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. 2025 Sep 3;82(11):1103–1112. doi: 10.1001/jamapsychiatry.2025.2311

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

A Systematic Review and Meta-Analysis

Gonzalo Salazar de Pablo 1,2,3,✉, Claudia Aymerich 1,4, Juan Pablo Chart-Pascual 1,5, Marco Solmi 6,7,8,9,10, Javier Torres-Cortes 11, Nessma Abdelhafez 1,2, Ana Catalan 4,12, Olivier Corbeil 13,14, Nicoletta Adamo 1,2, Philip Shaw 1, Paolo Fusar-Poli 11,15,16,17, Samuele Cortese 18,19,20,21,22
PMCID: PMC12409658  PMID: 40900605

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.

This systematic review and meta-analysis evaluates the association between psychosis or bipolar disorder and stimulant treatment among individuals with attention-deficit/hyperactivity disorder.

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.

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition characterized by persistent and impairing inattention and/or hyperactivity/impulsivity that are inconsistent with development. Medications are part of the multimodal treatment strategy for the management of individuals with ADHD, with stimulants as first-line option in many clinical guidelines.1 Stimulants, alongside benefits, are associated with adverse effects,2 although most can be managed.3

Among other adverse events, psychotic or manic symptoms can occur during treatment with stimulants.4 Psychotic symptoms, appearing most frequently in adults,5 are often short lived and tend to resolve after treatment discontinuation.6 However, symptoms may persist, leading to the development of a new-onset psychotic disorder, for which antipsychotic medications may be required.4

While manic symptoms have also been reported in association with stimulant treatment, a meta-analysis7 failed to find an increase in manic symptoms in those treated with stimulants compared to placebo. However, that review only focused on individuals with established bipolar disorder (BD) at baseline. As such, the occurrence of BD in individuals with ADHD without BD exposed to stimulants remains unclear.

To our knowledge, no meta-analysis to date has estimated the magnitude of the occurrence of psychosis or BD following stimulant treatment for ADHD, nor the factors moderating possible risk. We aimed to fill this gap by estimating the occurrence of psychosis or BD after exposure to stimulants for ADHD and assessing any possible moderating factors which can affect the development of these symptoms.

Methods

This study was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (eTable 1 in Supplement 1) and Meta-Analysis of Observational Studies in Epidemiology (MOOSE) (eTable 2 in Supplement 1) reporting guidelines. Our protocol was preregistered in PROSPERO (CRD42024616752).

Literature Search

PubMed, Web of Science, Ovid/PsycINFO, and Cochrane Central Register of Reviews were searched with no language restrictions, from inception until October 1, 2024. Search strategy and syntax and databases searched are available in eMethods 1 in Supplement 1. To identify eligible trials, we also screened the MED-ADHD database.8,9 Unpublished data and information were gathered (eMethods 2 in Supplement 1).

Inclusion and Exclusion Criteria

We included studies of any design (observational or interventional) conducted in individuals with DSM or International Classification of Diseases–defined ADHD evaluating stimulant medication and in which the percentage of individuals who presented with psychotic symptoms, a psychotic disorder, or mania or BD following medication initiation was reported. We excluded reviews, clinical cases, abstracts, or protocols; studies conducted in individuals with other disorders; studies without information on the development of psychosis or mania or BD; and studies reporting rates of BD or psychosis only before treatment initiation.

Data Extraction

Three authors (C.A., J.P.C., and J.T.C.) independently extracted data into a Microsoft Excel spreadsheet. Variables extracted can be found in eMethods 3 in Supplement 1.

