THERAPY IN PRACTICE CNS Drugs 2009; 23 <1): 1.171172.7047/09AXXH.0001/S4W5/0

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Psychopharmacological Treatment ofOppositional Defiant DisorderAtilla Turgay

Toronto ADHD Clinic, University of Toronto, Toronto, Ontario, Canada

ContentsAbstract 11. Symptomatology and Diagnostic Criteria for Oppositionai Defiant Disorder (ODD) 22. General Considerations in the Pharmacoiogical Treatment of ODD 43. Drugs Used in the Treatment of ODD ; 5

3.1 Stimulants 53.2 Atomoxetine 73.3 Antidepressants 83.4 a2-Agonists 83.5 Mood Regulators 93.6 Antipsychotics 93.7 Medication Combinations 11

3.7.1 Stimulants and Cionidine 113.7.2 Stimuiants and Antidepressants 113.7.3 Stimulants and Antipsychotics 12

4. Treatment Aigorithm for ODD 124.1 ODD Aione 124.2 ODD + ADHD, Without Anxiety, Mood or Tic Disorders 124.3 ODD + ADHD + Either Tic and/or Anxiety Disorders 124.4 ODD + Mood Disorders + ADHD 124.5 Other Muitipie Co-Morbidities 13

5. Conclusion 13

Abstract Oppositional defiant disorder (ODD) consists of an enduring pattern of unco-operative, defiant and hostile behaviour toward authority figures that does notinvolve major antisocial violations and is not accounted for by the developmentalstage of the child. The rate of ODD in children and adolescents in the generalpopulation has been reported to be between 2% and 16%. The InternationalClassification of Diseases 10th Revision (ICD-10) classifies ODD as a mild formof conduct disorder (CD), and it has been estimated that up to 60% of patients withODD will develop CD. Therefore, ODD should be identified and treated as earlyand effectively as possible.

In more than one-half of patients with attention-deficit hyperactivity disorder(ADHD), ODD is also part of the clinical picture. There is strong evidence in theliterature to suggest that ODD and ADHD overlap; many medications that areused to treat ADHD may also be efficacious in the treatment of ODD. A fewstudies have reported the positive effects of psychostimulants or atomoxetine in

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the treatment of ODD associated with ADHDi. Patients with ODD and CD withsevere aggression may respond well to dsperidone, with or without psychostimu-lants. Mood regulators, a2-agonists and antidepressants may also have a role assecond-line agents in the treatment of ODD and its co-morbidities.

This review describes the diagnosis, differentialdiagnosis and co-morbidities of ODD in childrenand adolescents. The evidence for transition of ODDto a more severe pathology such as conduct disorder(CD) is also reviewed. Questionnaires that are use-ful aids in the diagnosis and differential diagnosis ofODD and its treatment are outlined. The major focusis the pharmacological treatment of ODD and itscommon co-morbid disorders, with practical clinicalsuggestions provided for selecting medications fortreatment.

1. Symptomatology and DiagnosticCriteria for Oppositional DefiantDisorder (ODD)

Oppositional defiant disorder (ODD) consists ofan enduring pattern of uncooperative, defiant andhostile behaviour toward authority figures that doesnot involve major antisocial violations and is notaccounted for by the developmental stage of thechild. ODD is one of the most common disorders inchildhood and is often associated with other mentaldisorders; it can result in significant functional im-pairment.

In the DSM-IV-TR,['l ODD comes under thegeneral diagnostic grouping of 'attention-deficithyperactivity and disruptive behaviour disorders'.According to the DSM-IV-TR diagnostic criteria,the essential feature of ODD is a recurrent pattern ofnegativistic, defiant, disobedient and hostile beha-viour toward authority figures that persists for atleast 6 months and is characterized by the frequentoccurrence of at least four of the following eightbehaviours: (i) often loses temper; (ii) often argueswith adults; (iii) often actively defies or refuses tocomply with adults' requests or rules; (iv) oftendeliberately annoys people; (v) often blames othersfor his or her mistakes; (vi) is often touchy or easilyannoyed: (vii) is often angry and resentful; and

(viii) is often spiteful or vindictive.''' ODD shouldbe considered a disorder only when the behavioursare more frequent and intense than unaffected peersand when they cause dysfunction in social, academ-ic or work-related situations.'^'

The International Classification of Diseases 10thRevision (ICD-10)'^' diagnostic criteria for ODD areanalogous to those of the DSM-IV-TR. In theICD-10, ODD is viewed as a mild form of conductdisorder (CD), and is characterized by negative,argumentative and defiant behaviours such as argu-ing with adults (table I). The ICD-10 has co-morbiddiagnostic categories of 'hyperkinetic CD' (for indi-viduals meeting diagnostic criteria for attention-deficit hyperactivity disorder [ADHD] and CD),'depressive CD' (for individuals who meet the diag-nostic criteria for CD as well as one of the mooddisorders) and 'mixed disorders of conduct andemotions'.

The ICD-10 differs from the DSM-IV-TR withrespect to its treatment of ODD. The ICD-10 viewsODD as a mild variant of CD, i.e. ODD is consid-ered a subtype of CD rather than a separate diag-nosis.'"' The DSM-IV-TR criteria do not allow aclinical diagnosis of ODD in some cases, as evi-denced in the following statement: "Oppositionalbehaviour is a common associated feature of mooddisorders and psychotic disorders presenting in chil-dren and adolescents and should not be diagnosedseparately if the symptoms occur exclusively duringthe course of a mood or psychotic disorder".''' TheDSM-rV-TR allows for the co-occurrence of ADHDand ODD, but does not allow for the diagnosis ofODD in adults over the age of 18 years who meet thecriteria for antisocial personality disorder. CD usu-ally presents with a poor prognosis and approxi-mately half of the adolescents with CD may presentwith antisocial personality disorder in adulthood.Many patients with CD also have co-morbid sub-

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Psychopharmacological Treatment of Oppositional Defiant Disorder

Stance abuse. Because of this connection betweenODD and CD, ODD should be regarded seriouslyand should be treated effectively as early as poss-ible.

The current diagnostic criteria for DSM-FV-TRhave internal consistency and good predictive andnegative predictive value. The test-retest reliabilityis good for parents, but poor when the child is theinformant.!'! Parent-teacher agreement on ODDsymptoms seem to be quite high.'^l

Negativistic and defiant behaviours are ex-pressed by persistent stubbornness, resistance to di-rections and unwillingness to compromise, give inor negotiate with adults and peers. Defiance mayalso involve deliberate and persistent testing of lim-its, usually by ignoring orders, arguing and failing toaccept blame for misbehaviour."'^!

ODD is more common in males than in femalesand shows a relatively high degree of stability overdevelopment.'^' It is most severe within the homeenvironment, particularly during the childhoodyears, but may become equally severe in school insome children by the time they reach adolescence. Apattern of negative and coercive behaviour is oftenseen among other family members of the affectedchild. Over time, ODD is likely to be associated with

low self-esteem, low frustration tolerance, temperoutbursts, poor peer relations and, eventually, poorschool performance. Patients with ODD may beisolated from healthier children and adolescents,may be suspended frequently from school becauseof behavioural problems and may experience signif-icant friction in peer and family relationships, lead-ing to disturbances in object relationships and anegative impact on the development of self-esteem,healthy personality and self image.'*"'^'

Oppositional behaviours are common in mooddisorders (e.g. dysthymic disorder, major depressionor bipolar disorder). Many autistic children mayshow defiance and opposition, and some symptomsof ODD can also be seen in patients with organicbrain disorder. DSM-IV-TR allows for the co-mor-bid diagnosis of ADHD, ODD and mental retarda-tion, if the oppositional behaviour is markedly great-er than is commonly observed among individuals ofcomparable age, sex and severity of mental retarda-tion.I"! The presence of ODD in children and adoles-cents with ADHD may make treatment more com-plicated.

