It’s winter 2030. Work is going badly, your love life is in tatters. Feeling irritable and melancholic, you reach for your computer and call up Normopsych, an on-line drugs service specialising in personality restructuring. After downloading your life history and personality profile data and completing virtual reality tests of rejection sensitivity and mood, you sit back in your chair. A few seconds later the screen fills with a rotating, three-dimensional image of the brain. A handful of neurotransmitter pathways are flashing ominously. The diagnosis reads: ‘Serotonin levels 15 per cent below par in limbic system. Boost with 100 milligrams per day of MoodStim and AntiGrief.’
Before you dismiss this scenario as a cheap and pointless parody of something from Brave New World, consider the following views on the future of neuroscience. From Richard Restak, a neuropsychiatrist attached to various universities in Washington DC: ‘Researchers are on the verge of chemical attempts to modify character . . . Most of the new drugs will be aimed not so much at patients as at people who are already functioning on a high level . . . altering for the good their internal moods.’ From Malcolm Lader, a psychiatrist at the Institute of Psychiatry in London: ‘I don’t see any fundamental technical obstacle to altering personality with drugs. After all, the traits that make up personality are rooted in neurochemicals.’ And from Jerome Kagan of Harvard University, who studies the biological basis of shyness: ‘Fifty years from now we may have drugs that can alter personality profiles. Things are moving very fast’.
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Hardly a week goes by without a magazine or newspaper telling us, with the mandatory mixture of horror and fascination, about the pharmacopia of the 21st century, replete with pills which can turn wallflowers into social butterflies and couch potatoes into go-getting executives. Indeed, for a minority of psychiatrists, the era of the personality pill has already arrived. The controversial antidepressant Prozac, which has had the media in a tailspin for the past two years, offers a powerful taste of things to come, argues American psychiatrist Peter Kramer in his book Listening to Prozac. The drug can not only restore depressed people to their premorbid states, he writes, but it can also transform personalities. It can make people ‘feel better than well’.
The glamorous mnemonic Kramer coined for this effect of Prozac – cosmetic psychopharmacology – has turned him into the high priest of personality as malleable neurochemistry. And his compelling, if contentious and speculative, account of how Prozac seemingly transformed the lives of a half dozen or so healthy people suffering from mild personality disorders – obsession with housework, shyness, and so on – has long since reached the dinner tables of the chattering classes.
But amid all the chatter and acres of newsprint, few people seem to have noticed that Prozac is only the tip of a pharmacological iceberg. Other high-tech psychoactive drugs, distinguished like Prozac by the precision of their biochemical action, are beginning to reach the marketplace. And the pharmaceuticals companies plan many more. If you talk to psychiatrists about the prospects for cosmetic psychopharmacology, you quickly realise that the controversy about the efficacy and social desirability of Prozac is only the trailer for a much bigger debate.
At issue will be questions that strike at the heart of modern psychiatry. Can drugs developed as therapies for serious mental illnesses, such as depression, obsessive-compulsive disorder and anxiety attacks, also benefit people with minor personality disorders – people who have never suffered from depression, say, but have a gloomy outlook, people who have never suffered from anxiety attacks but who are uptight and anxiety prone? If so, where do you draw the line between therapy and enhancement, between medicine and personality engineering?
SMART BOMBS FOR SIMPLE MINDS?
There is a simple reason why these questions must now be asked: the ability of neuroscience to produce biochemically specific drugs which affect the brain has outstripped our understanding of how the brain works. Neuroscientists have spent the past two decades identifying new neurotransmitters and the receptors that respond to them. As their knowledge has accumulated, they have steadily refined their techniques for selecting compounds that can influence the workings of specific neurotransmitter pathways.
Now they are enjoying the payoff: the birth of a new generation of psychoactive drugs which are being hailed as the pharmacological equivalents of ‘smart’ bombs. While older psychoactive drugs, LSD, amphetamines and tricyclic antidepressants (such as imipramine) tend to lash out indiscriminately at different neurotransmitter pathways, these new drugs seem to strike their neurochemical targets much more cleanly, producing fewer serious side effects.
Prozac is the example par excellence. The billion-dollar-a-year celebrity drug took 15 years to develop. And evidence so far suggests that Prozac interferes only with those neural circuits whose functioning depends on the neurotransmitter serotonin, blocking molecules on the surfaces of neurons which normally act to absorb serotonin (see figure 1). As a result, Prozac’s action is mainly confined to boosting the amount of serotonin circulating in the brain. Or so everyone assumes. Older antidepressants such as the tricyclics act in a similar way, boosting levels of the neurotransmitter norepinephrine. But they also interfere with the dopamine neurotransmitter system, and this partly explains why people get hooked on them. Prozac has plenty of listed side-effects – nausea and loss of libido for instance – but nothing to compare with the sedative and addictive effects of the older antidepressants.
