Bitter Pills

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Before delving into how, and how well, the SSRIs work, whether they're overprescribed and the sundry other medical, ethical and ideological questions that swirl around these drugs, it's worth acknowledging that depression in its most severe form is a crippling condition. Over time, sufferers of melancholic depression (formerly known as endogenous depression) lose the ability to feel joy, excitement, empathy - just about anything except a gnawing dread. They eat without appetite and their sleeping patterns are shot to bits. Imagine being alone at 3 a.m., having just awoken from a nightmare. That, depressed people say, is a hint of how they feel in every waking moment. It's horrible - so horrible that most sufferers need little convincing that what they're experiencing is more than just sadness but the effects of a disease that has taken root in their brain. When they prescribe antidepressants, most doctors are working from the idea that depression has somatic underpinnings: that it arises from an imbalance of certain neurotransmitters in the synapses - or spaces - between nerve cells in the brain. While science has implicated dopamine and noradrenaline in depression, and some of the newest antidepressants target these, it's branded a shortage of serotonin as the main culprit. Found in large concentrations not just in the brain but in various parts of the body, including the gut, serotonin plays a role in regulating - among other functions - mood, sleep and appetite.

If depression is a disease, it seems logical that the most effective way to treat it is with biological agents. Secreted into the synapses, serotonin is normally partially reabsorbed by the brain cells that released it. SSRIs block this reabsorption, allowing more serotonin to accumulate in the synapses. The result, hopefully, is that the patient begins to feel better within a few weeks. But how solid is the chemical-imbalance model of depression? That depends on whom you ask. The drug companies present it as fact. On its website, Pfizer, maker of the blockbuster SSRI sertraline (Zoloft), asserts that antidepressants "work by correcting the chemical imbalance in your brain." The Australian mental health lobby group beyondblue is slightly more circumspect in its literature, saying "severe depression appears to be associated with a reduction in the chemicals of the brain." Depression comes in various types and shouldn't be thought of as an "it," says Gordon Parker, a professor in the school of psychiatry at the University of New South Wales. But because the more severe form tends to run in families and involves physical symptoms such as sleep and appetite disturbance, and because its onset can't be explained as a reaction to a traumatic event such as a bereavement, it seems "there are some depressions that are quintessentially biological . . . very much chemically underpinned."

Not everyone's convinced. And not everyone will be until there's a biological test for depression instead of the series of questions doctors use now. Don't hold your breath waiting for that, says British academic Moncrieff: "I believe that human emotions will never be located in a simple biochemical formula." The chemical-imbalance theory is nonsense, says Adelaide psychiatrist Jureidini. SSRIs alter a patient's serotonin levels within days, he says, but their antidepressant effect - if there is any - doesn't occur for several weeks. "The idea that there's a serotonin deficiency that explains depression is such a gross oversimplification as to be completely misleading," Jureidini says. "A lot of doctors and others are prone to wishful thinking. It'd be nice if this was all scientific and we could give a drug to correct a chemical imbalance and nobody had to think about how complicated it is to become depressed and what the reasons might be for it . . . But it doesn't work like that."

Debate over a physical cause of depression tends to become bogged in uncertainty over cause and effect. Does a spontaneous chemical abnormality trigger the bad feelings we call depression, or might years of unresolved anxiety and festering discontent cause chemical disturbances - disturbances that might fix themselves once sufferers put their lives in order? By slowly unraveling the extraordinary complexity of neurotransmitter interaction, scientists are learning more about how the brain works. But they still wouldn't claim to know the half of it. Pinning depression on a chemical imbalance is problematic when what constitutes normal brain chemistry has yet to be defined. "I think what we have to tell trainee psychiatrists is that this is a far more complex area than we previously thought," says Dr. Louise Newman, director of the New South Wales Institute of Psychiatry. While there's a "suggestion" of a chemical imbalance in some cases of depression, she adds, the next generation of psychiatrists "needs to know the limitations of the evidence."

Given the gaps in the science behind the SSRIs and their risk of serious side effects (about half of all users experience side effects ranging from mild to severe), you might think doctors would be very selective in prescribing them - writing scripts only for those people in a deep and prolonged misery that can't be traced to everyday problems. But caution doesn't seem to rule here. In Australia, about 85% of those annual 12 million antidepressant scripts are written not by psychiatrists but by G.P.s, typically at the end of a consultation lasting 20 min. or less.

Prescriber information on the SSRIs in America contains an extraordinary sentence missing from the versions seen by Australian doctors - extraordinary in the context of a debate in which advocates of the drugs assert that depressed people who aren't treated are at heightened risk of contemplating and attempting suicide. "The average risk of such events in patients receiving antidepressants was 4%," the U.S. warning reads, "twice the placebo risk of 2%." In other words, drugs meant to stop depressed people from getting even more depressed or killing themselves may double their chances of doing just that. For the skeptics, that's more evidence they are right.