The IADB is situated in the North of the Netherlands, covering an area of 3.4 million inhabitants. The IADB.nl is a pharmacy drug prescription database in the North of the Netherlands covering a population of 500,000. All prescriptions for persons living in the IADB area are prospectively and consecutively entered into the pharmacy database. These prescriptions are, regardless of prescriber, insurance or reimbursement status, except over-the-counter (OTC) drugs and drugs dispensed during a hospital stay. So, all prescribed drugs (except in hospital use and OTC drugs) delivered to this population are available in the database. We have compared the drug use in our database with national prescription databases and found for all main drug groups comparable prevalences of drug use among sex and different age groups. Based on that, the IADB.nl can be considered as a database that is representative for the Netherlands regarding drug exposure. We have a methodological article in preparation on this topic.

Each prescription record comprises information about the drug, side effects, date of dispensing, amount dispensed, dose regimen and the prescribing physician. The indication for the prescription is not known. All drugs are coded according to the Anatomical Therapeutic Chemical (ATC) classification [¹¹, ¹²]. For each patient, there are sex, date of birth, family physician and a unique, anonymous identifier. Due to a high patient pharmacy commitment in the Netherlands and sophisticated pharmacy software, the prescription records for each patient are virtually complete [¹³].

In the Netherlands, general practitioners hold a key position in health care. They are the first health care professionals to see people when they are ill, and they act as gatekeepers to secondary care. Most cases that present to a general practice are taken care of by the general practitioner alone. Sometime after primary treatment, the care for the patient is shifted back from hospital to general practice. When the care for the patient is shifted back to general practice, the general practitioner is responsible for the prescription of drugs. The most common indication for prescribing drugs in general practice is cardiovascular diseases, followed by diabetes mellitus and depression, respectively [¹⁴].

In the Netherlands, endocrine and psychotropic medications are prescription drugs and cannot be obtained OTC. In the Netherlands, endocrine therapy is not indicated for the prevention of breast cancer, also not in high-risk women.

All women who were over 20 years of age during the study period 1994–2006 and had at least one prescription of anti-oestrogens (tamoxifen, fulvestrant) or aromatase inhibitors (anastrazole, letrozole, exemestane) were selected. Women with at least one prescription of anti-oestrogens or aromatase inhibitors were included in the analysis when there was information in the IADB database for a minimum of 180 days before the start date of adjuvant hormonal treatment. The analysis was based on these anti-oestrogens and aromatase inhibitors because these products are the preferred endocrine treatments for breast cancer in the Netherlands.

To compare the use of psychotropic medication among women using anti-oestrogens with the use of psychotropic medication among women not using anti-oestrogens, there were two options. Firstly, we could use the data of all women not using anti-oestrogens and correct for bias due to age and time in follow-up in the analysis. The second option was to draw a stratified sample of women not using anti-oestrogens from the cohort and correct in this way for bias due to age and time in follow-up. The reference population included women without any prescription of anti-oestrogens or aromatase inhibitors. In addition, women with any prescription of anti-neoplastic and immuno-modulating agents (ATC classification group L) were excluded. From this group, three to four women were matched for age at the start date of the anti-oestrogens or aromatase inhibitors prescription and family physician of the women in the index group. This start date was considered as the “theoretical” start date for women in the reference population. Women in the reference population could only be matched if there was information available in the IADB for at least 180 days before the theoretical start date. On average, there was a match of 3.7 reference women per woman with hormone receptor-positive breast cancer.

Psychotropic medication was classified with the use of the following ATC codes: N05B (anxiolytics), N05C (hypnotics and sedatives) and N06A (anti-depressants).

For females treated with endocrine therapy, the date of the first prescription of anti-oestrogens or aromatase inhibitors was considered as the starting date in the analysis. The women from the reference population received the starting date from the women with hormone receptor-positive breast cancer to whom they were matched.

