Clinical data supports the development of insulin as a future treatment for memory and mood disorders?

The aging population will contribute to an expansion of the already massive Alzheimer's disease therapy market.  The number of sufferers is expected to grow from 16 million patients to 21 million by 2010 in the seven major pharmaceutical markets driving sales in these regions worth $4.7 billion.  This figure is set to increase to $6.1 billion by the year 2005 and $ 7.8 billion by the year 2010 (for a full analysis of this field click here or here).  Alzheimer’s disease is associated with a number of symptoms including memory dysfunction and later on in the course of disease, anxiety and aggression.

The loss of memory is however, by no means restricted to Alzheimer’s disease and it has been estimates that as many as 180 million people world wide suffer from memory disorders.  For example vascular dementia, an umbrella term for dementia caused by transient ischemic attacks, stroke, traumatic brain injury and arteriosclerosis, can cause memory loss depending on the region of the brain affected. Psychiatric conditions that cause disturbances of thought or mood (such as schizophrenia or major clinical depression) can also have secondary effects on learning and memory.  Then of course a slow decline in the ability to perform in tests of cognitive ability appears to occur as a “normal” part of the aging process.  Finally, individuals with “mild cognitive impairment” (MCI) have ongoing memory problems similar to those associated with Alzheimer’s disease but without other losses like confusion, attention problems, and difficulty with language. Although 80% of patients with MCI go on to develop Alzheimer’s disease within 5 years, the FDA has acknowledged MCI as a separate clinical entity.  According to some analysts the development of a therapeutic agent able to improve memory in these disorders could drive sales worth a total of $35 billion in a pharmaceutical market segment that is growing in excess of 17% per year.

A growing body of data suggests links between the regulation of glucose metabolism and memory performance.  The cause for this relationship is not entirely clear but appears to be related to mechanisms both related and unrelated to the etiology of Alzheimer’s disease. Type 2 diabetes is twice as prevalent in Alzheimer disease versus non-Alzheimer disease suggesting that reduced levels of insulin in diabetes may in fact be a risk factor for developing Alzheimer disease.  The reason for this is unclear however animals with Alzheimer’s-like pathologies respond to diet-induced insulin resistance with an increase in the level of beta-amyloid Abeta1-40 and Abeta1-42 peptide generation, a hall mark of Alzheimer disease-like neuropathology. This corresponded with impaired performance in a spatial water maze task, a model used for the development of memory enhancing anamnesics.

In addition to possible effects of low insulin levels on amyloid build up which may represent a relatively long-term event, hypoinsulinemia may also have a more acute effect.  Insulin has been shown to have direct effects on neuronal function, and more recently it has been reported that insulin signaling plays a direct role in synaptic plasticity by modulating activities of excitatory and inhibitory receptors such as glutamate and GABA receptors, and by triggering signal transduction cascades leading to alteration of gene expression that is required for long-term memory consolidation. Insulin receptors are prevalent in limbic and hippocampal regions of the brain suggesting that low levels of insulin may result in memory dysfunction and contribute to mood disorders.  Conversely endogenous insulin may be expected to have a positive effect on these parameters.  Although the endogenous administration of insulin may confer certain CNS benefits, especially to patients with mood or memory disorders, the risk of metabolic imbalance could preclude such an indication; more specifically hypoglycemia causes memory impairment both in diabetic and non-diabetic individuals thereby potentially limiting any CNS benefits of insulin.

One strategy for exploiting the anamnesic properties of insulin while minimizing the risk of metabolic adverse effects would be through the use of intranasal administration which has been shown to facilitate the delivery of proteins to the CNS (for an analysis of drug delivery technology click here).  The efficacy of this strategy has recently been evaluated by researchers at the .

In their paper due to be published in the November edition of the journal Psychoneuroendocrinology, Benedict and colleagues report the data of an 8 week double-blind investigation into the effects of intranasal administration of insulin on healthy humans.  This group found that the prolonged intra-nasal administration of insulin significantly increased the speed of word recall. Moreover, insulin administration reportedly manifested signs of enhanced mood, such as reduced anger and enhanced self-confidence. Adverse effects were not observed and neither glucose nor plasma insulin levels were affected.

These provocative data indicate a direct action of prolonged intranasal administration of insulin on brain functions, improving memory and mood in the absence of systemic side effects. These findings could be of relevance for the treatment of patients with memory disorders especially those associated with concurrent mood disorder such as Alzheimer's disease, schizophrenia or depression.  Further studies including those in selected patient groups are eagerly awaited.

Source: Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004 Nov;29(10):1326-34.

This article is highlighted in the August 23^rd edition of DailyUpdates-Metabolic & Hormonal Disorders, ’s unique bulletin of breaking journal articles and press releases for the drug discovery community.  To access the article and to view today’s bulletin click here