27 March 2019

Amphetamine linked to higher ADHD psychosis

Clinical Mental Health Paediatrics

Young people with ADHD are more likely to develop psychosis if they’re taking amphetamine than methylphenidate, a large US study suggests.

We’ve known for more than a decade that stimulants slightly elevate the risk of psychosis in patients with ADHD, but it’s been unclear whether some stimulants are safer than others.

Now, a study has revealed that taking amphetamine is associated with a 65% increased risk of new-onset psychosis compared with methylphenidate.

The Boston-based researchers examined insurance claims data for over 221,000 patients with ADHD who were aged 13-25 and who had taken either amphetamine or methylphenidate.

To address possible confounding factors, patients in different treatment arms were matched according to their sociodemographic and psychiatric characteristics. There was no difference in the rate of substance or alcohol use disorders between the two groups. Amphetamine and methylphenidate both work by inducing the release of dopamine, but amphetamine more closely mirrors the changes in neurotransmission observed in psychosis, which could explain the effect seen in the study, the authors hypothesised.

The study findings seemed to fit with a previous meta-analysis showing that methylphenidate had a better safety profile than for amphetamine in young patients, Associate Professor Samuele Cortese, a UK-based psychologist, wrote in an accompanying editorial.

But, due to its observational nature, “the current study should not be considered definitive”, he said.  A major drawback of the study was the lack of comparison with rates of psychosis in the general population,  Dr Dianne Grocott, a psychiatrist based in Melbourne, said.

In the study, psychosis occurred for one in 660 patients (0.1% of patients in the amphetamine group and 0.2% of the methylphenidate group). But, in the general population in Australia, psychosis occurs in 3% of people, which is much higher than the rates in the study. “Thus, it is not clear whether stimulant medication increases or protects against psychosis,” Dr Grocott said.

Similarly, Professor David Coghill, a psychiatrist at The University of Melbourne, said the major limitation of the study was that it did not measure rates of psychosis in patients with ADHD who were not taking any medication.

ADHD is known to be associated with psychosis, so it was possible that it was the condition, not the drugs, that was raising the rates of psychosis in the study, he said.

A 2016 Hong Kong study, co-authored by Professor Coghill, showed that there was no difference in the incidence of psychosis when patients with ADHD were taking methylphenidate compared to when these patients stopped taking their medication.

To his knowledge, a similar study has not yet been conducted for amphetamine.

An interesting finding of the NEJM study, he said, was that the difference in psychosis rates between the drugs was present when the prescribing doctor was a GP or paediatrician but disappeared when the prescribing doctor was a psychiatrist.

It could be that psychiatrists were better able to screen for psychosis and were more cautious in prescribing for at-risk patients.

“Of course, for anyone who is being prescribed any of these ADHD medications, it’s really important to screen for other mental health problems before you start,” Professor Coghill said.

“And it’s even more important to continue screening while people are taking the medication.”

NEJM 2019, 21 March