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Isotretinoin and antidepressant pharmacotherapy: A prescription sequence symmetry analysis
Isotretinoin and antidepressant pharmacotherapy: A prescription sequence symmetry analysis Kimberly Hersom, MPH,a Maureen P. Neary, PhD,b Hugh P. Levaux, PhD,a Winslow Klaskala, PhD,b and John S. Strauss, MDc San Francisco, California; Nutley, New Jersey; and Iowa City, Iowa Background: Isotretinoin is indicated for the treatment of severe, recalcitrant nodular acne. Spontaneous reports have suggested a possible association between isotretinoin and depression that has not been supported by prior studies. Depression has been reported in patients with acne and is common among adolescents. Objective: The objective of this study was to investigate whether there is an association between isotretinoin use and onset of depression. Methods: A large retrospective database study was performed through a review of pharmacy claims to evaluate the order of first-recorded isotretinoin and antidepressant dispensings in incident users. The study included 2821 patients, aged 12 to 49 years, who filled isotretinoin prescriptions between June 1, 1999, and March 31, 2000. The ratio of the number of patients who filled isotretinoin prescription first versus second was computed, with adjustment for variations in physician prescribing patterns; a ratio significantly greater than 1.0 indicates a depression-invoking relationship. Similar analyses of minocycline were performed. Results: Adjusted ratios for all antidepressants and by class were not significantly greater than 1.0. Similar results were found for minocycline. Conclusion: The results do not support an association between the use of isotretinoin and the onset of depression. (J Am Acad Dermatol 2003;49:424-32.)
A
cne affects an estimated 17 million people in the United States, making it the most prevalent skin disease. Acne may occur in individuals from 12 to 49 years old. Eighty-five to ninety percent of adolescents and young adults between
From Quintiles Late Phase,a Hoffmann-La Roche, Inc,b and University of Iowa Health Care.c Funding source: Hoffmann-La Roche, Ltd, Basel, Switzerland, funded this research through a contract with Quintiles Late Phase. Disclosure: Drs Klaskala and Neary are employed by Hoffmann-La Roche, Inc, and Dr Strauss is a consultant to Hoffmann-La Roche, Inc. None of the authors has any stock or other equity interest in Hoffmann-La Roche, Inc. Poster and oral presentations of this study were made at the 62nd Annual Meeting of the Society for Investigative Dermatology in Washington, DC, on May 9-12, 2001, and at the 17th International Conference on Pharmacoepidemiology in Toronto, Ontario, Canada, on August 23-26, 2001. Accepted for publication April 2, 2003. Reprints not available from authors. Copyright © 2003 by the American Academy of Dermatology, Inc. 0190-9622/2003/$30.00 ⫹ 0 doi:10.1067/S0190-9622(03)02087-5
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the ages of 12 and 24 years have some degree of acne. Approximately 16% of males and 9% of females have moderate to severe acne.1-4 The main goal of acne treatment is to prevent physical scarring by limiting the number of lesions and the duration of the disease, thereby minimizing the psychologic impact of the disease.1,3,5 The psychologic impact of acne is well documented, particularly in adolescents.5-12 Adolescents report levels of social, psychologic, and emotional problems that are as great as those reported by patients with chronic disabling diseases.13,14 Studies have shown that adolescents with mild to moderate acne are at higher risk for depression and suicidal ideation and have lower self-esteem than their counterparts without acne.6,12 Females consistently report higher levels of anxiety and depression related to their acne than do males.9 Effective dermatologic treatment of acne has been shown in some studies to decrease symptoms of depression and anxiety and to significantly improve other psychologic parameters.5,10,11 However, the emotional status of some
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treated patients appears to be somewhat resistant to change, indicating that acne can contribute to longterm psychosocial impairment.9 Isotretinoin, a retinoid, is indicated for the treatment of severe, recalcitrant nodular acne. It has been used by approximately 12 million people worldwide since its introduction in 1982, including 5 million people in the United States.15 Spontaneous reports have suggested a possible “signal” for a relationship between isotretinoin use and depressive symptoms.16-18 However, several retrospective studies performed to date using national and international databases and one clinical trial have not supported such a relationship.19-24 The potential association between isotretinoin use and depression may be confounded by severe acne, which is an indication for isotretinoin use and has a recognized association with depression.17 Because of the high background prevalence of depressive symptoms in patients with acne, it is difficult to distinguish between drug-related and non-drug-related depressive symptoms, such as environmental or physiologically induced symptoms. In addition, there is no known biologic mechanism of action to support such a causal relationship. The current study was performed to further address the possible association between isotretinoin therapy and the onset of depression by use of a unique methodologic approach and a large prescription database. The primary objective of this study was to investigate the potential association between isotretinoin use and the onset of depression in an observational study using data collected from the Quintiles Informatics Database. This was accomplished by evaluating the prescription order of isotretinoin and antidepressants among incident users of both drugs. Asymmetry in the prescription order of isotretinoin and antidepressants would indicate an association. The null hypothesis assumes no association between the initiation of isotretinoin (index drug) and subsequent initiation of antidepressant (marker drug) therapy (ie, risk ratio of 1.0). The secondary objective of this study was to examine the validity of the results by performing a similar analysis with a cohort of patients treated with minocycline (index drug), an agent not suspected to cause depression, and antidepressants (marker drug) with use of the same prescription claims database.
METHODS The current study used a retrospective design, applying the sequence symmetry method (see Appendix at www.eblue.org; published online only) to evaluate data from a large nationwide prescription
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database. Sequence symmetry analysis infers causality based on the sequence of filled prescriptions, which are considered indicators for clinical events. The method allows for the measurement of patient propensity to fill the index drug before the marker drug; where the index drug is the drug thought to produce a given side effect and the marker drug is the drug used to alleviate the given side effect.25 The sequence in which antidepressants and isotretinoin were first prescribed and dispensed to a large population of isotretinoin users was analyzed. The prescription database contains adjudicated pharmacy claims, reflecting use of pharmacy benefits, for approximately 90 million patients nationwide. This database includes data from approximately 38,000 pharmacies interacting with more than 1200 commercial and governmental payers throughout the United States. The analysis relies on real-world data, so this allows for greater external validity of results. Sequence symmetry method Sequence symmetry analysis proceeds in three steps. First, patients who filled incident prescriptions of both index and marker drugs during a defined period of time are identified. Second, patients are classified on the basis of the temporal order of the alternative sequences of prescription events. The “causal” group consists of patients who filled the index drug first (isotretinoin or minocycline) and the marker drug second (antidepressant), whereas conversely the “noncausal” group consists of patients who filled the index drug second and the marker drug first. Finally, the estimate of risk is calculated by taking the ratio of the number of patients in the “causal” to the “noncausal” groups.26,27 Patients taking the index and marker drugs may have risk factors common to both pharmaceuticals. The distinct feature of the sequence symmetry method is that patients serve as their own controls. Confounders, such as age, sex, or physician office visits, are effectively controlled because these factors do not predict the order in which an individual patient fills two prescriptions.27 Previous studies using sequence symmetry analysis have either confirmed or rejected associations across different therapeutic areas and patient populations. With use of a statewide California hospital discharge database, a common relationship between myocardial infarction and subsequent congestive heart failure was confirmed in the order of hospital admissions, whereas a relationship believed to be minimal between congestive heart failure and acute cholecystitis showed only a small association.26 In another example, positive signals for a variety of drugs known to cause nausea were detected by
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Table I. Antidepressants included in the isotretinoin and minocycline analyses Therapeutic class
Antidepressant
SSRIs
Citalopram Fluoxetine Fluvoxamine Paroxetine Sertraline
Secondary and tertiary amine tricyclics
Amitriptyline Clomipramine Doxepin Imipramine hydrochloride Imipramine pamoate Trimipramine Amoxapine Desipramine Nortriptyline Protriptyline
Other antidepressants*
Bupropion Maprotiline Mirtazapine Nefazodone Trazodone Venlafaxine Amitriptyline hydrochloride/ perphenazine Amitriptyline/chlordiazepoxide
*Monoamine oxidase inhibitors were not included because of their primary use in chronic depression.
