Connecting the dots and finding the way forward: Pharmacological, neuromodulatory, and psychotherapeutic interventions for the complex treatment of adult ADHD

Attention-deficit/hyperactivity disorder (ADHD) persists into adulthood in up to 60% of cases, affecting 2.5-6.8% of adults worldwide, with high comorbidity rates of mood, anxiety, and substance use disorders, and significant functional impairments, such as reduced quality of life, increased mortality, and economic burden. This review synthesizes etiological factors, including neuroimaging evidence of fronto-striatal and default mode network disruptions, high heritability up to 70-80% driven by common, polygenic and rare variants, and environmental risk factors. Treatment emphasizes multimodal approaches, with stimulants as first-line pharmacotherapy due to their superior efficacy over non-stimulants like atomoxetine and viloxazine. Novel agents in development, such as centanafadine triple reuptake inhibitor and solriamfetol target core symptoms and comorbidities, showing promising phase III results. Despite the high effect sizes of pharmacological treatment for ADHD, obstacles such as acceptance and adherence remain challenging. Neuromodulatory interventions, including transcranial direct current stimulation (tDCS) and neurofeedback, demonstrate moderate effects on inattention and executive function. Psychotherapeutic options, particularly cognitive-behavioral therapy (CBT)-based interventions, improve symptom management and emotional regulation, often as adjuncts to medication. The review highlights the need for personalized strategies addressing adherence, comorbidity, and long-term outcomes, emphasizing integrated care to mitigate ADHD's lifelong impact.