Conference Coverage

Long-term effects of ketamine uncertain


 

REPORTING FROM NPA 2018

– Low doses of ketamine, an N-methyl-D-asparate glutamate receptor antagonist, can produce benefits that are unprecedented in the history of treating major depression, according to David Feifel, MD, PhD.

“When have we ever had the ability to be sitting in front of a patient who is extremely suicidal and have an intervention that will work within [an] hour that will remediate that?” he asked at an annual psychopharmacology update held by the Nevada Psychiatric Association. “Ketamine is that tool. If nothing else, that’s what ketamine already presents to us in this field.”

Dr. David Feifel

Dr. David Feifel

However, much remains to be learned about its ideal role in the care of patients with treatment-resistant major depression. For example, ketamine’s benefits are transient, and it’s unclear how to best maintain those effects. Another limitation is that it cannot be self-administered because of the dissociative “trip” patients experience, said Dr. Feifel, professor emeritus of psychiatry at the University of California, San Diego. “They need to be monitored in a medical setting,” he said. “In addition, chronic repeated administration has not been well studied, [and] the long-term side effects are uncertain.”

Then there’s the potential for abuse. “Will repeated use induce addiction in treatment-resistant depression patients?” he asked. “What about other long-term side effects?”

A recent consensus statement authored by Gerard Sanacora, PhD, MD, and associates acknowledged that data on the long-term effects of using ketamine in psychiatry practice are limited or nonexistent (JAMA Psychiatry. 2017 Apr 1;74[4]:399-405), even though an increasing number of clinicians are providing off-label ketamine for depression and other psychiatric disorders. First synthesized in the 1960s, ketamine’s primary site of action in the central nervous system seems to be the thalamocortical projection system, said Dr. Feifel, who has been providing the drug to patients since 2008. In a handout that accompanied his talk, he wrote that ketamine “selectively depresses neuronal function in parts of the cortex and thalamus while stimulating parts of the limbic system, including the hippocampus. This process creates what is termed a functional disorganization of nonspecific pathways in midbrain and thalamic areas.”

Ketamine creates acute subjective experiences that vary with doses, including a sense of “melting into people or things” at lower doses, and visions and hallucinations at higher doses. “Patients will tell me that they deliberately tried to move their hands and feet, to make sure they were still connected to their bodies,” Dr. Feifel said. “There’s often a sensation of moving through space. At higher doses, they often experience a profound sense of connection to all things, an ineffable universal unity that can change their perspective on themselves and their depression. It’s very profound.”

Antidepressant benefits with ketamine are usually dramatic, said Dr. Feifel, who also is founder and director of the Kadima Neuropsychiatry Institute in La Jolla, Calif. The drug is most commonly administered as an IV infusion over a 40 minute period at a dosage of 0.5 mg/kg. It also can be administered orally, intranasally, and intramuscularly. “Patients may achieve response and even remission of depression within a day, even when the depression was previously medication refractory,” he said. “The benefits are usually lost in 3-21 days. Maintenance treatment with ketamine, scheduled once every 2-4 weeks, can maintain the treatment gains. Dissociative and psychotomimetic effects are common but very seldom problematic.”

Dr. Feifel noted that ketamine’s remarkable results have piqued the interest of pharmaceutical companies. “But it is off patent – non proprietary,” he said. “Several novel agents by different pharmaceutical companies quickly have been developed and are in development. Some have modified pharmacology and are claimed to produce less acute dissociative/psychedelic effects. Janssen is developing intranasal esketamine for acutely suicidal patients that has been fast-tracked by the FDA.”

Dr. Feifel reported having no financial disclosures.

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