Cracked (12 page)

We must face the very real possibility that we are far from the primary disturbance in depression. The changes [in serotonin] may all be secondary to other abnormalities which have not been taken into account at all … In spite of all the numerous investigations and very exciting leads that are now opening up, we are perhaps only in a slightly better position than Sanctorius of Padua … [when he said some three hundred years ago]: “Where the bond of union is between the mind and the animal fluids, God Almighty alone knows …”
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Coppen's theory that the “animal fluid” of serotonin may be crucial in shaping our mental lives cleared the path for the second generation of antidepressants: the SSRIs (selective serotonin reuptake inhibitors). These newer medications included, as we have already seen, drugs like fluoxetine (Prozac), Paroxetine (Paxil, Seroxat), Sertraline (Zoloft), fluvoxamine (Luvox), Citalopram (Celexa), etc. All of these were thought to alter mood irregularities by inhibiting the reuptake of serotonin by neurons in the brain. All of these, in other words, assumed that Coppen's theory of the chemical imbalance (this time of serotonin) was correct.

But
was
his theory correct? That is the crucial question. A question we cannot hope to answer without first getting a handle upon some of the very basics of neuroscience. I promise I'll be very brief.

The brain is famously made up of about one billion nerve cells called neurons. Each of these neurons resembles a piece of string with little branches coming off it called dendrites. The neurons do not actually touch each other, but they do communicate with each other by way of discharging chemicals into the tiny gaps sitting between them. These gaps are called synapses, and the chemicals that flood them are called neurotransmitters. They are called neurotransmitters because they “transmit” complex electrical messages from one neuron to another, ensuring that these neurons are in a constant and highly complex conversation.

To simplify things greatly: when neuron A has received enough transmitters from surrounding neurons, it “fires” its own transmitters to other neurons around it. When thousands of neurons are triggering each other in this way, this is called a cascade. And cascades are thought to be what facilitate our thoughts, perceptions, and emotions.

Neurotransmitters are therefore widely acknowledged to be crucial to how our brains operate. This is why people who speculate about chemical imbalances say that if there's a deficiency in these chemicals, this will impair our brain's functioning. And this is where antidepressants like SSRIs come in: they aim to increase the amount of neurotransmitters sitting in the synapses. And they do this by cutting off what we might call “backflow.”

For example, imagine waves rolling onto a beach. The waves roll in and then out. That's pretty much how neurotransmitters work: they roll into the synapse, deposit their message in the neighboring neuron, and then roll back out again. What SSRIs try to do is inhibit that rolling-back action, which essentially means that more of the chemical stays in the synapse for more of the time, resulting in higher levels. Different antidepressants target different types of neurotransmitters, but broadly speaking there are thought to be three neurotransmitters that matter most: serotonin and norepinephrine, which are considered most relevant to depression, and dopamine, which is considered crucial for major mental illnesses like schizophrenia.

So that, in short, is the basic neuroscience behind the chemical imbalance theory. Mental illness is caused by irregularities in neurotransmitter levels, which can be altered by psychiatric drugs. The theory is seductively simple and has remained so for now nearly fifty years. But what matters most to us is whether during that entire time the theory has ever been proven correct.

3

Dr. Alec Coppen, the architect of the serotonin theory of depression and thus the intellectual grandfather of one of the most prescribed pills in history—the SSRI antidepressant—was more than happy to help me answer this question when I called him at his home in London in April 2012.

As soon as Coppen started to speak, I felt immediately transported into another era—he had one of those near-extinct 1940s BBC newscaster accents, which betrayed his public school education of the 1930s and the fact that he is now ninety years of age. Coppen is still as active as ever, especially when it came to championing the virtues of the drug Lithium on the telephone (an enthusiasm I could not empathize with, given Lithium's nasty negative effects and troubled history: in the late 1800s it stopped being used to treat gout because in high doses it was fatal, while in the 1940s it was finally banned from the soft drink 7UP because of its toxic qualities). Nonetheless, I waited while Coppen talked enthusiastically about the drug, until the moment arrived when I could jump in.

“So Dr. Coppen,” I interrupted once Coppen had paused for thought, “do you think Lithium works because it acts upon certain chemical imbalances like serotonin?”

“Eh, yes, I think there's some serotonin effect,” responded Coppen, noticing I'd changed the subject.

“And since you think Lithium works on these chemicals,” I continued, “do you think this might provide evidence for the chemical imbalance theory? I mean, if drugs increase neurotransmitter levels, and drugs also treat depression, perhaps depression is therefore caused by a deficiency in these neurotransmitters. Do you believe this is so?”

“Well, yes, indeed.”

“So tell me, Dr. Coppen,” I said, now getting to the point, “what would you therefore say to those people who argue that the chemical imbalance theory is still unsubstantiated?”

Coppen went silent for a moment before responding in a way that surprised me. “I think there is a lot of evidence for the theory, actually. I don't think people are working on it today because it's generally accepted.”

I was surprised to hear this, because in all my interviews with psychiatrists of different persuasions (from the most humanistic to the most biologically reductionist) this was the first time someone had said they believed there was a lot of evidence for the theory, or in other words that the theory was largely supported. This is not to say that there aren't people out there who actually believe this. It's just to say that it's rare to find anyone who will declare this position openly and without caveats. And there is a plain reason why—
the theory isn't supported
. And there are three separate reasons, I heard again and again, that explain as to why.