Data Synthesis

Our outcomes were the percentage of individuals (95% CI) exposed to stimulants who developed psychotic symptoms, a psychotic disorder, or BD. We also compared the development of psychotic symptoms in individuals exposed to amphetamines and those exposed to methylphenidate based on studies comparing head-to-head these 2 medications and providing the percentage of individuals who developed psychotic symptoms on each of them, using odds ratios (ORs) with 95% CIs. Given the expected study heterogeneity, random-effects meta-analyses were conducted,10 with DerSimonian-Laird estimators. We used the logit transformation to stabilize the variances. Publication bias was assessed using the Egger test.11 Heterogeneity was assessed using Q statistics. The proportion of the total variability in the effect size estimates was evaluated with the I2 statistic12 and considered statistically significant when P was <.05. We estimated the 95% prediction interval, the range in which we expect the effect of the association will lie for 95% of future studies.13

We conducted subgroup analyses for psychotic symptoms outcome to estimate any difference in the results according to the design of the studies (observational vs clinical trials), diagnostic criteria (DSM any version vs ICD any version, with or without additional validated measures), continent (Europe vs Asia vs North America), the use of registry data (yes vs no), explicit mention that participants did not have the outcome of interest at baseline, explicit mention that other medications were excluded, and duration of follow-up (<1 year vs 1-5 years vs >5 years). Furthermore, we conducted meta-regression analyses for our primary outcome whenever 7 or more studies (as in previous studies14,15) were available for each regressor, to estimate the association between the development of psychotic symptoms and percentage male, age, duration of follow-up, year of publication, and sample size. We did a final meta-regression assessing the dose-response relationship between dose (mg/d) of methylphenidate and the development of psychotic symptoms, although only 5 studies provided these data (we considered 1 mg of methylphenidate equivalent to 0.6 mg of lisdexamfetamine per day).16 Additional leave-one-out sensitivity analyses evaluated the stability of the meta-analytic findings when each study was removed at a time. Based on our findings, we applied Grading of Recommendations Assessment, Development and Evaluation (GRADE)17 (which sets 4 categories for rating quality of evidence—high, moderate, low, and very low—based on study design, risk of bias, inconsistency, indirectness, and imprecision) and the US Preventive Services Task Force grading system18 (eMethods 4 in Supplement 1) to classify the evidence and support evidence-based recommendations. P values for meta-analyses were 2-sided, with α = .05. P values for heterogeneity analyses were 1-sided. Comprehensive meta-analysis version 3 was used to perform the analyses.

Risk of Bias Assessment

We used the Newcastle-Ottawa scale (NOS) for cohort studies and the Cochrane risk of bias tool, version 2, for randomized clinical trials (eTable 3 and eMethods 5 in Supplement 1).

Results

From 1414 nonduplicated citations initially retrieved, 16 studies were finally included (see Figure 1 for the PRISMA diagram, Table 1 for main characteristics of the included studies, eTable 4 in Supplement 1 for other characteristics, and eTable 5 in Supplement 1 for reasons for exclusion), encompassing in total 391 043 individuals (mean [range] age, 12.6 [8.5-31.1] years; 288 199 [73.7%] male and 102 844 [26.3%] female). A total of 76.8% of individuals with ADHD met criteria for the combined presentation, 16.4% for predominantly inattentive presentation, and 8.5% for predominantly hyperactive-impulsive presentation. We included 1 double-blind randomized clinical trial,32 1 open-label randomized clinical trial26 and 1 naturalistic nonrandomized study,19 while the rest were longitudinal cohort studies.

Figure 1. PRISMA Flow Diagram.

Figure 1.

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Table 1. Main Characteristics of the Included Studies.

