Chapter 38: Depression & Inflammation ARE Linked

 Another excellent article explaining why inflammation can cause depression.

Strong link seen between depression, inflammation

Clinical Psychiatry News, June, 2006 by Damian McNamara

SAN JUAN, P.R. -- Growing evidence points to an association between inflammation and depression, according to a presentation at the annual meeting of the American College of Psychiatrists.

For example, depressed patients have elevated inflammatory markers--such as interleukin-6 and C-reactive protein. In fact, the levels of proinflammatory cytokines correlate with the severity of depressive symptoms in studies. In addition, administration of cytokine antagonists can effectively reverse depressive symptoms in patients, Dr. Andrew H. Miller said.

"We really stand at a point that is very exciting in terms of novel therapies and translation of research," Dr. Miller said. "The notion quite simply is that stress or depression affects the HPA [hypothalamic-pituitary-adrenal] axis, [affects] the endocrine system, alters the immune system, and leaves patients open to diseases."

Physicians from many specialties already recognize that inflammation plays a key role in cardiovascular disease, diabetes, metabolic syndrome, and cancer, said Dr. Miller, professor in the department of psychiatry and behavioral sciences at Emory University, Atlanta.

"We did not want to be left out in terms of psychiatry," said Dr. Miller, who also is director of the psychiatric oncology program at the Winship Cancer Institute at Emory.

There are multiple possible mechanisms whereby inflammation could cause depression. Inflammatory cytokines released peripherally might reach the brain through active transport, passage through leaky regions in the blood-brain barrier, or transmission through afferent nerve fibers (vagus nerve), Dr. Miller said. There is a cytokine network in the central nervous system, and glia and microglia are the richest source of cytokines in the brain. Neurons also produce and express cytokines.

"We've learned these cytokines have access to the brain and ... ultimately can change behavior," Dr. Miller said. Inflammatory cytokines cause anhedonia (an inability to experience pleasure), fatigue, cognitive dysfunction, and other flu-like symptoms in sick patients. In addition, researchers induced behavioral changes that resemble major depression in human and animal studies with administration of proinflammatory cytokines.

Some therapeutic cytokines cause depression. For example, interferon-[alpha] (IFN-[alpha]) is used to treat viral infections and cancer because it is a potent inducer of the inflammatory cytokine network, especially interleukin-6, Dr. Miller said. "Oncologists told us early on this drug causes a lot of depression."

A total of 60% of patients treated with IFN-[alpha] reported depressed mood in one study (Neuropsychopharmacology 2002;26:643-52). Dr. Miller and his associates also found a 45% incidence of major depression among patients with malignant melanoma treated with IFN-[alpha] (N. Engl. J. Med. 2001;344:961-6).

The good news is that paroxetine (Paxil) aggressively blocked development of depression. "Just 11% developed depression, so there was a fourfold reduction with this pretreatment.

"There is a caveat. If you give a drug that causes release of dopamine--for example, paroxetine--that dopamine becomes oxidized and in the long term can damage basal ganglia," Dr. Miller said in response to a question from a person attending the meeting. "So we're using dopamine antagonists to block this until we get more information about what we are doing to patients."

Physician reaction to his study varied, Dr. Miller said. "The people who got on us the most for that study with paroxetine were the ones who were treating hepatitis C. They said we'd expose a lot of people to antidepressants who don't really need them." However, "with melanoma, many patients will not go back on interferon therapy, and giving antidepressant prophylaxis might help."

In another study, patients with psoriasis treated with the cytokine antagonist etanercept experienced reversal of their depressive symptoms (Lancet 2006;367:29-35). Improvement in depression was independent of the drug's effect on disease progress.

The wider picture may be a link between stress, depression, and illness, Dr. Miller said. In one study in review, patients with major depressive disorder exhibited an exaggerated inflammatory response to stress.

