psychopharm for very young children context and guidelines

Copyright @ 2007 American Academy of Child and Adolescent Psychiatry. Unauthorized reproduction of this article is prohibited.

Psychopharmacological Treatment for Very YoungChildren: Contexts and Guidelines

MARY MARGARET GLEASON, M.D., HELEN LINK EGGER, M.D., GRAHAM J. EMSLIE, M.D.,

LAURENCE L. GREENHILL, M.D., ROBERT A. KOWATCH, M.D.,

ALICIA F. LIEBERMAN, PH.D., JOAN L. LUBY, M.D., JUDITH OWENS, M.D.,

LAWRENCE D. SCAHILL, M.S.N., PH.D., MICHAEL S. SCHEERINGA, M.D., M.P.H.,

BRIAN STAFFORD, M.D., M.P.H, BRIAN WISE, M.D., M.P.H., AND CHARLES H. ZEANAH, M.D.

ABSTRACT

Systematic research and practice guidelines addressing preschool psychopharmacological treatment in very young

children are limited, despite evidence of increasing clinical use of medications in this population. The Preschool

Psychopharmacology Working Group (PPWG) was developed to review existing literature relevant to preschool

psychopharmacology treatment and to develop treatment recommendations to guide clinicians considering psychophar-

macological treatment in very young children. This article reviews the developmental considerations related to preschool

psychopharmacological treatment, presents current evidence bases for specific disorders in early childhood, and

describes the recommended algorithms for medication use. The purpose of this effort is to promote responsible treatment

of young children, recognizing that this will sometimes involve the use of medications. J. Am. Acad. Child Adolesc.

Psychiatry, 2007;46(12):1532Y1572. Key Words: preschool, treatment, psychopharmacology.

In 2000 the American Academy of Child andAdolescent Psychiatry_s Research Forum highlightedthe developmental, logistical, and ethical challenges

related to preschool psychopharmacological research(Greenhill et al., 2003). The group recommended thedevelopment of guidelines for the pharmacologicaltreatment of preschoolers with psychiatric disorders.Where randomized controlled data were not available,the group recommended that guidelines be derivedfrom clinical experience and community standards. Todate, our field lacks these guidelines. Thus, cliniciansand families face a delicate balancing process, weighingthe risks of medications with the risks of not interveningin complex clinical situations that are resistant tononpharmacological interventions. The risks associatedwith psychiatric disorders are not insignificant; pre-school psychiatric disorders can be associated with childcare expulsion, inability to participate in familyactivities, impaired peer relationships, high-risk beha-viors (Byrne et al., 2003; Egger and Angold, 2006;Gilliam, 2005), and future mental health problems(e.g., Lavigne et al., 1998).

WORKING GROUP METHODS

The Preschool Psychopharmacology WorkingGroup (PPWG) was established in response to the

Accepted July 10, 2007.Dr. Gleason is with the Bradley Hasbro Research Center and the Tulane

Institute of Infant and Early Childhood Mental Health; Dr. Egger is with theCenter for Developmental Epidemiology, Duke University Medical School; Dr.Emslie is with the University of Texas Southwestern Medical Center; Dr.Greenhill is with the New York State Psychiatric Institute; Dr. Kowatch is withthe Department of Psychiatry, Cincinnati Children_s Hospital Medical Center;Dr. Lieberman is with the Department of Psychiatry, University of California,San Francisco; Dr. Luby is with the Department of Psychiatry, WashingtonUniversity School of Medicine; Dr. Owens is with the Department of Pediatrics,Brown University Medical School; Dr. Scahill is with the Child Study Center atYale University; Dr. Scheeringa is with the Division of Child and AdolescentPsychiatry at the Tulane University Health Sciences Center; Dr. Stafford is withthe Departments of Pediatrics and Psychiatry at the Children_s Hospital, Denver;Dr. Wise is with the University of Colorado Health Sciences Center; Dr. Zeanahis with the Division of Child and Adolescent Psychiatry at Tulane UniversityHealth Sciences Center.

This project was supported by a grant from the AACAP Abramson Fund.The authors would like to acknowledge the important contributions of the

young children and families with whom we work, and the valuable feedbackreceived from the Early Childhood Clinical Research team at Bradley Hospital.

Correspondence to Mary Margaret Gleason, M.D., Bradley Hasbro ResearchCenter, 1 Hoppin Street, Providence, RI 02903; e-mail: [email protected].

