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The efficacy of stimulant drugs such as methylphenidate (MPH) and dextroamphetamine in reducing symptoms and normalizing function in children with attention-deficit hyperactivity disorder (ADHD) has been convincingly established (1). Between 70% and 80% of affected children show a positive response to the first drug tried, and up to 90% show a positive response if an alternative stimulant is used (2); however, ongoing benefit requires ongoing treatment (3). Remission of ADHD has been reported to occur in 20% to 30% of diagnosed children over periods of 2 to 3 years (4,5), while follow-up studies ranging across 3 to 8 years have found persistence of ADHD diagnosis and ADHD-related problems in between 40% and 80% of cases (5–10). Since stimulant drugs are therefore an effective treatment for a chronic disorder, we might expect that most children who are medically treated for ADHD remain on therapy more or less continuously for years. However, it is impossible to discern from the existing literature whether this is true. Estimates of children’s persistence with stimulant therapy vary: one study found that only about one-half of a cohort of children who commenced MPH therapy were still taking MPH 10 months after commencement (11), while another study showed an average length of 7 to 8 years on stimulants (12). Differences in study settings and measures of persistence make it difficult to draw general conclusions, and it is often unclear how investigators have dealt with periods of time off therapy, which appear to occur quite frequently (13), when calculating overall duration of active therapy. To address these issues, we examined persistence with MPH therapy in a population-based cohort of children and youth aged under 19 years at the time of their first prescription. We conducted the study over a 7-year period in the 1990s, using multiple measures of persistence and pre- determined strategies for dealing with discontinuities and potential censoring effects. At the time of the study, approximately 85% of stimulant prescriptions in British Columbia were for MPH (personal communication, D Rhodes, IMS Health, 2002), which is similar to data reported from the US (14). We describe persistence with and continuity of therapy in terms of overall duration, number of prescriptions received, occurrence of multiple bouts of therapy, and duration of such bouts. Further, we examine factors that might influence persistence with MPH therapy, specifically, age and sex of patients and the specialty type of the physician providing the initial prescription. MethodsStudy Design and Setting Data Sources The British Columbia Linked Health Dataset (BCLHD) is a repository of administrative health records that are part of the provincial medicare program. The BCLHD is linked for individual residents of the province across files that cover basic demographic information, physician contacts, hospital separations, and vital events (15). We accessed BCLHD data for background demographic characteristics of patients and information on the prescriber’s specialty type. Overall Study Population and Subsidiary Cohorts MeasuresPersistence With Therapy The number of prescriptions received is a count of the total number of prescriptions of MPH dispensed to a child during the study period. Continuity of Therapy We calculated the duration of discrete bouts of active therapy as days from the first prescription to the last before a gap of 4 months or longer with no prescription-filling activity. For example, if prescriptions for MPH were dispensed to a patient in January, April, July, October, and December of one year, the duration of therapy would be about 11 months. Conversely, if prescriptions were received in January, April, October, and December, approximately 2 bouts of 3 months and 2 months, respectively, would be recorded. Chronicity of Therapy Designation Data Organization, Management, and Analysis In our large data set, some cases were excluded because of missing data; others were excluded because the available data appeared to represent highly exceptional situations, and we were unable to verify their accuracy. Instances of missing data, such as unknown patient sex, involved less than 1% of study cases and are not explicitly mentioned in the text. Two outlier situations recognized in our data set were very short intervals (that is, under 7 days) between successive prescriptions and apparent prescription of very high dosages of MPH (>100 mg daily). These cases collectively accounted for about 2.5% of our database cases, and their exclusion is specifically indicated in the text. We present our data mainly as descriptive statistics. In comparing persistence among various groups of patients, we elected not to perform tests of statistical significance for 2 reasons. First, statistical inference is used to estimate population parameters from values obtained from sampling that population. The values we report are derived from the entire population; thus it would be