A stratified precision medicine trial targeting α2A-adrenergic receptor agonism as a treatment for the cognitive biotype of depression

Cognitive impairments are a major contributor to psychosocial dysfunction in major depressive disorder, yet mechanistically selective treatments targeting these impairments are lacking. Here, in line with a precision medicine approach, we evaluated guanfacine immediate release (GIR), an α_2A receptor agonist, as a novel treatment aimed at enhancing cognitive control circuit function and behavioral performance in a neurobiologically defined subtype of depression, the cognitive biotype NCT04181736. This biotype was prospectively identified based on impairments in both cognitive control circuitry and associated behavioral performance. Seventeen participants with major depressive disorder meeting these prospective criteria completed 6-8 weeks of GIR treatment (target dose of 2 mg per night), consistent with our preregistered per-protocol analysis plan. GIR significantly increased activation and connectivity within the cognitive control circuit. The clinical response (defined as a ≥50% reduction on the 17-item Hamilton Depression Rating Scale (HDRS)) was achieved by 76.5%, of patients, exceeding conventional antidepressant response rates, and 84.6% also achieved remission (HDRS score of ≤7). GIR also led to significant improvements in cognitive control performance, global life satisfaction and quality of life. Here we demonstrate both clinical efficacy and circuit target engagement of GIR as a mechanistically selective treatment for the cognitive biotype of depression.