Drugs Ther Perspect (2016) 32:104–109 DOI 10.1007/s40267-015-0269-y

DISEASE MANAGEMENT

Effective treatment of attention-deficit hyperactivity disorder also helps control symptoms of comorbid oppositional defiant disorder Adis Medical Writers1

Published online: 15 December 2015  Springer International Publishing Switzerland 2015

Abstract The most common comorbidity of attentiondeficit hyperactivity disorder (ADHD) is oppositional defiant disorder (ODD), and children with this combination have increased symptom severity and impairment. Treatment strategies include education, behavioural management therapy approaches, providing school and academic supports, and the use of stimulant or non-stimulant ADHD medications, depending on symptom severity and consideration of child and parental wishes. Effective ADHD treatment is also helpful for comorbid ODD symptoms.

meet full criteria for ODD [3]. The combination is associated with greater symptom severity and daily impairment, as well as a poorer prognosis than either disorder alone [2, 3]. In addition, an earlier age of comorbid ADHD and ODD is associated with persistence of the ADHD diagnosis into adolescence and young adulthood, and predicts higher rates of later anxiety and depression [4]. This article provides a summary of a review by Connor on the management of children with comorbid ADHD and ODD [3].

Clinical assessment is a multi-step procedure Children with ADHD often have ODD Attention-deficit hyperactivity disorder (ADHD) is a common developmental neurobiological condition of childhood characterized by age-inappropriate degrees of hyperactivity/impulsivity and inattention to tasks that require sustained attention and concentration [1]. Oppositional defiant disorder (ODD) is an externalizing behaviour disorder characterized by difficulties with emotional and behavioural regulation that frequently brings the child into conflict with authority figures [1]. In the clinical setting, ODD is the most common ADHD comorbidity [2]. Although the reported prevalence of concurrent ADHD and ODD is variable, data suggest that 45–84 % of ADHD children and adolescents will

& Adis Medical Writers [email protected] 1

Diagnosis of co-occurring ADHD and ODD requires a multi-informant, multi-modal evaluation using interview data from caregiver and child, as well as observer- and selfreport rating scales [5, 6]. Using multiple informants, combining diagnostic reports from parents, teachers and youth self-reports will facilitate better clinical decision making than relying solely on parent reports [2]. Clinical assessment and evaluation should be a multistep procedure, beginning with completion and scoring of a valid broad band measure of psychopathology [3]. Various multi-informant rating scales that assess general dimensions of psychopathology and symptom severity in ADHD and ODD are available, including the following [3]: • • • • •

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Child Behaviour Checklist (general); Conners 3 Rating Scale Long Form (general); Behavioural Assessment System for Children (general); Swanson, Nolan and Pelham-IV Rating scale (ADHD and ODD symptom severity); Vanderbilt ADHD Rating Scale (ADHD, ODD, conduct disorder and school performance).

105

Patient care guidelines Child presents with possible ADHD and comorbid ODD

• • •

Perform a multi-source, multi-modal clinical evaluation Establish diagnosis Develop a treatment plan with family Obtain informed consent/child assent

No

• •

Comorbid conditions present?

Provide psycho-education and support Evidence-based psychosocial therapy (behaviour management training) for family Educational supports as necessary

Yes

Treat comorbid conditions

Drug therapy required (based on symptom severity, functional impairment, parent preference and cultural factors)

Optimize ADHD medication starting with stimulants • Methylphenidate • Amphetamine

• • •

Inadequate treatment response

•

• •

At each step of therapy Monitor outcomes, including symptom severity and daily impairment Evaluate treatment-emergent adverse events Continue psycho-education as necessary Reaffirm consent/assent for treatment

Switch to noradrenergic agent or add noradrenergic agent to ongoing stimulant Atomoxetine α2A-agonists

Severe aggression and conduct problems present

Add atypical antipsychotic (e.g. risperidone) to ongoing stimulant

Fig. 1 Suggested management of paediatric patients with attention-deficit hyperactivity disorder (ADHD) and comorbid oppositional defiant disorder (ODD) [3]

The clinician can then use this information to follow-up in the second step, which is a clinical interview of the child and parent, both separately and together [3]. The use of highly specific questions about symptoms of psychopathology can improve the diagnostic reliability of the clinical interview [7]. Once a diagnosis of ADHD and ODD is established, the next step is completion and scoring of a specific symptom scale, as this will provide a baseline prior to beginning treatment [3]. Additional testing may be required to identify the presence of learning disabilities and any other associated psychiatric comorbid conditions [3].

