Some therapeutic areas – rare diseases, the more intractable cancers – have a need for more intense drug development efforts because there is nothing that works for them.

Then, there’s depression.

The need for better antidepressants is “tremendous,” Gerard Sanacora told BioWorld Insight. The disease “remains within the leading four causes of disability in the developed world, despite the fact that we have 30 FDA-approved therapies.”

“I believe our current medications are actually pretty good,” he added. But they are nevertheless suboptimal or ineffective for a large fraction of people that take them. And even for those who do benefit from them, those benefits take weeks to kick in.

One issue with antidepressants is that although there are dozens of them, they only go after a narrow swath of targets. Current antidepressants target the monoamines – serotonin, norepinephrine, and dopamine – and their transporters.

Another challenge comes with conducting clinical trials for antidepressants, which have problems at both ends of the double-blind spectrum. When they are blinded, such trials suffer heavily from the placebo effect, which has led to several Phase III flameouts. In the biotech world, the most notable of those failures was TC-5124 developed by Targacept Inc. and Astrazeneca plc. (See BioWorld Today, Nov. 9, 2011.)

But in at least one case, the problem has been entirely the opposite. Ketamine is a drug that has gained a lot of attention due to its rapid antidepressant effects – it can improve the mood of depressive patients within hours, including those who have not benefitted from treatment with other antidepressant drugs. (See BioWorld Today, May 21, 2013 and Aug. 20, 2010.)

But its side effects include changes in cognition and perception that make it “very difficult to maintain the blind,” Sanacora said. Bluntly put, ketamine (street name: Special K) is a popular drug of abuse, and individuals taking the drug as part of a clinical trial can end up “high as a kite” – a state of affairs that is not lost on them or their doctors.

Now, Sanacora, who is at Yale University, and colleagues at Yale and Astrazeneca have reported new data on a related drug, lanicemine, which may offer solutions to both of those problems.

Their findings appeared in the Oct. 15, 2013, issue of Molecular Psychiatry.

Lanicemine, which is in Phase II trials, targets NMDA – the same receptor as ketamine. NMDA is a type of glutamate receptor that is opened by high levels of neural activity, but it does not block that receptor for as long as ketamine does. This finding means that its effects may be different than those of ketamine.

In their paper, Sanacora and his colleagues reported both animal studies aimed at understanding how lanicemine works, and the results of several clinical trials testing the drug in healthy and depressed individuals.

They identified a dose of lanicemine that had therapeutic effects without the unwanted side effects, which enabled them to conduct a double-blind placebo-controlled trial in about 150 volunteers. In that study, three weeks of treatment with lanicemine significantly improved patients’ mood.

“This paper significantly adds to the evidence that targeting glutamatergic mechanisms could be useful.” A number of companies are trying to develop NMDA receptor-targeting antidepressants. Neurop Inc., Biocrea GmbH and Evotec AG are in the discovery phase. Vistagen Inc. hopes to develop its AV-101, which is in Phase I trials for neuropathic pain, in depression as well. And Naurex Inc. is in Phase II with its GLYX-13. (See BioWorld Today, Dec. 7, 2012.)

Another important finding in the work now reported in Molecular Psychiatry was that the drug continued to be effective with repeated administration, and that those effects lasted for at least five weeks after treatment ended.

Ketamine has been tested only with regard to short-term effects of one-time administration, which can certainly be useful, especially in suicidally depressed patients, but does not amount to a long-term fix or cure.

“It’s nice that you can get someone to feel better for four days, but I don’t think that’s what everybody is looking for,” was Sanacora’s dry summary of the benefits of one-time drug administration.