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Depressive drugs causing suicides

Inflammation Linked to Mild Depression in Caregivers

Oct 19 2003

Even mild depression can substantially unbalance the human immune system and that change can be pivotal in setting older Americans up for developing serious age-related diseases.

These findings, published in the Archives of General Psychiatry, are the latest from a quarter-century-long body of research aimed at unraveling the link between increased stress and weakened immunity.

“A key conclusion from this study is that a person’s mental health really does matter,” explained Janice Kiecolt-Glaser, professor of psychiatry and psychology at Ohio State University. “From this work, we get a clear picture of how the body responds differently depending on whether a person is even mildly depressed or not.”

The researchers looked at a group of 47 people who were either current or former caregivers at the time of the study. In the case of each of these people, their spouse either had Alzheimer’s disease or some other form of progressive dementia. This group was matched with a somewhat larger control group of people who were not caregivers.

Blood samples were drawn from each person in the study just before they received their annual influenza vaccination and then again approximately two weeks after the injection. In addition to analyzing the blood samples, each participant completed a survey form intended to gauge their level of depression.

Kiecolt-Glaser and colleague Ronald Glaser, a professor of molecular virology, immunology and genetics, had predicted there would be a link between a person’s depressive status and the levels of a specific immune system component – Interleukin-6 (IL-6) – found in the blood.

The survey showed that present and former caregivers had modest levels of depression, Kiecolt-Glaser said. “These people are not clinically depressed. On the other hand, clearly things are not right with their world,” she said.

“Caregivers felt ‘blue’ and probably were suffering from some kind of sleep disturbance. They also reported having less energy than normal. All these symptoms had been there for some time.”

When the blood samples were analyzed, the depressed caregivers’ IL-6 levels were 30 percent higher two weeks after the influenza vaccination while the non-depressed participants’ IL-6 levels were essentially unchanged, Glaser said.

“The absence of an overall increase in IL-6 from baseline to after vaccination in the control group is consistent with what we would have expected,” Glaser said.

“Generally speaking, there is very little inflammatory response – including the production of IL-6 – in people who have already been exposed to the virus for which they are being vaccinated.

“Because these were older people, most of them already had been exposed to influenza virus. Therefore, the significant increase in IL-6 that we found in the caregivers after vaccination is unexpected and important, primarily because it suggests that even low levels of depression are associated with an increased IL-6 response to an antigen,” he said.

Sustained higher-than-normal levels of IL-6 have been linked to long-term inflammation which, in turn, is implicated in a host of age-related illnesses. These include cardiovascular disease, osteoporosis, arthritis, type-2 diabetes, certain lymphoproliferative diseases and cancers, Alzheimer’s disease and periodontal disease, the researchers said.

“Chronic inflammation has been suggested as one key biological mechanism that may fuel declines in physical function leading to frailty, disability and, ultimately, death,” they wrote.

“The immune system has to be balanced,” Glaser said. “If it is accelerated, that is bad and if it is weakened, that is also bad. The body is as amazingly fine-tuned as is a good watch.”

The researchers used influenza vaccinations in this study as a surrogate for other pathogens and the public shouldn’t interpret these results as reasons to avoid the vaccinations, Kiecolt-Glaser said.

“These findings provide a good reason why people should definitely get a flu shot no matter what,” she said. “Earlier studies showed that if you are depressed, then you are more likely to get sick. This research shows that there are long-term changes taking place in your immune system so we should be more cautious as we age.”

Along with Kiecolt-Glaser and Glaser, other researchers on the project included William Malarkey, professor of internal medicine; John Sheridan, professor of oral biology; and Theodore Robles, a doctoral student in psychology.

This research was supported by the National Institutes of Health, the National Institute of Health Clinical Research Center, Ohio State University’s Comprehensive Cancer Center and the National Science Foundation.

Journal Report
05/03/2005

Depression may be linked to inflammatory signals of heart disease

DALLAS, May 3 – Men who are depressed have higher levels of inflammatory markers associated with coronary heart disease than men who are not, according to a study reported in Circulation: Journal of the American Heart Association.