Psychosocial therapy involves the whole family Developing a treatment plan, including the provision of psycho-education and evidence-based psychosocial therapy (Fig. 1), should involve the entire family [3]. In addition, children with ADHD and comorbid ODD often require

educational supports and school-based intervention targeting symptomatic behaviours and associated impairment of social or academic functioning. Psycho-education includes clear explanations regarding the nature of the illness, prognosis with and without treatment, as well as the risks and benefits of treatment options [3]. Psychosocial therapies based on behavioural therapy principles are generally more effective than insight-oriented psychosocial therapies in this patient population [8]. In particular, behaviour management training (BMT) is designed to interrupt dysfunctional parenting practices, such as coercive family process, in which negative interpersonal interactions become reciprocally reinforcing, with parents often using punitive measures that lead to increased aggression and defiance in the child [3]. Some of the key elements of BMT include helping parents provide consistent approaches to the child’s defiant behaviours and to express praise and positive emotions towards the child in at least equal measure to negative communications. In

106 Table 1 Summary of the results of randomized, placebo-controlled trials in children with ADHD and comorbid ODD and/or conduct problems, as reviewed by Connor [3]) Comparators MPH 0.7 mg/kg twice daily vs. PL [14]

No. of children (condition) 91 (ADHD)

Measure: results IOWA Conners Rating Scale: significant improvement with MPH vs. PL in ODD/aggressive symptoms

MPH 0.1–0.5 mg/kg vs. PL [15]

31 (ADHD with tic and ODD)

IOWA Conners Rating Scale, Abbreviated Conners Rating Scale: significant improvement with MPH vs. PL in oppositional symptoms

MPH (91%) vs. MAS XR (9%) at individually optimized dose [16]

65 (ADHD ? ODD/CD and aggression)

Conners Global Index-parent report, Modified Overt Aggression Scale: 49 % of children responded to stimulant optimization, with reduced ODD and aggressive symptoms

MAS XR 10–40 mg/day vs. PL [9]

246 (ADHD ? ODD) ? 62 (ODD alone)

SNAP-IV ODD subscale: significant improvement with MAS XR vs. PL in ODD symptoms among ADHD ? ODD children, but not in those with ODD alone

ATO 0.5, 1.2 and 1.8 mg/kg/day vs. PL [17]

182 (ADHD alone) ? 115 (ADHD ? ODD)

Conners Rating Scale-ODD susbscale: significant improvement with ATO 0.5 and 1.8 mg/kg (but not 1.2 mg/kg) vs. PL in ODD symptoms among ADHD ? ODD children

ATO 1.2 mg/kg/day vs. PL [18]

226 (ADHD ? ODD)

SNAP-IV ODD subscale: no significant between-group difference (LOCF analysis)

ATO 0.5, 1.2 and 1.8 mg/kg/day vs. PL [19]

184 (ADHD alone) ? 113 (ADHD ? ODD)

Conners Rating Scale-ODD subscale: significant improvement with ATO vs. PL in ODD symptoms

CLO (B0.6 mg/day) vs. MPH (B60 mg/day) as monotherapy or combined [20]

61 (ADHD alone) ? 61 (ADHD ? ODD)

Abbreviated Conners Rating Scale (parent and teacher): parents reported a significant effect for CLO on oppositional symptoms; however, teachers reported no effect of CLO ± MPH on ODD symptoms

