Context of Psychotropic Drug Delivery Modulates its Neurobehavioral Effects: the Case of Methylphenidate

Pharmacotherapy is substantially hindered by poor drug targeting, resulting in low specificity and efficacy. Here, we tested a novel, non-invasive targeting approach (termed functional-pharmacology), which couples drug administration with a task that activates the drug’s sites-of-action in the brain, thus possibly improving absorption and efficacy. Methylphenidate (MPH) or Placebo were administered to healthy subjects, which then performed a cognitive induction or a control task. N-Back fMRI before and after drug-task coupling measured therapeutic effects. Only following MPH, subjects that performed better in the cognitive induction task showed greater improvements in N-back performance. Moreover, only under MPH-Cognitive induction condition, there existed a significant correlation between improved recruitment of N-Back rDLPFC activation, and a concurrent improvement in task performance. Importantly, mediation analysis suggested a causal role of rDLPFC activation in these coupling effects. Our results support the functional-pharmacology concept feasibility and efficacy, hence opening a new horizon for patient-tailored, context-driven drug therapy.