The pharmacological and non-pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: A systematic review with network meta-analyses of randomised trials

Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed psychiatric disorders in children and adolescents. Recent estimates suggest that ADHD affects about 3–7% of young people worldwide [1–2], producing considerable impact on health services and the community [3–5]. ADHD is a childhood-onset disorder characterized by a persistent pattern of symptoms of developmentally inappropriate and impaired inattention and/or hyperactivity/impulsivity, with difficulties often continuing into adulthood. The diagnosis of the disorder also requires the presence of symptoms across more than one setting (e.g., home and school) and requires that the symptoms needed for diagnosis result in academic, social, or occupational impairment [6–8].

In recent years, the management of ADHD has become increasingly complex as new therapies are introduced in clinical practice. The comparative efficacy and safety of pharmacological and non-pharmacological treatments are largely unknown, mainly because of the paucity of head-to-head trials. A wide variety of interventions have been used for the treatment of ADHD, including pharmacological and psychological interventions, herbal and homeopathic remedies, and dietary management. Despite the extensive body of research into the epidemiology and pathophysiology of ADHD, less emphasis has been placed on methodologically sound comparative research questions evaluating and comparing different ADHD treatment options. For example, which ADHD treatment modality works best in children and adolescents, psychological interventions, pharmacological therapy or both? Among broad groups of treatment interventions, is there any particular treatment which is clinically superior (or inferior) to others? Is there a unique role of complementary and alternative medicine used in the treatment of children and adolescents with ADHD? Although the evidence is not strong, pharmacological treatment using stimulant medication is generally recommended for school-age children and adolescents with ADHD, along with implementation of psychological interventions based on behavioural approaches [9–11]. Very frequently, however, parents consider using complementary and alternative medicine as a therapeutic option for controlling the core ADHD symptoms. Randomised trials and systematic reviews have evaluated the effects of pharmacological and non-pharmacological interventions in children and adolescents with ADHD [12–19], but most research has been limited to a particular treatment approach only without considering all available treatment alternatives, comparators and outcome measures of clinical importance.

Knowledge gaps in the current evidence base present opportunities for the application of novel evidence synthesis methods to complex networks of trials and interventions, as well as rigorous comparative evaluations of multiple treatments for ADHD. Relatively new methods have been developed to analyse such complex trial data, including network meta-analysis, which helps to integrate and synthesise diverse results to determine the relative merits of multiple treatments. Network meta-analysis has been recommended as a next generation tool for evidence synthesis when a heterogeneous set of treatments and trials is included in the same review [20–24]. Network meta-analysis may also be of particular use when included interventions are not only heterogeneous, but complex in nature (e.g., treatments that may operate through a variety of causal pathways) [23, 25–28]. To our knowledge, none of the previous research has attempted to establish evidence-based comparative effects of all pharmacological and non-pharmacological ADHD treatments in a comprehensive systematic review using network meta-analyses.

Accordingly, we aimed to compare the efficacy and safety of pharmacological, psychological and complementary and alternative medicine interventions for the treatment of ADHD in children and adolescents. We used network meta-analyses comparing multiple interventions to integrate direct and indirect evidence into unified networks of all available randomised trials.

This systematic review was conducted and reported in accordance with the reporting guidance provided in the PRISMA statement extension for systematic reviews incorporating network meta-analysis [29] (S1 Checklist). We developed a systematic review protocol and registered with PROSPERO (CRD42014015008) [30]. Our methods are briefly described here (and explained in more detail in S1 Text and in the published protocol [30]).

ADHD is one of the most commonly diagnosed and treated psychiatric disorders in childhood. In many Western countries, the prescribing rates have increased dramatically, with wide variations in medical practice [53–56] that have led to remarkable controversies and public debate around the clinical (and social) management of ADHD [57–60]. Our analysis of 190 studies that enrolled 26,114 participants randomly assigned to 52 different interventions (grouped in 32 therapeutic classes) has evaluated the comparative effects of multiple pharmacological and non-pharmacological treatments used in children and adolescents with ADHD.

