratio of use for adolescents and young adults in 2002–2010 was used to extrapolate use in 2000–2001.
Based on our analysis of scientific and newspaper coverage, we chose the following periods of intense media coverage of regulatory warnings: a) January 2003 to December 2004, and b) January 2007 to December 2008. The control periods were: a) January 2000 to December 2002, b) January 2005 to December 2006, and c) January 2009 to December 2009
To assess whether trend changes in antidepressant use were associated with the combined and long-term effects of both periods of regulatory warnings and scientific and newspaper coverage, we performed time-series analyses for overall SSRI, TCA and other ADs use, and per specific SSRI. The algorithm that describes the principle of our time-series analyses based on change-points was previously reported
Differences in SSRI use (mean) within Dutch age groups were compared with an ANOVA test, assuming that the means of each age group were equal. A Tukey HSD (honest significant difference) post-hoc test was used to determine which age group’s means were significantly different from one another. Statistical significance was set at P<0.05. Analyses were performed using the statistics software program “R” version 2.12.2
The use of SSRIs increased in the NL from 16.7 in January 2000 to 27.9 DDDs/1000/day in July 2010, while in the UK, SSRI use doubled from 24.7 in January 2000 to 50.1 DDDs/1000/day in December 2009. The use of other ADs increased from 3.3 in 2000 to 8.3 DDDs/1000/day in December 2005 in the NL, and from 3.4 in 2000 to 12.1 DDDs/1000/day in December 2009 in the UK. TCAs use increased from 4.2 in January 2000 to 5.2 DDDs/1000/day in December 2005 in the NL, whereas in the UK, TCAs use increased from 9.5 in January 2000 to 10.6 DDDs/1000/day in December 2009. On average, the UK population used 1.5-fold more SSRIs, 1.1-fold more other ADs, and 2.1-fold more TCAs than the Dutch did; both populations are comparable with respect to gender and age distributions (
Netherlands | United Kingdom | |||||||||
Population characteristics | 2000 | 2009 | Growthrate (%) | 2000 | 2009 | Growthrate (%) | ||||
Population | 15,987,075 | 16,574,989 |
|
58,981,904 | 61,990,973 |
|
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Female (%) | 8,017,633 | (50.5) | 8,329,391 | (50.5) |
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30,296,500 | (50.7) | 31,399,890 | (50.6) |
|
|
||||||||||
0–20 Y | 3,873,008 | (24.4) | 3,933,585 | (23.9) |
|
12,076,300 | (20.2) | 11,227,401 | (18.1) | − |
20–65 Y | 9,838,500 | (62.0) | 10,080,387 | (61.1) |
|
38,362,500 | (64.2) | 40,680,109 | (65.6) |
|
>65 Y | 2,152,442 | (13.6) | 2,471,815 | (14.9) |
|
9,316,600 | (15.6) | 10,083,462 | (16.3) |
|
Regression analyses indicated a short and temporal effect of the regulatory warnings on overall SSRI use in the NL. From 2000, SSRI use increased in a trend that continued until November 2004 (
Dotted lines represent a change in use trend and therefore a new, or the end of a segment. *The grey periods represent the periods of media coverage of regulatory warnings.
When analyzing individual SSRI use in the NL, citalopram and escitalopram showed rapid growth (
Dotted lines represent a change in use trend and therefore a new, or the end of a segment. *The grey period illustrates the periods of media coverage of regulatory warnings.
As in the NL, the use of citalopram and escitalopram increased exponentially in the UK in the period under survey. Fluoxetine, the most frequently used SSRI in the UK, demonstrated a modest increase of 11.2 to 13.9 DDD/1000/day during the period 2000–2010. Fluvoxamine use also demonstrated a consistent decrease during the entire study period in the UK, as was also documented in the NL. Overall paroxetine use decreased from 7.3 in January 2000 to 4.3 DDD/1000/day in December 2009 (
Dutch GPs prescribed the largest share of SSRIs (mean: 80.4%, 95% CI: 80.3; 80.6,
Dotted lines represent a change in use trend and therefore a new, or the end of a segment. *The grey period illustrates the periods of media coverage of regulatory warnings.
