Millions of people who suffer the debilitating symptoms of depression — which include low mood and energy, poor sleep and changes to appetite — see no relief from existing medications, which can take weeks to start working, if they work at all. But a new drug called GLYX-13 has shown promise in clinical trials, especially in treating those who’ve experienced only minimal improvement from current antidepressants. So far, GLYX-13 has been tested in more than 500 patients and in the latest trial of 386 participants more than half saw their depression symptoms improve — some in as few as two hours, though more typically in a day or two — says Richard C. Shelton, MD, PhD, who has conducted drug trials for GLYX-13 maker Naurex Inc., of Evanston, Illinois.
The fast onset and lack of major side effects through two phases of clinical trials make GLYX-13 “a big deal,” says Dr. Shelton, a professor and vice chair of research at the University of Alabama, Birmingham’s Department of Psychiatry and Behavioral Neurobiology. Currently available antidepressants such as Prozac or Paxil may take at least two to four weeks or more to show any signs of improvement and might require months more of dosage or changes to a patient’s regimen to relieve a depressed person’s misery, putting them at increased risk of suicide.
“The rapid response is important,” agrees Harry M. Tracy, PhD, publisher of NeuroPerspective, a newsletter that tracks companies developing psychiatric drugs. “Half the people on GLYX-13 did not do better, but you know that within a day or two, whereas it feels like an eternity for people waiting for depression to respond to [existing] drugs — weeks on end — and they don’t know if it’s even going to work.”
The scale of depression is daunting. About 350 million people globally suffer from the condition (also called major depressive disorder), according to the World Health Organization. That includes an estimated 25.2 million Americans, about 7% to 8% of the U.S. population, and roughly one-third to one-half of sufferers find no relief from existing antidepressants and psychotherapy, Shelton says. Depression is a leading cause of suicide in the U.S., claiming the lives of 40,600 people in 2012, the Centers for Disease Control and Prevention reported in its latest data. Such grim data reveals the critical need to develop alternative drugs.
Most existing antidepressants work the same way, boosting serotonin or other neurotransmitter chemicals that relay information in the brain. A handful of potential new depression drugs, including GLYX-13, work differently. One that has drawn excitement and controversy is ketamine, which was approved by the Food and Drug Administration decades ago as an anesthetic. Like GLYX-13, ketamine must be injected intravenously. Small studies around the country showed that ketamine worked so dramatically that trial subjects sometimes felt their crippling depression symptoms evaporate in hours, says Shelton, who was also an investigator on ketamine drug trials.
But possible side effects include hallucinations, bladder problems and high blood pressure, making ketamine less appealing for widespread use, and susceptible to abuse (as a street drug it goes by names like “Special K” and “Jet,” according to the nonprofit Foundation for a Drug-Free World). Despite these risks, patients desperate for relief have been paying steep prices for ketamine at clinics around the U.S., raising concern that the drug use hasn’t been adequately studied for its long-term impact on health.
Ketamine appears to block receptors for NMDA (N-methyl-D-aspartate) that work with the neurotransmitter glutamate. But it’s not clear exactly how. Naurex says GLYX-13 affects NMDA as well, but avoids the side effects of ketamine by “modulating” – rather than blocking — the same receptor. Baltimore-based Cerecor Inc., meanwhile, has a similar drug called Cerc-301 in clinical trials of 135 patients; Cerc-301 blocks only a portion of the same receptor as well.
Naurex founder and chief scientific officer Joseph R. Moskal, PhD, who discovered the lead molecule GLYX-13, says, “the NMDA receptor in the brain is an important signaling system and if you modulate it, you can control how the brain cells communicate with one another. That communication has become dysfunctional with depression. So we’re trying to restore it so the synapses are firing, basically.”
In the latest completed GLYX-13 clinical trial 386 patients were given a weekly IV injection of the drug for a time, then went off it to force a relapse of their depression symptoms before being put back on the drug. When patients started relapsing into depression, GLYX-13 was restarted to see whether improvement could be revived. In addition to confirming that GLYX-13 is able to alleviate symptoms if a patient misses a dose, the induced relapse was used to determine ideal dosing amounts and timing, which will be tested in the next clinical trial.
For the 193 participants who saw improved symptoms from GLYX-13 in this study, the benefits lasted up to a week, and repeated doses of the drug caused a cumulative improvement in symptoms. And when relapse was induced, depressive symptoms still did not reach the depths of the patients’ pre-study depression, Naurex reported at the annual meeting of the American College of Neuropsychopharmacology.
Naurex plans to begin phase-3 trials to establish longer-term tolerance and effectiveness of GLYX-13 during the summer of 2015, with ambitions of FDA approval in 2019. Despite the good news that promising drugs like these are in the pipeline, some people might opt to give up on treatment rather than go to a doctor or clinic for weekly one-minute injections, as opposed to taking a pill. The next-generation of the Naurex drug, called NRX-1074, is taken in pill form and has progressed to a second phase of clinical trials.