Few studies have examined the safety and tolerability of ADHD medications (stimulants and atomoxetine) extending beyond six months, and none beyond a few years. A pair of Swedish neuroscientists at Uppsala University Hospital set out to explore longer-term outcomes. They conducted a six-year prospective study of 112 adults diagnosed with ADHD who were being treated with ADHD medications (primarily MPH, but also dexamphetamine and atomoxetine).

They found that at the end of that period, roughly half were still on medication, and half had discontinued treatment. There were no significant differences between the two groups in age, sex, ADHD severity, or comorbidity. The average ADHD score for the entire cohort declined very significantly, from a mean of 37 to a mean of 26, with a less than one in a thousand odds of that being due to chance. There was also no sign of drug tolerance or of a need to increase dosage over time.

All 55 adults who discontinued treatment had taken MPH for at least part of the time. Eleven had also been treated with dexamphetamine (DEX) and 15 with atomoxetine (ATX). The average time on treatment was just under two years. Almost a third quit MPH because they perceived no beneficial effect. Since they were on average taking higher doses at discontinuation than at initiation, that is unlikely to have been due to suboptimal dosage. Almost another third discontinued for various adverse mental effects, including hyperactivity, elation, depressive moods, aggression, insomnia, fatigue, and lethargy. Another one in eleven quit when they lost contact with the prescribing physician. In the case of ATX, almost half quit because of what they perceived as adverse mental effects.

Among the 57 adults who remained on medication, four out of five reported a strong beneficial effect. Only two reported minimal or no effect. Compared with the group that discontinued, the group that remained on medication was far more likely to agree with the statements, “My quality of life has improved,” and “My level of functioning has improved.” Yet as the authors caution, it is possible “that the subjects’ subjective ratings contain a placebo-related mechanism in those who are compliant with the medication and pursue treatment over time.” In fact, the authors reported that there were no significant differences in ADHD scores or ADHD severity between the group that quit and the group that remained on medication, even though, on average, the group that quit had been off medication for four years at follow-up.

We cannot explain why the patients who quit treatment showed similar levels of ADHD symptoms to those who continued treatment. It is possible that some patients remit symptoms over time and do not require sustained treatment. But we must keep in mind that there was a wide range of outcomes in both groups. Future work needs to find predictors of those who will do well after treatment withdrawal and those who do not.

Any decision on whether to maintain a course of medication should always weigh expected gains against adverse side effects. Short of hard evidence of continuing efficacy beyond two years, adverse events gain in relative importance. With that in mind, it is worth noting that this study reports that among those who remained on MPH, many reported side effects. More than a quarter complained of decreased appetite, one in four of dry mouth, one in five of anxiousness and of increased heart rate, one in six of decreased sexual desire, one in nine of depressed mood, and one in eleven of insomnia.

This study breaks important ground in looking at long-term effects of medication. It reaffirms findings elsewhere of the efficacy of ADHD medications. But contrary to the authors’ conclusion, the data they present suggests the possibility that permanently medicating ADHD patients may not be more efficacious than discontinuation beyond a certain point, especially when balanced against adverse side effects.

But this is just one study with a relatively small sample size. This suggests a need for additional studies with larger sample sizes to pursue this question with greater statistical reliability.

REFERENCES
Dan Edvinsson and Lisa Ekselius, “Long-Term Tolerability and Safety of Pharmacological Treatment of Adult Attention-Deficit/Hyperactivity Disorder,” Journal of Clinical Psychopharmacology, vol. 38, no. 4 (2018).