using a large prescription database.28 Studies evaluating potential depression-provoking effects of calcium channel blockers and angiotensin-converting enzyme inhibitors revealed significant asymmetry in the prescription orders with antidepressants, whereas conversely cholesterol-lowering drugs revealed no asymmetry in the prescription order with antidepressants.27,29 The validity of study results depends on the specificity of available pharmacotherapy for the adverse event in question.25 In the current study, antidepressants were used as the marker drug for depression for two reasons. First, prescription antidepressant drugs are the standard pharmacotherapy for depression in the United States.30 Second, previous sequence symmetry studies have successfully used antidepressants as an indicator for depression.27,29,31 Measures By use of sequence symmetry analysis, the following three statistics were computed: the crude sequence ratio, the null-effect sequence ratio, and the adjusted risk ratio. The crude sequence ratio is the ratio of the number of patients in the “causal”
group over the number of patients in the “noncausal” group. The crude sequence ratio is a measure of the degree of asymmetry between the two patient groups; it does not take into account any variations in the prescribing trends of the index or marker drugs during the study time frame.28 The null-effect sequence ratio determines the expected sequence ratio given no cause-effect relationship between the two drugs. The null-effect sequence ratio measures differential change in prescribing patterns during the study period, which could confound the crude sequence ratio. The adjusted risk ratio uses the null-effect sequence ratio as the reference value to adjust the crude sequence ratio, thereby quantifying the risk attributable to the index drug while controlling for changes in prescribing patterns.27,29 Patients in the final study cohort were classified into one of two groups (“causal” and “noncausal”) on the basis of the prescription order of the index and marker drugs. The crude sequence ratio was computed as the ratio of the number of patients in the “causal” group over the number of patients in the “noncausal” group. The crude sequence ratio was modified by the null-effect sequence ratio to yield the adjusted risk ratio and generate 95% CIs.27 Antidepressants used in this study were categorized into three therapeutic classes: selective serotonin reuptake inhibitors (SSRIs), secondary and tertiary amine tricyclics (amines), and other antidepressants (other), according to the classification system used by Diversified Pharmaceutical Services, now known as Express Scripts, a major US pharmacy benefit management company (Table I). Monoamine oxidase inhibitors were not included in this study because they are generally used to treat chronic depression and are not indicative of treatment-emergent depression. The crude and adjusted risk ratios were calculated for the index drugs and all antidepressants combined as well as for each of the three therapeutic antidepressant classes. An adjusted risk ratio greater than 1.0 would indicate a depression-invoking relationship. Minocycline, which is the primary antibiotic therapy prescribed for the treatment of moderate and severe acne, was selected as an index drug to examine the validity of the isotretinoin results. In addition, minocycline is also used to treat a variety of bacterial and protozoal infections and rheumatoid arthritis. Depression is not a known side effect of minocycline therapy. Therefore, it would be expected that the risk ratio for the minocycline analysis would not differ significantly from 1.0.
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Data source Data for this study were obtained from the Quintiles Informatics Database. The claims data are passively collected by recording the transaction history of one of the largest electronic data interchange networks in the country. The prescription database contains adjudicated pharmacy claims for approximately 90 million patients, reflecting utilization of pharmacy benefits, from approximately 38,000 pharmacies interacting with more than 1200 commercial and governmental payers throughout the United States. The database contains pharmacy data from all 50 states, Puerto Rico, and other US territories, representing all 261 metropolitan statistical areas. Patients of all ages and both sexes are represented in the data. Each pharmacy transaction contains an encrypted identification number that is unique to each patient. By use of the encrypted identification number, patient-specific pharmacy claims can be linked and analyzed over a period of time. Given that more than 500 million pharmacy claims are added to the database each year, the volume of claims is sufficient to minimize any “noise” created by irregular prescribing patterns or regional physician practices that often confound claims analyses. The pharmacy file contains transactions from January 1, 1998, to the present and is updated with approximately 1.5 million claims each day. It is estimated that 78% of all pharmacy claims in the United States are filed electronically, of which approximately 40% are archived in this database. All physician specialties, including primary care, dermatology, and psychiatry, are represented in the pharmacy data. Patient population Construction of study database for comparative analyses. The process for selecting the isotretinoin and minocycline cohorts for the comparative analyses is provided in Fig 1. This involved the extraction of a study database (from which the isotretinoin and minocyline cohort groups would be selected) from the source database, a large nationwide prescription database. The source database for this study contained all prescriptions filled at participating pharmacies from July 1, 1998, through March 31, 2000, including approximately 5.6 million prescriptions for antidepressants during this time period. This database contained variables of interest that included prescription issue date, prescription filling date, patient demographics, and medication type and dosage. When a prescription is filled, all data for the prescription are automatically entered into the
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Fig 1. Study population selection process. This figure provides the study design that develops the two groups that were analyzed: the “causal” group includes patients who filled their isotretinoin prescriptions first and the “noncausal” group includes patients who filled their antidepressant prescriptions first.
source database. This involves an electronic, fully computerized data entry process at the pharmacy level. For the purpose of this analysis, a subset database, the study database, of all filled prescriptions between June 1, 1999, and March 31, 2000, was constructed from the nationwide pharmacy database according to the study inclusion and exclusion criteria. The characteristics of the source database do not allow for identification of continually enrolled patients. It is expected, however, that any potential bias introduced into the study because of this limitation would be proportionate across both “causal” and “noncausal” study groups. For the assembly of the isotretinoin cohort, all incident users of both isotretinoin and antidepressants were selected from the study database within the age group likely to be treated for acne. Therefore, the prescription inclusion and exclusion criteria would not be expected to have any relationship with either isotretinoin use or depression, as measured by antidepressant dispensings. Because the study subjects were identified as incident users of isotretinoin and/or antidepressants, their selection was dependent on their having had filled prescription(s) for isotretinoin and/or antidepressants but was not related to whether they actually used isotretinoin and/or had clinical depression. However, patients not receiving antidepressant therapy for depression would not be included in the prescription filling study. A preliminary analysis of the data in the isotretinoin cohort did not reveal any significant differences in demographic factors between “causal” and “noncausal” groups that would suggest possible con-
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Table II. Demographics of isotretinoin and minocycline cohorts Isotretinoin cohort (n ⴝ 2821)*
Age group (y) 12–17 18–24 25–34 35–49
Male
Female
498 (17.7) 228 (8.1) 130 (4.6) 129 (4.6)
349 (12.4) 485 (17.2) 544 (19.2) 453 (16.1)
Minocycline cohort (n ⴝ 7360)† Male
Female
892 (12.1) 930 (12.7) 380 (5.2) 1024 (13.9) 297 (4.0) 1632 (22.2) 395 (5.4) 1796 (24.4)
*Sex unknown for 5 patients. † Sex unknown for 14 patients.
founding. Therefore, a stratified analysis by demographic parameters was not further pursued. A comparative study using a minocycline cohort was also performed to validate the findings of the isotretinoin and antidepressant analysis. This analysis included the study of a cohort of patients treated with both minocycline (index drug), an agent not suspected to cause depression, and with antidepressants (marker drug) by use of the same study design and methods and selected from the same source database. This allowed for the methodologic comparison, in terms of validity, of the results obtained from the minocycline cohort with those obtained from the isotretinoin cohort. Selection of prescriptions for PSSA analyses. Specifically, all isotretinoin, minocycline, and antidepressant prescriptions filled during the July 1, 1998, through March 31, 2000, period were extracted from the large source database. From this subset of data (the study database), those patients having prescriptions for both the index and marker drugs were identified. Incident uses of both the index and marker drugs were then identified by the waiting time distribution method, as described by Hallas27 and Hallas et al.32 The waiting time distribution method starts from the premise that, under usual circumstances and with correction for seasonality in prescribing patterns, incident dispensing is relatively constant across short (monthly) time periods. Empirical data were used to establish the period of time required to reach a plateau in the frequency of incident drug dispensing in a given database. At the beginning of the distribution, a large number of patients are prevalent users. As the time window expands, the frequency of incident dispensings decreases until it reaches a plateau indicating that, from that time on (ie, after June 1, 1999, in this study), patients presenting their first index and marker prescriptions are considered new, incident users. Therefore, only pa-
tients who incurred their first recorded index and marker drug prescriptions between June 1, 1999, and March 31, 2000, were included in the analysis. Isotretinoin cohort. The Quintiles Informatics Database contains records on 128,652 isotretinoin users and 5,642,261 antidepressant users over the period from July 1, 1998, to March 31, 2000. From these patients, 17,348 incident and prevalent users of both drugs were identified. The analysis was restricted to patients in the usual age group of isotretinoin users; therefore, 1195 patients were excluded from the analysis because their age was not between 12 and 49 years (n ⫽ 1058) or their claims did not contain a valid date of birth (n ⫽ 137). A total of 13,186 patients filled their first recorded isotretinoin or antidepressant prescriptions before June 1, 1999 (ie, the first day of the study period); these individuals were considered prevalent users and were excluded from further analysis. An additional 146 patients were dropped from the analysis because they filled their first prescriptions for both drugs on the same day. Of the remaining 2821 patients, 1439 filled the antidepressant prescription first and 1382 filled the antidepressant prescription second. Table II provides the age and sex distribution for the isotretinoin cohort: 65% of patients were female and 55% of patients were between 12 and 24 years of age. These figures are consistent with published literature on persons with both acne and psychiatric disorders.16,17 Minocycline cohort. The Quintiles Informatics Database contains records on 407,303 minocycline users and the same number of antidepressant users as the isotretinoin analysis over the period from July 1, 1998, to March 31, 2000. From these patients, 67,580 users of both drugs were identified. This analysis was restricted to patients of the same age as the isotretinoin analysis; therefore, 11,788 patients were excluded from the analysis because they were not between 12 and 49 years old (n ⫽ 11,274) or because their claims did not contain a valid date of birth (n ⫽ 514). Another 48 patients were excluded from further analysis because their minocycline prescription supply was less than 21 days, indicating that minocycline was probably not intended for acne therapy. A total of 47,647 patients filled their first recorded minocycline or antidepressant prescriptions before June 1, 1999 (ie, the first day of the study period); these individuals were considered prevalent users and were excluded from further analysis. An additional 737 patients were dropped from the analysis because they filled the first prescription for both drugs on the same day. Of the remaining 7360 patients, 3751 filled the antidepres-
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Table III. Results from the isotretinoin analysis, by antidepressant class
Marker drug
All antidepressants SSRI antidepressants Amine antidepressants Other antidepressants
Study population (N)
“Causal” group (n)
“Noncausal” group (n)
Crude sequence ratio
Null effect sequence ratio
Adjusted risk ratio (95% CI)
2821 1735 374 712
1382 874 174 334
1439 861 200 378
0.96 1.02 0.87 0.88
0.99 1.02 0.97 0.93
0.97 (0.92–1.02) 0.99 (0.93–1.06) 0.90 (0.78–1.04) 0.95 (0.85–1.05)
Table IV. Demographics of causal and noncausal groups in the isotretinoin analysis
Sex* Male Female Age group (y) 12–17 18–24 25–34 35–49
“Causal group” (isotretinoin first, antidepressant second) (n ⴝ 1382)
“Noncausal group” (antidepressant first, isotretinoin second) (n ⴝ 1439)
Total study group (n ⴝ 2821)
494 (35.8) 886 (64.2)
491 (34.2) 945 (65.8)
985 (35.0) 1831 (65.0)
441 (31.9) 370 (26.8) 296 (21.4) 275 (19.9)
409 (28.4) 343 (23.8) 380 (26.4) 307 (21.3)
850 (30.1) 713 (25.3) 676 (24.0) 582 (20.6)
*Sex unknown for 5 patients.
sant prescription first and 3609 filled the antidepressant prescription second. Table II provides the age and sex distribution for the minocycline cohort. Patients in the minocycline cohort were slightly older and had a larger proportion of females (73.3%) than the isotretinoin cohort.
