Different Changes in Brain Functional Networks Following 12-Week Psychostimulant Treatment in Attention-Deficit/Hyperactivity Disorder Youth With and Without Familial Risk for Bipolar I Disorder.

OBJECTIVE

Although psychostimulants are the first-line treatment for attention-deficit/hyperactivity disorder (ADHD) and can normalize associated brain network abnormalities, their neural effects in ADHD youth with a family history of bipolar I disorder (BD) have not yet been systematically investigated.

METHOD: This study investigated the effects of 12-week mixed amphetamine salts-extended release (MAS-XR) treatment on brain functional networks and symptom changes in ADHD youth with ("high-risk" [HR]) and without ("low-risk" [LR]) a first-degree relative with BD. LR received 12-week open-label MAS-XR and HR were randomized to MAS-XR or placebo (PLA). Healthy controls (HC) were included for comparative purposes. Resting-state functional magnetic resonance imaging scans were acquired at baseline and week 12. Global and nodal network topological metrics were evaluated based on functional connectivity matrices using graph theoretical analysis.

RESULTS

A total of 135 youth were included (HC, n = 45; LR-MAS, n = 46; HR-MAS, n = 28; HR-PLA, n = 16). For comparisons between HR-MAS and LR-MAS groups, significant group-by-time interactions were identified in global efficiency, characteristic path length, left superior parietal gyrus degree, and right amygdala efficiency. Relative to the HC group, all baseline abnormalities were normalized at week-12 in the LR-MAS group, whereas a decrease in right amygdala efficiency uniquely emerged in the HR-MAS group. Significant correlations were identified between changes in network topology and ADHD symptoms. Connectome-based predictive modeling analysis revealed that baseline network dysconnectivity predicted ADHD treatment outcomes in the HR-MAS group only.

CONCLUSION

These findings provide novel evidence that ADHD youth with and without BD familial risk exhibit different changes in brain network topology and associated symptoms following 12 weeks of psychostimulant treatment.

PLAIN LANGUAGE SUMMARY: Although psychostimulants can alter brain network connectivity in youth with attention-deficit/hyperactivity disorder (ADHD), their effects in ADHD youth with a family history of bipolar disorder (BD) have not been investigated. This double-blind randomized controlled study compared the effects of psychostimulants on brain networks in a total of 135 youth. Results indicate that ADHD youth with and without BD family history exhibit different brain network changes. These findings suggest that ADHD in conjunction with BD family history may have a neurobiological profile that is distinct from ADHD alone without such a family history.

CLINICAL TRIAL REGISTRATION INFORMATION: Neuroimaging Study of Risk Factors for Adolescent Bipolar Disorder (NERF); https://clinicaltrials.gov/study/NCT02478788.