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7 Sep 2020

Mosheva M et al. Int Clin Psychopharmacol 2020; Epub ahead of print

Clinical evidence has shown that methylphenidate and amphetamines are equally effective in the first-line treatment of ADHD; however, data on second-line treatment approaches for individuals who do not respond to first-line treatment, as well as management of ADHD and comorbid psychiatric conditions such as disruptive behaviours and anxiety disorders, are limited. This study reviews these issues and proposes potential answers to these questions.

Second-line treatment selection for ADHD: to switch or not to switch?

Many children with ADHD fail first-line treatment either due to insufficient symptom improvement and/or intolerable side effects (Frank et al, 2015). If first-line treatment with a stimulant fails, guidelines recommend treatment with a stimulant from a different stimulant class (CADDRA, 2018; NICE, 2018); however, there are scant data to support this recommendation.

A study by Arnold (2000) showed that most individuals with ADHD respond well to both methylphenidate and amphetamine, and response was not impacted by the order in which the drugs were administered. However, this analysis included studies in which all subjects, not only those who did not respond to treatment, were switched to a different stimulant class; therefore, this study does not provide additional data to support whether switching to a different stimulant class provides improved response in individuals with ADHD who do not respond to first-line treatment.

A study by Dittmann et al (2014) demonstrated that both atomoxetine and lisdexamfetamine improved ADHD symptoms in individuals with prior failure of stimulant medication, but lisdexamfetamine was superior to atomoxetine in time of clinical response, proportion of subjects who responded and magnitude of therapeutic response.

ADHD and comorbid disruptive disorders: to add or not to add antipsychotics?

Disruptive disorders such as oppositional defiant disorder and conduct disorder are common comorbid conditions found in individuals with ADHD. Current guidelines recommend stimulants as first-line treatments for children in combination with parent training programmes followed by second-line treatment with the atypical antipsychotic, risperidone, for those who do not respond to first-line therapy (Gorman et al, 2015). The majority of studies demonstrating the efficacy of risperidone in mitigating aggressive behaviour in ADHD were conducted in individuals with borderline intelligence or intellectual disability (Aman et al, 2004; Springtime et al, 2005). Two studies in children with intelligence within the normal range found that risperidone* was as effective as methylphenidate in improving ADHD symptoms (Arabgol et al, 2015; Günther et al, 2006). Head-to-head studies comparing the efficacy of risperidone* and stimulants in patients with ADHD and aggressive/disruptive behaviours are needed.

ADHD and anxiety: to add or not to add antidepressants?

Anxiety occurs in approximately one-third of children (Gillberg et al, 2004) with ADHD, and guidelines recommend stimulants and atomoxetine as first-line treatment (Pliszka et al, 2006; Bolea-Alamañac et al, 2014; Caye et al, 2019). Given that there is limited evidence supporting the efficacy of atomoxetine and guanfacine over stimulants in treating core ADHD symptoms, the authors recommend stimulants as the first choice for treating ADHD with comorbid anxiety.

In summary, optimal second-line treatment for individuals who do not respond to first-line treatment is unclear. Based on a review of the evidence, the authors proposed that, in individuals with ADHD and comorbid aggressive/disruptive behaviours, stimulants may be the optimal first-line treatment followed by second-line treatment with risperidone.* In addition, the authors suggested that initial treatment with a stimulant may be the most appropriate option for individuals with ADHD and anxiety, and if there is no response or limited response, switching to atomoxetine or adding atomoxetine to the treatment regimen may be considered.

Read more about treatment dilemmas in ADHD here

This overview is not exhaustive of all recommendations and should not be used as the basis to treat patients. Please refer to the relevant complete guideline documents and your local prescribing information.


*Risperidone is not licensed for the treatment of ADHD

Aman MG, Binder C, Turgay A. Risperidone effects in the presence/absence of psychostimulant medicine in children with ADHD, other disruptive behavior disorders, and subaverage IQ. J Child Adolesc Psychopharmacol 2004; 14: 243-254.

Arabgol F, Panaghi L, Nikzad V. Risperidone versus methylphenidate in treatment of preschool children with attention-deficit hyperactivity disorder. Iran J Pediatr 2015; 25: e265.

Arnold LE. Methylphenidate vs. amphetamine: comparative review. J Atten Disord 2000; 3: 200-211.

Bolea-Alamañac B, Nutt DJ, Adamou M, et al. Evidence-based guidelines for the pharmacological management of attention deficit hyperactivity disorder: update on recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2014; 28: 179-203.

Brent D, Emslie G, Clarke G, et al. Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: the TORDIA randomized controlled trial. JAMA 2008; 299: 901-913.

Canadian ADHD Resource Alliance (CADDRA). Canadian ADHD Practice Guidelines, Fourth Edition. Toronto, ON; CADDRA, 2018.

Caye A, Swanson JM, Coghill D, et al. Treatment strategies for ADHD: an evidence-based guide to select optimal treatment. Mol Psychiatry 2019; 24: 390-408.

Dittmann RW, Cardo E, Nagy P, et al. Treatment response and remission in a double-blind, randomized, head-to-head study of lisdexamfetamine dimesylate and atomoxetine in children and adolescents with attention-deficit hyperactivity disorder. CNS Drugs 2014; 28: 1059-1069.

Frank E, Ozon C, Nair V, et al. Examining why patients with attention-deficit/hyperactivity disorder lack adherence to medication over the long term: a review and analysis. J Clin Psychiatry 2015; 76: e1459-e1468.

Gillberg C, Gillberg IC, Rasmussen P, et al. Co-existing disorders in ADHD – implications for diagnosis and intervention. Eur Child Adolesc Psychiatry 2004; 13(Suppl 1): i80-i92.

Gorman DA, Gardner DM, Murphy AL, et al. Canadian guidelines on pharmacotherapy for disruptive and aggressive behaviour in children and adolescents with attention-deficit hyperactivity disorder, oppositional defiant disorder, or conduct disorder. Can J Psychiatry 2015; 60: 62-76.

Günther T, Herpertz-Dahlmann B, Jolles J, et al. The influence of risperidone on attentional functions in children and adolescents with attention-deficit/hyperactivity disorder and co-morbid disruptive behavior disorder. J Child Adolesc Psychopharmacol 2006; 16: 725-735.

Mosheva M, Dar N, Rima Madi L, et al. Pharmacotherapy of attention-deficit hyperactivity disorder: common quandaries, dilemmas and challenges. Int Clin Psychopharmacol 2020; Epub ahead of print.

NICE guideline 2018. Attention deficit hyperactivity activity disorder: diagnosis and management. Available at: Accessed September 2020.

Pliszka SR, Crismon ML, Hughes CW, et al. The Texas Children’s Medication Algorithm Project: revision of the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2006; 45: 642-657.

Pringsheim T, Hirsch L, Gardner D, et al. The pharmacological management of oppositional behaviour, conduct problems, and aggression in children and adolescents with attention-deficit hyperactivity disorder, oppositional defiant disorder, and conduct disorder: a systematic review and meta-analysis. Part 2: antipsychotics and traditional mood stabilizers. Can J Psychiatry 2015;  60: 52-61.

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