Posted by jrbecker on November 4, 2003, at 1:56:16
http://www.galter.northwestern.edu:2160/cgi/content/full/302/5646/810
Science. 2003 Oct 31;302(5646):810-3.
Future Brightening for Depression Treatments
Constance Holden
Without fully understanding what causes depression or how the disease takes hold in the brain, researchers are racking up early successes with a wide variety of new treatment strategies
Treatment for depression badly needs a lift. Antidepressants usually help only about 70% of the people who try them, a modest success rate that hasn't changed for decades. The reason: "Virtually all are variations on a theme established 40 years ago," says Dennis Charney, head of the Mood and Anxiety Disorders Research Program at the National Institute of Mental Health (NIMH) in Bethesda, Maryland. The drugs increase the amount of serotonin or norepinephrine, or both, in the brain, usually by preventing the chemicals from being absorbed back into the neurons that released them. The persistence of this theme "is a bit disappointing after 50 years of intense neuroscience research," says Florian Holsboer, director of the Max Planck Institute for Psychiatry in Munich, Germany.But a spate of research findings over the past few years are bringing a new sense of optimism to the field. Although the biology underlying depression is still cryptic (see previous story), the new findings have suggested a variety of strategies to perk up the depressed brain. And the hunt for new drug targets is unveiling depression's commonalities with a host of other diseases and conditions, including Parkinson's, Alzheimer's, Cushing syndrome, pain, and epilepsy. Treatment of the world's most common mental health problem--and one of the major causes of debilitation worldwide--may soon be entering a new era.
A decade ago, the "monoamine" hypothesis still held sway. "We thought depression was caused by too little serotonin," one of several neurotransmitters in the monoamine family, says Eric Nestler of the University of Texas Southwestern Medical Center in Dallas. And the notion was bolstered by the fact that drugs like Prozac, which boosts serotonin levels, were bringing relief to unprecedented numbers of patients. "Now we know that was naïve," says Nestler. Indeed, although abnormally low levels of a serotonin metabolite have been found in the spinal cords of violent-suicide victims, scientists "have not been able to determine that depressed people have a deficiency" in serotonin, says Charles DeBattista, director of the Depression Research Clinic at Stanford University.
Overtaking the monoamine hypothesis in recent years has been the stress hypothesis, which posits that depression is caused when the brain's stress machinery goes into overdrive. The most prominent player in this theory is the hypothalamic-pituitary-adrenal (HPA) axis. The hypothalamus produces a substance, corticotropin- releasing hormone (CRH), which stimulates the pituitary gland, which in turn triggers the release of glucocorticoids, stress hormones such as cortisol, from the adrenal glands atop the kidneys.Abundant animal research shows that stress hormones are bad for neurons. They decrease the amounts of key ingredients in the chemical broth that keeps neurons healthy and sprouting, such as brain-derived neurotrophic factor (BDNF). And long-term stress can reshape the brain. For instance, it shrinks the hippocampus, a subcortical structure involved in memory that is also a key site of antidepressants' actions.
Bolstering the stress hypothesis is research by Charles Nemeroff of Emory University School of Medicine in Atlanta, Georgia, showing that there are critical periods in early childhood during which abuse or other emotional stress can permanently disrupt the HPA axis. Such trauma often leads to "hypersecretion" of CRH, a classic symptom of HPA-axis disruption, and is associated with depression in adulthood.
Animal models, too, show that early stress, such as that induced by maternal deprivation, causes depression-like behavior, such as giving up on swimming in a forced swim test. Such animals also hypersecrete CRH. "Many of the established neurobiological findings in depression may indeed be due to early life stress," when the young nervous system is still tender and impressionable, according to Nemeroff. His research has revealed that among adults who have been sunk in depression for 2 years or longer, 45% experienced abuse, neglect, or parental loss as children. "It just blew our socks off," Nemeroff says.
Depressed animals also have stunted neurogenesis, or birth of new neurons, in the hippocampus (Science, 3 January, p. 32). In the past few years, findings on neural growth and neurogenesis have led some researchers to hope that they have arrived at the Holy Grail of depression. They suspect that at the heart of the disease--and the reason stress is depressing--is suppression of the growth of new neurons in the hippocampus. Scientists led by Ronald Duman of Yale University found that neurogenesis in the adult rat hippocampus escalates in response to all antidepressant treatments, including electroconvulsive therapy (ECT)--one mechanism presumably being through stimulation of BDNF. And this year a team led by René Hen of Columbia University reported that if neurogenesis is blocked in rats, antidepressants don't work (Science, 8 August, pp. 757 and 805).
