MPEP a prototypical glutamate (mGlu5) receptor antagonist with similar anxiolytic efficacy compared to diazepam but with reduced cognitive adverse effects.

Anxiety disorders affect 20% of the total population across the seven major markets and are commonly treated with antidepressants. Adverse effects lead to treatment discontinuation in as many as 16% of patients driving the drug development sector to identify alternative approaches to anxiety. Benzodiazepines are treated cautiously by many physicians for reasons of dependency and withdrawal problems, as well as adverse effects including cognitive impairment. Glutamate (mGlu5) receptor antagonists are being developed as an improved class of anxiolytics and here we highlight the efficacy of MPEP, the prototypical mGlu5 receptor antagonist, which was similar compared to that of diazepam but at anxiolytic doses produces less cognitive decline

Anxiety disorders are considered the most prevalent of psychiatric disorders. However, poor diagnosis rates and treatment outcomes mean that there is still considerable scope for manufacturers to move into the anxiety market. Although a fifth of the total population across the seven major markets suffers from an anxiety disorder only a quarter of these individuals are diagnosed and therefore treated.

Of the 19 million American that suffer one of the anxiety conditions, many are treated with antidepressants such as paroxetine which is considered a gold standard treatment for anxiety disorders across the seven major markets. However a third of patients require second-line therapy due to either insufficient efficacy or excessive side effect. Efficacy is a particular problem during the first few weeks of treatment given the slow onset time of many antidepressants while as many as 16% of patients with anxiety disorders discontinue paroxetine treatment due to side effects. High-potency benzodiazepines, such as diazepam, which bind to a site on the GABA receptor and act as receptor agonist, relieve symptoms of anxiety quickly however tolerance and problems upon withdrawal have led physicians to use this class as a long-term treatment of anxiety cautiously.

One problem associated with long-term benzodiazepine use is cognitive decline and a recent meta analysis has reported that cognitive ability may not return to pre-treatment levels once treatment has been terminated. Benzodiazepines are the most frequently prescribed antianxiety drugs in the elderly and in this population, given their susceptibility to cognitive decline, alternate therapeutic approaches may be of particular use.

Metabotropic glutamate (mGlu) receptors modulate glutamatergic transmission in the CNS and represent a target for neurological and psychiatric disorders. MPEP is a highly potent and selective prototypical mGlu5 receptor antagonist developed by Novartis and characterized by good bioavailability and brain penetration. Anxiolytic-like activity has been reported in a number of animal models and since efficacy has been shown to be independent of any benzodiazepine-like mechanism, mGlu5 receptor antagonists offer an alternative approach to the treatment of anxiety. Efficacy is observed at doses far below those doses affecting spontaneous activity and rotarod performance however the effects of oral MPEP on cognition were, up until now, unknown. Since the mGlu5 receptor is highly expressed in the hippocampus, a key area of cognitive function, MPEP could potentially affect cognition. This possibility is supported by the finding that intracerebral administration of MPEP impairs spatial and working memory. The featured Psychopharmacology study was designed to evaluate the cognitive effects of oral MPEP.

In their study Roche researchers set out to establish a clear efficacious dose range of MPEP following oral administration in various models of anxiety. Using identical dosing conditions the effect of anxiolytic doses of MPEP was then determined in models of working and spatial memory.

Ballard et al report that MPEP had a significant anxiolytic effect at 10-30 mg/kg (po), comparable in magnitude to diazepam, in two conflict (Geller-Seifter and Vogel) models of anxiety as well as in the conditioned emotional response model. There was no effect of MPEP up to 30 mg/kg on working or spatial memory. In contrast, diazepam significantly impaired performance in both of these assays of cognitive function.

This important and well controlled study demonstrates that at doses that produce similar anxiolytic activity, MPEP has considerably less effect on cognition than does diazepam. These data therefore suggest that mGlu5 receptor antagonists and specifically MPEP may offer an effective yet safe alternative to antidepressants and benzodiazepines in the treatment of anxiety.


Entry date Monday, April 11, 2005

Psychopharmacology (Berl). 2005 Mar 1; [Epub ahead of print]

Source: LeadDiscovery