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Patterns of antidepressant use in community practice
Psychiatry and Primary Care Recent epidemiologic studies have found that most patients with mental illness are seen exclusively in primary care medicine. These patients often present with medically unexplained somatic symptoms and utilize at least twice as many health care visits as controls. There has been an exponential growth in studies in this interface between primary care and psychiatry in the last 10 years. This special section, edited by Wayne J. Katon, M.D., will publish informative research articles that address primary care-psychiatric issues.
Patterns of Antidepressant Use in Community Practice Gregory E. Simon, M.D., M.P.H., Michael VonKorff, Sc.D., Edward H. Wagner, M.D., M.P.H., and William Barlow Ph.D.
Abstract: Computerized pharmacy records from a large staffmodel health maintenance organization were used to examine patterns of antidepressant use by prima y care physicians and psychiatrists. Based on timing of prescription refills, patients treated by psychiatrists were more likely than those treated in primary care to continue medication for more than 30 days (35% vs 25%, p < 0.00001) and more likely to reach a prescribed daily dose of 100 mg of imipramine or the equivalent (48% vs 40%, p < 0.00001). Patients treated with newer antidepressants were significantly more likely to continue freatment past 30 days (range from 75% for fluoxefine to 54% for doxepin, p < 0.00002) and to reach an adequate daily dose (range from 52% for fluoxetine to 26% for doxepin, p < 0.00001). Psychiatrists more often prescribed newer antidepressants, and much of the difference befween specialties could be explained by drug selection. These findings suggest more intensive antidepressant treatment than in earlier reports, especially in prima y care. More intensive treatment with newer antidepressants may reflect more tolerable side effects, but these observational data are liable to selection bias. Any potenfial advantages of newer antidepressant medications must be balanced against significantly higher costs.
Introduction Depressive illness produces a large and preventable burden of personal suffering and social cost. Center for Health Studies, Group Health Cooperative of Puget Sound, Seattle, Washington. Address reprint requests to: Gregory Simon, Center for Health Studies, 1730 Minor Ave. #1600, Seattle, WA 98101-1448.
GeneralHospital Psychiatry 15,399408,1993 O1993ElsevierScience PublisbingCo.,Inc. 655Avenue of the Americas, New York, NY 10010
At any point in time, approximately 2% of adults suffer from current major depression with nearly 6% experiencing major depression at some point in life Ill. In addition to emotional suffering, depressive illness results in a level of disability typical of major medical illness 121, significant loss of productivity 131, and greater use of medical care [41. Although available antidepressant medications are safe and effective, many patients with depression receive inadequate treatment. In a sample of outpatients treated with antidepressants at university medical centers, Keller et al. [5,6] found that only 27 of 70 (39%) were prescribed at least 200 mg/day of imipramine or the equivalent. Kotin et al. [71 noted adequate doses (150 mg/day of imipramine or the equivalent) in only 8 of 21 (38%) patients hospitalized for persistent depression. Bridges [8] described low antidepressant doses in a sample of British patients referred for psychosurgery because of treatment failure, but specific details on dosing were not provided. Primary care physicians provide the majority of care for patients with depression [9,10], and reports of antidepressant use in primary care also suggest low intensity of treatment. In a survey of psychotropic medication use by 361 British general practice patients, Johnson Ill] found that only 20% of those treated with tricyclic antidepressants received doses of greater than 75 mg/day. Over half of patients prescribed a psychotropic medication
399 ISSN0163-8343/93,'$6.00
G. E. Simon et al.
discontinued treatment during the first month. In a group of 241 primary care patients selected for high levels of psychologic distress and health care utilization, Katon et al. [12] found that approximately 30% of those treated with antidepressants received adequate doses (100 mg/day of imipramine or the equivalent). The same report described early discontinuation of antidepressant treatment among a general sample of health maintenance organization (HMO) patients; only 40% of those starting treatment received two or more refills during the following 6 months. Other reports of smaller primary care samples describe similar low antidepressant dosage levels 113,141. In surveys of knowledge about antidepressant prescribing, primary care physicians often endorse dosage levels and duration of treatment less than recommended 115-171 Although previous reports suggest a need for improvement in antidepressant prescribing, the available data on treatment intensity are limited. First, most prior descriptions of antidepressant prescribing are now more than 10 years old. Of the reports cited above, only two 112,131 included patients treated since 1982. The last decade has seen the increasing use of newer antidepressant medications and a new generation of physicians trained since the development of effective antidepressant treatment. Second, some findings may not be generalizable because of small sample sizes [7,8,13,141, inclusion of patients treated in training settings 113,141, or inclusion of patients treated for indications other than depression [12]. Only the studies of Johnson [ll] and Keller [5,61 include large samples of patients with depression treated by community practitioners. Third, prior studies have relied on prescribed doses given in pharmacy or medical records to measure treatment intensity. Given the problems with treatment adherence described above, the dosage and duration prescribed may significantly overestimate the intensity of treatment actually received. Data from chart or prescription records can only assess physicians’ intentions, not patients’ actual medication use. Fourth, most previous studies provide little information on factors predicting adequacy of treatment. One exception is the report by Katon et al. [12] of greater adherence among patients treated with newer antidepressants. This relationship, however, may be confounded by the inclusion of patients with diagnoses other than depression and the mixing of primary care and psychiatric patients. Though previous reports typically attribute low intensity of 400
treatment to prescribing physicians’ lack of skill or knowledge, none have examined the relationship between skill level and treatment intensity. Conceptually, the quality of antidepressant treatment patients receive reflects characteristics of the physician (knowledge about antidepressant use, skill in building a treatment alliance), the patient (motivation to take antidepressants, susceptibility to side effects), and the medication (convenience, sideeffect profile). Efforts to improve pharmacotherapy of depression should examine the relative influence of each of these factors. This report describes the use of computerized pharmacy records to examine antidepressant treatment received by a large sample of enrollees in a staff-model HMO. This report extends the work by Katon in an earlier sample from this same setting. Dose and duration of antidepressant treatment were compared with recommended standards. Characteristics of patients, prescribing physicians, and medications prescribed were examined as potential predictors of the dose and duration of antidepressant treatment.
Methods Study Setting Group Health Cooperative of Puget Sound (GHC) is a large staff-model HMO serving approximately 370,000 residents of western Washington state. Primary care is provided by approximately 360 physicians with each full-time physician responsible for a defined panel of approximately 1600 patients. Over 95% of physicians providing primary care to adults are trained in family medicine, with most of the remainder trained in internal medicine. Approximately 20 psychiatrists provide care for both self-referred and physician-referred patients. Over 90% of primary care physicians and psychiatrists are certified by appropriate specialty boards. GHC’s computerized information systems include data on all outpatient visits to GHC clinics and all outpatient prescriptions filled at GHC pharmacies. Previous surveys of GHC enrollees have found that over 95% of prescriptions for antidepressants are filled at GHC pharmacies.
Selection of Study Sample Potential subjects were GHC patients aged 18-60 beginning antidepressant treatment from July 1989 to July 1990. The study sample was drawn from all
Patterns of Antidepressant
CASE A
. . . . . . . . .
4 4
starting antidepressants after a recent treatment failure. Consequently, any episode of treatment might include one or more prescriptions or refills and could include prescriptions for different antidepressants. Any patient might have more than one episode during the study interval, but only the first episode for any patient was included. Examples are shown in Figure 1.
..a........
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Figure 1. Organization of prescription fills into episodes of care. In Case A, pharmacy records showed three antidepressant fills (new or refill) during the study period. Because the longest interval between fills was 56 days, all were classified in the same episode. Case B also had three antidepressant fills, but 98 days elapsed between the second and the third. Consequently, the first two fills were considered to be one episode and the third fill was considered to be a separate episode consisting of only one prescription fill.
GHC psychiatric care clinics
clinics
for which
and
from
computerized
those
primary
diagnostic
data
over age 60 were excluded because greater variability in dosing among older patients would preclude evaluation of dosage levels. Those under 18 were excluded because of greater variability in dosing and indications for antidepressant use. Finally, we excluded patients treated with less commonly prescribed antidepressants (e.g., clomipramine, monoamine protriptyline, maprotiline, oxidase inhibitors, amoxapine) because the number of patients treated with each of these agents was too small to allow comparison among medications. These prescriptions combined accounted for 6% of psychiatrist patients and 3% of primary care patients.
were
available
(see
below).
