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To examine patterns and recent trends in multi-class psychotropic treatment among youth visits to office-based physicians in the United States.
Annual data from the 1996–2007 National Ambulatory Medical Care Surveys were analyzed to examine patterns and trends in multi-class psychotropic treatment within a nationally representative sample of 3466 child and adolescent visits to office-based physicians in which a psychotropic medication was prescribed.
There was an increase in the percentage of child visits in which psychotropic medications were prescribed that included at least two psychotropic classes. Across the twelve year period, multi-class psychotropic treatment rose from 14.3% of child psychotropic visits (1996–1999) to 20.2% (2004–2007) (AOR: 1.89; 95% CI: 1.22–2.94, p<.01). Among medical visits in which a current mental disorder was diagnosed, the percentage with multi-class psychotropic treatment increased from 22.2% (1996–1999) to 32.2% (2004–2007) (AOR: 2.23, 95% CI: 1.42–3.52, p<.001). Over time, there were significant increases in multi-class psychotropic visits in which ADHD medications, antidepressants, or antipsychotics were prescribed, and a decrease in those visits in which mood stabilizers were prescribed. There were also specific increases in co-prescription of ADHD medications and antipsychotic medications (AOR: 6.22, 95% CI: 2.82–13.70, p<.001) and co-prescription of antidepressant and antipsychotic medications (AOR: 5.77, 95% CI: 2.88–11.60, p<.001).
Although little is known about the safety and efficacy of regimens that involve concomitant use of two or more psychotropic agents for children and adolescents, multi-class psychotropic pharmacy is becoming increasingly common in outpatient practice.
Psychotropic medications are recommended for the treatment of a range of child and adolescent mental disorders.1 In large-scale short-term placebo-controlled trials, 56% of youth diagnosed with attention-deficit/hyperactivity disorder (ADHD) and treated as outpatients responded to stimulant medication monotherapy,2 61% of depressed adolescents responded to antidepressant monotherapy,3,4 and 55% of youth with common anxiety disorders also responded to antidepressant monotherapy.5 Controlled trials have also evaluated antipsychotic medications for schizophrenia,6 and antipsychotics as well as mood stabilizers as monotherapies for bipolar disorder in youth.7–11 Efficacy of medication treatments in these trials has been less robust, and side effect concerns and drop out rates remain considerable.12
Community practice patterns reveal that a substantial proportion of child and adolescent mental health outpatients are treated with psychotropic medications.13–17 An estimated 85% of youth diagnosed with ADHD and treated as outpatients are prescribed stimulant medications,14 60% of youth outpatients with bipolar disorder are prescribed mood stabilizers,18 and 57% of depressed youth outpatients are treated with antidepressant medications.19
Little is known about the safety and efficacy of regimens that involve concomitant use of two or more psychotropic agents in the outpatient mental health care of children and adolescents.16 Research on this topic has been largely confined to uncontrolled, unblinded, or retrospective reports.20–29 Case reports,20–23 case series,24–26 and retrospective chart reviews,27–29 are limited in the extent to which they can systematically evaluate the safety, tolerability, and efficacy of these complex regimens. Much of the available research on complex regimens involving youth has focused on medication combinations from within the same broad class. For example, there is some empirical support for concomitant use of two mood stabilizers for pediatric bipolar disorder30 and augmentation of methylphenidate with the non-stimulant atomoxetine for youth with ADHD.31 The few controlled studies that have evaluated multi-class psychotropic treatment combinations in youth provide little evidence of improved outcomes over monotherapy regimens.32,33
Polypharmacy refers to the “administration of many drugs together” or “the administration of excessive medication.” 34 Whereas no specific number of concurrently prescribed medications can unequivocally define polypharmacy, in the present study we were interested in trends in the concurrent prescription of two or more psychotropic drugs from across medication classes. Despite a paucity of research evaluating the safety and efficacy of various forms of multi-class psychotropic treatment in youth, many children appear to be treated with multi-class psychotropic regimens.33 Estimates of multi-class treatment in child mental health care, which likely vary by treatment setting, range from 12% to 52% of those receiving at least one psychotropic medication.14,16,35–39 The most commonly reported combinations of multi-class psychotropic pharmacy appear to be co-prescription of a stimulant medication and an antidepressant medication,14,36,40 and co-prescription of an antidepressant and an antipsychotic medication.37 In some youth outpatient populations, there is evidence of increasing psychotropic polypharmacy.14,15,41,42 However, the breadth and extent of this trend remains poorly defined.