RESULTS Isotretinoin analysis Table III summarizes the results for the isotretinoin analysis, for all antidepressants combined and by antidepressant class. A total of 1382 patients exhibited the “causal” prescription order (isotretinoin followed by antidepressants), whereas 1439 patients followed the “noncausal” prescription order (antidepressants followed by isotretinoin), yielding a crude sequence ratio of 0.96. When they were analyzed by antidepressant class, the crude sequence ratios ranged from 0.87 (amines) to 1.02 (SSRIs). Overall prescribing patterns for antidepressants did not deviate significantly from the overall prescribing patterns for isotretinoin during the study period. This resulted in only very modest adjustment factors (ie, null effect sequence ratio ranging from 0.93 to 1.02). Accordingly, the adjusted risk ratio for all antidepressants combined was only slightly higher than the crude sequence ratio (0.97; 95% CI, 0.92-1.02). When analyzed by antidepressant class, SSRI prescribing increased relative to isotretinoin;
therefore, the adjusted risk ratio was slightly less than the crude sequence ratio (0.99; 95% CI, 0.931.06). Table IV provides the sex and age distribution of patients in the “causal” and “noncausal” groups. These results indicate that the “causal” and “noncausal” groups are well balanced with respect to sex and age. Isotretinoin did not exhibit a pattern suggesting a depression-provoking effect when analyzed by antidepressant class or in aggregate; all adjusted risk ratios had point estimates below 1 (0.90 to 0.99). In addition to the equal distribution of patients, as shown in Fig 2, the time between the initial isotretinoin and antidepressant prescriptions is consistent between the two patient groups and does not provide any temporal irregularities that would suggest a causal association. Minocycline analysis Table V summarizes the results for the minocycline analysis, for all antidepressants combined and by antidepressant class. A total of 3609 patients initiated minocycline therapy first (causal), whereas 3751 patients initiated antidepressant therapy first (noncausal), yielding a crude sequence ratio of 0.96. When analyzed by antidepressant class, the crude sequence ratios ranged from 0.83 (other) to 1.05 (SSRIs).
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Fig 2. Distribution of patients in causal and noncausal groups: months between initial isotretinoin and antidepressant prescriptions. Patients were classified into two groups, “causal” and “noncausal,” on the basis of the temporal order of the first recorded isotretinoin and antidepressant prescriptions. The “causal” group filled their isotretinoin prescriptions first, whereas conversely, the “noncausal” group filled their antidepressant prescriptions first.
The null effect sequence ratio was 0.98 for all antidepressants combined and ranged from 0.86 to 1.05 by antidepressant class. Accordingly, the adjusted risk ratio for all antidepressants combined was 0.98 (95% CI, 0.95-1.02). When analyzed by antidepressant class, SSRI prescribing increased relative to minocycline; therefore, the adjusted risk ratio was slightly less than the crude sequence ratio (1.00; 95% CI, 0.96-1.04). As expected, the prescription order of minocycline and antidepressants was symmetric. As in the isotretinoin analysis, the time between initial minocycline and antidepressant prescriptions was consistent between the two patient groups and did not indicate any temporal irregularities that would suggest a causal association (Fig 3).
COMMENT The current study involved the application of a unique statistical method, sequence symmetry analysis, to analyze two large cohorts of patients treated with antidepressants and isotretinoin (2821 patients) or minocycline (7360 patients). Claims were extracted from a nationwide prescription database that contains records for approximately 90 million patients. The sequence symmetry method uses patients as their own controls, thereby minimizing any potential biases caused by variations in patient characteristics. As stated previously, sequence symmetry analysis is a validated method that has been successfully used in prior studies to confirm suggested associations across various therapeutic areas using prescription claims databases and a hospital discharge data-
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Fig 3. Distribution of patients in causal and noncausal groups: months between initial minocycline and antidepressant prescriptions. Patients were classified into two groups, “causal” and “noncausal,” on the basis of the temporal order of the first recorded minocycline and antidepressant prescriptions. The “causal” group filled their minocycline prescriptions first, whereas conversely, the “noncausal” group filled their antidepressant prescriptions first.
base.26-28 This technique uses the null effect sequence ratio to adjust for changes in physician prescribing patterns during the study period that may result from reimbursement changes or increased patient demand for selected medications. It is anticipated that the large sample sizes available for the isotretinoin and minocycline analyses minimized any further effect of variable physician prescribing.31 Adjusted risk ratios from the isotretinoin analysis, by antidepressant class and in the aggregate, were consistently below 1.0, suggesting that isotretinoin does not have a depression-provoking effect. In addition, patient frequencies between “causal” and “noncausal” groups are similar by age and sex. Similar results indicating no association with the onset of depression for the minocycline cohort provide powerful support to the isotretinoin results. When the results are interpreted, it should be noted that, despite the strict study selection criteria, it is possible that some of the patients identified as incident users might actually be prevalent users. This would occur in patients who had previous prescriptions for isotretinoin or antidepressants that were not recorded in the database. For example, patients with chronic depressive disorders could have depressive episodes separated by periods greater than the 11-month time frame used to exclude prevalent users in the current study. Additionally, some prescriptions may not be captured in the database because of patients changing health plans, thereby potentially misclassifying patients as incident users. This could occur because continuous enrollment during the study period could not be verified in this database. However, misclassification of incident patients would not be expected to occur
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Table V. Results from the minocycline analysis, by antidepressant class
Marker drug
All antidepressants SSRI antidepressants Amine antidepressants Other antidepressants
Study population (N)
“Causal” group (n)
“Noncausal” group (n)
Crude sequence ratio
Null effect sequence ratio
Adjusted risk ratio (95% CI)
7360 4447 1063 1850
3609 2277 494 838
3751 2170 569 1012
0.96 1.05 0.87 0.83
0.98 1.05 0.86 0.88
0.98 (0.95–1.02) 1.00 (0.96–1.04) 1.01 (0.93–1.10) 0.94 (0.88–1.00)
disproportionately across “causal” and “noncausal” groups—particularly given the size of the Quintiles Informatics Database, the study selection criteria, and the comparative cohort analyses. Finally, it is expected that the 11-month waiting time eliminated most true prevalent cases.32 It should also be noted that, although antidepressant therapy is the standard of care for depression, misclassification of patients could result if antidepressant therapy is used as an indicator for depression. Antidepressants may be used for indications other than depression, such as migraine or pain management. Because antidepressants are overwhelmingly prescribed for depressive symptoms or disorders, such cases remain minimal.30 It should also be noted that some patients with depressive symptoms may have received drug therapies other than antidepressants, psychotherapy without antidepressant therapy, or no medical treatment at all. Such cases would be rather limited because of the liberal prescribing of antidepressants in the United States. However, as in the case of potential misclassification of incident users, any bias introduced should not occur disproportionately between the “causal” and “noncausal” groups. Finally, because antidepressant therapy is being used as an indicator for depression in this study, causal inference can only be made about the initiation of antidepressant use, not of true depression. Because isotretinoin is prescribed for patients with severe recalcitrant nodular acne, they may be prone to depression because of their acne and not because of the ingestion of the drug.6,8 Given the severe nature of the disease for which isotretinoin is indicated, the disease could confound the results by producing a false signal, indicating an association between isotretinoin use and depression. However, no such signal was observed in this study. Finally, as in all claims data analyses, inferences can only be made about prescription fillings and this may not accurately reflect patient compliance with the prescribed therapy. In summary, the results of this study provided no evidence for an association between isotretinoin and depression, as measured by initiation of antidepres-
sant therapy. The hypothesis that the use of isotretinoin has a depression-invoking effect is not supported by the findings. The results for minocycline, a common antibiotic therapy for acne, and antidepressant use were similar. We thank Dr John McLane for his significant contributions to the design of the study and involvement in the drafting of the unpublished study report. We also thank Dr Susan Ackermann for her significant contributions in the critical review of the unpublished study report and the manuscript. Finally, we thank Elise M. Pelletier, MS, Dr Buddy Hutchins, and Dave P. Miller, MS, for statistical consulting and programming. Dr Levaux, as principal investigator of the study herein, had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analyses. Study concept and design: Levaux, Hersom, Neary, Klaskala; analysis and interpretation of data: Hersom, Levaux, Klaskala, Neary; drafting of the manuscript: Hersom, Neary, Levaux, Strauss; critical revision of the manuscript for important intellectual content: Strauss, Klaskala, Levaux, Neary, Hersom; statistical expertise: Hersom, Neary; obtained funding: Levaux, Hersom; administrative, technical, or material support: Hersom, Neary; study supervision: Levaux, Neary. REFERENCES 1. National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. Questions and answers about acne. NIH Publication No. 01-4998. Available from http:// www.nih.gov/niams/healthinfo/acne/acne.htm. Revised March 1999. Accessed October 2001. 2. Krowchuk DP, Lucky AW. Managing adolescent acne. Adolesc Med 2001;12:355-74. 3. Healy E, Simpson N. Acne vulgaris. BMJ 1994;308:831-3. 4. Rademaker M, Garioch JJ, Simpson NB. Acne in schoolchildren: no longer a concern for dermatologists. BMJ 1989;298:1217-9. 5. Krowchuk DP, Stancin T, Keskinen R, Walker R, Bass J, Anglin TM. The psychosocial effects of acne on adolescents. Pediatr Dermatol 1991;8:332-8. 6. Gupta MA, Gupta AK. Depression and suicidal ideation in dermatology patients with acne, alopecia areata, atopic dermatitis and psoriasis. Br J Dermatol 1998;139:846-50. 7. Pearl A, Arroll B, Lello J, Birchall NM. The impact of acne: a study of adolescents’ attitudes, perceptions and knowledge. N Z Med J 1998;111:269-71. 8. Koo JY, Smith LL. Psychological aspects of acne. Pediatr Dermatol 1991;8:185-8.
