Several reports indicate an increase in the use of multiple psychotropic treatment regimens among children, (1,2) yet this practice lacks an evidence base. Estimates of multiple psychotropic prevalence range from 60% in a residential treatment center, (3) to 30% in children admitted to a 15-bed unit in Canada (4) and in children classified as seriously emotionally disturbed receiving care through a managed Medicaid waiver program (Kiser et al, personal communication), to 11% in university-affiliated outpatient clinics. (5) This trend has increased notably among youth since the introduction of selective serotonin renptake inhibitors (SSRIs). (2) On our unit at the University of Maryland School of Medicine. the most frequent combinations have included mood stabilizers with an antidepressant or antipsychotic (n = 11; 9.4%), an antidepressant with a stimulant (n = 11: 9.4%), a stimulant with clonidine (n = 8; 7.0%), and a mood stabilizer, an antidepressant, an antipsychotic, and clonidine (n = 6; 5.0%).
This trend has heightened public concern because, aside from stimulants, few controlled studies of the efficacy and/or safety of monotherapy in children and adolescents exist. The frequency with which youth are exposed to multipsychotropic regimens far outpaces the availability of scientific evidence regarding their safety and efficacy. Current prescribing practices are based either on extrapolation from adult research or clinical experience, (6) with little knowledge of dosing, tolerability, or drug interactions in children and adolescents. (7) A Special Interest Group held a professional discussion on these issues at the annual meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) in Miami in October 2003.
Regardless of practice setting, child and adolescent psychiatrists, as well as pediatricians, are faced increasingly with difficult clinical decisions regarding medication management of children with respect to multiple psychotropic medications. Use of multidrug regimens with children and adolescents is challenging from a variety of standpoints:
* Comorbidity and complex symptom presentations
* Developmental issues
* Multiple pressures on children from multiple settings such as at home, in school, and in the community
* Limited knowledge of dosing, tolerability, or drug interactions in children and adolescents, requiring extrapolation from adult research or clinical experience
* Discontinuities in treatment
* Lack of complete medication histories
Participants in the Special Interest Group discussed each of these topics and illustrated them with case examples.
The use of multidrug regimens with children often is associated with difficult-to-treat cases (failures of monotherapy) or complex cases presenting with higher numbers of diagnoses and higher levels of social dysfunction. Connor et al's study demonstrated that exposure to multiple medications was associated with a greater number of lifetime diagnoses, the total number of psychiatric placements, and admission to a residential care setting from an inpatient facility, (3) perhaps indications of case complexity. Child and adolescent clinicians face unique challenges sorting through diagnostic comorbidities and symptom complexities presented by their child and adolescent patients. Thus, children are often treated for target symptoms, and medication regimens maybe more indicative of psychosocial crises than definable psychopathology. There is pressure from (1) parents, (2) teachers, and (3) mental health clinicians to add medicines for crisis stabilization before optimizing present medications or eliminating those that are not beneficial.
Children function within multiple contexts (e.g., family, school, and peer settings) that influence their mood, behavior, and compliance with medications, as well as the observation and reporting of their symptoms and level of functional impairment. Consequently, assessment, diagnosis, and treatment of child and adolescent psychiatric illness are even more challenging than for adults. Multiple contexts also mean multiple demands on children to act/ react in socially desirable ways--and multiple pressures on prescribers to use medications to alter children's behaviors.
Dynamic and significant developmental growth between childhood and adolescence and the potential negative impact of psychotropic medication on normal developmental trajectories are further complicating factors. Changes in weight, height, body mass, brain development, and metabolic and immunologic functioning during a psychiatric illness's course add to the complexity of appropriate dosing and the patient's tolerance of psychotropic medication. (7-9)
The paucity of efficacy and safety data is accompanied by clinical concerns about the risks associated with multipsychotropic regimens for children and adolescents' This apprehension is associated with the uncertainty regarding an increased risk of side effects and/or adverse drug events. For example, Pataki and colleagues reported increased side effects (e.g., nausea, dry mouth, tremor) and a significant increase in ventricular heart rate among youth who received a combination of methylphenidate and desipramine. (10) Furthermore, fatalities of youths taking multiple psychotropics have been reported in the literature, (11-13) and serious questions have been raised about the suicide potential of many SSRIs in young people.
The child mental health service delivery system adds to the challenges. Within child mental health service delivery, fragmentation is a way of life, resulting in service duplication and gaps in service coordination. This translates into treatment broken into discrete segments based on the specific physician or program used, often meaning that during the course of an illness, children are treated in multiple settings and placed on medications by different providers with little coordination. Tracing this medication history backward to determine the indication and response to any specific agent becomes nearly impossible. This inability to develop an accurate medication life history makes understanding and managing multidrug regimens extremely difficult.