The present report examines recent national trends in multi-class youth psychotropic treatment in a large and representative sample of visits to office-based physicians across a twelve year period (1996–2007). Among visits in which a psychotropic medication was prescribed, we examine patterns of multi-class youth psychotropic pharmacy in relation to single-class psychotropic pharmacy by patient socio-demographic and clinical characteristics. We further examine time trends in multi-class psychotropic treatment overall and by medication class.
Data were drawn from 12 consecutive years of the US National Ambulatory Medical Care Survey (NAMCS; http://www.cdc.gov/nchs/ahcd/about_ahcd.htm) from 1996 to 2007. NAMCS is a multistage probability survey of visits to office-based physicians of all medical specialties engaged primarily in direct patient care. The survey response rate varied from 62.9% to 77.1% (median=67.7%). A systematic random sample of visits to each physician was drawn during a randomly selected 1-week period (N=317,416). We limited the sample to 27,979 child (ages 6–17) patient visits in which a physician was seen. The sample for most analyses was further limited to visits in which the child was prescribed at least one of five major psychotropic medication classes: ADHD medications, antidepressants, antipsychotics, mood stabilizers, and sedative-hypnotics (N=3,466 visits). Psychiatrists comprised 24.7% of the prescribing physicians in this sample, and contributed 50.3% (N=1,754) of all psychotropic visits.
For each visit, the physician or a member of the physician’s staff provided information about patient socio-demographic and clinical characteristics as well as psychotropic medications prescribed, supplied or administered at the visit.
NAMCS recorded all medications that were ordered, supplied, administered, or continued during each visit. Up to six medications were recorded in each visit in NAMCS 1996–2002. Starting in 2003, the maximum number of medications recorded was increased to eight. To make the years comparable, we limited the maximum number of medications to six in all years. ADHD medications included amphetamine, amphetamine/dextroamphetamine combination, atomoxetine, clonidine, dexmethylphenidate, dextroamphetamine, guanfacine, methylphenidate, and pemoline. We included clonidine and guanfacine as psychotropic medications only if the patient did not have hypertension. Antidepressants included amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine, protriptyline, selegiline, sertraline, tranylcypromine, trazodone, trimipramine, and venlafaxine. Antipsychotic medications included aripiprazole, chlorpromazine, clozapine, fluphenazine, haloperidol, loxapine, mesoridazine, molindone, olanzapine, perphenazine, pimozide, quetiapine, risperidone, thioridazine, thiothixene, trifluoperazine, triflupromazine, and ziprasidone. Prochlorperazine, promethazine, droperidol, and prochlorperazine, which are primarily used for non-psychiatric indications, were not included. Mood stabilizers included carbamazepine, lamotrigine, lithium and valproate/divalproex. We included anticonvulsants (carbamazepine, lamotrigine, valproate/divalproex) as psychotropic medications only if the patient did not have a seizure disorder diagnosis. Sedative-hypnotics included alprazolam, butabarbital, chloralhydrate, chlordiazepoxide, chlorazepate, clonazepam, diazepam, diphenhydramine, esczopiclone, estazolam, flurazepam, hydroxyzine, lorazepam, meprobamate, nitrazepam, oxazepam, phenobarbital, secobarbital, temazepam, triazolam, zaleplon, and zolpidem. We included phenobarbital as a psychotropic medication only if the patient did not have a seizure disorder diagnosis. Psychotropic visits were classified into single-class psychotropic pharmacy visits, in which the patient was prescribed psychotropic agent(s) from only one medication class (ADHD medications, antidepressants, antipsychotics, mood stabilizers and sedative-hypnotics), and multi-class psychotropic visits, in which the patient was prescribed two or more psychotropic agents from across different psychotropic medication classes.