Specialty | General Practitioner | Specialists | Unidentified | |||||||||
SSRI/Year | 2000 | 2009 | 2000 | 2009 | 2000 | 2009 | ||||||
Citalopram | 0.3 | (2.2) | 7.6 | (32.8) | 0.4 | (12.5) | 1.8 | (35.9) | 0.02 | (7.1) | 0.2 | (52.4) |
Escitalopram |
0.002 | (0.0) | 1.2 | (5.3) | 0.01 | (0.5) | 0.7 | (13.8) | 0.001 | (0.3) | 0.02 | (6.5) |
Fluoxetine | 2.5 | (18.8) | 2.0 | (8.6) | 0.5 | (16.6) | 0.6 | (11.6) | 0.06 | (17.3) | 0.0 | (6.3) |
Fluvoxamine | 1.6 | (12.1) | 1.1 | (4.9) | 0.4 | (14.0) | 0.2 | (4.7) | 0.03 | (10.0) | 0.0 | (4.4) |
Paroxetine | 8.4 | (62.8) | 9.4 | (40.2) | 1.5 | (44.8) | 1.0 | (19.0) | 0.20 | (59.5) | 0.1 | (21.7) |
Sertraline | 0.5 | (4.0) | 1.9 | (8.3) | 0.3 | (10.5) | 0.7 | (14.9) | 0.01 | (4.4) | 0.0 | (9.6) |
|
13.3 | (100) | 23.3 | (100) | 3.1 | (100) | 5.0 | (100) | 0.33 | (100) | 0.4 | (100) |
|
(79.5) | (81.1) | (18.5) | (17.4) | (2.0) | (1.5) |
Data available from October 2004.
In the NL, SSRI use in pediatrics, adolescents, and adults modestly decreased after the first period of media coverage of the warnings, and then recovered. Initially, the use of SSRIs increased in young adults; however, by the end of the first period of media coverage the use dropped until 2010. SSRI use by the elderly grew during the entire study period (data not presented). Specific Dutch SSRI trends revealed a growth in the use of citalopram, escitalopram, and sertraline across all age groups (
*The grey period illustrates the period of media coverage of regulatory warnings.
The regulatory authorities issued several warnings restricting the use of SSRIs less than 18 years of age between 2003–2004 due to uncertainties regarding the benefit/risk balance, and included further restrictions for young adults (18–24-years-old) in 2007–2008
The present study has several strengths and limitations. The main strengths of this paper are the long-term analysis of trends of antidepressant use in the UK and the NL (based on national data), the comparison between two northern European countries, and the inclusion of all classes of antidepressants (not only those subject to safety advisories). Although media coverage represents only one of the many factors that may influence use (other factors might be reimbursement systems and policies, guidelines or patient compliance), our choice of the periods of media coverage of regulatory warnings is substantiated by a systematic analysis, which is also an important strength of the present study
The periods of media coverage of regulatory warnings had a limited and temporal effect on overall SSRI use in both the UK and NL. Significant reductions in SSRI use were not clearly observed during these periods. Overall SSRI use doubled during the period 2000–2010, which has been previously reported for other countries as well
Recent research on prescribing behaviors in the UK demonstrated that the increase in the prescriptions of antidepressants was not attributed to an increase of new patients (initiation), but to an increase in the number of long-term prescriptions
Towards the end of our study period in 2008, two important systematic reviews were published calling into question the effectiveness of SSRIs not only in pediatrics, but in adults and elderly, as well. In a meta-analysis, Kirsch et al. concluded that antidepressants were no better than placebo, and that in more severely depressed patients these drugs showed some effect, but only because of a poor response to placebo
Specific SSRI use in the NL was comparable with the UK to a limited extent. Citalopram, escitalopram, and sertraline use also showed upward trends in the period under survey, albeit with limited signs of diminished use towards the end of the survey period and after the periods of media coverage of regulatory warnings. The Dutch GP guideline for the treatment of depression in adults recommends either a TCA or an SSRI as first-line treatment, giving priority to fluvoxamine, paroxetine, sertraline and a lower priority to fluoxetine due to the long-half life
Notwithstanding the modest reduction in paroxetine use in the NL, we measured significant drops in use for pediatrics, adolescents, and young adults prior to the period of media coverage of regulatory warnings. Therefore, no direct association between the periods of media coverage of regulatory warnings and decreased paroxetine use was found in young groups. Conversely, both periods of media coverage of regulatory warning were associated with decreased paroxetine use in adults and elderly, although the warnings (and updates) were originally not thought to affect these age groups. Presumably, disadvantages regarding the use of paroxetine, such as the high risk of withdrawal effects or akathisia, could have caused this reduction in use
The timing of the media coverage of regulatory warnings about the suicidality risk associated with SSRI use coincided with changes in overall use in the NL and UK from 2000–2010. The results of this study demonstrate that short-term investigations only provide a snapshot of the potential implications of media coverage and regulatory warnings. We confirmed a strong, but not causal, association between periods of intense media coverage of regulatory warnings and significant changes in SSRI use over a ten-year period in both countries. However, our long-term assessment illustrated that the changes were temporal, drug-specific and more pronounced in pediatrics and young adults. The twofold increase in SSRI use over the 10-year period indicates that regulatory warnings and media coverage may come and go, but they do not have a significant impact on the overall upward trend of SSRI use as a drug class in both countries.
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