Use
Indication for Treatment During the study period, diagnostic data from visit encounter forms were entered into computerized visit records at a sample of GHC primary care clinics. Each antidepressant treatment episode initiated by a primary care physician was linked to the computer record of the immediately preceding primary care visit. The diagnosis coded on the encounter form for that visit was considered the indication for prescription. Computerized diagnostic data were not available for psychiatric visits, so computer records of psychiatric episodes could not be sorted by indication.
Patients
Identification of Antidepressant Treatment Episodes Automated pharmacy records were used to identify all prescription fills (either new or refill) for antidepressant medication in the study sample. Individual prescription fills were then organized into episodes of antidepressant treatment using the following algorithm. Any two prescription fills (new or refill) separated in time by 90 days or less were placed in the same treatment episode whereas consecutive prescription fills more than 90 days apart were classified in separate episodes. This relatively long interval was selected to exclude patients re-
Calculation of Antidepressant
Dose and Duration
Patient requests for antidepressant refills were considered more accurate than physicians’ prescriptions instructions as a measure of actual medication use. Consequently, the dose and duration of antidepressant treatment received were calculated from the quantity and timing of antidepressant medication dispensed. Calculated dose and duration should reflect treatment received, but may not reflect treatment prescribed. Samples of 50 patient refill records were manually reviewed by the senior author to verify the accuracy of computed dose and duration, and no errors were detected. Computer algorithms are detailed below. The duration of each episode was computed as the time between the first prescription fill and the estimated stopping date on which the last prescription fill of the episode should have been completely consumed. For this calculation, the time taken to consume the final refill was assumed to be the same as that taken to consume the previous one. This procedure is illustrated in Figure 2. For patients switching antidepressant drugs during a treatment episode, computed duration includes the time taking any antidepressant. For episodes with only one prescription fill, duration of treatment could not be estimated from patients’ refill behavior and was based on the physician’s initial
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timates of antidepressant dosing as doses are calculated only for patients who continue treatment after the first prescription.
4 Rx OOXEPIN
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OOXEPIN
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DURATION - 27 + 42 + 42 = 121 DAYS DAILY DOSE = 22 mg x 190 I 42 DAYS -
107 ma/day
Figure 2. Calculation of duration and dose. This episode included three prescription fills. The time taken to consume the final prescription fill was presumed to be the same as the time needed to consume the previous fill (42 days). Duration of treatment was calculated as the time from the first to the last fill plus this inferred duration for the final fill (37 days + 42 days + 42 days). Daily dose was calculated from the final interprescription interval (that between the last and second-to-last fills). The total quantity of medication dispensed at the second-tolast fill (50 mg X 90 pills = 4500 mg) was divided by the number of days needed to consume that fill (42 days).
prescription. After a review of pharmacy records for 100 of these episodes showed prescribed quantity to be always less than a one-month supply (when taken at the prescribed rate), duration of treatment for episodes with one fill was presumed to be 30 days or less. Daily antidepressant dose for each episode was calculated using the quantity of antidepressant dispensed (mg/pill x number of pills dispensed) divided by the number of days until the next prescription fill. The final interprescription interval (time between the second-to-last and last fills) was used for this calculation, allowing maximum time to reach an effective dose. Dosage calculation is illustrated in Figure 2. For episodes with only two prescription fills, the only available interprescription interval begins with the initial prescription and thus may include an initial period of gradually increasing dose. In these cases, the computed average dose may underestimate the final dose achieved. For episodes with only one fill, calculation of daily dose was not possible, because the actual rate of medication use could not be observed. We considered using prescribed dose as a secondary measure of dose consumed, but rejected this strategy as too inaccurate. These single-fill episodes were typically initial prescriptions calling for step-wise increases in dose. Because these single-fill episodes all involved early treatment discontinuation, one cannot assume that the final, highest dosage level was actually reached. Because the dosage consumed could not be calculated from refill records or accurately inferred from the prescribing physician’s instructions, episodes with only one fill were excluded from calculation of daily dose. This exclusion may result in optimistic es-
402
Antidepressant dosage levels were evaluated according to a standard “adequate” dose based on expert opinion and manufacturer’s recommendations. This standard was set at 100 mg/day for amitriptyline, desipramine, doxepin, imipramine, and trazodone; at 50 mg/day for nortriptyline; and at 20 mg/day for fluoxetine.
Statistical Analysis Univariate comparisons included cross-tabulations and Chi-square performed with the SAS software package (SAS, Cary, NC). Multivariate analyses utilized logistic regression performed with the EGRET software package (Statistics and Epidemiology Research Corporation, Seattle, WA). The effect of variability among individual physicians was examined using a logistic regression model with random effects, a technique allowing the estimation of the overall contribution of variability among physicians without examining each physician individually 1181. Reported p-values are based on a likelihood ratio criterion.
Results Study Sample The procedures above identified 3905 patients treated with antidepressants by primary care physicians. The diagnosis coded on the corresponding visit registration form was depression for 37% of episodes, pain (headache, back pain, and chronic abdominal pain) for 19%, stress/anxiety for lo%, fatigue for 3%, and “other” diagnoses for 31%. This final category may include some cases of depression that were assigned primary medical diagnoses or hand-written diagnoses not captured by computer. Consequently, the proportion of antidepressant treatment for the indication of depression may have been higher than 37%. Subsequent analyses, though, were restricted to episodes with a specific diagnosis of depression. Although this restriction may exclude some cases of depression given other diagnoses, it assures the exclusion of antidepressant prescriptions for nondepression indications. For the 977 patients treated by psychiatrists, computerized diagnostic data were not available. For a
Patterns of Antidepressant Use
Table 1. Choice of initial antidepressant medication according to physician specialty % Primary care (N = 1455)
% Psychiatry w = 977)
17 14 20 12 7 16 14
3 7 18 8 14 36 14
Amitriptyline Doxepin Imipramine Desipramine Nortriptyline FIuoxetine Trazodone
Duvafion of Treatment
10% random sample of psychiatrist episodes, chart review found a diagnosis of depression for 98 of 105 episodes (93%). For the remaining episodes, primary diagnosis was panic disorder for six cases and obsessive-compulsive disorder for one. Because of the low prevalence of indications other than depression, all psychiatrist-initiated episodes were included in subsequent analyses. The combined sample had mean age of 39.1 years (SD 9.5), and 75% were female. Patients treated by psychiatrists and those treated by primary care physicians did not differ in gender or age distribution.
Medication
Selection
Psychiatrists were more likely than primary care physicians to initiate treatment with newer anti-
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depressants (Table 1). First-generation tricyclic antidepressants (amitriptyline, doxepin, and imipramine) were the initial choice in 51% of primary care episodes diagnosed as depression compared with 28% of episodes treated by psychiatrists. Psychiatrists showed a corresponding increase in use of newer antidepressants such as nortriptyline and fluoxetine.
180d
Figure 3. Likelihood of continuing antidepressant medication after initial prescription according to specialty of prescribing physician.
Early discontinuation of antidepressant medication was common. Figure 3 compares duration of treatment among patients treated in primary care to that among patients treated by psychiatrists. For both groups, discontinuation of treatment was greatest during the first month and continued at a slow but steady rate thereafter. Primary care patients were more likely to discontinue treatment during the first month (35% vs 24%, p < 0.00001) but discontinuation rates were similar after day 31. In most cases of early discontinuation, the initial prescription was never refilled (29% of all primary care episodes vs 19% of all psychiatry episodes). Figure 4 shows duration of treatment according to the initial drug prescribed for primary care episodes only. As with the specialty differences described above, differences in continuation rates appeared during the first month and were relatively stable thereafter. Early (1 month) discontinuation rates ranged from 25% for fluoxetine to 46% for doxepin (p = 0.00001). In general, older antidepressants were more likely to be discontinued early. A parallel analysis of psychiatrist-treated episodes showed a similar pattern (earlier discontinuation for older medications) but the differences among medications were less marked (data not shown). Patient gender and age were weaker predictors of treatment adherence. Females had slightly lower rates of discontinuation during the first month (30% vs 33%, p = 0.09). Patients aged 31-50 were slightly less likely to discontinue than those older or younger (36% for age l&30,28% for age 31-40, 30% for age 41-50,35% for age 51-60, p = 0.005). Logistic regression was used to examine the combined effects of prescriber specialty and medication selection on the likelihood of continuing treatment beyond 30 days. Results are shown in Table 2. In the combined model, the effects of medication selection and prescriber specialty were both slightly smaller than their effects when considered 403
G. E. Simon et al.
significant differences in adherence among individual physicians do occur, but much of this effect is explained by medication selection.