Mental disorder diagnoses were recorded based on ICD-9-CM codes (290–319). Up to 3 diagnoses were recorded for each visit. Specific diagnoses were classified into 5 broad categories: (i) disruptive behavior disorders [ICD-9-CM: 312.0–312.2, 312.30–312.38, 312.4–312.9, 313.81, 313.89, 314.0, 314.2–314.9], (ii) mood disorders [ICD-9-CM: 296.0–296.9, 300.4, 301.13, 311], (iii) anxiety disorders [ICD-9-CM: 293.84, 300.0–300.02, 300.09, 300.2, 300.21–300.23, 300.29, 300.3, 300.7, 308.0–308.9, 309.21, 309.81, 312.39, 313.0, 313.21, 313.23], (iv) adjustment disorders [309.0–309.9, except 309.21, 309.81], and (v) pervasive developmental disorders (PDD), mental retardation (MR), and psychotic disorders [ICD-9-CM: 291.0–295.9, 297, 298.0–298.9, 299, 301.2–301.22, 314.1].
Primary source of payment was classified as private insurance, public insurance, self-pay or “other”.
Other variables used in multivariate analyses included patient’s age group (6–12 years vs. 13–17 years), sex, race-ethnicity (white vs. minority), number of mental disorder diagnoses (1 vs. ≥ 2 diagnoses), visit status (returning patient vs. new patient), and physician specialty (psychiatry and psychiatric subspecialties vs. all others).
Analyses were conducted in two stages. First, we compared the patterns and clinical correlates of multi-class psychotropic visits in relation to single-class psychotropic visits. Next we assessed time trends in multi-class psychotropic treatment for all medication groups and for individual medication groups adjusting for the effects of all demographic and clinical correlates associated with multi-class psychotropic visits at p<.10 (i.e., age group, race-ethnicity, diagnostic status, comorbidity, source of payment, and physician specialty).
All analyses were adjusted for visit weights, clustering, and stratification of data using design elements provided by the National Center for Health Statistics. When adjusted for these design elements, NAMCS data represent annual visits to office-based physicians in the United States.43,44 We examined time trends in the prescription of multi-class psychotropic treatment using multivariate binary logistic models. Survey year was transformed by subtracting 1996 from the year and dividing the results by 11. Thus the transformed value was 0 for the year 1996 and 1 for the year 2007. The odds ratios associated with this transformed variable of survey year represent a change in the odds of multi-class psychotropic visits during the entire study period from 1996 to 2007. Analyses were conducted using the STATA 10 software.45
Between 1996 and 2007, 8.8% (N=3,466) of 27,979 youth visits to U.S. office-based physicians were associated with prescription of a psychotropic medication from the 5 classes described above. A majority of these psychotropic visits (70.7%) were associated with a mental disorder diagnosis. Among psychotropic visits, the most common current diagnostic category carried was disruptive behavior disorders, which includes ADHD (49.2%); followed by mood disorders (21.5%); anxiety disorders (5.6%); PDD, MR, and psychotic disorders (4.0%); and adjustment disorders (3.2%). Psychotropic visits, relative to non-psychotropic visits, included a larger percentage of males (61.7% vs. 49.9%, respectively) [F(1,5260)=96.17, p<.001], youth aged 13–17 years (46.3% vs. 42.7) [F(1,5260)=7.35, p<.01], white children and adolescents (78.2% vs. 72.0%) [F(1,5260)=16.72, p<.001], youth with multiple mental disorder diagnosis (78.4% vs. 0.6%) [F(1,5260)=2497.44, p<.001], and returning patients (91.4% vs. 86.6%) [F(1,5260)=31.16, p<.001]. A majority of child psychotropic visits were provided by non-psychiatrist physicians (64.0%).
