Association of Antidepressant Prescription Filling With Treatment Indication and Prior Prescription Filling Behaviors and Medication Experiences

Antidepressants are the most frequently prescribed class of psychotropic drugs1–3 used by clinicians to treat not only depression but also a wide range of other indications, including anxiety, insomnia, and pain.4 Despite their popular use, meta-analyses of clinical trials evaluating antidepressant use for depression have not found clear evidence of a meaningful benefit of antidepressants compared with placebo, with many efficacy trials being susceptible to numerous biases.5–7 Antidepressant use for indications besides depression is also controversial due to these other indications oftentimes being not approved (off-label) for many antidepressants and insufficiently evaluated in clinical trials.8

In light of these concerns, pharmacoepidemiologic studies evaluating the real-world effectiveness and safety of antidepressant use for different indications could provide valuable insights into the actual benefits and risks of antidepressant use at the population level. To this end, it is important to understand patterns of antidepressant use in real-world settings, including patients’ prescription filling behaviors and how they relate to clinicians’ intentions for prescribing antidepressants—namely, the indication. Among naive antidepressant users, measuring levels of prescription filling helps estimate the proportion of antidepressant prescriptions leading to the actual initiation of use, which could differ across indications. Among prevalent antidepressant users, levels of prescription filling could also vary across indications due to a variety of factors, including differences in treatment directives, effectiveness, or adverse drug events by indication, the latter of which is more likely when off-label drug use is not backed by strong scientific evidence.9

To date, no studies have measured indication-specific levels of prescription filling for antidepressants using a validated measure of treatment indication. In addition, few studies have measured the impact of patients’ prior prescription filling behaviors and medication experiences on future prescription filling behaviors for antidepressants. To address these knowledge gaps, we used data from a unique electronic prescribing system linked to dispensing data to measure the prevalence of antidepressant prescription filling by indication and evaluate the association of prescription filling with the indication for antidepressant treatment and patients’ prior prescription filling behaviors and experiences with medications, independent of other drug and patient factors. We also evaluated whether the relationship of antidepressant prescription filling with treatment indication differed between naive and non-naive users.

METHODS Study Design and Setting

This cohort study took place in the Canadian province of Quebec, where the provincial health insurance agency—the Régie de l’Assurance Maladie du Québec (RAMQ)—covers the cost of essential medical services for all residents. By law, all residents must have drug insurance through either a private plan (ie, group or employee benefit plan) or the public drug insurance plan administered by the RAMQ.10 Approximately 50% of Quebec residents are registered in the public drug insurance plan, including the elderly, welfare recipients, and persons not insured through an employer.

Data Source and Study Population

The Medical Office of the XXIst Century (MOXXI) is an indication-based electronic prescribing and drug management system used by consenting primary care physicians in 2 major urban centers in Quebec, Canada.11 Since 2003, ∼200 physicians (25% of eligible) and over 100,000 patients (26% of all who visited a MOXXI physician) have consented to participate in the MOXXI program. In general, MOXXI physicians are younger than nonparticipating physicians, while MOXXI patients are older and have more health problems than nonconsenting patients.12

MOXXI features numerous functionalities for enhancing drug safety and coordination of care for patients.11 The MOXXI prescribing tool requires physicians to document at least 1 treatment indication per prescription by using a drop-down menu containing on-label and off-label indications without distinction or by typing the indication(s) into a free-text field. These physician-documented indications were previously validated and had excellent sensitivity (98.5%) and positive predictive value (97.0%).13 The MOXXI prescribing tool also requires physicians to document the reasons for prescription stops or changes using a drop-down menu listing options related to safety (eg, adverse drug reaction) or effectiveness (eg, ineffective treatment), which have also been validated.14

Administrative health data for MOXXI patients were obtained by linking individuals via their unique health care number to provincial health administrative databases, which provided dispensing data from the public drug insurance plan, as well as information on demographics, diagnoses, hospitalizations, and medical services received. These databases are valid and reliable sources of data for pharmacoepidemiologic and health services research.15,16

This study was approved by the McGill Institutional Review Board.

Inclusion and Exclusion Criteria

The unit of analysis was the antidepressant prescription, which represented a physician’s authorization to dispense medication to a patient for a given regimen and duration (including any subsequent refills over the valid period of the prescription) for either new or modified treatment.17 Prescriptions were included if they were issued between January 1, 2003, and December 31, 2012, for a medication approved to treat depression (Supplement 1, Supplemental Digital Content 1, https://links.lww.com/MLR/C346) and if the patient was at least 18 years old, was enrolled in the public drug insurance plan and had at least 1 year of historical dispensing data available in the public drug insurance database on the prescription date to distinguish new from continued antidepressant users. Prescriptions were excluded if they were for antidepressants not covered under the public drug insurance plan (escitalopram, desvenlafaxine, and duloxetine) or monoamine oxidase inhibitors, which were rarely prescribed (Fig. 1).