CD frequently overlaps with ODD, but accordingto DSM-IV-TR criteria, a diagnosis of ODD shouldnot be made in the presence of CD or other psychiat-

Table I. International Classification of Diseases, 10th Revision (ICD-10) conduct disorders (CDs) and related diagnostic categoriesP'

Category Characteristics

Subtypes

Oppositional defiant disorder (ODD)

Unsocialized CD

Socialized CD

CD confined to the family context

CD unspecified

Co-morbid diagnostic categories

Hyperkinetic CD

Depressive CD

Mixed disorders of conduct and emotions

Specifiers

Age of onset

Level of severity

'A mild form of CD

Analogous to DSM-IV-TR CD with the additional criterion of a laci< of connection withpeers and/or an absence of lasting friendships

Analogous to DSM-IV-TR CD with the additional criterion of evidence of normalconnection with peers

CD in which the individual's disturbance occurs only in the family environment

Individual meets the criteria for CD, but specific subtype cannot be established

Individual meets the diagnostic criteria for attention-deficit hyperactivity disorderand CD

Individual meets the diagnostic criteria for CD and one of the mood disordersIndividual meets the criteria for CD and additional neurotic, stress-related orsomatoform disorder according to the ICD-10 criteria

Childhood onset: at least one CD symptom occurs before the age of 10 yearsAdolescent onset: CD symptoms occur after the age of 10 yearsMild, moderate or severe

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rie disorders. Verbal aggression is more common inpatients with ODD, although many patients withODD may have mild physical aggression but do notmeet the full criteria for CD. Serious, ongoing phys-ical aggression is more commonly associated withCD. Researchers continue to address the indepen-dence of ODD and CD but recognize their inter-relatedness and continuity.'^'''-'^^ Support for sepa-rate diagnoses rests primarily on the developmentalasymmetry between ODD and CD. Research hassuggested that most children who meet the criteriafor CD prior to puberty will also have met thecriteria for an earlier diagnosis of ODD. However,approximately 75% of children who meet the clin-ical criteria for a diagnosis of ODD do not progressto a diagnosis of CD during the next 3 years. Fur-thermore, there are a significant number of childrenwho develop CD during adolescence without indica-tion of a prior diagnosis of ODD.'^"'^'''""l Barkley'^'estimated that perhaps 60% of patients with ODDwill develop CD and will have a high risk forsubstance and tobacco use.

2. General Considerations in thePharmacoiogical Treatment of ODD

Very few controlled studies are available on thetreatment of ODD with psychoactive medications.In many studies of patients with co-morbid ADHDand ODD, ADHD is the focus of the study butpatients with both ADHD and ODD have been in-cluded. The overlap of ADHD, ODD and CD hasbeen well documented in many studies;'^"'-" there-fore an overlap in treatment can be expected. Thus,reports regarding effective medications in the treat-ment of ODD are often derived from the sub-analy-ses of studies designed for the treatment ofADHD."''"^''' Many of the studies of patients withADHD and ODD have examined the use ofpsychostimulants. Much less is known about theutility of nonstimulant medications in treating co-morbid ADHD and ODD; however, several studieshave examined the use of noradrenergic agents forthese conditions.'""-'^i There have been no studiesexamining drug therapy in patients with ODD with-out co-morbid disorders. Therefore, some of the

improvements in ODD symptoms seen in these stud-ies may not be directly related to the medicationeffects on ODD; rather, it may be possible thatimprovements in ODD symptoms may be related toachieving increased control of ADHD symptoms.'"""

As ODD is associated with multiple co-morbiddisorders, combined drug treatment strategies maybe required. Medication use in the treatment of ODDwithout co-morbid ADHD may be limited to pa-tients who do not respond to psychosocial interven-tions and who maintain serious oppositional beha-viour, defiance and aggression as part of the overallclinical picture. Many patients with ODD are sus-pended from school or are referred to special classesfor children with serious behavioural problems. Forthese children, psychostimulants or atomoxetinemay be effective. In patients who have failed torespond to either of these medications, TCAs, cloni-dine or guanfacine may be indicated.'^) For patientswho have serious disruptive behaviours and who donot respond to the medications previously men-tioned, the clinician should evaluate the presence orabsence of mood swings and mood disorders inorder to determine the need for a trial with moodregulators.

More than one-half of patients with ADHD alsohave ODD. Patients with co-morbid ODD andADHD will benefit from ADHD medications,which have positive effects on ODD symptoms.Psychostimulants and atomoxetine are consideredfirst-line medications in the treatment of ADHD,while TCAs and a2-agonists, e.g. clonidine, can beused as second-line medications for patients withADHD and ODD.

Longer acting psychostimulant formulationssuch as Adderall XR®, Concerta® and Ritalin LA®are generally more appropriate in the treatment ofpatients with ADHD and co-morbid ODD thanshort-acting formulations of psychostimultants suchas methylphenidate or dexamfetamine (dextroam-phetamine) because of higher remission and com-pliance rates, and higher teacher and parent prefer-ences.'^*' There is also less risk for medicationabuse. However, a recent European review of theuse of long-acting agents in hyperkinetic disorders

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Psychopharmacological Treatment of Oppositional Defiant Disorder

recommends that both long-acting and short-actingdrugs should be available, with the choice deter-mined by individual patient circumstances.'^^'

Some patients exhibit ODD symptoms from earlymorning until bedtime. For these patients, ODDsignificantly interferes with the quality of life of thepatient and their family. These patients may respondbetter to atomoxetine than psychostimulants, be-cause atomoxetine has a longer duration of effectthan all psychostimulants. Because of their sleep-suppressant effects, psychostimulants may be un-suitable for use in patients who need medication tocontrol oppositional behaviour after dinner and atbedtime; atomoxetine may also be useful in thesepatients.

The dose of medication for patients with ODDand ADHD may need to be higher than that adminis-tered to patients who have ADHD withoutODD.[''°'̂ '̂5 '̂ Combination treatments may be indi-cated for highly complicated cases that do not res-pond well to one medication alone. Patients whohave had ADHD and ODD for many years maydevelop major depression, particularly in adoles-cence. Major depression in these patients may notrespond to TCAs and, therefore, these patients maybenefit from the combination of psychostimulantsand SSEUs. Patients with ADHD, tics or Tourette'ssyndrome and co-morbid ODD may also benefitfrom treatment with atomoxetine or clonidine be-cause product monographs of stimulants indicatethat stimulants are contraindicated in patients withtics or Tourette's syndrome.'^*'

3. Drugs Used in the Treatment of ODD

3.1 Stimulants

Historically, psychostimulant medications havebeen first-line medications for ADHD, with reportsof use dating back to 1937 for amfetamine (amphet-amine) products and 1957 for methylphenidate.''*'The behavioural effects of stimulants were first de-scribed by Bradley in 1937'̂ '̂ in a group of childrenwho had mixed ADHD and other behavioural prob-lems severe enough to warrant residential treatment.The children's behaviour improved dramatically

when they received Benzedrine® (a racemic mixtureof d- and /-amfetamine).'^'' It was 30 years later(1967) that Conners and co-workers'*°' used dex-amfetamine in a double-blind study to treat a groupof adolescents with behavioural problems. Regula-tory approval of psychostimulant medication oc-curred during the 1960s.

Psychostimulants such as methylphenidate anddexamfetamine, together with their sustained-re-lease versions, have been the standard and mostcommon drug therapies used in the treatment ofADHD for many years. Stimulants are well toleratedand highly effective medications, with up to 75% ofindividuals with ADHD responding to the first stim-ulant selected, and a response rate of 80-90% if twodifferent stimulants are tried consecutively.'"-^^'These medications appear to be quite effective inimproving symptoms of inattention, hyperactivity,impulsitivity and oppositional behaviour.''*"'̂ '̂

The rating scales most commonly used to mea-sure the effects of stimulants on ADHD, the Inatten-tion/Overactivity With Aggression (IOWA)-Con-ners questionnaire,'*'' the Conners' Parent RatingScales-Revised (CPRS-R)'^^' and the Conners'Teacher Rating Scales-Revised (CTRS-R),'̂ "*' havemany questions relating to ODD symptoms. Morerecent studies with longer acting psychostimulantshave utilized the Swanson, Nolan and Pelham(SNAP) questionnaire,"*' which has eight DSM-IVODD symptoms as part of the scale. It has becomeclear that psychostimulants are effective in control-ling both ADHD and ODD symptoms.'*^'

For children with ADHD or ADHD/ODD, in theclassroom setting, stimulants decrease the tendencyto interrupt, fidget and finger tap, and increase on-task behaviours.'*^*" In the home setting, stimulantsimprove parent-child interactions, on-task behav-iours and compliance. In social settings, stimulantsimprove peer nomination ranking of social standingand increase attention while playing baseball.'*^'Many studies in children with ADHD and aggres-sion have demonstrated the positive effects of stimu-lant medication in aggression control and improve-ment in noncompliance.'*^'

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The MTA (Multimodal Treatment of ADHD)study conducted by the National Institute of MentalHealth was a comprehensive long-term treatmentstudy of child psychiatric disorders.''*"' As 40% ofthe ADHD patients also had ODD, the sub-analysisof this study also generated useful information re-garding the effects of psychostimulants on ODDsymptoms. For most ADHD symptoms, children inthe combined or medication treatment groups show-ed significantly greater improvement than those giv-en intensive psychosocial treatment alone or thosetreated in the community. In a direct comparison ofADHD core symptoms, combined treatment was notsuperior to medication management alone, and med-ication management was also superior to behaviourtreatment alone and treatment in the community.Children with ADHD and ODD benefited morefrom combined therapy; for children with ADHDwithout ODD, both medication alone and combinedtreatments were equally effective. With the veryhigh cost associated with combined treatment, it canbe concluded that the presence of ODD in ADHDpatients makes the cost of treatment higher, and theresponse rate to medication alone is not sufficientwhen ODD is co-morbid with ADHD. It can bepostulated that early and effective interventions forbehavioural problems in patients with ADHD,before the establishment of a full picture of ODD,may represent savings in healthcare delivery to these