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9. Kellett SC, Gawkrodger DJ. The psychological and emotional impact of acne and the effect of treatment with isotretinoin. Br J Dermatol 1999;140:273-82. 10. Gupta MA, Gupta AK, Schork NJ, Ellis CN, Voorhees JJ. Psychiatric aspects of the treatment of mild to moderate facial acne: some preliminary observations. Int J Dermatol 1990;29:719-21. 11. Rubinow DR, Peck GL, Squillace KM, Gantt GG. Reduced anxiety and depression in cystic acne patients after successful treatment with oral isotretinoin. J Am Acad Dermatol 1987;17:25-32. 12. Niemeier V, Kupfer J, Demmelbauer-Ebner M, Stangier U, Effendy I, Gieler U. Coping with acne vulgaris: evaluation of the chronic skin disorder questionnaire in patients with acne. Dermatology 1998;196:108-15. 13. Mallon E, Newton JN, Klassen A, Stewart-Brown SL, Ryan TJ, Finlay AY. The quality of life in acne: a comparison with general medical conditions using generic questionnaires. Br J Dermatol 1999;140:672-6. 14. Lasek RJ, Chren MM. Acne vulgaris and the quality of life of adult dermatology patients. Arch Dermatol 1998;134:454-8. 15. Roaccutane periodic safety update report, Sept 1, 2000 –Aug 31, 2001. Nutley (NJ); Hoffmann-LaRoche, Inc; 2001. Submitted to the European Agency for the Evaluation of Medical Products (EMEA). 16. Burrall BA. Isotretinoin: dosing, safety, and a new formulation. Proceedings of the 59th annual meeting of the American Academy of Dermatology; 2001 March 2-7; Washington DC. Washington: The Academy; 2001. 17. Wysowski DK, Pitts M, Beitz J. An analysis of reports of depression and suicide in patients treated with isotretinoin. J Am Acad Dermatol 2001;45:515-9. 18. Jacobs DG, Deutsch NL, Brewer M. Suicide, depression, and isotretinoin: is there a causal link? J Am Acad Dermatol 2001;45: S168-75. 19. Jick SS, Kremers HM, Vasilakis-Scaramozza C. Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch Dermatol 2000;136:1231-6. 20. Transcripts from FDA Dermatologic and Opthalmic Drug Advisory Committee Meeting Sept 18-19, 2000. Safety issue workup: review of all spontaneous reports of psychiatric onditions— reporting period: market introduction (1982) through April 30, 1999. May 31, 2000. Nelson Robert C. Available from: http://www. fda.gov/ohrms/dockets/ac/cder00.htm#DermatologicandOphthal mic. Revised April 25, 2001. Accessed September 2001. 21. Transcripts from FDA Dermatologic and Opthalmic Drug Advisory Committee Meeting Sept 18-19, 2000. Clinical review: clinical psychiatric analysis of suicide cases, Douglas Jacobs, MD.
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22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
Available from: http://www.fda.gov/ohrms/dockets/ac/ cder00.htm#Dermatologic and Ophthalmic. Revised April 25, 2001. Accessed September 2001. Neary MP, Klaskala W, McLane J, Ackermann SP. Epidemiological study of adverse events in Accutane users and matched nonusers: retrospective analysis of major US health plan claims database. Proceedings of the 17th International Conference on Pharmacoepidemiology; 2001 Aug 23-26; Toronto, Ontario, Canada. Toronto: The Conference; 2001. Strauss JS, Leyden JJ, Lucky AW, Lookingbill DP, Drake LA, Hanifin JM, et al. Safety of new micronized formulation of isotretinoin in patients with severe recalcitrant nodular acne: a randomized trial comparing micronized isotretinoin with standard isotretinoin. J Am Acad Dermatol 2001;45:196-207. Rohrback JM, Feldman SR, Krowchuk DP, Felischer AB. Incidence of acne and depressive disorders in isotretinoin users. Proceedings of the 62nd annual meeting of the Society for Investigative Dermatology; 2001 May 9-12; Washington, DC. Washington: The Society; 2001. Petri H, Leufkens H, Naus J, Silkens R, van Hessen P, Urquhart J. Rapid method for estimating the risk of acutely controversial side effects of prescription drugs. J Clin Epidemiol 1990;43:433-9. Cher DJ. Myocardial infarction and acute cholecystitis: an application of sequence symmetry analysis. Epidemiology 2000;11: 446-9. Hallas J. Evidence of depression provoked by cardiovascular medication: a prescription sequence symmetry analysis. Epidemiology 1996;7:478-84. Bytzer P, Hallas J. Drug-induced symptoms of functional dyspepsia and nausea; a symmetry analysis of one million prescriptions. Aliment Pharmacol Ther 2000;14:1479-84. Lindberg G, Hallas J. Cholesterol-lowering drugs and antidepressants: a study of prescription symmetry. Pharmacoepidemiol Drug Safety 1998;7:399-402. National Institute of Mental Health. Depression research at the National Institute of Mental Health. Available from http://www. nimh.nih.gov/publicat/depresfact.htm. Updated April 13, 1999. Accessed October 2001. Petri H, de Vet HC, Naus J, Urquhart J. Prescription sequence analysis: a new and fast method for assessing certain adverse reactions of prescription drugs in large populations. Stat Med 1988;7:1171-5. Hallas J, Gaist D, Bjerrum L. The waiting time distribution as a graphical approach to epidemiologic measures of drug utilization. Epidemiology 1997;8:666-70.
Appendix. Application of the prescription sequence symmetry analysis method The analysis used in this study applied the statistical method known as prescription sequence symmetry analysis (PSSA), which involves the measurement of incidence and which thereby is used to calculate a rate ratio or risk ratio (see reference 27 in article). This calculation refers to a ratio of the probability that isotretinoin use causes antidepressant use versus the probability that antidepressant use causes isotretinoin use. For patients prescribed both isotretinoin (minocycline) and antidepressants, the probability that the antidepressant was prescribed last will depend on when the isotretinoin (minocycline) was prescribed. Below is a description of the formulas used for the calculation of the null effect sequence ratio in the analyses for the isotretinoin cohort. The analyses for minocycline cohort were performed in a similar manner. The adjusted risk ratio uses the null effect sequence ratio as the reference value to adjust the crude sequence ratio, thereby quantifying the risk attributable to the index drug while controlling for changes in prescribing patterns. Estimation of the null effect sequence ratio and adjusted rate ratio. The PSSA method, as described by Hallas (see reference 27 in article), was applied in this study. Thereby, for patients prescribed both isotretinoin (I) and an antidepressant (AD) during the study period, the probability that the antidepressant was prescribed last depends on when isotretinoin was prescribed. If isotretinoin was prescribed on the first day of the study period, the sequence would be I 3 AD, whereas if isotretinoin was prescribed on the last day, the sequence would be AD 3 I. For patients beginning isotretinoin therapy on a specific index day, m, the probability of an I 3 AD sequence is given by the following equation:
冘 AD
where m or n are consecutive days of the study period, excluding the run-in period, is the last day of the study period, AD is the number of patients who presented their first antidepressant prescriptions on the index day, and is the average probability of an I 3 AD sequence for all days,
冘
is the total number of patients having incedent antidepressant fillings one or more days after incident isotretinoin prescription filling on index day m, and
冘 AD
⫽
⫽m⫹1
冘
⫽1
AD
⫽1
is the total number of patients having incident antidepressant fillings in the isotretinoin cohort study. The overall probability of an I 3 AD sequence, ␣, is calculated as the average for all days, weighted by the number of incident isotretinoin therapies on each day, as follows:
冋 冉
冘I
␣ ⫽
m⫽1
m
·
冘 AD
⫽m⫹1
冘 I · 冘 AD
冊册
m
m⫽1
m
m⫽1
where m or n are consecutive days of the study period, excluding the run-in period, is the last day of the study period, AD is the number of patients who presented their first antidepressant prescriptions on the index day m, I is the number of patients who presented their first prescriptions for isotretinoin on the index day. The null effect sequence ratio, rn, is then calculated as follows:
AD
⫽m⫹1
rn ⫽
␣ 1 ⫺ ␣
The adjusted rate ratio is then calculated by adjusting the crude sequence ratio by the null effect sequence ratio.