FIGURE 1FIGURE 1:

Flow chart of antidepressant prescriptions used in the analysis. Eligible antidepressant prescriptions for the study were used to construct cumulative survival curves, stratified by treatment indication and therapy status, and estimate odds ratios for the association between treatment indication and antidepressant nonadherence at 90 days, adjusted for other drug and patient factors. A subset of eligible antidepressant prescriptions for which the patient had at least 1 year of historical prescribing data available in the MOXXI (Medical Office of the XXIst Century) system was used to estimate the association of antidepressant nonadherence with prior prescription filling behaviors and experience with medications (treatment ineffectiveness and adverse drug reactions in the past year), also adjusted for other drug and patient factors.

Antidepressant Prescription Filling

The study outcome of interest was not filling an antidepressant prescription within 90 days of its issuance, reflecting the concept of nonadherence for indications with a more chronic nature, like depression and anxiety, where not filling an antidepressant prescription may represent a deviation from the planned treatment. Filled prescriptions were tracked using linked dispensing data from the public drug insurance plan, where prescriptions were considered filled if any brand of the prescribed drug was dispensed to the patient within 90 days. As only a negligible proportion (0.1%) of patients both did not fill the index prescription and died or became ineligible for the public drug insurance plan within 90 days, we treated all patients as if they were followed for the complete period.

Potential Determinants of Antidepressant Prescription Filling Treatment Indication

Treatment indications for antidepressant prescriptions were retrieved from the MOXXI system and classified using the clinical definitions under the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) coding into the following categories: (1) depressive disorders; (2) anxiety-related disorders, including panic disorders, phobias, and stress disorders; (3) insomnia; (4) pain, including chronic pain, neurogenic pain, and dorsalgia; or (5) miscellaneous indications, including migraine, fibromyalgia, vasomotor symptoms of menopause, nicotine dependence, and pruritus, among others. If multiple indications were documented (1.7% of prescriptions), the indication entered first was used.

Therapy Status

Prescriptions were classified as being for new or ongoing antidepressant therapy, where prescriptions for new antidepressant therapy were those where the patient did not have any antidepressants dispensed in the previous year.

Prior Prescription Filling Behaviors and Experience With Medications

As patients’ past prescription filling behaviors could be predictive of future prescription filling behaviors for antidepressants,18 the proportion of prescriptions in the past year that were filled within 90 days was measured and analyzed separately for chronic disease-modifying medications and symptom-relieving medications19 (Supplement 2, Supplemental Digital Content 2, https://links.lww.com/MLR/C347). To assess the potential impact of patients’ prior experiences with medications on future prescription filling behaviors for antidepressants, the presence of any prescriptions in the past year that had been modified due to ineffective treatment or an adverse drug reaction was measured and analyzed separately for antidepressants and non-antidepressant medications. All these variables were measured only for the subset of prescriptions where the patient had been enrolled in MOXXI for at least 1 year at the time of the prescription (Fig. 1).

Other Patient and Drug Factors Possibly Influencing Prescription Filling

Other patient and drug-related factors that could affect prescription filling behaviors for antidepressants were measured and treated as adjusting covariates, including patient age and sex,18,20–25 copayment plan for medications (no copayment, partial copayment of 25% per prescription to a maximum of $600 annually, or maximum copayment of 25% per prescription to a maximum of $1000 annually),25 comorbidities in the Charlson Comorbidity Index,26 and health services use in the past year (number of outpatient visits, number of non-antidepressant drugs dispensed, any emergency department (ED) visit, any hospitalization, and continuity of care measured as the proportion of outpatient visits to the prescribing physician).18,20,24,25 The pharmacological class of the prescribed antidepressant and whether the antidepressant had been prescribed on a “take-as-needed” basis was also measured from the MOXXI system.

Statistical Analysis

Cumulative survival curves showing the percentage of unfilled prescriptions on days 0–90 after the prescription date were constructed, stratified by treatment indication and therapy status. The reported 95% confidence intervals (CIs) around the percentage of unfilled prescriptions at 90 days corresponded to the values at the 2.5th and 97.5th percentiles of the distribution across 1000 bootstrap resamples of the study data using a 2-stage cluster bootstrap27 to account for multilevel clustering of prescriptions within patients, who in turn were nested within physicians.

