(Continued)

But how much do we know about how these drugs affect youngsters? "The truth is, it hasn't been studied much," says James Leckman, a child psychiatrist at Yale University. Can drugs designed for and tested in adults even be expected to work in children? Their bodies are different and their brains are still developing. Some studies suggest that administering these drugs to children could alter the structure and chemistry of their brains - at best providing a cure, but at worst trading a mild mental illness for a more serious one.

Many drugs used to treat children with psychiatric problems have only recently begun to be evaluated for their age group. The exceptions are stimulants such as Ritalin, used to treat ADHD, several of which have been approved for children. Most antidepressants, antipsychotics and mood stabilisers are prescribed for children "off label", on the strength of a reasonable performance in adults. In 1997, the US Food and Drug Administration (FDA) was given the power to request that drug companies do clinical trials specifically in children in exchange for six extra months of patent protection.

The clinical trials that have been carried out in minors aren't always reassuring. For instance, in studies of selective serotonin reuptake inhibitors, or SSRIs - used to treat depression, anxiety, OCD and anorexia nervosa - few show that the drug worked better in children with depression than a placebo. A paper in the British Medical Journal this April reviewed six studies of SSRIs in children, and concluded that for depression, efficacy was "exaggerated", adverse effects "downplayed" and added benefit over placebo was "of doubtful clinical significance" (vol 328, p 879). "The evidence that they work is skimpy," agrees Normand Carrey, a child psychiatrist at Dalhousie University in Halifax, Canada.

And to make things worse, these studies also reveal that children are prone to more severe side effects. Agitation, irritability and disinhibition, which occasionally affect adults, are much more likely to show up in younger SSRI users. In clinical trials, about one in four under-18s taking SSRIs had serious behavioural reactions, such as uncontrollable rages or violent impulses like jumping out of a window, says Jane Garland of the University of British Columbia in Vancouver. In a study on paroxetine (known as Paxil in the US and Seroxat in the UK) in adolescents, she says, 7.5 per cent of the patients taking the drug had to be treated in hospital for adverse effects. None taking a placebo did. Ritalin also has more side effects in young people, says Carrey. The younger the patient, the more severe they are.

Today only Prozac is approved in the US for use in children with depression, although not everyone believes it should be. The drug did get a pat on the back this June, when a large US government-funded study showed it to be considerably more effective than either placebo or talk therapy. Still, the FDA intends to hold public meetings on the use of all SSRIs in children. The decision follows publication of a series of papers this spring, including the British Medical Journal study, which revealed that evidence showing lack of effectiveness and increased agitation and suicidal tendencies was glossed over in both the published and unpublished work. In fact, the attorney-general of New York state is suing GlaxoSmithKline, the maker of Paxil, for alleged fraud in not making public all five studies it carried out on the drug, and instead highlighting only the most favourable one.

It comes as no surprise to researchers in the field when modern psychoactive drugs act differently in children. Making adult drugs right for younger patients involves more than just adjusting for lower weight - their bodies have less fat, more water, a higher metabolism and raging hormones. What's more, developing brains are profoundly different from the mature brains these drugs were designed for, says Garland.

A child's central nervous system has more of almost everything: neurons, connections, neurotransmitters and growth factors. In adults, low levels of the neurotransmitter serotonin have been linked to low moods, and SSRIs work by blocking the absorption of serotonin in the brain and, some think, by stimulating the growth of new neurons. But this raises some interesting questions. Children are already undergoing neurogenesis, Carrey points out. While extra neurons may be a good thing for a depressed adult, they may have completely different implications for a depressed child.

Serotonin levels also appear to differ with age: children's brains synthesise much more than adults'. Diane Chugani at Wayne State University in Detroit found that under-fives produced twice as much serotonin as adults. Thereafter, levels declined slowly toward puberty. Many neurotransmitters, including dopamine, the brain chemical affected by Ritalin, and GABA, which is implicated in anxiety disorders, also show huge variations across the early years. Most are higher early on and come down with age, but the picture is complicated, says Chugani.

Throughout development, receptors all over the brain are blinking on and off. Simply put, the childhood brain is a moving target. "Drugs of many different classes would be expected to behave differently in children," says Chugani, "not only because of levels of neurotransmitters, but also because receptors are different and how they're distributed may be different." That's why it's so important that drugs be studied directly in children, she says, and not extrapolated from adult findings.

Carrey agrees. He was intrigued by a handful of studies that suggested that the same mental disorders were somehow different in children than in adults. One study was of children and adults with OCD; another investigated people who were overly aggressive. The findings in both suggested that young people with these disorders may have overactive serotonin systems - exactly the opposite to what is found in adults. The obvious question was whether antidepressants would work differently in adults and children.

Carrey and his colleagues started to address the question in studies of old and young rats. They found that antidepressants didn't seem to alter a hormonal response controlled by the serotonin system in younger animals the way they did in older ones. He thinks this may be because younger animals' brains are already awash with serotonin, so the SSRI simply couldn't boost serotonin's effect any further. What's more, the serotonin systems in their brains are probably too immature to respond properly to antidepressants.

Carrey is also comparing Ritalin in the young and old. Some years ago, questions were raised about whether the drug, which is pharmacologically very similar to cocaine, might predispose children to serious drug abuse. The idea was that years of Ritalin use might "prime" a child's brain to trigger strong cravings for cocaine even after just one exposure to it. In a landmark paper, Nora Volkow, then at Brookhaven National Laboratory in New York state, showed that injected Ritalin acted almost identically to cocaine in adults. "Nobody's bothered to look at how Ritalin affects the developing brain," notes Carrey.