0890-8567/07/4612-15322007 by the American Academy of Childand Adolescent Psychiatry.

DOI: 10.1097/chi.0b013e3181570d9e

S P E C I A L C O M M U N I C A T I O N

1532 J . AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 46:12, DECEMBER 2007


clinical needs of preschoolers being treated withpsychopharmacological agents and the absence ofsystematic practice guidelines for this age group. Thecentral aim of this working group is to develop bestpractice algorithms for the use of psychopharmacolog-ical agents in preschool children based upon literaturereview, clinical experience, and expert consensus. Thisdiscussion of psychopharmacological treatment ofseverely impaired young children is provided as anattempt to promote an evidence-informed, clinicallysound approach to considering medications in this agegroup. It is not intended to promote the use ofmedications. We anticipate that application of thesealgorithms will result in a reduction in the use ofpsychopharmacological agents for young children. Theworking group includes professionals with expertise inearly childhood psychiatric disorders, psychopharma-cology, general and behavioral pediatrics, clinicalpsychology, and neurodevelopmental processes.

The working group has met in person and reviewedmaterial via multiple conference calls and e-mail com-munication. Articles were identified through PubMedand PsycINFO searches for the period 1990Y2007 usingthe search terms preschool, psychopharmacology,medications, childhood, stimulants, anti-depressants, SSRI, neuroleptic, antipsychotic,mood stabilizer, ADHD, depression, anxiety,OCD, PTSD, sleep disorder, insomnia,aggression, DBD, conduct disorder, opposi-tional defiant disorder, bipolar disorder, safety, andprescribing. We reviewed all of the identified preschoolpsychopharmacology publications as were relevant.Because of the important influence of older child andadolescent data on prescribing for preschool children, wealso reviewed the highest level of evidence in older children.

The group developed treatment algorithms to guidepsychopharmacological treatment of preschool psychia-tric disorders using the systematic literature review,survey responses from practicing clinicians (unpub-lished PPWG survey), and the research and clinicalexpertise of the working group. The algorithms are notintended to suggest certainty where none exists. Eachstep of the algorithm is labeled with the level ofevidence that supports the step to allow clinicians toconsider systematic approaches to treatment, to beaware of data as well as extant gaps in evidence base, andto understand the basis for recommendations. Thealgorithms that were developed represent the groups

best attempt to integrate data and clinical experience;however, clinicians may determine that an alternativeapproach is indicated in a particular clinical situation.

Algorithms can facilitate clinical decisions byexplicitly identifying clinical decision points, definingstrategic (what to do) and tactical (how to do it)processes (Emslie et al., 2004b). They are intended tobe user-friendly and reduce unnecessary variance inclinical practice patterns. Algorithm implementation,study of clinical outcomes, and a growing research basewill guide future changes in treatment recommenda-tions (Gilbert et al., 1998).

OVERVIEW OF PRESCRIBING PRACTICES

Of preschoolers with psychiatric disorders, only asmall proportion are referred for mental healthtreatment, and the primary treatment modality formost very young children is psychotherapeutic ratherthan psychopharmacological (AACAP, 1997b; Eggerand Angold, 2006; Lavigne et al., 1993). Studies usingvaried methods yielded estimates that 3 to 9/1,000 U.S.preschoolers received prescriptions for psychotropicmedications in the 1990s (DeBar et al., 2003; Zitoet al., 2000). Rates of stimulants and "-agonistprescriptions increased dramatically between 1991 and1995 in Medicaid populations (Zito et al., 2000). From1991Y1995, prescription rates for Medicaid-enrolledpreschoolers approximately doubled, with the mostnotable increases in atypical antipsychotic and anti-depressant use, with stable rates of stimulant prescrip-tions (Cooper et al., 2004; Patel et al., 2005; Zito et al.,2007; Zuvekas et al., 2006). These population-basedstudies do not link the prescription with clinicalinformation, and it is possible that some prescriptionswritten for infants or very young children may, in fact, beintended to treat uninsured parents.

In addition, these studies do not examine complemen-tary and alternative medication (CAM) use. In a survey ofparents in an emergency room (mean age 5.3 years; n =103), 16% of parents reported giving their child a CAMagent for relaxation (Lanski et al., 2003). Although thedetails of the use of CAM in preschoolers are beyond thescope of this article, CAM is a factor in preschoolersexposure to psychotropic agents (Chan, 2002).

