Prozac’s downer

At the height of the so-called Prozac Revolution in the early 1990s, fans of the drug made some grand claims for the new pharmaceutical marvel on the block.

It does not only eradicate depression, said the proselytisers, but can also combat a vast range of ills including bulimia nervosa, obsessive-compulsive disorder, panic attacks, obesity, alcoholism, PMT, sensitivity, lack of confidence, low self-esteem and jealousy. It truly was a wonder drug.

Since those heady days, however, the reputations of Prozac and other selective serotonin reuptake inhibitors (SSRI) have taken a beating, not least when GlaxoSmithKline was forced to abandon the claim that its SSRI, Seroxat, had no withdrawal symptoms. Worse might be on the way – a growing number of people is beginning to suspect that rather than being panaceas, these drugs might be no more than glorified placebos.

In August 2003, the Federal Drug Administration (FDA), the body that registers drugs in the USA, issued a warning suggesting that Paxil, another SSRI made by GlaxoSmithKlein, should not be given to children because of a potential ‘increased risk of suicidal thinking and suicide attempts’. The FDA also claimed that ‘there is no evidence that Paxil is effective in children or adolescents with MDD [major depressive disorder]’ and that clinical trials ‘found that Paxil did not work any better than placebo in the treatment of MDD’ among children.

This might seem like a rather strong statement from a body like the FDA – but some have suggested that the FDA ought to have had suspicions about the efficacy of SSRIs a good deal earlier. In a paper entitled The Emperor’s New Drugs, American Professor Irving Kirsch analysed the data supplied to the FDA by the major drug companies about the trials that led to the six leading SSRIs being registered. The trials showed that the placebos the SSRIs were tested against were on average 80 per cent as effective as the SSRIs at combating depression. The 20 per cent difference is, says Kirsch, ‘clinically insignificant’.

That small difference may well have been even smaller, but many of the trials that returned an unwelcome result were discounted as ‘flawed’. So many unwelcome results were discounted that 23 per cent of patients involved in trials for citalopram (marketed as Celexa), and 38 percent in sertraline (Zoloft) trials, never counted in the final figures.

It is worth noting that to register a drug, the FDA requires that two trials show it to perform better than placebo. One of the drugs needed nine trials to return two positive ones, the other seven being rejected. ‘The whole thing is a pseudo-science’, says Kirsch. ‘These trials do not show that the drugs are significantly better than placebos.’

This is not isolated evidence. A paper published in the British Medical Journal in May 2003 showed that out of 42 SSRI trials carried out in Sweden, SSRIs outperformed placebos in 21, while in the other 21 the placebo had a higher anti-depressant effect. The authors of the paper pointed out that the ‘successful’ trials were reported much more extensively than the ‘unsuccessful’ ones, which were practically ignored in journals. Such selective reporting implants the idea that SSRIs are effective, while suppressing negative data.

At first glance, it might seem improbable to suggest that anti-depressants are placebos. But some of the stranger behaviours of anti-depressants also match those seen with placebos. Like anti-depressants, placebos are efficacious for a wide range of unrelated ailments; they work better on adults, who are more aware of the supposed effects, than on children; the well-documented fact that some people can take many anti-depressants and feel no effect, then take another with a very similar chemical make up that ‘works for them’, is also a hallmark of placebos.

Placebos given in big, colourful capsules with well-known brand names printed on the side tend to have the best effects. You might expect that a Prozac placebo would work best of all. And it does. In the FDA trials results, Prozac placebos had 89 per cent of the effects of Prozac. None of this proves beyond doubt that anti-depressants are placebos, of course. But if they were, they would behave exactly as they do.

But isn’t it known that low serotonin levels cause depression – and don’t SSRIs correct the chemical balance in the brain? While the serotonin theory of depression is widely disseminated and accepted, it remains unproven. The interaction of neurotransmitters is little understood, and the effect on mood is complex. The claim that these drugs are ‘selective’ is also misleading: only five per cent of the body’s serotonin is found in the brain, and it is thought that SSRIs raise the serotonin levels all through the body, not just in some ‘depression centre’ in the brain. Even Eli Lilly, the makers of Prozac, claim only that their drug ‘may help to correct this imbalance by increasing the brain’s own supply of serotonin’.

It is worth bearing in mind that in the past 30 years many other biological explanations for depression have been suggested, including excessive cortisol in the blood, a deficit of norepinephrine, low blood sugar, an over-active thyroid or various hormonal changes. Explanations come and go, and with them cures. Maybe it’s time for some Prozac reaction.

Jeremy Hazlehurst is a freelance journalist.