Source Country Study design ADHD criteria (presentation) Sample size, No. Age, mean (SD; range), y Female, % Medication for ADHD Race and ethnicity Outcome Duration of follow-up QA (NOS score or RoB rate)
Baweja et al,19 2016 US Naturalistic non-randomized clinical trial DSM-IV, DSM-V (NA) 38 9.4 (1.7; children) 28 Stimulants 26.3% Racial or ethnic minority Mania (symptoms); bipolar disorder 6 wk 5, Moderate quality
Björkenstam et al,20 2020 Sweeden Longitudinal cohort ICD-9, ICD-10 (NA) 13 237 NA; adolescents) 60.2 MPH, INN, AMP NA Psychosis (disorder) Up to 14 y 8, High quality
Cherland and Fitzpatrick,21 1989 Canada Longitudinal cohort DSM-III, DSM-IV (NA) 98 NA; 4-18) 24.0 MPH, pemoline NA Psychosis (symptoms); bipolar disorder 7 y 9, High quality
Coghill et al,22 2017 Multicountry Longitudinal cohort DSM-IV-TRb (79.9% combined, 17.8% predominantly inattentive, 2.2% predominantly hyperactive-impulsive) 314 11.4 (2.9; 6-19) 20.4 LDX 98.7% White Psychosis (symptoms) 2 y 9, High quality
Cortese et al,23 2015 Italy Longitudinal cohort DSM-IV (84.7% combined, 11.7% predominantly inattentive
3,6% predominantly hyperactive-impulsive)		 1426 10.7 (2.8; 6-18) 11.9 MPH NA Psychosis (symptoms) 5 y 8, High quality
Dalsgaard et al,24 2015 Denmark Longitudinal cohort DSM-IV, ICD10 (65.9% combined, 19.7% predominantly hyperactive-impulsive, 14.4% inattentive) 208 31.1 (6.6 at follow-up; children and adolescents at baseline) 12.0 Stimulants NA Psychosis (disorder) Until adulthood (mean [SD], 31.1 [6.6] y) 6, Moderate quality
Elmaghraby et al,25 2024 US Longitudinal cohort ICD-9, ICD-10 (NA) 4358 10.2 (3.6; 6-18)a 31.4a MPH, AMP 83.5% White, 5.0% Black or African-American, 1.7% Asian, 7.4% other, 2.5% NA Psychosis (symptoms) 7.7 y (mean duration) 6, Moderate quality
Golubchik and Weizman,26 2018 Israel Open-label randomized clinical trial DSM-IV-TRc (NA) 60 12.5 (2.5; 8-18) 41.7 MPH NA Psychosis (symptoms) 12 wk Some concerns
Hamard et al,27 2024 Multicountry Longitudinal cohort ICD (NA) 5221 17.2 (3.6; 13-25) 38.8 MPH, AMP NA Psychosis (symptoms) NA 9, High quality
MacKenzie et al,28 2016 Canada Longitudinal cohort DSM-IV (NA) 17 11.8 (4.0; 6-21) 50.0 MPH, LDX, INN NA Psychosis (symptoms) NA 8, High quality
Moran et al,29 2019 US Longitudinal cohort ICD-9 (NA) 221 846 NA; 13-25) 37.3 MPH, AMP NA Psychosis (symptoms) 155- 162 d (median duration) 7, High quality
Park et al,30 2022 South Korea Longitudinal cohort ICD-10 (NA) 3508 8.9 (2.7; children & ADOL) 16.6 MPH NA Psychosis (symptoms) 1.5 y 9, High quality
Shyu et al,31 2015 Taiwan Longitudinal cohort ICD-9 (NA) 53 600 9.4 (3.3; children) 20.2 MPH NA Psychosis (disorder) ADHD diagnosis to 2012 (maximum 12 y) 9, High quality
Takahashi, et al,32 2014 Japan Randomized clinical trial DSM-IV-TR (43.3% combined, 0.7% predominantly hyperactive-impulsive, 56.0% inattentive) 283 33.7 (9.0; 18-64) MPH NA Psychosis (disorder) 8 wk Low risk
Tillman and Geller,33 2006 US Longitudinal cohort DSM-IVd (NA) 81 9.7 (2.0; 7-16) 17.0 NA/ any NA Bipolar disorder 6 y 5, Moderate quality
Wang et al,34 2016 Taiwan Longitudinal cohort ICD-9 (NA) 86 747 8.5 (3.1; children) 18,9 NA./ any NA Bipolar disorder Mean (SD), 5.1 (3.1) y 9, High quality
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Abbreviations: ADHD-RS-IV, ADHD Rating Scale IV; AMP, amphetamine; INN, dexamphetamine; K-SADS-PL, Kiddie Schedule for Affective Disorders and Schizophrenia–Present and Lifetime Version; LDX, lisdexamfetamine; MPH, methylphenidate; NA, not available; NOS, Newcastle-Ottawa Scale; QA, quality assessment; RoB, risk of bias (Cochrane); WASH-U-K-SADS, Washington University Kiddie Schedule for Affective Disorders and Schizophrenia.