Dispensed Dose
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Fewer than half of episodes had a dispensed dose that met or exceeded recommended standards. Results are shown in Table 3. Because the daily dose of antidepressant medication dispensed could not be calculated for episodes including only one prescription, these results consider only episodes in which the initial prescription was refilled. Patients treated by psychiatrists were more likely than those treated by primary care physicians to reach an adequate level of dispensed dose (48% vs 39%, p = 0.0004). Likelihood of an adequate dispensed dose varied significantly among antidepressants (p < O.OOOOl),ranging from 26% for doxepin to 51% for fluoxetine. Patients initiating treatment with newer antidepressants were more likely to reach an adequate dosage level, with this advantage more evident among primary care patients. Patient age and gender were less strongly related to dosage level. As with the analysis of duration described above, middle-aged patients were more likely to reach an adequate dispensed dose than those older or younger (36% for age 18-30, 43% for age 31-40,48% for age 41-50,40% for age 51-60, p = 0.009). Likelihood of reaching an adequate dosage level did not differ by gender (42% for males vs 45% for females, p = 0.22). Logistic regression was used to examine the combined effects of provider specialty and medication selection (Table 4). In the combined model,
--. -
(ll=253)
I
I
90d
120d
190d
Figure 4. Likelihood of continuing antidepressant medication after initial prescription according to medication prescribed.
separately. This finding suggests that some of the effect of prescriber specialty on duration is explained by medication selection and vice versa. A logistic regression model with random effects was used to evaluate whether variation among individual physicians concerning likelihood of early discontinuation was greater than predicted by chance. In a model containing patient age and gender, addition of physician as a random effect did make a significant contribution (p = 0.007). Addition of this physician effect to a model containing medication selection, however, did not contribute significantly to prediction of adherence (p = 0.28) and did not change the odds ratios associated with medication selection. These findings suggest that
Table 2. Logistic regression
model to predict likelihood
of continuing
antidepressant
beyond 30 days.
Odds ratio for model containing Specialty only Doxepin Amitriptyline Imipramine Desipramine NortriptyIine FIuoxetine Trazodone Primary Care Psychiatry
Medication only
1.00 1.72 (1.43-2.07)
1.02 1.84 1.25 1.72 2.30 1.20
1.00 (0.73-l .44) (1.33-2.54) (0.88-l .79) (1.X3-2.49) (1.68-3.14) (0.86-l .67) -
Combined model 1.00 1.07 (0.76-l .51)
(1.26-2.41) (0.86-l .75) (1.03-2.20) (1.44-2.74) (0.79-1.55) 1.00 1.50 (1.23-1.83) 1.75 1.23 1.51 1.99 1.11
Odds ratios (with 95% confidence intervals) are shown for model including prescriber specialty, model including initial medication prescribed, and model including both. All odds ratios adjusted for age and gender.
404
Patterns of Antidepressant
Table 3. Portion of antidepressant treatment episodes with adequate dispensed prescriber specialty and initial drug prescribed
dose according
Use
to
% of Episodes meeting standard Dosage standard (mg/day)
% Psychiatry (N = 769)
% Primary care (N = 1030)
% Total (IV = 1799)
100 100 100 100 50 20 100
34 N/A 45 46 47 50 52 48
22 28 34 40 62 53 48 39
26 31 39 42 53 51 49 43
Doxepin Amitriptyline Imipramine Desipramine Nortriptyline Fluoxetine Trazodone Total
the strong effect of medication selection was unaffected, but the odds ratio comparing psychiatrists and primary care physicians was no longer significantly different from 1. This finding suggest that much of the influence of prescriber specialty on adequacy of dispensed dose can be explained by medication selection, but the effect of medication selection is not explained by differences between providers. As with the analysis of duration above, logistic regression with random effects was used to evaluate variation among individual physicians in likelihood of reaching an adequate dispensed dose. Addition of physician as a random effect did not make a significant contribution to either a model containing patient age and gender (p = 0.207) or a model also containing medication selection (p = 0.161). Addition of this physician effect had mini-
Table 4. Logistic regression (see text).
mal impact on the effect of medication selection. These findings suggest that individual physicians do not differ significantly in the likelihood of patients achieving an adequate dispensed dose of antidepressant.
Discussion These data indicate somewhat more intensive antidepressant treatment among psychiatry and primary care patients than suggested by earlier reports. Physician factors (both specialty differences and differences among individual providers) were only moderate predictors of treatment intensity. Patients treated with newer antidepressants were significantly more likely to continue treatment beyond the first month and to reach an adequate level of prescribed dose.
mode1 to predict likelihood
of receiving
an adequate dispensed
daily dose
Odds ratio for model containing Specialty only Doxepin Amitriptyline Imipramine Desipramine Nortriptyline Trazodone Fluoxetine Primary Care Psychiatry
1.00 1.41 (1.16-1.71)
Medication only
1.35 1.91 2.20 3.40 2.95 3.16
1.00 (0.86-2.13) (1.28-2.84) (1.40-3.44) (2.18-5.31) (1.93-4.50) (2.15-4.64) -
Both 1.00 (0.87-2.18) (1.26-2.80) (1.39-3.43) (2.07-5.09) (1.89-1.41) (2.04-4.44) 1.00 1.17 (0.95-1.43)
1.38 1.88 2.19 3.25 2.89 3.01
Odds ratios (with 95% confidence intervals) are shown for model including prescriber specialty, model including initial medication prescribed, and model including both. All odds ratios adjusted for age and gender.
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Interpretation of these pharmacy refill data is limited by the absence of clinical information. First, these data do not indicate how many subjects met customary criteria for treatment with antidepressants. The primary care sample was limited to patients with a visit diagnosis of depression, but no further data were available on severity of illness. In the psychiatry sample, random chart audits indicated that over 90% of patients were treated for depression; chart data were typically inadequate to systematically rate severity. The inclusion of a small number of psychiatric patients treated for other indications may also affect these results (if those patients received dose or duration of treatment different from those treated for depression). Second, the groups compared (primary care vs psychiatry, older antidepressants vs newer) may have differed in severity of illness or other factors related to intensity of antidepressant treatment. The higher doses and longer treatment in psychiatric patients may reflect the greater severity of illness in specialty populations. Comparison of older and newer antidepressants may be biased by systematic differences in depression severity or motivation to continue treatment. Third, these data do not indicate whether differences in dose and duration of treatment actually lead to differences in outcome. If lower doses or briefer treatment were confined to milder or more transient illness, then the supposed shortcomings of practice identified here may have been clinically appropriate. The absence of chnical data must be balanced against the advantages of a population-based, naturalistic sample. Clinical trials of antidepressant medication typically include patients carefully selected for homogeneity of illness and likelihood of adherence to antidepressant treatment. In contrast, the patients in this sample are typical of those actually treated with antidepressants in a large HMO population. Clinical trial protocols typically call for strict dosing guidelines and intensive follow-up. In contrast, these data reflect the actual practice of over 300 physicians working in the busy, less controlled environment of usual care. The computer algorithms used above should accurately reflect the dose and duration of antidepressant treatment actually dispensed, but will in some cases not reflect the dose and duration consumed. Computed dosage reflects average dose consumed between two prescription fills and will not detect periods of higher and lower dosage. Failure to consume all medication dispensed prior to the final refill in an episode would result in an 406
overestimate of dose consumed. Failure to consume all of the final refill in an episode would result in an actual treatment duration shorter than estimated. These sources of error should typically produce an overestimate of dose and duration and should not lead to any bias in comparison of different providers or different medications. Any judgments about the quality of physician practice should be made cautiously. First, the standards for dose and duration of antidepressant treatment applied here were developed in referral psychiatric settings and may not be appropriate in this population. Episodes of depression treated in community samples of primary care patients may be less severe or shorter in duration than those seen in specialty settings. Lower antidepressant doses or shorter duration of treatment may not necessarily lead to poorer outcomes in primary care patients. Second, these data reflect the quantity of antidepressant medication dispensed by the pharmacy, not that prescribed by the physician. Patients who were prescribed adequate treatment but either discontinued treatment early or consumed a lower dose than prescribed would be reported in our results as being inadequately treated. Considering the above limitations, overall adequacy of antidepressant treatment in primary care appeared better than expected. The proportion of psychiatrist-treated episodes meeting the “adequate” dosing standard (48%) is almost identical to those reported in earlier studies by Keller et al. [5,61 and Kotin et al. [71. Those reports, however, evaluated prescribed antidepressant doses that are likely to be higher than the dispensed doses used in this study. In addition, those studies included more severely ill referral samples. The proportion of primary care episodes in this study exceeding the “adequate” standard (39%) compares favorably with the 20% of primary care patients in Johnson’s study 1111 and the 30% reported by Katon et al. [121 receiving a comparable level of treatment. The other primary care studies above include small samples and provide insufficient data for comparison. The observed 35% rate of discontinuation during the first month of treatment among primary care patients in this sample is lower than the 50% rate among British primary care patients described by Johnson Ill]. The higher discontinuation rate reported by Katon et al. in an earlier sample from the same HMO may reflect greater treatment discontinuation among patients receiving antidepressants for indications other than depression.