Across the twelve year period, 863 (19%) of the 3,466 of child psychotropic visits included multi-class psychotropic treatment. Table 1 presents patterns and clinical correlates of multi-class psychotropic visits in relation to single-class psychotropic treatment. Distributions for multi-class psychotropic visits significantly differed from single-class visits with regard to age group, mental disorder diagnosis, comorbidity, source of payment, and physician specialty. As compared to single-class psychotropic visits, multi-class psychotropic visits were associated with older patient age, mental disorder diagnoses, multiple mental disorder diagnoses, and public insurance payment. Whereas mood disorders were diagnosed in less than 1 in 6 single-class psychotropic visits, almost half of multi-class psychotropic visits included a mood disorder diagnosis. The percentages of anxiety disorders; adjustment disorders; and PDD, MR, and psychotic disorder diagnoses were roughly three to four times higher among multi-class than single-class psychotropic visits. While most of single-class psychotropic visits were provided by non-psychiatrist physicians, most of the multi-class psychotropic visits were provided by psychiatrists.
Antidepressants were the most common co-prescribed medication class in multi-class visits followed by ADHD medications, antipsychotics, mood stabilizers, and sedative-hypnotics (Table 2). The percentage of pairwise multi-class medication combinations ranged from ADHD medications and antidepressants (7.3% of psychotropic visists) to antipsychotics and sedative-hypnotics (0.6%). Only 34.6% of visits in which ADHD medications were co-prescribed with antidepressants (the most frequent pairwise between-class combination), indicated the presence of both a disruptive behavior disorder and a mood or anxiety disorder.
Between 1996–1999 and 2004–2007, there was an approximately 75% increase in the proportion of child and adolescent visits that mentioned a psychotropic medication (from 6.0% in 1996–1999 to 10.6% in 2004–2007). During this period, there was also a significant increase in the percentage of child psychotropic medication visits that included at least two psychotropic classes (Table 3). Across the twelve year period multi-class psychotropic visits rose from 14.3% (1996–1999) to 20.2% (2004–2007) of youth visits including a psychotropic medication. Among psychotropic visits with mental disorder diagnoses, the percentage with multi-class psychotropic visits increased from 22.2% (1996–1999) to 32.2% (2004–2007) (AOR: 2.23, 95% CI: 1.42–3.52, p<.001). Moreover, there were significant increases in multi-class psychotropic visits in which ADHD medications, antidepressants, or antipsychotics were prescribed, and a decrease in visits in which mood stabilizers were prescribed (see Figure 1, details in Table 3). Across this twelve year period, there was not a significant increase in comorbid mental disorder diagnoses among psychotropic visits: 16.5% (1996–1999) and 20.1% (2004–2007) (OR: 1.13, 95% CI: 0.71–1.79, p=0.61).
