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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-modification in NDDs may be promising and can spare regulatory barriers.The literature of these psychotropics in early stage and pre-symptomatic AD,PD,and HD is reviewed and propitious findings follow.Mild cognitive impairment(MCI) phase of AD:salutary human randomized controlled trial findings 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 findings show promise.Pre-symptomatic PD:lithium and valproate AMS findings are encouraging.Early HD:uncontrolled clinical data indicate non-progression with lithium,fluoxetine,donepezil,and memantine.Pre-symptomatic HD:lithium and valproate are auspicious in AMS.Many other promising findings awaiting replication(valproate in MCI;lithium,valproate,fluoxetine in pre-symptomatic AD;lithium in early PD;lithium,valproate,fluoxetine in pre-symptomatic PD;donepezil in early HD;lithium,fluoxetine,memantine in pre-symptomatic HD) are reviewed.Dose- and stage-dependent effects are considered.Suggestions for signal-enhancement in human trials are provided for each NDD stage.
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 significantly unrewarding. Preclinical evidence suggests that repurposing quetiapine, lithium, Valproate, fluoxetine, donepezil, and memantine for early and pre-symptomatic disease-modification in NDDs may be promising and can spare regulatory barriers. The literature of these psychotropics in early stage and pre-symptomatic AD, PD, and HD are reviewed and propitious findings follow. Mild cognitive impairment (MCI) phase of AD: salutary human randomized controlled trial findings for low-dose lithium and, in selected patients, donepezil await replication. Pre-symptomatic AD: human epidemiological data that that lithium reduces AD risk. Animal model studies (AMS) reveal encouraging results for quetiapine, lithium, donepezil, and memantine. Early PD: valproate AMS findings show promise. Pre-symptomatic PD: lithium and valproate AMS findings are encouraged. Early HD: uncontrolled clinical data indicate non-progression with lithium, fluoxetine, donepezil, and memantine. Pre-symptomatic HD: lithium and valproate are auspicious in AMS. Other promising findings awaiting replication (valproate in MCI; lithium , valproate, fluoxetine in pre-symptomatic AD; lithium in early PD; lithium, valproate, fluoxetine in pre-symptomatic PD; donepezil in early HD; lithium, fluoxetine, memantine in pre- symptomatic HD) dependent effects are considered. Suggestion for signal-enhancement in human trials are provided for each NDD stage.