P S Y C H O P H A R M A C O L O G Y P E R S P E C T I V E S Assistant Editor: Christopher J. Kratochvil, M.D.

This column aims to discuss practical approaches to everyday issues in pediatric pharmacotherapy. The cases anddiscussions specifically target aspects of clinical care related to psychopharmacology for which we do not haveadequate applicable controlled trials. Given the need to address symptoms in youths with complex, severe, andcomorbid disorders, recommendations are likely to be ‘‘off label’’ from the perspective of the U.S. Food andDrug Administration (FDA). We fully appreciate that for virtually all disorders medication is only one aspectof comprehensive care. This column focuses primarily on psychopharmacological management. The responsesfrom the expert clinicians are not meant to be practice guidelines but rather examples of thought processes thatmay go into pharmacotherapy decision making.

Christopher J. Kratochvil, M.D.

Pharmacological Management of Agitation and Aggressionin an Adolescent With Autism

CHRISTOPHER J. KRATOCHVIL, M.D., ROBERT L. FINDLING, M.D.,

CHRISTOPHER J. MCDOUGLE, M.D., LAWRENCE SCAHILL, M.S.N., PH.D.,

AND STEPHANIE HAMARMAN, M.D.

AUTISM VIGNETTE

A 13-year-old boy with autism and severe mental retar-dation presented to the inpatient psychiatric unit due toa recent increase in agitation and physical aggression.Following the closure of his group home, he movedto a similar one. He has not adjusted well to the changesin setting and staff. A behavioral specialist began work-ing with the patient and the group home staff to addresshis increased pacing, anger outbursts, and minor phys-ical aggression. When he struck a staff member, he wastransported to the emergency department and psychiat-

rically hospitalized. Current medications include parox-etine 20 mg each morning, divalproex sodium 250 mgtwice daily, and quetiapine 50 mg twice daily.

HOW WOULD YOU ADDRESS THIS

PHARMACOLOGICALLY?

Robert L. Findling, M.D.

Before thinking about medications, there are otherissues to consider. The hardest part of pharmacotherapyhas nothing to do with writing prescriptions. It has todo with careful clinical assessment of the patient. Thefirst question to ask is ‘‘why now?’’ It appears that thisyoung man has had a relatively recent, acute decompen-sation occurring after the move to a new group home. Isthere something different about the group home? Is thisyouth being victimized in this new setting? The age ofthe patient should be considered. Around puberty, youthswith pervasive developmental disorders may start to de-velop conditions that appear to be mood disorder‘‘equivalents.’’ What are the other symptoms besides ag-gression? Could this be a new-onset seizure disorder?Could there be an unrecognized medical problem caus-ing discomfort?If these possibilities have been considered, then one

might begin to look at the current medications. Are anyof the agents new and chronologically related to thesebehaviors? Decompensations have been reported in youths

Accepted March 28, 2005.Dr. Kratochvil is with the Department of Psychiatry, University of Nebraska

Medical Center, Omaha; Dr. Findling is with the Departments of Psychiatry andPediatrics, University Hospitals of Cleveland/Case Western Reserve University,Cleveland; Dr. McDougle is with the Department of Psychiatry, Indiana Uni-versity School of Medicine, Indianapolis; Dr. Scahill is with the Yale Child StudyCenter, Yale University, Hartford, CT; Dr. Hamarman is with the Stanley S.Lamm Institute for Child Neurology and Developmental Medicine and Down-state Medical School, State University of New York, New York.

Dr. Kratochvil is supported by grant 5K23MH06612701A1 from the Na-tional Institute of Mental Health.

Based on a topic suggested by Derek Richardson,M.D., andMartin Drell, M.D.Case vignette created to exemplify a complex clinical problem and does not refer toany specific patient.

Correspondence to Dr. Christopher J. Kratochvil, University of NebraskaMedical Center, 985581 Nebraska Medical Center, Omaha, NE 68198-5581; e-mail: ckratoch@unmc.edu.

0890-8567/05/4408–0829�2005 by the American Academy of Child

and Adolescent Psychiatry.

