# Reduced risk of cause-specific hospitalisations and all-cause hospitalisation/mortality during treatment with attention-deficit/hyperactivity disorder medications in the course of bipolar disorder: a Swedish registry-based within-subject cohort study

## TL;DR

This study found that adding ADHD medications like lisdexamfetamine and methylphenidate to standard bipolar disorder treatments may reduce hospitalization risks.

## Contribution

The study provides new evidence that ADHD medications can reduce psychiatric and substance-related hospitalizations in bipolar disorder patients.

## Key findings

- Add-on stimulant ADHD medications were linked to lower psychiatric hospitalization risks.
- Lisdexamfetamine and methylphenidate reduced substance-use-related hospitalizations.
- No increased risk for mania-related or somatic hospitalizations was observed.

## Abstract

Comorbid attention-deficit/hyperactivity disorder (ADHD) increases the burden in bipolar disorder (BD). Concerns about the risk/benefit balance of ADHD treatment have been raised.

This study aimed to investigate the association between hospital admissions and add-on ADHD medications to antipsychotics and/or mood-stabilisers (APs/MSs) compared with AP/MS alone in BD.

Individuals with BD prescribed ADHD medications in Sweden during 2006–2021 were identified from national registers of inpatient care, specialised outpatient care, sickness absence and disability pension. ADHD treatment was defined as stimulants (mostly methylphenidate and lisdexamfetamine, rarely amphetamine, dexamphetamine) and non-stimulants (atomoxetine, modafinil). Add-on ADHD treatment to concomitant AP/MS was compared with treatment periods with AP/MS without ADHD treatment, using within-individual models where individuals acted as their own control. Adjusted HRs (aHRs) and CIs (95% CIs) were calculated for the primary outcome of psychiatric hospitalisation, and for the secondary outcomes: substance-use-related, somatic or mania-related hospitalisations, and all-cause hospitalisation/mortality.

Altogether, 17 971 individuals (mean age=32.0±11.6 years, males=37.6%, ADHD=88.9%, follow-up=8.9±4.4 years) with BD who used any ADHD treatment were included. compared with the use of AP/MS alone, add-on stimulant use was related to a lower risk of psychiatric hospitalisations (aHR=0.89, 95% CI 0.85 to 0.93), substance-related hospitalisations (aHR=0.75, 95% CI 0.70 to 0.81) and all-cause hospitalisations/mortality (aHR=0.90, 95% CI 0.87 to 0.93), but was not associated with increased risk for somatic (aHR=1.00, 95% CI 0.90 to 1.12) or mania-related hospitalisations (aHR=0.93, 95% CI 0.72 to 1.20). Of commonly used specific ADHD medications, add-on lisdexamfetamine (aHR=0.81, 95% CI 0.75 to 0.87) and methylphenidate (aHR=0.92, 95% CI 0.88 to 0.97) were associated with decreased risk of psychiatric hospitalisations while add-on atomoxetine was not. Findings on substance-use-related hospitalisations were significant only for stimulants, specifically lisdexamfetamine (aHR=0.70, 95% CI 0.61 to 0.79) and methylphenidate (aHR=0.80, 95% CI 0.74 to 0.86).

Among individuals with BD who received ADHD medications, add-on lisdexamfetamine and methylphenidate were associated with lower risks of psychiatric and substance-use-related hospital admissions, compared with AP/MS use alone. No significant association was found between ADHD medication use and mania-related hospitalisations or somatic admissions when these medications were used together with AP/MS. Larger samples are needed to reach adequate statistical power and conclusive findings on atomoxetine, dexamfetamine and modafinil.

The findings of this study suggested that the treatment of comorbid ADHD could be considered after adequate mood-stabilisation in patients with BD.