Party drug turned 'miracle' cure for depression spurs hype and stubborn hope

The notion that a party drug could be repurposed into a "miracle" cure for severe, treatment-resistant depression is an almost irresistible story line in the popular press. And there's no reason why it can't be recycled using results from the same small, short-duration study design that long ago attracted some of the world's largest research organizations still engaged in researching new drugs in one of the most difficult fields in R&D.

Researchers in the U.K. can attest to that. Major news groups like the BBC and Reuters jumped on the results of a study of the Oxford Health NHS Foundation Trust demonstrating the dramatic impact of ketamine--a generic anesthetic often used to induce a quick and illicit high--on severely depressed patients. Out of 28 severely depressed patient treated with low doses of ketamine, 8 showed an improvement and four improved so much they were no longer classified as depressed.

In some cases the treatment effect lasted briefly. In some cases the effect lasted up to three months. Researchers heralded the results as "dramatic" and new, according to the BBC.

The results may be dramatic, but there's nothing new about the effect. And at least one unexplained clinical failure at AstraZeneca ($AZN) highlights just how hard it will be to turn this party drug into the "miracle" cure heralded in headlines.

Researchers have known for years that Special K--as it is known on the streets--can have a huge short-term effect on depression. As a result, Johnson & Johnson ($JNJ) has advanced an intranasal version of the drug, called esketamine, into Phase II. The pharma giant has proclaimed this project as one of their top experimental drugs. And clinicaltrials.gov reveals that a Phase II that started last fall is due to read out in a year.

AstraZeneca had a version of ketamine--AZD6765--in Phase II but quickly and quietly killed the project recently after it failed the second of two mid-stage studies. At the time, AstraZeneca offered no detailed explanation of the data or what went wrong with the program. The news about failure also attracted none of the big coverage associated with success.

The advantage of ketamine is that it appears to repair damage to the brain's complex neuronal signaling system. In trials, the drug has had an astonishing impact on patients, but the effect has often been ephemeral. And there have been serious concerns about potential side effects, even at low doses. 

But this is one drug that remains the subject of intense interest, helped along by the headlines that follow the work. A year ago, academic researchers in the U.S. set up a trial with 72 hard-to-treat subjects, with one group getting a low-dose infusion of ketamine while another arm was infused with a different sedative with no known antidepressive effect. The ketamine arm recorded a 63.8% response rate, compared with 28% in the control arm. After a week, the response rate for ketamine declined to 45.7%, which was still significantly higher than the control arm.

One of the reasons why there's so much interest in ketamine is that depression is one of the toughest diseases to treat. New experimental drugs have been killed by unexpectedly high placebo responses, which apparently often can't be anticipated. And patients often cycle through a series of therapies in search of one that will work. 

The need is there. The interest is there. But there's a long and difficult clinical trial journey ahead before any prospective product hits the market. -- John Carroll, editor-in-chief (email | Twitter)

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