GXR 1–4 mg/day vs. PL [10]

217 (ADHD ? ODD)

Conners Rating Scale-ODD subscale: significant improvement with GXR vs. PL in ODD symptoms, and reductions in ODD symptoms significantly correlated with reductions in ADHD symptoms

GXR 1–4 mg/day vs. PL added to ongoing stimulant [21]

274 (ADHD ? ODD with suboptimal response to stimulant)

Conners Rating Scale-ODD subscale: significant improvement with adjunctive GXR vs. adjunctive PL in oppositional symptoms

RIS 0.25–3 mg/day vs. PL added to ongoing 168 (ADHD and ODD or CD NCBRF-Disruptive Total: significant improvement with RIS stimulant and parent management symptoms and severe vs. PL augmentation therapy in ODD symptoms and in training [22] aggression) aggressive behaviours ADHD attention-deficit hyperactivity disorder, ATO atomoxetine, CD conduct disorder, CLO clonidine, GXR guanfacine extended release, LOCF last observation carried forward, MPH methylphenidate, MAS XR mixed amphetamine salts extended release, NCBRF-Disruptive Total Nisonger Child Behavior Rating Form Disruptive-Total Subscale, ODD oppositional defiant disorder, PL placebo, RIS risperidone, SNAP-IV Swanson, Nolan, and Pelham rating scale

isolation, psychosocial therapies may be only partially effective in children with more severe symptoms or in highly stressed and/or conflicted families [3].

the presence of ODD symptoms may decrease compliance with regard to taking ADHD medication [11]. Stimulants are first-line drug therapy

Pharmacological treatment may also be required The decision to add medication to BMT is based on symptom severity, functional impairment, parent preference and cultural factors (Fig. 1) [3]. Drugs used for the treatment of ADHD are equally effective on ADHD symptoms in children with or without comorbid ODD [9]. In children with both conditions, ODD symptoms may also improve with ADHD medication, but ODD does not improve with drug treatment when not comorbid with ADHD [9, 10]. Of note,

Stimulant medications (methylphenidate and amphetamine preparations) are the recommended first-line pharmacotherapy for children with ADHD with or without ODD (Fig. 1) [12]. Approximately 65–75 % of children with ADHD respond to initial treatment with a stimulant, and the response rate may increase to 80–90 % if a second stimulant is tried; therefore, clinicians should consider use of both methylphenidate and amphetamine formulations before using non-stimulant drugs [3]. Dose optimization of stimulants is also important, and this is achieved by starting

107 Table 2 Medications approved by the US FDA to treat ADHD in children C6 years of age and adolescents (unless otherwise indicated), as reviewed by Connor [3] Trade name

Total daily dose

Delivery system

Effect duration (h)