1
A
cne affects an estimated 17 million people in the United States, making it the most prevalent skin disease. Acne may occur in individuals from 12 to 49 years old. Eighty-five to ninety percent of adolescents and young adults between
From Quintiles Late Phase,a Hoffmann-La Roche, Inc,b and University of Iowa Health Care.c Funding source: Hoffmann-La Roche, Ltd, Basel, Switzerland, funded this research through a contract with Quintiles Late Phase. Disclosure: Drs Klaskala and Neary are employed by Hoffmann-La Roche, Inc, and Dr Strauss is a consultant to Hoffmann-La Roche, Inc. None of the authors has any stock or other equity interest in Hoffmann-La Roche, Inc. Poster and oral presentations of this study were made at the 62nd Annual Meeting of the Society for Investigative Dermatology in Washington, DC, on May 9-12, 2001, and at the 17th International Conference on Pharmacoepidemiology in Toronto, Ontario, Canada, on August 23-26, 2001. Accepted for publication April 2, 2003. Reprints not available from authors. Copyright © 2003 by the American Academy of Dermatology, Inc. 0190-9622/2003/$30.00 ⫹ 0 doi:10.1067/S0190-9622(03)02087-5
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the ages of 12 and 24 years have some degree of acne. Approximately 16% of males and 9% of females have moderate to severe acne.1-4 The main goal of acne treatment is to prevent physical scarring by limiting the number of lesions and the duration of the disease, thereby minimizing the psychologic impact of the disease.1,3,5 The psychologic impact of acne is well documented, particularly in adolescents.5-12 Adolescents report levels of social, psychologic, and emotional problems that are as great as those reported by patients with chronic disabling diseases.13,14 Studies have shown that adolescents with mild to moderate acne are at higher risk for depression and suicidal ideation and have lower self-esteem than their counterparts without acne.6,12 Females consistently report higher levels of anxiety and depression related to their acne than do males.9 Effective dermatologic treatment of acne has been shown in some studies to decrease symptoms of depression and anxiety and to significantly improve other psychologic parameters.5,10,11 However, the emotional status of some
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treated patients appears to be somewhat resistant to change, indicating that acne can contribute to longterm psychosocial impairment.9 Isotretinoin, a retinoid, is indicated for the treatment of severe, recalcitrant nodular acne. It has been used by approximately 12 million people worldwide since its introduction in 1982, including 5 million people in the United States.15 Spontaneous reports have suggested a possible “signal” for a relationship between isotretinoin use and depressive symptoms.16-18 However, several retrospective studies performed to date using national and international databases and one clinical trial have not supported such a relationship.19-24 The potential association between isotretinoin use and depression may be confounded by severe acne, which is an indication for isotretinoin use and has a recognized association with depression.17 Because of the high background prevalence of depressive symptoms in patients with acne, it is difficult to distinguish between drug-related and non-drug-related depressive symptoms, such as environmental or physiologically induced symptoms. In addition, there is no known biologic mechanism of action to support such a causal relationship. The current study was performed to further address the possible association between isotretinoin therapy and the onset of depression by use of a unique methodologic approach and a large prescription database. The primary objective of this study was to investigate the potential association between isotretinoin use and the onset of depression in an observational study using data collected from the Quintiles Informatics Database. This was accomplished by evaluating the prescription order of isotretinoin and antidepressants among incident users of both drugs. Asymmetry in the prescription order of isotretinoin and antidepressants would indicate an association. The null hypothesis assumes no association between the initiation of isotretinoin (index drug) and subsequent initiation of antidepressant (marker drug) therapy (ie, risk ratio of 1.0). The secondary objective of this study was to examine the validity of the results by performing a similar analysis with a cohort of patients treated with minocycline (index drug), an agent not suspected to cause depression, and antidepressants (marker drug) with use of the same prescription claims database.
METHODS The current study used a retrospective design, applying the sequence symmetry method (see Appendix at www.eblue.org; published online only) to evaluate data from a large nationwide prescription
Hersom et al 425
database. Sequence symmetry analysis infers causality based on the sequence of filled prescriptions, which are considered indicators for clinical events. The method allows for the measurement of patient propensity to fill the index drug before the marker drug; where the index drug is the drug thought to produce a given side effect and the marker drug is the drug used to alleviate the given side effect.25 The sequence in which antidepressants and isotretinoin were first prescribed and dispensed to a large population of isotretinoin users was analyzed. The prescription database contains adjudicated pharmacy claims, reflecting use of pharmacy benefits, for approximately 90 million patients nationwide. This database includes data from approximately 38,000 pharmacies interacting with more than 1200 commercial and governmental payers throughout the United States. The analysis relies on real-world data, so this allows for greater external validity of results. Sequence symmetry method Sequence symmetry analysis proceeds in three steps. First, patients who filled incident prescriptions of both index and marker drugs during a defined period of time are identified. Second, patients are classified on the basis of the temporal order of the alternative sequences of prescription events. The “causal” group consists of patients who filled the index drug first (isotretinoin or minocycline) and the marker drug second (antidepressant), whereas conversely the “noncausal” group consists of patients who filled the index drug second and the marker drug first. Finally, the estimate of risk is calculated by taking the ratio of the number of patients in the “causal” to the “noncausal” groups.26,27 Patients taking the index and marker drugs may have risk factors common to both pharmaceuticals. The distinct feature of the sequence symmetry method is that patients serve as their own controls. Confounders, such as age, sex, or physician office visits, are effectively controlled because these factors do not predict the order in which an individual patient fills two prescriptions.27 Previous studies using sequence symmetry analysis have either confirmed or rejected associations across different therapeutic areas and patient populations. With use of a statewide California hospital discharge database, a common relationship between myocardial infarction and subsequent congestive heart failure was confirmed in the order of hospital admissions, whereas a relationship believed to be minimal between congestive heart failure and acute cholecystitis showed only a small association.26 In another example, positive signals for a variety of drugs known to cause nausea were detected by
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Table I. Antidepressants included in the isotretinoin and minocycline analyses Therapeutic class
Antidepressant
SSRIs
Citalopram Fluoxetine Fluvoxamine Paroxetine Sertraline
Secondary and tertiary amine tricyclics
Amitriptyline Clomipramine Doxepin Imipramine hydrochloride Imipramine pamoate Trimipramine Amoxapine Desipramine Nortriptyline Protriptyline
Other antidepressants*
Bupropion Maprotiline Mirtazapine Nefazodone Trazodone Venlafaxine Amitriptyline hydrochloride/ perphenazine Amitriptyline/chlordiazepoxide
*Monoamine oxidase inhibitors were not included because of their primary use in chronic depression.
using a large prescription database.28 Studies evaluating potential depression-provoking effects of calcium channel blockers and angiotensin-converting enzyme inhibitors revealed significant asymmetry in the prescription orders with antidepressants, whereas conversely cholesterol-lowering drugs revealed no asymmetry in the prescription order with antidepressants.27,29 The validity of study results depends on the specificity of available pharmacotherapy for the adverse event in question.25 In the current study, antidepressants were used as the marker drug for depression for two reasons. First, prescription antidepressant drugs are the standard pharmacotherapy for depression in the United States.30 Second, previous sequence symmetry studies have successfully used antidepressants as an indicator for depression.27,29,31 Measures By use of sequence symmetry analysis, the following three statistics were computed: the crude sequence ratio, the null-effect sequence ratio, and the adjusted risk ratio. The crude sequence ratio is the ratio of the number of patients in the “causal”
group over the number of patients in the “noncausal” group. The crude sequence ratio is a measure of the degree of asymmetry between the two patient groups; it does not take into account any variations in the prescribing trends of the index or marker drugs during the study time frame.28 The null-effect sequence ratio determines the expected sequence ratio given no cause-effect relationship between the two drugs. The null-effect sequence ratio measures differential change in prescribing patterns during the study period, which could confound the crude sequence ratio. The adjusted risk ratio uses the null-effect sequence ratio as the reference value to adjust the crude sequence ratio, thereby quantifying the risk attributable to the index drug while controlling for changes in prescribing patterns.27,29 Patients in the final study cohort were classified into one of two groups (“causal” and “noncausal”) on the basis of the prescription order of the index and marker drugs. The crude sequence ratio was computed as the ratio of the number of patients in the “causal” group over the number of patients in the “noncausal” group. The crude sequence ratio was modified by the null-effect sequence ratio to yield the adjusted risk ratio and generate 95% CIs.27 Antidepressants used in this study were categorized into three therapeutic classes: selective serotonin reuptake inhibitors (SSRIs), secondary and tertiary amine tricyclics (amines), and other antidepressants (other), according to the classification system used by Diversified Pharmaceutical Services, now known as Express Scripts, a major US pharmacy benefit management company (Table I). Monoamine oxidase inhibitors were not included in this study because they are generally used to treat chronic depression and are not indicative of treatment-emergent depression. The crude and adjusted risk ratios were calculated for the index drugs and all antidepressants combined as well as for each of the three therapeutic antidepressant classes. An adjusted risk ratio greater than 1.0 would indicate a depression-invoking relationship. Minocycline, which is the primary antibiotic therapy prescribed for the treatment of moderate and severe acne, was selected as an index drug to examine the validity of the isotretinoin results. In addition, minocycline is also used to treat a variety of bacterial and protozoal infections and rheumatoid arthritis. Depression is not a known side effect of minocycline therapy. Therefore, it would be expected that the risk ratio for the minocycline analysis would not differ significantly from 1.0.