A few studies have examined patterns of prescriptionsfor children with psychiatric diagnoses. Across a varietyof populations including community, HMO, and

MEDICATION TREATMENT IN PRESCHOOLERS

1533J . AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 46:12, DECEMBER 2007


Medicaid, the majority of prescriptions written forpreschoolers are for stimulants (DeBar et al., 2003;Luby et al., 2007; Zito et al., 2007). In an HMOpopulation including 743 preschoolers with emotionalor behavioral problems, 16% (n = 120) of diagnosedchildren received psychopharmacological treatment,most commonly monotherapy with a stimulant(DeBar et al., 2003). In this study, stimulant use wasclearly linked to attention-deficit/hyperactivity disorder(ADHD) and "-agonists to sleep and aggression. Theauthors could not discern an association betweenantidepressant use and diagnoses or symptoms. In acommunity sample, Luby et al. (2007) reported that12% (17/123) of preschoolers with a DSM-IV diagnosishad received medication for at least 1 month. In bothstudies, slightly less than 80% of preschoolers whoreceived psychopharmacological treatment also receivedpsychotherapy. A total of 33% of the communitysample and 74% of the HMO sample received theirprescription from a primary care provider. In higherrisk populations, such as medically complex toddlerswith ADHD and psychiatrically hospitalized youngchildren, reports describe higher rates of psychophar-macological treatment (57%Y79%) and more prevalentuse of more than one medication (Pathak et al., 2004;Rappley et al., 1999; Rappley et al., 2002).

Taken together, these early studies of preschool psy-chopharmacological practice suggest that the majority ofpreschoolers with mental heath problems do not receivepsychopharmacological treatment. Access to othermental health services appears variable. Prescriptionpatterns support the value of clearly defined treatmentrecommendations for rational use of medications.

SPECIAL CONTEXTS OF PRESCHOOLPSYCHOPHARMACOLOGY

Treatment decisions involving young children includeconsideration of developmentally specific assessmentsand diagnosis, attention to neurodevelopmental andethical factors, and the existing evidence base.

Assessment

Although a comprehensive discussion of assessmentin preschool children is beyond the scope of this article,a comprehensive, developmentally sensitive, and con-textually relevant assessment is a prerequisite toconsideration of treatment. A number of resources

can be used to guide this process (AACAP, 1997b;Carter et al., 2004; DelCarmen-Wiggins and Carter,2004; Zeanah et al., 2000). An assessment of apreschooler includes multiple appointments, usesmultiple informants, and usually occurs within thecontext of a multidisciplinary team. A preschoolpsychiatric evaluation should address a child_s emo-tional and behavioral symptoms, relationship patterns,medical history, developmental history and status, aswell as parental and other environmental stressors andsupports (e.g., Egger et al., 2006a). In addition, earlychildhood development is particularly sensitive to thequality of the caregiverYchild relationship, as well asfamily, child care, community, and cultural contexts,which may influence the clinical presentation, caseformulation, and treatment plan (e.g., Seifer et al.,2001; Zeanah et al., 1997).

Structured, validated approaches to preschoolpsychiatric assessments can enhance the informationobtained in an assessment. These approaches includebrief parent report questionnaires focused on childsymptomatology, such as the Infant-Toddler SocialEmotional Assessment (Briggs-Gowan, 1998) or theChild Behavior Checklist 1Y5 (Achenbach andRescorla, 2000), diagnostic interviews including thePreschool Age Psychiatric Assessment (Egger et al.,2006b), and structured observations of parentYchildinteractions, such as the Clinical Problem SolvingProcedure (Crowell and Fleischmann, 2000).

A comprehensive preschool psychiatric assessment isimpractical in a primary care setting, where manychildren receive their prescriptions (DeBar et al., 2003;Goodwin et al., 2001). In any setting, a rationalpreschool treatment plan must be founded upon anadequate history and mental status examination thatallow a reasonable biopsychosocial formulation. For aprimary care prescriber, multiple appointments, collec-tion of collateral information from other caregivers, andconsultation with the child_s mental health specialistprovide the foundation for treatment decisions whileallowing a primary care provider to practice within thescope of his or her knowledge.