Number one: The main evidence for the theory is arrived at deductively—because antidepressant drugs like SSRIs increase our serotonin levels, and because antidepressants alleviate depression, depression is therefore probably caused by some kind of serotonin deficiency. Now, although the syllogism is deceptively neat (and therefore remarkably beguiling), critics say it is nevertheless logically flawed. In the first place, it's clear that antidepressants don't alleviate depression for the chemical reasons most people believe. As the last three chapters have shown, we can account for a positive effect of an antidepressant largely in terms of its placebo effects, not in terms of its rebalancing chemical imbalances. It is therefore wrong to say the chemical imbalance theory is supported because antidepressants work, since antidepressants probably work for non-chemical reasons.

Number two: Even if antidepressants did work for chemical reasons, critics point out this would still not substantiate the chemical imbalance theory. If my headache feels better when I take some aspirin, I do not conclude that my headache was therefore caused by a deficiency of aspirin in my brain. Arguing deductively in this way is simply poor reasoning. After all, my headache could have been caused by one of many factors—noisy neighbors, a late night, too much wine, and so on. All the aspirin has done is interfere with my capacity to experience my headache, rather than topped up the chemicals whose deficit was its supposed cause.

Now finally to argument number three, the argument referred to time and again as the strongest against the chemical imbalance theory, which goes like this: Despite thousands of studies conducted by researchers who have tried to show that a serotonin or norepinephrine deficiency is responsible for depression, not one has yet been able to provide
direct
evidence that this is so. For instance, studies of the neurotransmitter norepinephrine say very contradictory things; there are as many concluding that people with depression have
high
levels of norepinephrine as there are concluding that depressed people have
low
levels.
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Furthermore, the largest recent meta-analysis of serotonin studies, conducted at the University of Amsterdam, has shown that low serotonin does not act as a depressant because when it was lowered in healthy individuals it produced no decrease in mood at all. As the authors summarized: “Although previously the monoamine systems were considered to be responsible for the development of MDD [major depressive disorder], the available evidence to date does not support a direct causal relationship with MDD.”
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These facts are consistent with earlier studies showing that special drinks that deplete serotonin and norepinephrine levels do not actually produce depressive symptoms (e.g., when depressed people take them, their mood does not worsen; when non-depressed people take them, they remain chirpy; the only slight fluctuation is found in some people who, having recovered from depression, suffered some minor “transient depressive symptoms” but certainly not full-blown depression).
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Research like the above not only challenges the idea that serotonin and norepinephrine are causative agents in mental illness, but is consistent with what research on the third major neurotransmitter, dopamine, also tells us. As the psychiatrist Daniel Carlat summarized:

For years, the going explanation for schizophrenia was the “dopamine hypothesis”; because anti-psychotics block the action of the neurotransmitter dopamine, it seemed reasonable to presume that psychosis must be caused by too much dopamine. You can't measure dopamine directly in the brain, but you can measure the main byproduct in the spinal fluid. More than a dozen studies have compared levels of dopamine metabolites in schizophrenics … In most studies, there were no differences, and in a few, the levels were lower in schizophrenics, exactly the opposite of what would be predicted by the dopamine hypothesis. Other studies, looking at post-mortem brains or PET scans of living patients, have been inconclusive, partly because most of the patients have already been taking antipsychotics. This means that any alterations found in dopamine receptors are as likely to be an artifact of the medication as they are to reflect the underlying cause of schizophrenia … It is crucial that we realize how much we know and how much we do not know. In virtually all of the psychiatric disorders—including depression, schizophrenia, bipolar disorder, and anxiety disorders—the shadow of our ignorance overwhelms the few dim lights of our knowledge.
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Carlat's last point is in agreement with a recent and definitive review of all basic antidepressant research published in the
New England Journal of Medicine
. This revealed that “numerous studies of norepinephrine and serotonin metabolities in plasma, urine, and cerebrospinal fluid, as well as postmortem studies of the brains of patients with depression, have yet to identify the purported deficiency reliably.”
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In other words, and to quote the leading journal
The Pharmacological Basis of Therapeutics
, the data for the neurotransmitter hypothesis of mood disorder “are inconclusive and have not been consistently useful either diagnostically or therapeutically.”

In recent years such disproving research has begun to erode the profession's faith in the chemical imbalance theory. This has led increasing numbers of prominent figures in the mental health profession to declare their defection publically. To pique your interest in this sea change, here are a few quotations I've managed to gather:

“Many neuroscientists no longer consider a chemical imbalance theory of depression and anxiety to be valid.” (Dr. David D. Burns, Professor of Psychiatry, Stanford University)

“Chemical imbalance is sort of last-century thinking. It's much more complicated than that.” (
Dr. Joseph Coyle
, Professor of Neuroscience, Harvard Medical School)

“After decades of trying to prove [the chemical-imbalance theory] researchers have still come up empty-handed.” (Marcia Angell, former editor,
The New England Journal of Medicine
)

“Despite pseudoscientific terms like ‘chemical imbalance,' nobody really knows what causes mental illness. There's no blood test or brain scan for major depression.” (Dr. Darshak Sanghavi, clinical fellow, Harvard Medical School)

“We do not know the etiology of really any of the mental disorders at the present time.” (previous Director of Research, American Psychiatric Association)

“Research has yet to identify specific biological causes of any of these [mental] disorders.” (US Congressional Report entitled “The Biology of Mental Disorders, New Developments in Neuroscience”)

“The results of decades of neurotransmitter-depletion studies point to one inescapable conclusion: low levels or serotonin, norepinephrine, or dopamine do not cause depression.” (Professor Irving Kirsch, Harvard Medical School)

“We still don't know the relationship between biology and the mental disorders.” (Carol Bernstein, previous president of the American Psychiatric Association)

“Patients have been diagnosed with chemical imbalances, despite that no test exists to support such a claim, and that there is no real conception of what a correct chemical balance would look like.” (Dr. David Kaiser,
Psychiatric Times
)