Duman says the so-called neurotrophic theory ties in nicely both with what is known about the effects of stress on the brain and with findings that the hippocampus and other parts of the brain, especially the prefrontal cortex, are shrunken in chronically depressed patients. And neurogenesis, which takes weeks to create fully functioning neurons, "provides a ready explanation for the perplexing fact that antidepressant treatments typically require weeks to become effective" even though the drugs raise monoamine levels almost immediately, notes Barry Jacobs of Princeton University, one of the originators of the neurogenesis theory.
Just how powerful this theory is depends on whom you talk to. Duman thinks "that's really the hottest thing going right now." Jacobs adds that "the stress hypothesis has been waiting for neurogenesis ... to explain how it works." He notes that the neurotrophic theory encompasses not just the birth of new cells but also the growth of neural projections such as axons and dendrites and enhanced malleability of neural connections called synapses.
But others are more cautious. "As soon as you get out of the hippocampus, everybody starts to fight," says brain imager Helen Mayberg of the University of Toronto, Canada, because the most important brain areas for depression may be elsewhere. Nestler agrees that "many other areas of the brain figure at least as prominently" in depression. And even within the hippocampus things aren't so clear. "You don't see [hippocampal shrinkage] early in depression; ... if it were part of underlying etiology, you'd be seeing it early," says Mayberg. Holsboer is also skeptical. He says that so far scientists have established only correlation--and no cause-and-effect relationship--between neurogenesis in "a remote area of the brain" and antidepressants.
While scientists continue to argue about the architecture of depression, however, enough has been discovered in recent years to give them a number of new levers to manipulate. Some of these strategies tie into the stress hypothesis or lend support for the role of the hippocampus, but others are agnostic with respect to the causes or key pathophysiology of depression.
Ease the pain
The betting, according to Charney, is that the first genuinely new antidepressant will be some compound that blocks the effects of a neuropeptide known as substance P. Discovered in the 1930s, substance P has been implicated in a number of diseases that involve chronic inflammation as well as in pain and anxiety. It is prevalent in brain regions such as the prefrontal cortex that are associated with emotional regulation, and it is released in response to stress. Substance P-containing fibers also innervate the hippocampus. Substance P is most famous for regulating pain signals to the spinal column, but it would fit into a variety of depression scenarios. There is some evidence, for example, that substance P antagonists stimulate neurogenesis in the hippocampus.As is often the case in antidepressant history, Merck, the company exploring substance P, was originally looking into its antagonists for a different purpose--in this case as possible painkillers. That didn't pan out, but Merck researchers decided to see if it had an effect on stress and depression. A clinical trial showed that the company's experimental drug, a substance P antagonist called MK-869, performed comparably to the selective serotonin reuptake inhibitor Paroxetine (Science, 11 September 1998, p. 1640). High hopes that the drug would be the next blockbuster antidepressant were dashed by a "failed" trial--one in which the response to a placebo was so high that it swamped effects from both the experimental drug and the established drug.
Merck is back in the game now, however, with phase III trials on the compound currently under way. Other companies are pursuing substance P antagonists as well. "This is probably the most around-the-corner novel antidepressant," says Husseini Manji, chief of the Laboratory of Molecular Pathophysiology at NIMH.
De-stressing
Compounds based on substance P antagonists may be further along, but many researchers are more excited by the potential for medication directed at the hyperactive HPA axis. Some are focusing on antagonists to CRH, the stress-induced hormone produced by the hypothalamus that eventually leads to production of cortisol and other glucocorticoids; others are seeking to block cortisol itself.CRH antagonists are likely to produce a range of effects. The hormone appears to have many functions in addition to stimulating the pituitary: CRH receptors are found throughout the cortex and in limbic structures such as the amygdala, which processes fear and other emotions. Indeed, animal studies have shown that CRH, when administered directly into the brain, produces not only behaviors analogous to anxiety and depression but also depression's "vegetative" symptoms: disrupted eating, sleeping, and sexual habits. Holsboer calls CRH "the driving force in precipitation of depressive symptoms." He says that anxiety and depression are very closely linked and that CRH is a common factor: "Most people who have depression in later life had a hyperanxious personality when younger."
