Traditional antidepressants may not be effective as we once thought–some studies suggest that SSRIs fare little better than placebos–so the hunt for drug therapies that work via different mechanisms is underway. Recently, researchers showed that treatment with ketamine drastically reduced depression symptoms in patients suffering from a depressive episode almost immediately after administration.
Though the results were intriguing, ketamine–a sedative and anesthetic approved for both human and veterinary care–produces psychotomimetic effects (effects that mimic psychosis) in some patients. It’s sold as a recreational street drug, “Special K,” precisely because of those effects. So scientists have been looking for ways to harness the power of NMDA receptor agonists without sending patients into a k-hole.
Reduction in suicidal ideation after treatment with ketamine versus placebo, via ScienceDirect
Ketamine is a NMDAR (N-methyl-D-aspartate receptor) antagonist. An antagonist is a chemical that binds to a receptor in the brain, and though it does not provoke a response itself, it blocks or hinders agonist-mediated responses. An agonist is a chemical that often mimics a naturally occurring compound. It binds to a receptor on a cell and triggers a response.
For example, heroin and methadone are opioid receptor agonists. They attach to opioid receptors, mimicking naturally occurring chemicals within the brain, and trigger the cell to release the dopamine that reduces pain and makes us feel good. Naloxone, which can immediately reverse the effects of a heroin overdose, is an opioid receptor antagonist. It binds to opioid receptors with greater affinity than opioid agonists, but does not produce euphoric effects, which is how it can stop an OD.
A partial agonist is a chemical that binds to a receptor, but only has partial efficacy relative to full agonists. In our opioid receptor example, buprenorphine is a partial opioid agonist, so it binds to receptors without fully activating them or deactivating them. Buprenorphine can halt the symptoms of opioid withdrawal without getting you high.
Unlike the latest class of antidepressant medications, SSRIs, which work by blocking the reuptake of neurotransmitter serotonin, ketamine works on an entirely different neurotransmitter, glutamate. Glutamate is the most abundant excitatory neurotransmitter in our nervous system. It is thought to pay an important role in learning and memory. According to the NIH, ketamine works by blocking the receptors critical for receiving glutamate's signals. This improves the brain cell's electrical flow and reduces symptoms of depression. But while ketamine has unwanted side-effects, studies using it suggest that a drug that regulates glutamate signaling in the brain could make for a better antidepressant.
Neuropharmacuetical company Naurex Inc. has found one such potential drug, NMDAR partial agonist GLYX-13, and has just concluded phase IIa of human trials to promising results. The firm found over 100 test subjects, all of whom had been insufficiently responsive to treatment with another antidepressant agent during their current depressive episode, and administered GLYX-13 or placebo intravenously. Like ketamine treatment, subjects reported reduction of symptoms of depression within hours, but because GLYX-13 is only a partial agonist (ketamine is a full agonist) the new compound achieved these results without the accompanying psychotomimetic effects. Naurex theorizes that GLYX-13 modulates the receptor in just the right way, inhibiting the receptors enough to promote mood-elevating effects without causing the dissociative effects possible with full antagonists.
I spoke with Ashish Khanna, vice president of corporate development at Naurex, who said that the company would likely seek an indication for the drug as a later line of intervention for depression. One out of every three individuals with depression does not respond to SSRI treatment, so a drug that works in an entirely different way could be useful in treating these people. Khanna said that the “excitement around ketamine and drugs like it stems not only from the rapid effect–much different from SSRIs–but also from the patient populations who have been evaluated. It’s helping patients who aren’t helped by other drugs.”
Daily doses of SSRIs can often take weeks to take effect, and in severely depressed or suicidal patients this waiting period can be too long. Though the effects of both ketamine and GLYX-13 last only about seven days, at least they work immediately.
The brain -- and the relationship between a host of complex neurotransmitters and mood disorders -- is obviously not fully understood. New research on NMDA receptors and glutamates relationship to depression is an exciting forefront for neurobiological medicine. As one class of drugs, one that has been relied upon for decades, is shown to be therapeutically ineffective, there’s sure to be another class of drugs hot on its heels.
Follow Kelly Bourdet on Twitter