Abstract: The quest for neuroprotective drugs to slow the progression of neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), has been largely unrewarding. Preclinical evidence suggests that repurposing quetiapine, lithium, valproate, fluoxetine, donepezil, and memantine for early and pre-symptomatic disease-modifcation in NDDs may be promising and can spare regulatory barriers. Te literature of these psychotropics in early stage and pre-symptomatic AD, PD, and HD is reviewed and propitious fndings follow. Mild cognitive impairment (MCI) phase of AD: salutary human randomized controlled trial fndings for low-dose lithium and, in selected patients, donepezil await replication. Pre-symptomatic AD: human epidemiological data indicate that lithium reduces AD risk. Animal model studies (AMS) reveal encouraging results for quetiapine, lithium, donepezil, and memantine. Early PD: valproate AMS fndings show promise. Pre-symptomatic PD: lithium and valproate AMS fndings are encouraging. Early HD: uncontrolled clinical data indicate non-progression with lithium, ?uoxetine, donepezil, and memantine. Pre-symptomatic HD: lithium and valproate are auspicious in AMS. Many other promising fndings awaiting replication (valproate in MCI; lithium, valproate, ?uoxetine in pre-symptomatic AD; lithium in early PD; lithium, valproate, ?uoxetine in pre-symptomatic PD; donepezil in early HD; lithium, ?uoxetine, memantine in pre-symptomatic HD) are reviewed. Dose- and stage-dependent e?ects are considered. Suggestions for signal-enhancement in human trials are provided for each NDD stage.

Key words: drug repositioning, neuroprotective agents, psychotropic drugs, neurodegenerative diseases, mild cognitive impairment, humans, animals, animal models