inappropriate to apply inferential techniques. Second, tests of statistical probability may appear hugely significant when performed with the large number of cases employed in population-level research, and for this reason, results may be misinterpreted and misleading. ResultsDescription of Population and Subsidiary Cohorts From this overall population, we worked primarily with data from 16 945 patients whose first recorded prescription of MPH was after the first 4 months of the study window. The restricted data set used for analyses involving prescriber specialty type comprised 13 289 patients. Persistence and Continuity With Therapy  *Excludes children with single prescription only Figure 2 depicts the distribution of the number of prescriptions to children over the 7-year study period. There is considerable skewing toward children receiving relatively few prescriptions (that is, 5 or fewer), but about one-fifth of patients received prescriptions over a longer term. The mean (SD) number of prescriptions received during the study period was 6.6 (7.9).  With respect to the number and continuity of prescriptions, one-third of all patients (33%) were categorized as short-term and about one-fifth (18%) as chronic. The remaining 49% fell into the intermediate group. Influences on Persistence With Therapy   Finally, the specialty type of the physician who provided the child’s initial prescription for MPH was related to persistence on 2 measures. The mean (SD) number of prescriptions received by children whose initial prescription was from a psychiatrist was 7.9 (9.6), compared with 5.4 (5.5) and 6.3 (8.1) for first prescriptions from pediatricians, GPs, and FPs, respectively. Also, patients were more likely to be classified as chronic than short-term if their initial prescription was written by a psychiatrist rather than a pediatrician, GP, or FP (odds ratio 1.77; 95%CI, 1.55 to 2.02) (Table 1).
DiscussionThis study shows the average therapy duration was 19 months, with a total receipt of fewer than 7 prescriptions in a 7-year period, indicating a lower degree of persistence with MPH therapy than usually reported. Various studies have found persistence to be at least 2 years in over 80% of children (17), with up to 4 years in 77% of boys and 50% of girls (18) and an average persistence of 3 years (9). The present study reports on persistence with MPH among children in a general population setting. The other studies are based on observations of cohorts that have been carefully selected, closely monitored, and intensively supported by clinicians or researchers. They only report the course of the subset of patients who were found to be positive responders to stimulant drugs, or they describe persistence with stimulants in general, not just MPH (9,18). Two community-based surveys that found an average length of time on stimulants to be 50 months (19) and patient age to be between 7 and 9 years (12), respectively, based their estimates on data from children who were actively on medication at the time of the survey. This would exclude a substantial number of stimulant-prescribed patients who might have taken medication for a shorter time period had they not discontinued treatment. Studies involving the general population typically find lower rates of persistence than do studies from other settings, though variability is found even within the small group of population-based studies that exist. In contrast to our present findings, a study from Long Island county found that about 73% of children received just 1 or 2 prescriptions over a 1-year follow-up period (20), while in a prescription database study from the Netherlands, 50% of children had discontinued stimulant medications between 10 and 20 months after commencement (21). The Long Island study was conducted in 1986, while the present study and the Netherlands study were conducted in the 1990s. The possibility that period or era effects may explain these differences is supported by the fact that rates of persistence in the Netherlands were found to be higher later in the decade (21). This interpretation raises the question of whether contemporary patients are better educated, better prepared, or better supported by their physicians than those in the past. Our estimates of overall persistence might have been somewhat lower had we been able to exclude periods when a patient might have discontinued (rather than temporarily interrupted) his or her course of therapy. Continuity of MPH therapy has not received much research attention, though discontinuation followed by resumption of therapy was reported by parents to have occurred at least once in 40% of children during a 3-year follow-up study (13), a figure close to the 33% of children found to experience more than 1 bout of therapy in our 7-year study. Our finding that about one-third of subjects had more than 2 bouts of therapy shows that multiple discontinuities are not a rare occurrence among children on MPH in the general population. Our definition of discontinuation of therapy, namely, a 