DOI: 10.1097/01.chi.0000166380.68392.4b

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 44:8, AUGUST 2005 829

with autism in association with treatment with quetia-pine (Findling et al., 2004) or serotonin selective reup-take inhibitors (SSRIs). An important question to consideris whether these medications are helping this patient. Ifnot, these agents should be discontinued. Presumingthis is an average-size 13-year-old, the divalproex andquetiapine could be tapered off over 3 or so days as theseare low doses. To avoid a potential rebound effect fromdiscontinuing paroxetine, I would reduce the dose to10 mg for 1 week followed by 5 mg for 1 more week.If this patient has none of these potential confound-

ing issues at play, I would consider treatment with ris-peridone. Risperidone is the agent with the greatestamount of data supporting its use in severe dysfunc-tional behaviors and pervasive developmental disorders(ResearchUnits on Pediatric Psychopharmacology, 2002;Shea et al., 2004). Atypical antipsychotics are not inter-changeable; what is applicable regarding risperidonemay not be applicable for other agents of this class.I would start treatment at 0.5 mg/day and increase

by 0.5 mg every 3 or so days, typically not exceeding3 mg/day. I generally prescribe risperidone once dailyin the morning, in accord with several treatment studies.However, some clinicians prefer to have risperidone ad-ministered once daily in the evening or split the doseand administer twice daily. There are no data on whichschedule is better.

Christopher J. McDougle, M.D.

Changing the primary living arrangement of an in-dividual with autism can result in the emergence of be-havioral symptoms such as those displayed by thispatient. As was done in this case, an assessment by a be-havioral specialist is an important first step in assistingthe patient with this transition. It is also important tonot make radical changes in a psychopharmacology reg-imen based on one significant aggressive event, partic-ularly in the context of major changes in the patient’senvironment. Assuming that the behavioral symptomsare persistent and interfering, I first would check thedivalproex sodium blood level, having the blood drawnin the morning before administering any medication. Ifthe blood level was 80 mg/mL or lower, I would increasethe dose of divalproex sodium from 250 mg twice dailyto 250 mg each morning and 500 mg at bedtime. Iwould recheck the divalproex sodium blood level in1 week and continue to increase the dose in 250-mgincrements until the blood level approaches 100 mg/mL

(the upper limit of the therapeutic range) and the pa-tient has received the target dose for a minimum of2 weeks. To date, there have been no published dou-ble-blind, placebo-controlled studies of divalproex so-dium describing the consistent reduction of aggressionand agitation in persons with autism. However, this re-duction is observed clinically, particularly in adolescentsand adults. Divalproex sodium does not have the risk oftardive dyskinesia associated with antipsychotic medica-tions. If the patient’s behavioral symptoms persist ona therapeutic dose of divalproex sodium, I would beginincreasing the quetiapine in 50-mg increments, in atwice-daily dosing regimen, every 3 days as tolerated,to a maximum dose of 400 to 600 mg/day.

I would hesitate to increase the paroxetine and mightattempt to discontinue it. There have been no publisheddouble-blind, placebo-controlled studies of SSRIs show-ing benefit in children and adolescents with autistic dis-order. In fact, many of the published open-label reportshave described an increase in irritability and agitationwith SSRI treatment (McDougle and Posey, 2003).

Lawrence Scahill, M.S.N., Ph.D.

There are several issues that I would consider. First, Iwould address whether the medication regimen is sta-ble. The child’s behavior could be related to a recentchange in medication. For example, an increase in pa-roxetine from 10 to 20 mg might induce SSRI activa-tion. I would consider the purpose of these medications.Were these medications initiated to reduce explosive be-havior and aggression? If so, was the behavior pattern atbaseline similar to the current behavior pattern? Fur-thermore, has this combination of medications beensuccessful in reducing the target symptoms? If the targetsymptoms were indeed the same and the benefits havebeen equivocal, I would consider switching to risperi-done, which has more empirical support for reducingtantrums and aggression.

