What are the long‐term outcomes of ADHD treatment?

As outlined by Cortese et al ¹ , there has been considerable progress in the understanding of the epidemiology, genetic risk, clinical features and management of adult attention‐deficit/hyperactivity disorder (ADHD). However, as this condition is increasingly being recognized and treated in millions of children, adolescents and adults worldwide, the remaining knowledge gaps also become more apparent, and the need to address these gaps more urgent.

In my meetings with patients with ADHD and their relatives, patient organizations and health care professionals, certain questions and concerns keep coming up: How will my future look like? What are the consequences of having ADHD and, in particular, what is the long‐term outcome of ADHD treatment?

Although many different interventions have been developed for ADHD, the most effective and by far the most studied treatment is that with stimulant drugs, such as amphetamines and methylphenidate. Like many other important discoveries, the beneficial effects of stimulants can be traced back to accidental observations, including that Benzedrine (amphetamine sulfate) had a calming effect in children with behavioral disorders ² . Since the systematic testing of stimulants in ADHD started in the 1960s³, it has been demonstrated that they provide immediate symptomatic relief of ADHD symptoms such as inattention, impulsivity and hyperactivity ³ .

Recent meta‐analyses confirm that stimulants and atomoxetine have significant effects in reducing ADHD symptoms after 12 weeks of treatment in children and adults ⁴ . However, as pointed out by Cortese et al, “at about 52 weeks, no medication has supporting evidence of being more efficacious than placebo”. A conservative interpretation may be that initial treatment effects disappear after one year of treatment. However, this conclusion is inconsistent with clinical observations, naturalistic treatment studies and registry‐based research. Several open‐label extension studies have documented that the efficacy observed during the initial placebo‐controlled phase was either maintained or improved during follow‐up periods of several years ⁵ .

As already noticed in the first clinical trials ³ , treatment response and side effects of stimulant therapy in ADHD are extremely variable, and difficult to predict based on clinical observations. Most adolescents and adults discontinue their ADHD medications during the first year of treatment ⁶ , but some adults with ADHD report sustained treatment effects for decades. Although it is unclear whether better treatment adherence/persistence contributes to more favorable long‐term outcomes ⁷ , naturalistic studies suggest beneficial effects in multiple life domains.

Effect sizes based on aggregated data from thousands of individuals have limited value in clinical practice, where treatment decisions regarding prescription of ADHD medications to individual patients are mainly based on trial and error. An alternative could be to introduce a data‐driven personalized approach. So far, there is limited evidence that stratification of ADHD patients into subgroups based on clinical features improves treatment efficacy or long‐term outcomes. However, recent biomarker studies, in particular molecular genetic research, suggest that ADHD is a highly heterogenous condition, with multiple risk factors implicating distinct pathophysiological mechanisms and different clinical trajectories. Future treatment studies should systematically explore how the wealth of genomic data collected from ADHD patients can be used for patient stratification and “genome guided” personalized interventions ⁸ .

Cortese et al argue that longer‐lasting randomized controlled trials (RCTs) are needed to establish long‐term effects, but also acknowledge the practical, financial and ethical challenges associated with such trials. They mention the possibility of supplementing conventional RCTs with discontinuation‐controlled trials. These latter trials in patients who already are on stable medication may be easier to conduct and probably better mirror clinical practice than conventional RCTs, as only a minority of adults treated with ADHD medications would be eligible for those RCTs ⁹ .

As all published RCTs have limited duration and cannot predict long‐term (years or decades) treatment effects, such data will need to come from other study designs. “Real‐world” registry studies have the advantages of large sample sizes (millions of individuals), less selected and more relevant study populations, potentially many years of observations, and the prospect of exploring multiple outcomes and interactions. Moreover, prescription registry data can detect rare outcomes and complications, while RCTs are underpowered to catch them. Scandinavian prescription registry studies show that, during periods of stimulant medication, ADHD patients are less likely to be involved in criminal acts or accidents, or to experience severe psychiatric comorbidities. However, registry studies also show that stimulant treatment is associated with an increased risk of cardiovascular diseases. More longitudinal data are needed to evaluate the long‐term effects of stimulant use on other outcomes, such as quality of life and work participation. Although registry studies have limitations, including the inherent problem of proving causality, they will probably be – with triangulation of evidence from different data sources – the major source of new insights into the long‐term trajectory of ADHD and its treatment.

In addition to the urgent need to establish the long‐term efficacy and safety of ADHD treatments, this field is facing new and overarching challenges, including questions about societal consequences of treating an increasing proportion of the population with psychoactive substances. ADHD symptoms and impairments are dimensionally distributed in the general population, without obvious borders between typical and “pathological” or “neurodivergent” behaviors. This is recognized in the DSM‐5, that specifies different levels of severity within the categorical diagnosis of ADHD.

As suggested by Cortese et al, a provisional diagnosis of “unspecified ADHD” could be applied to people who do not fulfil the diagnostic criteria of impairment across multiple settings. This implies that more people would be diagnosed. Critics argue that increasing the number of people who receive a diagnosis of ADHD (or any other condition) involves a “medicalization” and inevitably more (pharmacological) treatment. This is probably not correct. In all areas of medicine, diagnoses are used not only to select people for treatment, but also to avoid unnecessary treatment, for instance if the condition is considered mild or transient, or if there are no proven treatments available. Thus, the application of more differentiated diagnoses of mild or “unspecified” ADHD could potentially lead to fewer people being treated.

In summary, we need more data and new tools to explore many aspects of adult ADHD etiology, management and long‐term outcomes. This research agenda should be adapted to a new clinical reality marked by increasing rates of several psychiatric disorders. Society is rapidly changing; people at all ages are increasingly being exposed to massive amounts of potentially addictive and “neurotoxic” electronic devices and social media. Although causality has not been formally proven, there seems to be a correlation between social media use and ADHD, anxiety and mental distress. It is imperative to explore how such new and emerging risk factors could add to and interact with established environmental and genetic risks.