Diagnosis

In clinical practice psychiatric diagnosis generallydrives treatment planning. Applying diagnoses canfacilitate the clinical application of research findingsfocused on that diagnosis and can provide a common

GLEASON ET AL.



language to describe complex clinical syndromes. Inclinical practice, most but not all impaired preschoolerswill meet full criteria for a diagnosis (Keenan et al.,1997). For those who do not, applying standardnosologies and recognizing subthreshold disorders canfocus treatment planning.

Two diagnostically sensitive nosologies have beendeveloped to address concerns about the DSM-IV slack of attention to young children: the ResearchDiagnostic Criteria: Preschool Age (AACAP TaskForce on Research Diagnostic Criteria: Infancy Pre-school Age, 2003) and the Diagnostic Criteria: 0Y3R(Zero to Three Diagnostic Classification Task Force,2005). The Research Diagnostic Criteria: PreschoolAge are developmentally sensitive, evidence-informedmodifications of the DSM-IV criteria intended tointroduce reliability into the assignment of diagnoses topreschoolers, particularly in the research setting. Therecently revised Diagnostic Criteria: 0Y3R also addressdevelopmentally specific clinical presentations of men-tal health problems, focused primarily on infants andtoddlers and their relationships with caregivers.

Overall, using developmentally sensitive criteria,psychiatric disorders can be reliably assessed in childrenas young as 2 years old (Egger et al., 2006b). Empiricalsupport for specific preschool diagnoses is somewhatvariable. Some disorders, including major depressivedisorder (Luby et al., 2003a; Luby et al., 2003b; Lubyet al., 2003c; Luby et al., 2004b), posttraumatic stressdisorder (PTSD; Scheeringa et al., 2001; Scheeringaet al., 1995; Scheeringa et al., 2004; Scheeringa et al.,2005), disruptive behavior disorders (Keenan andWakschlag, 2002; Keenan and Wakschlag, 2004),ADHD (Lahey et al., 2004; Lahey et al., 1998), andautism (Lord et al., 2006) have empirical evidence thatsupports convergent and predictive validity. Otherdisorders, including many anxiety disorders, have notbeen empirically tested in preschoolers. Reliable andvalid diagnostic criteria are necessary to develop empiri-cally supported treatments for preschool disorders.

Nonpharmacological Treatment

Clinical decision making includes consideration ofalternative therapies. Thus, prescribers should be awareof the growing (but still limited) evidence base forpsychotherapeutic interventions in preschoolers. Evidence-supported models of treatment are effective in decreas-ing aggression and behavioral problems in young

children with disruptive behavior disorders (Eyberg,1988; Hood and Eyberg, 2003; Webster-Strattonet al., 2004), reducing child traumatic stress disordersymptoms (Cohen and Mannarino, 1997; Liebermanet al., 2005; Lieberman et al., 2006). Psychother-apeutic interventions for preschoolers with PTSD(Scheeringa et al., in press) and mania-like symptoms(Luby et al., in press) have also shown promisingpreliminary outcomes, although randomized con-trolled trials have not yet been published. In ourexperience, access to these evidence-based psychother-apeutic interventions can be variable and may belimited by a number of variables including providertraining, third-party payer restrictions, and parentalmotivation to participate.

Neurodevelopmental Processes

Biology also influences consideration of psychophar-macological treatment in young children. The impactof early and/or prolonged exposure to psychotropicmedications in the preschool period has not beensystematically studied, but research highlights thesensitivity of the developing brain. Synaptic density,dopamine receptor density, and cerebral metabolic ratespeak in the first 3 years of life and decline oversubsequent decades (reviewed in Shonkoff and Phillips,2000; Vitiello, 1998). In animal models early exposureeither to psychotropic agents or stressors can perma-nently affect distribution of the neurotransmitterreceptors (e.g., Maciag et al., 2005; Matthews, 2002;Yannielli et al., 1999). Similarly, abnormal infantpsychophysiological processes are associated with fetalexposure to maternal psychopathology (Engel et al.,2005; Lundy et al., 1999; Yehuda et al., 2005). Thesefindings highlight the potential central nervous systemsensitivity to exogenous factors including medicationsas well as endogenous stress responses.

Longitudinal studies of childrens early exposure topsychotropic medications are limited to fetal andneonatal exposure from maternal antidepressant treat-ment, which provide mixed results. Although prenatalantidepressant exposure is associated with measurablechanges in infant pain responsivity and toddler motorskills (Casper et al., 2003; Oberlander et al., 2005;Oberlander et al., 2006), no cognitive differences orincreased rates of internalizing or externalizing symp-toms have been observed in preschool follow-up (Misriet al., 2006; Nulman et al., 1997; Oberlander et al.,




2007). These results highlight the need for futureinvestigations examining longitudinal studies of pre-schoolers exposed to psychotropic medications, aboutwhom no neurodevelopmental findings have beenpublished.

