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28 Jun 2018

Caye A et al. Mol Psychiatry 2018; Epub ahead of print

Please note that the treatments described in this publication may not be licensed in your country, please refer to your own local country prescribing information for further details.

A wide range of pharmacological and non-pharmacological options are available for the treatment of ADHD. Over the past decade, a number of meta-analyses have assessed the efficacy of pharmacological, non-pharmacological and combined treatment for the management of ADHD symptoms, with the available evidence appearing to support the use of pharmacological treatments in the short term; however, evidence for long-term efficacy of these treatment options remains unclear. As such, and due to the increasing range of available treatment options for ADHD, informed selection of appropriate treatment options is becoming more challenging for clinicians. This review aimed to provide a summary of the efficacy, safety and tolerability of the available treatment options, supplemented by expert opinion on plausibility, to guide appropriate treatment selection and optimal management of ADHD.

Pharmacological treatment is currently the mainstay for the treatment of ADHD in most clinical settings and guidelines (with the exception of preschool-aged children). Psychostimulants (methylphenidate and amfetamines) are currently the most widely used medications, with non-stimulants (guanfacine, atomoxetine, clonidine) recommended for patients who do not respond/tolerate psychostimulants or are contraindicated.

Atomoxetine is considered an important treatment option in ADHD guidelines, particularly in patients in whom psychostimulants are contraindicated, or who have psychiatric comorbidities such as bipolar disorder or substance-use disorder. Results from randomised clinical trials and several meta-analyses suggested that atomoxetine has an acceptable safety and tolerability profile, but has a smaller effect size than psychostimulants. Importantly, atomoxetine has been shown to effectively reduce ADHD symptoms in children and adults with common psychiatric comorbidities, such as anxiety disorder, while not exacerbating, or improving, the symptoms of the comorbid disorder. The available evidence surrounding other non-stimulants, including the α2-agonists clonidine and guanfacine, suggests that they have lower effect size when compared with psychostimulants, but similar to atomoxetine, in meta-analyses. There is some evidence to suggest that guanfacine may be useful as an adjunctive treatment to psychostimulants.

Additionally, there are a number of new drugs currently in development for ADHD. Some, currently showing favourable results in Phase II and III clinical trials, have similar mechanisms of action (MOAs) to the currently available pharmacological treatment options, and will therefore likely have similar side-effect profiles and contraindications. However, preclinical studies of drugs with novel targets, for example sodium-channel blockers, are also underway, although it should be noted that despite their novel MOAs for ADHD, these drugs are likely to be acting on the same brain circuits, albeit downstream of noradrenaline and dopamine modulation, as currently available medications. Thus, the authors summarised that significant advances in pharmacological treatment options for ADHD should not be expected in the coming years, with novel mechanisms of delivery of existing medications being the main focus of new drug development.

The primary recommended alternatives to pharmacological treatment for ADHD are behavioural parent training and social skills training; these are the recommended first-line treatments for very young children with ADHD, and in fact most ADHD guidelines recommend behavioural therapy for ADHD in any situation, either alone or in combination with medication, although evidence to support this is conflicting. The Multimodal Treatment for ADHD (MTA) study, in which children with ADHD were randomised to receive either methylphenidate alone or in combination with behavioural child- and parent-training over 14 months, found no significant difference in efficacy between combined treatment and medication alone. Results from subsequent studies, however, have suggested positive effects of behavioural and combination therapy for ADHD, particularly in preschool-aged children. The authors concluded that the evidence surrounding the efficacy of behavioural interventions for ADHD is difficult to integrate and summarise, and that further studies are needed in this field. They also emphasised the likelihood that the suitability of the available behavioural interventions varies between patients, and that the apparent lack of adverse effects may cause some patients and their caregivers to prefer behavioural therapy over pharmacological treatment.

Other non-pharmacological treatment options for ADHD include:

  • Cognitive training, which aims to improve neuropsychological functioning (e.g. attention and inhibitory control). Results from recent meta-analyses indicate that although cognitive training has moderate efficacy in improving neuropsychological functioning in ADHD patients, the effects on ADHD symptom improvement were unclear, with effect size and significance depending on whether the rater was blinded or unblinded, leading the authors of this review to conclude that cognitive training appears to confer no effect on core ADHD symptoms or other functional outcomes.
  • Neurofeedback, which aims to improve self-control over brain activity patterns and is monitored through real-time electroencephalogram data. Although results from open-label trials suggested a moderate to large effect size for the improvement of ADHD symptoms using neurofeedback, meta-analyses determined that effect size was reduced and significance lost when only probably-blinded raters were used, leading the authors to summarise that, based on the available evidence, neurofeedback does not effectively improve core ADHD symptoms. Additionally, the authors noted that neurofeedback is a specialised intervention requiring complex equipment, and usually requires patients to attend 20–40 sessions. Thus, clinicians and caregivers should take into account the feasibility and cost implications of this treatment option for ADHD patients.
  • Dietary modifications, which can include removal of artificial food colourings (AFCs) from the diet, or restriction of several foods over a short time period (the few foods diet; FFD). The available evidence surrounding dietary modifications in ADHD indicates that both the FFD and removing AFCs have significant, although small, effects on ADHD symptoms, with few adverse effects observed. However, the authors noted that the FFD requires intense food restriction to allow the ideal diet to be identified, such that some patients may view this as an unfeasible or unappealing option.

The authors concluded that psychostimulant medication appears to be the most effective medication option, but that non-stimulant treatments should be considered in some cases, while non-pharmacological therapies represent a useful option in young children or in cases presenting mild ADHD symptoms. They emphasised that ADHD treatment selection should be a shared decision-making process, involving the clinician, the patient with ADHD and their parents/caregivers, and that the age of the patient and the severity of ADHD symptoms should be major considerations. Additionally, psychiatric comorbidities should be considered when selecting the most appropriate treatment, both in terms of potential for drug abuse/misuse and in terms of the effects of the treatment on the symptoms of the comorbidity, as well as on ADHD symptoms. The authors recommended that clinicians should prioritise treatment of comorbid disorders, with treatment selection for ADHD then based on the symptoms that remain. The feasibility and cost implications of different treatment options should also be considered; the authors noted that some effective non-pharmacological options may be less accessible to patients outside central urban areas of developed countries, as well as more expensive and time consuming, than pharmacological alternatives. Finally, the authors recommended routine follow-up to monitor symptoms and assess the patient’s response to the selected treatment, with adjustment of treatment where necessary to optimise patient outcomes.

Read more about treatment optimisation in ADHD here

Caye A, Swanson JM, Coghill D, et al. Treatment strategies for ADHD: an evidence-based guide to select optimal treatment. Mol Psychiatry 2018; Epub ahead of print.

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