What's the point of neuroscience? Why do we spend billions of dollars investigating those three pounds of flesh inside the head? Sure, human nature is interesting, and self-knowledge is a virtuous pursuit, but let's be honest: we study the brain because we don't want to die. Because we want cures for awful afflictions. Because we're desperate to avoid depression and addiction and dementia. The only way to justify the terrific expense of biomedical research is medicine.

Here's the bad news: I think neuroscience has yet to deliver on its therapeutical potential. We've learned an astonishing amount about the brain in recent years - a ten year old textbook is totally obsolete - but all this shiny new knowledge has yet to heal us. As a result, we're still stuck with pills and treatments that are frustratingly ineffective.

Consider depression. Every year, approximately 7 percent of us will be afflicted to some degree by the awful mental state that William Styron described as a “gray drizzle of horror . . . a storm of murk.” This is a big societal problem, which is why 24.4 million prescriptions were filled for fluoxetine (the generic version of Prozac) in 2010 in America.

The first thing to say about fluoxetine is that it's an old drug, having been introduced in the early 1970s. (Like many medical treatments, it was discovered largely by accident, when researchers realized that a common anti-histamine had anti-depressant properties.) Until recently, scientists assumed they knew how fluoxetine/Prozac worked. The story was simple: depression results from a neurotransmitter imbalance in the brain, in which patients suffer from a shortage of chemical happiness. The little blue pills cheer us up because they give the brain what it has been missing - a dose of serotonin.

There's only one problem with this theory of anti-depressants: it's almost certainly wrong, or at the very least woefully incomplete. Experiments have since shown that lowering people's serotonin levels does not make them depressed, nor does it worsen their symptoms if they are already depressed. And then there's the "Prozac lag": although anti-depressants increase the amount of serotonin in the brain within hours, their beneficial effects are not usually felt for weeks.

Despite our causal ignorance, anti-depressants remain an essential balm for millions of people, allowing them to escape from that recursive loop of woe. And yet, it's also clear that anti-depressants are

often disturbingly ineffective and, in many clinical trials, appear little better than a placebo. (See Irving Kirsch for a partiuclarly critical take.)

Furthermore, even when the drugs prove effective, their efficacy remains mysterious. Although there are some exciting new hypotheses about the power of Prozac - I'm particularly interested in the neurogenesis story - we still don't understand why this category of drugs is the best we've got, even after forty years of well funded R&D. (Of course, this mystery hasn't interfered with the popularity of the pills: As Schopenhauer once noted, people tend to treat causes “like a hired cab that one dismisses when one reaches the destination.” All we really care about is the health benefit - the causal story is just a sales ploy, a way to reassure patients that our success isn’t dumb luck, even when it is.)

And this returns us to the current state of neuroscientific research into depression. Last week, the field recieved a jolt of bad news: a hyped new compound from Glaxo (GSK372475) proved utterly useless. In two well done clinical trials, the drug failed to make people feel better.

Why is this news? Drugs fail all the time. (According to one recent analysis, more than 40 percent of drugs fail Phase III clinical trials. The odds are even worse for brain pills.) What makes the dismissal of GSK372475 noteworthy is that it looked so good on paper. The molecule is a potent triple reuptake inhibitor (TRI), blocking the breakdown of serotonin, noradrenaline and dopamine. While Prozac only alters serotonin, other successful anti-depressants, such as venlafaxine, block the reuptake of serotonin and noradrenaline. So it seemed like a good idea to also interfere with the reuptake of dopamine, especially since decades of research have suggested that more dopamine in the synapse is reliably associated with feelings of pleasure and reward. (Why do you think cocaine feels nice?) Although we still don't understand how blocking the reuptake of various neurotransmitters cheers us up, we have yet to improve on that mechanism of action, which is why drug companies are still investing in expensive clinical trials for reuptake inhibitors.

But that logic didn't pan out. Not only did depressed patients on GSK372475 get better more slowly than those on placebo, they were also hit with a bevy of side-effects, including insomnia and nausea.

Pharmaceutical failures like this are a sobering reminder that the brain and its afflictions remain deeply mysterious. Despite the billions of dollars poured into depression research, we still don't understand the causal mechanisms of the illness, which means we don't even know which drug actions to screen for. We can't even imitate our past successes.

Given such struggles, it’s not surprising that drug companies are dramatically scaling back research into the brain. (Most recently, four leading drug firms, including Merck and GlaxoSmithKline, announced that they were cutting neuroscience R&D. They cited the disconnect between scientific funding and pharmaceutical sucess.) The organ is simply too complicated, too full of networks and pathways we don't comprehend.

I don't want to overdo the pessimism - betting against science is a losing game. But I think we need to be honest about the payoff of basic research, at least so far. We've learned so much, but we have yet to learn what really matters, whether it's the neural underpinnings of depression or the triggers of Alzheimer's or the genetic snippets behind, well, everything. The brain isn't just complicated - it seems to be more complicated than we can imagine.

So how does Prozac work? The sad answer is that we're still not sure. And that means we don't know how to come up with something better.

PS. The Neuroskeptic has a typically great post on the failed trial.