May 21, 2018
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Club drug may zap depression when other medications fail

By Jason Gale, Makiko Kitamura and Allison Connolly, Bloomberg News

Donald says he thought he’d died minutes after ketamine, a popular club drug known as Special K, was infused into his vein at a Sydney hospital in March.

“I couldn’t see anything except pure white,” recalled the 63-year-old depression suffer, who declined to be identified by his last name. “I thought, ‘oh well, I must have died.'”

His vision normalized within a couple of hours, he said. So did his mood, giving Donald respite from the debilitating depression that had defied a dozen antidepressants he’d taken over decades.

The former academic’s experience is part of broader tests to determine whether ketamine, a hallucinogen commonly used to anesthetize horses, can offer a new avenue for relieving the low mood and self-esteem and feelings of hopelessness that plague as many as 121 million people worldwide.

“This could really be a game-changer,” said James W. Murrough, an assistant professor in the departments of psychiatry and neuroscience at New York’s Mount Sinai School of Medicine, which has several ketamine studies under way. “There is a real need for something that works quickly.”

Ketamine, used as an anesthetic during the Vietnam War, was deemed revolutionary when it was discovered in the early 1960s just after psilocybin, which gives “magic mushrooms” their mind-altering potential. Research on psychedelic drugs was curtailed after experimentation outside labs led to widespread abuse, said Charles S. Grob, professor of psychiatry at the University of California, Los Angeles.

“The hallucinogens were really the cutting edge of psychiatric research,” Grob said.

Now that doctors have a better grasp of how the brain works, they’re realizing their colleagues in the 1950s and early 1960s were on to something. Pharmaceutical companies are interested as well. London-based AstraZeneca and a unit of New Brunswick, N.J.-based Johnson & Johnson have drugs in mid-stage patient studies designed to work in a similar way, but with better results.

Animal tests show ketamine promotes the growth of brain nerve-cells and their connections that are the cornerstones of learning and memory. Scientists are trying to see if the compound has the same dramatic effect in severely depressed and suicidal people. The research has already shed new light on the biological mechanisms of depression.

Ketamine may help patients who don’t respond to conventional antidepressants, such as Eli Lilly’s Cymbalta or H. Lundbeck’s Lexapro, which don’t work on about a third of those who try them, says Alana Simorellis, an analyst with Decision Resources Inc. in Waltham, Mass. It may also benefit people who need urgent relief from suicidal tendencies, so long as the drug is given under the supervision of doctors in a hospital, she said.

Modern antidepressants typically target the serotonin and noradrenaline brain receptor systems. While the drugs take two to six weeks to work on mood and self-esteem, they can improve energy and motivation sooner, giving a suicidal patient greater volition to end their lives, Grob said.

“There is really no medical intervention for acute suicidality, which is a medical and psychiatric emergency,” said Mount Sinai’s Murrough, who is running a trial to investigate the drug’s potential to prevent suicide. “It’s a huge unmet need.”

Besides Sydney and New York, ketamine is being investigated for depression at sites in Boston, Houston and Miami, as well as Changzhou, China; Grenoble, France; Geneva, Switzerland; and Aberdeen, Scotland, according to data compiled by Bloomberg.

Janssen Research & Development, a unit of J&J, is beginning studies in the United States and Europe of a different molecular structure of ketamine, as well as a novel compound targeting the same mechanism of action in patients with depression.

“We’re really interested in ketamine because of some of the earlier work done in academic medical centers and the effectiveness that it’s shown,” said Greg Panico, a spokesman.

Some rival drugmakers, including GlaxoSmithKline, the London-based maker of the Paxil and Wellbutrin depression medications, have given up on research in the field.

Designing medicines that modify the actions of large molecules in the brain is hard, says Clare Stanford, professor of experimental psychopharmacology at University College London, and only real innovation will pay off.

“If you’re developing something new, it’s got to be really new, otherwise it’s not worth developing,” Stanford said. “It will be too expensive and you won’t be able to recoup the cost.”

Already sales of existing drugs are falling. Global antidepressant revenue will drop an estimated 24 percent to $8.54 billion by 2020 as bestsellers such as Pfizer’s Effexor and Lilly’s Cymbalta face generic competition, according to Decision Resources. Sales of Lilly’s Prozac alone topped $2.6 billion a year before it lost U.S. patent protection in 2001.

Ketamine targets brain receptors activated by a transmitter called glutamate that’s important for synapses — the electrical and chemical signaling neurons use to communicate. Their activation in the hippocampus and the cerebral cortex — areas of the brain involved in memory, mood and cognition — are thought to be especially important in treating depression.

Antidepressants including Prozac also cause changes in synapses, though not as quickly as ketamine, said Murrough. It may be speed that gives ketamine an advantage for depression, which has been linked with alterations and abnormalities in glutamate levels, he said.

“These effects seem to occur over weeks with standard antidepressants and with ketamine, they occur rapidly,” Murrough said. “What Prozac did in two to four weeks, ketamine in a single dose was doing in one day” in experiments with animal models, he said.

Brain images of depressed people suggest the condition may be caused by atrophy in the hippocampus. Ketamine increases the growth of new synapses, much like electroconvulsive therapy or ECT, said Colleen Loo, a psychiatrist leading a study of the drug at Sydney’s Black Dog Institute.

Donald, the patient who thought he’d died on ketamine, is one of five people with treatment-resistant depression recruited so far in Loo’s placebo-controlled study. She wants 35 more to understand the drug’s effects on blood pressure, heart rate, and various psychiatric and neuropsychological measures. A second trial will investigate how its impact could be sustained.

Donald says his mood improved for as long as two days after receiving ketamine. “On the days of the treatment, I felt quite calm, relaxed and positive,” he said. “I was disappointed that it didn’t have this wonderful, long-lasting effect, but there is definitely something going on there.”

A positive mood response lasting as long as a few weeks has been observed so far in trial participants, some of whom didn’t respond to ECT, Loo said.

“The fact that some people who have failed ECT can respond to ketamine is amazing,” she said. “It’s a paradigm shift.”

Ketamine, with a reputation as a mind-distorting club drug, should be investigated with caution, said M. Margarita Behrens, a scientist at the Salk Institute in La Jolla, Calif. The medicine, whose street name is a play on Kellogg’s Special K breakfast cereal, initially disinhibits brain circuitry, causing over excitement in response to a stimulus.

The effects are transient and disappear when the drug is eliminated from the system. When taken repetitively, though, ketamine can change the way inhibitory neurons behave, she said.

It’s possible that ketamine’s antidepressant action derives from this mechanism and that, by disinhibiting the brain, the drug brings a depressive person into a normal state, but a normal person into psychosis, Behrens said.

“If not used carefully we could end up curing depression with schizophrenia,” she said.

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