Chemicals imbalance

M. Paleologou, R. M. Berry, and B. I. Fleming, "Bipolar Membrane Electro dialysis A New Solution to the Problems of Chemical Imbalance iu Kraft Mills," 78th Finnual Meeting, Technical Section, Canadian Tulp and Taper Association, Preprints A,Jan. 28—29, 1992, pp. KM—KSl. 

And yet I remain convinced that antidepressant drugs are not effective treatments and that the idea of depression as a chemical imbalance in the brain is a myth. When I began to write this book my claim was more modest. I believed that the clinical effectiveness of antidepressants had not been proven for most of the millions of patients to whom they are prescribed, but I also... 

The conventional view of depression is that it is caused by a chemical imbalance in the brain. The basis for this idea was the belief that antidepressant drugs were effective treatments. Our analyses showing that most - if not all - of the effects of these medications are really placebo effects challenges this widespread view of depression. In Chapter 41 examine the chemical-imbalance theory. You may be surprised to leam that it is actually a rather controversial theory and that there is not much scientific evidence to support it. While writing this chapter I came to an even stronger conclusion. It is not just that there is not much supportive evidence rather, there is a ton of data indicating that the chem-... 

Much of what 1 write in this book will seem controversial, but it is all thoroughly grounded on scientific evidence - evidence that I describe in detail in this book. Furthermore, as controversial as my conclusions seem, there has been a growing acceptance of them. NICE has acknowledged the failure of antidepressant treatment to provide clinically meaningful benefits to most depressed patients the UK government has instituted plans for providing alternative treatments and neuroscientists have noted the inability of the chemical-imbalance theory to explain depression.6 We seem to be on the cusp of a revolution in the way we understand and treat depression. 

In the next chapter I examine the data behind the chemical-imbalance theory. Others have argued that these data provide only weak support for this conventional view.381 go a step further. I do not think the data are weak at all. They are in fact rather strong. But rather than supporting the chemical-imbalance theory of depression, they contradict it. It now seems beyond question that the traditional account of depression as a chemical imbalance in the brain is simply wrong. 

Depression, we are told over and over again, is a brain disease, a chemical imbalance that can be adjusted by antidepressant medication. In an informational brochure issued to inform the public about depression, the US National Institute for Mental Health tells people that depressive illnesses are disorders of the brain and adds that important neurotransmitters - chemicals that brain cells use to communicate - appear to be out of balance . This view is so widespread that it was even proffered by the editors of PLoS [Public Library of Science] Medicine in their summary that accompanied our article. Depression, they wrote, is a serious medical illness caused by imbalances in the brain chemicals that regulate mood , and they went on to say that antidepressants are supposed to work by correcting these imbalances. 

The editors wrote their comment on chemical imbalances as if it were an established fact, and this is also how it is presented by drug companies. Actually it is not. Instead, even its proponents have to admit that it is a controversial hypothesis that has not yet been proven.1 Not only is the chemical-imbalance hypothesis unproven, but I will argue that it is about as close as a theory gets in science to being disproven by the evidence. 

To understand the chemical-imbalance theory, it will be helpful to first review some basic aspects of how the brain functions. The human brain contains about ioo billion nerve cells called neurons. Each neuron is like an electrical wire with many branches. When a neuron fires, electrical impulses travel along its length from one end to the other. When an impulse reaches the end of a branch, it may stimulate the next neuron, influencing whether or not it fires. 

After neurotransmitter molecules have influenced the firing of a receiving neuron (more technically called a postsynaptic neuron), some of them are destroyed by enzymes in the synaptic cleft (the synapse), some are reabsorbed by the sending presynaptic neuron in a process that is called reuptake , and the rest remain in the space between the two neurons. The chemical-imbalance hypothesis is that there is not enough serotonin, norepinephrine and/or dopamine in the synapses of the brain. This is more specifically termed the monoamine theory of depression, because both serotonin and norepinephrine belong to the class of neurotransmitters called monoamines. 

