Drug Bypassing Dopamine Could Broaden Antipsychotic Arsenal

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 effects.

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, respectively).

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 posted at<www.nature.com/nm/journal/v13/n9/abs/nm1632.html>. An abstract of “D-serine Efficacy as Add-on Pharmacotherapy to Risperidone and Olanzapine for Treatment-Refractory Schizophrenia” is posted at<www.journals.elsevierhealth.com/periodicals/bps/article/PIIS0006322304013800/abstract>.▪