Some observational studies have linked depression with heart disease, which includes angina, non-fatal and fatal heart attacks, but the mechanism underlying the association is unknown.

Lead author Jean P. Empana, M.D., M.P.H., D.H., in the epidemiology department at Paul Brousse Hospital in Villejuif, France, said, “This is the first study investigating the respective contributions to coronary heart disease (CHD) of depression and inflammatory markers. Previous reports investigating the association between depression and individual inflammatory markers have produced conflicting results. In this study, we investigated a wide range of inflammatory markers.”

Researchers used data from the PRIME Study, a prospective study evaluating coronary heart disease factors in healthy middle-aged men inIreland and France. They reviewed baseline blood samples of 304 men who developed heart disease within five years and 585 men who did not (controls). The men were healthy at baseline and were an average age of 55. Researchers noted levels of four inflammatory markers in their blood: C-reactive protein (CRP); fibrinogen; interleukin-6 (IL6); and adhesion cellular molecule -1 (ICAM-1).

The participants also answered questions evaluating negative perceptions of life, including statements such as, “I feel helpless.” The presence of depressive mood was defined as a depression score in the fourth quartile or higher at the baseline.

As expected, the average level of major cardiovascular risk factors and inflammatory markers were “significantly higher” in the men who developed heart disease than the controls. In addition, depressive mood was present in 28.3 percent of the cases versus 19.7 percent in the controls. Researchers noted a low but statistically significant correlation between depression score and IL6, CRP and ICAM-1, but not fibrinogen.

The average CRP level was 46 percent higher in men with depressive mood than in those without. Likewise, the average IL6 levels were 16 percent and ICAM-1 levels were 10 percent higher in depressed men.

Empana said this is the first study to find an association with ICAM-1 and depressive mood in a healthy population, suggesting that depressive mood is associated with endothelial dysfunction in a healthy (free of prior CHD) population.

This is of particular importance since endothelial dysfunction is thought to be one major step in the initiation of atherosclerosis. Endothelial dysfunction refers to change in the properties of the endothelium (part of the inner lining of the blood vessel) leading in particular to a procoagulant (instead of anticoagulant) activity and to the liberation in the blood flow of pro-inflammatory molecules. Endothelial dysfunction can be estimated indirectly by measuring circulating ICAM-1 levels, and more directly by evaluating the ability of the blood vessels to dilate in response to an increase in blood pressure. The causes of endothelial dysfunction are multiple and include endothelial injuries by smoking, hypertension, diabetes, or infectious agents.

One surprise of the study was that depressive mood was more frequent in French men than Irish men even though the incidence of heart disease is higher in Ireland. When analyzed by country, French men with the highest (4th quartile or higher) depression scores were 44 percent more likely to develop CHD than other French men with lower scores. Those in Belfast, Ireland with the highest depression scores were 18 percent more likely to develop CHD than other Irish men. However, researchers noted that the sample size was too small to reliably detect whether these figures were statistically different.

After adjusting for other factors, men with depressive mood had about a 50 percent increase in the odds ratio of developing CHD within five years.

“There is an association between depression and CHD, but inflammation doesn’t seem to bridge the two as definitively as we may have expected,” Empana said.

The cause of the association between depressive disorders and inflammatory markers is largely unknown. For instance, depressive disorders can elevate concentrations of IL6 through hormones that can stimulate its release from adipose tissue. Alternatively, Interleukins might contribute to depressive disorders by stimulating hormones from central nervous structures that might be implicated in depression.

Co-authors are D. Henry Sykes, M.D.; Gerald Luc, M.D.; Irene Juhan-Vague, M.D., Ph.D.; Dominique Arveiler, M.D.; Jean Ferrieres, M.D., M.Sc.; Philippe Amouyel, M.D., Ph.D.; Annie Bingham, M.A.; Michele Montaye, M.D.; Jean Bernard Ruidavets, M.D.; Bernadette Haas, M.D.; Alun Evans, M.D.; Xavier Jouven, M.D., Ph.D.; and Pierre Ducimetiere, Ph.D.