Three studies published together in the journal Biological Psychiatry last December tackled that question in animal models. All three found effects that persisted into adulthood. Cindy Brandon and her team at the Chicago Medical School found that taking Ritalin during adolescence made a rat more likely to self-administer cocaine, suggesting they craved rewards more and might be more likely to become addicts later. Underpinning their behaviour were long-lasting neuronal changes. But both William Carlezon at Harvard Medical School and Carlos Bolaños at the University of Texas Southwestern Medical Center in Dallas found the opposite when the drug was given earlier, in the rat equivalent of childhood: then adult rats were less likely to seek rewards. It would be foolish to extrapolate too far, but this work hints that if you're going to treat children with stimulants, better do it in childhood rather than adolescence.

These studies and others raise the disturbing question of whether giving such drugs in childhood will trigger permanent changes in the brain. Neurotransmitters act as developmental signals in the young brain along with their everyday job of trading nerve impulses. Serotonin, for instance, modulates events like cell division, differentiation and migration, and construction of new nerve connections. In animals, raising or lowering the levels of serotonin can disrupt these processes, with lifelong effect. Says Carrey: "I think right now my findings indicate that these are drugs that modify the nervous system, and we have to be cautious."

There are hints that this is true for human patients too. At Wayne State University in Detroit, David Rosenberg has found structural and chemical changes in the brains of young people who are taking psychotropic drugs. He studied children with OCD who were treated off-label with paroxetine and found shrinkage in the thalamus, the brain's main sensory filter.

The good news is that their thalamuses were overly large to begin with, which may have been part of the problem. The drug reduced them to a more normal size. But it shows why a proper diagnosis is so important. Schizophrenia, for instance, is associated with an abnormally small thalamus - something no doctor would want to induce. "It underscores why we have to be careful about using medications," says Rosenberg. "This is altering brain chemistry and anatomy."

Rosenberg's team is studying how persistent these changes are. "The question we're looking into is: what happens to the chemistry and structure when you stop?" They also want to find markers for who might benefit most from drug therapy. "What was exciting about this finding was that the bigger the size of the thalamus [beforehand], the more likely the person was to respond."

Another vexing question is whether medicating a young brain could in fact turn one mental illness into another. So far, there is more anecdote than evidence on this front, but Carlezon's work in rats, for instance, indicates that Ritalin treatment before adolescence could spell an adulthood of depression. Rats on Ritalin exhibited what he called "learned helplessness" in adulthood - under stress, they gave up on tasks rather quickly, something he believes parallels human depression. He thinks stimulants may affect nerve connections made during development.

And Jane Costello at Duke University in Durham, North Carolina, found that whether treated or not, a child who has had a brush with one psychiatric disorder will be much more likely to have another. In a paper in press, Leckman and Andres Martin from Yale show that drugs may further increase the chance of such "conversion events". Examining four years of insurance records for 100,000 claimants, they found that young people treated with antidepressants - tricyclics and SSRIs - were more likely to be later diagnosed with bipolar disorder than people whose depression wasn't treated with drugs. It looks as if these drugs are a contributing factor, Leckman says. Interestingly, he notes that these medications are increasingly used in younger and younger groups. "It happens to correspond to a time when bipolar disorder is on the rise," he says.

Of course, illnesses themselves might also have long-lasting detrimental effects on the brain. "Having gone through major depression," says Leckman, "a person may not be the same." And as with the shrinking thalamus in Rosenberg's OCD patients, there is a flipside to all this: drugs taken early in life might tackle the source of the disease.

Chugani, for one, believes childhood is both a time of vulnerability and of opportunity. Her main clinical work is with autism. Her studies of serotonin synthesis have revealed that young autistic children have markedly lower levels in their brains than their non-autistic counterparts. Work in rats and mice has shown that the developing brain needs just the right amount of serotonin to get the thalamus to connect properly to the cortex; one problem in autism may be that a lack of serotonin prevents axons from making that connection. "Too much or too little and they don't form properly," says Chugani. She thinks that augmenting serotonin function in the brains of autistic children could have lifelong implications - permanently reversing some of the deficits of the disease.

She has reason to be hopeful. Evidence from the lab of René Hen at Columbia University in New York suggests there are certain windows of opportunity for neurotransmitters like serotonin to work their magic. Hen and his team have been working with mice genetically altered so that specific serotonin receptors can be turned on and off. For example, when one of the receptors for serotonin, the 1A receptor, is not functioning, a mouse will be very anxious. If you keep the 1A receptor switched off for the first three weeks of life, then turn it on for the rest, the mouse will still be anxious. But if you switch it on for the first three weeks, then switch it off ever after, the animal will never display this anxiety. Clearly, a mouse's temperament is at least partly set up during those first critical three weeks.

The more we know about what happens in these critical windows, the more we can imagine such permanent interventions. But we're not there yet; we're not even close. Where we are is surrounded by uncomfortable alternatives.

Intensive forms of talk therapy, while sometimes as good as or even better than medication, can be expensive and hard to come by. We need more professionals, and more money to fund them. Basic science has to study young animals and develop drugs specific to children's needs. Leaving a child to the ravages of mental illness is scarcely an option. "Depression," Rosenberg says, "is a lethal illness." Up to 20 per cent of depressed youngsters commit suicide. Kids with psychiatric problems of all kinds face a potentially bleak future if they fail to receive treatment. They have more troubles in school, in holding down jobs, in relationships. One way or another, mental illness costs.