Already chemists’ shelves are filling up fast with Prozac wannabes, compounds with brand names like Zoloft and Paxil which, like Prozac, act selectively on serotonin. And this is only the beginning. Information processing in the brain depends on upwards of two dozen neurotransmitters interacting with scores if not hundreds of molecular receptors, many of which could end up as targets for Prozac-style drugs. Hardly a month passes without neuroscientists reporting a new type or subtype of brain receptor, its gene or chemical structure.
But having a firm grasp of the brain’s molecular alphabet does not necessarily mean you understand its language – or can rationally go about rewriting personality traits. While research into the way individual neurons and their molecular receptors respond to neurotransmitters, or drug molecules, is blossoming like never before, neuroscience remains almost totally ignorant about how neurotransmitters and networks of neurons act together in the brain to produce complex mental states such as depression or anxiety. This knowledge gap leaves the field wide open for debate about personality-altering drugs.
QUIRKS OF TEMPERAMENT
On one side stand Kramer and other committed believers in the coming of cosmetic psychopharmacology. At the level of neurochemistry, they say, personality traits such as persistent melancholia and introversion are merely quieter expressions of the kinds of brain chemistry that lead to clinical conditions like depression. As such, these mood disorders (or deep-seated quirks of temperament, if you prefer) can be modifed with the same kinds of drugs. The reason Prozac can rewrite someone’s whole personality is that mental illness and temperament are both written in the same kind of neurochemical ink.
Or so Kramer and like-minded psychiatrists contend. But to psychiatrists of a more traditional bent this is at best wild-eyed speculation. Mental illnesses and serious disorders, they say, are more likely to stem from tangible biological deficits, such as defective neurotransmitter receptors, which lie well outside the realms of normal neurochemistry. Just because you can compensate for such deficits with drugs, doesn’t mean you can reshape personality? Take depression, say traditionalists. Acc-ording to one theory, it may be caused not so much by a surfeit or deficit of any one neurotransmitter as by the brain being, in effect, trapped in a gloomy neurochemical state. Prozac-like drugs may act like chemical switches helping depressed brains to regain their equilibrium. To a healthy brain, however, such help may be redundant. As Larry Siever, a psychiatrist at Mount Sinai Medical school, puts it: ‘You can try to heat up a thermostat by putting your hands around it, but if it’s a bright sunny day nothing much happens.’
Who will be vindicated in this debate it is impossible to say. But right now the traditionalists are on the defensive – and not just because of the the runaway public response to Prozac. In laboratories and clinics everywhere the traditional divisions between mental illness and the extremes of everyday personality, between the science of the abnormal mind and that of the normal mind, are beginning to unravel.
Increasingly, researchers looking for the biological and social roots of traits such as shyness and aggression are focusing on neurochemicals that have long been implicated in mental illness – particularly, serotonin, norepinephrine and dopamine. Increasingly, too, researchers are applying the brain imaging techniques of PET and MRI to studying how the building blocks of normal behaviour might be encoded in the structures of the brain. We all recognise a shy or outgoing person when we meet one. But do these familar labels tie into particular patterns of neural activity, into particular forms of neurochemistry and structures of neuroanatomy? Are these patterns the same in all shy or outgoing people? Only now are researchers beginning to tackle such questions in earnest.
Over the past few years, researchers have used PET to identify a variety of neural centres that flicker into action as people perform specific mental tasks – reading, looking at different kinds of visual images, listening to Mozart, even playing musical instruments. It is easy to imagine the same kind of approach being applied to moods and personality traits: ‘Think of something sad while I image your cerebral cortex . . . now think of something that makes you happy . . . anxious . . . threatened.’
Here’s a foretaste of the possibilities. A team in the US has used PET to trace an abnormal pattern of brain activity in people with obsessive-compulsive disorder, an illness that often leads to fanaticism about cleanliness and housework. The problem may stem from the way certain patterns of brain activity get stuck in a loop. Touch a normal person with a dirty rag, for instance, and the brain responds by passing a signal through three main structures – the prefrontal cortex, the basal ganglia and the thalamus. But do the same with an obsessive-compulsive person and the signal cycles through these structures endlessly. The signal itself is part of the normal repertoire of brain responses. What seems to be missing is the ability to turn it off. A drug that could correct that problem might prevent the symptoms. Could it also help people with very mild symptoms of obsessive-compulsive disorder – ‘normal’ people who endlessly line up their pencils?
Many people see dangers in this approach. If mental illness and quirks of temperament are on the same continuum, won’t the ups and downs of ordinary life be seen as medical problems? Others question science’s ability to make sense of the vagaries and complexities of personality, let alone its ability to leap the huge distances from molecules to behaviour and from brain images to neurochemistry. But that is not deterring psychobiologists from looking for – and even claiming to find – basic building blocks of temperament and character from which they believe all personalities are constructed.