The MTA study examined the moderating effectsof ODD co-morbidity on ADHD treatment res-ponse, as well as the response of ODD symptoms toADHD treatment.l'^l The presence of ODD did notalter the overall pattern of findings, indicating arelative superiority of medication treatment overpsychosocial or community standard interventions.ODD symptomatology, as measured by the SNAPrating scale, also showed improvement with med-ication treatment. Secondary analyses of the MTAstudy suggest that success rates for the treatment ofODD with co-morbid ADHD improve by approxi-mately 20% when psychosocial treatment is addedto medication

During the last few years, there has been majorprogress in the development of new formulations ofmethylphenidate (e.g. Concerta®, Metadate CD™,Methylin® and Ritalin LA®) and amfetamine mixedsalts (Adderal XR®), which have extended the dura-tion of action of these agents. The use of long-actingmedications is recommended over short-actingmedications by national professional organizationssuch as the Canadian ADHD Resource Alliance.'^*'Although initial titration with immediate-releasestimulant preparations is recommended, particularlyfor stimulant-naive children and adolescents, con-version to one of the rapidly increasing choices ofeffective longer acting preparations is strongly sug-gested for optimal control of ADHD symptoms.Children and adolescents with ADHD and ODDrequire continuous symptom control and stabili-ty, and may benefit more from longer acting psy-chostimulants. Higher remission rates, parent andteacher preferences, improved compliance andbetter maintenance of privacy, particularly for ado-lescents, are some of the main reasons leading to therecommendations of preference of longer actingmedications proposed by national ADHD associa-tions.'^*' A recent review of studies comparing thelong-acting methylphenidate formulation (Con-certa®) with the immediate-release methylphenidateformulation (Ritalin®) has provided evidence thatchildren with ADHD who took equal amounts ofmethylphenidate demonstrated much higher rates ofremission of ADHD symptoms with Concerta®.'^^'Symptoms of ODD also responded better to Con-certa® than to Ritalin®.'^*'

Effect sizes for changes in behaviour and atten-tion in short-term trials with psychostimulantsrange from 0.8 to 1.0, which is quite a significanteffect.'*'! Double-blind, placebo-controlled studiesreport moderate adverse effects in 4-10% of chil-dren treated. Delay in sleep onset, reduced appetite,stomach ache, headache and jitteriness are the mostfrequently cited adverse effects of methylpheni-date.'**' A review of the meta-analytic studies andrecent guidelines on the use of psychostimulantssupport the use of these medications for opposition-al and aggressive behaviour in the absence of

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Psychopharmacological Treatment of Oppositional Defiant Disorder

Short-term trials of stimulants (mostoften <3 months in duration) have reported robustefficacy of methylphenidate, dexamfetamine andpemoline, with equal efficacy among stimu-janfs [59.60,67,69,70] short-term trials have reported im-provements in the most common ADHD symptoms,and improvements in behavioural symptoms, in-cluding overt aggression, as long as medication istaken consistently.'*^'

A recent meta-analysis of all studies dealing withaggressive behaviour in children and adolescentsconcluded that stimulants exerted à medium to largeeffect (effect size = 0.78) and risperidone exerted astrong effect size (0.9). Limited studies withatomoxetine did not show a strong positive effect(effect size = 0.18) in controlling aggression.t™' Theeffect sizes in treating aggressive behaviour weremoderate for lithium (0.4) and guanfacine (0.4), andsmall for antidepressants (0.3). As most patientswith ODD have aggressive behaviours, the effectsize on aggressive behaviour should be consideredwhen choosing medication for treating this disorder.

3.2 Atomoxetine

Atomoxetine is a specific noradrenaline (nore-pinephrine) transporter inhibitor. It is a nonstimulantmedication, which has received US FDA approval,and is not classified as a controlled substance. Short-term, placebo-controlled studies'̂ '̂̂ ''̂ - '̂ and long-term use indicate that atomoxetine may be a reliableand well tolerated alternative to stimulant drugs inthe treatment of ADHD inattentive, hyperactive-impulsive and combined types. The studies usedConners' rating scales and DSM-IV symptom-based, clinician-completed rating scales.'•̂ •̂̂ '•̂ ''l Pa-tients maintained treatment gains during the long-term study,'^^' and the adverse effect profile seemedto be acceptable, with no serious problems. In-creased risk of suicidal ideation, as well as rareserious adverse effects on the liver and heart havebeen reported with atomoxetine.^^ '̂

One of the major advantages of atomoxetine,compared with other ADHD medications, is its longduration effect, which alleviates behavioural prob-lems and inattention early in the mornings and late

in the evenings. Results of an 8-week, randomized,placebo-controlled trial of once-daily atomoxetinein a total of 197 children with ADHD (aged 6-12years) revealed that medication efficacy on thehome behaviours of children persists into the even-ing and the following early morning.'^^' Atomoxe-tine seems to be effective for as long as 24 hoursfollowing a single morning administration; it alsohelps to control anxiety symptoms and tics.''*'Atomoxetine was found to be effective in the treat-ment of ODD and ADHD co-morbidities.'"^ Newresearch findings with atomoxetine in treatment-resistant patients with ADHD has established thefunctional use of plasma concentrations to guideatomoxetine doses.'^''

Newcorn et al.'^^' reported on atomoxetine treat-ment in children and adolescents with ADHD andco-morbid ODD. Of 297 children and adolescentsrandomly assigned to receive medication, 293 hadcomplete information regarding the presence or ab-sence of lifetime ODD. Of these, 115 (39.3%) metDSM-IV-TR criteria for ODD. Atomoxetine1.8 mg/kg/day (but not 1.2 mg/kg/day) was superiorto placebo in reducing symptoms of ADHD amongyouths with ADHD and ODD, as assessed by theADHD Rating Scale IV-Parent Version. Changes inADHD and oppositional symptoms were associatedwith improvements in broader functioning. Effect-size measurements indicated medium to large ef-fects on oppositional symptoms in the ODD group,comparable to those associated with stimulant treat-ment of aggression-related behaviours in ADHD.The effect sizes for changes in oppositional beha-viour were also consistent with those obtained inthis treatment group on measures of ADHD symp-toms. Youths with and without ODD differed intheir dose-response characteristics, with patientswithout ODD showing a maximal response at1.2 mg/kg/day and patients with ODD showing agreater response at 1.8 mg/kg/day.

Additional research is required to establishatomoxetine as a treatment for ODD and to evaluatewhether higher doses are required when ODD co-morbidity is present.

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3.3 Antidepressants

The pharmacokinetics of and treatment responsesto TCAs are different in children than in adolescentsor adults. Prepubertal children are prone to rapiddramatic swings in blood concentrations (from toxicto ineffective levels) and should be given divideddoses to produce more stable concentrations.'^^"'''The short half-life of TCAs in prepubertal childrencan produce daily withdrawal symptoms if med-ication is administered only once daily. TCAsshould be tapered over a 2- to 3-week period. Fivecases of unexplained sudden death have occurredduring treatment with desipramine, three of whichwere following exercise in prepubertal children.'̂ '̂ 1A causal relationship between the medication andthe deaths has not been established.

TCAs such as imipramine or desipramine, whichhave been effective in treating ADHDJ'^'''' can beconsidered; however, patients with associated anxie-ty or mood disorders (major depression or dys-thymic disorders) may benefit from the newer anti-depressants, such as the SSRIs. The specific impacton ODD symptoms in these clinical conditions is notwell established.

A trial with TCAs may be considered for patientswith ADHD and ODD who do not respond topsychostimulants and atomoxetine, or who have de-veloped tics and/or Tourette's syndrome while tak-ing psychostimulants. A starting dosage of 10 mgtwo or three times daily, with a gradual dosageincrease up to a maximum of 2-3 mg/kg/day undercareful cardiac monitoring with ECG, can be con-sidered.il'•561

Bupropion, a mixed dopaminergic/noradrenergicagonist, has been shown to be effective in treatingchildren with ADHD.'"'56' However, most studies ofbupropion in ADHD are limited by their small sam-ple sizes and focus on symptoms of aggression,not ODD. Bupropion has a favourable adverse ef-fect profile, with low cardiotoxicity. A newer slow-release formulation of bupropion is a potential can-didate for the treatment of co-morbid ADHD andalcohol/substance use disorder, for several reasons.First, its status as an indirect dopamine agonist andenhancer of noradrenaline (norepinephrine) bio-

availability is positive.''* '̂ Having both noradrener-gic and dopaminergic mechanisms may make it auseful agent for the treatment of ADHD. Bupropionmay decrease hyperactivity and aggression, and per-haps improve cognitive performance in childrenwith ADHD and CD.'̂ '-^^] Qne double-blind, cross-over study found the efficacy of bupropion to bestatistically equal to methylphenidate in childrenand adolescents with ADHD.'^^' Although similar toother nonstimulant medications, the behavioural ef-fects of bupropion may be greater than the cogni-tive effects. Bupropion is administered in two orthree doses, beginning with a low dose (37.5 or50 mg) twice daily, with titration over 2 weeks to ausual maximum of 250 mg/day in children and300-400 mg/day in adolescents. The most seriouspotential adverse effect with this drug is a decreasein the seizure threshold, seen most frequently in pa-tients with eating disorders or at dosages >450 mg/day.

