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New Scientist vol 182 issue 2445 - 01 May 2004, page 42
The discovery of brain damage in people with depression has thrown long-standing theories about the condition into disarray. But it could lead to more effective treatments, reports Peter Farley
MOST people thought psychiatrist Yvette Sheline was wasting her time. It was the late 1990s, and high-resolution brain scans were becoming more widely available, when she decided to study the brain anatomy of her depressed patients. The mainstream view, however, was that depression was caused by a chemical imbalance in the brain, so at first no one would even fund the project. "It really went against the grain of thinking at that time," says Sheline.
But eventually, she and her colleagues at Washington University in St Louis managed to get a small grant to scan 10 women who had suffered recurrent bouts of major depression and 10 closely matched controls. To everyone's amazement, a brain region buried deep beneath the cerebral hemispheres, the hippocampus, was up to 15 per cent smaller in the women with depression. And the longer each woman had been depressed, the smaller her hippocampus.
The results could not be explained by the leading theory of depression, which holds that the condition is caused by low levels of neurotransmitters called monoamines in the brain. These small molecules - including serotonin - pass signals from one neuron to the next, so their depletion would put brain communication on a go-slow. The theory seemed watertight after the huge success of antidepressant drugs, which are classified according to their effects on neurotransmitters. For example, Prozac is known as an SSRI, or selective serotonin reuptake inhibitor, because it increases serotonin levels. Then there are NARIs, which increase noradrenaline, and NASSAs and SNARIs, which increase both.
The theory had stood for 40 years, and is widely referenced in popular culture. But the anatomical differences seemed to blow it apart. Depression was clearly more than a simple matter of depleted neurotransmitters. And there was the disturbing possibility that depression might cause, or be caused by, permanent brain damage.
Though no one disputes the idea that chemicals like serotonin play a crucial role in regulating mood, the findings began to bring to the fore some nagging doubts about the monoamine theory of depression. "We've been telling depressed patients that they're low on serotonin and that they can be cured by replacing that serotonin," says George Zubenko, an expert on the genetics of depression at the University of Pittsburgh in Pennsylvania. "It's an appealingly simple story, but it's almost certainly wrong."
For example, while it is known that a single dose of an antidepressant drug is enough to boost neurotransmitter levels within hours, there is usually a delay of several weeks before it brings any relief to the patient. And although modern antidepressants might have fewer side effects than older drugs, they are hardly a miracle cure. Only about half of the patients who take them experience a complete remission of their symptoms, and some of this improvement is attributable to a strong placebo effect. Even more worrying, the most basic tenet of the theory has never been proved directly. Apart from a small number of severely depressed people, most patients appear to have normal monoamine levels in their brains.
But Sheline's findings didn't seem to make things any clearer. Her favoured explanation came from a theory formulated by Robert Sapolsky of Stanford University in California and Bruce McEwen of Rockefeller University in New York. Through the 1980s, they had shown that the hippocampus of animals experiencing chronic stress shrinks. For example, subordinate male vervet monkeys that were constantly harassed by dominant troop members died younger than their peers, and had far fewer cells in their hippocampus.
In response to stress, specialised cells in the brain release a cascade of hormone signals that stimulate the adrenal glands to produce cortisol, a powerful steroid. This has survival value when triggered in acute "fight-or-flight" situations by mobilising the body's energy reserves. But according to Sapolsky and McEwen the cumulative effect of cortisol is devastating to the body and brain (see "Body and soul"). It prunes the delicate branching extensions called dendrites through which hippocampal neurons receive inputs from other cells, and it may kill off some cells completely. And because a healthy hippocampus exerts a dampening influence on cortisol secretion, once this structure has been damaged, a crucial shut-off valve is put out of action and a vicious physiological cycle is set into motion.
It was well known that cortisol levels are raised in depressed humans, so Sheline thought it made sense that her depressed patients suffered the same hippocampal shrinkage seen in animals. But how did it explain the symptoms of depression? The most important job of the hippocampus is learning and memory, and although people with depression can develop memory problems, it certainly is not the most obvious symptom. The region also connects with parts of the brain that control mood and emotions, but it seemed hard to believe that damage to the hippocampus alone could cause the diverse collection of symptoms seen.
However, it wasn't long before other imaging and post-mortem studies uncovered anatomical differences in other parts of depressed patients' brains. In the prefrontal cortex, which is thought to play a crucial role in the negative ruminations and other disturbed thought patterns of depression, researchers found abnormally small neurons and fewer of the brain's support cells, called glia. At the same time, the amygdala, a structure that controls the expression of fear and anxiety, appears to be enlarged in many patients. Although it is not clear that stress is responsible for these changes too, they may begin to explain the sorts of symptoms people experience.
But the findings gave little cause for optimism. Depression - the major symptoms of which were still largely described in psychological terms – was suddenly seen to share features with serious neurodegenerative diseases such as Parkinson's and Alzheimer's. Brain damage is infinitely more difficult to treat than a chemical imbalance, and a new theory was needed to account for these complex new findings. What, for example, triggered the stress system to go haywire in the first place? Why did some people react to stress in this way, while others could withstand it without any ill effects?