PERSONALITY MAPS
More important, psychobiologists believe it may eventually be possible to relate these ‘maps’ of personality directly to levels of different neurotransmitters in different parts of the brain. That wouldn’t necessarily open the door to altering rationally the composition of a healthy individual’s personality. But it would certainly have an enormous impact on the way we see ourselves and, perhaps, the way doctors diagnose illnesses.
Some of the most influential findings are coming from Jerome Kagan, a child psychologist at Harvard University who is trying to trace the biological roots of the ‘inhibited’ behaviours typically seen in shy people. Everyone accepts that inhibition, like any other behaviour pattern, is the result of a cocktail of social learning – or character – and genetic predisposition – or temperament. Kagan believes it is possible to identify the genetic component by studying the behaviour of infants and then moni-toring them as they grow older. Based on close observations of 300 individuals, he believes that about 15 per cent of babies are born predisposed to developing into timid, and fearful infants.
More revealingly, Kagan has found that they tend to have higher-than-average heart rates and produce unusually high levels of the hormone cortisol and norepinephrine – both well known markers for stress and fear. As they grow up, these children are more likely to have intense fears of going to bed alone or of violence. They are also the children most likely to remain shy until the age of at least seven. These children, speculates Kagan, may be born with an unusally low biological threshold for fear. And that trait, in turn, could stem from having an overly sensitive amygdala, a tiny brain structure that when activated signals the heart to race, palms to sweat and norepineprine to swirl around the brain.
This line of research has bolstered some controversial ideas about norepinephrine and personality. Hypersensitivity in general – to some small rejection by a lover, to slights from work colleagues and so on – may be liked to an excess of norepinephrine, say some researchers, while a deficit of norepinephrine may lead to poor concentration and an inability to work out what is important. The logic here is that our fight-or-flight response to danger evolved in part as a mechanism for focusing the mind of threatening things in our environment. The lions and tigers are, for most of us, long gone. What remains is the threat of unmet deadlines, social rejection and anxiety about missing the last train home. Does this mean that drugs which rein in norepinephrine could be used to treat inhibition in otherwise normal people?
It’s far too early to know, says Kagan. Shyness in general may turn out to have nothing to do with norepinephrine. Everyone investigating the biological basis of personality has been obsessed with amines (dopamine, norepinephrine and serotonin), but inhibition could just as easily be governed by a hormone, says Kagan. ‘We know the amygdala is loaded with receptors for corticotrophin releasing hormone. The inference about amines is just a guess.’ So too is the assumption that inhibition is caused by any one brain state. ‘We can’t yet point to particular neural circuits and say they’re involved in inhibition,’ says Kagan.
What is clear is that character can overwhelm temperament. In Kagan’s study, up to 90 per cent of shy-born infants eventually lost their inhibitions as a result of experience, underlining the fact that the personalities of adults are a complex tangle of genetics and life experience. Can they be teased apart? Robert Cloninger, a psychiatrist and geneticist at Washington University in St Louis, believes they can, and with this aim in mind he has recently developed a complicated questionnaire-based system. Right now he is reaping the first fruits of his labour.
In December last year, Cloninger and his colleagues reported striking results from studies of different groups of people, some healthy, some suffering from illnesses such as depression. Based on these, Cloninger is convinced temperament consists of four basic, heritable components: reward dependence, harm avoidance, novelty seeking and persistence. And layered on top of these, he argues, are three, learned components of character: self-direction, cooperation and self-transcendence.
The details are complex, but each component can be thought of as a sliding scale. Someone who sits high on the reward dependence scale, for example, ‘is highly dependent on emotional supports and intimacy with others, highly sensitive to social cues . . . extremely sensitive to rejection from even minor slights,’ writes Cloninger. At the opposite end of the scale are socially detached people who never share intimate feelings with others and are unmotivated by an ambition to please. Other psychiatrists have come up with broadly similar theories. In some, reward dependence approximates to rejection sensitivity and novelty-seeking to impulsiveness. Science, says Cloninger, is gradually producing a ‘gold standard’ measure of personality.
Ambitious words, but what will it tell us about the neurochemistry of personality and its susceptibility to modification by drugs? Can clear links be forged between the model and neurochemistry? Cloninger believes so and is try to make his model clinically predictive.
In one study, Cloninger and his colleagues asked if they could use the four-dimension model of temperament to spot patients with depression who would respond most effectively to a Prozac-like antidepressant, rather than to imipramine. ‘In the case of the women,’ says Cloninger, ‘we found exactly what Kramer speculates in his book – individuals who are very high in harm avoidance and reward dependence tend to respond best to antidepressants like Prozac’.