Statements and conclusions of study authors that are published in the American Heart Association scientific journals are solely those of the study authors and do not necessarily reflect association policy or position. The American Heart Association makes no representation or warranty as to their accuracy or reliability.

Activation of the inflammatory response system:
A new look at the etiopathogenesis of major depression

by
van West D, Maes M.
Clinical Research Center for Mental Health (CRC-MH),
Antwerp, Belgium.
Neuroendocrinol Lett 1999;20(1-2):11-17


ABSTRACT
Major depression is accompanied by various direct and indirect indicators of a moderate activation of the inflammatory response system (IRS). Increased production of proinflammatory cytokines, such as interleukin-1 (IL-1), IL-6 and interferon (IFNgamma), may play a crucial role in the immune and acute phase response in depression. Lower serum zinc and changes in the erythron are indirect indicators of IRS activation in depression. The reciprocal relationships between IRS activation and hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity, alterations in HP thyroid (HPT)-axis function and the availability of tryptophan to the brain led us to hypothesize that these neuroendocrine changes in depression are indicators of IRS activation and that a combined dysregulation of the IRS, the turnover of serotonin (5-HT) and the HPA-axis is an integral component of depression. The IRS activation model of depression provides an explanation for the psycho-social (external stress) as well as organic (internal stress) etiology of major depression. Antidepressive treatments with various antidepressive agents, including SSRIs, tricyclic and heterocyclic antidepressants, have in vivo and in vitro negative immunoregulatory effects, suggesting that their antidepressant efficacy may be attributed, in part, to their immune effects.

A mind under seige

Phyllida Brown

16 June 2001

Could an overactive immune system be the trigger for some people's life-threatening depression? If so, we might just be on the way to a cure, says Phyllida Brown

A FIFTY-year-old woman living in Japan is infected with a potentially fatal virus, hepatitis C. Doctors bombard her body with a powerful drug to boost her immune response. The drug beats back the virus, but has horrific side effects. She becomes inexplicably moody, rapidly sinking into a depression so savage that the woman douses herself in oil and sets herself alight.

Fortunately, her suicide attempt fails and she recovers fully. But the woman's terrifying experience is not unique. Over the past few years, there's been a steady trickle of bizarre reports of people becoming suicidal after taking alpha interferon and interleukin-2, two popular immune-boosting drugs. Hundreds of others have become seriously depressed.

But here's the rub. Patients and doctors are not rounding on the makers of these drugs. Instead, everyone tends to think the psychological side effects are a price worth paying for drugs that can combat cancer, hepatitis and other life-threatening infections. Indeed even the terrible suicidal urges themselves are now turning out to have a silver lining. They are awakening interest in one of the most promising new avenues in depression research since Prozac left the labs.

Most of us associate depression with being run down and having poor immunity to infections. The startling side effects of the immune-boosting drugs turn that notion on its head. They suggest that some people who are depressed may actually be suffering from an over-heated immune system, and that damping down inflammation could offer a brand new way to treat routine clinical depression--while making billions for the pharmaceuticals industry into the bargain. It's a theory that recasts depression--one of the great plagues of our time--as a chronic inflammatory disease like rheumatoid arthritis.

In an inflammatory attack, immune cells rev each other up by pumping out substances known as inflammatory cytokines. Drugs like interferon are simply artificial versions of these substances. That's why they boost immunity so well--and why, according to the new "immune theory" of depression, they also induce such dark moods in some patients. If the body's own supplies of cytokines stay too high for too long, maybe they too become toxic to mood and trigger depression.

The case is far from proven but evidence is mounting. "At the beginning I was very reluctant to get into this question because depression is such a can of worms," says neurobiologist Robert Dantzer of France's national medical research agency INSERM at the University of Bordeaux 2. "But when we saw the way these drugs affected patients, it made me sure that it was worth it."

The first inkling of a connection between mood and inflammation came around 1990. Michael Maes, a psychiatrist now at the University of Maastricht in the Netherlands, was investigating claims that depressed people are unusually vulnerable to infections and cancer, a theory that could be explained by a lacklustre immune system. But when Maes looked at immune cells from depressed people such as natural-killer cells, monocytes and macrophages, he found instead that the cells were more active than normal, and spewed out more inflammatory cytokines. "We had expected to find just the opposite," admits Maes.