Other organ systems also develop during the firstyears of life. In preschoolers, medication absorption,distribution, and metabolic processes can have a signifi-cant impact on the pharmacokinetics of medications,generally meaning that children need higher doses toachieve comparable plasma levels (Cote, 2005; Crom,1994). In practice, this pattern must be balancedwith our knowledge that preschoolers also experiencemore side effects than older children and adults(e.g., Greenhill et al., 2006; Wigal et al., 2006).Taken together, developmental pharmacokinetic issuesand sensitivity to adverse effects make dosing medica-tions in young children a delicate balance.

Regulatory and Ethical Context

Finally, and not insignificantly, regulatory and ethicalconsiderations in preschool psychopharmacologicaltreatment must be considered. A Food and DrugAdministration (FDA) indication reflects empiricalsupport, although the lack of an indication does notnecessarily reflect a lack of evidence (AAP Committee onDrugs, 2002). In the United States, only a smallproportion of medications are approved for use inpediatrics and medications are commonly used off-label (AAP Committee on Drugs, 2002; Shah et al.,2007). Four psychiatric medicationsVhaloperidol,dextroamphetamines, chlorpromazine, and risperidone-are approved for children under age 6 years (Greenhill,1998). The FDA has developed incentives to encouragethe development and testing of medications for children,but to date progress is limited for children under 6(Balakrishnan et al., 2006; FDA, 2002; Grieve et al.,2005). Recently, concerns about the safety of medica-tions in children have resulted in further regulatoryactions including black box warnings on selectiveserotonin reuptake inhibitors (SSRIs) in the UnitedStates and temporary suspension of mixed amphetaminesalts because of concerns of possible adverse cardiovas-cular effects in Canada in 2005 (FDA, 2005a; FDA,2005b).

In this context, although off-label use of medicationsis acceptable, informed consent requires clear, thoroughdiscussions with parents about the FDA status of a

medication and the level of evidence supporting therecommendation, potential risks, benefits, and alter-natives to its use (Jensen, 1998). In the context of apreschoolers psychiatric disorder, parental distressrelated to the child_s disorder or other pressures mayaffect a parents participation in the informed consentprocess (Spetie and Arnold, 2007). Thus, in preschooltreatment planning, the ethical principles of autonomy,justice, and beneficence are worthy of special attention(Spetie and Arnold, 2007).

CONSIDERING PSYCHOPHARMACOLOGICALTREATMENT

The contextual factors reviewed here render rationalprescribing considerably more challenging for pre-school children compared to older children. Jensenhas argued, however, that these diagnostic, neurode-velopmental, metabolic, and regulatory considerationsdo not comprise a universal proscription against theuse of medication in young children (Jensen, 1998,p. 588). A child with moderate to severe symptomsand functional impairment that persist despite appro-priate psychotherapeutic interventions may be betterserved by a carefully monitored medication trial thanby continuing other ineffective treatments. For somechildren, the safety concerns and developmental risksrelated to the psychiatric disorder may outweigh safetyconcerns related to planful psychopharmacologicaltreatments. Our group recommends that trial ofevidence-supported psychosocial treatments precedepsychopharmacological treatments. In the authors_view, psychopharmacological treatment is not indicatedfor preschoolers with only mild or single-contextsymptomatology or impairment.

Evidence Base

The algorithm section of this article describes thedetails of diagnosis-specific treatment reports, whichinclude one multisite, randomized placebo-controlledtrial (Greenhill et al., 2006), as well as case reports andopen trials (see Table 1). Although these studies providethe foundation for further studies of preschoolpsychopathology and treatment, there is not yet abroad evidence base for the use of most psychotropicmedications in children under 6 years of age. In thecurrent context clinicians must also consider studiesusing older populations and their own clinical experiences

GLEASON ET AL.



TABLE1

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GLEASON ET AL.



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psychopharm for very young children context and guidelines

Documents

treatment recommendations

clinical use of medications

specific disorders

practice guidelines

thedevelopment of guidelines

developmental epidemiology

abstractsystematic research

early childhood mental