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Data source Data for this study were obtained from the Quintiles Informatics Database. The claims data are passively collected by recording the transaction history of one of the largest electronic data interchange networks in the country. The prescription database contains adjudicated pharmacy claims for approximately 90 million patients, reflecting utilization of pharmacy benefits, from approximately 38,000 pharmacies interacting with more than 1200 commercial and governmental payers throughout the United States. The database contains pharmacy data from all 50 states, Puerto Rico, and other US territories, representing all 261 metropolitan statistical areas. Patients of all ages and both sexes are represented in the data. Each pharmacy transaction contains an encrypted identification number that is unique to each patient. By use of the encrypted identification number, patient-specific pharmacy claims can be linked and analyzed over a period of time. Given that more than 500 million pharmacy claims are added to the database each year, the volume of claims is sufficient to minimize any “noise” created by irregular prescribing patterns or regional physician practices that often confound claims analyses. The pharmacy file contains transactions from January 1, 1998, to the present and is updated with approximately 1.5 million claims each day. It is estimated that 78% of all pharmacy claims in the United States are filed electronically, of which approximately 40% are archived in this database. All physician specialties, including primary care, dermatology, and psychiatry, are represented in the pharmacy data. Patient population Construction of study database for comparative analyses. The process for selecting the isotretinoin and minocycline cohorts for the comparative analyses is provided in Fig 1. This involved the extraction of a study database (from which the isotretinoin and minocyline cohort groups would be selected) from the source database, a large nationwide prescription database. The source database for this study contained all prescriptions filled at participating pharmacies from July 1, 1998, through March 31, 2000, including approximately 5.6 million prescriptions for antidepressants during this time period. This database contained variables of interest that included prescription issue date, prescription filling date, patient demographics, and medication type and dosage. When a prescription is filled, all data for the prescription are automatically entered into the
Hersom et al 427
Fig 1. Study population selection process. This figure provides the study design that develops the two groups that were analyzed: the “causal” group includes patients who filled their isotretinoin prescriptions first and the “noncausal” group includes patients who filled their antidepressant prescriptions first.
source database. This involves an electronic, fully computerized data entry process at the pharmacy level. For the purpose of this analysis, a subset database, the study database, of all filled prescriptions between June 1, 1999, and March 31, 2000, was constructed from the nationwide pharmacy database according to the study inclusion and exclusion criteria. The characteristics of the source database do not allow for identification of continually enrolled patients. It is expected, however, that any potential bias introduced into the study because of this limitation would be proportionate across both “causal” and “noncausal” study groups. For the assembly of the isotretinoin cohort, all incident users of both isotretinoin and antidepressants were selected from the study database within the age group likely to be treated for acne. Therefore, the prescription inclusion and exclusion criteria would not be expected to have any relationship with either isotretinoin use or depression, as measured by antidepressant dispensings. Because the study subjects were identified as incident users of isotretinoin and/or antidepressants, their selection was dependent on their having had filled prescription(s) for isotretinoin and/or antidepressants but was not related to whether they actually used isotretinoin and/or had clinical depression. However, patients not receiving antidepressant therapy for depression would not be included in the prescription filling study. A preliminary analysis of the data in the isotretinoin cohort did not reveal any significant differences in demographic factors between “causal” and “noncausal” groups that would suggest possible con-
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Table II. Demographics of isotretinoin and minocycline cohorts Isotretinoin cohort (n ⴝ 2821)*
Age group (y) 12–17 18–24 25–34 35–49
Male
Female
498 (17.7) 228 (8.1) 130 (4.6) 129 (4.6)
349 (12.4) 485 (17.2) 544 (19.2) 453 (16.1)
Minocycline cohort (n ⴝ 7360)† Male
Female
892 (12.1) 930 (12.7) 380 (5.2) 1024 (13.9) 297 (4.0) 1632 (22.2) 395 (5.4) 1796 (24.4)
*Sex unknown for 5 patients. † Sex unknown for 14 patients.
founding. Therefore, a stratified analysis by demographic parameters was not further pursued. A comparative study using a minocycline cohort was also performed to validate the findings of the isotretinoin and antidepressant analysis. This analysis included the study of a cohort of patients treated with both minocycline (index drug), an agent not suspected to cause depression, and with antidepressants (marker drug) by use of the same study design and methods and selected from the same source database. This allowed for the methodologic comparison, in terms of validity, of the results obtained from the minocycline cohort with those obtained from the isotretinoin cohort. Selection of prescriptions for PSSA analyses. Specifically, all isotretinoin, minocycline, and antidepressant prescriptions filled during the July 1, 1998, through March 31, 2000, period were extracted from the large source database. From this subset of data (the study database), those patients having prescriptions for both the index and marker drugs were identified. Incident uses of both the index and marker drugs were then identified by the waiting time distribution method, as described by Hallas27 and Hallas et al.32 The waiting time distribution method starts from the premise that, under usual circumstances and with correction for seasonality in prescribing patterns, incident dispensing is relatively constant across short (monthly) time periods. Empirical data were used to establish the period of time required to reach a plateau in the frequency of incident drug dispensing in a given database. At the beginning of the distribution, a large number of patients are prevalent users. As the time window expands, the frequency of incident dispensings decreases until it reaches a plateau indicating that, from that time on (ie, after June 1, 1999, in this study), patients presenting their first index and marker prescriptions are considered new, incident users. Therefore, only pa-
tients who incurred their first recorded index and marker drug prescriptions between June 1, 1999, and March 31, 2000, were included in the analysis. Isotretinoin cohort. The Quintiles Informatics Database contains records on 128,652 isotretinoin users and 5,642,261 antidepressant users over the period from July 1, 1998, to March 31, 2000. From these patients, 17,348 incident and prevalent users of both drugs were identified. The analysis was restricted to patients in the usual age group of isotretinoin users; therefore, 1195 patients were excluded from the analysis because their age was not between 12 and 49 years (n ⫽ 1058) or their claims did not contain a valid date of birth (n ⫽ 137). A total of 13,186 patients filled their first recorded isotretinoin or antidepressant prescriptions before June 1, 1999 (ie, the first day of the study period); these individuals were considered prevalent users and were excluded from further analysis. An additional 146 patients were dropped from the analysis because they filled their first prescriptions for both drugs on the same day. Of the remaining 2821 patients, 1439 filled the antidepressant prescription first and 1382 filled the antidepressant prescription second. Table II provides the age and sex distribution for the isotretinoin cohort: 65% of patients were female and 55% of patients were between 12 and 24 years of age. These figures are consistent with published literature on persons with both acne and psychiatric disorders.16,17 Minocycline cohort. The Quintiles Informatics Database contains records on 407,303 minocycline users and the same number of antidepressant users as the isotretinoin analysis over the period from July 1, 1998, to March 31, 2000. From these patients, 67,580 users of both drugs were identified. This analysis was restricted to patients of the same age as the isotretinoin analysis; therefore, 11,788 patients were excluded from the analysis because they were not between 12 and 49 years old (n ⫽ 11,274) or because their claims did not contain a valid date of birth (n ⫽ 514). Another 48 patients were excluded from further analysis because their minocycline prescription supply was less than 21 days, indicating that minocycline was probably not intended for acne therapy. A total of 47,647 patients filled their first recorded minocycline or antidepressant prescriptions before June 1, 1999 (ie, the first day of the study period); these individuals were considered prevalent users and were excluded from further analysis. An additional 737 patients were dropped from the analysis because they filled the first prescription for both drugs on the same day. Of the remaining 7360 patients, 3751 filled the antidepres-
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Table III. Results from the isotretinoin analysis, by antidepressant class
Marker drug
All antidepressants SSRI antidepressants Amine antidepressants Other antidepressants
Study population (N)
“Causal” group (n)
“Noncausal” group (n)
Crude sequence ratio
Null effect sequence ratio
Adjusted risk ratio (95% CI)
2821 1735 374 712
1382 874 174 334
1439 861 200 378
0.96 1.02 0.87 0.88
0.99 1.02 0.97 0.93
0.97 (0.92–1.02) 0.99 (0.93–1.06) 0.90 (0.78–1.04) 0.95 (0.85–1.05)
Table IV. Demographics of causal and noncausal groups in the isotretinoin analysis
Sex* Male Female Age group (y) 12–17 18–24 25–34 35–49
“Causal group” (isotretinoin first, antidepressant second) (n ⴝ 1382)
“Noncausal group” (antidepressant first, isotretinoin second) (n ⴝ 1439)
Total study group (n ⴝ 2821)
494 (35.8) 886 (64.2)
491 (34.2) 945 (65.8)
985 (35.0) 1831 (65.0)
441 (31.9) 370 (26.8) 296 (21.4) 275 (19.9)
409 (28.4) 343 (23.8) 380 (26.4) 307 (21.3)
850 (30.1) 713 (25.3) 676 (24.0) 582 (20.6)
*Sex unknown for 5 patients.
sant prescription first and 3609 filled the antidepressant prescription second. Table II provides the age and sex distribution for the minocycline cohort. Patients in the minocycline cohort were slightly older and had a larger proportion of females (73.3%) than the isotretinoin cohort.