The surprise results did fit in with some other vague hints that depression and inflammation are entwined. Depressed people tend to have slightly raised temperatures, which suggests that they are suffering from some chronic inflammation. They are also three times as likely to die of heart disease--often caused by arteriosclerosis, itself an inflammatory condition of the linings of arteries.

Still, Maes's results languished in obscurity, being contradicted by other studies almost as often as they were confirmed--until, that is, Dantzer decided to take a second look at some old rat studies he had done in the late 1980s.

When you inject rats with parts of bacterial cell walls called lipopolysaccharides, their temperatures rise, their sleep patterns change, they become less sociable and stop eating. And it isn't the bits of bacteria that trigger this so-called "sickness behaviour", but the immune response to those bits. An injection of the cytokine interleukin-1 (IL-1), which marauding macrophages produce when they meet bacteria, makes the animals behave in exactly the same way. In other words, the rat studies showed that inflammatory cytokines directly influence behaviour.

"For the first time it became clear," says Dantzer. "Sickness behaviour is like fear--it is a state that makes the animal reorganise its priorities." Just as the sight of a predator makes animals release hormones that drive the "flight-or-fight" response, infection triggers the release of cytokines, which make the animal rest and conserve its resources to fight the infection. And of course, sickness behaviour is not exclusive to rats--think of the last time you got flu.

At first, researchers were puzzled at how the cytokines could affect behaviour. How could great big molecules like IL-1 get across the barrier that protects the brain from all the potentially dangerous chemicals sloshing around in the blood?

It turned out they didn't need to. The exact mechanism is still a mystery, but it seems that another set of far smaller signalling molecules, such as nitric oxide and prostaglandins, tell the brain that a part of the body is inflamed. Once in the inner sanctum, these molecules instruct the brain's glial cells to make their own supplies of inflammatory cytokines. These cytokines act on receptors in areas of the brain such as the hippocampus, the cerebellum, and--crucially--the hypothalamus, which is involved in regulating both mood and temperature. "The brain builds a representation of the disease in the body," says Dantzer.

By the mid-1990s, Dantzer was wondering whether sickness behaviour wasn't in some way comparable with depression, and, if so, whether antidepressants could prevent sickness behaviour. After all, some of the symptoms are similar to depression-- disturbed sleep, for instance, or a lack of interest in food or sex.

Dantzer's results were dramatic. He injected rats repeatedly with the antidepressant tianeptine, before treating them with pieces of bacterial wall or IL-1 (Psychopharmacology, vol 24, p 50). The antidepressant sharply reduced the sickness behaviour created by the treatments. What's more, the rats' brains made much smaller amounts of their own IL-1, and much larger amounts of another cytokine, IL-10, which soothes inflammation. "It looks like some antidepressant drugs are working like some anti-inflammatory agents," concludes Dantzer.

The next piece in the puzzle was to take a closer look at those people who get depressed while taking immune-boosting drugs. From about 1996 onwards, study after study showed that about one-third of patients taking cytokine drugs get depressed, sometimes seriously. The trouble is that they also have life-threatening illnesses such as cancer or hepatitis so it's hardly surprising they should feel despair.

To get around that problem, Dantzer's PhD student Lucile Capuron assessed the psychological state of patients with advanced skin or kidney cancers before and during treatment with interleukin-2 (IL-2) or alpha interferon. The results, which appeared last year in the Journal of Clinical Oncology, left Dantzer in no doubt.

Both drugs appeared to induce depression, but there were also some clear differences. The patients on alpha interferon developed symptoms after a few weeks, while people on IL-2 took only a few days. More subtly, the patients taking alpha interferon tended to have slower reaction times, while patients on IL-2 were more likely to have memory problems. To Danzter, such differences are a telling sign that the depression is a specific side effect of the drugs, rather than simply general despair at being ill.