Among the compounds close to clinical trials is a drug developed at NIMH by stress researcher Philip Gold that inhibits CRH in vitro. The agency is currently doing toxicity studies with the drug, called antalarmin; "if these turn out well, the NIMH will initiate human clinical trials," says Manji. Several companies are also trying to develop CRH antagonists. Neurocrine Biosciences in San Diego, California, began a clinical trial but abandoned it when subjects started manifesting elevated liver enzymes. Now it's starting toxicity testing with a number of other compounds, says Dmitri Grigoriadis, director of CRH development.
But preliminary as the field may be, it's an "area of great excitement," says Charney. He sees CRH antagonists as having potential to treat a broad spectrum of depression and anxiety disorders, including posttraumatic stress disorder. "There will be a lot of disappointed clinical neuropharmacologists like me if these turn out to not be effective," he says.
Related drugs operate at the other end of the HPA axis by blocking receptors for the glucocorticoids (primarily cortisol) produced by the adrenal glands. A group at Stanford University headed by Alan Schatzberg has identified what it believes is a subgroup of depressed patients who would respond to treatment with glucocorticoid receptor antagonists. These are people diagnosed with psychotic depression, in which each episode is characterized by delusions such as that one's insides are rotting. "Research over the last 17 years has revealed that cortisol is extremely elevated in psychotically depressed patients," says DeBattista.The drug they are testing is mifepristone, originally developed as a steroid to block the excess cortisol secreted by patients with Cushing syndrome. (It also blocks progesterone and is better known as RU-486, the abortifacient drug.) Cushing's, says DeBattista, has a psychiatric syndrome that closely parallels psychotic depression. In a preliminary trial with five psychotically depressed patients, four got better on the drug. DeBattista says the results of the first big double-blind trial should be published shortly. Because the drug blocks the receptor, and not the production of cortisol itself, it reduces cortisol only in the bloodstream and doesn't raise risks from cortisol deficiency.
Too much excitement
There's been growing interest in drugs that modulate glutamate, the brain's main excitatory transmitter. Too much glutamate is toxic to neurons, but it's so pervasive that the danger of inducing dangerous side effects once loomed over the prospect of glutamate-based drugs. Now that many types of glutamate receptors have been discovered, there is hope that ways will be found to selectively manipulate this neurotransmitter (Science, 20 June, p. 1866).Of particular interest is the NMDA glutamate receptor. Substances that block it have been found to be powerful antidepressants; the only problem is that some also cause psychotic reactions. Because of that, says Ian Paul of the University of Mississippi Medical Center in Jackson, "drug companies are very, very tentative about trying to explore other types of NMDA receptor antagonists."
Nonetheless, NIMH is pushing ahead. Charney says the agency is doing a study now with memantine, an NMDA receptor antagonist used to treat dementia. Another drug of interest is riluzole, which reduces glutamate release and is used to treat amyotrophic lateral sclerosis (Lou Gehrig's disease). A preliminary trial has shown some effect with severely depressed patients, says Charney.
Another drug candidate augments the activity of the glutamate AMPA receptor. "It's not clear why potentiating AMPA should be an antidepressant," says Paul. Apparently it raises levels of BDNF, and animal studies have shown that the drug works well in a rat model of depression. AMPA potentiators have been used in clinical trials for Alzheimer's disease; NIMH is currently planning to try the drug out on depression.
Growth industry
Much more preliminary are ideas for drugs that directly stimulate nerve growth or neurogenesis. "It's a matter of finding the right molecule," says Charney: one that will, among other things, pass through the blood-brain barrier. "We don't have one right now." The main candidates at present are phosphodiesterase (PDE) inhibitors: drugs to inhibit the breakdown of cyclic AMP, part of a cascade that improves cell survival and plasticity. The cascade is known to be upregulated by antidepressants.A nonspecific PDE inhibitor called rolipram was tested in several large-scale, placebo-controlled clinical studies in the 1980s. But although the drug was effective as an antidepressant, it produced a bad side effect: nausea. Now, Charney says, several companies are tinkering with more selective PDE-4 inhibitors. They "look very good in depression, and perhaps learning and memory," says Charney.