4-month period with no prescription filling activity, should have ensured that temporary but planned interruptions in a course of therapy, such as school vacation or a medication-free trial period, were not counted as discontinuations in therapy. It is not clear why patients should stop and restart medication during the course of treatment for a chronic condition. The frequency and brevity of discrete therapy bouts, averaging 6 to 7 months in this study, is a cause for some concern, because patients do not receive therapeutic benefit while off medication. It is possible that some of our subjects were incorrectly classified as having broken off active therapy when they had not. Some investigators have deemed a total of 14 weeks off medication in a year to indicate discontinuation (13), while others have taken 180 consecutive days without prescription activity as the threshold level (21). Employing a shorter period of time increases the risk of misclassifying patients as having terminated therapy when they have not, whereas the use of longer periods tends to miss those that did indeed stop medication therapy only to resume it later. Future research into how patients persist with stimulants and other drugs would be facilitated through some consensus on the definition of discontinuity. An important contribution of the present study is the clear illustration that variability is an integral characteristic of persistence at the population level. Our chronicity of therapy measure, which incorporates 3 key dimensions of persistence, namely, duration, continuity, and number of prescriptions, provides a convenient and useful way to define sub- populations of patients taking medication. A substantial proportion of patients (one-third of the total) appear not to persist with MPH, while another one-fifth show high persistence and continuity. The remaining one-half of all children receiving a prescription show intermediate degrees of persistence. The size of the short-term group in this study (that is, 33%) is consistent with a recent report from the US that about one-third of patients taking stimulants received only 1 or 2 prescriptions over a 1-year period (22); this is not out of keeping with expectations based on the proportion of children who fail to tolerate or respond to MPH (3). Conversely, a larger proportion of short-term cases would have raised concerns. The landmark Multimodal Treatment Study of ADHD showed that high degrees of persistence are possible with careful patient selection, drug titration, and follow-up (23). We suggest that the chronicity of therapy measure employed in the present study be considered a potentially useful indicator of the quality of medical care received by children and families in various settings, with a large proportion of short-term cases flagging possible shortcomings with patient selection, education, monitoring, or support. The design of this study allowed us to examine a limited number of factors associated with persistence with therapy, and it was interesting to find fairly consistent age and sex effects across some measures. Findings of lower persistence among older children (that is, aged over 10 years) and youth are consistent with clinical experience and reports of poorer compliance among teenagers (24), though little has been published on this topic in relation to compliance with stimulant drugs (25). Lower persistence among girls has also been reported (11,13,18). The present findings therefore corroborate existing evidence and illustrate a further dimension of the problem of undertreatment and inadequate treatment of girls with ADHD (26). Our findings of persistence in relation to physician factors are intriguing–a higher degree of persistence is associated with MPH therapy initiated by a psychiatrist. This could be attributed to differences in the way that different physician specialties manage children with ADHD (27), which is consistent with the notion that persistence may be related to aspects of clinical care provided. However, differences in the case mix among psychiatrists, pediatricians, and family practitioners may also be responsible. Several study limitations need to be acknowledged. First, we derived our findings from analyses of administrative data, which are not primarily designed to address research questions and whose validity can be questioned (28). While there has been no comprehensive evaluation of the completeness and accuracy of British Columbia’s Triplicate Prescription Program database, the legal requirement to report all prescriptions of MPH suggests that coverage of all cases would be close to complete. Also, the data captured are concrete, with no margin for ambiguities regarding coding of diagnoses and treatment, which can affect database analytic studies (29). Second, our study was restricted to persistence with MPH therapy so that findings should not be construed as describing persistence with psychostimulants as a general class of medications. This aspect of our study design limits, but does not preclude, comparisons