"There is an interesting possible link between depression and a wide variety of medical disorders where inflammation plays a role," Dr. Miller said. It "may explain high comorbidity of some medical conditions with depression.

"Psychiatry is now catching up to other medical specialties in recognizing the adverse effects of inflammation," Dr. Miller added. "Psychiatrists need to keep an eye on this. The idea that the immune system might affect the brain and vice versa presents a lot of novel targets for treating psychiatric disorders."

BY DAMIAN MCNAMARA

Miami Bureau

COPYRIGHT 2006 International Medical News Group

COPYRIGHT 2008 Gale, Cengage Learning

My Summary of the Article:  Strong link seen between depression, inflammation

Clinical Psychiatry News, June, 2006 by Damian McNamara

1.  Patients with depression have elevated inflammatory markers in their blood such as interleukin-6 and C-reactive protein.  

 2.  The levels of elevated inflammatory markers in the blood of depressed patients, called proinflammatory cytokines, correlate with the severity of depressive symptoms. 

 3.  Administration of cytokine antagonist drugs can effectively reverse depressive symptoms in patients.
 4.  Stress or depression affects the HPA [hypothalamic-pituitary-adrenal] axis, affects the endocrine system, alters the immune system, and leaves people open to diseases.

 5.  Inflammatory cytokines may reach the brain by transport through the blood, giving them passage through leaky regions in the blood-brain barrier, or transmission through nerve fibers to the central nervous system.

 6.  Inflammatory cytokines in the brain cause the inability to experience pleasure (anhedonia), fatigue, cognitive dysfunction, and flu-like symptoms in sick patients.

 7.  When researchers administered proinflammatory cytokine drugs in human and animal studies it induced behavioral changes that resembled major depression.

 8.  Interferon is a drug called a therapeutic cytokine used to treat viral infections and cancer.  It induces the inflammatory cytokine network, especially interleukin-6, and causes depression in patients taking the drug.

 9.  Dr. Andrew H. Miller and his associates found a 45% incidence of major depression among patients with malignant melanoma treated with IFN-[alpha], another therapeutic cytokine.

10.  Patients taking Paxil while using a therapeutic cytokine were relieved of depression symptoms.  This may help patients stay on a therapeutic cytokine drug that is causing depression.

11.  Patients with psoriasis were treated with the cytokine antagonist drug etanercept (Enbral). They experienced reversal of their depressive symptoms even if the drug wasn't effective on the psoriasis.
12.  Patients with major depressive disorder showed an exaggerated inflammatory response to stress.
13.  There is a possible link between depression and a wide variety of medical disorders where inflammation plays a role.
14.  Psychiatry is now catching up to other medical specialties in recognizing the adverse effects of inflammation.
15.  The immune system affecting the brain, and the brain affecting the immune system presents a lot of new ways to treat psychiatric disorders.

Cytokines were talked about so much in the above article, I wanted to learn more about them.  The following article is from BioPortal / Cytokines. 

  What are Cytokines? 

Cytokines, also known as immune factors, are protein produced naturally by the cells and organs of the human immune system. They act on other immune system cells modulating the body's response to disease and infection. Cytokines can also regulate the growth of new blood cells in the bone marrow.

Cytokines play a crucial role in the immune system response to all kinds of disease. They interact with organs and cells, alone and in combination with each other. The diverse role that cytokines serve in the immune system make them an ideal target for intervening or bolstering immune responses. Using recombinant DNA technology cytokines can be created in a laboratory. They have many treatment applications including cancer, multiple sclerosis, anaemia, and rheumatoid arthritis.

  Types of Cytokines

There are several types of cytokines with different varieties within each type. The following are the cytokines naturally produced by the body and the immune cells that produce them: 

Interferons (IFNs) have three main varieties. Produced by a number of immune system cells. Eg: White blood cells.  

Interleukins (ILs) have more than ten varieties. Produced by the white blood cells (leukocytes). 

