The study population’s flow chart is illustrated in figure 1. A total of 16 125 adults initiated new use of an ADHD drug during the 13-year-long study period; 8284 (51.4%) were women, and the median age was 33 (IQR 25–43) years. The majority (11 289/16 125=70%) of new users received ADHD medication from one drug class during the study period, a quarter (4033/16,125=25.1%) from two drug classes, and under 5% (785/16 125=4.9%) received a prescription for three or more ADHD drug classes. Following new use, 112 were admitted for psychosis or mania within a year. Of these, 61 (54.5%) were hospitalised for first-onset psychosis or mania, and, importantly, none of these were receiving more than one ADHD medication upon admission.

Flow chart of the study population. ADHD, attention deficit hyperactivity disorder.

The mean incidence of new ADHD drug use was 5.8 per 1000 inhabitants during the study period, rising from 2.5 in 2010 to 11.3 in 2022 per 1000 inhabitants. A nearly sixfold increase in the absolute number of new adult users per year was observed over the study period, from 591 in 2010 to 3309 in 2022. Overall, the incidence of such treatment was three times higher in the 18–39 years age group (9.5 per 1000) compared with those aged 40 or older (3.1 per 1000). The drug most frequently dispensed for the first time during the first half of the study period was methylphenidate. However, there has been a massive surge in the use of lisdexamphetamine since 2017, resulting in it being the most commonly prescribed new ADHD medication for adults in Iceland since 2021. The number of new adult prescriptions per year for lisdexamphetamine (mainly), dexamphetamine or amphetamine for adults, for example, increased from 54 in 2017 to 2233 in 2022. During the same period, the number of new adult prescriptions per year for methylphenidate only rose from 1204 to 1321.

Of the 61 patients hospitalised during the study period, 48 were admitted for first-onset psychosis and 13 for first-onset mania (p<0.001). The majority were males, 40 (65.6%), and 7 out of 10 were in the age category 18–39 years at the time of hospitalisation (table 1). The majority, 43 (70.5%), of hospitalisations were observed in patients who had been exposed to only one ADHD drug class during the study period, while 14 (23.9%) had initiated medicines from two ADHD drug classes, for example, first trying methylphenidate and later lisdexamphetamine, and four (6.6%) from three ADHD drug classes. The median length of admission was 8 days (IQR 4–17).

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Patient characteristics and clinical factors associated with first-onset psychosis or mania

The risk of hospitalisation remained relatively similar for those 61 individuals who were admitted throughout the year following initiation of treatment (figure 2). The median time from ADHD drug exposure to hospitalisation for first-onset psychosis or mania was 172 days, and the mean time was 174.4 days. Thus, almost half of the hospitalisations occurred more than half a year after the onset of treatment.

A Kaplan-Meier survival curve illustrating the time to hospitalisation for new-onset psychosis or mania within 1 year following the initiation of new ADHD medication use. ADHD, attention deficit hyperactivity disorder.

Methylphenidate was the most common ADHD drug used by those admitted (25/61=41%), in line with being the most prescribed stimulant overall during the study period. It was followed by amphetamines (21/61=34.4%) and finally atomoxetine (15/61=24.6%). Prior to 2017, no cases of psychosis or mania were identified that were directly linked to prescribed lisdexamphetamine, dexamphetamine or other amphetamines for ADHD. The pattern changed as of 2017–2018, after dexamphetamine and subsequently lisdexamphetamine were registered in Iceland. The majority of admitted cases (65.6%) during the remainder of the study period followed the use of prescribed lisdexamphetamine (figure 3).

The risk of hospitalisation for first-onset psychosis and mania. ATC, anatomic therapeutic chemical

Upon admission, only 11% of patients reported or admitted to some form of abuse of the ADHD drug they had been prescribed. Around one in two, or 50.8%, of those hospitalised had ever received a diagnosis of a substance abuse disorder according to their electronic medical records at the time of the admission. Not unexpectedly, this was most common in the atomoxetine group, where it applied to two out of three (10/15=66.7%), while recorded for just under half in the amphetamines group (10/21=47.6%) and in the methylphenidate group (11/25=44.0%). Within 1 year of discharge, 42 of the 61 patients (68.9%) had been represcribed an ADHD drug. One in four (11/42=26.2%) of those who were represcribed an ADHD drug after discharge were readmitted for psychosis or mania within a year.

The estimated absolute risk of admission for first-onset psychosis or mania within a year of commencing ADHD medication was 0.38%. The calculated estimate of the risk in the general population of all other such first-onset admissions for adults aged 18–67 years in 2018–2020 was 0.048% per year. Around 25% of that risk (0.012%) stemmed from admissions linked to the use of psychoactive substances (F1X.5) and 28% (0.013%) from manic or mixed episodes. The estimated RR within a year of ADHD drug initiation for first-onset admissions due to first-onset psychosis or mania was thus 7.99 (95% CI 6.06, 10.54), the proportional attributable risk 87.5% and the NNH 302 (95% CI 271, 340). The absolute risk of first-onset psychosis or mania was highest among individuals who started therapy with atomoxetine (0.60%), followed by amphetamines (0.33%) and finally methylphenidate (0.19%).