Ketamine-like drug lifts depression without the trip

A drug similar to ketamine has been shown to work as an antidepressant, without the psychosis-like side effects associated with the party drug.

In 2000, ketamine was seen to alleviate depression almost immediately in people for whom other treatments had failed. Larger clinical trials have since corroborated the findings. The drawback is that ketamine can cause hallucinations and other psychotic symptoms, making it unsuitable for use as a treatment.

These effects also make it difficult to conduct randomised, placebo-controlled trials – the gold standard in clinical medicine – as it is obvious which participants have been given the drug. This meant that there was a possibility that the beneficial effects seen in previous trials were inflated.

So a team led by Gerard Sanacora of Yale University and Mike Quirk of pharmaceutical firm AstraZeneca looked for an alternative compound. They decided to test lanicemine, a drug originally developed to treat epilepsy that targets the same brain receptors as ketamine.

Depression relief

The team gave 152 people with moderate-to-severe depression and a history of poor response to antidepressants either lanicemine or a placebo three times a week, for three weeks. They were allowed to continue taking any medications they were already on.

Before and after the trial the participants’ level of depression was rated on a 60-point scale. After three weeks, those taking lanicemine were less depressed by an average of 13.5 points – 5.5 points better than those who took the placebo. The improvement was still statistically significant up to two weeks after the treatment ended. Dizziness was the only common side effect.

“What this tells us is some of the concerns around ketamine might not be such big problems as originally thought,” says Quirk. “There are ways around them with the right molecule.”

One downside is that unlike ketamine, lanicemine did not work immediately; it took two to three weeks of treatment for the effects to be seen. However, an initial exploratory study in 34 people not taking any other medication did show rapid benefits, so the team speculates that the delay may be caused by the other drugs the participants of the primary study were taking. The improvement in symptoms was also not as pronounced as it was with ketamine in previous trials, but further trials will be need to directly compare the two.

Alternative target

Even with these caveats, the work is an important step forward. Depression recently overtook hypertension as the leading cause of disability in the West, and the World Health Organization estimates this will be the case worldwide by 2020. This is worrying as about a third of people don’t respond to the current antidepressants.

The hope is that ketamine-like drugs offer a real alternative as they work via a different chemical in the brain. Rather than boosting the neurotransmitter serotonin to improve neural signalling in the brain, ketamine and drugs like it boost glutamate, which is thought to stimulate the regrowth of brain cells that may have atrophied.

“This could be revolutionary – the first new drug treatment for depression in 50 years,” says former UK government adviser David Nutt, based at Imperial College London, who was not involved in the work.

“This is a real breakthrough,” says Valerie Curran, a psychopharmacologist at University College London. “It’s great that ketamine’s psychotic-like effects were minimal with lanicemine, but disappointing it didn’t show ketamine’s rapid onset.”

The next step is to conduct more clinical trials to look at the safety and efficacy of lanicemine with more prolonged treatment.

Journal reference: Molecular Psychiatry, DOI: 10.1038/MP.2013.130