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“As a scientific venture, the theory that low serotonin causes depression appears to be on the verge of collapse. This is as it should be; the nature of science is ultimately to be self-correcting. Ideas must yield before evidence.” (Dr. Jonathan Rottenberg,
Psychology Today
)

“A simplistic biological reductionism has increasingly ruled the psychiatric roost … [we have] learned to attribute mental illness to faulty brain biochemistry, defects of dopamine, or a shortage of serotonin. It is bio-babble as deeply misleading and unscientific as the psycho-babble it replaced.” (Andrew Skull, Professor of History of Psychiatry, Princeton University,
Lancet
)

There is no point piling up more quotations. By now you get the picture: the public defections continue because after nearly fifty years of investigation into the chemical imbalance theory, there is not one piece of convincing evidence that the theory is actually correct.

So if the chemical imbalance theory is now on its knees, where can psychiatry go from here? In what biological substrate can it now locate the causes of mental disorder? Perhaps the fascinating discoveries of genetics can lead the way out of the current impasse? Let's have a look at the evidence.

4

Up until about ten years ago, if you were studying any of the social sciences at university you'd have likely encountered a question like the following in an examination: What primarily determines whom you become—your nature or how you are nurtured? In other words, are you a product of your inherited biology or the environment in which you were raised?

Ten years ago, if a student had taken a forceful side in this debate, it is possible he might have still received top marks. This is because a decade ago the academic community was still at war over this issue, making an either/or answer intellectually possible. Today, however, the situation has changed. Given the huge advances in genetics over the last ten years, the scientific community has had to fundamentally revise its position. It now broadly accepts that it is virtually impossible to understand how our biology works outside the context of our environment. This has seen the either/or debate retreat to the wings, and bio/social complexity assume center stage.

To put the new genetics in the simplest terms (which, I have to say, isn't easy), virtually no neurological disorders or psychological problems have been demonstrated to result from the mutation of a single gene. Rather, they are now known to involve molecular disturbances that implicate multiple genes and the signals that control their expression.
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In other words, the popular idea that so-and-so gene causes so-and-so mental trait has been surpassed by the notion that it is
interactions
between our genes and their environment that actually shape us. This is because we now know there to be thousands of molecules attached to our DNA that can literally turn our genes on and off. These molecules, or “epigenetic markers” as they are more technically known, actually alter and develop as an individual adapts to his or her environment.

Dr. Nessa Carey, a former Senior Lecturer in Molecular Biology at Imperial College, London, summarizes this new genetics for me rather well: “We have our set of genes, but those genes can be switched on or switched off, and they can be switched on to higher or lower volume levels depending on the environmental stimuli. And epigenetics is a bit like the volume control on an MP3 player. Your MP3 player contains the tracks that you have loaded onto it, the ones you choose to play and how loudly you choose to play them, that's controlled by epigenetics.”

The equation this new idea obliges us to embrace therefore runs something like this: because our environment affects these molecules, and because these molecules can turn our genes on or off, the environment can no longer be seen as irrelevant to how our genes determine our functioning and development.

Studies of rats have illustrated this point well. Baby rats born to mothers that displayed little affection (that licked their pups rarely) were given to foster mothers that were very affectionate (that licked them a lot). After dissection, it was clear that the affectionately raised rats had brain characteristics different from those receiving little affection: affectionately raised rats possessed more receptors in the neurons of their hippocampus—receptors that are considered crucial stepping-stones in slowing down the production of stress hormones. It turns out that a stretch of DNA serving as a switch for a gene related to these neural receptors had been suppressed in the less–affectionately raised rats. This meant that the rats receiving less affection (fewer licks) were far more stressed as adults than those that had received more. The conclusion is that adult personality differences related to stress weren't determined by genes inherited from their biological mothers, but were an outcome of how they were raised as pups.
81

The same groups of researchers performed a related study of human beings. This involved analyzing the brains of thirty-six people postmortem. Twelve of these people had died of natural causes, while the rest (twenty-four) had committed suicide. And of the twenty-four suicide victims, twelve of these had been abused as children, whereas the other twelve had not. When the brains of these three groups were compared, the group that had suffered childhood abuse again stuck out. People in this group shared the same pattern of fewer receptors linked to stress hormones, as those found in the non-affectionately raised mice. Their brains, via epigenetic changes, had reacted to the environmental abuse—leading them to grow in a direction different from brains receiving environmental care.
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Studies like these show that genes can be “switched on or off” by molecules that are themselves altered by environmental factors.
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We know, for example, that there are two genes strongly associated with hereditary breast cancer (BRCA1 and BRCA2). But we also know these genes are responsible for only about 10 percent of all breast cancers (and that only about a further 10 percent to 20 percent of breast cancers are related to any kind of gene or variant). This means that most women who develop breast cancer may not be hereditarily disposed to do so.
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But even if they are hereditarily disposed, it also means they won't necessarily develop the condition. As the American Society for Clinical Oncology (ASCO) asserts, a woman with a 75 percent chance of developing breast cancer may remain perfectly healthy, while a woman with a 25 percent chance of developing breast cancer may eventually develop the disease.
85
Again, the presence of the relevant gene alone is not enough to account for the disease's onset. The environment influencing epigenetic factors play a crucial role.