Our main findings have potential implications for informing evidence-based treatment selection, but also establishing recommendations in clinical practice guidelines as well as the future design of new studies. Some treatments for the management of ADHD differed in both clinical and statistical aspects. In terms of response, behavioural therapy (alone or in combination with stimulants), stimulants and non-stimulants seemed significantly more efficacious than placebo; stimulants seemed superior to behavioural therapy, cognitive training and non-stimulants; and behavioural therapy in combination with stimulants seemed superior to monotherapy with stimulants or non-stimulants. Among single drug agents, methylphenidate, amphetamine, atomoxetine, guanfacine, clonidine and modafinil seemed significantly more efficacious than placebo (even though less clear confidence with clonidine and modafinil). Methylphenidate and amphetamine seemed more efficacious than atomoxetine and guanfacine. In terms of acceptability, behavioural therapy and stimulants (and their combination), showed the best profile of acceptability leading to significantly fewer discontinuations that did placebo. Methylphenidate and clonidine seemed superior to placebo, whereas methylphenidate and clonidine seemed better accepted than atomoxetine (even though limited evidence for clonidine). Most of the efficacious pharmacological treatments (particularly, stimulants) were associated with anorexia, weight loss and insomnia.

One of the most important clinical implications is that behavioural therapy, particularly given by parents and with active child and teacher involvement, is the only non-pharmacological intervention that was found to be associated with statistically significant benefits in our analyses. Cognitive training, neurofeedback, dietary therapy (such as restricted elimination diet), polyunsaturated fatty acids, amino acids, minerals, herbal therapy, homeopathy, and physical activity cannot be recommended as evidence-based interventions for global functioning and core ADHD symptoms until better evidence of their comparative efficacy is reported in well-designed and conducted clinical trials. However, a healthy, balanced diet and regular exercise should be emphasised for all children and adolescents, including those with ADHD [7]. Stimulants such as methylphenidate and amphetamine may represent the best options amongst the pharmacological interventions for ADHD, and non-stimulants such as atomoxetine, guanfacine and (less studied) clonidine may be considered secondary treatment options, respectively. Other unlicensed medications have gained popularity in the mental health treatment of young people (such as modafinil, antidepressants such as bupropion and antipsychotic agents), but the evidence for these therapies (not indicated in ADHD) is currently very limited. Similarly, concerns have been raised about the benefit-risk profile of the use in ADHD of these agents outside of approved indications [40,61–64].

Our systematic review suggests that treatment effects are larger when behavioural therapy is combined with stimulants (with very low quality of evidence). The clinical decision to combine these interventions should be driven by the symptoms presented, the needs of the children and their family and the availability of healthcare services. The value of combined treatment for ADHD is recognized as an area of interest because it might lead to potential beneficial effects in different domains [65]. Combining behavioural therapy with stimulants may enhance attentional processes and reduce impulsive responding, and may be a way of reducing the dosage and duration of pharmacological treatment, and thus addressing concerns about the potential harms associated with the use of pharmacotherapy [9,65]. The Multimodal Treatment for children with ADHD (MTA) study, a randomised trial that compared stimulant methylphenidate, intensive behavioural therapy, and combination of both methylphenidate with intensive behavioural therapy with a community control, is considered the largest (n = 579 participants) and perhaps the most methodologically sound investigation of combination treatment for ADHD [19,66]. In line with our findings, results of the MTA study suggested a benefit from combination treatment over stimulant monotherapy when categorical measures of excellent response were used [67], but the effects were considered small in magnitude and subsequent trials of smaller sample size reported conflicting results [68–71]. Our finding that combination of stimulants and non-stimulants treatment (such as methylphenidate plus clonidine, atomoxetine, or guanfacine) appears to be effective for ADHD may challenge some guidance on the management of ADHD, as commonly no clear recommendations are made for (or against) combining these two pharmacological treatments. In our opinion, concerns about widespread adoption of this therapeutic strategy could be justified despite the potential benefits of combination drug regimens, because available information on the balance between potential benefits and safety are incompletely characterized in the biomedical literature [72–77].

There are multiple and diverse clinical practice guidelines worldwide for the management of ADHD [9–11,40,78–80], such as those developed by the National Institute for Health and Care Excellence (NICE) [9] and by the Scottish Intercollegiate Guidelines Network (SIGN) in the UK [78], and by the American Academy of Pediatrics (AAP) [79] and the American Academy of Child and Adolescent Psychiatry (AACAP) [80] in the US. Some of the most important differences between them are that US guidelines recommend the use of pharmacological treatment for children with mild ADHD or pre-school children; conversely, the UK guidelines state that pharmacological treatment should be reserved for those ADHD children with severe symptoms and impairment, or moderate levels of impairment who have refused non-pharmacological interventions, or whose symptoms have not responded sufficiently to behavioural interventions. Generally, some of these guidelines recognise that if pharmacological treatment is prescribed, it should be provided in conjunction with behavioural therapy. Thus, considering the overall benefit-risk balance of the multiple interventions, the interpretation of our findings may support a stepwise approach following UK recommendations, which suggests that increased access to behavioural therapy and pharmacological treatment (as indicated) would improve symptomatic and functional outcomes for children and adolescents with ADHD.