a

Data from the full sample at diagnosis.

b

Complemented with ADHD-RS-IV.

c

Complemented with K-SADS-PL and ADHD-RS-IV.

d

Complemented with WASH-U-K-SADS.

Meta-Analytical Results

Overall, 2.76% (95% CI, 0.73-9.88), 2.29% (1.52-3.40), and 3.72% (0.77-16.05) of individuals with ADHD who had been prescribed stimulants developed psychotic symptoms (k = 10; n = 237 035), a psychotic disorder (k = 4; n = 91 437), and BD (k = 4; n = 92 945), respectively (Figures 2 and 3). Prediction intervals were 0.0% to 82.7%, 0.0% to 79.3%, and 0.0% to 98.2%, respectively.

Figure 2. Outcome in Individuals With Attention-Deficit/Hyperactivity Disorder (ADHD) Exposed to Stimulant Medication.

Figure 2.

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Figure 3. Development of Psychosis and Bipolar Disorder in Individuals With Attention-Deficit/Hyperactivity Disorder Exposed to Stimulant Medication.

Figure 3.

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Leave-one-study-out analyses for the development of psychotic symptoms can be found in eFigure 1 in Supplement 1, resulting in pooled estimates ranging from 1.75% (95% CI, 0.44-6.78) to 4.35% (95% CI, 2.39-7.79). Heterogeneity across the included studies was statistically significant for psychotic symptoms (I2 = 99.6%; Q = 2813.50; P < .001), psychotic disorders (I2 = 97.5%; Q = 80.27; P < .001), and BD (I2 = 95.7%; Q = 70.04; P < .001), indicating high variability in the effect size estimates.

Subgroup Analyses and Publication Bias

Differences were found between the studies according to the continent in which they were carried out (Q = 145.42; P < .001): 6.27% (95% CI, 0.83-34.96), 1.59% (95% CI, 1.23-2.06), and 0.34% (95% CI, 0.15-0.77) of individuals with ADHD who had been prescribed stimulants developed psychotic symptoms in North America (k = 5; n = 226 969), Asia (k = 2; n = 4108), and Europe (k = 2; n = 1737), respectively. Differences were found between the studies according to the duration of follow-up (Q = 16.07; P < .001): 7.24% (95% CI, 2.91-16.88), 0.68% (95% CI, 0.19-2.38), and 0.20% (95% CI, 0.07-0.57) individuals with ADHD who had been prescribed stimulants developed psychotic symptoms in studies with a follow-up of more than 5 years (k = 3; n = 4625), 1 to 5 years (k = 3; n = 5248), and of less than 1 year (k = 2; n = 221 924), respectively. Other explored predictors did not influence the results (eTable 6 in Supplement 1).

Higher proportion of females (β, 0.012; 95% CI, 0.002 to 0.023; k = 7) (eFigure 3 in Supplement 1), smaller sample size (β, −0.0001; 95% CI, −0.0001 to 0.0001; k = 10) (eFigure 4 in Supplement 1) and a higher stimulant dose (β, 0.243; 95% CI, 0.118 to 0.368; k = 5) (eFigure 5 in Supplement 1) were associated with an increase in the likelihood of occurrence of psychotic symptoms. There was no association between mean age of the participants (β, −0.007; 95% CI, −0.473 to 0.459; P = .98) or year of publication (β, −0.113; 95% CI, −0.297 to 0.072; P = .23) and the development of psychotic symptoms. There was a nonsignificant trend of an association between duration of follow-up and the development of psychotic symptoms (β, 0.454; 95% CI, −0.001 to 0.909; P = .05). Details on the meta-regression analyses are provided in eTable 7 in Supplement 1. No indication of publication bias was found (eTable 8 and eFigure 3 in Supplement 1).