Patterns of Antidepressant
Early discontinuation was the clearest shortcoming of antidepressant treatment identified in this sample. Although one may argue whether the current recommendations for dosage or treatment duration are appropriate in primary care, most early discontinuation in this sample occurred during the first few weeks. Many patients failing to refill the original antidepressant prescription may have never started taking the medication or discontinued after only a few days. Because antidepressant side effects are typically most severe during the first days of treatment and therapeutic benefit often does not occur for 2 weeks or more, physicians prescribing antidepressants should anticipate problems with adherence and emphasize the need for patience. Closer follow-up during the initial weeks of treatment may improve adherence. Physician factors had less effect than expected, both as primary influences on treatment intensity and as confounders of the relationship between treatment intensity and medication selection. Prescriber specialty was a moderate predictor of both duration and dose, but controlling for medication selection moderately reduced the effect of specialty on dose and significantly reduced its effect on duration. Conversely, adjusting for physician specialty had less effect on the large variations in dose and duration among different antidepressants. Use of a random effects model to assess the extent of variability among individual primary care physicians found a modest effect on duration which became insignificant after controlling for medication selection. Adjustment for between-physician variability had minimal effect on the large differences in dose and duration observed among various antidepressants. These results imply that drug selection is a major contributor to differences between physicians in the dose and duration of antidepressant treatment patients actually receive. These data suggest that the intensity of treatment actually received may vary substantially among different antidepressants. Patients treated with newer antidepressants were more likely to continue treatment beyond 30 days and reach an adequate dispensed dose. Excluding primary care prescriptions for indications other than depression produced a somewhat different pattern of results than that described by Katon, but confirmed the finding of significant differences among antidepressants in adherence rates. These observational data do not reveal whether differences between medications reflect differences in patient selection (more motivated or more severely ill patients re-
Use
ceiving newer medications) or intrinsic differences between drugs (more tolerable side effects, more convenient dosing). The differences among antidepressants in dose and duration seen in this naturalistic sample might not be observed in the highly controlled environment of a typical randomized trial. The high levels of patient motivation and supervision in most clinical trials could mask true differences in adherence. Such an effect may be most apparent in primary care where little time is available for patient education about adherence and side effects. Approximately 15% of episodes included switches from one antidepressant to another. Despite these “crossover” cases, dose and duration were computed based on the initial medication prescribed. This potential misclassification will have little effect on the analysis of early discontinuation, but may affect comparisons of dose or late discontinuation. Such a nonselective misclassification should make differences among medications more difficult to detect. Any potential advantages of newer antidepressants in adherence or tolerability must be weighed against their significantly greater cost. Monthly costs for an average dose of antidepressant medication range from less than $5 to more than $50 with newer antidepressants typically costing significantly more. In this study sample, a shift in antidepressant prescribing to exclusive use of the newest antidepressants (fluoxetine and trazodone) would increase the total cost of antidepressant drugs approximately fourfold. If such a shift improved the effectiveness of depression treatment, however, the increased cost could be offset by decreased health care costs and improved patient function. Such cost-offset effects have yet to be demonstrated in a controlled clinical trial. These findings do support a multidimensional model of antidepressant treatment intensity. According to refill records, treatment duration and dose were influenced by both physician factors and medication factors. These data show a stronger influence of drug selection than of physician training, but our data on physician characteristics were limited. The observed pattern of differences among antidepressants suggests that side effects and convenience of dosing may significantly influence patients’ adherence to treatment. Differences among medications were typically smaller for psychiatric patients than for those treated in primary care. This finding suggests that differences in side effects may have less influence on adherence for patients followed more closely in specialty clinics. We were 407
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not able to examine patient characteristics that may influence treatment adherence. Patients’ motivation for treatment, depression severity, and clinical course may have even greater influence on dose and duration of treatment. The naturalistic data reported here are liable to selection bias and lack the clinical information necessary to judge the significance of differences in dose or duration of treatment. Despite these shortcomings, these data do suggest differences among antidepressants in the dose and duration of treatment that patients actually receive. These differences were at least as large as those between psychiatrists and primary care physicians. All available antidepressants have equal efficacy, but differences in convenience or tolerability could lead to differences in effectiveness. Given the markedly higher cost of newer antidepressants, a recommendation for broader use of newer agents will require more definite evidence of a difference in effectiveness. The results of this study suggest the need for randomized studies of the effectiveness and cost of antidepressant medications carried out under the “real world” conditions of community practice.
Drs. Wayne Katon, John Rush, and Yve Lecrubier provided consultation on antidepressant dosing standards. Katie Saunders and Deborah Timfin assisted with computer programming. This work was supported by National Institute of Mental Health Grants MH47765 and MH41739 and by a grant from Efi Lilly & Co.
