Neurocognitive Disorders: Systematic Review of Approved (2008-2024) and Pipeline Phase III Medications.

OBJECTIVE: Neurocognitive disorders (NCDs), which include delirium, major and mild NCDs such as Alzheimer's disease (AD), and other forms of dementia, constitute a significant and growing public health burden, affecting tens of millions of individuals worldwide. This systematic review aims to examine the medications approved by the United States Food and Drug Administration (FDA) for NCDs from 2008 to 2024, as well as those in the pipeline in Phase III, and to describe the mechanism of action, clinical indications, dosing, evidence for efficacy, and adverse effects. METHODS: We searched the literature using the PubMed database for studies published from January 1, 2008, to December 31, 2024, focusing on FDA-approved psychiatric medications and Phase III pipeline medications, using the keywords "neurocognitive" OR "dementia" OR "Alzheimer*" AND "psychopharm*" OR "medic*" OR "pharm*." Two reviewers performed an independent assessment of the resulting publications and reached a consensus on the eligible studies to include in the systematic review. RESULTS: From 2008 to 2024, the FDA approved eight medications for major and mild NCDs, including monoclonal antibodies, acetylcholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor antagonists, and an atypical antipsychotic. Additionally, we identified 22 pipeline medications currently in Phase III clinical trials for NCDs as of December 31, 2024, including biologics and neuroprotective agents, among others. No medications for delirium were FDA-approved or in Phase III, although agents for a variety of encephalopathies have been developed. CONCLUSION: Significant advancements in the pharmacological management of NCDs have been made during this period, including developing disease-modifying therapies for AD. However, available medications primarily provide symptomatic relief, and challenges persist in the implementation of disease-modifying treatments due to adverse effects and high costs of care. The pipeline of Phase III clinical trials includes many emerging agents with novel mechanisms of action, and ongoing trials will prove essential to confirm the efficacy and safety of these therapies.