Multivariable alternating logistic regression was used to estimate the association of treatment indication with failing to fill an antidepressant prescription within 90 days, independent of other patient and drug factors. Alternating logistic regression, implemented using PROC GENMOD in SAS, was used to adjust the main effect estimates for multilevel clustering of prescriptions in the context of a dichotomous outcome.28 To determine if the association of treatment indication was modified by therapy status, a 2-way interaction term was included in the model. The independent association of failing to fill an antidepressant prescription with prior prescription filling behaviors and experience with medications was assessed in a separate multivariable model that included only the subset of patients with at least 1 year of prior prescribing data in MOXXI (Fig. 1).

All statistical analyses were performed using SAS (SAS Institute Inc., Cary, NC) software, version 9.4.

RESULTS

A total of 38,751 antidepressant prescriptions written by 154 physicians for 9284 patients met the study inclusion criteria; 29,670 (76.6%) of these prescriptions had 1 year of historical MOXXI prescribing data available for the patient (Fig. 1). Antidepressant prescriptions were most commonly prescribed for depressive disorders (55.5%), anxiety-related disorders (21.6%), insomnia (11.0%), and pain (6.5%). Depressive disorders accounted for a lower proportion of prescriptions for new (47.0%) compared with ongoing (56.6%) antidepressant therapy.

Treatment Indication and Therapy Status

Prescriptions for new antidepressant therapy were filled faster than those for ongoing antidepressant therapy (Fig. 2), with a median time-to-fill of 2 and 7 days, respectively. By indication, the median time-to-fill for new therapy prescriptions was shortest for insomnia (1 d) and longest for miscellaneous indications (4 d), while for ongoing therapy, was shortest for depression and insomnia (7 d) and longest for pain (9 d). Rates of prescription filling among new and ongoing therapy prescriptions reached a plateau after ∼15 and 30 days, respectively.

FIGURE 2FIGURE 2:

Percentage of antidepressant prescriptions not filled at 0–90 days, by treatment indication and therapy status. The cumulative survival curves show the percentage of antidepressant prescriptions for new (Panel A) or ongoing (Panel B) antidepressant therapy that were not dispensed to the patient over 90 days, stratified by treatment indication. Prescriptions for new antidepressant therapy were defined as those where the patient did not have an antidepressant dispensed in the previous year. Prescriptions for ongoing therapy were defined as those were the patient had an antidepressant dispensed in the previous year and were issued for reasons such as switching to a different antidepressant, modifying the dosage, or renewing the prescription.

Among new antidepressant therapy prescriptions, the proportion of unfilled prescriptions was highest for pain (39.3%) and lowest for insomnia (25.3%) (Fig. 2). Among ongoing antidepressant therapy prescriptions, the proportion of unfilled prescriptions was also highest for pain (6.3%), while depressive disorders and anxiety-related disorders tied for the lowest percentage of unfilled prescriptions at 3.6%.

In the multivariable analysis, the odds of not filling an antidepressant prescription was 28% higher when antidepressants were newly prescribed for anxiety-related disorders [odds ratio (OR),1.28; 95% CI, 1.05–1.57] compared with depressive disorders, but 26% lower when antidepressants were newly prescribed for insomnia (OR, 0.74; 95% CI, 0.56–0.98) (Table 1). Conversely, for ongoing antidepressant therapy, the odds of not filling an antidepressant prescription was 57% higher when antidepressants were prescribed for insomnia (OR, 1.57; 95% CI, 1.24–2.00) and 54% higher when prescribed for miscellaneous indications (OR, 1.54; 95% CI, 1.20–1.97), compared with depressive disorders. For all indications except insomnia, prescriptions for new antidepressant therapy were associated with a statistically significant higher odds of not being filled within 90 days compared with prescriptions for ongoing antidepressant therapy.