Although evidence supporting the use of quetiapinefor explosive behavior and aggression in youths withpervasive developmental disorders is minimal, it is un-likely that the current dose is adequate. Before switchingto another atypical antipsychotic such as risperidone,the dose of quetiapine should be increased to 250 to350 mg. Given that the patient is on an inpatient ser-vice, this increase could be accomplished relativelyquickly. In light of the medications that he is taking,a check on safety indices such as pancreatic and hepatic

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enzymes as well as fasting triglyceride, glucose, and val-proate levels is also warranted if not recently obtained. Ifthe medication regimen has been stable and not impli-cated in the behavioral changes, the most obvious expla-nation is the change in residence.I would determine what was learned from the behav-

ior therapy consultant. Aggressive behavior in an ado-lescent with autism andmental retardationmay occur inspecific situations, e.g., during transitions, when beingpulled away from a preferred repetitive activity or in thecontext of routine demands that the child would ratheravoid. Information about the antecedents and the re-sults of this boy’s aggression might help in understand-ing the function of the behavior. Once the function ofthe behavior is identified, intervention strategies couldbe initiated to control behavior and enhance medicationeffectiveness.Last, I am increasingly skeptical about the value of

multiple medications in this type of patient. In the bestcircumstances, multiple medications successfully targetmore than one problem or permit the use of lower dosesof medications and lower adverse effect burden. In othersituations, the first medication may not have been pre-scribed for an adequate time period at an optimal doseto judge efficacy. In such cases, the second medicationmay have been added prematurely. A thorough reviewof the target symptoms and treatment response mightreveal unconvincing rationale for the current regimenand lead to appropriate simplification of the medicationregimen.

Stephanie Hamarman, M.D.

This autistic, severely retarded boy appears to be suf-fering from increasing akathisia and anger outbursts.Therefore, my pharmacologic management would in-clude tapering and ultimately eliminating paroxetine,which may be contributing to the akathisia. Simul-taneously, I would increase and ultimately maximizequetiapine in an effort to improve both his anger out-bursts/physical aggression as well as to facilitate sleep.This agent has the advantage of having minimal effectson weight and limited adverse cognitive effects, whichmay also be important. Finally, I would maintain hispresent dose of divalproex sodium.Paroxetine may increase jitteriness and agitation and

may be responsible for the increased pacing. Becausethis patient requires an atypical antipsychotic for mood

stabilization and control of temper tantrums, irritabil-ity, and anger management, the use of paroxetine doesnot appear to be justified. Paroxetine does need to betapered as rapid withdrawal can result in flulike symp-toms. I would recommend paroxetine 10 mg for 1 weekand then discontinue.As the patient appears to be tolerating quetiapine

with at least a partial response, I would maximize thisagent. Two open-label studies in youths with autismfailed to show benefit with quetiapine, but dosing strat-egies, treatment resistance, and methodological limita-tions precluded definitive conclusions (Findling et al.,2004; Martin et al., 1999). Quetiapine can be rapidlytitrated, a strategy well suited for inpatient managementin which both time to response and length of hospitalstay are important. Since quetiapine’s binding on thedopamine-2 receptor is brief and blockade of dopa-mine-2 is probably responsible for quetiapine’s antiagi-tation effect (Lieberman, 2004), frequent dosing (twoor three times daily) is preferred. I would maintain que-tiapine 50 mg at bedtime to facilitate sleep because low-dose quetiapine saturates the histamine-1 receptor.However, I would increase the morning dose (100 mgeach day if necessary) over a couple weeks to capitalizeon possible improvements in affect and cognition thatcan be obtained from quetiapine’s blockade of other se-rotonin receptors (5-HT2 and 5-HT1D). I might splitthe treatment into three equal doses for morning, noon,and late afternoon if it was not working at twice-dailydoses. I might divide the daytime dose, giving equalamounts in the morning and at noon while maintainingthe small dose at night. For example, on the first hos-pital day, increase the quetiapine to 100 mg in themorning (or 50 mg A.M. and 50 mg noon) and givean evening 50-mg dose. Depending on improvement,increase on the second day to 200 mg in the morning(or 100 mg A.M. and 100 mg noon), maintaining the50 mg at night, and on the third hospital day, increasethe daytime dose to 300 mg, and on fourth day to400 mg and so on.At this time I would keep the child’s divalproex so-