Risperidone, bupropion, and methylphenidate were, respectively, the most commonly prescribed antipsychotic, antidepressant, and ADHD medications in multi-class psychotropic visits in 2004–2007 (20.1%, 13.2%, and 28.3% of multi-class visits, respectively). Risperidone was prescribed in 36.0% of multi-class psychotropic visits involving an antipsychotic medication (82 of 225 such visits), bupropion was prescribed in 19.0% of multi-class psychotropic visits involving an antidepressant medication (44 of 254 such visits), and methyphenidate was prescribed in 46.8% of multi-class psychotropic visits involving an ADHD medication (121 of 246 such visits). In addition, multi-class psychotropic prescribing occurred in 61.5% of all youth visits in which risperidone was prescribed (82 of 130 such visits), in 57.7% of all visits in which bupropion was prescribed (44 of 84 such visits), and in 19.7% of all visits in which methylphenidate was prescribed (121 of 411 such visits) (data not shown). The visits involving concomitant use of medications in years 2004–2007 were not limited to a small group of physicians—the 254 visits involving concomitant prescription of antidepressants and other psychotropic medications came from 131 unique physician practices. Similarly, the 246 visits involving concomitant prescription of ADHD medications and other psychotropic medications came from 115 unique practices, and the 225 visits involving concomitant prescription of antipsychotics with other psychotropic medications came from 92 unique practices. Overall, of the 518 unique physician practices conducting the 1,483 psychotropic visits involving children and adolescents between 2004–2007, 156 practices (30.1%) reported multi-class psychotropic visits. The proportion of physicians prescribing medications from different groups concomitantly was greater among psychiatrists than other physicians. Of 119 unique psychiatrists prescribing psychotropic medications between 2004–2007, 93 (78.2%) prescribed medications from different groups concomitantly; whereas only 63 (15.8%) of the 399 unique non-psychiatrists physicians prescribing psychotropic medications in this period prescribed medication from different groups concomitantly.
Over time, there were specific increases in the co-prescription of ADHD and antipsychotic medications (AOR=6.22, 95% CI=2.82–13.70, p<.0001) and the co-prescription of antidepressant and antipsychotic medications (AOR=5.77, 95% CI=2.88–11.60, p<.0001). The other eight possible pairwise multi-class combinations remained stable across time (data not shown).
The findings of this study should be interpreted in the context of several limitations. First, despite adjustment for several visit and patient characteristics, including diagnosis, insurance and physician speciality, we cannot exclude the possibility that the trends reflect residual confounding due to unmeasured differences among patient groups across survey years. Second, it is also not possible to determine previous clinical response to single-class psychotropic regimens or measure the effects of multi-class psychotropic pharmacy on clinical outcomes. It is also possible that some of the multi-class psychotropic treatment represents cross-tapering as part of psychotropic switching. Third, the survey underestimates the number of psychotropic medications used by patients who may be receiving mental health care from more than one physician. NAMCS does not provide population prevalence estimates but prevalence estimates of diagnoses and treatments in a representative sample of visits to office-based physicians. Fourth, because the surveys are limited to office-based practices, the results do not generalize to other treatment settings where children may receive mental health care. Fifth, limited numbers of visits preclude multi-class treatment estimates for specific diagnostic groups such as distinguishing bipolar disorder from major depressive disorder, or smaller demographic groups such as racial-ethnic minorities, as well as polypharmacy trends stratified by physician specialty. Sixth, diagnostic determinations may vary over time with changing practice patterns. Without structured diagnostic interviews, it is not possible to examine these variations. Moreover, roughly 29% of psychotropic visits were not associated with a mental disorder diagnosis. The extent to which this may have been due to underdiagnosis, failure to document diagnosed mental disorders, or non-psychiatric targets is not clear. Finally, because NAMCS records visits rather than patients, some patient duplication may occur during the 1-week sampling period. Despite these limitations, the NAMCS offers a rare national statistical portrait of multi-class psychotropic treatment trends in youth office-based medical practice.
In recent years, multi-class psychotropic treatment has become increasingly common in the office-based medical care of American children and adolescents. During the study period, the proportion of outpatient medical visits in which psychotropic medications from two or more medication classes were prescribed to children increased from one in seven visits to one in five visits. This finding extends earlier reports of increasing overall psychotropic medication treatment of children and adolescents,13–15,18 and increasing psychotropic co-prescribing.35–38,40 The results also parallel the broader literature documenting increased psychotropic co-prescribing trends in adult medical care.46–50
While it is reassuring that youth multi-class psychotropic pharmacy is concentrated among treatment provided by psychiatrists and patients with indications of more complex psychopathology, the safety and effectiveness of these regimens in youth remain poorly characterized. Despite advances in our understanding of the short-term efficacy and safety of many classes of psychotropic medications as monotherapies for youth,2–5 there are currently few controlled evaluations of multi-class psychotropic treatment regimens in this age group. Relevant research is largely limited to small or retrospective studies21,23,25–27 and these studies have yielded mixed findings regarding safety and tolerability of these regimens.