To assess whether the start of psychotropic medication was increased, the cohort of female breast cancer survivors (index group, n = 2,172) was compared with an age- and family physician-matched group of women without cancer (the reference population, n = 8,129), and the incidence risk ratio (IRR) and the 95% confidence intervals (95% CI) were calculated. The IRR was calculated as the incidence rate (IR) of the index group divided by the IR of the reference group [¹⁰]. For calculation of the IR, given the distribution of the data, 1 year before the starting date of adjuvant therapy was chosen as the starting point for follow-up. The number of patient days in the database was measured from this starting point for follow-up up until either the prescription date of psychotropic medication or the last known date of that person in the database. The incidence of drug prescribing was calculated as the number of incidence cases divided by the total number of patient days at risk. An incidence case was defined as a woman who did not receive a prescription for this medication for the last 180 days.

To assess the prescriptions of psychotropic medication over time, the half-year prevalence of these psychotropic medication prescriptions and the 95% CIs were calculated in the index as well as the reference group. The half-year prevalence was defined as the proportion of women having a psychotropic medication prescription during a half year and was calculated as the number of women who use psychotropic medication per 182 days (half year), divided by the total number of women present in that period. All statistical analyses were performed by Excel and SPSS 16.0. A p value of less than 0.05 was considered to be statistically significant.

In the IADB database, there were 2,172 female breast cancer patients treated with endocrine therapy. The reference group consisted of 8,129 women. The median age of the breast cancer patients treated with endocrine therapy was 64 (20–93), with a median follow-up time of 2.6 years. The median age of women in the reference group was 62 (20–93), with a median follow-up time of 3.8 years (see Table 1). The number of women per year that started with tamoxifen, fulvestrant, anastrazole, letrozole and exemestane is shown in Table 2.

There are significantly more starting prescriptions of psychotropic medication for female breast cancer patients treated with endocrine therapy when compared to women in the reference group (see Table 3). This increase is observed for all three groups of psychotropic medication, anxiolytics (IRR 2.07, 95% CI 1.87–2.29), hypnotics and sedatives (IRR 2.59, 95% CI 2.34–2.87) and anti-depressants (IRR 1.46, 95% CI 1.28–1.65). Table 4 presents the specific drugs in the three psychotropic groups that were mostly prescribed. Of the 552 breast cancer patients who started anxiolytics, 313 received oxazepam. Of the 580 who started with hypnotics and sedatives, 383 received temazepam. Among the 331 who started an anti-depressant, 144 received amitriptyline, and 66 (20%) received the combination paroxetine and tamoxifen (Table 4).

The prevalence of psychotropic medication use (anxiolytics, hypnotics and sedatives and anti-depressants) is presented in Fig. 1. The prevalence of psychotropic medication use (prevalence 0.45, 95% CI 0.43–0.47) is significantly increased among breast cancer patients using endocrine therapy when compared to the reference group (prevalence 0.32, 95% CI 0.31–0.32). In the period a half year after the start, there is still an increase of psychotropic medication use, although from this period, a decrease is observed.

In Fig. 2, the prevalence of psychotropic use among the female breast cancer patients treated with endocrine therapy is stratified for anxiolytics, hypnotics and sedatives and anti-depressants. Before the start of hormonal therapy, anxiolytics are most frequently prescribed, followed by hypnotics and sedatives, and anti-depressants. After the start of hormonal therapy, hypnotics and sedatives are prescribed most frequently. In the period 6 months before the start of hormonal therapy, the prevalences of anxiolytics and hypnotics and sedatives are significantly increased as compared with the use of these drugs longer before. For anxiolytics, the prevalence is 0.26 (95% CI 0.24–0.27), and for hypnotics and sedatives, the prevalence is 0.24 (95% CI 0.23–0.26) (Fig. 2). The prevalence of anti-depressant use is not increased.

There are no conflicts or interests.

This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

^aIndex group—women with at least one prescription of tamoxifen, fulvestrant, anastrazole, letrozole or exemestane were considered as breast cancer patients treated with endocrine therapy

^bReference group—an age- and family physician-matched group of women any prescription of tamoxifen, fulvestrant, anastrazole, letrozole or exemestane

^cTime of follow-up—time in observation

A starter is defined as a woman who did not receive a prescription for this drug for at least 180 days. The database is relative stable since 1999

BC breast cancer