References Regier DA, Boyd JH, Burke JD, et al: One-month prevalence of mental disorders in the United States. Arch Gen Psychiatry 45:977-986, 1988 Wells KB, Stewart A, Hays RD, et al: The functioning and well-being of depressed patients: results from the Medical Outcome Study. JAMA 262:914-919, 1989 Broadhead WE, Blazer DG, George LK, Tse CK: Depression, disabilitv davs and davs lost from work in a prospective epidemiologic su&ey. JAMA 264:25242528, 1990
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4. Kessler LG, Bums BJ, Shapiro S, et al: Psychiatric diagnoses of medical service users: evidence from the Epidemiologic Catchment Area program. Am J Public Health 77:X3-24, 1987 5. Keller MB, Klerman GL, Lavori PW, Fawcett JA, Coryell W, Endicott J: Treatment received by depressed patients. JAMA 248:1848-1855, 1982 6. Keller MB, Lavori PW, Klerman GL, et al: Low levels and lack of predictors of somatotherapy and psychotherapy received by depressed patients. Arch Gen Psychiatry 43:458-466, 1986 7. Kotin J, Post RM, Goodwin FK: Drug treatment of depressed patients referred for hospitalization. Am J Psychiatry 130:1139-1141,1973 8. Bridges PK: “ . . . and a small dose of antidepressant might help.” B J Psychiatry 142:626-628, 1983 9. Schurman RA, Kramer PD, Mitchell JB: The hidden mental health network: treatment of mental illness by nonpsychiatrist physicians. Arch Gen Psychiatry 42: 89-94, 1985 10. Beardsley RS, Gardocki GJ, Larson DB, Hidalgo J: Prescribing of psychotropic medication by primary care physicians and psychiatrists. Arch Gen Psychiatry 45:1117-1119, 1988 11. Johnson DAW: A study of the use of antidepressant medication in general practice. B J Psychiatry 125: 186-192, 1974 12. Katon W, VonKorff M, Lin E, Bush T, Onnel J: Adequacy and duration of antidepressant treatment in primary care. Med Care 30(1):67-76, 1992 13 Magruder-Habib K, Zung WWK, Feussner JR, Alling WC, Saunders WB, Stevens HA: Management of general medical patients with symptoms of depression, Gen Hosp Psychiatry 11:201-206, 1989 14 Haggerty JJ, Evans DL, McCartney CF, Raft D: Psychotropic prescribing patterns of nonpsychiatric residents in a general hospital in 1973 and 1982. Hosp Community Psychiatry 371357-361, 1986 15. Ketai R: Family practitioners’ knowledge about treatment of depressive illness. JAMA 235:2600-2603, 1976 16. Ketai RM, Hull AL: Tricyclic antidepressant prescribing habits: a comparison of family physicians and psychiatrists. J Fam Pratt 7:1011-1014, 1978 17. Fauman MA: Tricvclic antidepressant urescrintion bv general hospital physicians: Am J I%ych&ry 137: 490-491, 1980 18. Statistics and Epidemiology Research Corporation: EGRET Reference Manual. Seattle: Cytel Software; 1990
Patterns of Antidepressant Use in Community Practice Gregory E. Simon, M.D., M.P.H., Michael VonKorff, Sc.D., Edward H. Wagner, M.D., M.P.H., and William Barlow Ph.D.
Abstract: Computerized pharmacy records from a large staffmodel health maintenance organization were used to examine patterns of antidepressant use by prima y care physicians and psychiatrists. Based on timing of prescription refills, patients treated by psychiatrists were more likely than those treated in primary care to continue medication for more than 30 days (35% vs 25%, p < 0.00001) and more likely to reach a prescribed daily dose of 100 mg of imipramine or the equivalent (48% vs 40%, p < 0.00001). Patients treated with newer antidepressants were significantly more likely to continue freatment past 30 days (range from 75% for fluoxefine to 54% for doxepin, p < 0.00002) and to reach an adequate daily dose (range from 52% for fluoxetine to 26% for doxepin, p < 0.00001). Psychiatrists more often prescribed newer antidepressants, and much of the difference befween specialties could be explained by drug selection. These findings suggest more intensive antidepressant treatment than in earlier reports, especially in prima y care. More intensive treatment with newer antidepressants may reflect more tolerable side effects, but these observational data are liable to selection bias. Any potenfial advantages of newer antidepressant medications must be balanced against significantly higher costs.
Introduction Depressive illness produces a large and preventable burden of personal suffering and social cost. Center for Health Studies, Group Health Cooperative of Puget Sound, Seattle, Washington. Address reprint requests to: Gregory Simon, Center for Health Studies, 1730 Minor Ave. #1600, Seattle, WA 98101-1448.
GeneralHospital Psychiatry 15,399408,1993 O1993ElsevierScience PublisbingCo.,Inc. 655Avenue of the Americas, New York, NY 10010
At any point in time, approximately 2% of adults suffer from current major depression with nearly 6% experiencing major depression at some point in life Ill. In addition to emotional suffering, depressive illness results in a level of disability typical of major medical illness 121, significant loss of productivity 131, and greater use of medical care [41. Although available antidepressant medications are safe and effective, many patients with depression receive inadequate treatment. In a sample of outpatients treated with antidepressants at university medical centers, Keller et al. [5,6] found that only 27 of 70 (39%) were prescribed at least 200 mg/day of imipramine or the equivalent. Kotin et al. [71 noted adequate doses (150 mg/day of imipramine or the equivalent) in only 8 of 21 (38%) patients hospitalized for persistent depression. Bridges [8] described low antidepressant doses in a sample of British patients referred for psychosurgery because of treatment failure, but specific details on dosing were not provided. Primary care physicians provide the majority of care for patients with depression [9,10], and reports of antidepressant use in primary care also suggest low intensity of treatment. In a survey of psychotropic medication use by 361 British general practice patients, Johnson Ill] found that only 20% of those treated with tricyclic antidepressants received doses of greater than 75 mg/day. Over half of patients prescribed a psychotropic medication
399 ISSN0163-8343/93,'$6.00
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discontinued treatment during the first month. In a group of 241 primary care patients selected for high levels of psychologic distress and health care utilization, Katon et al. [12] found that approximately 30% of those treated with antidepressants received adequate doses (100 mg/day of imipramine or the equivalent). The same report described early discontinuation of antidepressant treatment among a general sample of health maintenance organization (HMO) patients; only 40% of those starting treatment received two or more refills during the following 6 months. Other reports of smaller primary care samples describe similar low antidepressant dosage levels 113,141. In surveys of knowledge about antidepressant prescribing, primary care physicians often endorse dosage levels and duration of treatment less than recommended 115-171 Although previous reports suggest a need for improvement in antidepressant prescribing, the available data on treatment intensity are limited. First, most prior descriptions of antidepressant prescribing are now more than 10 years old. Of the reports cited above, only two 112,131 included patients treated since 1982. The last decade has seen the increasing use of newer antidepressant medications and a new generation of physicians trained since the development of effective antidepressant treatment. Second, some findings may not be generalizable because of small sample sizes [7,8,13,141, inclusion of patients treated in training settings 113,141, or inclusion of patients treated for indications other than depression [12]. Only the studies of Johnson [ll] and Keller [5,61 include large samples of patients with depression treated by community practitioners. Third, prior studies have relied on prescribed doses given in pharmacy or medical records to measure treatment intensity. Given the problems with treatment adherence described above, the dosage and duration prescribed may significantly overestimate the intensity of treatment actually received. Data from chart or prescription records can only assess physicians’ intentions, not patients’ actual medication use. Fourth, most previous studies provide little information on factors predicting adequacy of treatment. One exception is the report by Katon et al. [12] of greater adherence among patients treated with newer antidepressants. This relationship, however, may be confounded by the inclusion of patients with diagnoses other than depression and the mixing of primary care and psychiatric patients. Though previous reports typically attribute low intensity of 400
treatment to prescribing physicians’ lack of skill or knowledge, none have examined the relationship between skill level and treatment intensity. Conceptually, the quality of antidepressant treatment patients receive reflects characteristics of the physician (knowledge about antidepressant use, skill in building a treatment alliance), the patient (motivation to take antidepressants, susceptibility to side effects), and the medication (convenience, sideeffect profile). Efforts to improve pharmacotherapy of depression should examine the relative influence of each of these factors. This report describes the use of computerized pharmacy records to examine antidepressant treatment received by a large sample of enrollees in a staff-model HMO. This report extends the work by Katon in an earlier sample from this same setting. Dose and duration of antidepressant treatment were compared with recommended standards. Characteristics of patients, prescribing physicians, and medications prescribed were examined as potential predictors of the dose and duration of antidepressant treatment.
Methods Study Setting Group Health Cooperative of Puget Sound (GHC) is a large staff-model HMO serving approximately 370,000 residents of western Washington state. Primary care is provided by approximately 360 physicians with each full-time physician responsible for a defined panel of approximately 1600 patients. Over 95% of physicians providing primary care to adults are trained in family medicine, with most of the remainder trained in internal medicine. Approximately 20 psychiatrists provide care for both self-referred and physician-referred patients. Over 90% of primary care physicians and psychiatrists are certified by appropriate specialty boards. GHC’s computerized information systems include data on all outpatient visits to GHC clinics and all outpatient prescriptions filled at GHC pharmacies. Previous surveys of GHC enrollees have found that over 95% of prescriptions for antidepressants are filled at GHC pharmacies.
Selection of Study Sample Potential subjects were GHC patients aged 18-60 beginning antidepressant treatment from July 1989 to July 1990. The study sample was drawn from all
Patterns of Antidepressant
CASE A
. . . . . . . . .