Results Based on Type of Stimulant Exposure

The meta-analytical occurrence of psychotic symptoms was significantly higher among individuals exposed to amphetamines than among those exposed to methylphenidate (OR, 1.57; 95% CI, 1.15-2.16; k = 3; n = 231 325). See the eResults in Supplement 1 for results from individual studies.

Quality Assessment

The quality of the cohort studies was good in 10 studies (71.4%) and moderate in 4 studies (28.6%). One RCT was evaluated as low risk of bias32 and the other as having some concerns.26 GRADE and US Preventive Services Task Force recommendations are reported in Table 2.

Table 2. Grading of Recommendations Assessment, Development and Evaluation (GRADE) and US Preventive Services Task Force (USPSTF) Grading.

GRADE approach USPSTF grading

  • Quality of evidence

  • Study design: studies were primarily observational, which starts at a low GRADE rating for observational studies.

  • Risk of bias: 75% of studies were rated as good quality and 25% as moderate, indicating a low risk of bias overall.

  • Inconsistency: significant heterogeneity (I2 > 95%) was observed in most outcomes.

  • Indirectness: direct evidence exists for the population of interest (patients with DSM/International Classification of Diseases–defined ADHD taking stimulant medications).

  • Imprecision: confidence intervals are wide, particularly for subgroup analyses, indicating potential imprecision; prediction intervals are even wider.

  • Publication bias: no evidence of publication bias was found (Egger test and funnel plots).

  • Certainty of evidence

  • High certainty: not applicable due to limited evidence and high heterogeneity.

  • Moderate certainty: psychosis development in patients with ADHD prescribed stimulants is supported by meta-analytic evidence and individual study results but limited by heterogeneity and imprecision.

  • GRADE evidence rating

  • Psychosis development: low.

  • Bipolar disorder development: very low.

  • Subgroup analyses (duration of follow-up, continent): very low.

  • Magnitude of net benefit

  • Potential harms: development of psychosis or bipolar disorder, the first particularly with but not limited to amphetamine use.

  • Potential benefits: effective management of ADHD symptoms and functional improvements.

  • USPSTF grade: C

  • Selective use of stimulant medications is recommended, with methylphenidate preferred over amphetamines, with shared decision-making and monitoring for adverse outcomes.

  • Strength of recommendation

  • Psychotic symptoms occur in approximately 2.8% of individuals with ADHD taking stimulant medication (higher with amphetamines).

  • Psychotic disorders occur in 2.3% and bipolar disorder in 3.7% of individuals with ADHD taking stimulant medication.

  • Caution is warranted when prescribing stimulants, especially for those at higher risk (eg, those exposed to amphetamines, at clinical high risk, or with a family history of psychosis).

  • Recommendation

  • Recommendation for monitoring of patients with ADHD prescribed stimulants, particularly closely for amphetamines.

  • Summary recommendations

  • Monitoring practices: clinicians should monitor patients with ADHD closely for psychotic symptoms, especially those prescribed amphetamines (>5 y).

  • Shared decision-making: engage patients and caregivers in discussions about risks vs benefits, considering individual factors such as age, sex, and ADHD subtype.

  • Research needs: high heterogeneity and imprecision highlight the need for further studies comparing stimulants and nonstimulants, with longer follow-up periods to refine risk estimates.
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Abbreviation: ADHD, attention-deficit/hyperactivity disorder.

