Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht, and Kendle, Utrecht
Department of Pharmacoepidemiology and Pharmacotherapy, UIPS, Utrecht and SIR, Institute for Pharmacy Practice Research, Leiden
Department of Pharmacoepidemiology and Pharmacotherapy, UIPS, Utrecht
Department of Epidemiology, Maastricht University, Maastricht
Department of Pharmacoepidemiology and Pharmacotherapy, UIPS, Utrecht, The Netherlands
Correspondence: Welmoed E. E. Meijer, Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), PO Box 80082, 3508 TB Utrecht, The Netherlands. Tel: +31 30 2537324; fax: +31 30 2539166; e-mail: W.E.E.Meijer{at}pharm.uu.nl
Declaration of interest This study received unconditional grant support from Eli Lilly and Company.
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ABSTRACT |
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Aims To evaluate dosing lapses in patients chronically treated with selective serotonin reuptake inhibitors (SSRIs) in uncontrolled circumstances.
Method In a prospective observational study we evaluated compliance data in chronic users of SSRIs using electronic drug exposure monitors.
Results During a 3-month follow-up we found that 50/69 (72.5%) patients missed at least one dosing day and 20/69 (29.0%) missed two or more consecutive days.
Conclusions About 30% of patients treated with short-acting SSRIs had dosing lapses of 2 or more days, which, as described in prior studies, is long enough to result in clinically relevant deterioration of mental status.
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INTRODUCTION |
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These findings raise the question of the frequency and duration of spontaneously occurring omissions of scheduled doses of SSRIs during routine clinical management of depression. The aim of this observational prospective study, therefore, was to assess the incidence and duration of missed doses for patients prescribed SSRIs in clinical practice.
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METHOD |
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Study design
Relevant clinical information was provided by the prescribing physician,
including indication and psychiatric comorbidity. Information on the dosing
regimen of the SSRI was recorded at the pharmacy and validated by the
prescriber. Data on compliance were gathered through electronic drug exposure
monitors (eDEMs): medicine containers with a built-in microchip that register
the time and date of each opening and closing of the package. During the
observation period of 3 months, the eDEM was filled at the pharmacy at the
time of each refill. All patients were instructed by the pharmacist on the use
of the eDEM. Information was presented to the patient, stating the goal of the
study and the use of the eDEM.
The observation period started with the first opening of the eDEM by the patient after the first dispensing in the pharmacy. Refill date or dosing changes were evaluated and compared with the computerised medication history available from the pharmacy. The observation period continued until 3 months after the first opening by the patient, or earlier if therapy ended or the patient dropped out of the study.
Electronic monitoring
The eDEM information included the times and dates of individual bottle
openings provided as calendar and chronology plots. A calendar plot reflects
the number of openings of the eDEM. In a chronology plot, the hour and number
of openings during each successive 24-h period are depicted. Patients with
eDEM information were categorised according to the number of (consecutive)
days of non-dosing found. Lapses of 2, 3, 4 and 5 or more consecutive days of
non-dosing were counted per patient.
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RESULTS |
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Information about the indication was provided by the prescriber for a subset of the patients (n=51). Depressive disorder (45.1%), followed by anxiety disorder (17.6%) and other disorders (3.6%), including obsessive-compulsive disorder, bulimia or sleep disturbances, were indicated as single diagnoses. A substantial number of the patients received an SSRI for treatment of multiple diagnoses (33.3%), most often depressive disorder and anxiety disorder (17.6%) but also other combinations (15.7%). According to the patient, the main indication for which the SSRI was prescribed had been present for 4.2 years and the average duration of treatment had been 2.0 years.
Medication histories derived from computerised dispensing data in the pharmacies' computers were used to evaluate the use of psychotropic co-medication. Of all patients with dosing data, benzodiazepines were used in 23 patients (33%), including 16 (23%) chronic users. Antipsychotics were used by four patients (5.8%). Multiple use of antipsychotics and/or benzodiazepines was seen in three patients. In these patients, multiple days of non-dosing were recorded, resulting in only 51-64% of days on which the prescribed doses were taken.
Compliance data
The median duration of monitoring was 89 days (range 30-90). In total 5914
days of monitoring were registered. Patients were recorded as taking a single
dose, as prescribed, on 89% of these monitored days. On 477 of the monitored
days (8.1%), no dose was recorded as having been taken. On 164 of the
monitored days (2.8%), more than the prescribed single dose was recorded as
having been taken.
A total of 50 of the 69 patients (72.5%) were observed to have had at least 1 day on which a dose was omitted (range= 1-18 single days per patient; median=3 days). Sixteen patients had at least one lapse of 2 consecutive days of omitted doses (range=1-3; median=1). Nine patients had at least one lapse of 3 or more consecutive days of omitted doses, distributed between 3, 4 and 5 consecutive days. The range of lapses in dosing lasting 3 or more days was 1-6. A total of 29.0% (20/69) of patients had at least 2 consecutive days of non-dosing. These 20 patients had a total of 47 dosing lapses of at least 2 days (range= 1-8 lapses), resulting in an average of 2.4 lapses per patient during the 86-day follow-up period.
The distribution of interdose intervals using 24±6 h as the central category was recorded. The majority of the patients had a dosing time between 06.00 and 12.00 a.m.; a total of 20.3% of all patients had irregular intervals of administration, defined as >25% of the dosages taken outside a 6-h period. Patients with irregular dosing intervals showed significantly more days of non-dosing (10/14) compared with patients with regular dosing (10/55) (P<0.01).