4 4
starting antidepressants after a recent treatment failure. Consequently, any episode of treatment might include one or more prescriptions or refills and could include prescriptions for different antidepressants. Any patient might have more than one episode during the study interval, but only the first episode for any patient was included. Examples are shown in Figure 1.
..a........
“DAVI
A7 DAVO
:
b .
4’ :m =: . . . . . . . . .. . . . .. . .. . CASE
B
rfk
. . . . . . .
. . . . . . . . . . . .
Figure 1. Organization of prescription fills into episodes of care. In Case A, pharmacy records showed three antidepressant fills (new or refill) during the study period. Because the longest interval between fills was 56 days, all were classified in the same episode. Case B also had three antidepressant fills, but 98 days elapsed between the second and the third. Consequently, the first two fills were considered to be one episode and the third fill was considered to be a separate episode consisting of only one prescription fill.
GHC psychiatric care clinics
clinics
for which
and
from
computerized
those
primary
diagnostic
data
over age 60 were excluded because greater variability in dosing among older patients would preclude evaluation of dosage levels. Those under 18 were excluded because of greater variability in dosing and indications for antidepressant use. Finally, we excluded patients treated with less commonly prescribed antidepressants (e.g., clomipramine, monoamine protriptyline, maprotiline, oxidase inhibitors, amoxapine) because the number of patients treated with each of these agents was too small to allow comparison among medications. These prescriptions combined accounted for 6% of psychiatrist patients and 3% of primary care patients.
were
available
(see
below).
Use
Indication for Treatment During the study period, diagnostic data from visit encounter forms were entered into computerized visit records at a sample of GHC primary care clinics. Each antidepressant treatment episode initiated by a primary care physician was linked to the computer record of the immediately preceding primary care visit. The diagnosis coded on the encounter form for that visit was considered the indication for prescription. Computerized diagnostic data were not available for psychiatric visits, so computer records of psychiatric episodes could not be sorted by indication.
Patients
Identification of Antidepressant Treatment Episodes Automated pharmacy records were used to identify all prescription fills (either new or refill) for antidepressant medication in the study sample. Individual prescription fills were then organized into episodes of antidepressant treatment using the following algorithm. Any two prescription fills (new or refill) separated in time by 90 days or less were placed in the same treatment episode whereas consecutive prescription fills more than 90 days apart were classified in separate episodes. This relatively long interval was selected to exclude patients re-
Calculation of Antidepressant
Dose and Duration
Patient requests for antidepressant refills were considered more accurate than physicians’ prescriptions instructions as a measure of actual medication use. Consequently, the dose and duration of antidepressant treatment received were calculated from the quantity and timing of antidepressant medication dispensed. Calculated dose and duration should reflect treatment received, but may not reflect treatment prescribed. Samples of 50 patient refill records were manually reviewed by the senior author to verify the accuracy of computed dose and duration, and no errors were detected. Computer algorithms are detailed below. The duration of each episode was computed as the time between the first prescription fill and the estimated stopping date on which the last prescription fill of the episode should have been completely consumed. For this calculation, the time taken to consume the final refill was assumed to be the same as that taken to consume the previous one. This procedure is illustrated in Figure 2. For patients switching antidepressant drugs during a treatment episode, computed duration includes the time taking any antidepressant. For episodes with only one prescription fill, duration of treatment could not be estimated from patients’ refill behavior and was based on the physician’s initial
401
G. E. Simon et al.
timates of antidepressant dosing as doses are calculated only for patients who continue treatment after the first prescription.
4 Rx OOXEPIN
w ma *aa
OOXEPIN
OOXEPIN
mm*
mm*
,a#
.a#
DURATION - 27 + 42 + 42 = 121 DAYS DAILY DOSE = 22 mg x 190 I 42 DAYS -
107 ma/day
Figure 2. Calculation of duration and dose. This episode included three prescription fills. The time taken to consume the final prescription fill was presumed to be the same as the time needed to consume the previous fill (42 days). Duration of treatment was calculated as the time from the first to the last fill plus this inferred duration for the final fill (37 days + 42 days + 42 days). Daily dose was calculated from the final interprescription interval (that between the last and second-to-last fills). The total quantity of medication dispensed at the second-tolast fill (50 mg X 90 pills = 4500 mg) was divided by the number of days needed to consume that fill (42 days).
prescription. After a review of pharmacy records for 100 of these episodes showed prescribed quantity to be always less than a one-month supply (when taken at the prescribed rate), duration of treatment for episodes with one fill was presumed to be 30 days or less. Daily antidepressant dose for each episode was calculated using the quantity of antidepressant dispensed (mg/pill x number of pills dispensed) divided by the number of days until the next prescription fill. The final interprescription interval (time between the second-to-last and last fills) was used for this calculation, allowing maximum time to reach an effective dose. Dosage calculation is illustrated in Figure 2. For episodes with only two prescription fills, the only available interprescription interval begins with the initial prescription and thus may include an initial period of gradually increasing dose. In these cases, the computed average dose may underestimate the final dose achieved. For episodes with only one fill, calculation of daily dose was not possible, because the actual rate of medication use could not be observed. We considered using prescribed dose as a secondary measure of dose consumed, but rejected this strategy as too inaccurate. These single-fill episodes were typically initial prescriptions calling for step-wise increases in dose. Because these single-fill episodes all involved early treatment discontinuation, one cannot assume that the final, highest dosage level was actually reached. Because the dosage consumed could not be calculated from refill records or accurately inferred from the prescribing physician’s instructions, episodes with only one fill were excluded from calculation of daily dose. This exclusion may result in optimistic es-
402
Antidepressant dosage levels were evaluated according to a standard “adequate” dose based on expert opinion and manufacturer’s recommendations. This standard was set at 100 mg/day for amitriptyline, desipramine, doxepin, imipramine, and trazodone; at 50 mg/day for nortriptyline; and at 20 mg/day for fluoxetine.
Statistical Analysis Univariate comparisons included cross-tabulations and Chi-square performed with the SAS software package (SAS, Cary, NC). Multivariate analyses utilized logistic regression performed with the EGRET software package (Statistics and Epidemiology Research Corporation, Seattle, WA). The effect of variability among individual physicians was examined using a logistic regression model with random effects, a technique allowing the estimation of the overall contribution of variability among physicians without examining each physician individually 1181. Reported p-values are based on a likelihood ratio criterion.
Results Study Sample The procedures above identified 3905 patients treated with antidepressants by primary care physicians. The diagnosis coded on the corresponding visit registration form was depression for 37% of episodes, pain (headache, back pain, and chronic abdominal pain) for 19%, stress/anxiety for lo%, fatigue for 3%, and “other” diagnoses for 31%. This final category may include some cases of depression that were assigned primary medical diagnoses or hand-written diagnoses not captured by computer. Consequently, the proportion of antidepressant treatment for the indication of depression may have been higher than 37%. Subsequent analyses, though, were restricted to episodes with a specific diagnosis of depression. Although this restriction may exclude some cases of depression given other diagnoses, it assures the exclusion of antidepressant prescriptions for nondepression indications. For the 977 patients treated by psychiatrists, computerized diagnostic data were not available. For a
Patterns of Antidepressant Use
Table 1. Choice of initial antidepressant medication according to physician specialty % Primary care (N = 1455)
% Psychiatry w = 977)
17 14 20 12 7 16 14
3 7 18 8 14 36 14
Amitriptyline Doxepin Imipramine Desipramine Nortriptyline FIuoxetine Trazodone
Duvafion of Treatment
10% random sample of psychiatrist episodes, chart review found a diagnosis of depression for 98 of 105 episodes (93%). For the remaining episodes, primary diagnosis was panic disorder for six cases and obsessive-compulsive disorder for one. Because of the low prevalence of indications other than depression, all psychiatrist-initiated episodes were included in subsequent analyses. The combined sample had mean age of 39.1 years (SD 9.5), and 75% were female. Patients treated by psychiatrists and those treated by primary care physicians did not differ in gender or age distribution.
Medication
Selection
Psychiatrists were more likely than primary care physicians to initiate treatment with newer anti-
100%
60%
60% 11
.