The complexity of the new genetics makes those who have accepted the old genetic reductionism seem flatly out of date. I remember giving a talk some years ago at a seminar at Oxford University's John Radcliff Hospital. At one point I said that many mental health professionals regrettably used simplistic genetic reductionism to avoid the complexity of thinking through the various social, economic, and environmental factors influencing who we are, what we do, and who we become.

At the end of my talk a senior psychiatrist approached me, looking none too happy. “James, you've got it wrong,” he said curtly and authoritatively. “I have patients who are absolutely convinced their troubles are genetic, and who believe any intervention ignoring this is a complete waste of time. And most of these patients are right, especially if there is a history of depression in their family.”

I remember replying that a history of family depression proves nothing definitively—perhaps the family atmosphere or culture passed on over generations was the corrosive factor. I also said that reductionist beliefs often breed a destructive attitude in many patients, leading them to think, as one of my patients put it, “As my mother and grandmother had depression, I figure I'm biologically doomed to follow them.” This kind of fatalism, I responded, is not only scientifically unjustified but is potentially psychologically damaging—it makes people believe that no matter what they do, they are biologically doomed to suffer.

After making my points, this particular psychiatrist merely sighed and shook his head. “Well, James, for me most cases of depression have clear genetic markers, and even if science can't show this yet, it will do so in the future.”

Statements like these are unhelpful and betray a now-discredited way of thinking that dominated genetics over fifteen years ago. Back then there was great anticipation of finding singular gene mutations to account for most emotionally or cognitively related problems. This was inspired by a few interesting discoveries related to what are now known as the organic brain diseases. Perhaps the best-known example is Huntington's disease. This is caused by a gene carried on Chromosome 4 that destroys brain cells on the frontal lobes, leading to impairments in cognitive functioning. But these clear-cut cases in the realm of mental health are very much the exception.

Most genetic influences on disease are greatly more complicated than those early pioneers of the genome project could have dreamed. For instance, in the realm of psychiatry there is no known gene or clear genetic variants for around 97 percent of all the mental disorders now contained in the current
DSM
and
ICD
. And even where genes may be implicated, in disorders like bipolar disorder and schizophrenia, research now reveals such mind-boggling complexity that nothing definitive can be said. A researcher who scanned the genetic sequences of twenty thousand normal people and then compared them with the sequences of ten thousand patients diagnosed with schizophrenia, for example, found that more than ten thousand different gene variants could have a role in the onset of schizophrenia. Furthermore, this study did not take the findings of epigenetics into account (the environmentally susceptible molecules that interfere with these genetic variants).
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Of course, there have been periods of great excitement. In 2003, for example, a study was published in the journal
Science
in which the researchers asked why stressful experiences lead to depression in some people but not in others. After analyzing 847 patients over time, the researchers found that those who had one or two copies of a gene variant that interfered with serotonin transport were three times as likely to develop depression if subjected to certain stressful life events, like losing a job or getting divorced. This study was thought to provide evidence of a gene-by-environment interaction, in which an individual's response to environmental stresses is moderated by his or her genetic makeup.
87

This finding generated a great deal of excitement until another study, published a few years later, failed to replicate these findings. The researchers in this next study assessed over fourteen thousand people via a meta-analysis of fourteen studies. But the conclusion that was reached dampened the previous excitement: “This meta-analysis yielded no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined.”
88

Nobody wants the efforts of geneticists to be frustrated. We all desire scientists to succeed and lead us out of the dark. But given the developments in fields like epigenetics (not to mention the disappointments brought about by non-replicable findings), all we can do today is embrace a position thoroughly littered with caveats. It goes something like this: where genetics play a role in our mental lives, they do so via a given, yet-defined, constellation of genes that
may
predispose a person to an
unknown
degree
of vulnerability to developing a given form of mental distress
if
other social or psychological conditions trigger it, and
if
environmentally influenced epigenetic factors permit it. Such tentativeness is now slowly trickling through to the mental health establishment, as can be seen from the World Health Organization's (WHO) recent official statement on the causes of depression:

Depression is a complex disorder which can manifest itself under a variety of circumstances and due to a multiplicity of factors … biological (genetic and biochemical), sociological (stressors), and psychological (development and life experiences) factors interact to produce a picture of depression. Research during the last fifty years indicates that there is no single factor which can explain the cause for depression.
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The WHO does not say genes or biochemical imbalances cause depression. All it says is all anyone can say: of course our biology is implicated in mental distress, just as it is implicated in any emotional, physical, or mental state that is experienced as either positive or negative. But precisely how it's implicated, and precisely to what degree, we do not as yet really know. As long as we are alive, the things we feel, see, and think
can
affect our brains. But today exceedingly little is known about what the effects may be, so it is possible that little or nothing of our emotional suffering actually
originates
in the brain.

5

“The problem, you see,” said David Oaks as he once again recalled his hunger strike, “is that there is no proof for the things we were told: that our problems were due to brain-based diseases. And this is why the APA ducked our requests. It couldn't scientifically justify what we were led to believe as patients.”

“Do you think that patients today are receiving the same message you heard long ago?”

“I don't think, I
know
,” said Oaks decisively, “and this is misleading a lot of people into believing that only bio-psychiatry can offer a way out.”