Physicians ultimately must weigh the benefits-to-risk ratio for each patient. Many providers, however, are uncertain about managing such patients; they might he uncertain about how to determine which medication, if any, should be discontinued, and they may he averse to assuming responsibility for management of complex regimens that they might not have initiated. This ultimately may result in ineffective treatment and children remaining more medications than necessary. (14) In such cases, risks to the children represent a balance between the unknown short-and long-term risks associated with exposure to multiple psychotropic medications with those of changing or discontinuing medications. Although medications can cause many troublesome side effects, the discontinuation of medicines can also cause difficulties for patients. Stopping a medicine may lead to decompensation of patients' present mental health and make them more vulnerable to illness relapse. Additionally, several medication types can cause withdrawal syndromes if stopped abruptly or tapered too quickly, such as SSRIs and atypical antipsychotics, as well as clonidine. A final consideration, particularly important in child psychiatry, is that the prescribing of any medication can have a strong psychological impact. Removing medications may cause considerable anxiety to patients and their families and may eliminate powerful placebo effects.
A STRATEGY FOR IMPROVEMENT
The increasing number of children taking multiple psychotropic medications creates a challenging situation for practitioners. Addressing these concerns involves: (1) developing strategies to aid clinicians in treatment optimization by assessing the appropriateness, benefits, and potential risks of complex psychotropic regimens, and (2) exploring methods for improving physician decision making. Development of a decision-assistance tool was described by the University of Maryland, Baltimore, faculty (of which the authors are members) during the Special Interest Group meeting at the AACAP conference.
The first task was to articulate our concerns within a conceptual framework. We chose to conceptualize multiple psychotropic medication by using the economic concept of decreasing marginal returns. (15) Certain medications within a therapeutic regimen contribute to a substantial proportion of the therapeutic response achieved, while others provide only marginal additional benefits with increased short- and long-term risks and additional resources consumed. In other words, as the number of medications increase, the marginal effects decrease. Within this framework it became clear that improving the management of multidrug regimens meant optimizing the regimen rather than simply reducing the number of medications that a child was exposed to.
By reviewing the literature on simultaneous use of multiple psychotropic medications in children (16-18) and existing models of clinical pharmacology and rational therapeutics, an approach to rational therapeutics promoted in the pharmacology literature was identified. (19) This approach includes assessment and definition of the presenting problem or circumstance, establishment of therapeutic goals, evaluation of patient factors that could alter dose or selection of treatment, and the development of parameters to monitor therapeutic and toxic effects.
First, we developed strategies for standardizing the assessment and definition of the presenting problem or circumstance and the establishment of therapeutic goals. This entailed development of tools to aid in the collection of admission information regarding diagnosis (current and life history of), development of the disorder(s), and medication history. We then employed a consultation model to address management of multidrug regimens, including evaluation of patient factors that could alter dose or selection of treatment, and the development of parameters to monitor therapeutic and toxic effects. In the consultation model, a consultation team trained in the use of the multidrug regimen drug assistance tool reviewed the child's history, current status, and multidrug regimen using the tool and developed a medication-management plan composed of a prioritized listing of recommended steps to optimize the regimen. This plan was communicated to the treating physician, who decided whether to implement the recommended changes in the child's medication regimen and remained medically responsible for the patient's care.
From the literature on rational versus irrational polypharmacy (more about which in a moment), a list of factors necessary for evaluating a multidrug regimen was constructed. Four essential factors emerged: indication, tolerability, adherence, and effectiveness. Thus, to better distinguish the relative merits and negative aspects of each medication, each agent within the regimen needs to be evaluated on: empirical evidence for indication/symptom, safety and/or tolerability concerns, adherence factors, and marked/moderate improvement in the patient's condition. Each indicator is assigned a weighted score, which is then summed to obtain a total score for each agent. The total score is an indication of the rationale for maintaining, adjusting, or discontinuing an agent in the multidrug regimen. The weighting system takes into account the benefit:risk ratio of the particular drug, with higher scores demonstrating a greater benefit relative to safety concerns. For example, a nine year old African American male on paroxetine, methylphenidate (Concerta), and clonidine would have each medication reviewed. If paroxetine received a total score of 7, methylphenidate 6, and clonidine-2,recommendations derived from the tool would include maintenance of the paroxetine and methylphenidate with a consideration/review of discontinuing clonidine. We are currently in the process of studying how much our new system has reduced our use of multiple psychotropic regimens.