TABLE 1 - Association of Treatment Indication With Not Filling an Antidepressant Prescription Within 90 Days, by Antidepressant Therapy Status Variables No. of Prescriptions (N=38,751) % Unfilled at 90 d Adjusted OR (95% CI) for Not Filling the Prescription Within 90 d Treatment indication, by antidepressant therapy status*  New therapy   Depressive disorders 2059 36.7 1.00 (reference)   Anxiety-related disorders 972 31.8 1.28 (1.05–1.57)   Insomnia 617 25.3 0.74 (0.56–0.98)   Pain 382 39.3 0.93 (0.62–1.40)   Miscellaneous indications 348 35.9 1.10 (0.82–1.48)  Ongoing therapy   Depressive disorders 19,445 3.6 1.00 (reference)   Anxiety-related disorders 7399 3.6 1.02 (0.89–1.17)   Insomnia 3635 6.1 1.57 (1.24–2.00)   Pain 2146 6.3 1.27 (0.95–1.70)   Miscellaneous indications 1748 6.0 1.54 (1.20–1.97) Antidepressant therapy status,* by treatment indication  Depressive disorders   Ongoing therapy 19,445 3.6 1.00 (reference)   New therapy 2059 36.7 2.53 (1.98–3.24)  Anxiety-related disorders   Ongoing therapy 7399 3.6 1.00 (reference)   New therapy 972 31.8 3.18 (2.53–4.00)  Insomnia   Ongoing therapy 3635 6.1 1.00 (reference)   New therapy 617 25.3 1.19 (0.89–1.59)  Pain   Ongoing therapy 2146 6.3 1.00 (reference)   New therapy 382 39.3 1.85 (1.12–3.05)  Miscellaneous indications   Ongoing therapy 1748 6.0 1.00 (reference)   New therapy 348 35.9 1.82 (1.28–2.58)

*Therapy status was classified as new antidepressant therapy if the patient did not have any antidepressants dispensed from any prescriber in the past year.

†From a multivariable model that additionally included all drug and patient factors shown in Table 3.

CI indicates confidence interval; OR, odds ratio.


Prior Prescription Filling Behaviors and Experience With Medications

Poor prescription filling behaviors in the past year were associated with increased odds of not filling an antidepressant prescription (Table 2). Compared with patients who filled ≥75% of their prescriptions for chronic disease-modifying medications in the past year, the odds of not filling a new or continuing antidepressant prescription was over 2.5 times higher among patients who filled < 50% of their chronic disease prescriptions in the past year (OR, 2.57; 95% CI, 1.85–3.57). Patients with no prescriptions for chronic disease-modifying medications in the past year also had a statistically significant higher odds of not filling their antidepressant prescriptions (OR, 1.16; 95% CI, 1.02–1.31). A similar, albeit attenuated association was observed for symptom-relieving medications.

TABLE 2 - Association of Prior Prescription Filling Behaviors and Medication Experiences With Not Filling an Antidepressant Prescription Within 90 Days Variables No. of Prescriptions* (N=29,670) % Unfilled at 90 d Adjusted OR (95% CI) for Not Filling the Prescription Within 90 d Prescription filling behaviors in the past year  Chronic disease-modifying medications   75%–100% of prescriptions filled 20,992 3.8 1.00 (reference)   50% to <75% of prescriptions filled 690 18.6 1.40 (0.92–2.11)   0% to <50% of prescriptions filled 856 71.3 2.57 (1.85–3.57)   No essential medications prescribed 7132 8.5 1.16 (1.02–1.31)  Symptom-relieving medications   75%–100% of prescriptions filled 13,315 3.6 1.00 (reference)   50% to <75% of prescriptions filled 1335 7.6 1.41 (1.10–1.80)   0% to <50% of prescriptions filled 1426 32.3 1.64 (1.34–2.00)   No symptom-relieving medications prescribed 13,594 8.1 1.09 (0.94–1.26) Experiences with medications in the past year  Antidepressants   Prescription stopped or changed due to ineffective treatment    No 25,731 7.1 1.00 (reference)    Yes 3939 7.8 1.21 (1.02–1.43)   Prescription stopped or changed due to an adverse drug reaction    No 28,953 7.2 1.00 (reference)    Yes 717 7.1 0.81 (0.51–1.30)  Other medications besides antidepressants   Prescription stopped or changed due to ineffective treatment    No 23,784 7.3 1.00 (reference)    Yes 5886 6.9 1.02 (0.92–1.14)   Prescription stopped or changed due to an adverse drug reaction    No 27,849 7.2 1.00 (reference)    Yes 1821 7.2 0.99 (0.81–1.20)

*Only antidepressant prescriptions where the patient had been enrolled in the MOXXI (Medical Office of the XXIst Century) program for at least 1 year were included in this analysis to ensure that patients had at least 1 year of prior prescribing data available

†From a multivariable model that additionally included all variables in Table 1 (treatment indication, therapy status, and a 2-way interaction between treatment indication and therapy status) and all drug and patient factors shown in Table 3.

CI indicates confidence interval; OR, odds ratio.