There have been some positive reports about theeffects of the serotonin-noradrenaline reuptake in-hibitor (SNRI) venlafaxine on ADHD symptoms inadults,'*'''^^' but there are as yet no controlled studiesin children that have a major focus on not onlyADHD symptoms but also the common co-morbiddisorder, ODD.

3.4 a2-Agonist$

The a2-agonists, cionidine and guanfacine, maybe considered as second-line medications for thetreatment of ADHD.

Studies with cionidine in patients with ADHDhave reported treatment effectiveness.'̂ *-^ '̂ A pilotstudy of methylphenidate, cionidine or the combina-tion of these agents in ADHD co-morbid with ag-gressive ODD or CD showed positive effects ofcionidine on behavioural problems, including ODDsymptoms.'^^' In a meta-analysis of 11 randomized,double-blind, controlled studies from 1980 to 1999,cionidine demonstrated a moderate effect size of0.58 on symptoms of ADHD alone and with co-morbid CD, developmental delay and tic disor-ders.'^^' Results from an open-label pilot study ofcionidine (maximum optimal dosage 0.4 mg/day) in

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Psychopharmacological Treatment of Oppositional Defiant Disorder

aggressive children indicate that this medicationmay be associated with reductions in aggression andhave only mild adverse effects.t^ '̂

The following patient groups may be consideredfor a trial with clonidine or guanfacine: patients withADHD and CD, patients with ADHD and severeODD, ADHD patients with tics or Tourette's syn-drome, and patients with ADHD and ODD who donot respond to treatment with psychostimulants andatomoxetine. Clonidine and guanfacine remain use-ful in selected ADHD patients who respond better tothese medications than other drugs, but the magni-tude of efficacy and/or the tolerability of these medi-cations have limited their use. Well controlled stud-ies with larger sample sizes are required to furtherdefine their role. Clonidine and guanfacine have notbeen approved by the FDA for the treatment ofADHD and ODD.

3.5 Mood Regulators

The most commonly used and studied mood reg-ulators for aggression and mood dysregulation arelithium, carbamazepine and valproate (valproicacid).

Two placebo-controlled studies demonstratedthat, at therapeutic concentrations, lithium was effi-cacious and well tolerated for the short-term treat-ment of aggressive inpatient children and adoles-cents with CD.'^°'^" A third study found no differ-ences between lithium and placebo in a smallsample of inpatient adolescents with CD; however,lithium was administered for only 2 weeks.''^' Acontrolled trial comparing lithium, haloperidol andplacebo showed that both lithium and haloperidolwere efficacious for the treatment of inpatient ag-gressive children with CD, but lithium was bettertolerated than haloperidol.I'^i

A small pilot study'''*' of carbamazepine showedeffectiveness in reducing aggressive behaviour inhospitalized adolescents with aggressive behaviourand CD. However, when administered in dosages of400-800 mg/day in a small, double-blind, placebo-controlled study of 22 prepubertal children, carba-mazepine at therapeutic concentrations was not sig-

nificantly better than placebo for the control ofaggressive behaviour.''^'

There have been no studies published to dateregarding the effectiveness and tolerability of lamo-trigine in the treatment of ODD.

For children and adolescents with ADHD andbipolar disorders, either mood regulators or risper-idone or the combination of these agents may beconsidered.''^' When bipolar disorder symptoms areunder control, patients with ADHD may require thecareful addition of psychostimulants or atomoxe-tine. Clinicians should closely monitor patients withbipolar disorder and ODD to ensure that psychos-timulant use does not provoke a manic or hypoman-ic episode. In summary, highly complicated cases ofbipolar disorder, ADHD and CD may require closeconsultation with a child and adolescent psychiatristand a highly specialized clinic to support generalpractitioners and paediatricians in treating these pa-tients.'""*'

In patients with mood disorders, ODD andADHD, mood regulators may have a role in treat-ment. ODD symptoms may improve with the effec-tive treatment of the mood disorder and the ADHD.

3.6 Antipsychotics

One of the most significant reasons for reviewingthe use of antipsychotic medications in the treatmentof ODD is the close links between ODD and aggres-sive behaviour, and ODD and CD. Methylphenidatehas been found to be significantly more effectivethan placebo, and well tolerated in the treatment of alarge group of outpatients (children and adolescents)with CD. Most of these patients also had ODD."^'The adverse effect profile of psychostimulants maymake them preferable to antipsychotics for treatingthese patients. Patients who do not respond to trialswith psychostimulants may still present a danger tothemselves and others because of verbal and physi-cal aggression. These symptoms may require a trialwith newer generation atypical antipsychotics.

Atypical antipsychotics are used to treat aggres-sive and oppositional behaviours that do not respondto other medications. Risperidone is the most stud-ied medication in this category, with placebo-con-

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10 Turgay

trolled, multicentre trials in patients with CD andODD, with or without ADHD. Risperidone wasreported to be superior to placebo and well toleratedin the short-term treatment of a small group ofoutpatient children and adolescents with ODD andCD.'9^'

The effectiveness of risperidone has also beendemonstrated in children with ODD and CD with asub-average IQ, autism or other pervasive develop-mental disorders, and other disruptive behaviourdisorders (DBDs), with or without ADHD.'^^'^' Arandomized controlled trial of risperidone in thetreatment of aggression in hospitalized adolescentswith sub-average cognitive abilities showed effec-tiveness in oppositional behaviour and aggres-sion.'^^' A double-blind, placebo-controlled, multi-site study established the role of risperidone in con-trolling oppositional, defiant, aggressive and self-injurious behaviour of children with autism andother pervasive developmental disorders."°°' Ad-verse effects, including sedation with secondarycognitive effects, hypotension, extrapyramidalsymptoms, tardive dyskinesias and obesity, shouldbe weighed up against the possible benefits of phar-macological treatment.

A randomized, double-blind, placebo-controlledstudy was conducted to determine whether risper-idone was effective in reducing symptoms of disrup-tive behaviours (such as aggression, impulsivity,defiance of authority figures and property destruc-tion) associated with ODD, CD and DBDs not other-wise specified (NOS) in children with a sub-averagejQ [101] jj^g jj.jgj consisted of a 1-week, single-blind,placebo run-in period and was followed by a 6-weektreatment phase. 110 children (aged 5-12 years,inclusive) with an IQ of 36-84, a DBD and ascore of >24 on the Conduct Problem subscale ofthe Nisonger Child Behavior Rating Form(NCBRF)''°^' were involved. Eighty percent of pa-tients had co-morbid ADHD. The risperidone dos-ages ranged from 0.02 to 0.06 mg/kg/day. The mostcommon adverse effects included somnolence,headache, appetite and weight increase. Risperidoneappeared to be an adequately tolerated and effectivetreatment in children with sub-average IQ and se-

vere DBDs such as aggression and destructive beha-viour.'""'

A long-term study also investigated the safetyand efficacy of risperidone in DBDs in children withsub-average IQ."°^' DBDs were defined as ODD,DBD-NOS and CD, as per DSM-IV diagnostic cri-teria. This 48-week, open-label extension study ofrisperidone was conducted in 77 children diagnosedwith a DBD and either borderline intellectual func-tion, or mild or moderate mental retardation whohad participated in the above outlined study.'""'Participants received an oral solution of risperidoneadministered at a once-daily dose of between 0.02and 0.06 mg/kg for a maximum of 54 weeks."°^'Somnolence, headache and weight gain were themost common adverse effects. The degree of seda-tion was mild and transitional, and was not asso-ciated with cognitive deterioration. Approximatelyhalf of the 8.5 kg average weight gain was attributa-ble to normal growth. At the study endpoint, themean prolactin level was statistically significantlygreater than baseline in male participants only, butwas still <20 ng/mL, which is within the normalrange. Twenty participants experienced mild ormoderate extrapyramidal symptoms, although nonewithdrew for this reason. The authors concluded thatrisperidone was effective and safe in controllingDBDs in children between the ages of 5 and12 years, with or without ADHD."°^'

Similar findings on the effects of risperidone insevere ODD and CD with aggression in childrenwith sub-average intelligence with or withoutADHD have been reported in an almost mirror-image US multicentre study.''""' The effects of ris-peridone in the presence/absence of psychostimu-lant medicine in children with ADHD, other DBDsand sub-average IQ were reported''"^' as a sub-analysis of the study by Snyder et al.,"°" with aspecific focus on the anti-ADHD effects of risper-idone. The analysis included 155 children withmental retardation or borderline intellectual func-tioning who presented with either CD or ODD.''°^'All children had serious aggressive behaviours. Thechildren were divided into four subgroups (with3 5 ^ 3 patients in each) - placebo only, psychostim-

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Psychopharmacological Treatment of Oppositional Defiant Disorder 11

ulant only, placebo plus risperidone, or risperidoneplus psychostimulant. Within each randomizedtreatment group, actual weight gain was com-parable, regardless of concomitant stimulant use.The addition of risperidone to a psychostimulantresulted in significantly better control of hyperactiv-ity (p < 0.001) than was achieved with stimulanttreatment alone, without causing an increase in ad-verse events. The study concluded that, in this typeof patient population, risperidone was effective incontrolling ADHD, aggression, and CD or ODDsymptoms.''"^'

For patients with severe aggression and ODD orCD with or without ADHD (who do not respond topsychostimulants and atomoxetine), the recommen-ded starting dosage of risperidone is 0.02 mg/kg/day. The dosage can be increased gradually up to0.06 mg/kg/day."'ioi.iO3-iO5] xhe use of risperidone,with or without sedating medications, for the man-agement of adult patients with variable agitation andaggression in emergency settings has also been re-ported, "»«•'o '̂

The maintenance of positive effects, with im-provements in weight control and decreases in pro-lactin levels after the initial few months of risper-idone use, has been reported.''"^' Concerns regard-ing initial weight gain and prolactin increases arediminishing.