The pleasure principle
Although virtually all drugs directed at monoamines affect serotonin or norepinephrine or both, some researchers are intrigued by another neurotransmitter from this class: dopamine. Most investigators are dubious about its potential, noting that tinkering with the brain's reward system--which communicates by means of dopamine--could be a recipe for a drug of abuse. On the other hand, says Duman, that's what makes it interesting. "One of the key hallmarks of depression is anhedonia," or an inability to experience pleasure. A drug called Merital (nomifensine) that blocks dopamine reuptake was briefly marketed in the 1980s. It was effective, but it was taken off the market because it caused a type of anemia in some patients.NIMH is now exploring another possibility: pramipexole, a dopamine receptor agonist used to treat Parkinson's disease. The drug showed antidepressant activity in rats, and it upregulates chemicals that have neurotrophic effects. "We're encouraged that this will work in some people," says Charney. The NIMH intramural division is running a preliminary clinical trial with the drug.
Rewiring diagrams
Chemicals are not the only way to treat depression. Although many people still associate ECT with One Flew Over the Cuckoo's Nest, it is "the most effective antidepressant modality we have," says Manji. The effects of ECT are so broad that it's not clear what the active ingredients are. In addition to inducing seizures, it jacks up serotonin levels, blocks the effects of stress hormones, and stimulates neurogenesis in the hippocampus, among other things.Now a family of other brain stimulation techniques--with more precise targeting and fewer side effects--may be in the offing. One is transcranial magnetic stimulation (TMS), which uses a magnetic field to induce current in the brain (Science, 18 May 2001, p. 1284). Another is deep brain stimulation, which involves planting electrodes in the brain and has been useful for some Parkinson's patients. A third is vagus nerve stimulation (VNS), originally developed to treat epilepsy.
Harold Sackeim, head of biological psychiatry at Columbia University, thinks the field is blooming. Although in the past ECT has been thought to have general effects all over the brain, Sackeim says the evidence is now "irrefutable" that it has to be directed at specific circuits to be effective. When seizures are induced, they have to take place in the prefrontal lobe. Seizures cause release of inhibitory transmitters, primarily GABA, a phenomenon that fits with the fact that "many of our new anticonvulsants"--such as lamotrigine, which boosts GABA--"are increasingly used in depression," says Sackeim. ECT-related therapies can also be effective--contrary to previous beliefs--without inducing seizures, provided the stimulation is in the right place, says Sackeim. Currently a company called Neuronetics in Malvern, Pennsylvania, is conducting a national trial in hopes of getting government approval of TMS for depression. It will compare TMS with "sham" TMS for 20 minutes a day, 5 days a week, for 6 weeks.
Trials are also in progress with VNS, which has already been approved by the U.S. Food and Drug Administration (FDA) for treatment-resistant epilepsy. A stimulator is implanted in the chest and is connected to electrodes around the left vagus nerve in the neck. The stimulator gives a 30- second jolt every 5 minutes. Although the vagus nerve is traditionally associated with control over the heart and gut, Sackeim points out that it's also intimately hooked up with brain areas that--you guessed it--enhance neurotransmission of serotonin and norepinephrine. Results from clinical trials have not been overwhelming--only 30% of patients responded in the second trial--but Sackeim says improvements seem to grow with time. He's optimistic that "VNS may become the first nonpharmacological therapy for depression to be approved by FDA since ECT."
The first and still an effective treatment for depression, however, is decidedly low-tech. Repeated studies have shown that psychotherapy works as well as medication for mild depression. And in more serious cases, antidepressant drugs work best when they're coupled with psychotherapy. A study about to be published by Emory's Nemeroff shows that even people who were abused as children, and thus presumably have skewed HPA axes, recover best if they are treated with psychotherapy as well as drugs.
Aside from seeing therapists, depressed people will still be popping monoamine-based antidepressants for the immediate future. But Charney promises more treatment options soon. "There has been far more success in treating this illness than understanding it," he says. But thanks to advances in genetics, neurochemistry, and brain imaging, he says, "I view our field as at a threshold for major new discoveries"--discoveries that will set both diagnosis and treatment of mental illness on a firm scientific base.
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