Then, just this spring, Andrew Miller at Emory University in Atlanta announced in The New England Journal of Medicine that a Prozac-like drug called paroxetine actually protects people who take alpha interferon for skin cancer from depression brought on by the immune-boosting drug.

"It's exciting, because in psychiatry we don't do a whole lot of prevention," says Miller. Miller even suspects that antidepressants could help a wider group of hospital patients who may be exposed to sudden surges in their own levels of inflammatory cytokines. For example, he says, inflammatory cytokines soar in people who have major heart surgery as their immune systems respond to their wounds. Up to 30 per cent get depressed soon after the operation. Treating them with antidepressants before surgery could spare them this extra mental suffering, says Miller.

Still, the bigger question remains: does inflammation also play a role in depression that is triggered by more familiar messy circumstances like bereavement, divorce, trauma and persistent stress?

To settle that question, neurobiologists will have to learn more about how inflammatory cytokines interact with mood-altering neurotransmitters and hormones. So far, there are tantalising hints that the cytokines could alter those chemicals enough to help tip vulnerable minds over the edge (see "How can the body's immune system cause depression?" p 36). But the puzzle is complex and incomplete.

Another question is whether the link with inflammation is evidence of something more disturbing--namely, that clinical depression is really caused by some sort of mysterious infectious agent. To be fair, viruses can cause inflammation, and a few years ago German researchers thought they had found one that might trigger depression--a Borna virus that normally infects the nervous systems of horses and sheep (New Scientist, 27 July, 1996, p 14). But the excitement evaporated as others failed to repeat the German results, and today there is no evidence that you can "catch" depression.

Of course for people with depression, the most pressing issue is better treatments. One option is to try tackling depression with anti-inflammatory drugs. There is no evidence that familiar anti-inflammatories such as ibuprofen would help. But St John's Wort, which many people take to combat symptoms of depression, is also an anti- inflammatory. And over in Bordeaux, Dantzer says there have been rumours that certain drugs that block inflammatory cytokines significantly lift people's mood. For example, an antibody called infliximab, designed to ease joint pain in patients with rheumatoid arthritis, is rumoured to induce a feeling of well-being even before the inflammation has begun to subside.

At least one rheumatology expert emphatically endorses that claim. "I have been consistently struck by the comments of patients on an enhanced sense of well-being ever since we treated the first patients," says Ravinder Maini, at the Kennedy Institute of Rheumatology in London. Anecdotes aside, at least one rheumatoid arthritis trial found patients scored higher on "vitality" and "social functioning" after taking this type of drug (The New England Journal of Medicine, vol 343, p 1594).

Drugs companies are understandably keen to find out whether these "anti-cytokine" drugs can help depressed patients too. One in five of us will get depressed at some point in our lives and, since older people are more vulnerable, the figures are destined to climb as populations age. Yet existing antidepressants are far from perfect and don't work for everyone.

Even if anti-cytokines could help only some of the millions who get depressed every year, that would still be a dramatic health gain and a multibillion-dollar money spinner for the pharmaceuticals industry. And although researchers are keeping quiet about the details, at least two groups are gearing up to start trials within the year. "This will be the proof of the pudding," says Miller. "The need for these trials is tremendous."

A lot of people's health--and a lot of dollars for the drugs companies--are resting on these results.-

The role of corticotropin releasing factor
in depressive illness: a critical review

by
Mitchell AJ Department of Liaison Psychiatry,
Addenbrooke's Hospital,
Cambridge, UK.
Neurosci Biobehav Rev 1998 Sep; 22(5):635-51

Corticotropin-releasing factor (CRF) is the principal neuropeptide involved in regulating the stress response. When centrally administered to animals it produces somatic changes analogous to those seen in both depression and anxiety. In humans, it is capable of reproducing the hormonal changes which are characteristically seen in depressed patients.

We just Hope all the Psychiatrist are reading this! The answer is Not a antidepressant if you want to FIX these patients.

I just wonder the women who have post partum depression they get a antidepressant but is anyone doing anything for the inflammation? These patients end up behind bars as we are blind to their illness. Ikhan

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