3.7 Medication Combinations

3.7.1 Stimulants and Cionidine

One of the most common medication combina-tions currently used in the treatment of ADHD is astimulant taken with cionidine. Anecdotal clinicalexperience and, more recently, controlled stud-jgj [109,110] support the usefulness of this combina-tion, particularly in children with severe ADHDwith aggressive behaviour, and for children who arenot well managed on a stimulant alone. The combi-nation of cionidine and psychostimulants may allowfor a lower dose of stimulant medication.'""^

Some clinicians add cionidine before bedtime tocancel out the sleep-suppressant effects of stimu-lants.""' The addition of cionidine to psychostimu-lants may improve the ability to fall asleep, whether

insomnia is due to ADHD over-arousal, opposition-al refusal, or stimulant effect or rebound.'"^^

However, questions have been raised about thesafety of the combination of cionidine and stimu-lants.""' Four deaths have been reported to the FDAof children who at one time had been taking bothmethylphenidate and cionidine; the evidence linkingthese medications to the deaths is tenuous at thistime.''°'l Pending additional data, caution is advisedwhen treating children with cardiac or cardio-vascular disease, when combining cionidine withadditional medications, or if the dosage of med-ication is different from product monographs ortreatment guidelines. Caution is also advised whenadministering methylphenidate monotherapy tochildren, adolescents and adults with possible cardi-ac problems. Paediatric cardiology consultation isrecommended for questionable cardiac problems.

Cionidine or guanfacine are considered first-lineagents in tic disorders and Tourette's syndrome dis-order because of their modest efficacy and relativelybenign adverse effect profile compared with anti-psychotic agents. A 16-week, randomized, double-blind, multicentre trial conducted in 136 childrenwith ADHD and a chronic tic disorder evaluatedcionidine, methylphenidate, and combined treat-ment with cionidine and methylphenidate comparedwith placebo. Efficacy was reported for cionidineand methylphenidate monotherapy and the greatestbenefit occurred with combined treatment withcionidine and methylphenidate (p < 0.0001 vs place-

3.7.2 Stimulants and Antidepressants

The combination of methylphenidate and imi-pramine has been associated with a syndrome ofconfusion, affective liability, marked aggression andsevere agitation.'""*' Methylphenidate may interferewith the hepatic metabolism of imipramine, result-ing in a longer half-life and elevated blood concen-trations.'"^^

Gammon and Brown"'^l combined fluoxetineand methylphenidate for the treatment of ADHDand co-morbid depressive disorder, and reported theeffectiveness and safety of this combination. The

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12 Turgay

sample size was small and it is hoped that theseresults will be replicated with a larger study.

3.7.3 Stimulants and Antipsycttotics

In three double-blind, placebo-controlled studiesof children with ODD and/or CD (with or withoutADHD) and sub-average IQ, the combination ofdexamfetamine and risperidone has been found to beeffective and well tolerated.['°'''°3.'05]

4. Treatment Algorithm for ODD

The following suggested algorithmic approachfor the treatment of ODD was developed through theintegration of the evidence-based literature re-viewed in sections 1-3 and the clinical experience ofthe author. This proposed algorithmic approach isincluded in this publication to initiate discussion anddebate, since no medication algorithm for ODDcurrently exists in the literature.

4.1 ODD Alone

Step 1: A comprehensive evaluation is requiredto establish the presence of co-morbid disorders and/or to rule out these disorders: use a general psycho-pathology screening and rating scale'̂ ^"^ '̂ or a struc-tured interview.

Step 2: For a single diagnosis of ODD, in theabsence of other psychiatric disorders, psychosocialinterventions should be attempted first.

Step 3: If psychosocial interventions do not pro-vide improvement within the first 2-3 months,either psychostimulants (which have proven effec-tiveness in the treatment of ODD) or atomoxetine(which has shown effectiveness in the treatment ofODD) may be tried. If the patient does not respondto the first medication, a second medication from adifferent class can be tried. If aggression is partof the clinical picture, the first two trials shouldbe either a methylphenidate- or amfetamine-basedmedication. For example, if a methylphenidate-based medication is tried and the patient does notrespond, the next trial can be an amfetamine-basedpsychostimulant or atomoxetine. Since patients withODD do not comply well with taking medication,long-acting medications are recommended in order

to increase compliance, which can be monitored byparents in the mornings. If the first two trials werewith psychostimulants, and an adequate response isnot achieved, then a trial with atomoxetine is indi-cated. Children and adolescents with serious behav-ioural issues who do not respond to psychosocialinterventions followed by psychostimulants oratomoxetine may be considered for a trial with ris-peridone.

4.2 ODD + ADHD, Without Anxiety, Moodor Tic Disorders

For most patients with ODD and co-morbidADHD, aggression is part of the clinical pic-ture; either methylphenidate- or amfetamine-basedpsychostimulants should be tried first (see step 3 asdetailed in section 4.1 ).

4.3 ODD + ADHD + Either Tic and/orAnxiety Disorders

Atomoxetine can be tried first. For patients whohave not responded to a trial with atomoxetine,either a methylphenidate- or amfetamine-based trialmay follow. For patients who have not respondedto any of these drugs, a trial with imipramine canbe undertaken. For patients with ADHD + ODD +tic disorders without anxiety disorders, clonidineor guanfacine may be tried. Patients with severeaggressive behaviours who do not respond to psy-chostimulants and who continue to be a threat totheir own safety or the safety of others, may requirethe use of risperidone alone or in combination withpsychostimulants until the aggressive behavioursare under control.

4.4 ODD + Mood Disorders + ADHD

For patients with severe mood disorders, an ef-fective antidepressant (possibly an SSRI) can beinitiated. After the clearance of major mood disordersymptoms, the treatment of the remaining ODD andADHD symptoms may require additional medica-tions. The safety of combining atomoxetine withantidepressants has not yet been established; how-ever, the safety of the combination of SSRIs orTCAs with psychostimulants has been well estab-

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Psychopharmacological Treatment of Oppositional Defiant Disorder 13

A methylphenidate- or amfetamine-based psychostimulant can therefore be combinedwith antidepressant medication. For adults withODD and mood disorders, imipramine or desipra-mine can also be considered, as TCAs are effectivein treating ADHD symptoms. In children and ado-lescents, TCAs were not found to be effective intreating major

4.5 Other Multiple Co-Morbidities

For patients whose multiple co-morbid condi-tions associated with ODD do not fit into any of thecombinations described above, an urgent consulta-tion with a clinic or clinician specializing in thetreatment of ODD is advised. Children and adoles-cents with ODD (with or.without ADHD) who havedepression and suicidal thoughts have a high risk forself-injurious behaviour and suicide. An urgentchild and adolescent psychiatric consultation maysupport the primary care physicians dealing withthese complicated patients.'̂ ^1

Over the last few years American, Canadian andEuropean reviews and position papers, as well asbooks, have been published that have includedguidelines for the use of medications in the treat-ment of ADHD and ODD.I^^"^""^! These reviewpapers and practice parameters have recommendeda 'multimodal and extensive' approach involvingindividual and family therapeutic, psychosocial ap-proaches and medication in the treatment of ODD.

5. Conclusion

ODD is a common disorder in childhood andadolescence, in both clinical and nonclinical sam-ples. Simple ODD without other co-morbid disor-ders is a serious clinical syndrome, often leading toisolation and socialization difficulties. In somecases, it can lead to more serious psychopathology,such as CD and substance abuse.

The presence of ODD increases the risk of havingco-morbid ADHD and CD. Official diagnostic clas-sification systems and evidence-based studies ofODD clearly establish the links between ODD,ADHD and CD. There is significant support in theresearch to indicate that some patients with ODD

develop CD, and ODD seems to be a milder versionof CD. Hence, ODD should be identified and treatedas early and as effectively as possible.