with studies describing persistence with all psychostimulants (9,12,13,18,19,21). As previously mentioned, MPH was certainly the main medication prescribed to children at the time of this study. In addition, recently acquired provincial prescription data suggest that, during the years 1996 and 1997, only about 7% of all stimulant patients received a prescription for more than one stimulant type (unpublished data). Switching from MPH to another stimulant would therefore have been an infrequent occurrence, with limited impact on overall persistence patterns. A third limitation is that a wider range of medications for treating children with ADHD has recently become available to Canadian physicians. Future research will have to examine the possible effects of newer once daily prescriptions on patients’ patterns of persistence. Finally, because our findings are derived from records of the British Columbia population, there may be some limitations in generalizing these results to other provinces or health care systems. Certain implications of our findings for medical practice, health policy, and research have already been mentioned, including the possibility of using persistence with therapy as a potentially useful, albeit indirect, indicator of the quality of care provided by physicians to patients with ADHD in community settings. The large group categorized as intermediate with respect to chronicity of therapy also requires further investigation. It is likely that the 20% to 30% of patients who are said to no longer require medications after 1 or 2 years of therapy (3–5) are found within this intermediate group. It would be helpful, however, to have additional information on the characteristics of patients and practitioners in this large group and to study the effects of interventions aimed at modifying persistence patterns within it. All the following are worthy of investigation as factors influencing persistence with stimulant medications: 1) type and severity of ADHD, presence of comorbid conditions, and child’s attitude toward medication; 2) physician’s specialty type and approach to assessment, patient and (or) parent’s education, and management (that is, titration and follow-up visits) on the part of the physician initiating stimulant medication; 3) family stress and parent’s attitudes toward medication; and 4) teacher and school attitudes. Apart from quality of care issues, our findings represent a benchmark for researchers who need to know whether a cohort they are following is representative of the general population in terms of persistence. In addition, the methodology used here can serve as a model for studying persistence with other chronic medication regimes. Finally, knowledge of how children in the general population persist with stimulant therapy is important in the face of expressed concerns about long-term effectiveness and safety of ADHD medications (30). Widespread failure to take medication properly and persistently has been suggested as a possible explanation for lack of evidence of long-term effectiveness of medication therapy (31). This study supports the legitimacy of that claim and underlines the need to improve understanding of nonadherence and of measures aimed at improving adherence, especially among girls. At the same time, the low prevalence of long-term users observed in our study allows us to conclude that relatively few children, perhaps only one-fifth of those exposed to stimulation medications, would be at potential risk were long-term adverse effects ever identified. Funding and SupportThis research was supported by a grant from the British Columbia Health Research Foundation (grant 212-95-1) and by an investigator award from the Sunny Hill Foundation for Children. AcknowledgementsWe are grateful to Harold Yip for his persistence in data analysis. References1. American Academy of Pediatrics, Committee on Quality Improvement. Clinical practice guideline: treatment of the school-aged child with attention-deficit/hyperactivity disorder. Pediatrics 2001;108:1033–44. 2. Elia J. Drug treatment for hyperactive children. Therapeutic guidelines. Drugs 1993;46:863–71. 3. DuPaul GJ, Barkley RA, Connor DF. Stimulants. In: Barkley RA, editor. Attention-deficit hyperactivity disorder: a handbook for diagnosis and treatment. New York: Guilford Press; 1998. 4. Sleator EK, Von Neumann A, Sprague RL. Hyperactive children. A continuous long-term placebo-controlled follow-up. JAMA 1974;229:316–7. 5. Lambert NM, Hartsough CS, Sassone D, Sandoval J. Persistence of hyperactivity symptoms from childhood to adolescence and associated outcomes. Am J Orthopsychiatry 1987;57:22–32. 6. Cohen P, Cohen J, Brook J. An epidemiological study of disorders in late childhood and adolescence: II. Persistence of disorders. J Child Psychol Psychiatry 1993;34:869–77. 7. Mannuzza S, Klein RG, Bonagura N, Malloy P, Giampino TL, Addalli KA. Hyperactive boys almost grown up: V. Replication of psychiatric status. Arch Gen Psychiatry 1991;48:77–83. 