DANIEL KONDORecent research indicates that a loss of the ability to properly regulate inflammatory processes, brought on by different forms of physical or mental stress, may be one of the factors associated with the occurrence and prolonged symptoms of depression in certain people. There is also preliminary evidence that patients whose blood contains high levels of proteins linked to excessive activation of the immune system are less responsive—when they do respond—to the remedies usually employed against this psychiatric problem. The factors listed as possible causes of a dysregulated immune system come from known traumatic events, such as the death of a close family member or news of a serious illness, or even from habits linked to lifestyle, such as a lack of physical exercise, and obesity.
In a study published in January 2014 in the journal Translational Psychiatry, a team led by a Brazilian biochemist, Livia A. Carvalho, of the University College London (UCL) Department of Epidemiology and Public Health, found that 44 of the 47 genes linked to the anti-inflammatory response had a high activation pattern in the most common type of leukocytes, the white blood cells of the body’s defense, in patients with severe depression who were not taking medications. Two genes associated with glucocorticoid (cortisol) receptors, hormones important in regulating how the immune system functions and its response to stress, showed little activity in people with psychiatric problems. The study compared gene expression in 47 people with depression with 42 healthy individuals. “It is possible that about 30% of cases of depression are linked to processes involving a small, but chronic, inflammation,” says Carvalho. This inflammation can alter the mental state of some more susceptible people, because it triggers, among other changes, changes in the production of neurotransmitters such as serotonin, which is important for a healthy brain.
Another recent article by Carvalho suggests that some people with an excessively responsive inflammatory system benefit little from the use of antidepressants. She and her British colleagues measured cortisol levels and several types of cytokines, small proteins that stimulate or inhibit the body’s inflammatory response, in the blood of 19 patients with depression who benefited little from medical treatment and 21 people without psychiatric problems. The results of the study, which appeared in the Journal of Affective Disorders in late 2012, indicate that people with prolonged depression have higher concentrations of cortisol and cytokines, which stimulate the immune system response. Maybe that’s why, says Carvalho, antidepressants do not alleviate the symptoms of depression in some individuals.
Her group, which is based in London, has been one of the most actively engaged in research on whether inflammation is one of the mechanisms by which psychological stress sets in motion many types of illness, such as depression, cardiovascular problems and processes linked to premature aging. But obviously it is not the only one. Although schizophrenia is the central focus of the work of Daniel Martins de Souza, Department of Biochemistry of the Institute of Biology of the University of Campinas (IB-Unicamp), some of his most recent studies of the proteome (a set of proteins produced by the body) have focused on depression. These studies also suggest that molecules essential to the inflammation process appear to play a role in modulating the efficacy of the drugs used to treat depression.
In an article published in February 2014 in the journal Biological Psychiatry, Souza demonstrated that levels of integrin proteins (essential to the inflammatory response) and ras proteins (produced by a gene associated with certain types of cancer) were higher in patients with depression who had not improved after being treated with antidepressants than in people who had benefited from the use of these drugs. “We are looking for biological markers that may indicate whether or not the patient will respond to treatment,” says Souza, who returned to Brazil in early 2014 after working for two years in the Department of Psychiatry of Ludwig Maximilian University (LMU) and collaborating at the Max Planck Institute of Psychiatry, both located in Munich.
The study analyzed 1,919 protein concentrations in the leukocytes of 20 patients with chronic depression who participated in a study carried out by German institutions. Their molecule levels were measured at the time the patients were admitted to the university hospital and after receiving antidepressants for six weeks. About 30 proteins showed different levels before and after people began to be medicated. Among people who improved their psychiatric condition with medication, the researchers found that the concentration of most proteins decreased after 42 days of treatment. The opposite occurred in individuals who did not respond to treatment with antidepressants. In these patients, the levels of proteins rose. “Our data suggest that antidepressants affect similar biological processes in people who respond and those who do not respond to treatment, but in opposite directions,” says Souza, who is involved in a Young Investigator project funded by FAPESP in the area of neuroproteomics and psychiatric diseases.
In addition to understanding the role of inflammatory processes in triggering depression, studies by Carvalho, Souza and other researchers are also attempting to find molecular markers that indicate whether a depressed person is showing signs of improvement while taking antidepressants. “Ideally we would like to have a blood test to show whether or not a patient will respond to treatment,” says Carvalho, who, since 2008, has been investigating whether inflammatory cytokines, such as interleukin 6, may be such a marker. Studies done at UCL indicate that this substance, triggered by dangerous and stressful situations, is able to alter brain function and is present at high levels in patients with depression. “Some studies even suggest that interleukin-6 may be useful in predicting who will develop symptoms of depression in the future,” she says.