At Yale University, Ronald Duman and his colleagues began to see ways of adapting the old theories to take account of the new brain findings. After all, treatment with Prozac and other antidepressants is often amazingly successful. Maybe the monoamine theory was not entirely wrong. They noticed that Prozac and some of the other drugs increased levels of a substance called brain-derived neurotrophic factor, or BDNF, in the hippocampus. BDNF was originally identified as a "growth factor" involved in the development of the nervous system, but it is now known to be important for sustaining and protecting neurons in the adult brain. Duman, along with his colleagues George Henninger and Eric Nestler, now at the University of Texas Southwestern Medical Center in Dallas, proposed a "neurotrophic theory" of depression, in which the antidepressant effects of drugs like Prozac could be attributed to the way they keep cells alive in the hippocampus.
Then, three years after Sheline's work, came a remarkable discovery about the brain that cast all these findings in a wholly new light. It had long been thought that new neurons are born only during brain development, and that if neurons die during adulthood they cannot be replaced. But within months of each other, researchers from two different teams - Fred Gage of the Salk Institute in San Diego, California and Elizabeth Gould of Princeton University - showed that the adult hippocampus can, in fact, make new brain cells. The brain damage seen in depression might not just be a result of cells dying, but also a lack of cells being born - a process called neurogenesis. And, on a more practical note, perhaps the condition might be reversible.
Duman seized on neurogenesis as a logical extension of his theory that antidepressants keep hippocampal cells alive by boosting BDNF levels. Working in parallel, he and Gould's colleague Barry Jacobs soon established that Prozac seemed to induce neurogenesis in the hippocampus (New Scientist, 12 February 2000, p 24).
To prove the causal link, Duman joined forces with René Hen of Columbia University in New York, testing the idea in mice. When moved to a new location, mice become too anxious to feed normally. This effect, known as novelty-suppressed feeding, is used as a model of depression and anxiety. When the team gave such mice antidepressant drugs, after a few weeks they became much less anxious and fed normally. However, if they were also exposed to precisely targeted, low-dose X-rays - which suppress neurogenesis in the hippocampus - they remained anxious. Neurogenesis must be the key to antidepressant treatment.
Duman went on to show that all the other classes of antidepressants, as well as electroconvulsive therapy (ECT), stimulate the birth of new hippocampal cells by increasing levels of BDNF. In other studies, Gage and Carl Cotman of the University of California in Irvine, showed that even physical exercise - known to improve depressive symptoms in humans - could induce neurogenesis. Duman's group even found that it took three to four weeks for Prozac to eliminate symptoms of despair in depressed mice - precisely the time it takes the drug to induce neurogenesis.
Although neurogenesis is at the heart of Prozac's action, the drug's effect on serotonin levels is still the vital first step. Raising serotonin ups the levels of a protein known as CREB inside nerve cells, which in turn increases BDNF levels, eventually giving rise to neurogenesis.
Armed with this knowledge, Duman and other scientists realised that there might be many more effective ways to treat depression, by directly influencing the chemical cascades inside the cell rather than by manipulating neurotransmitters in the synapse. These more direct methods should be faster-acting with fewer side effects and, the researchers hope, should bring relief to the millions of patients who do not respond to
existing treatments. "If we can target some of these intracellular sites," Duman says, "I think it has the promise of being much more effective."
In fact, Duman and his colleagues have already shown they can completely reverse the behavioural effects of depression in rats in just three days with a single infusion of BDNF into their brains. Direct injections into the human brain are hardly practical, but there are drugs that can raise CREB and BDNF levels, known as phosphodiesterase inhibitors. One company, Memory Pharmaceuticals in Montvale, New Jersey, is about to start phase I clinical trials of one of these drugs in depressed patients. Originally designed to enhance memory in conditions like Alzheimer's disease, the drugs have already been found to have antidepressant effects in laboratory animals.
But some mysteries remain, particularly about how the condition is triggered in the first place. Dennis Charney, who heads the Mood and Anxiety Disorders Program at the National Institute of Mental Health, Maryland, thinks the key is patients' enlarged amygdalas. According to Charney, the hormone produced by the brain that triggers the release of cortisol from the adrenal glands during stress is also produced by the amygdala, where it acts as a neurotransmitter.
Its work as a neurotransmitter is normally independent of the stress response, but Charney and McEwen speculate that people prone to depression produce too much of it. If they had a genetic predisposition for an enlarged, overactive amygdala this could mimic the effects of being continuously under stress. In turn, this could begin the cycle of damage to the hippocampus and prefrontal cortex (see "The depressed brain"). Charney says that drugs being developed to block the actions of this transmitter have worked very well in animal studies, and he is optimistic that they will be a valuable new treatment for depression.
But there is still a long way to go. Depression is complex, and probably involves many genes acting in concert with environmental triggers. According to psychiatrist Glenda MacQueen of McMaster University in Hamilton, Ontario, there are four main roads into depression: genetic predisposition; neglect or abuse early in life; a "whittling away" of neural structures from chronic stress over a lifetime; or a major traumatic event in adulthood. "For any individual, there's a varying weight and probability from each of those factors," MacQueen says.
So the root cause of depression may be different for different people – and perhaps the best course of treatment will vary from person to person too. "I think that's the holy grail: what set it off in the first place?"
Neurogenesis, lyder tiltalende..
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