The majority of the patients reported no problems with the eDEM and a minority found the device impractical compared with the blisterpack that they were used to (10.1%). The majority (71.0%) assessed their knowledge of disease and treatment as sufficient. About two-thirds of patients (63.8%) were positive about using the devices feeling that feedback from the physician or pharmacist might help them to improve their compliance.
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DISCUSSION |
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Lapses in SSRI dosing in clinical practice
Michelson et al
(2000) reported a significant
increase in adverse events as early as the second day of placebo substitution
in patients using paroxetine. These adverse events are generally mild,
short-lived and self-limiting, but can be distressing and may lead to missed
working days and decreased productivity. The symptoms may be somatic (e.g.
dizziness, nausea, vomiting and/or flu-like symptoms) or psychological in
nature (anxiety, agitation, crying spells). Thus, there is a well-defined set
of clinical consequences of lapses in dosing taken by patients prescribed the
shorter acting SSRI antidepressants (paroxetine and sertraline). We have no
reason to assume that clinical effects of lapses in dosing differ in clinical
practice compared with the controlled situation described by Rosenbaum et
al (1998) and Michelson
et al (2000). Although
it would be interesting to study these effects in an observational design,
clinical data cannot be captured without interrupting the naturally occurring
dosing lapses.
Pharmacokinetics of individual SSRIs
Dosing time data are important in relation to the pharmacological duration
of action. The individual antidepressant drugs studied here differ widely in
their pharmacokinetic half-lives, from less than 24 h in the case of
paroxetine (Benet et al,
1996) to several days in the case of fluoxetine and a week or more
in the case of its active metabolite norfluoxetine
(Reynolds, 1993). These
differences in half-life are reflected in a widely different persistence of
therapeutic drug action, after dosing interruptions, as shown by the
placebo-substitution study of Rosenbaum et al
(1998). That study showed a
surprisingly rapid reversal of the antidepressant action of paroxetine, within
as little as 48 h of controlled substitution of placebos for active drug. A
key question emerging from that study has been whether the multiday
substitution of placebo for active drug was a realistic model of naturally
occurring forms of non-compliant dosing. Our study clearly shows that, in this
group of long-term users of SSRI antidepressants, the multiday lapse in dosing
does indeed occur in about three out of ten patients. One might reasonably
expect that such errors would occur even more often, and perhaps with longer
lapses in dosing, in patients who have just started treatment with
antidepressant drugs. Owing to the small sample size, we could not
differentiate between the individual SSRIs but we have no reason to assume
that the incidence of days of non-dosing differs between chronic users of
individual SSRIs. The present prescribing pattern of Dutch general
practitioners is reflected in the distribution of the SSRIs in this study. All
SSRIs included in this study were daily formulations and the consequences of
non-dosing in patients using the weekly formulation of fluoxetine, for
example, now licensed in the USA, are unknown.
Obviously, the interpretation of interdose interval data depends upon the duration of action of the drugs in question, which were widely disparate in this study, ranging from paroxetine at the shortest end to fluoxetine at the longest end, based on the data of Rosenbaum et al (1998). Although the numbers were too small to differentiate between the individual SSRIs, we found that patients with irregular dosing intervals showed significantly more lapses in dosing.
Underestimation of actual non-compliance
All patients were included by their pharmacist and, although we have no
information about the number of patients refusing to participate, it might be
possible that non-compliant patients were less motivated to participate in the
study, creating a selection bias. Moreover, the nine patients who lost the
device are more likely to be non-compliant patients.
Overall, the patients in this study were relatively healthy with little comorbidity, psychiatric or otherwise. However, we included a limited number of patients with concomitant use of antipsychotics, and these individuals showed low compliance with antidepressant medication. Patients included were under treatment for an average duration of 2.5 years with a relatively simple dosing scheme. Our study focused on patients prescribed SSRI antidepressants on a long-term basis, a group in which one might expect, if anything, somewhat better compliance than during the first several weeks of antidepressant therapy, when changes in prescription are frequent and medication-taking is as yet unrewarded by alleviation of depression. Our results therefore may be an underestimation of the actual non-compliance.
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Clinical Implications and Limitations |
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LIMITATIONS
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REFERENCES |
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Benet, L., Oie, S. & Schwartz, J. (1996) Design and optimalisation of dosing regimens: pharmacokinetic data. In Goodman & Gilman's The Pharmacological Basis of Therapeutics (eds J. G. L. L. Hardman, P. B. Molinoff, R. W. Ruddon, et al), p. 1769. New York: McGraw-Hill.
Haddad, P. (1997) Newer antidepressants and the discontinuation syndrome. Journal of Clinical Psychiatry, 7, 17-21.
Lejoyeux, M. & Ades, J. (1997) Antidepressant discontinuation: a review of the literature. Journal of Clinical Psychiatry, 7, 11-15.
Michelson, D., Fava, M., Amsterdam, J., et al
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Rosenbaum, J. F., Fava, M., Hoog, S. L., et al (1998) Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial. Biological Psychiatry, 44, 77-87.[CrossRef][Medline]
Urquhart, J. (1997) The electronic medication event monitoring lessons for pharmacotherapy. Clinical Pharmacokinetics, 32, 345-356.[Medline]
Received for publication February 23, 2001. Revision received July 4, 2001. Accepted for publication July 6, 2001.
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