40%
._
20%
+ Primary Care (n=1455) Oii
ri
I
I
30d
60d
I
I
BOd
120d
depressants (Table 1). First-generation tricyclic antidepressants (amitriptyline, doxepin, and imipramine) were the initial choice in 51% of primary care episodes diagnosed as depression compared with 28% of episodes treated by psychiatrists. Psychiatrists showed a corresponding increase in use of newer antidepressants such as nortriptyline and fluoxetine.
180d
Figure 3. Likelihood of continuing antidepressant medication after initial prescription according to specialty of prescribing physician.
Early discontinuation of antidepressant medication was common. Figure 3 compares duration of treatment among patients treated in primary care to that among patients treated by psychiatrists. For both groups, discontinuation of treatment was greatest during the first month and continued at a slow but steady rate thereafter. Primary care patients were more likely to discontinue treatment during the first month (35% vs 24%, p < 0.00001) but discontinuation rates were similar after day 31. In most cases of early discontinuation, the initial prescription was never refilled (29% of all primary care episodes vs 19% of all psychiatry episodes). Figure 4 shows duration of treatment according to the initial drug prescribed for primary care episodes only. As with the specialty differences described above, differences in continuation rates appeared during the first month and were relatively stable thereafter. Early (1 month) discontinuation rates ranged from 25% for fluoxetine to 46% for doxepin (p = 0.00001). In general, older antidepressants were more likely to be discontinued early. A parallel analysis of psychiatrist-treated episodes showed a similar pattern (earlier discontinuation for older medications) but the differences among medications were less marked (data not shown). Patient gender and age were weaker predictors of treatment adherence. Females had slightly lower rates of discontinuation during the first month (30% vs 33%, p = 0.09). Patients aged 31-50 were slightly less likely to discontinue than those older or younger (36% for age l&30,28% for age 31-40, 30% for age 41-50,35% for age 51-60, p = 0.005). Logistic regression was used to examine the combined effects of prescriber specialty and medication selection on the likelihood of continuing treatment beyond 30 days. Results are shown in Table 2. In the combined model, the effects of medication selection and prescriber specialty were both slightly smaller than their effects when considered 403
G. E. Simon et al.
significant differences in adherence among individual physicians do occur, but much of this effect is explained by medication selection.
Dispensed Dose
20%
-~Trclrodona(n=202)*mlprmlm +Dompin
0%
Start
(n402) @=210)
I 30d
.
-*No~rlptyilno-(n-407). +Amnrlptylin~
4 60d
Fewer than half of episodes had a dispensed dose that met or exceeded recommended standards. Results are shown in Table 3. Because the daily dose of antidepressant medication dispensed could not be calculated for episodes including only one prescription, these results consider only episodes in which the initial prescription was refilled. Patients treated by psychiatrists were more likely than those treated by primary care physicians to reach an adequate level of dispensed dose (48% vs 39%, p = 0.0004). Likelihood of an adequate dispensed dose varied significantly among antidepressants (p < O.OOOOl),ranging from 26% for doxepin to 51% for fluoxetine. Patients initiating treatment with newer antidepressants were more likely to reach an adequate dosage level, with this advantage more evident among primary care patients. Patient age and gender were less strongly related to dosage level. As with the analysis of duration described above, middle-aged patients were more likely to reach an adequate dispensed dose than those older or younger (36% for age 18-30, 43% for age 31-40,48% for age 41-50,40% for age 51-60, p = 0.009). Likelihood of reaching an adequate dosage level did not differ by gender (42% for males vs 45% for females, p = 0.22). Logistic regression was used to examine the combined effects of provider specialty and medication selection (Table 4). In the combined model,
--. -
(ll=253)
I
I
90d
120d
190d
Figure 4. Likelihood of continuing antidepressant medication after initial prescription according to medication prescribed.
separately. This finding suggests that some of the effect of prescriber specialty on duration is explained by medication selection and vice versa. A logistic regression model with random effects was used to evaluate whether variation among individual physicians concerning likelihood of early discontinuation was greater than predicted by chance. In a model containing patient age and gender, addition of physician as a random effect did make a significant contribution (p = 0.007). Addition of this physician effect to a model containing medication selection, however, did not contribute significantly to prediction of adherence (p = 0.28) and did not change the odds ratios associated with medication selection. These findings suggest that
Table 2. Logistic regression
model to predict likelihood
of continuing
antidepressant
beyond 30 days.
Odds ratio for model containing Specialty only Doxepin Amitriptyline Imipramine Desipramine NortriptyIine FIuoxetine Trazodone Primary Care Psychiatry
Medication only
1.00 1.72 (1.43-2.07)
1.02 1.84 1.25 1.72 2.30 1.20
1.00 (0.73-l .44) (1.33-2.54) (0.88-l .79) (1.X3-2.49) (1.68-3.14) (0.86-l .67) -
Combined model 1.00 1.07 (0.76-l .51)
(1.26-2.41) (0.86-l .75) (1.03-2.20) (1.44-2.74) (0.79-1.55) 1.00 1.50 (1.23-1.83) 1.75 1.23 1.51 1.99 1.11
Odds ratios (with 95% confidence intervals) are shown for model including prescriber specialty, model including initial medication prescribed, and model including both. All odds ratios adjusted for age and gender.
404
Patterns of Antidepressant
Table 3. Portion of antidepressant treatment episodes with adequate dispensed prescriber specialty and initial drug prescribed
dose according
Use
to
% of Episodes meeting standard Dosage standard (mg/day)
% Psychiatry (N = 769)
% Primary care (N = 1030)
% Total (IV = 1799)
100 100 100 100 50 20 100
34 N/A 45 46 47 50 52 48
22 28 34 40 62 53 48 39
26 31 39 42 53 51 49 43
Doxepin Amitriptyline Imipramine Desipramine Nortriptyline Fluoxetine Trazodone Total
the strong effect of medication selection was unaffected, but the odds ratio comparing psychiatrists and primary care physicians was no longer significantly different from 1. This finding suggest that much of the influence of prescriber specialty on adequacy of dispensed dose can be explained by medication selection, but the effect of medication selection is not explained by differences between providers. As with the analysis of duration above, logistic regression with random effects was used to evaluate variation among individual physicians in likelihood of reaching an adequate dispensed dose. Addition of physician as a random effect did not make a significant contribution to either a model containing patient age and gender (p = 0.207) or a model also containing medication selection (p = 0.161). Addition of this physician effect had mini-
Table 4. Logistic regression (see text).
mal impact on the effect of medication selection. These findings suggest that individual physicians do not differ significantly in the likelihood of patients achieving an adequate dispensed dose of antidepressant.
Discussion These data indicate somewhat more intensive antidepressant treatment among psychiatry and primary care patients than suggested by earlier reports. Physician factors (both specialty differences and differences among individual providers) were only moderate predictors of treatment intensity. Patients treated with newer antidepressants were significantly more likely to continue treatment beyond the first month and to reach an adequate level of prescribed dose.
mode1 to predict likelihood
of receiving
an adequate dispensed
daily dose
Odds ratio for model containing Specialty only Doxepin Amitriptyline Imipramine Desipramine Nortriptyline Trazodone Fluoxetine Primary Care Psychiatry
1.00 1.41 (1.16-1.71)
Medication only
1.35 1.91 2.20 3.40 2.95 3.16
1.00 (0.86-2.13) (1.28-2.84) (1.40-3.44) (2.18-5.31) (1.93-4.50) (2.15-4.64) -
Both 1.00 (0.87-2.18) (1.26-2.80) (1.39-3.43) (2.07-5.09) (1.89-1.41) (2.04-4.44) 1.00 1.17 (0.95-1.43)
1.38 1.88 2.19 3.25 2.89 3.01
Odds ratios (with 95% confidence intervals) are shown for model including prescriber specialty, model including initial medication prescribed, and model including both. All odds ratios adjusted for age and gender.