Most of our knowledge regarding the pharmaco-therapy of ODD is based on co-morbidity studies ofODD with ADHD and/or CD. It is unfortunate thatthere is a lack of strong, evidence-based studiesregarding the treatment of simple ODD, particularlyin community samples. It is hoped that future re-search will shed light on this area as there are manyODD patients with severe and long-standing symp-toms who do not respond to psychosocial interven-tions and/or are not motivated to pursue such treat-ment alternatives.

A few controlled studies of patients with co-morbid ODD and ADHD indicate that ADHD medi-cations are also effective in treating ODD. The dosesof medication may need to be higher when ODD isassociated with ADHD. It is hoped that research inthe near future will focus on ODD-specific researchwith patients in community samples. As the MTAstudy'̂ ^^ demonstrated, the presence of ODD in chil-dren and adolescents with ADHD may require psy-chosocial and psychoeducational interventions ad-ded to medication treatment.

Future studies on the comparative effectivenessof psychosocial and medication approaches andtheir combination in the management of ODD withor without its common co-morbidities may clarifythe most effective treatment alternatives for ODD.This may empower those in the health and mentalhealth systems to treat patients with ODD, and mayaid in the prevention of more serious psychopatholo-gies, including CD.

Acknowledgements

No sources of funding were used to assist in the prepara-tion of this review. The author has no conflicts of interest thatare directly relevant to the content of this review.

References1. American Psychiatric Association. Diagnostic and statistical

manual of mental disorders. 4th ed., text revision. Washington,DC: American Psychiatric Association, 2000

2. Barkley R. Attention deficit hyperactivity disorder, a handbookfor diagnosis and treatment. New York: The Guilford Press,2006

© 2009 Adis Data Information BV. Aii righits reserved. CNS Dmgs 2009; 23(1)

14 Turgay

3. World Health Organization. International classification of dis-eases (ICD-10). Geneva: World Health Organization, 1994

4. Essau CA. Conduct and oppositional defiant disorders: epidemi-ology, risk factors and treatment. Mahwah (NJ): LawrenceEarlbaum Associates, 2003

5. Hinshaw SP. On the distinction between attentional deficit/hyperactivity and conduct probletns/aggression in childpsychopathology. Psychological Bulletin 1987; 101: 443-63

6. Ansari R, Turgay A, Ng D, et al. ADHD cotnorbidity in psychi-atric disorders: subtype and gender relationships [poster]. In:New research abstracts: American Psychiatric Association An-nual Meeting; 2004 May 1-6; New York. Arlington (VA):American Psychiatric Association, 2004: 89

7. Turgay A. Treatment of comorbidity in conduct disorder. DirPsychiatry 2003; 23: 137-49

8. Turgay A, Joseph L, Nag SA, et al. Oppositional defiant disor-der, conduct disorder and ADHD relationships [abstract]. On-tario Psychiatric Association Annual Scientific Conference;

' 2003 Jan 30; Toronto (ON)9. Turgay A, Joseph L, Nag SA, et al. High risk of conduct and

mood disorders in children and adolescents with ADHD andoppositional defiant disorder [abstract]. Ontario PsychiatricAssociation Annual Scientific Conference; 2003 Jan 28-30,Toronto (ON)

10. Turgay A. The aggressive and impulsive child: innovations inthe assessment and treatment of attention deficit hyperactivitydisorder and disruptive behaviour disorders. Paediatr ChildHealth 2004; 9 SuppI. 9: 3B

11. Turgay A. Aggression and disruptive behavior disorders inchildren and adolescents. Expert Rev Neurother 2004; 4 (4):623-32

12. Turgay A. The diagnosis of disruptive behavior disorders.Paediatr Child Health 2004; 9 SuppI. B: 4-7B

13. Vitiello D, Jensen PS. Disruptive behavior disorders. In: KaplanHI, Sadock BJ. Comprehensive textbook of psychiatry: IV.Vol. 2. Baltimore (MD): Williams and Wilkins, 1995: 2311-9

14. Ansari R, Turgay A, Ng D, et al. ADHD in child and adolescentpsychiatric disorders: gender and subtype relationships [post-er]. In: New research abstracts: American Psychiatric Associa-

• tion Annual Meeting; 2004 May 1-6; New York. Arlington(VA): American Psychiatric Association, 2004: 88

15. Biederman J, Faraone S, Milberger S, et al. A prospective fouryear follow-up study of attention-deficit hyperactivity andrelated disorders. Arch Gen Psychiatry 1996; 53: 437-46

16. Lahey BB, Loeber R, Quay HC, et al. Oppositional defiant andconduct disorder: issues to be resolved for DSM -IV. J AmAcad Child Adolesc Psychiatry 1992; 29: 620-6

17. Turgay A, Ansari R, Schwartz M, et al. Comorbidity differencesin ADHD throughout the life cycle [abstract]. Scientific andclinical report session of the American Psychiatric AssociationAnnual Scientific Meeting; 2005 May 21-26; Atlanta (GA)

18. Herjanic B, Campbell W. Differentiating psychiatrically dis-turbed children on the basis of a structured interview.J Abnorm Child Psychol 1977; 5: 127-34

19. Shaffer D, Fisher P, Lucas CP, et al. Diagnostic interviewschedule for children, version IV (NIMH DISC-IV): descrip-tion, differences from previous versions, and reliability ofsome common diagnosis. J Am Acad Child Adolesc Psychia-try 2000; 39: 28-38

20. Ambrossini P, Metz C, Probucki K, et al. Videotape reliabilityof the third revised edition of the K-SADS. J Am Acad ChildAdolesc Psychiatry 2000; 39: 49-58

21. Achenbach T. Assessment and taxonomy of child and adoles-cent psychopathology. Beverly Hills (CA): Sage, 1985

22. Offord DR, Boyle MH, Szatmari P, et al. Ontario child healthstudy: II. Six-month prevalence of disorder and rates of serviceutilization. Arch Gen Psychiatry 1987; 44: 832-6

23. Gadow KD, Sprafkin J. Child symptom inventory. Stonybrook(NY): Checkmate Plus, 1987

24. Conners CK. Conners' rating scales revised: instruments for usewith children and adolescents. North Tonawanda (NY): MultiHealth Systems, 1997

25. Conners CK, Parker JDA, Citarenios G, et al. The revisedConners' parent rating scale (CPRS-R): factor structure, relia-bility, and criterion validity. J Abnorm Child Psychol 1997;26: 257-68

26. Turgay A. ADHD and disruptive behavior disorders screeningand rating scale. West Bloomfield (MI): Integrative TherapyInstitute, 1994

27. Harada Y, Saitoh K, Iida J, et al. The reliability and validity ofthe oppositional defiant behavior inventory. Eur Child AdolescPsychiatry 2004; 13 (3): 185-90

28. Loeber R, Wung P, Keenan K, et al. Developmental pathways indisruptive child behavior. Dev Psychopathol 1993; 55: 102-33

29. Anderson JC, Williams S, McGee R, et al. DSM-lII disorders inpréadolescent children: prevalence in a large sample fromgeneral population. Arch Gen Psychiatry 1987; 44: 69-76

30. Faraone SV, Biederman J, Keenan K, et al. Separation of DSM-111 attention deficit disorder and conduct disorder: evidencefrom a family genetic study of American child psychiatricpatients. Psychol Med 1991; 21: 109-21

31. Loeber R. The natural histories of juvenile conduct problems,substance use and delinquency: evidence for developmentalprogressions. In: Lahey BB, Kazdin AE, editors. Advances inclinical child psychology. Vol. 2. New York: Plenum, 1998:73-124

32. Walker LL, Lahey BB, Russo MF, et al. Anxiety, inhibition, andconduct disorder in children: I. Relations to social impairment.J Am Acad Child Psychiatry 1991; 30: 187-91

33. Lahey BB, Loeber R. Framework for a developmental model of. oppositional defiant disorder and conduct disorder. In: RouthDK, editor. Disruptive behavior disorders in childhood. NewYork: Plenum, 1994: 139-80

34. Ferguson DM, Horwood LJ, Lynskey MT. Prevalence and co-morbidity of DSM-III-R diagnosis in a birth cohort of 15 yearsolds. J Am Acad Child Adolesc Psychiatry 1993; 32: 1127-34

35. Farrington DP, Loeber R, Van Kämmen WB. Longer-termcriminal outcomes of hyperactivity-impulsivity-attention defi-cit and conduct problems in childhood. In: Robins LN, Rut-ter M, editors. Straight and devious pathways to adulthood.New York: Cambridge University Press, 1990: 62-81

36. Hinshaw SP, Lahey B, Hart L. Issues of taxonomy and comor-bidity in the development of conduct disorder. Dev Psy-chopathol 1992; 5: 31-49

37. McGee R, Freehan M, Williams S, et al. DSM-III disordersfrom age 11 to 15 years. J Am Acad Child Adolesc Psychiatry1992; 31: 50-9