Frequency of administration

Short-acting methylphenidate formulations Ritalin

2.5–60 mg

Tablet

3–4

Multiple times daily

Methylin

5 mg to lesser of 2.0 mg/kg or 60 mg

Solution/chewable tablet

4

Multiple times daily

Focalina

2.5 mg to lesser of 1.0 mg/kg or 20 mg

Tablet

4

Multiple times daily

Intermediate-acting methylphenidate formulations Ritalin SR

20–60 mg

Sustained-release tablet

5–6

Twice daily

Metadate ER

10 mg to lesser of 2.0 mg/kg or 60 mg

Beaded capsule

6–8

Single dose to cover school hours

Methylin ER

10 mg to lesser of 2.0 mg/kg or 60 mg

Beaded capsule

6–8

Single dose to cover school hours

Ritalin LA

10–60 mg

Beaded capsule

7–9

Single dose to cover school hours

10 mg to lesser of 2.0 mg/kg or 60 mg

Beaded capsule

8–9

Single dose to cover school hours



Metadate CD

Long-acting methylphenidate formulations Concerta

18 mg to lesser of 2.0 mg/kg or 72 mg

Osmotic-release capsule

9–12

Single dose to cover school and after school hours

Focalin XRa

5 mg to lesser of 1.0 mg/kg or 30 mg

Beaded capsule

9–12

Single dose to cover school and after school hours

Quillivant XR

20–60 mg

Extended-release suspensiona

9–12

Single dose to cover school and after school hours

Daytrana

10 mg to lesser of 1.0 mg/kg or 30 mg

Transdermal patch system

9–12

Patch worn for up to 9 h for 12-h effectiveness

Short-acting amphetamine formulations Adderallb,c

2.5 mg to lesser of 1.0 mg/kg or 40 mg

Tablet

5–6

Once or twice daily

Dexedrinec

2.5–40 mg

Tablet

4

Multiple times daily

2.5–40 mg

Tablet

4

Multiple times daily

Dextrostat



Long-acting amphetamine formulations Adderall XRb

5 mg to lesser of 1.0 mg/kg or 30 mg

Beaded capsule

10

Single dose to cover school hours

Dexedrine spansule

5 mg to lesser of 1.0 mg/kg or 40 mg

Capsule

10

Single dose to cover school hours

Vyvanse

20 mg to lesser of 10 mg/kg or 70 mg

Capsule

10

Single dose to cover school hours

Non-stimulants (drug name)

a

Stratterae (atomoxetine)

0.5 mg/kg to lesser of 1.4 mg/kg or 100 mg

Capsule

24

Once or twice daily

Intuniv (guanfacine XR)

1–4 mg

Extended-release tablet

24

Once daily

Extended-release tablet

12

Twice daily

0.1–4 mg Kapvay (clonidine ER) Contains dexmethylphenidate

b

Contains mixed amphetamine salts

c

Approved for children C3 years of age and adolescents

d

Contains lisdexamfetamine

e

Not approved for co-administration with stimulants

108

with a low dose and titrating upward every 3–7 days within the established dosage guidelines until optimal response is achieved or intolerable adverse events occur [3]. Several randomized, placebo-controlled trials have demonstrated the efficacy of these drugs in children with ADHD and comorbid ODD and/or conduct problems (Table 1). In addition, a meta-analysis of 28 studies with stimulants in children and adolescents with ADHD and aggression/oppositional symptoms showed a robust effect on symptoms of ODD, aggression and conduct problems [13]. There are many different formulations of stimulants (Table 2), and long-acting once-daily formulations may be desirable to encourage compliance in children with ADHD and comorbid ODD [3]. For children with difficulty swallowing tablets or capsules, a long-acting suspension is available, as are transdermal patch preparations and beaded capsule formulations that can be opened and the contents sprinkled on applesauce [3]. Combining or switching drugs may be useful If dose-optimized treatment with stimulant monotherapy provides a suboptimal response, adding a drug from another class may be considered (Fig. 1) [3]. For example, a placebo-controlled trial in children and adolescents with ADHD and comorbid ODD symptoms who had suboptimal response to stimulant monotherapy showed a significant improvement when guanfacine extended-release was used as adjunctive therapy [21]. Although data are not as robust for non-stimulant agents as for stimulants, there is evidence to support the efficacy of atomoxetine (a norepinephrine reuptake inhibitor), guanfacine extended-release (an a2A-adrenergic agonist) and clonidine (a sympatholytic) in the treatment of ADHD and/or ODD symptoms (Table 1). Available non-stimulant formulations available for use in this clinical setting are included in Table 2. When all else fails, consider adding risperidone For ADHD children with severe symptoms, overt aggression and/or conduct problems who do not respond to the therapeutic approach outlined above, the addition of risperidone (an atypical antipsychotic) to ongoing stimulant treatment may be considered (Fig. 1). Although this approach has demonstrated some benefits [22, 23], this is not an approved indication for the drug, and close monitoring for metabolic adverse events, insulin resistance and weight gain is important [24]. Compliance with ethical standards The article was adapted from Pediatric Drugs 2015;17(5):361–71 [3] by salaried employees of Adis/Springer and was not supported by any external funding.

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