Tumour Necrosis Factors (TNFs) have two main varieties. Produced by a number of immune system cells. Eg: T-Cells, white blood cells.  

Colony Stimulating Factors (CSFs) have many varieties and names. Produced by T-Cells and macrophages. 

Erythropoietin (Epoetin/EPO) has several varieties. Mainly produced by the kidney (10-15 percent originating in the liver). 

Thymopoietin has three main varieties. Produced by the thymus.

The Science - How do Cytokines Work?

Cytokines work in ways very similar to hormones. They are released by immune cells into the circulation or locally in a tissue. Cytokines interact with receptors on target immune system cells. This interaction triggers a cascade of biochemical reactions such as the release of other cytokines, cell division, or cell differentiation, that leads to a given event. Each type and variety of cytokine has distinct effects on specific targets: 

Interleukin 2 (IL-2) - This is the only variety of IL that is currently used therapeutically. It Interacts with T-cells that have been activated by an infection and triggers T-cell division increasing the number in circulation. IL-2 also stimulates the division of B-Cells and works in the bone marrow to promote the differentiation of stem cells into immune cells.

Interferon - Has numerous therapeutic applications including:

  Stimulating activity in other immune system cells,

  Inhibiting growth in some types of cancer cells,

  Increasing immune cell capacity to bind foreign particles,

  Modulating the production of antibodies, and 

  Inhibiting viral protein synthesis, through a system of interactions.

Erythropoietin - Stimulates stem cells in the bone marrow to differentiate into mature red blood cells. 

Colony Simulating Factors - Stimulate stem cells in the bone marrow to differentiate into immune cells called "neutrophils." Neutrophils are an important component of the body's inflammatory response to infection. CSF's can also stimulate activity in other immune system cells.

Cytokines can also work in combination to produce different effects in the body. Some therapies combine more than one cytokine to achieve their results.

  Biotechnology and Cytokines

Therapeutic cytokines are produced through recombinant DNA techniques. The human gene that codes for the desired cytokine is inserted into a host cell, such as the bacteria species E-coli, yeast, or the cells of mammals or insects. The cells then act as factories, producing the desired human protein.

Proteins produced by non-human cells (like those produced through yeast or E-coli) will vary slightly from the those produced naturally in the body. Small variations in structure can cause therapeutic cytokines to behave differently from their natural counterparts. Therefore, recombinant cytokines are studied further to determine if they will behave differently due to the variations.

I want to ask my psychiatrist if anti-inflammatory drugs may help my depression symptoms, or if there are other cytokine antagonist drugs that would be more effective.  This short abstract of an article talks about cytokine-based therapies.  An Overview of Cytokines and Cytokine Antagonists as Therapeutic Agents

Donnelly, R. P., Young, H. A. and Rosenberg, A. S. (2009), An Overview of Cytokines and Cytokine Antagonists as Therapeutic Agents. Annals of the New York Academy of Sciences, 1182: 1–13. doi: 10.1111/j.1749-6632.2009.05382.x

Keywords:

• cytokines;
• inflammation;
• interferons;
• interleukins;
• receptors

Cytokine-based therapies have the potential to provide novel treatments for cancer, autoimmune diseases, and many types of infectious disease. However, to date, the full clinical potential of cytokines as drugs has been limited by a number of factors. To discuss these limitations and explore ways to overcome them, the FDA partnered with the New York Academy of Sciences in March 2009 to host a two-day forum to discuss more effective ways to harness the clinical potential of cytokines and cytokine antagonists as therapeutic agents. The first day was focused primarily on the use of recombinant cytokines as therapeutic agents for treatment of human diseases. The second day focused largely on the use of cytokine antagonists as therapeutic agents for treatment of human diseases. This issue of the Annals includes more than a dozen papers that summarize much of the information that was presented during this very informative two-day conference.

I hope research in the link between inflammation and depression will lead to new, effective treatment options for depression!