Discussion

To our knowledge, this is the first systematic review and meta-analysis to estimate the occurrence of psychotic symptoms, a psychotic disorder, or BD following treatment with stimulants in individuals with ADHD. We found that 2.8%, 2.3%, and 3.7% of individuals with ADHD who had been prescribed stimulants developed psychotic symptoms, a psychotic disorder, and BD, respectively. Amphetamines were associated with 57% higher odds for the occurrence of developing psychotic symptoms compared to methylphenidate. Given the substantial heterogeneity, our pooled estimates should be interpreted as indicative of average occurrence rates across diverse clinical and methodological contexts, rather than precise risks applicable to specific populations. The wide prediction intervals further reflect this uncertainty, underscoring the need for caution in applying these findings to individual clinical settings.

Although not remarkably high, a 2.8% development of psychotic symptoms represents a nonnegligible figure and lends further meta-analytic support to the 2007 US Food and Drug Administration (FDA) change in the drug label for stimulants, alerting on the possible occurrence of psychotic symptoms.35 Previous studies in which individuals with ADHD developed psychosis requiring the use of antipsychotics have found lower percentages.29 This may be due to the delays in receiving adequate interventions, also known as duration of untreated psychosis, which has been estimated as 42.6 weeks worldwide.36 Notably, our results should be considered alongside the fact that a childhood diagnosis of ADHD is associated with an increase in risk of a subsequent psychotic disorder later on in life, with a relative risk of 4.74.37 Furthermore, our findings should be interpreted considering that the global incidence of psychosis in the general population is 26.6 per 100 000 person-years,38,39 and that the offspring of affected parents have also an increased risk of developing mental disorders.40 Two studies,41,42 in which the risk of psychosis was evaluated (in individuals not limited to those with ADHD) during periods with and without methylphenidate treatment, did not find a significant association between methylphenidate use and increased risk of psychosis. This casts doubts on possible cause-effect relationship. To our knowledge, analogous studies specifically on amphetamines are currently lacking. Considering all the relevant included studies, we found low-level evidence of a causal effect between stimulants and psychosis. The downgrade of the evidence to low was due to substantial heterogeneity (as reflected by I2 values), indirectness due to variability in definitions and populations, and imprecision arising from wide CIs.

Overall, the possible mechanisms underlying the development of psychosis and BD in individuals treated with stimulants require further elucidation. It is thought that they may be mediated by dopaminergic excess or disfunction.16,43 Given the lack of a clear cause-effect relationship, it is possible that some individuals may rarely develop psychosis or mania after exposure to stimulants and some may be sensitive even after taking low doses of stimulants.4,35 The higher risk of psychotic symptoms in the long term does not strongly support an immediate, direct causal effect and, rather, suggests that psychotic symptoms may reflect the course of ADHD itself. Conversely, the association between follow-up duration and psychotic symptoms in our meta-regression was nonsignificant. Variability in study length alone does not account for the observed heterogeneity. This reinforces the view that while the pooled estimates provide meaningful average risks, they likely encompass a wide spectrum of underlying clinical scenarios, patient populations, and methodological approaches. There are other specific factors to be taken into consideration. Stimulants seem to cause psychosis more often at high doses and with parenteral use,44 but we were not able to evaluate this relationship given the nature of the available data. Frequency of stimulant use has been associated with psychosis, while sociodemographic factors have not.45 Contrary to meta-analytical evidence for the development of psychosis from clinical high-risk populations where a lower proportion of female individuals was associated with an increased risk of psychosis,46 in our meta-regressions, female sex was associated with an increase in risk of development of psychosis. Furthermore, sleep deprivation seems to play an important role in the development of psychotic symptoms.47 A study48 including individuals with and without a diagnosis of ADHD found that stimulant initiation was associated with an increased risk of hospitalization for psychosis or mania in the subsequent 60 days (OR, 1.86), while our findings suggest that the risk increases in the long term. Notably, another study49 found that earlier-onset methamphetamine use and being male were more specifically related to transient psychotic symptoms, while a family history of a primary psychotic disorder and comorbid major depression were specifically related to persistent psychotic symptoms.