8. Biederman J, Faraone S, Milberger S, Curtis S, Chen L, Marrs A, and others. Predictors of persistence and remission of ADHD into adolescence: results from a four-year prospective follow-up study. J Am Acad Child Adolesc Psychiatry 1996;35:343–51. 9. Barkley RA, Fischer M, Edelbrock CS, Smallish L. The adolescent outcome of hyperactive children diagnosed by research criteria: I. An 8-year prospective follow-up study. J Am Acad Child Adolesc Psychiatry 1990;29:546–57. 10. Goodman R, Ford T, Meltzer H. Mental health problems of children in the community: 18 month follow up. BMJ 2002;324:1496–7. 11. Firestone P. Factors associated with children’s adherence to stimulant medication. Am J Orthopsychiatry 1982;52:447–57. 12. Safer DJ, Krager JM. The increased rate of stimulant treatment for hyperactive/inattentive students in secondary schools. Pediatrics 1994;94:462–4. 13. Thiruchelvam D, Charach A, Schachar RJ. Moderators and mediators of long-term adherence to stimulant treatment in children with ADHD. J Am Acad Child Adolesc Psychiatry 2001;40:922–8. 14. Safer DJ, Zito JM. Pharmacoepidemiology of methylphenidate and other stimulants for the treatment of attention deficit hyperactivity disorder. In: Greenhill LL, Osman BB, editors. Ritalin: theory and practice. New York: Mary Anne Liebert; 2000; p 7–26. 15. Chamberlayne R, Green B, Barer ML, Hertzman C, Lawrence WJ, Sheps SB. Creating a population-based linked health database: a new resource for health services research. Can J Public Health 1998;89:270–3. 16. Miller AR, Lalonde CE, McGrail KM, Armstrong RW. Prescription of methylphenidate to children and youth, 1990 1996. CMAJ 2001;165:1489–94. 17. McBride MC. An individual double-blind crossover trial for assessing methylphenidate response in children with attention deficit disorder. J Pediatr 1988;113:137–45. 18. Eichlseder W. Ten years of experience with 1,000 hyperactive children in a private practice. Pediatrics 1985;76:176–84. 19. Angold A, Erkanli A, Egger HL, Costello EJ. Stimulant treatment for children: a community perspective. J Am Acad Child Adolesc Psychiatry 2000;39:975–84. 20. Sherman M, Hertzig ME. Prescribing practices of Ritalin: The Suffolk County, New York study. In: Greenhill LL, Osman BB, editors. Ritalin: theory and patient management. New York: Mary Ann Liebert; 1991. p 187–93. 21. Schirm E, Tobi H, Zito JM, de Jong-van den Berg LT. Psychotropic medication in children: a study from the Netherlands. Pediatrics 2001;108:E25. 22. Shatin D, Drinkard CR. Ambulatory use of psychotropics by employer-insured children and adolescents in a national managed care organization. Ambul Pediatr 2002;2:111–9. 23. MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 1999;56:1073–86. 24. Johnson SB. Chronic diseases of childhood: assessing compliance with complex medical regimes. In: Krasnegor NA, Epstein L, Johnson SB, Yaffe SJ, editors. Developmental aspects of health compliance behavior. Hillsdale (NJ): Lawrence Erlbaum Assoc; 1993. p 177–9. 25. Swanson J. Compliance with stimulants for attention-deficit/hyperactivity disorder: issues and approaches for improvement. CNS Drugs 2003;17:117–31. 26. Biederman J, Faraone SV, Mick E, Williamson S, Wilens TE, Spencer TJ, and others. Clinical correlates of ADHD in females: findings from a large group of girls ascertained from pediatric and psychiatric referral sources. J Am Acad Child Adolesc Psychiatry 1999;38:966–75. 27. Miller A. Appropriateness of psychostimulant prescription to children: theoretical and empirical perspectives. Can J Psychiatry 1999;44:1017–24. 28. Iezzoni LI. Assessing quality using administrative data. Ann Intern Med 1997;127:666–74. 29. Roos LL, Roos NP, Cageorge SM, Nicol JP. How good are the data? Reliability of one health care data bank. Med Care 1982;20:266–76. 30. Schachter HM, Pham B, King J, Langford S, Moher D. How efficacious and safe is short-acting methylphenidate for the treatment of attention-deficit disorder in children and adolescents? A meta-analysis. CMAJ 2001;165:1475–88. 31. Brown RT, Borden KA, Wynne ME, Spunt AL, Clingerman SR. Compliance with pharmacological and cognitive treatments for attention deficit disorder. J Am Acad Child Adolesc Psychiatry 1987;26:521–6. Author(s)Manuscript received October 2003, revised, and accepted February 2004. 1. Faculty, Centre for Community Child Health Research, BC Research Institute for Children’s and Women’s Health, Children’s and Women’s Health Centre of British Columbia, Vancouver, British Columbia; Clinical Associate Professor, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia. 2. Associate Professor, Department of Psychology, University of Victoria, Victoria, British Columbia. 3. Research Associate, Centre for Health Services and Policy Research, University of British Columbia, Vancouver, British Columbia. Address for correspondence: Dr AR Miller, Room L 408, Centre for Community Child Health Research, Children’s and Women’s Health Centre of British Columbia, 4480 Oak Street, Vancouver, BC, V6H 3V4 e-mail: amiller@cw.bc.ca
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