RESULTS Isotretinoin analysis Table III summarizes the results for the isotretinoin analysis, for all antidepressants combined and by antidepressant class. A total of 1382 patients exhibited the “causal” prescription order (isotretinoin followed by antidepressants), whereas 1439 patients followed the “noncausal” prescription order (antidepressants followed by isotretinoin), yielding a crude sequence ratio of 0.96. When they were analyzed by antidepressant class, the crude sequence ratios ranged from 0.87 (amines) to 1.02 (SSRIs). Overall prescribing patterns for antidepressants did not deviate significantly from the overall prescribing patterns for isotretinoin during the study period. This resulted in only very modest adjustment factors (ie, null effect sequence ratio ranging from 0.93 to 1.02). Accordingly, the adjusted risk ratio for all antidepressants combined was only slightly higher than the crude sequence ratio (0.97; 95% CI, 0.92-1.02). When analyzed by antidepressant class, SSRI prescribing increased relative to isotretinoin;
therefore, the adjusted risk ratio was slightly less than the crude sequence ratio (0.99; 95% CI, 0.931.06). Table IV provides the sex and age distribution of patients in the “causal” and “noncausal” groups. These results indicate that the “causal” and “noncausal” groups are well balanced with respect to sex and age. Isotretinoin did not exhibit a pattern suggesting a depression-provoking effect when analyzed by antidepressant class or in aggregate; all adjusted risk ratios had point estimates below 1 (0.90 to 0.99). In addition to the equal distribution of patients, as shown in Fig 2, the time between the initial isotretinoin and antidepressant prescriptions is consistent between the two patient groups and does not provide any temporal irregularities that would suggest a causal association. Minocycline analysis Table V summarizes the results for the minocycline analysis, for all antidepressants combined and by antidepressant class. A total of 3609 patients initiated minocycline therapy first (causal), whereas 3751 patients initiated antidepressant therapy first (noncausal), yielding a crude sequence ratio of 0.96. When analyzed by antidepressant class, the crude sequence ratios ranged from 0.83 (other) to 1.05 (SSRIs).
430 Hersom et al
Fig 2. Distribution of patients in causal and noncausal groups: months between initial isotretinoin and antidepressant prescriptions. Patients were classified into two groups, “causal” and “noncausal,” on the basis of the temporal order of the first recorded isotretinoin and antidepressant prescriptions. The “causal” group filled their isotretinoin prescriptions first, whereas conversely, the “noncausal” group filled their antidepressant prescriptions first.
The null effect sequence ratio was 0.98 for all antidepressants combined and ranged from 0.86 to 1.05 by antidepressant class. Accordingly, the adjusted risk ratio for all antidepressants combined was 0.98 (95% CI, 0.95-1.02). When analyzed by antidepressant class, SSRI prescribing increased relative to minocycline; therefore, the adjusted risk ratio was slightly less than the crude sequence ratio (1.00; 95% CI, 0.96-1.04). As expected, the prescription order of minocycline and antidepressants was symmetric. As in the isotretinoin analysis, the time between initial minocycline and antidepressant prescriptions was consistent between the two patient groups and did not indicate any temporal irregularities that would suggest a causal association (Fig 3).
COMMENT The current study involved the application of a unique statistical method, sequence symmetry analysis, to analyze two large cohorts of patients treated with antidepressants and isotretinoin (2821 patients) or minocycline (7360 patients). Claims were extracted from a nationwide prescription database that contains records for approximately 90 million patients. The sequence symmetry method uses patients as their own controls, thereby minimizing any potential biases caused by variations in patient characteristics. As stated previously, sequence symmetry analysis is a validated method that has been successfully used in prior studies to confirm suggested associations across various therapeutic areas using prescription claims databases and a hospital discharge data-
J AM ACAD DERMATOL SEPTEMBER 2003
Fig 3. Distribution of patients in causal and noncausal groups: months between initial minocycline and antidepressant prescriptions. Patients were classified into two groups, “causal” and “noncausal,” on the basis of the temporal order of the first recorded minocycline and antidepressant prescriptions. The “causal” group filled their minocycline prescriptions first, whereas conversely, the “noncausal” group filled their antidepressant prescriptions first.
base.26-28 This technique uses the null effect sequence ratio to adjust for changes in physician prescribing patterns during the study period that may result from reimbursement changes or increased patient demand for selected medications. It is anticipated that the large sample sizes available for the isotretinoin and minocycline analyses minimized any further effect of variable physician prescribing.31 Adjusted risk ratios from the isotretinoin analysis, by antidepressant class and in the aggregate, were consistently below 1.0, suggesting that isotretinoin does not have a depression-provoking effect. In addition, patient frequencies between “causal” and “noncausal” groups are similar by age and sex. Similar results indicating no association with the onset of depression for the minocycline cohort provide powerful support to the isotretinoin results. When the results are interpreted, it should be noted that, despite the strict study selection criteria, it is possible that some of the patients identified as incident users might actually be prevalent users. This would occur in patients who had previous prescriptions for isotretinoin or antidepressants that were not recorded in the database. For example, patients with chronic depressive disorders could have depressive episodes separated by periods greater than the 11-month time frame used to exclude prevalent users in the current study. Additionally, some prescriptions may not be captured in the database because of patients changing health plans, thereby potentially misclassifying patients as incident users. This could occur because continuous enrollment during the study period could not be verified in this database. However, misclassification of incident patients would not be expected to occur
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Table V. Results from the minocycline analysis, by antidepressant class
Marker drug
All antidepressants SSRI antidepressants Amine antidepressants Other antidepressants
Study population (N)
“Causal” group (n)
“Noncausal” group (n)
Crude sequence ratio
Null effect sequence ratio
Adjusted risk ratio (95% CI)
7360 4447 1063 1850
3609 2277 494 838
3751 2170 569 1012
0.96 1.05 0.87 0.83
0.98 1.05 0.86 0.88
0.98 (0.95–1.02) 1.00 (0.96–1.04) 1.01 (0.93–1.10) 0.94 (0.88–1.00)
disproportionately across “causal” and “noncausal” groups—particularly given the size of the Quintiles Informatics Database, the study selection criteria, and the comparative cohort analyses. Finally, it is expected that the 11-month waiting time eliminated most true prevalent cases.32 It should also be noted that, although antidepressant therapy is the standard of care for depression, misclassification of patients could result if antidepressant therapy is used as an indicator for depression. Antidepressants may be used for indications other than depression, such as migraine or pain management. Because antidepressants are overwhelmingly prescribed for depressive symptoms or disorders, such cases remain minimal.30 It should also be noted that some patients with depressive symptoms may have received drug therapies other than antidepressants, psychotherapy without antidepressant therapy, or no medical treatment at all. Such cases would be rather limited because of the liberal prescribing of antidepressants in the United States. However, as in the case of potential misclassification of incident users, any bias introduced should not occur disproportionately between the “causal” and “noncausal” groups. Finally, because antidepressant therapy is being used as an indicator for depression in this study, causal inference can only be made about the initiation of antidepressant use, not of true depression. Because isotretinoin is prescribed for patients with severe recalcitrant nodular acne, they may be prone to depression because of their acne and not because of the ingestion of the drug.6,8 Given the severe nature of the disease for which isotretinoin is indicated, the disease could confound the results by producing a false signal, indicating an association between isotretinoin use and depression. However, no such signal was observed in this study. Finally, as in all claims data analyses, inferences can only be made about prescription fillings and this may not accurately reflect patient compliance with the prescribed therapy. In summary, the results of this study provided no evidence for an association between isotretinoin and depression, as measured by initiation of antidepres-
sant therapy. The hypothesis that the use of isotretinoin has a depression-invoking effect is not supported by the findings. The results for minocycline, a common antibiotic therapy for acne, and antidepressant use were similar. We thank Dr John McLane for his significant contributions to the design of the study and involvement in the drafting of the unpublished study report. We also thank Dr Susan Ackermann for her significant contributions in the critical review of the unpublished study report and the manuscript. Finally, we thank Elise M. Pelletier, MS, Dr Buddy Hutchins, and Dave P. Miller, MS, for statistical consulting and programming. Dr Levaux, as principal investigator of the study herein, had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analyses. Study concept and design: Levaux, Hersom, Neary, Klaskala; analysis and interpretation of data: Hersom, Levaux, Klaskala, Neary; drafting of the manuscript: Hersom, Neary, Levaux, Strauss; critical revision of the manuscript for important intellectual content: Strauss, Klaskala, Levaux, Neary, Hersom; statistical expertise: Hersom, Neary; obtained funding: Levaux, Hersom; administrative, technical, or material support: Hersom, Neary; study supervision: Levaux, Neary. REFERENCES 1. National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. Questions and answers about acne. NIH Publication No. 01-4998. Available from http:// www.nih.gov/niams/healthinfo/acne/acne.htm. Revised March 1999. Accessed October 2001. 2. Krowchuk DP, Lucky AW. Managing adolescent acne. Adolesc Med 2001;12:355-74. 3. Healy E, Simpson N. Acne vulgaris. BMJ 1994;308:831-3. 4. Rademaker M, Garioch JJ, Simpson NB. Acne in schoolchildren: no longer a concern for dermatologists. BMJ 1989;298:1217-9. 5. Krowchuk DP, Stancin T, Keskinen R, Walker R, Bass J, Anglin TM. The psychosocial effects of acne on adolescents. Pediatr Dermatol 1991;8:332-8. 6. Gupta MA, Gupta AK. Depression and suicidal ideation in dermatology patients with acne, alopecia areata, atopic dermatitis and psoriasis. Br J Dermatol 1998;139:846-50. 7. Pearl A, Arroll B, Lello J, Birchall NM. The impact of acne: a study of adolescents’ attitudes, perceptions and knowledge. N Z Med J 1998;111:269-71. 8. Koo JY, Smith LL. Psychological aspects of acne. Pediatr Dermatol 1991;8:185-8.
