Ketamine's Antidepressant Effect Offers Drug-Development Target

A new study in mice sheds light on why ketamine, an injectable drug used to induce anesthesia in surgery, has a rapid and sustained effect in treating depression.

Researchers are implicating receptors activated by the neurotransmitter glutamate in the drug's mechanism of action, a finding that may provide targets for combating depression.

All available antidepressants commonly take weeks to begin achieving results, but ketamine alleviates depressed mood almost immediately. Patients feel better within hours after receiving an intravenous infusion of ketamine, according to Carlos Zarate and colleagues at the National Institute of Mental Health (NIMH). Their randomized, placebo-controlled, crossover trial was published in the August 2006 Archives of General Psychiatry. One day after receiving an intravenous infusion of ketamine hydrochloride (0.5 mg/kg), 71 percent of the 17 patients with treatment-resistant major depression met the response criteria, and 29 percent reached remission; none taking placebo met the response or remission criteria at this time point.

In a new study published online on July 23 in Biological Psychiatry, the same group of NIMH researchers presented biochemical evidence to support the role of N-methyl d-aspartate (NMDA) receptors and alpha-amino-3-hydroxy-5 methylisoxazole-4-propionic acid (AMPA) receptors in facilitating the antidepressant effect of ketamine. Both are receptors that, bound by the neurotransmitter glutamate, regulate the flow of ions across the cellular membrane and the electrical potentials inside and outside the neuron.

The researchers simulated depressive behavior in mice and studied the changes after injecting the “depressed” mice with ketamine. As seen previously in humans, a single injection of ketamine effectively countered the artificially induced “depression” in mice. The effect became apparent as fast as 30 minutes after injection and remained apparent two weeks later. The control mice treated with saline or imipramine did not exhibit residual antidepressant effect when they were retested after two weeks.

To confirm that NMDA receptors are involved in this process, the mice were injected with two other chemicals. One is an NMDA antagonist like ketamine; the other selectively binds to a subunit in the NMDA receptor. Both chemicals exerted antidepressant effects similar to ketamine with a shorter duration.

The authors speculated that the antidepressant effect of blocking NMDA receptors is carried out through subsequent activation of AMPA receptors relative to NMDA receptors. The findings supported this hypothesis. Giving mice an AMPA receptor antagonist blocked the antidepressant effect of ketamine, suggesting that AMPA-receptor activation is downstream to NMDA antagonism in the mood-alteration process.

“After the positive results from the clinical trial of ketamine [from the 2006 study], we decided to use the mouse depression model to study how the NMDA and AMPA interaction figures into ketamine's rapid effect on depression,” said Husseini Manji, M.D., a co-author of the new study and the 2006 human study and director of the Mood and Anxiety Disorders Program at NIMH, in an interview with Psychiatric News. “Ketamine is probably not going to be useful for treatment because of its psychotomimetic side effects. So we are interested in a specific NMDA receptor subunit called NR2B. It can help us narrow the molecular target and develop drugs with similar therapeutic effects as ketamine, but hopefully without the psychotomimetic, dissociative side effects.”

The labeling information for ketamine lists the side effects as primarily central nervous system reactions ranging from pleasant dreamlike states and vivid imagery to hallucinations and delirium, sometimes accompanied by confusion, excitement, and irrational behavior. Ketamine may also cause increased blood pressure and stimulation of the cardiovascular system and carry some risk of dependence and abuse.

In this study, the mice were given a drug called Ro25-6981 that specifically targets the NR2B subunit in NMDA receptors. The NR2B antagonist indeed reversed depressive behavior in mice, although the effect did not last as long as that of ketamine. Manji said that preliminary human studies of a particular NR2B antagonist so far have shown little psychotomimetic side effects.

The researchers suggested that adding AMPA agonists to low doses of NMDA antagonists could be a potential approach to treating depression. “One of the directions our research is taking is to look into whether modulating the AMPA receptors can sustain the antidepressant effect after it is 'jump-started' by ketamine,” said Manji.

As a continuation of the NIMH ketamine clinical trial, riluzole, a modulator of glutamate release and AMPA receptors and FDA-approved for treating amyotrophic lateral sclerosis, is being given to patients with treatment-resistant depression who had responded to a single dose of ketamine. Another AMPA modulator and glutamate-release inhibitor, lamotrigine, FDA-approved for treating bipolar disorder, is also being studied in a clinical trial by researchers at Mt. Sinai School of Medicine in New York. Both studies are listed on the ClinicalTrials.gov Web site as ongoing. This study is funded by Mt. Sinai School of Medicine and the National Alliance for Research on Schizophrenia and Depression.

An abstract of “Cellular Mechanisms Underlying the Antidepressant Effects of Ketamine: Role ofα -Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid Receptors” is posted at<http://journals.elsevierhealth.com/periodicals/bps/content/0600666abs>.▪