THE UNCERTAIN STATE OF RESEARCH
As the preceding emphasizes, the frequency with which youth are exposed to multipsychotropic regimens far outpaces the availability of scientific evidence regarding their safety and efficacy. (7) Methods for closing this gap and for improving the standard of care are as yet not well defined. Clinically relevant work in this area to date has resulted in efforts to differentiate between the use of multiple psychotropic medications as 'justifiable' versus 'unjustifiable' or 'rational' versus 'irrational.' Kingsbury and colleagues further divide 'rational polypharmacy' by the extent of support from scientific studies. (20) The authors distinguish between validated (i.e., supported by double-blind clinical trials) and empirical (i.e., supported by case reports or theory) polypharmacy. Others postulate that irrational polypharmacy results from insufficient trials of monotherapy (e.g., inadequate dose, time frame, etc.), symptom-based prescribing, clinical encounter time constraints, managed care restrictions, and insufficient attention to psychosocial issues. (21-22) Based on a review of the literature, however, several clinical justifications for using multiple medication regimens exist. (18,21,23-25)
The Special Interest Group at the AACAP meeting in October 2003 concluded that significant work remains to be done to help clinicians deal with this complex issue, and finding tools to help the clinician make effective multidrug decisions is important.
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(3.) Connor DF, Ozbayrak KR, Kusiak KA, et al. Combined pharmacotherapy in children and adolescents in a residential treatment center. J Am Acad Child Adolesc Psychiatry 1997;36: 248-54.
(4.) Ahsanuddin KM, Ivey JA, Schlotzhauer D, et al. Psychotropic medication prescription patterns in 100 hospitalized children and adolescents. J Am Acad Child Psychiatry 1983;22:361-4.
(5.) Kaplan SL, Busner J. Prescribing practices of inpatient child psychiatrists under three auspices of care. J Child Adolesc Psychopharmacol 1997;7: 275-86.
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(7.) Jensen PS, Bhatara VS, Vitiello B, et al. Psycho-active medication prescribing practices for U.S. children: Gaps between research and clinical practice. J Am Acad Child Adolesc Psychiatry 1999;38:557-65.
(8.) Coyle JT. Psychotropic drug use in very young children, JAMA 2000;283:1059-60.
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(10.) Pataki CS, Carlson GA, Kelly KL, et al. Side effects of methylphenidate and desipramine alone and in combination in children. J Am Acad Child Adolesc Psychiatry 1993;32:1065-72.
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(13.) Sallee FR, De Vane CL, Ferrell RE. Fluoxetine-related death in a child with cytochrome p-450 2D6 genetic deficiency. J Child Adolesc Psychopharmacol 2000;10:27-34.
(14.) Rizzo JA. Physician uncertainty and the art of persuasion. Soc Sci Meal 1993;37:1451-9.
(15.) Feldstein PJ. Health Care Economics. 4th ed. Albany, N.Y.: Delmar Learning;1993.
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(19.) Nierenberg DW, Melmon KL. Introduction to clinical pharmacology and rational therapeutics. In: Carruthers SG, Hoffman BB, Melmon KL, Nierenberg DW, eds. Melmon and Morrelli's Clinical Pharmacology. 4th ed. New York: McGraw-Hill;2000:l-62.
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(23.) Nayak D. In defense of polypharmacy. Psychiatr Ann 1998;28:190-6.
(24.) Jacob KS. The use of multiple psychotropic medication in the treatment of mental disorders. Aust N Z J Psychiatry 1995;29:186-8; discussion 189.
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Pharmacologic treatments are rarely one-size-fits-all. Patients and their health conditions are far too individualized for that. Yet providers have struggled with the challenge of adapting drug regimens to the needs of different populations, including children. Adding to the difficulty, studies of psychiatric drugs' effects on children and adolescents are few and far between. This raises serious questions about whether these young mental health consumers are being treated effectively or even safely. In this installment of Behavioral Health Management's yearlong series on Pharmacologic Trends in Behavioral Health, David B. Pruitt, MD, and Laurel J. Kiser, PhD, MBA, of the University of Maryland School of Medicine, review pediatric multipsychotropic prescribing regimens used by many physicians and their organization's suggested response to them.
David B. Pruitt, MD, is Professor of Psychiatry/Pediatrics and Director of the Division of Child and Adolescent Psychiatry at the University of Maryland School of Medicine. Dr. Pruitt is a member of the University of Maryland, Baltimore, Workgroup on Multiple Psychotropic Medication Use in Children and the American Academy of Child and Adolescent Psychiatry, of which he is also a Past President.
Laurel J. Kiser, PhD, MBA, is Associate Professor in the Division of Services Research in the Department of Psychiatryat the University of Maryland School of Medicine. Dr. Kiser is also a member of the Workgroup.
For more information, write to Dr. Pruitt at 701 W. Pratt St., #422, Baltimore, MD 21201; phone (410) 328-3522; fax (410) 328-0202; or e-mail dpruitt@psych.umaryland.edu.