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9. Kellett SC, Gawkrodger DJ. The psychological and emotional impact of acne and the effect of treatment with isotretinoin. Br J Dermatol 1999;140:273-82. 10. Gupta MA, Gupta AK, Schork NJ, Ellis CN, Voorhees JJ. Psychiatric aspects of the treatment of mild to moderate facial acne: some preliminary observations. Int J Dermatol 1990;29:719-21. 11. Rubinow DR, Peck GL, Squillace KM, Gantt GG. Reduced anxiety and depression in cystic acne patients after successful treatment with oral isotretinoin. J Am Acad Dermatol 1987;17:25-32. 12. Niemeier V, Kupfer J, Demmelbauer-Ebner M, Stangier U, Effendy I, Gieler U. Coping with acne vulgaris: evaluation of the chronic skin disorder questionnaire in patients with acne. Dermatology 1998;196:108-15. 13. Mallon E, Newton JN, Klassen A, Stewart-Brown SL, Ryan TJ, Finlay AY. The quality of life in acne: a comparison with general medical conditions using generic questionnaires. Br J Dermatol 1999;140:672-6. 14. Lasek RJ, Chren MM. Acne vulgaris and the quality of life of adult dermatology patients. Arch Dermatol 1998;134:454-8. 15. Roaccutane periodic safety update report, Sept 1, 2000 –Aug 31, 2001. Nutley (NJ); Hoffmann-LaRoche, Inc; 2001. Submitted to the European Agency for the Evaluation of Medical Products (EMEA). 16. Burrall BA. Isotretinoin: dosing, safety, and a new formulation. Proceedings of the 59th annual meeting of the American Academy of Dermatology; 2001 March 2-7; Washington DC. Washington: The Academy; 2001. 17. Wysowski DK, Pitts M, Beitz J. An analysis of reports of depression and suicide in patients treated with isotretinoin. J Am Acad Dermatol 2001;45:515-9. 18. Jacobs DG, Deutsch NL, Brewer M. Suicide, depression, and isotretinoin: is there a causal link? J Am Acad Dermatol 2001;45: S168-75. 19. Jick SS, Kremers HM, Vasilakis-Scaramozza C. Isotretinoin use and risk of depression, psychotic symptoms, suicide, and attempted suicide. Arch Dermatol 2000;136:1231-6. 20. Transcripts from FDA Dermatologic and Opthalmic Drug Advisory Committee Meeting Sept 18-19, 2000. Safety issue workup: review of all spontaneous reports of psychiatric onditions— reporting period: market introduction (1982) through April 30, 1999. May 31, 2000. Nelson Robert C. Available from: http://www. fda.gov/ohrms/dockets/ac/cder00.htm#DermatologicandOphthal mic. Revised April 25, 2001. Accessed September 2001. 21. Transcripts from FDA Dermatologic and Opthalmic Drug Advisory Committee Meeting Sept 18-19, 2000. Clinical review: clinical psychiatric analysis of suicide cases, Douglas Jacobs, MD.
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Available from: http://www.fda.gov/ohrms/dockets/ac/ cder00.htm#Dermatologic and Ophthalmic. Revised April 25, 2001. Accessed September 2001. Neary MP, Klaskala W, McLane J, Ackermann SP. Epidemiological study of adverse events in Accutane users and matched nonusers: retrospective analysis of major US health plan claims database. Proceedings of the 17th International Conference on Pharmacoepidemiology; 2001 Aug 23-26; Toronto, Ontario, Canada. Toronto: The Conference; 2001. Strauss JS, Leyden JJ, Lucky AW, Lookingbill DP, Drake LA, Hanifin JM, et al. Safety of new micronized formulation of isotretinoin in patients with severe recalcitrant nodular acne: a randomized trial comparing micronized isotretinoin with standard isotretinoin. J Am Acad Dermatol 2001;45:196-207. Rohrback JM, Feldman SR, Krowchuk DP, Felischer AB. Incidence of acne and depressive disorders in isotretinoin users. Proceedings of the 62nd annual meeting of the Society for Investigative Dermatology; 2001 May 9-12; Washington, DC. Washington: The Society; 2001. Petri H, Leufkens H, Naus J, Silkens R, van Hessen P, Urquhart J. Rapid method for estimating the risk of acutely controversial side effects of prescription drugs. J Clin Epidemiol 1990;43:433-9. Cher DJ. Myocardial infarction and acute cholecystitis: an application of sequence symmetry analysis. Epidemiology 2000;11: 446-9. Hallas J. Evidence of depression provoked by cardiovascular medication: a prescription sequence symmetry analysis. Epidemiology 1996;7:478-84. Bytzer P, Hallas J. Drug-induced symptoms of functional dyspepsia and nausea; a symmetry analysis of one million prescriptions. Aliment Pharmacol Ther 2000;14:1479-84. Lindberg G, Hallas J. Cholesterol-lowering drugs and antidepressants: a study of prescription symmetry. Pharmacoepidemiol Drug Safety 1998;7:399-402. National Institute of Mental Health. Depression research at the National Institute of Mental Health. Available from http://www. nimh.nih.gov/publicat/depresfact.htm. Updated April 13, 1999. Accessed October 2001. Petri H, de Vet HC, Naus J, Urquhart J. Prescription sequence analysis: a new and fast method for assessing certain adverse reactions of prescription drugs in large populations. Stat Med 1988;7:1171-5. Hallas J, Gaist D, Bjerrum L. The waiting time distribution as a graphical approach to epidemiologic measures of drug utilization. Epidemiology 1997;8:666-70.
Appendix. Application of the prescription sequence symmetry analysis method The analysis used in this study applied the statistical method known as prescription sequence symmetry analysis (PSSA), which involves the measurement of incidence and which thereby is used to calculate a rate ratio or risk ratio (see reference 27 in article). This calculation refers to a ratio of the probability that isotretinoin use causes antidepressant use versus the probability that antidepressant use causes isotretinoin use. For patients prescribed both isotretinoin (minocycline) and antidepressants, the probability that the antidepressant was prescribed last will depend on when the isotretinoin (minocycline) was prescribed. Below is a description of the formulas used for the calculation of the null effect sequence ratio in the analyses for the isotretinoin cohort. The analyses for minocycline cohort were performed in a similar manner. The adjusted risk ratio uses the null effect sequence ratio as the reference value to adjust the crude sequence ratio, thereby quantifying the risk attributable to the index drug while controlling for changes in prescribing patterns. Estimation of the null effect sequence ratio and adjusted rate ratio. The PSSA method, as described by Hallas (see reference 27 in article), was applied in this study. Thereby, for patients prescribed both isotretinoin (I) and an antidepressant (AD) during the study period, the probability that the antidepressant was prescribed last depends on when isotretinoin was prescribed. If isotretinoin was prescribed on the first day of the study period, the sequence would be I 3 AD, whereas if isotretinoin was prescribed on the last day, the sequence would be AD 3 I. For patients beginning isotretinoin therapy on a specific index day, m, the probability of an I 3 AD sequence is given by the following equation:
冘 AD
where m or n are consecutive days of the study period, excluding the run-in period, is the last day of the study period, AD is the number of patients who presented their first antidepressant prescriptions on the index day, and is the average probability of an I 3 AD sequence for all days,
冘
is the total number of patients having incedent antidepressant fillings one or more days after incident isotretinoin prescription filling on index day m, and
冘 AD
⫽
⫽m⫹1
冘
⫽1
AD
⫽1
is the total number of patients having incident antidepressant fillings in the isotretinoin cohort study. The overall probability of an I 3 AD sequence, ␣, is calculated as the average for all days, weighted by the number of incident isotretinoin therapies on each day, as follows:
冋 冉
冘I
␣ ⫽
m⫽1
m
·
冘 AD
⫽m⫹1
冘 I · 冘 AD
冊册
m
m⫽1
m
m⫽1
where m or n are consecutive days of the study period, excluding the run-in period, is the last day of the study period, AD is the number of patients who presented their first antidepressant prescriptions on the index day m, I is the number of patients who presented their first prescriptions for isotretinoin on the index day. The null effect sequence ratio, rn, is then calculated as follows:
AD
⫽m⫹1
rn ⫽
␣ 1 ⫺ ␣
The adjusted rate ratio is then calculated by adjusting the crude sequence ratio by the null effect sequence ratio.
1