dium stable. This would allow a more accurate assess-ment of the effects of increasing the level of quetiapineand removal of paroxetine. I would not increase dival-proex sodium because of its potential to produce theside effects of foggy cognition and weight gain. The pa-tient is already impaired, functioning cognitively likea 3- to 5-year-old. Avoiding the need for divalproex

PSYCHOPHARMACOLOGY PERSPECTIVES

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blood levels during titration is an added benefit in thisseverely mentally retarded patient. Weight gain issuesalso favor quetiapine, in which weight gain is typicallydose related and of intermediate level (American Dia-betes Association et al., 2004). Because of concernsabout glucose and lipid metabolism with all atypicalantipsychotics, I would obtain a baseline fasting glucose(or hemoglobin A1C if fasting studies are not practical)and check a lipid panel (triglycerides, total cholesterollevel, and HDL cholesterol). I would also measureweight and abdominal waist circumference and monitorblood pressure throughout therapy.

Disclosure: Dr. Kratochvil has received grant support from orbeen a consultant and/or member of a speaker’s bureau for Eli Lilly,GlaxoSmithKline, Forest, Cephalon, Novartis, McNeil, Organon,AstraZeneca, and Pfizer. Dr. Findling receives or has received researchsupport from or been a consultant and/or member of a speaker’s bureaufor Abbott, AstraZeneca, Bristol-Myers Squibb, Celltech-Medeva, For-est, GlaxoSmithKline, Johnson & Johnson, Eli Lilly, New River, No-vartis, Otsuka, Pfizer, Shire, Solvay, and Wyeth. Dr. McDougle hasreceived grant support from or been a consultant and/or member ofa speaker’s bureau for AstraZeneca, Bristol-Myers Squibb, Eli Lilly,Janssen Pharmaceutical, PediaMed Pharmaceuticals, and Pfizer. Dr.

Scahill has consulted for Janssen Pharmaceutical, Pfizer, and Bristol-Myers Squibb. Dr. Hamarman has received grant support from or beena consultant and/or member of a speaker’s bureau for AstraZeneca,Bristol-Myers Squibb, Eli Lilly, Janssen Pharmaceutical, McNeil,Orphan Medical, and UCB-Pharma.

REFERENCES

American Diabetes Association, American Psychiatric Association, AmericanAssociation of Clinical Endocrinologists, North American Association forthe Study of Obesity (2004), Consensus development conference on an-tipsychotic drugs and obesity and diabetes. Diabetes Care 27:596–601

Findling RL, McNamara NK, Gracious BL et al. (2004), Quetiapine in nineyouths with autistic disorder. J Child Adolesc Psychopharmacol 14:287–294

Lieberman J (2004), Quetiapine. In: The American Psychiatric Publisher’sTextbook of Psychopharmacology, 3rd ed., Schatzberg A, Nemeroff C,eds. Arlington, VA: American Psychiatric Press, pp 473–486

Martin A, Koenig K, Scahill L, Bregman J (1999), Open label quetiapine inthe treatment of children and adolescents with autistic disorder. J ChildAdolesc Psychopharmacol 9:99–107

McDougle CJ, Posey DJ (2003), Autistic and other pervasive developmentaldisorders. In: Pediatric Psychopharmacology: Principles and Practice,Martin A, Scahill L, Charney DS, Leckman JF, eds. New York: OxfordUniversity Press, pp 563–579

Research Units on Pediatric Psychopharmacology Autism Network (2002),Risperidone in children with autism and serious behavioral problems.N Engl J Med 347:314–321

Shea S, Turgay A, Carroll A et al. (2004), Risperidone in the treatment ofdisruptive behavioral symptoms in children with autistic and other per-vasive developmental disorders. Pediatrics 114:e634–e641

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