If Cloninger and his colleagues are right, in the clinics of the 21st century, traditional concepts like depression and anxiety may end up being usurped by terms such as reward dependence and novelty seeking as doctors seek diagnostic measures that more accurately reflect brain chemistry. Up until now there has been little pressure for this to happen as the available drugs have been relatively crude. Smart bomb pharmacology, whatever else it may achieve, will surely change that.
MOOD BRIGHTENERS
It may also hasten the breakdown of traditional divisions between acute mental illnesses that run in cycles, like depression and schizophrenia, and milder personality disorders such as impulsiveness and introversion. ‘People have been asking questions about the origins of temp-erament since the time of Socrates,’ says Siever. ‘Now we have the tools to work out the vocab-ulary of temperamental states that underpin personality disorders.’ More and more doctors are acknowledging that there is a spectrum of behavioural symptoms, and possibly a corresponding spectrum of neurochemistry, he says.
Since the early 1980s Siever has been studying people who have what he describes as a schizotypal personality: introverted people who are extremely aloof and eccentric. They don’t think the CIA is watching their every movement but show milder signs of paranoia. The underlying psychological problem, says Siever, seems to be an inability to respond to social cues and rhythms, a trait that leaves the patients feeling disconnected from their environment and suspicious. At the level of brain chemistry, he argues, these people may be victims of milder expressions of the kinds of imbalances in dopamine implicated in schizophrenia.
Biochemical tests and brain imaging studies, for example, show that some of the patients have too much dopamine circulating around their frontal cortex, while others have too little dopamine in the limbic system. Most important of all, the patients seem to improve on drugs which act on dopamine receptors and are usually prescibed for schizophrenia.
Another fashionable theory says that a shortage of serotonin in the frontal lobes and in the limbic system may encourage impulsive behaviours like aggression. Evidence from animal research and biochemical studies in humans suggest serotonin may be part of the mechanism by which the brain connects behaviours like shoplifting or thumping a policeman with the inevitable consequences, argues Siever. But turning fascinating conjecture of this kind into evidence of concrete causative links between neurotransmitter systems and specific kinds of behaviour is no easy task.
Sceptics will point out that there is hardly a personality trait or mental illness left which hasn’t at some time been linked to dopamine or serotonin. Even seemingly clear-cut studies with drugs can be misleading. For example, a compound that acts on dopamine receptors may make someone less suspicious, but that doesn’t make it safe to assume dopamine causes suspicion; the drug may simply act to paper over the real neurochemical cracks. ‘Think of aspirin,’ says Steven Rose, an expert on memory at the Open University. ‘It solves the problem of toothache but it would be silly to argue that tooth ache is cause by a lack of aspirin.’
As for Prozac: far from nailing down the biological causes of depression, it has thrown everything into confusion. Until this pharmacological superstar arrived, animal research and cellular studies suggested that clinical depression might be caused by a deficit of receptors for norepinephrine. Now researchers are being forced to add serotonin to the equation as they accept that personality traits are sure to governed by the combined actions of several neurotransmitter systems. Cloninger is already working with theoretical physicists to help sort out the possible interactions that underlie the building blocks of personality he is studying.
Will accepting complexity in the ways in which temperament is related to patterns of neurotransmitter activity do anything to affect the public debate about cosmetic psychopharmacology? Probably not. It will certainly not hinder the flow of new psychoactive drugs into clinics, for pharmacologists have all the necessary tools to develop candidate compounds. Nor will it stop some people from taking drugs as personality uppers or mood brighteners. Consumers are likely simply to ask whether a drug helps them and whether it has side effects. And sometimes not even that. Already hard-pressed executives in the US have begun seeking extra-helpings of concentration from Ritalin, a potentially addictive stimulant that boosts norepinephrine levels and is normally prescribed for children diagnosed with attention-deficit disorder. Can anyone say how many of the 10 million people who have been prescribed Prozac suffer from clinical depression rather than ennui? Or perhaps ennui is simply on its way to becoming a recognised disorder. If history is any guide, the next two decades will see a gradual expansion of psychiatric categories into the realms of normality as psychiatrists and pharmaceuticals companies indulge their habit of defining as abnormal anything that responds to drug treatments. Once you start prescribing drugs for people who are impulsive but don’t have a severe gambling problem or who are eccentric and aloof but not psychotic aren’t you on the slippery slope towards the ‘improvement’ of personality rather than the treatment of disorder?
Not necessarily, argues Siever. The problem, he insists, is in principle no different from the situation with rising blood pressure or the hardening of coronary arteries. Both take place progressively, yet doctors have no difficulty agreeing on where to start treatments. But what if people looking for a quick, if temporary and biologically costly, mood change disagree? Couldn’t they accuse doctors of pharmacological Calvinism, of denying people their inalienable right to a happier life? Apparently not: ‘There are plenty of substances out there which such people can take,’ says Siever. ‘Nicotine and alcohol for a start.’