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Few medicines in the history of pharmaceuticals have been greeted with as much exultation as a green-and-white pill containing 20 milligrams of fluoxetine hydrochloride - the chemical we know as Prozac and which Elizabeth Wurtzel immortalised in her 1994 book Prozac Nation.
Fast forward to 2012 and the same antidepressants that inspired such enthusiasm have become the new villains of modern psychopharmacology - overhyped, overprescribed chemicals, symptomatic of a pill-happy culture. In The Emperor's New Drugs, the psychologist Irving Kirsch asserted that antidepressants work no better than sugar pills.
In fact, the very theory for how these drugs work has been called into question. For decades, a central theory in psychiatry has been that antidepressants worked by raising serotonin levels in the brain. In depressed brains, the serotonin signal had somehow been "weakened" because of a chemical imbalance in neurotransmitters. Prozac and Paxil were thought to increase serotonin levels, thereby strengthening the signals between nerve cells - as if a megaphone had been inserted in the middle.
But this theory has been widely criticised. Jonathan Rottenberg, writing in Psychology Today, skewered the idea thus: "As a scientific venture, the theory that low serotonin causes depression appears to be on the verge of collapse. "
Is the "serotonin hypothesis" of depression really dead? Have we spent nearly 40 years heading down one path only to find ourselves no closer to answering the question how and why we become depressed? Must we now start from scratch?
Science may be self-correcting, but occasionally it overcorrects - discarding theories that instead need to be rejuvenated. The latest research suggests that serotonin is, in fact, central to the functioning of mood, although its mechanism of action is vastly subtler and more magnificent than we ever imagined. Prozac, Paxil and Zoloft may never turn out to be the "wonder drugs" that were once advertised. But they have drastically improved our understanding of what depression is and how to treat it.
In 2003, in Boston, I began treating a 53-year-old woman with advanced pancreatic cancer. Dorothy had no medical problems until she developed an ominous sign known to every cancer specialist: painless jaundice. Painless jaundice can have many causes, but the one that oncologists know best, and fear most, is pancreatic cancer.
The suddenness of the diagnosis struck her like an intravenous anaesthetic, instantly numbing everything. As we started chemotherapy in the hospital, she spent her mornings in bed sleeping or staring out of the window. Most disturbing, she lapsed into selfneglect. Her previously well-kept hair grew into a matted coil. The clothes remained unchanged. There were even more troubling signs: tiny abrasions in the skin that were continuously picked at, food left untouched by the bedside table and a gradual withdrawal of eye contact. One morning, I walked into what seemed like a daily emotional flare-up : someone had moved a pillow on the bed, Dorothy had been unable to sleep and it was somehow her son's fault.
This grief, of course, was fully provoked by the somberness of her diagnosis - to not grieve would have been bizarre in these circumstances - but she recognised something troubling in her own reaction and begged for help. I contacted a psychiatrist. With her consent, we prescribed Prozac.
In the first weeks, nothing happened. But in a month and a half, there were noticeable changes. Her hair was clean and styled. Her cuts had disappeared, and her skin looked good. Yet she still felt sad beyond measure, she said. The drug certainly affected many of the symptoms of depression, yet had not altered the subjective "feeling" of it. It healed the flaws in her skin but not all the flaws in love.
Any sane reader of this case would argue that a serotonin imbalance was not the initiating cause of Dorothy's depression;it was, quite evidently, the diagnosis of a fatal disease. Should we be searching for a chemical cause and cure? Pause for a moment, though, to consider the physiology of a heart attack. A heart attack can be set off by a variety of causes yet aspirin is an effective treatment. Might major depression be like a heart attack, with a central common pathway and with serotonin as its master regulator?
But such a line of inquiry can't tell us whether the absence of serotonin causes depression. For that, we need to know if depressed men and women have measurably lower levels of serotonin in their brains. In 1975, a study showed that depressed patients typically tended to have lower levels of brain serotonin compared with controls. But in 1987, when researchers in Scandinavia performed a similar experiment with newer tools, serotonin levels were found to be higher in depressed patients. Further experiments only deepened these contradictions.
We may not understand how serotonin-enhancing antidepressants work, but do we know whether they work at all? In the late 1980s, studies examined the effect of Prozac on depressed subjects. Several of these trials showed Prozac reduced the symptoms of depression when compared with a placebo.
These slippery, seemingly contradictory studies converge on a surprisingly consistent picture. First, patients with severe depression tend to respond most meaningfully to antidepressants, while patients with moderate or mild depression do not. Second, in a majority of those who do respond, serotonin very likely plays an important role, because depleting serotonin in depressed patients often causes relapses. And third, the brain-as-soup theory - with the depressed brain simply lacking serotonin - was far too na?ve.
As is often the case in science, a radically different line of inquiry emerged when at Columbia University, another neuroscientist, Renê Hen, began to feed his mice Prozac. Over the next few days, their behaviours changed: anxiety decreased, and the mice became more adventurous. They looked for food in novel environments. And newborn neurons appeared in the hippocampus. But when Hen selectively blocked the birth of neurons in the hippocampus, the adventurousness and food-exploration instincts vanished. Prozac's positive effects, in other words, depended on the birth of nerve cells in the hippocampi.
PACEMAKER FOR THE BRAIN
Hen's experiments have profound implications for psychiatry and psychology. Antidepressants like Prozac and Zoloft, Hen suggested, may transiently increase serotonin in the brain, but their effect is seen only when new neurons are born. Might depression be precipitated by the death of neurons in certain parts of the brain? In Alzheimer's disease, areas of the brain involved in cognition degenerate, resulting in the characteristic dementia. In Parkinson's disease, nerve cells involved in coordinating movement degenerate, resulting in the characteristic trembling. Might depression also be a degenerative disease - an Alzheimer's of emotion, a dementia of mood?
And how, exactly, might the death of neurons in the tiny caul of the hippocampus (a part of the brain typically associated with the storage of memory) cause this disorder of mood? And how, then, does the birth of cells heal this feeling? Are new circuits formed that restore vitality?
If an answer to these questions exists, it may emerge from the work of Helen Mayberg, a neuroscientist at Emory University. When Mayberg stimulated the subcallosal cingulate, a minuscule bundle of nerve cells that sit near the hippocampus, with tiny bursts of electricity, she found that about 75 per cent of patients experienced powerful changes in their moods. The stimulator can be implanted in patients and works like a depression pacemaker.
At first glance, Mayberg's studies would appear to bypass the serotonin hypothesis. After all, it was electrical, not chemical, stimulation that altered mood. But researchers found that if they blocked the serotonin signal in the brains of depressed rats, the pacemaker no longer worked.
A remarkable and novel theory for depression emerges from these studies. Perhaps some forms of depression occur when a stimulus - genetics, environment or stress - causes the death of nerve cells in the hippocampus.
There are, undeniably, important gaps in this theory - and by no means can it claim to be universal. But the most profound implications have to do with how to understand the link between the growth of neurons, the changes in mood and the alteration of behavior. Perhaps antidepressants like Prozac and Paxil primarily alter behavioral circuits in the brain and consequently change mood.
In time, the insights generated by these new theories will most likely lead to new antidepressants. These drugs may make Prozac and Paxil obsolete - but any new treatment will owe a deep intellectual debt to our thinking about serotonin in the brain. Our current antidepressants are thus best conceived not as medical breakthroughs but as technological breakthroughs. They are chemical tools that have allowed us early glimpses into our brains and into the biology of one of the most mysterious diseases known to humans.
Mukherjee is the author of Emperor of All Maladies: A Biography of Cancer.
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