Given the frequency and increasing prevalence of multi-class psychotropic treatment in children, there is a pressing need for clinical trials to evaluate the safety and efficacy of these complex combinations. Between 1996 and 2007, antidepressant and ADHD medication combinations were the most prevalent multi-class psychotropic regimen. Accordingly, this regimen appears to be a promising candidate for controlled evaluations.
The use of antipsychotic medications in conjunction with other classes of psychotropic medication in children also appears to be on the rise. One published controlled trial evaluating the combined use of antipsychotic and stimulant medications in youth did not find that this combination offered improved clinical outcomes over psychotropic monotherapy options.32 To date no prospective clinical trials have evaluated use of second generation antipsychotoics in conjunction with other psychotropic medication classes in youth. Several antipsychotics used as monotherapies have FDA approved indications in children and adolescents. However, evaluations of these medications used as monotherapies in child populations have produced somewhat mixed efficacy findings and adverse metabolic effects of second-generation antipsychotic medications appear to pose a particular challenge.51–55
Several possible factors may have contributed to the recent increase in multi-class psychotropic treatment in children’s outpatient care. First, greater patient, parent, or physician emphasis on symptom reduction with diminishing concern regarding polypharmacy may have contributed to the trend.56 Second, an increasing number of psychiatrists are specializing in pharmacotherapy, to the exclusion of psychosocial treatments.57 Limitations in the availability and accessibility of psychosocial interventions may place heavy clinical demands on the pharmacological dimensions of child and adolescent mental health care. Third, some physicians may generalize to children and adolescents psychotropic prescribing practices that have been evaluated in adult populations.58–60 Fourth, changes in patient characteristics, including increasing severity of illnesses or comorbidities61–63 might play a role in the trend toward multi-class treatment, though the overall trend in our study persisted after adjusting for psychiatric diagnosis and comorbidity. Finally, the availability of new psychotropic medications during the study period and the presumably large number of patients who exhibit only partial symptomatic responses to monotherapy likely contributed to the increased use of complex pharmacological regimens.
While the contributions of the above factors to the observed trends in multi-class psychotropic treatment remain to be elucidated in future research, a number of physician training programs, quality improvement initiatives, and explicit criteria have been developed in an effort to restrain the growth of polypharmacy in mental health care.46,49,64–66 Yet despite these efforts, the overall rate of multi-class psychotropic treatment in child outpatient practice has increased significantly in recent years. The increasing share of mental health care costs attributable to pharmaceutical expenditures that accompanies this practice risks increasing administrative mandates and coverage restrictions by third party payors.67 To guide optimal medication management, a new generation of research is needed to identify the clinical circumstances in which psychotropic regimens with multiple classes yield outcomes that are superior to optimized single class regimens.
This work was supported by AHRQ U18 HS016097 and NIH T32 MH016434.
The authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Disclosure: Dr. Olfson, in the past five years, has received investigator initiated grants from AstraZeneca, Bristol-Myers Squibb, and Eli Lilly and Co. He has served on the speakers’ bureau for Janssen Pharmaceutica, and as a consultant to Pfizer, AstraZeneca, Eli Lilly and Co., and Bristol-Myers Squibb. Dr. Mojtabai has received research funding and consulting fees from Bristol-Myers Squibb. Dr. Comer reports no biomedical financial interests or potential conflicts of interest.
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Dr. Jonathan S. Comer, College of Physicians and Surgeons, Columbia University and the New York State Psychiatric Institute, New York, New York.
Dr. Mark Olfson, College of Physicians and Surgeons, Columbia University and the New York State Psychiatric Institute, New York, New York.
Dr. Ramin Mojtabai, Bloomberg School of Public Health and Johns Hopkins University, Baltimore, Maryland.