Safety of Adjunct Low-Dose Methylphenidate Extended-Release for Cognitive Deficits in Stable Schizophrenia

BACKGROUND: Cognitive deficits in schizophrenia significantly impair functional outcomes, yet no approved pharmacological treatments exist. Low-dose psychostimulants, such as methylphenidate extended-release (ER), have shown preliminary promise for cognitive enhancement but raise concerns about psychosis exacerbation. This study evaluates the safety of low-dose methylphenidate ER in clinically stable schizophrenia patients. METHODS: An open-label, randomized, fixed-dose crossover trial (NCT05414058) was conducted at the Royal Ottawa Mental Health Centre from September 2022 to October 2024, enrolling 24 participants with schizophrenia spectrum disorders. Participants received 4 weeks of methylphenidate ER (18 mg for wk 1, 36 mg for wk 2 to 4) and 4 weeks of treatment-as-usual in a crossover design, with a follow-up at week 12. RESULTS: No serious adverse events occurred, and there was no evidence of psychotic symptom exacerbation. PANSS-6 scores showed no worsening attributable to treatment; detailed efficacy results are reported elsewhere. Vital signs showed minimal, nonsignificant changes: mean weight decreased by 2.28 lbs ( P >0.05), heart rate increased by 3.67 bpm ( P >0.05), and systolic blood pressure rose by 3.6 mmHg ( P >0.05). The CADDRA checklist indicated significant appetite reduction ( P <0.001), reduced fatigue ( P =0.002), and decreased sadness ( P <0.001) during treatment, with effects resolving post-treatment. One participant reported transient passive suicidal ideation, resolving without intervention. Eleven participants withdrew, primarily due to subjective side effects within the first 2 weeks. CONCLUSIONS: Low-dose methylphenidate ER appears safe in stable schizophrenia patients on antipsychotics, with no significant psychosis exacerbation and minimal physiological changes.