Subject:
Drugs in the Pipeline

Short Description:
Drugs Acting on Glutamate

Background:
You’re probably hearing a lot of talk about glutamate receptors as a new target for psychiatric therapeutics. As the most abundant excitatory neurotransmitter in the brain, glutamate is thought to play a role in many psychiatric conditions. Some existing drugs act on the glutamate system (eg, lamotrigine and memantine), but more are likely on the way. In fact, several lines of evidence suggest that glutamate function may be disrupted in psychosis and in mood disorders.

Psychosis
Drugs like PCP and ketamine inhibit the NMDA receptor (one of the main glutamate receptor subtypes, others being the AMPA receptor and the metabotropic or “mGluR” receptors). When abused, these drugs can cause a schizophrenia-like syndrome, complete with positive, negative, and cognitive symptoms. Moreover, glutamate synapses also appear to develop abnormally in schizophrenia, and hypofunction of the NMDA receptor has been observed in later stages of the disease (Moghaddam B and Javitt D, Neuropsychopharm 2012;37:4–15). One theory of schizophrenia is that faulty NMDA receptors—present on inhibitory interneurons—are indirectly responsible for the overproduction of glutamate in the prefrontal cortex, where glutamate acts on non-NMDA receptors in a disorganized fashion, possibly contributing to psychosis.Some new antipsychotics under development include drugs that enhance NMDA receptor function and thereby reduce cortical glutamate. Mechanisms of these drugs include the activation of secondary pathways like the metabotropic mGlu5 receptor on NMDA-containing cells (mGlu5 agonists) or the modulation of other metabotropic glutamate receptors found in the cortex (mGlu2/3 agonists). Also, since the NMDA receptor is a complex receptor with binding sites for co-activating molecules like the amino acid glycine, these sites are targets for so-called “allosteric modulators” which, when present, may enhance glutamate signaling at the NMDA receptor.Each of these mechanisms represents a target of current drug development. Results, however, have been mixed. Perhaps the most promising, LY2140023, an mGlu2/3 agonist from Eli Lilly, failed a phase III trial late last year. Roche is developing a glycine transport inhibitor called bitopertin which has shown reductions in negative symptoms in phase II trials. Other trials have focused on sarcosine, a dietary supplement that also works as a glycine transport inhibitor. mGlu5 agonists are still in preclinical (ie, animal) testing. These and other glutamatergic drugs may find a place in the treatment of psychosis in the near future.

Depression
The NMDA receptor has also received a great deal of attention in the treatment of depression, spurred by the observation that subanesthetic doses of intravenous ketamine, an NMDA antagonist, may have a rapid (within hours) and prolonged (up to two weeks) antidepressant effect (Zarate CA et al, Arch Gen Psychiatry2006;63(8):856–864). The mechanism appears to involve the sprouting of neural synapses in the brain and the reversal of stress-induced changes (Li N et al, Science 2010;329(5994):959–964). Some hospitals and clinics have begun to provide this off-label treatment to patients with treatment-resistant depression.Not surprisingly, the excitement surrounding ketamine has led to compounds believed to act similarly. One is GLYX-13, an NMDA partial agonist developed by Naurex, which showed promise in phase IIa trials. This intravenous agent boasts a similar time course of action as ketamine but fewer side effects. Another is AZD6765, an intravenous NMDA antagonist first developed by AstraZeneca as a neuroprotective agent for stroke patients. In treatment responders, sustained benefit isn’t seen until three weeks, calling into question any advantage over current antidepressants. Phase IIb trials for each of these agents are currently under way. Other glutamatergic drugs being studied for depression include an mGlu2/3 antagonist (Roche), an mGluR5 antagonist (Roche), and NMDA antagonists which bind to specific subunits (particularly NR2B) of the NMDA receptor complex.

TCPR’s Take: Currently available treatment options for psychosis and depression leave much to be desired. Lately, attention has been drawn to the glutamate synapse, with several drug companies jockeying to bring new glutamatergic drugs to market. These may represent a significant advance in psychiatric therapeutics, and might be useful adjuncts to existing treatments. Hopefully research will reveal the best use of these agents, specific patients who will benefit, and any possible side effects resulting from their use.