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The brain and infections

Drugs used to treat mental disturbances may bring about resistance to viruses, bacteria and tumors

HÉLIO DE ALMEIDAIn experiments on animals some drugs used to treat anxiety in humans have delayed the fighting of infections. Some antidepressants, including fluoxetine, one of the most widely used in the world, showed similar effects, weakening the organism’s defense against viruses and bacteria, while an antipsychotic, haloperidol, used in treating schizophrenia, activated defense cells, even though there was no imminent problem to resolve. Drugs planned to act upon the nervous system also act on the immune system, but this is not a one-way relationship: stimuli of the immune system may also reflect on the nervous system, in a game of reciprocal interference in which one or other assumes command of the organism. The conclusions of these studies, carried out in Brazil and in other countries, cannot yet be applied directly and immediately to human reality, for lack of a more extensive survey that associates drugs used against mental disturbances with possibly a greater incidence of infections, and even cancer. In practical terms, at least for the time being, people who take antidepressants in Brazil (some 17 million people) or tranquilizers (20 million) should not think about changing their treatment.

In May last year, veterinarian Monica Sakai confirmed an additional effect of diazepam, a drug widely used for controlling anxiety. In one of the experiments she did at McGill University in Montreal, in Canada, as part of her PhD at the University of São Paulo (USP), she noticed that diazepam bonded with specific proteins (receptors) in the nucleus of Ehrlich tumor cells; this is an experimental mouse tumor, similar to breast and prostate tumors in humans. This affinity indicated two things: first, that drugs from this group, the benzodiazepines, might favor the development of this type of tumor; the second is that this bond, “although undesirable at first sight, opens up excellent opportunities for looking for drugs that bond with these same receptors, but that fight the tumor”, says the veterinarian from USP João Palermo-Neto, coordinator of the research being carried out in collaboration with Vassilios Papadopoulos, from McGill University. According to Palermo-Neto, these effects on Ehrlich’s tumor were noticed with a drug dose that was equivalent to that used for treating anxiety in humans.

“As a psychiatrist I see no immediate clinical implications”, says Luiz Dratcu, a Brazilian doctor and head specialist at the psychiatric division at Guy’s Hospital, in London, one of the main teaching hospitals in the British public health service. He suggests a lot of caution with extrapolating the results obtained in a laboratory to humans. His argument is that there are no records of any cases of cancer or infection associated with the use of benzodiazepines, which have been prescribed to millions of people around the world for more than 50 years in variable doses and frequently for long periods of time. “Prescribed correctly benzodiazepines and antidepressants are safe drugs”, he says. “If there really was some critical association between these drugs and the development of tumors it would have already emerged.” Psychiatrist Jair Mari, a professor from the Federal University of São Paulo (Unifesp), suggests carrying out extensive epidemiological studies to check if what was seen in mice really happens in humans, too.

Studies that examine the possible impact of drugs against mental disturbances outside the nervous system are still rare, principally in Brazil. The psychoneuroimmunology group from the State University of Londrina (UEL), Paraná, evaluated possible alterations in the immune and hormonal system of 34 healthy people and 40 people suffering from depression who were taking antidepressants and being looked after in the university hospital’s outpatients’ clinic.  One of the conclusions was that “people with severe depression may present alterations in the production of hormones, like cortisol, and in the inflammatory response”, says Edna Reiche, a pharmacist and biochemist and one of the authors of the work that was published in 2002 in the Brazilian Journal of Medical and Biological Research.

It is still not clear if these alterations arise as a result of the use of antidepressants, but the implications of these phenomena may be far-reaching. “Defense cells multiply more intensely and incipient tumor cells, especially in inflamed tissue, may disguise themselves more easily.” According to Edna this intense and at times chronic inflammation may leave the organism more vulnerable to cancer and cardiac and auto-immune diseases of an inflammatory nature, like rheumatoid arthritis, particularly when there is a genetic predisposition and environmental conditions are unfavorable.

It is not only drugs that may weaken resistance to disease. Intense emotional stress may also deregulate immune system responses and contribute to the development of cancer, suggested Edna and the two other co-founders of the psychoneuroimmunology group at UEL, psychiatrist Sandra Vargas Nunes and bio-doctor Helena Morimoto, in Lancet Oncology in 2004. Now a group from University College London has confirmed the direct relationship between psychosocial stress and the increased incidence of cancer and a reduction in survival rates and increase in mortality of people with this disease, after analyzing 414 studies that investigated this interaction. In the work, which was published in Nature Oncology in 2008, the incidence of depression examined in isolation increased by 29% and mortality by 34%. Generally speaking, the effects vary according to the intensity of the stress, the type of cancer and the temperament of each person. Almost two thousand years ago, Claudius Galeno, a doctor from ancient Rome, had already observed that women who are classified as melancholic (today as depressed) are more susceptible to breast tumors than those with an extrovert temperament, then called sanguine.

