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Experimental Antidepressant Works Like Ketamine with Fewer Side Effects


Existing antidepressants available through prescription, which work through the brain’s serotonin system, take a few weeks to work, imperiling severely depressed patients, who can be at high risk for suicide. Ketamine also works in hours, but its usefulness is limited by its potential for dissociative side-effects, including hallucinations. It is being studied mostly for clues to how it works.


According to a study published online in Biological Psychiatry (30 November 2012), a drug that works through the same brain mechanism as the fast-acting antidepressant ketamine, improved treatment-resistant depression symptoms in minutes, with minimal untoward side effects. The experimental agent, called AZD6765, acts through the brain’s glutamate chemical messenger system. AZD6765, like ketamine, works by blocking glutamate binding to a protein on the surface of neurons, called the NMDA receptor. It is a less powerful blocker of the NMDA receptor, which may be a reason why it is better tolerated than ketamine.


Results showed that about 32% of 22 treatment-resistant depressed patients infused with ASD6765 showed a clinically meaningful antidepressant response at 80 minutes after infusion. The effect lasted for about half an hour, with residual antidepressant effects lasting two days for some. In contrast, 52% of patients receiving ketamine show a comparable response, with effects still detectable at seven days.


When both drugs are compared, it was demonstrated that a single infusion of ketamine produces more robust and sustained improvement, but most patients continue to experience some symptoms with both drugs. However, the authors deemed it noteworthy that depression rating scores were significantly better among patients who received AZD6765 than in those who received placebos, because, on average, these patients had failed to improve in seven past antidepressant trials, and nearly half failed to respond to electroconvulsive therapy (ECT). In addition, patients receiving ASD6765 reported only minor side effects, such as dizziness and nausea, which were not significantly different from those experienced with the placebo.


According to the authors, the results warrant further trials with AZD6765, testing whether repeated infusions a few times per week or higher doses might produce longer-lasting results.


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