Tweaked Ketamine Drugs Could Fight Depression

Ketamine could speed treatment for depression but has dangerous side effects. Derivative drugs are in development to deliver similar benefits safely.

Drugs such as Zoloft and Lexapro help millions of people cope with clinical depression, which can be disabling and even life-threatening. But they're not always the answer. As a 2012 study details, such conventional antidepressants don't help between 10 and 30 percent of depression patients, who either don't respond to them at all or only get partial relief. Older patients in particular suffer from so-called treatment resistant depression, in some cases because medications that they've been relying upon gradually stop working.

And there's another problem: Conventional antidepressant medications often take weeks or even months to start working. For a person with severe depression who may present a suicide risk, that time-lag could prove fatal.

That's why, in recent years, mental health researchers and psychiatrists have looked to an unconventional source - ketamine - an FDA-approved anesthetic and painkiller that's been around since 1970. It's also a popular street drug, due to its hallucinogenic effects.

Small-scale studies have shown that it can provide rapid, temporary relief to treatment-resistant depression. In a 2006 study, for example, researchers found that intravenous infusions of ketamine caused significant improvement in subjects' mood within two hours, and that 29 percent of patients' depressive symptoms were in remission by the next day. The effect lasted as long as a week.

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That's led a growing number of psychiatrists to administer ketamine as an "off-label" medication - meaning one that's not been approved as safe and effective for that use by the FDA, though doctors can still prescribe it. Such treatments can be costly, because they're often not covered by insurance, and dosages aren't standard. That's potentially worrisome, because ketamine can have powerful side effects.

"[Ketamine] makes people psychotic," explains Johns Hopkins Medical Institute neuroscientist and psychiatrist Dr. Solomon Snyder. "It also causes euphoria. That's why it's an abused drug." There's also concern that people with depression might get hold of illegal ketamine on the street and try to self-medicate, with disastrous results.

That's why researchers such as Snyder are looking to discover and develop substances based upon ketamine that could provide similar fast-acting relief for depression, without the risks or potential for abuse.

In a study published in January in the journal Molecular Psychiatry, Dr. Snyder and colleagues looked at a chemical compound called CGP3466B, which was developed as a possible treatment for Alzheimer's disease. While it didn't work for that use, Johns Hopkins researchers found that CGP3466B acted upon the same neural pathway as ketamine, and seemed to have the same antidepressant effects in animal tests.

Dr. Snyder hopes that a pharmaceutical company will try to develop CGP3466B as a drug for depression, but cautioned that it's not yet been established that it will work for human patients.

In another recent study, published in May in the journal Nature, researchers reported that chemicals produced when the body breaks down ketamine might be as effective of a treatment as ketamine itself, without the risks.

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University of Maryland medical school professor and researcher Dr. Todd Gould thinks that the discovery might lead to a new drug based on the ketamine metabolite Hydroxynorketamine. "We have gone up to very high doses in mice," Gould explains, "nearly 40-fold the antidepressant relevant dose, without any apparent negative side effects."

Gould says that the next step in the research is to do dose-ranging and long-term toxicology studies, which would help determine how much of the medication humans would need to take, and what the longer-term effects of using the medication would be. After that, the FDA would need to approve several study phases, which verify that the medication has the desired effect in people and produces better results than a placebo.

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