38. Nottelman ED, Jensen PS. Comorbidity of depressive disordersin children and adolescents: rates, temporal sequencing, courseand outcome. In: Esau CA, Petermann F, editors. Depressivedisorders in children and adolescents: epidemiology, risk fac-tors, and treatment. Northvale (NJ): Jason Aronson, 1999: 137-91

39. Arredondo DE, Butler SF. Affective comorbidity in psychiatri-cally hospitalized adolescents with conduct disorder of opposi-

© 2009 Adis Data Information BV. Ail riglits reserved. CNS Drugs 2009; 23(1)

Psychopharmacological Treatment of Oppositional Defiant Disorder 15

tional defiant disorder; should conduct disorder be treated withmood stabilizers? J Child Adolesc Psychopharmacol 1994; 4:151-8

40. MTA Cooperative Group. Moderators and mediators of treat-ment response for children with attention-deficit/hyperactivitydisorder. Arch Gen Psychiatry 1995; 56; 1088-96

4L Greene RW; Doyle AE. Toward a transactional conceptualiza-tion of oppositional defiant disorder; implications for assess-ment and treatment. Clin Child Fam Psychol Rev 1999; 2; 129-48

42. Cohen P, Flory M. Issues in the disruptive behavior disorders;attention deficit disorder without hyperactivity and the differ-ential validity of oppositional defiant and conduct disorders.In; Widiger T, editor. DSM-IV source book. Vol. 4. Washing-ton, DC; American Psychiatric Press, 1998; 463

43. Offord DR, Kraemer HC, Kazdin AE, et al. Lowering theburden of suffering from child psychiatric disorder; trade-offsamong clinical, targeted and universal interventions. J AmAcad Child Adolesc Psychiatry 1998; 37; 686-94

44. Lahey BB, Loeber R, Hart EL, et al. Four year longitudinalstudy of conduct disorder in boys; patterns and predictors ofpersistence. J Abnormal Psychology 1995; 104; 83-93

45. Turgay A, Joseph LW, Duncan P, et al. The presence of opposi-tional defiant disorder in ADHD increases the risks for conductdisorder and mood disorders. Canadian Psychiatric Associa-tion Annual Scientific Meeting; 2001 Nov 15-18; Montreal(QC)

46. Turgay A, Morgan A, Mok L, et al. Chronic and serious aggres-sive behavior in children and adolescents are commonly asso-ciated with psychiatric disorders [abstract]. Paediatr ChildHealth 2001; 6 Suppl. A; 14

47. Coy K, Speltz ML, DeKleyn M, et al. Social-cognitive process-es in preschool boys with and without oppositional defiantdisorder. J Abnorm Psychol 2001; 29; 107-19

48. Coie JD, Dodge KA. The development of aggression and antiso-cial behavior. In; Eisenberg N, editor. Handbook of childpsychology; social, emotional, and personality development.Vol. 3. New York; Wiley, 1998; 779-861

49. Offord D, Bennett K. Conduct disorder; long-term outcomesand intervention effectiveness. J Am Acad Child AdolescPsychiatry 1994; 33; 1069-78

50. Webster-Stratton C. Strategies for helping early school-agedchildren with oppositional defiant and conduct disorders; theimportance of home-school partnerships. School Psych Rev1993; 22; 437-57

5L Greene RW, Ablon JS, Goring JC, et al. Effectiveness of collab-orative problem solving in affectively dysregulated childrenwith oppositional-defiant disorder; initial findings. J ConsultClin Psychol 2004; 72 (6); 1157-64

52. Brestan EV, Eyberg SM. Effective psyehosocial treatments ofconduct-disordered children and adolescents; 29 years, 82studies, and 5272 kids. J Clin Child Psychol 1998; 27; 180-9

53. Kazdin AE. Parent management training; evidence, outcomes,and issues. J Am Acad Child Adolesc Psychiatry 1997; 36;1349-56

54. Schumann EM, Foote RC, Eyberg SM, et al. Efficacy of parent-child interaction therapy; interim report of a randomized trialwith short-term maintenance. J Clin Child Psychol 1998; 27;34-45

55. MTA Cooperative Group. 14-month randomized clinical trial oftreatment strategies for attention deficit hyperactivity disorder.Arch Gen Psychiatry 1999; 56; 1073-86

56. Turgay A, Jain U, Bedard AC, et al., on behalf of the CanadianADHD Resource Alliance (CADDRA). Canadian AD/HDpractice guidelines. Toronto (ON); Canadian AD/HD Re-source Alliance, 2008

57. Banaschewski T, Coghill D, Santosh P, et al Long-actingmedications for the hyperkinetic disorders; a systematic re-view and European treatment guideline. Eur Child AdolescPsychiatry 2006 Dec; 15 (8); 476-95

58. Newcom J, Spencer T, Biederman J, et al. Atomoxetine treat-ment in children and adolescents with attention-deficit/hyper-activity disorder and comorbid oppositional defiant disorder.J Am Acad Child Adolesc Psychiatry 2005; 44; 240-8

59. Bradley C. The behavior of children receiving benzedrine. Am JPsychiatry 1937; 94; 577-85

60. Conners CK, Eisenberg L, Barcai A. Effect of dextroam-phetamine on children; studies on subjects with learning disa-bilities and school behavior problems. Arch Gen Psychiatry1967; 17; 478-85

61. Waschbusch DA, Willoughby MT. Parent and teacher ratings onthe IOWA Conners Rating Scale. J Psychopathol Behav 2007;30; 180-92

62. Swanson JM, Kraemer HC, Hinshaw SP, et al. Clinical rele-vance of the primary findings of the MTA; success rates basedon severity of ADHD and ODD symptoms at the end oftreatment. J Am Acad Child Adolesc Psychiatry 2001; 40;168-79

63. Abikoff H, Gittelman R. Hyperactive children treated withstimulants; is cognitive training a useful adjunct? Arch GeneralPsychiatry 1985; 42; 953-61

64. Richters JE, Arnold LE, Jensen PS, et al. NIMH collaborativemulti-site multimodal treatment study of children with ADHD;I. Background and rationale. J Am Acad Child Adolesc Psy-chiatry 1995; 34; 987-1000

65. Hinshaw SP. Stimulant medication in the treatment of aggres-sion in children with attention deficits. J Clin Child Psychol1991; 12; 301-12

66. Steele M, Jensen PS, Quinn DM. Remission versus response asthe goal of therapy in ADHD; a new standard for the field?Clin Ther 2006; 28; 1892-908

67. Jensen P. Standards of the use of stimulants. Paediatr ChildHealth 2004; 9 Suppl. B; 8-12B

68. Barkley RA, McMurray M, Edelbroch C, et al. Side effects ofMPH in children with attention deficit hyperactivity disorder; asystemic placebo-controlled evaluation. Pediatrics 1990; 86;184-92

69. Pliszka SR, McCracken JT, Maas JW. Catecholamines in atten-tion-deficit-hyperactivity disorder; current perspectives. J AmAcad Child Adolesc Psychiatry 1996; 35; 264-72

70. Pappadopulos E, Woolston S, Chait A, et al. Pharmacotherapyof aggression in children and adolescents; efficacy and effectsize. J Can Acad Child Adolesc Psychiatry 2006; 15; 27-39

71. Dunn D, Turgay A, Weiss M, et al. Use of plasma concentrationto guide atomoxetine doses in ADHD patients [poster]. In;New Research Abstracts; American Psychiatric AssociationAnnual Meeting; 2005 May 21-26; Atlanta (GA). Arlington(VA); American Psychiatric Association, 2005; 187

72. Turgay A. Atomoxetine in the treatment of children, adolescentsand adults. Future Drugs 2006; 3 (1); 19-38

73. Faries DE, Yalcin I, Harder D, et al. Validation of the ADHDrating scale as a clinician administered and scored instrument.J Atten Disord 2001; 5; 107-15

74. Conners CK. Conners' rating scales-revised; technical manual.New York; Multi-Health Systems, 1997

© 2CX)9 Adis Data Information BV. All rights resen/ed. CNS Drugs 2009; 23 (1)

16 Turgay

75. Kelsey DK, Sumner CR, Casat CD. Once-daily atomoxetinetreatment for children with attention-deficit/hyperactivity dis-order, including an assessment of evening and morning beha-viour: a double-blind, placebo-controlled trial. Pediatrics2004; 114(l):el-8

76. Michelson D, Faries D, Wenichke J, et al. Atomoxetine in thetreatment of children and adolescents with ADHD: a random-ized, placebo-controlled, dose-response study. Pediatrics2001; 108: e83

77. Spencer T, Biederman J, Heilingestein J, et al. An open-label,dose-ranging study of atomoxetine in children with attentiondeficit hyperactivity disorder. J Child Adolesc Psychopharma-col 2001; 11 (3): 251-65