Overall, we deem that our results should not discourage clinical guidelines from recommending stimulants as first line treatments for ADHD. In any case, it is important for prescribers to inform patients and their families about the possibility of developing this adverse effect,50 carefully monitor for the risk of psychosis before the stimulants are started using self-rated questionnaires and, when applicable, psychosis risk assessment, and slowly titrate stimulant medications. In case of stimulant-induced psychosis, the medication should be stopped, and an alternative medication considered. Furthermore, patients should be considered to be at risk of future development of an enduring psychotic illness.51

While several clinical guidelines for ADHD do not address the management of psychosis occurring during stimulant treatment, National Institute for Health and Care Excellence (NICE) guidelines suggest that, if psychosis occurs due to stimulant use, the stimulant should be discontinued.37 Notably, data from the FDA show that signs and symptoms of psychosis usually disappear on stopping the stimulants in about 90% of cases, without the need to introduce an antipychotic.52 Based on our meta-analytic data, among stimulants, methylphenidate could be preferred to minimize the risk of psychosis, but the less favorable profile for amphetamines could be due to confounding by symptom severity. Second-line pharmacological treatments, such as atomoxetine, for which there is no evidence of increased risk of psychosis,53 would be another option.

Regarding the development of BD, 1 study54 found that mania/hypomania was frequently observed in patients with BD (up to 40%) in the 2 months after starting stimulants for the treatment of ADHD or bipolar depression. One in 13 adults with ADHD is diagnosed with BD while nearly 1 in 6 adults with BD has ADHD.55 Our results suggest a much lower risk in individuals with ADHD following prescription of stimulants, lower than the risk of developing BD in at-risk populations56 or individuals with depressive disorders57; the mechanisms underlying this association remaining unclear. Further research is warranted to better understand individual vulnerability and to explore whether specific stimulant types, dosages, or clinical characteristics may mediate this risk. There is very low-level evidence of a cause-effect relationship between stimulants and the development of BD in individuals with ADHD according to our GRADE rating. An important factor underlying this was imprecision due to CIs and prediction intervals being wide.

While underlying mechanisms for stimulant-induced mania remain poorly understood, they are hypothesized to involve dysregulation of dopaminergic and noradrenergic pathways. Stimulants enhance dopaminergic and noradrenergic neurotransmission by inhibiting reuptake and increasing the release of these neurotransmitters.58 NICE guidelines1 emphasize the importance of carefully evaluating comorbidities, including BD, before initiating stimulant treatment for ADHD, which is supported by our data. Specifically, NICE 2023 guidelines1 recommend a thorough psychiatric assessment, particularly in individuals with a family history of BD. Stimulants should be prescribed for ADHD after a comprehensive risk-benefit analysis has been conducted, and patients should be regularly monitored for the emergence of new manic/hypomanic symptoms.1 Over the past decade, a growing body of evidence has emerged highlighting the conditions in which individuals with established BD may still benefit from stimulants,59 but more research is needed given methodological issues of available studies (eg, heterogeneous samples and medication type/doses).60

Limitations

Our study has limitations. First, based on the available studies, it was not possible to differentiate the effect of the medication from that of ADHD itself as we could not include a consistent control group of individuals with ADHD who were not treated with stimulants. We also found only 3 studies comparing amphetamines and methylphenidate, making it difficult to weigh risks associated with individual agents rather than the stimulants as a whole. Future individual participant data meta-analyses may help address this gap. Second, we could not meta-analyze data on the development of manic symptoms with stimulants. Third, even though we explored heterogeneity with meta-regressions, we could not address this comprehensively, due to the paucity of relevant reported data, such as information on severity of ADHD, comorbid mental health conditions, medication dose or usage, or psychosocial functioning. Additionally, we could not assess the effect of different formulations, combination of different medications, or the effect of nonstimulant medications. Fourth, as studies included in the meta-analysis included a mixture of children and adolescents and young adults, we could not explore age effects. Of note, the clinical significance of psychotic symptoms in younger children is less clear than in adults.61 Fifth, we could not adequately control for the temporal sequence of medication use. Notably, in many countries, amphetamines are reserved for those who do not respond to or cannot tolerate methylphenidate, who may have more severe ADHD or more comorbid conditions. Sixth, most studies did not specify the percentage of individuals with psychosis or BD at baseline. Future studies should report psychiatric history rates to support causal inference. Seventh, some studies used electronic health record data, which may be less accurate than those obtained through direct clinical assessments.