Along with broad recognition that data from some clinical trials and treatment comparisons were sparse, and that more and higher-quality data could improve estimations and recommendations, aspects of the general approach of previous systematic reviews and meta-analyses [12–17,81–83] were challenged. For example, two recent Cochrane systematic reviews have suggested that stimulants such as amphetamines [12] and methylphenidate [13] may improve ADHD core symptoms compared to placebo (or no intervention) in children and adolescents; but overall quality of the evidence ranged from low to very low on most outcomes. However, no network meta-analyses to compare the relative effects of all existing interventions have been performed to address this knowledge gap. In contrast to the traditional meta-analysis methods which focus on reducing the evaluation to a single pair-wise comparison, network meta-analyses allow multiple intervention comparisons to be made. The strengths of this review also include the completeness of the search including multiple databases and trial registries, forward searching of unpublished data and hand searching of the grey literature, risk of bias assessment and reporting of confidence in treatment effects when interpreting each therapy comparison. We also used an a priori published protocol and followed established reporting guidelines [29,30].

There are some limitations to be noted regarding our study. We used established methods [32–34] to leverage a large number of existing systematic reviews and meta-analyses, to identify relevant studies. Although we believe this technique has performed well, our review may have missed studies due to differences in the eligibility criteria and coverage of the retrieved reviews. Similar to other reviews and meta-analyses [12–17,81–83], there is methodological and clinical heterogeneity in the included trials in terms of trial design, patient populations, and outcome measurement. Caution should be used when interpreting findings, considering the fact that not all treatments (particularly, non-pharmacological treatments) are represented in the trials that formed the evidence base. The primary outcomes of efficacy and acceptability were the most commonly and consistently reported outcomes across the network of trials. However, as we did not control the risks of type I errors in meta-analyses of primary outcomes, the presence of potential false positive findings cannot be excluded. As with individual clinical trials and pairwise meta-analyses, secondary outcomes and additional analyses (e.g., sensitivity analyses and subgroups analyses) should be regarded as exploratory and multiple testing [84,85] issues need to be considered when results are interpreted. Our review does not provide evidence that supports any stimulant over another, and does not reveal any significant differences between short-acting and long-acting formulations. Insufficient patient numbers and events to form well connected networks limited the analyses that could be conducted to account for dosage and intensity of non-stimulants and non-pharmacological treatments in the absence of more studies.

Although we adopted reproducible definitions, the heterogeneous reporting of events in studies posed a major challenge. None of the trials examined and reported all the outcomes of interest. The overall quality of the network meta-analyses evidence ranged from low to very low as assessed by the GRADE approach (the quality or confidence of evidence ratings were rated down by serious concerns of risk of bias in the randomised trials, imprecision of treatment effect estimates, and potential inconsistency) (see S7 Table). In fact, results on the primary outcomes for both the network meta-analyses and pairwise meta-analyses include small number of studies relative to the number of comparisons considered, resulting in low confidence in estimates for many key analyses and comparisons. Therefore, further high-quality trials are likely to have an important impact on the confidence of treatment effects estimates and may change the interpretation of our findings. At the study level, many trials appear to have several reporting or methodological issues, and an additional limitation was the very small sample sizes. Many trials had a high risk of bias (53%) or unclear risk of bias (45%) for at least one criterion, and most trials were funded by industry (50% of all trials; 77% of trials evaluating pharmacological treatments). Inclusion of funding source as a standard item for rating sponsorship bias and conflicts of interest [13,86] could make the risk of bias even more apparent than that reported in our review. In our opinion, these issues require further pragmatic action at the levels of planning, funding, conduct, and reporting of randomised trials [85,87–90]. Preexisting therapies, the settings in which psychological interventions were undertaken, how they were carried out, and potential factors responsible for response or failure are not always clearly reported in many ADHD trials and presents a challenge to treatment classification and knowledge translation. To the extent possible, we pursued sensitivity analyses including study-level covariates in network meta-regression models to infer about transitivity/consistency and to establish the robustness of our findings. Overall, we show that our results are robust to a variety of estimation procedures, but these analyses may be underpowered. We used study-level data instead of individual patient data, so the small number of studies limited the additional analyses that could be conducted to account for effect modifiers in the absence of patient-level data. There is also a limited ability of studies with a mean duration of about 12 weeks to inform long-term (chronic) management and treatment decisions. We selected for our primary efficacy outcome of response rate to use a dichotomous rather than continuous measure (e.g. standardized mean difference), because from a clinical perspective, syntheses of continuous outcomes measured on different scales can be difficult to interpret [30,31]. However, a limitation of this method is that there can be a substantial information loss when continuous outcome variables are dichotomised. Dichotomisation may also increase the risk of a positive result being a false positive [91–93]. Furthermore, we were unable to investigate other important outcomes such as remission and recovery (e.g. no longer meeting the criteria for the diagnosis of ADHD), potential serious adverse effects (e.g. ischaemic heart disease, hepatic damage and suicidal ideation/behaviour), or other aspects such as drugs abuse/misuse, resource allocation and costs [6–8,94–99]. Finally, our results might have limited generalizability (social, economic, educational and cultural context), because studies were mostly conducted in children and adolescents from Western countries. Consequently, our results should be interpreted with caution given the caveats mentioned above.