Another molecule that could be useful in predicting the effectiveness of antidepressants is the fibrinogen protein, which is essential for blood clotting. A recent study by Souza, also done while he was still in Germany, detected higher concentrations of this protein in patients who were unresponsive to treatment versus those who did respond. “We found a candidate marker for responsiveness to antidepressants,” says Souza.” Since two thirds of patients are unresponsive to the first attempts at treatment, it would be great to identify those with high levels of fibrinogen and consider alternative therapies.” If a heightened immune response could be a cause of psychiatric problems, fighting inflammation could be a complementary approach to the use of antidepressants. That’s why there are studies that are even testing the use of aspirin or anti-inflammatory diets, like the Mediterranean diet (rich in vegetables, fruits, olive oil and including little red meat) as additional therapies against depression.
Stress, sleep and aging
One advantage of Carvalho’s work in England is having a group of more than 10,000 middle-aged and older adults whose health, including psychiatric, is been monitored by researchers from University College London. This is known as the Whitehall II epidemiological study. This group of men and women, who were between 35 and 55 years of age at the start of the study, provided subgroups of patients that enabled Carvalho and her English colleagues to conduct a series of studies linking stress/inflammation to depression and other diseases.
One such recent work, published in March 2014 in the Proceedings of the National Academy of Sciences (PNAS) shows that healthy men, between the ages of 54 and 76, exposed to prolonged psychological stress—men with few friends, who are pessimistic about life and have an aggressive personality—have smaller telomeres and produce a less functional form of the enzyme that repairs this cellular structure. A reduction in the size of the telomeres, which protect the ends of chromosomes, is interpreted as an indicator of the cellular aging process. Smaller telomeres are a sign of biological degradation. “Psychological stress appears to accelerate the aging process, in part by triggering chronic inflammation,” says Carvalho. Two years ago, in another article in the same journal, Carvalho and her colleagues showed that men who slept five or fewer hours per day had telomeres 6% smaller than those who had seven hours of sleep per day. Both studies found that changes in the telomeres did not occur in women who participated in the studies. This may be due to the fact that women, because of their hormonal differences, respond to stress differently than men.
Much of the research relating depression to different forms of inflammation is done on middle-aged adults or the elderly. Carvalho has recently joined Brazilian university research groups to study this subject in younger populations with a distinctive profile. The team of Dr. Heloisa Bettiol, a pediatrician and professor at the University of São Paulo Ribeirão Preto School of Medicine (FMRP-USP), measured the levels of 42 cytokines linked to inflammation in a group of 1,400 pregnant women who were already being monitored by university researchers. One goal is to see whether mothers with high levels of inflammatory proteins are more likely to suffer from depression during pregnancy or after childbirth. “We are still tabulating the data and we will soon have data on this question,” says Dr. Bettiol.
Professor Kenya Mara Baiocchi de Carvalho, of the University of Brasília (UnB), took full advantage of the regional work of a large national study on the health of adolescents age12-17, the Erica project, to analyze the presence of proteins linked to inflammation in the blood of 1,400 adolescents from the federal capital. “We did not do a test to see if they were depressed, but some questions asked in the study may give us an idea whether the teenagers were subjected to psychological stress,” says Baiocchi. As in the case of Dr. Bettiol, the data are still being analyzed. But, if all goes well, new information on possible links between stress/inflammation and depression in the Brazilian population should be revealed.
Development of a predictive test for successful medication and understanding the molecular basis of schizophrenia through proteomics (nº 13/08711-3); Grant mechanism Young Researcher Program; Principal investigator Daniel Martins de Souza (IB-Unicamp); Investment R$926,108.49 (FAPESP).
CARVALHO, L.A. et al. Inflammatory activation is associated with a reduced glucocorticoid receptor alpha/beta expression ratio in monocytes of inpatients with melancholic major depressive disorder. Translational Psychiatry. 14 jan. 2014.
SOUZA, D.M. et al. Blood mononuclear cell proteome suggests integrin and ras signaling as critical pathways for antidepressant treatment response. Biological Psychiatry. 6 fev. 2014.