Intranasal Insulin(The University of New Mexico)

Introduction: This narrative review of systematic reviews and meta-analyses aims at compiling available evidence in various aspects of neurocognitive functioning in Bipolar Disorder (BD). Methods: We conducted a MEDLINE literature search and identified 38 relevant systematic reviews and metaanalyses. Results: Current evidence suggests that BD is associated with cognitive impairment across multiple domains and during all clinical states. However, there is a considerable cognitive heterogeneity within BD, which cannot be explained by clinical subtypes, and the pattern of neurocognitive impairment in BD overlaps with other psychiatric conditions such as major depression and schizophrenia. Residual depressive symptoms, poor clinical course and higher number of manic episodes may negatively impact cognitive performance, which is a major predictor of general functioning in BD. Evidence from available prospective studies does not support the notion of progressive cognitive decline in BD while some evidence exists to suggest patients may show some improvements in cognitive functioning following the first manic episode. Furthermore, a subset of patients may show premorbid cognitive abnormalities that could signal an early neurodevelopmental aetiology. Preliminary findings from small studies identify potential pro-cognitive effects of Cognitive Remediation, erythropoietin, intranasal insulin, lurasidone, mifepristone, repetitive Transcranial Magnetic Stimulation and transcranial Direct Current Stimulation in BD. Discussion: Longitudinal studies in high-risk individuals can provide a better understanding of the development and progression of neurocognitive impairment in BD. Largescale randomised control trials are needed to compare the pro-cognitive efficacy of various pharmacological and non-pharmacological interventions in different cognitive subgroups of patients at different stages of BD.

Individuals with Down syndrome are likely to develop clinical and neuropathological brain changes resembling Alzheimer's disease dementia by the ages of 35-40 years. Intranasal insulin is a potential treatment for neurodegenerative disease that has been shown to reduce amyloid plaque burden and improve verbal memory performance in normal as well as memory-impaired adults. Investigations have shown that rapid-acting insulins may result in superior cognitive benefits compared with regular insulin.

The primary objective of this study was to measure the safety and feasibility of intranasal rapid-acting glulisine in subjects with Down syndrome. Secondarily, we estimated the effects of intranasal glulisine on cognition and memory in Down syndrome.

A single-center, single-dose, randomized, double-blind, placebo-controlled, cross-over pilot study was performed to test the safety of intranasal glulisine vs placebo in 12 subjects with Down syndrome aged ≥ 35 years. Intranasal administration utilized the Impel NeuroPharma I109 Precision Olfactory Delivery (POD^®) device. The primary outcomes were the occurrence of any or related adverse and serious adverse events. Secondary post-treatment cognitive outcome measures included performance on the Fuld Object-Memory Evaluation and Rivermead Behavioral Memory Test.

Intranasal glulisine was safe and well tolerated in the Down syndrome population. No adverse or serious adverse events were observed.

Further investigations are necessary to better evaluate the potential cognitive-enhancing role of intranasal insulin in the Down syndrome population. CLINICALTRIALS.

NCT02432716.