“GIVE A RAT COCAINE”

Just ask investors who took a punt on TC-5214, the failed antidepressant from AstraZeneca and Targacept. Their rollercoaster ride crashed to a halt on Tuesday.

Back in July 2009 things looked very different as Targacept shares more than doubled after TC-5214 tested extremely well in a mid-stage study. That success could not be replicated in later, larger trials.

AstraZeneca and Targacept are not alone. Last October, Novartis halted work on another antidepressant called agomelatine, resulting in an $87 million charge, adding to other high-profile failures, such as Merck & Co’s aprepitant.

TC-5214 was designed to work in a novel way by modulating nicotine receptors in the brain - a scientific approach that reflects Targacept’s origins inside R.J. Reynolds Tobacco.

The idea seemed good but, compared to testing new medicines in other fields, working out if an antidepressant works is extremely difficult.

The biology of the disease is poorly understood and early tests on animals are not much use either, since mice cannot tell or show scientists what they are feeling.

“Depression is one of the worst areas for animal models,” said Nutt. “It contrasts very strongly with addiction, for example. You give a rat cocaine, it behaves like a human - it gets hyperactive, it runs around, it likes it, it wants more. Whereas in depression, the animal models have ... no obvious validity.”

THE PLACEBO EFFECT

Placebo drugs - or sugar pills - typically have a massive impact in lifting depression, underscoring the subtlety of the disease and the suggestibility of patients.

That makes it “very, very hard” to prove that a particular drug is actually working, according to GlaxoSmithKline’s research head Moncef Slaoui.

“You can have depression medicines that in absolute numbers may show a 5 percent difference versus placebo because there was a placebo response of 50 percent and a drug response of 55 percent,” he told Reuters. “Even with approved drugs sometimes you achieve the endpoint and sometimes you miss it.”