Conclusions

To our knowledge, this study provides the first pooled estimate of the occurrence of psychosis or BD in individuals with ADHD exposed to stimulant medication. This meta-analysis indicates a nonnegligible risk of psychosis and BD in patients with ADHD treated with stimulants, with amphetamines posing a higher risk than methylphenidate according to evidence from 3 studies. Our results underscore the crucial need for comprehensive psychoeducation, careful monitoring (for all psychostimulants), and discussion with patients and their caregivers about management strategies. Future research including randomized clinical trials or mirror-image studies comparing individuals exposed vs nonexposed to stimulants and preventive interventions is warranted.

Supplement 1.

eTable 1. PRISMA 2020 item checklist

eTable 2. MOOSE checklist

eTable 3. Quality assessment Newcastle Ottawa Scale criteria

eTable 4. Other characteristics of the included studies

eTable 5. Reasons for exclusion

eTable 6. Subgroup analyses psychotic symptoms

eTable 7. Meta-regressions psychotic symptoms

eTable 8. Egger’s tests

eFigure 1. Leave one study out analyses psychotic symptoms

eFigure 2. Forest plot development of psychosis comparing individuals exposed to amphetamines and methylphenidate

eFigure 3. Scatterplot relationship % females and development of psychosis symptoms

eFigure 4. Scatterplot relationship sample size and development of psychosis symptoms

eFigure 5. Scatterplot relationship stimulant dose and development of psychosis symptoms

eFigure 6. Funnel Plot psychosis symptoms

eMethods 1. Search Strategy

eMethods 2. Screening Strategy

eMethods 3. Data extraction strategy

eMethods 4. USPSTF Grading System

eMethods 5. Quality Assessment

eResults

jamapsychiatry-e252311-s001.pdf (609.6KB, pdf)
Supplement 2.

Data sharing statement

jamapsychiatry-e252311-s002.pdf (14.3KB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eTable 1. PRISMA 2020 item checklist

eTable 2. MOOSE checklist

eTable 3. Quality assessment Newcastle Ottawa Scale criteria

eTable 4. Other characteristics of the included studies

eTable 5. Reasons for exclusion

eTable 6. Subgroup analyses psychotic symptoms

eTable 7. Meta-regressions psychotic symptoms

eTable 8. Egger’s tests

eFigure 1. Leave one study out analyses psychotic symptoms

eFigure 2. Forest plot development of psychosis comparing individuals exposed to amphetamines and methylphenidate

eFigure 3. Scatterplot relationship % females and development of psychosis symptoms

eFigure 4. Scatterplot relationship sample size and development of psychosis symptoms

eFigure 5. Scatterplot relationship stimulant dose and development of psychosis symptoms

eFigure 6. Funnel Plot psychosis symptoms

eMethods 1. Search Strategy

eMethods 2. Screening Strategy

eMethods 3. Data extraction strategy

eMethods 4. USPSTF Grading System

eMethods 5. Quality Assessment

eResults

jamapsychiatry-e252311-s001.pdf (609.6KB, pdf)
Supplement 2.

Data sharing statement

jamapsychiatry-e252311-s002.pdf (14.3KB, pdf)

Articles from JAMA Psychiatry are provided here courtesy of American Medical Association

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