Patients who had an antidepressant prescription stopped or changed in the past year due to treatment ineffectiveness had 21% higher odds of not filling the index antidepressant prescription (OR, 1.21; 95% CI, 1.02–1.43) (Table 2). However, this association was not observed among patients who had prescriptions for non-antidepressant medications stopped or changed in the past year due to treatment ineffectiveness (OR, 1.02; 95% CI, 0.92–1.14). Adverse drug reactions in the past year to antidepressants and non-antidepressant medications were not associated with not filling antidepressant prescriptions.

Other Drug and Patient Factors

The odds of not filling an antidepressant prescription was lower for serotonin-norepinephrine reuptake inhibitors compared with every other pharmacological class of antidepressants, while the odds of not filling an antidepressant prescription was 49% higher when antidepressants were prescribed on a take-as-needed basis (OR, 1.49; 95% CI, 1.11–2.00) (Table 3). Compared with patients aged 18–50 years old, older patients were increasingly more likely to fill their antidepressant prescriptions. Compared with patients with no medication copayments, the odds of not filling an antidepressant prescription was 2- to 3-fold higher for patients with a partial copay (OR, 2.23; 95% CI, 1.73–2.89) or maximum copay (OR, 2.90; 95% CI, 2.42–3.47). The odds of not filling an antidepressant prescription decreased with greater numbers of non-antidepressant drugs dispensed in the past year but was greater among patients who had visited the ED or had greater numbers of outpatient visits in the past year.

TABLE 3 - Association of Other Drug and Patient Factors With Not Filling an Antidepressant Prescription Within 90 Days Variables No. Prescriptions (N=38,751) % Unfilled at 90 d Adjusted OR* (95% CI) for Not Filling the Prescription Within 90 d Drug factors  Pharmacological class   SSRI 16,471 5.9 1.00 (reference)   SNRI 7690 7.1 1.24 (1.07–1.42)   TCA§ 5095 10.5 1.77 (1.44–2.17)   Other 9495 9.0 1.48 (1.30–1.69)  Drug prescribed on a “take-as-needed” basis   No 37,967 7.3 1.00 (reference)   Yes 784 17.0 1.49 (1.11–2.00) Patient factors  Sex   Female 26,914 7.3 1.00 (reference)   Male 11,837 8.1 1.00 (0.88–1.14)  Age (y)   18–50 9476 12.3 1.00 (reference)   51–62 9885 6.8 0.72 (0.60–0.87)   63–72 9425 6.5 0.62 (0.53–0.74)   73+ 9965 4.7 0.50 (0.42–0.61)  Copayment plan for medications   No copayment (free) 12,139 3.5 1.00 (reference)   Partial copayment (up to 600 CAD/year) 7323 9.0 2.23 (1.73–2.89)   Maximum copayment (up to 1000 CAD/year) 19,289 11.0 2.90 (2.42–3.47)  Chronic conditions in the Charlson Comorbidity Index   Myocardial infarction    No 38,124 7.6 1.00 (reference)    Yes 627 4.0 0.79 (0.56–1.11)   Congestive heart failure    No 37,596 7.6 1.00 (reference)    Yes 1155 4.9 0.95 (0.67–1.37)   Peripheral vascular disease    No 37,843 7.6 1.00 (reference)    Yes 908 5.3 1.10 (0.70–1.73)   Cerebrovascular disease    No 37,840 7.6 1.00 (reference)    Yes 911 4.7 0.93 (0.71–1.24)   Dementia    No 37,598 7.7 1.00 (reference)    Yes 1153 3.5 0.77 (0.58–1.04)   Chronic pulmonary disease    No 31,011 7.9 1.00 (reference)    Yes 7740 5.9 1.00 (0.89–1.12)   Rheumatic disease    No 37,950 7.6 1.00 (reference)    Yes 801 3.8 0.87 (0.63–1.21)   Peptic ulcer disease    No 38,278 7.5 1.00 (reference)    Yes 473 7.8 1.17 (0.85–1.61)   Mild liver disease    No 37,989 7.6 1.00 (reference)    Yes 762 6.0 1.10 (0.80–1.50)   Diabetes without chronic complication    No 33,012 7.9 1.00 (reference)    Yes 5739 5.4 1.09 (0.94–1.25)   Diabetes with chronic complication    No 38,498 7.5 1.00 (reference)    Yes 253 6.7 1.07 (0.65–1.76)   Hemiplegia or paraplegia    No 38,521 7.5 1.00 (reference)    Yes 230 9.1 1.17 (0.75–1.84)   Renal disease    No 37,866 7.6 1.00 (reference)    Yes 885 4.3 1.03 (0.78–1.35)   Any malignancy    No 36,145 7.6 1.00 (reference)    Yes 2606 6.0 1.04 (0.88–1.24)  

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