Based on brain activity, d-methylphenidate and guanfacine show promise as a combination treatment for attention deficit hyperactivity disorder (ADHD) in children, according to a study published in the Journal of the American Academy of Child & Adolescent Psychiatry.

Researchers explored the neural mechanisms behind the 2 medications as combination therapy as well as monotherapy. D-methylphenidate on its own is ineffective in between 25% and 35% of children, the researchers said. Guanfacine is a nonstimulant approved for short-term ADHD treatment.

To assess how the medications affected brain functioning individually and together, the researchers conducted an 8-week randomized, double-blind comparative study using electroencephalography (EEG) data. The study included 172 children aged 7 to 14 years with ADHD. A total of 118 were boys. The participants in the 3 control arms took either d-methylphenidate or guanfacine alone or a combination. The researchers conducted clinical interviews with parents and with participants’ teachers at baseline.

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Researchers found “widespread effects of combination treatment on event-related power modulations in EEG sources localized within the midoccipital visual cortex and previously implicated in visual-attention deficits…as well as cognitive performance.” The 2 monotherapies produced more limited effects on brain activity.

D-methylphenidate significantly increased midoccipital theta during retrieval. Task accuracy improved on combined treatment, stayed the same with d-methylphenidate, and got worse with guanfacine.

Researchers noted the 8-week study period does not provide information on longer-term effects. The participants had few psychiatric comorbidities; therefore, results may not apply to the broader pediatric population.

“Taken together, the current findings point to different brain mechanisms of action of d-methylphenidate, guanfacine, and their combination, highlighting the role of midoccipital regions involved in top-down-controlled cognitive processes,” researchers concluded. “Future studies should investigate the clinical utility of the identified midoccipital EEG profile to objectively monitor response to combined stimulant and nonstimulant treatment in children with ADHD.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Michelini G, Lenartowicz A, Diaz-Fong JP, et al. Methylphenidate, guanfacine, and combined treatment effects on electroencephalography correlates of spatial working memory deficits in attention-deficit/hyperactivity disorderJ Am Acad Child Adolesc Psychiatry. Published online August 8, 2022. doi:10.1016/j.jaac.2022.06.017

This article originally appeared on Psychiatry Advisor