405
G. E. Simon et al.
Interpretation of these pharmacy refill data is limited by the absence of clinical information. First, these data do not indicate how many subjects met customary criteria for treatment with antidepressants. The primary care sample was limited to patients with a visit diagnosis of depression, but no further data were available on severity of illness. In the psychiatry sample, random chart audits indicated that over 90% of patients were treated for depression; chart data were typically inadequate to systematically rate severity. The inclusion of a small number of psychiatric patients treated for other indications may also affect these results (if those patients received dose or duration of treatment different from those treated for depression). Second, the groups compared (primary care vs psychiatry, older antidepressants vs newer) may have differed in severity of illness or other factors related to intensity of antidepressant treatment. The higher doses and longer treatment in psychiatric patients may reflect the greater severity of illness in specialty populations. Comparison of older and newer antidepressants may be biased by systematic differences in depression severity or motivation to continue treatment. Third, these data do not indicate whether differences in dose and duration of treatment actually lead to differences in outcome. If lower doses or briefer treatment were confined to milder or more transient illness, then the supposed shortcomings of practice identified here may have been clinically appropriate. The absence of chnical data must be balanced against the advantages of a population-based, naturalistic sample. Clinical trials of antidepressant medication typically include patients carefully selected for homogeneity of illness and likelihood of adherence to antidepressant treatment. In contrast, the patients in this sample are typical of those actually treated with antidepressants in a large HMO population. Clinical trial protocols typically call for strict dosing guidelines and intensive follow-up. In contrast, these data reflect the actual practice of over 300 physicians working in the busy, less controlled environment of usual care. The computer algorithms used above should accurately reflect the dose and duration of antidepressant treatment actually dispensed, but will in some cases not reflect the dose and duration consumed. Computed dosage reflects average dose consumed between two prescription fills and will not detect periods of higher and lower dosage. Failure to consume all medication dispensed prior to the final refill in an episode would result in an 406
overestimate of dose consumed. Failure to consume all of the final refill in an episode would result in an actual treatment duration shorter than estimated. These sources of error should typically produce an overestimate of dose and duration and should not lead to any bias in comparison of different providers or different medications. Any judgments about the quality of physician practice should be made cautiously. First, the standards for dose and duration of antidepressant treatment applied here were developed in referral psychiatric settings and may not be appropriate in this population. Episodes of depression treated in community samples of primary care patients may be less severe or shorter in duration than those seen in specialty settings. Lower antidepressant doses or shorter duration of treatment may not necessarily lead to poorer outcomes in primary care patients. Second, these data reflect the quantity of antidepressant medication dispensed by the pharmacy, not that prescribed by the physician. Patients who were prescribed adequate treatment but either discontinued treatment early or consumed a lower dose than prescribed would be reported in our results as being inadequately treated. Considering the above limitations, overall adequacy of antidepressant treatment in primary care appeared better than expected. The proportion of psychiatrist-treated episodes meeting the “adequate” dosing standard (48%) is almost identical to those reported in earlier studies by Keller et al. [5,61 and Kotin et al. [71. Those reports, however, evaluated prescribed antidepressant doses that are likely to be higher than the dispensed doses used in this study. In addition, those studies included more severely ill referral samples. The proportion of primary care episodes in this study exceeding the “adequate” standard (39%) compares favorably with the 20% of primary care patients in Johnson’s study 1111 and the 30% reported by Katon et al. [121 receiving a comparable level of treatment. The other primary care studies above include small samples and provide insufficient data for comparison. The observed 35% rate of discontinuation during the first month of treatment among primary care patients in this sample is lower than the 50% rate among British primary care patients described by Johnson Ill]. The higher discontinuation rate reported by Katon et al. in an earlier sample from the same HMO may reflect greater treatment discontinuation among patients receiving antidepressants for indications other than depression.
Patterns of Antidepressant
Early discontinuation was the clearest shortcoming of antidepressant treatment identified in this sample. Although one may argue whether the current recommendations for dosage or treatment duration are appropriate in primary care, most early discontinuation in this sample occurred during the first few weeks. Many patients failing to refill the original antidepressant prescription may have never started taking the medication or discontinued after only a few days. Because antidepressant side effects are typically most severe during the first days of treatment and therapeutic benefit often does not occur for 2 weeks or more, physicians prescribing antidepressants should anticipate problems with adherence and emphasize the need for patience. Closer follow-up during the initial weeks of treatment may improve adherence. Physician factors had less effect than expected, both as primary influences on treatment intensity and as confounders of the relationship between treatment intensity and medication selection. Prescriber specialty was a moderate predictor of both duration and dose, but controlling for medication selection moderately reduced the effect of specialty on dose and significantly reduced its effect on duration. Conversely, adjusting for physician specialty had less effect on the large variations in dose and duration among different antidepressants. Use of a random effects model to assess the extent of variability among individual primary care physicians found a modest effect on duration which became insignificant after controlling for medication selection. Adjustment for between-physician variability had minimal effect on the large differences in dose and duration observed among various antidepressants. These results imply that drug selection is a major contributor to differences between physicians in the dose and duration of antidepressant treatment patients actually receive. These data suggest that the intensity of treatment actually received may vary substantially among different antidepressants. Patients treated with newer antidepressants were more likely to continue treatment beyond 30 days and reach an adequate dispensed dose. Excluding primary care prescriptions for indications other than depression produced a somewhat different pattern of results than that described by Katon, but confirmed the finding of significant differences among antidepressants in adherence rates. These observational data do not reveal whether differences between medications reflect differences in patient selection (more motivated or more severely ill patients re-
Use
ceiving newer medications) or intrinsic differences between drugs (more tolerable side effects, more convenient dosing). The differences among antidepressants in dose and duration seen in this naturalistic sample might not be observed in the highly controlled environment of a typical randomized trial. The high levels of patient motivation and supervision in most clinical trials could mask true differences in adherence. Such an effect may be most apparent in primary care where little time is available for patient education about adherence and side effects. Approximately 15% of episodes included switches from one antidepressant to another. Despite these “crossover” cases, dose and duration were computed based on the initial medication prescribed. This potential misclassification will have little effect on the analysis of early discontinuation, but may affect comparisons of dose or late discontinuation. Such a nonselective misclassification should make differences among medications more difficult to detect. Any potential advantages of newer antidepressants in adherence or tolerability must be weighed against their significantly greater cost. Monthly costs for an average dose of antidepressant medication range from less than $5 to more than $50 with newer antidepressants typically costing significantly more. In this study sample, a shift in antidepressant prescribing to exclusive use of the newest antidepressants (fluoxetine and trazodone) would increase the total cost of antidepressant drugs approximately fourfold. If such a shift improved the effectiveness of depression treatment, however, the increased cost could be offset by decreased health care costs and improved patient function. Such cost-offset effects have yet to be demonstrated in a controlled clinical trial. These findings do support a multidimensional model of antidepressant treatment intensity. According to refill records, treatment duration and dose were influenced by both physician factors and medication factors. These data show a stronger influence of drug selection than of physician training, but our data on physician characteristics were limited. The observed pattern of differences among antidepressants suggests that side effects and convenience of dosing may significantly influence patients’ adherence to treatment. Differences among medications were typically smaller for psychiatric patients than for those treated in primary care. This finding suggests that differences in side effects may have less influence on adherence for patients followed more closely in specialty clinics. We were 407
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not able to examine patient characteristics that may influence treatment adherence. Patients’ motivation for treatment, depression severity, and clinical course may have even greater influence on dose and duration of treatment. The naturalistic data reported here are liable to selection bias and lack the clinical information necessary to judge the significance of differences in dose or duration of treatment. Despite these shortcomings, these data do suggest differences among antidepressants in the dose and duration of treatment that patients actually receive. These differences were at least as large as those between psychiatrists and primary care physicians. All available antidepressants have equal efficacy, but differences in convenience or tolerability could lead to differences in effectiveness. Given the markedly higher cost of newer antidepressants, a recommendation for broader use of newer agents will require more definite evidence of a difference in effectiveness. The results of this study suggest the need for randomized studies of the effectiveness and cost of antidepressant medications carried out under the “real world” conditions of community practice.
Drs. Wayne Katon, John Rush, and Yve Lecrubier provided consultation on antidepressant dosing standards. Katie Saunders and Deborah Timfin assisted with computer programming. This work was supported by National Institute of Mental Health Grants MH47765 and MH41739 and by a grant from Efi Lilly & Co.
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