There is still room for improvement in the design, conduct and reporting of trials in the field. The clinical research agenda of ADHD is incomplete and needs better designed and reported randomised trials to assess the benefits and harms of the multiple interventions available for the management of ADHD in the young people. In this respect, ADHD complex pathogenesis implicates multiple factors of a diverse nature that should be considered in clinical research [6–8]. A pertinent research agenda [100,101] which views ADHD dimensionally, but also integrating mental health services and interventions into priority care strategies, should be established in order to appreciate which treatments are best for ADHD children of different ages and in different communities. There is an urgent need for long-term randomised trials at low-risk of bias and with sufficient numbers of participants. It is important that future clinical trials report completely the methods and results for all outcomes of interest (including adverse events) using standardised outcome measures at similar time points to ensure include in future evidence syntheses. Reporting guidelines such as SPIRIT (Standard Protocol Items: Recommendations for Intervention Trials) [102] and CONSORT (Consolidated Standards of Reporting Trials) [103–106] should be rigorously adopted and implemented for study protocols and study reports, respectively.

In conclusion, although the quality of evidence is not strong, clinical differences may exist between the pharmacological and non-pharmacological treatments commonly used for the management of ADHD. Behavioural therapy and pharmacological treatment may improve the symptoms of ADHD and global functioning in the short-term. Our findings can help clinicians, healthcare providers, parents, and caregivers make informed decisions regarding treatment selection for the management of ADHD. An open and honest discussion with parents and older children about uncertainties of available treatments and the balance between benefits, costs, and potential harms should be established before starting treatment. In addition, there is an urgent need for high-quality randomised trials of the multiple treatments for ADHD in children and adolescents.

We would like to thank Mustafa Bilici, Per A Gustafsson, Harriet Hiscock and the trial investigators for providing their unpublished data for use in this work; and the European Medicines Agency for providing data access to study reports of guanfacine. We thank Concha Tomás (Health Sciences Library, University of Valencia) for helping to obtain the full-text articles. We would like to thank Alain Mayhew for his helpful comments on previous versions of this paper and for providing his feedback on our protocol. We thank Aurelio Tobías for providing his feedback on our protocol.We would like to thank the anonymous peer reviewers who offered us helpful comments on the submitted paper.

All relevant data are within the paper and its Supporting Information files.

Specific funding from the Alicia Koplowitz Foundation was received for this work. FCL and RTS are partially supported by the Generalitat Valenciana (PROMETEOII/2015/021) and CIBERSAM/Institute of Health Carlos III. BH is supported by a New Investigator Award from the Canadian Institutes of Health Research and the Drug Safety and Effectiveness Network. BH is also supported by a grant from the National Center for Complementary and Alternative Medicine (NCCAM) of the US National Institutes of Health. MJP is supported by an Australian National Health and Medical Research Council Early Career Fellowship (1088535). DM is supported by a University of Ottawa Research Chair. FCL and RTS did not receive additional external funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. FCL is the study guarantor.