Iproniazid and imipramine seemed to work as antidepressants, but how did they achieve their effects It would be another decade before the chemical-imbalance theory was launched. In 1965, Joseph Schildkraut at the National Institute of Mental Health in Washington, DC, published a groundbreaking paper in which he argued that depression was caused by a deficiency of the neurotransmitter norepinephrine in the gaps between neurons in the brain.8 Two years later Alec Coppen, a physician at West Park Hospital in Surrey, published another version of the chemical-imbalance theory. His version differed from Schildkraut s in that it put most of the blame on a different neurotransmitter, emphasizing serotonin rather than norepinephrine as the neurotransmitter that was lacking.9... 

What was the scientific basis for these chemical-imbalance theories As I noted above, norepinephrine and serotonin are now known to be neurotransmitters - chemicals that transmit nerve impulses from one neuron to another. But in the 1950s knowledge of neurotransmission was sketchy at best. The presence of norepinephrine in the nervous system was not demonstrated until 1954, and evidence that dopamine functions as a neurotransmitter was not reported until 1958. As late as i960 the idea that neurotransmission is largely chemical in nature, though advocated by a group of largely British scientists, was not yet widely accepted.10... 

Here then is the logic behind the first version of the chemical-imbalance theory. Iproniazid is a monamine oxidase inhibitor - it inhibits the oxidation of norepinephrine and serotonin in the synapses, thereby leaving more of these neurotransmitters available in the brain. When depressed people take iproniazid, they get better. Therefore insufficient norepinephrine and/or serotonin causes depression.12... 

There was a problem with this first version of the biochemical theory of depression. Iproniazid was not the only drug that had been reported to be effective as an antidepressant. Imipramine, the drug that had been tested by the Swiss psychiatrist Roland Kuhn, seemed to have similar effects. But imipramine is not an MAOI it does not inhibit the destruction of neurotransmitters in the synapse. So if antidepressants worked by inhibiting monoamine oxidase, why was imipramine effective How could its apparent effectiveness be reconciled with the chemical-imbalance theory ... 

Axelrod s discovery provided an answer to the question of why imipramine might alleviate depression, even if it did not inhibit the destruction of neurotransmitters in the brain. With the problem of imipramine solved, the chemical-imbalance theory seemed to work. Two different types of drugs relieve depression, the theory went,... 

But that was only one half of the logic behind the chemical-imbalance theory. The other half came from studies of reserpine, a drug that was extracted from Rauvolfia serpentina or the Indian snakeroot plant, which had historically been used to treat snakebite, hypertension, insomnia and insanity. In studies of animals, reserpine was reported to induce sedation and to decrease brain levels of norepinephrine, serotonin and dopamine. Clinical reports indicated that some people became severely depressed when taking reserpine.14 Putting these two findings together, it seemed likely that reserpine made people depressed because it decreased neurotransmitter levels. 

When the reserpine studies are added to the antidepressant studies, the logic behind the chemical-imbalance theory begins to look compelling. Drugs like reserpine that decrease monoamine neurotransmitters make people depressed. Drugs that increase these neurotransmitters by one means or another relieve their depression. Hence, depression is due to a monoamine deficiency. 

Part of the initial argument for the chemical-imbalance hypothesis was that reserpine supposedly decreases the availability of monoamines and thereby makes people depressed. But does it ... 

The re-examination of the clinical reports showing that most people who were given reserpine did not become depressed was not published until 1971, a few years after the chemical-imbalance theory had been popularized by Schildkraut and Coppen. But a decade before their influential articles were written, there had been a carefully controlled clinical trial on the effects of reserpine on mood.17 Far from confirming the belief that it made people depressed, the study seemed to show the reverse. Rather than making healthy people depressed, reserpine seemed to make depressed people better. As described by Michael Shepherd, the senior author of the study, in 1956 ... 

