Could a much-maligned club drug provide quick relief for tens of thousands of people suffering with treatment-resistant depression? Increasingly, a chorus of voices in the medical and scientific communities are answering “yes.”
The newest salve in the ongoing struggle against the world’s costliest and most widespread mental illness may be ketamine, a drug primarily used as a veterinary anesthetic but approved for limited human use and popular as an illegal street drug. Its novel properties put ketamine outside of the normal classes of accepted antidepressants that raise serotonin levels in many cases.
“Our studies with ketamine include patients for whom nothing has really worked,” said Dr. Ronald Duman, a professor of psychiatry and director of the Abraham Ribicoff Research Facilities at Yale University. “With very low doses of ketamine, two to three hours after [administration], patients show relief.”
Still, he said, “Clinicians are very cautious. There’s a lot of concern because ketamine is a drug of abuse.”
To fully understand the ketamine revolution and why it has intrigued doctors and researchers is to address some of the concerns and shortcomings of traditional antidepressants. Almost all of those medications act as antagonists for the chemicals they work on — that is, they block the binding and reabsorption of those compounds, which allows levels in the brain to build.
Ketamine, sold as Ketalar, is primarily used as a veterinary anesthetic. Source: NPR
Instead of the traditional transmission sites, ketamine works on receptors that release glutamate, a neurotransmitter that affects learning and neural activation. Many patients who have already run the pharmacological gamut in search of an effective treatment respond incredibly well to ketamine, raising hopes that the drug may succeed where brand-name SSRIs (Celexa, Prozac, and Paxil) and SNRIs (Efexor and Cymbalta) have failed.
Ketamine research received a timely shot in the arm about one year ago, when the results of a high-profile study were published in the American Journal of Psychiatry. The double-blind study, which enrolled a total of 73 patients at Baylor College of Medicine in Texas and the Icahn School of Medicine at Mount Sinai in New York, sought to establish whether ketamine was a more effective antidepressant treatment than a low doze of midazolam, a traditional hypnotic and anticonvulsant.
A single dose of ketamine improved depressive symptoms within 24 hours in 64 percent of the test subjects, most of whom remained clear of symptoms for seven to 10 days. The scientific community greeted these results with qualified enthusiasm. Drs. James Murrough and Dan Iosifescu, the study’s chief authors, concluded that the experimental results served to “further support NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression.” The NMDA receptors are the principle regulators of neural glutamate.
Recent scientific interest notwithstanding, ketamine has traveled a long and perilous road to arrive at the doors of mainstream medical acceptance. First synthesized in 1962 by Dr. Calvin Stevens of Parke-Davis, ketamine was intended to serve as a human anesthetic. After FDA approval, it was given to American troops in the later years of the Vietnam War. Expanded psychiatric use stateside allowed for the drug to be diverted onto the streets, where it found a home in the hippie counterculture with other “downers” like barbiturates and Quaaludes. But ketamine truly came into its own as a recreational drug in the 1990s, when it surfaced as a “club drug” alongside GHB, alkyl nitrates, 2C-B, and MDMA. On dance floors from New York City to Hong Kong, it was know as “Special K” and the “New Ecstasy,” gradually becoming an integral part of the then-booming rave subculture. A string of overdose-related deaths and negative publicity from the educational D.A.R.E. campaign rapidly reduced ketamine’s popularity in the last decade, as drug users began to turn towards opiate painkillers like Oxycodone and MS Contin, which are not only incredibly potent but legal as well.
Starting in the mid-2000s, however, universities and research institutions began to investigate the antidepressant properties of the drug as more failed to respond to traditional antidepressants. Today, multiple studies in the United States, Canada, and Europe are in the process of studying the drug’s psychiatric uses, looking beyond depression to illnesses like anxiety and bipolar disorder. In several states, ketamine is already being distributed legally for medical purposes.
“Private clinics are opening up that are offering ketamine off-label, mostly for neuropathic pain,” said Duman.
Quick relief and apparent resistance to other antidepressants are driving the interest. Traditional antidepressants increase the levels of serotonin and several other neurotransmitters. Tricyclics act primarily on serotonin and norepinephrine, MAOIs on melatonin, epinephrine, and phenethylamine, SSRIs on serotonin, SNRIs on serotonin and norepinephrine, and atypicals that mostly regulate dopamine.
Ketamine is even starting to pique the curiosity of the commercial sector. Naurex, a biopharmaceutical company based in Evanston has been developing and testing a ketamine-like compound known as GLYX-13 for several years. The company recently raised nearly $80 million from private investors like the Cowen Group to finance further research and expanded clinical trials. In a press release published Wednesday, Naurex’s president and CEO Dr. Norbert Riedel expressed optimism that GLYX-13 could open a new front in the fight against depression.
“Currently marketed antidepressants all work via similar pathways in the brain and do not adequately treat 45 percent of individuals with major depression,” Riedel said. “Repeated treatments with GLYX-13 produce a sustained response in patients who inadequately respond to marketed antidepressants.”
Riedel and others at Naurex have gone to pains to clarify that while GLYX-13 works like ketamine, it is chemically distinct and produces fewer of the unsettling dissociative effects ketamine is known for.
“The key takeaways are that Naurex has succeeded where others have struggled by creating a modulator of NMDA that gives a rapid, robust, and durable response without creating a psychomimetic effect,” said Ian Stone, a representative for Naurex.
Naurex’s decision to pursue GLYX-13 instead of ketamine points to the lingering concerns that many still feel about the drug’s use. Though depression patients would receive too little of the drug to bring on its occasionally distressing dissociative effects and hallucinations, reactions can vary considerably from person to person. And while ketamine is not physically addictive in the same way that illicit drugs like cocaine and heroin are, it is possible for users to develop a pronounced psychological dependence.
Still, ketamine seems poised to break into the public consciousness very soon. Government database ClinicalTrials.gov lists over thirty studies recruiting potential patients in the United States and Canada to investigate ketamine’s impact on everything from suicidal ideation to post-operative pain. And, according to Duman, American multinational Johnson & Johnson is currently developing a ketamine nasal spray that may revolutionize access to the drug. With such rapid momentum building, it is difficult to imagine that ketamine will be held back by the reputation of its checkered past for much longer.