Encouraging data on a new antipsychotic drug in phase 2 development have
generated excitement among researchers in psychiatry because the substance
acts on neurological pathways that depend on glutamate, an excitatory
neurotransmitter, and bypasses the dopamine system altogether. The findings
strengthen the hope that new drugs targeting glutamate-activated receptors
will soon become alternatives for patients with schizophrenia who suffer from
the sometimes serious side effects of current antipsychotics.
The substance (known as LY2140023), developed by Eli Lilly and Co., is
metabolized into an active molecule after it is absorbed by the body. The
active molecule is a selective agonist of a subtype of glutamate-activated
receptors called metabotropic glutamate 2/3 (mGlu2/3) receptors. This agonist
particularly changes the amount of glutamate released into the synapses in the
brain. In a randomized, double-blind, phase 2 clinical trial, LY2140023 was
compared with placebo and olanzapine (Zyprexa) in 196 patients with
schizophrenia. The study, sponsored by the manufacturer, was published online
in the letters section of Nature Medicine on September 2.
At the end of four weeks, patients treated with LY2140023 had a
statistically significant reduction on Positive and Negative Syndrome Scale
(PANSS) scores compared with those who received placebo; the effects were
similar to those in the patients who got olanzapine.
Researchers have long suspected that neurotransmission systems involving
glutamate are somehow distorted in the brain in schizophrenia patients. The
theory is based on the observation that substances like phencyclidine (PCP)
and ketamine can induce psychotic symptoms in healthy people and in animals.
PCP and ketamine appear to create this effect by blocking the N-methyl
d-aspartate (NMDA) receptor, an ionotropic receptor activated by glutamate.
Chemicals that modulate the NMDA receptor have been studied in schizophrenia
as well as mood disorders. In a 2005 study published in Biological
Psychiatry, Uriel Heresco-Levy, M.D., and colleagues reported significant
improvement in negative, positive, cognitive, and depression symptoms on the
PANSS in a double-blind, six-week crossover study of adjunctive treatment with
D-serine, an agonist of the NMDA receptor, in patients with refractory
schizophrenia who were already on either risperidone or olanzapine.
Meanwhile, metabotropic glutamate receptors in the brain have been linked
with learning and memory, perception of pain, and mood disorders, and new-drug
research targeting these receptors has been ongoing in recent years.
All currently available antipsychotic drugs, including the
second-generation antipsychotics, directly act on dopamine and serotonin
receptors and have some serious side effects, including extrapyramidal
symptoms, dyskinesia, weight gain, disturbance in glucose metabolism, and
elevated prolactin levels. Scientists hope the new class of glutamate
receptor—targeted drugs will reduce or eliminate these unwanted
In the clinical trial, the patients who received LY2140023 had a small
weight loss (0.51 kg), compared with no change in the placebo group and weight
gain (0.74 kg) in the olazapine group. No significant elevation of prolactin
levels was observed in any group. However, the trial lasted for only four
weeks, and the dropout rate was fairly high (58.7 percent, 20.6 percent, and
33.7 percent in the placebo, olanzapine, and the test drug groups,
The most common side effects seen with LY2140023 included insomnia, affect
lability, nausea, headache, somnolence, and blood creatine phosphokinase
increase. Patients on the drug seemed "more emotional than
before," the authors reported. A meaningful profile of the new drug's
side effects will have to wait for larger and longer clinical trials.
"The mGluR 2/3 agonist is potentially one of the most important
advances in psychiatry since the introduction of chlorpromazine,"
Jeffrey Lieberman, M.D., chair of the Department of Psychiatry at Columbia
University's College of Physicians and Surgeons and chair of APA's Council on
Research, told Psychiatric News.
Lieberman noted that the excitement in the psychiatric research community"
hinges on the replication of these results in a representative sample
of schizophrenia subjects in a new study. If its effectiveness is confirmed,
this drug may become the first antipsychotic that does not work directly
through the D2 receptor."
Perhaps more significant, Lieberman emphasized, the findings "provide
an important line of evidence to support the glutamate hypothesis of
schizophrenia originally proposed by [David] Javitt and [Stephen] Zukin and
expand the window into the pathophysiology of schizophrenia."
An abstract of "Activation of mGlu2/3 Receptors as a New
Approach to Treat Schizophrenia: A Randomized Phase 2 Clinical Trial" is
An abstract of "D-serine Efficacy as Add-on Pharmacotherapy to
Risperidone and Olanzapine for Treatment-Refractory Schizophrenia" is