In other words, the drug that was supposed to induce depression, according to the chemical-imbalance theory, actually relieved it, when it was carefully evaluated as a possible treatment in a placebo-controlled study. 

How is it that the chemical-imbalance theory was proposed and so widely accepted, when the only controlled scientific study that had been done indicated that one could relieve depression, rather than induce it, by giving patients a drug that increases brain levels of monoamines David Healy, in his comprehensive treatise on the history of antidepressants, provides an answer to this question.19 The study was simply ignored, despite having been published in The Lancet, one of the world s most prestigious medical journals. 

When Schildkraut introduced the monoamine theory of depression, he admitted that there was little direct evidence for it. Instead, it was based on the supposed effectiveness of antidepressant medication and the mistaken belief that reserpine makes people depressed. Schildkraut acknowledged that Most of this evidence is indirect, deriving from pharmacological studies with drugs such as reserpine, amphetamine and the monoamine oxidase inhibitor antidepressants which produce affective changes. 21 A half-century has passed since his chemical-imbalance theory of depression was introduced, and the presumed effectiveness of antidepressants remains the primary evidence in its support. But as we have seen, the therapeutic effects of antidepressants are largely due to the placebo effect, and this pretty much knocks the legs out from under the biochemical theory. 

When the chemical-imbalance theory was introduced more than 40 years ago, the main evidence in favour of it was the contention that antidepressants, which were thought to increase the availability of serotonin and/or other neurotransmitters in the brain, seemed to be effective in the treatment of depression. As Alec Coppen wrote in 1967, one of the most cogent reasons for believing that there is a biochemical basis for depression or mania is the astonishing success of physical methods of treatment of these conditions. 26 The situation has not changed very much since then. People still cite the supposed effectiveness of antidepressants as fundamental support for the chemical-imbalance hypothesis. This theory, they say, is supported by the indisputable therapeutic efficacy of these drugs .27... 

Although the therapeutic effectiveness of antidepressants seemed astonishing 40 years ago and still seems indisputable to many people today, it is, in fact, an illusion. As I have shown earlier in this book, the difference between the effects of antidepressants and placebos is clinically insignificant, despite clinical-trial methods that ought to enhance it. But strangely enough, it is not the ineffectiveness of antidepressants that seals the fate of the chemical-imbalance theory. Rather, it is their effectiveness. The problem is that too many different types of antidepressants work too well for the theory to make physiological sense. 

Different types of antidepressants are supposed to affect different neurotransmitters. Some are supposed to affect only serotonin, others are supposed to affect both serotonin and norepinephrine, and still others are supposed to affect norepinephrine and dopamine. But there is a relatively new antidepressant that has a completely different mode of action. It is a most unlikely medication, and the evidence for its effectiveness puts the last nail in the coffin of the chemical-imbalance theory of depression. 

I suppose that some ingenious minds will be able to find a way of accommodating the chemical-balance hypothesis to these data, but I suspect that the accommodation will require convoluted circumventions, like those used by the Flat Earth Society in their efforts to maintain their defunct theory in the face of photographic evidence from space. If depression can be equally affected by drugs that increase serotonin, drugs that decrease it and drugs that do not affect it at all, then the benefits of these drugs cannot be due to their specific chemical activity. And if the therapeutic benefits of antidepressants are not due to their chemical composition, then the widely proffered chemical-imbalance theory of depression is without foundation. It is an accident of history produced serendipitously by the placebo effect. 

The biochemical theory of depression is in a state of crisis. The data just do not fit the theory. The neurotransmitter depletion studies that I described earlier in this chapter show that lowering serotonin or norepinephrine levels does not make most people depressed. When administered as antidepressants, drugs that increase, decrease or have no effect on serotonin all relieve depression to about the same degree. And the effect of anti-depressants, which was the basis for proposing the chemical-imbalance theory in the first place, turns out to be largely a placebo effect. 

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