Psychosis and Bipolar in Attention-Deficit/Hyperactivity Disorder Treated With Stimulants

 

Gonzalo Salazar de Pablo, PhD1,2,3; Claudia Aymerich, PhD1,4; Juan Pablo Chart-Pascual, MD1,5
et al

Key Points

Question  What is the occurrence of psychosis or bipolar disorder (BD) in individuals with attention-deficit/hyperactivity disorder (ADHD) following stimulant treatment?

Findings  This systematic review and meta-analysis of 16 studies encompassing 391 043 participants found that the risk of psychosis and BD was nonnegligible in individuals with ADHD treated with stimulants. Occurrence of psychosis was higher in those treated with amphetamines compared to methylphenidate.

Meaning  A heterogeneous but nonnegligible occurrence of psychosis and BD following stimulants warrants psychoeducation, systematic monitoring, and appropriate management strategies.

Abstract

Importance  Individuals with attention-deficit/hyperactivity disorder (ADHD) may present with psychosis or bipolar disorder (BD) following treatment with stimulants. The extent to which this occurs is currently unclear.

Objective  To meta-analytically quantify the occurrence of psychosis or BD after exposure to stimulants in individuals with ADHD and assess possible moderating factors.

Data Sources  PubMed, Web of Science, Ovid/PsycINFO, and Cochrane Central Register of Reviews were searched from inception until October 1, 2024, without language restrictions.

Study Selection  Studies of any design with DSM or International Classification of Diseases–defined ADHD populations exposed to stimulants, where psychosis or BD outcomes were evaluated.

Data Extraction and Synthesis  PRISMA Preferred Reporting Items for Systematic Reviews and Meta-analyses and MOOSE Meta-analysis of Observational Studies in Epidemiology guidelines were followed, the protocol was registered, and the Newcastle-Ottawa scale and Cochrane risk of bias-2 tool were used for quality appraisal. Random-effects meta-analysis, subgroup analyses, and meta-regressions were conducted.

Main Outcomes and Measures  For the proportion of individuals developing psychotic symptoms, psychotic disorders, and BD, effect sizes are reported as percentages with 95% CIs. For the comparison between amphetamines and methylphenidate, effect sizes are presented as odds ratios with 95% CIs.

Results  Sixteen studies (N = 391 043; mean [range] age, 12.6 [8.5-31.1] years; 288 199 [73.7%] male) were eligible. Among individuals with ADHD prescribed stimulants, 2.76% (95% CI, 0.73-9.88; k = 10; n = 237 035), 2.29% (95% CI, 1.52-3.40; k = 4; n = 91 437), and 3.72% (95% CI, 0.77-16.05; k = 4; n = 92 945) developed psychotic symptoms, a psychotic disorder, and BD, respectively. Heterogeneity across the studies was significant (I² > 95%). Psychosis occurrence risk was significantly higher in individuals exposed to amphetamines than to methylphenidate (odds ratio [OR], 1.57, 95% CI, 1.15-2.16; k = 3, n = 231 325). Subgroup analyses showed significantly higher prevalence of psychotic symptoms in studies from North America and in those with longer follow-up periods. Increased psychosis occurrence was associated with a higher proportion of female participants, smaller sample sizes, and higher dose of stimulants.

Conclusions and Relevance  This systematic review and meta-analysis found a nonnegligible occurrence of psychotic symptoms, psychotic disorders, or BD in individuals with ADHD treated with stimulants. Amphetamines were associated with higher occurrence compared to methylphenidate. The included studies cannot establish causality, highlighting the need for further research, including randomized clinical trials and mirror-image studies comparing individuals exposed and not exposed to stimulants. Nonetheless, clinicians should inform patients about the increased occurrence of psychosis or BD when discussing stimulant pharmacotherapy and systematically monitor for these conditions throughout treatment.

https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2838206