78. Ryan ND. The pharmacologie treatment of child and adolescentdepression. Psychiatr Clin North Am 1992; 15: 29-40

79. Turgay A, Ansari R. Major depression with ADHD in childrenand adolescents. Psychiatry 2006; 3: 20-32

80. Riddle MA, Nelson JC, Kleinman CS, et al. Sudden death inchildren receiving Norpramine®: a review of three reportedcases and commentary. J Am Acad Child Adolesc Psychiatry1991;.30: 104-8

81. Conners CK, Cast CD, Guiltieri CT, et al. Bupropion hydrochlo-ride in attention deficit hyperactivity disorder. J Am AcadChild Adolesc Psychiatry 1996; 35: 1314-21

82. Simeon JG, Ferguson HB, Van Wyck Fleet J. Bupropion effectsin attention deficit and conduct disorders. Can J Psychiatry1986; 31:581-5

83. Barrickman LL, Perry PJ, Allen AJ, et al. Bupropion versusmethylphenidate in the treatment of attention-deficit hyperac-tivity disorder. J Am Acad Child Adolesc Psychiatry 1995; 34:649-57

84. Findling RL, Schwartz MA, Flannery DJ, et al. Venlafaxine inadults with attention-deficit hyperactivity disorder: an open-label clinical trial. J Clinical Psychiatry 1996; 57: 184-9

85. Hedges D, Reimherr FW, Rogers A, et al. An open trial ofvenlafaxine in adult patients with attention deficit hyperactivi-ty disorder. Psychopharmacol Bull 1995; 31: 779-83

86. Connor DF, Barkley RA, Davis HT, et al. A pilot study ofmethylphenidate, cionidine, or the combination in ADHD co-morbid with aggressive oppositional defiant or conduct disor-der. Clin Pediatr (Phila) 2000; 39: 15-25

87. Hunt D, Minderaa R, Cohen D. The therapeutic effect of cioni-dine in attention deficit disorder with hyperactivity: a compari-son with placebo and methylphenidate. Psychopharmacol Bull1986; 22: 229-36

88. Connor DF, Fletcher KE, Swanson J. A meta-analysis of cioni-dine for symptoms of attention-deficit hyperactivity disorder.J Am Acad Child Adolesc Psychiatry 1999; 38: 1551-9

89. Kemph JP, De Vane CL, Levin GM, et al. Treatment of aggres-sive children with cionidine: results of an open pilot study.J Am Acad Child Adolesc Psychiatry 1993; 32: 577-81

90. Campbell M, Adams P, Small A, et al. Lithium in hospitalizedaggressive children with conduct disorder: a double-blind andplacebo-controlled study. J Am Acad Child Adolesc Psychia-try 1995; 34: 445-53

91. Malone RP, Delaney MA, Luebbert JF, et al. A double-blindplacebo-controlled study of lithium in hospitalized aggressivechildren and adolescents with conduct disorder. Arch GenPsychiatry 2000; 57: 649-54

92. Rifkin A, Karajgi B, Dicker R, et al. Lithium treatment ofconduct disorders in adolescents. Am J Psychiatry 1997; 154:554-5

93. Campbell M, Small AM, Green WH, et al. Behavioral efficacyof haloperidol and lithium carbonate: a comparison in hospital-ized aggressive children with conduct disorder. Arch GenPsychiatry 1984; 41: 650-6

94. Kafantaris V, Campbell M, Padron-Gayol MV, et al. Carbama-zepine in hospitalized aggressive conduct disorder children: anopen pilot study [published erratum appears in Psychopharma-col Bull 1992; 28 (3): 220]. Psychopharmacol Bull 1992; 28:193-9

95. Cueva JE, Overall JE, Small AM, et al. Carbamazepine inaggressive children with conduct disorder: a double-blind andplacebo-controlled study. J Am Acad Child Adolesc Psychia-try 1996; 35: 480-90

96. Klein R, Abikoff H, Klass E, et al. Clinical efficacy of methyl-phenidate in conduct disorder with and without attention defi-cit hyperactivity disorder. Arch Gen Psychiatry 1997; 54:1073-80

97. Findling RL, McNamara NK, Branicky LA, et al. A double-blind pilot study of risperidone in the treatment of conductdisorder. J Am Acad Child Adolesc Psychiatry 2000; 39: 509-16

98. Aman MG, De Smedt G, Derivan A, et al. Double-blind, place-bo-controlled study of risperidone for the treatment of disrup-tive behavior disorders in children with subaverage intelli-gence. Am J Psychiatry 2002; 159: 1337-46

99. Buitilaar JK, van der Gaag RJ, Chohen-Kettenis P, et al. Arandomized controlled trial of risperidone in the treatment ofaggression in hospitalized adolescents with subaverage cogni-tive abilities. J Clin Psychiatry 2001; 62: 239-48

100. Shea S, Turgay A, Jones S, et al. Risperidone in the treatment ofbehavioral symptoms in children with autistic and other perva-sive developmental disorders. Pediatrics 2004; 114: 634-41

101. Snyder R, Turgay A, Aman M, et al. Effeets of risperidone onconduct and disruptive behavior disorders in children withsubaverage IQs. J Am Acad Child Adolesc Psychiatry 2002;41 (9): 1026-36

102. Aman MG, Tassé MJ, Rojahn J, et al. The Nisonger CBRF: achild behavior rating form for children with developmentaldisabilities. Res Dev Disabil 1996; 17 (1): 41-57

103. Turgay A, Binder C, Snyder R, et al. Long term safety andefficacy of risperidone for the treatment of disruptive behaviordisorders in children with subaverage IQs. Pediatrics 2002;100(3): e34

104. Findling RL, Aman MG, Eerdekens M, et al. Long-term, open-label study of risperidone in children with severe disruptivebehaviors and below-average IQ. Am J Psychiatry 2004; 161:677-84

105. Aman MG, Binder C, Turgay A. Risperidone effects in thepresence/absence of psychostimulant medicine in childrenwith ADHD, other disruptive behavior disorders, and subaver-age 10. J Child Adolesc Psychopharmacol 2004; 14 (2): 243-54

106. Yildiz A, Sachs GS, Turgay A. Pharmacological management ofagitation in emergency settings. Emerg Med J 2003; 20: 339-46

107. Yildiz A, Turgay A, Alpay M, et al. Observational data on theanti-agitation effect of risperidone tablets in emergency set-tings: a preliminary repon. Int J Psychiatr Clin Pract 2003; 7:217-21

108. Findling RL. Pharmacological options for treating disruptivebehavior disorders. Paediatr Child Health 2004; 9 Suppl. B:17-20B

© 2009 Adis Data Information BV. Ail rights reserved. CNS Drugs 2009; 23(1)

Psychopharmacological Treatment of Oppositional Defiant Disorder 17

109. Popper CW. Combining methylphenidate and clonidine: phar-macologie questions and news reports about sudden death.J Child Adolesc Psychopharmacol 1995; 5: 157-66

110. Hunt RD, Capper S, O'Donnell P. Clonidine in child andadolescent psychiatry. J Child Adolesc Psychopharmacol1990; 1: 87-102

111. Bukstein OG. Psychopharmacology of disruptive behavior dis-orders. In; Essau C, editor. Conduct and oppositional defiantdisorders: epidemiology, risk factors and treatment. Mahwah(NJ): Lawrence Erlbaum Associates, 2003: 319-55

112. Wilens TE, Biederman J, Spencer TJ. Clonidine for sleep distur-bances associated with attention deficit hyperactivity disorder.J Am Acad Child Adolescent Psychiatry 1994; 33; 424-6

113. Tourette's Syndrome Study Group. Treatment of ADHD inchildren with tics; a randomized controlled trial. Neurology2002; 58 (4); 527-36

114. Grob es , Coyle JT. Suspected adverse methylphenidate-imi-pramine interactions in children. J Dev Behav Pediatr 1986; 7;265-7

115. Carlson GA, Rapport MD, Kelly KL, et al. Methylphenidate anddesipramine in hospitalized children with comorbid behaviorand mood disorders: separate and combined effects on behav-ior and mood. J Child Adolesc Psychopharmacol 1995; 5; 191-204

116. Gammon GD, Brown TE. Eluoxetine and methylphenidate incombination for treatment of ADHD and comorbid depressivedisorder. J Child Adolescent Psychopharmacol 1993; 5; 191-204

117. Drabick DAG, Gadow DG, Loney J. Source-specific opposi-tional defiant disorder; comorbidity and risk factors in referredelementary schoolboys. J Am Acad Child Adolesc Psychiatry2007; 46: 92-101

118. American Academy of Child and Adolescent Psychiatry. Prac-tice parameter for the assessment and treatment of children andadolescents with oppositional defiant disorder. J Am AcadChild Adolesc Psychiatry 2007; 46; 126-41

119. Banaschewski T,RoessnerV,Dittman RW, etal. Non-stimulantmedications in the treatment of ADHD. Eur Child AdolescPsychiatry 2004; 13; 102-16

Correspondence; Prof. Dr Atilla Turgay, Toronto ADHDClinic, 1849 Yonge Street, Suite 314, Toronto, ON M4S 1Y2,Canada.E-mail; Turgay@sympatico.ca

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