Anyone who has ever had a severe bout of flu and has felt their body was heavy has witnessed these reciprocal interferences between the nervous, hormonal and immune systems. They may also have experienced temporary emotional depression – in this case the defense system is having an influence over the nervous and hormonal systems. Another example, also remembered by Palermo-Neto, has the opposite effect – the nervous system has an influence on the immune system: a worsening of the infection caused by the herpes virus, when painful sores break out on the lips or genitals after intense emotional crises, like the death of a family member.

One of the causes of this “cross-conversation” is a family of 12 proteins called TLRs (toll-like receptors) that are found on the surface of defense cells and neurons. These proteins are specialists when it comes to recognizing agents that cause illness, like viruses and bacteria, and they can be activated by the invading microorganisms themselves, by medication or by molecules produced by the organism itself. Once activated, TLRs induce the production of molecules known as cytokines, which stimulate the production of antibodies and cells that will fight the viruses and bacteria. Cytokines may also work on the so-called HPA axis: H for hypothalamus, a region in the brain; P for pituitary, a gland located at the base of the brain and also known as the hypophisis; and A for adrenal, a gland located on the kidneys. These proteins, the cytokines, may even eliminate neurons that control the appetite and obesity.

“Some cytokines may lead to the production of hormones, like cortisol, when we have the flu”, says Palermo-Neto, who began studying these connections some ten years ago. There is, however, no single effect. Some of the 30 cytokines produced by the organism may stimulate the nervous and hormonal systems while others inhibit them. The organism wins with this flexibility of the HPA axis, explains the researcher. An infection that activates the HPA axis may become, albeit only briefly, as important as the state of alert unleashed by hormones in danger situations. In practice, any one of the three systems may be activated by the same stimuli. “The cells of the immune system are unable to transmit electrical impulses, like the neurons, but have receptors (surface proteins) for neurotransmitters, like adrenalin and acetylcholine”, he says. “In the same way, neurons have receptors that are activated by cytokines that can change their electrical activity.”

Looked at all together these research projects suggest that illnesses that manifest themselves in the nervous system may originate in the immune system. Severe depression and dementia, for example, may result in imbalances in the hormonal, nervous and immune systems, as Brian Leonard, a researcher from the University of Maastricht, in the Netherlands argues in an article published in 2007 in Neurochemical Research. He bases this affirmation on two pieces of clinical evidence. The first is that chronic inflammation in depressed people may cause the constant loss of neurons throughout their lives. The other is that, even though there is no cause and effect relationship, severe depression is a common symptom among people who develop neurological diseases where there is a loss of neurons, like Alzheimer’s.

“These results suggest that psychiatrists need to pay more attention to the immune system”, comments biologist, Roberto Frussa Filho, a professor at Unifesp who in studies published in the 1990’s showed how haloperidol can slow down the growth of Ehrlich’s tumor, an effect that is opposite to that of the anxiolytics. Palermo-Neto agrees, as does Edna Reiche: “Psychiatrists could work more in multidisciplinary teams”. She believes that doctors, working jointly, could pay more attention not only to emotional disturbances or the treatment of cancer or infections, but also to the well-being, diet and social habits of sick people. That is what the group from Londrina is trying to do; in one of its most recent pieces of work that is now being concluded, the researchers noticed a drop in resistance to infections in children who had suffered from sexual abuse.

The projects
1. Neuroimmunomodulation: the effects of stress and cytokines on bidirectional relationships between the central nervous and immune systems (nº 04/14128-0); Modality Thematic project; Coordinator João Palermo-Neto – USP; Investment R$ 799,044.36 (FAPESP), R$ 50,000.00 (CNPq).
2. An assessment of the family network of children and adolescents who are the victims of domestic sexual violence and the immunological repercussions; Modality Post-graduate research project; Coordinator Sandra Odebrecht Vargas Nunes – UEL; Investment R$ 20,000.00 (Araucaria Foundation).
3. Depression, stress and the immune system; Modality Post-graduate research project; Coordinator Edna Maria Vissoci Reiche – UEL; Investment R$ 5,000.00 (University Hospital and UEL).
4. The pro-inflammatory mechanisms involved in the hypothalamiccontrol of hunger and thermogenesis (nº 04/09789-7); Modality Thematic project; Coordinator Lício Augusto Velloso – Unicamp; Investment R$ 1,094,670.17 (FAPESP)