Case 1: Depression and the Immune
Response
A 48 y/o woman who suffers of pulmonary
tuberculosis is receiving antibiotic therapy.
Her physician refers her to the psychiatrist
because loss of interest in activities or pleasure, anorexia, weight loss,
insomnia, fatigue, sense of worthlessness, loss of the ability to concentrate
and thoughts of death for the last two months.
Summary
In
the case shown above, it is clear that the patient presents with depression.
Recently, researchers have shown that there is a definite correlation between
depression and the body’s immune response; the correlation that has been found
deals with the release of cytokines during an immune response. Cytokines are
considered signaling peptides used by a diverse group of cells within the body
to communicate. When the body is immunologically compromised (in this case,
pulmonary tuberculosis), numerous cytokines are released in an attempt to have
the body working together to handle the newly introduced disease.
The
overall effects of cytokines can be copious, but specifically pertaining to
this case, effects include: neuropsychiatric symptoms. This can be seen as the
patient deals with loss of interest, sense of worthlessness, loss of ability to
concentrate and thoughts of death. It has been found that a specific cytokine,
such as INF-alpha, is tied to the effect of neuropsychiatric symptoms.
INF-alpha is responsible for causing fever, fatigue and lack of appetite.
Depression has been linked to this and other pro-inflammatory cytokines. These
pro-inflammatory cytokines are responsible for causing the symptoms associated
with depression in patients who do not have prior mental disorders. After many
studies, focusing on pro-inflammatory cytokines, they have shown to produce
psychiatric mood disruptions in those patients who were once free of any mood
disorders. The presented case shows that the tuberculosis is a full onset on
the lungs making this infection a cytokine-producing organ. These cytokines are
produced in a large amount that they arrive in the vascular region of the
brain. In part the brains astrocytes that make up the blood-brain barrier
intake cytokines as they too have receptors and produce these pro-inflammatory
cytokines, which in turn have negative psycho-neuronal effects on the patients
brain chemistry.
Patients
with autoimmune disorders are at higher risk to potentially develop behavioral
changes, mood swings and loss of interest in activities, which were once
pleasurable. Autoimmune diseases can be quite detrimental in the brain and
central nervous system (CNS) because of the immune response and antibodies
produced. The effects of the response causes further damage to neurons and
other types of brain cells. These autoimmune disorders then have the potential
of affected different features of the brain and CNS such as, areas dealing with
memory, behavior and mood. These disruptions will eventually produce a
decreased synthesis of neurotransmitters that are important in the activity of
many regions of the brain; more specifically, the immune response developed by
these diseases targets degradation in the amino acid, tryptophan. It is
currently known that tryptophan is the precursor to the neurotransmitter,
serotonin. This decrease in neurotransmitters (serotonin) leads to presentation
of behavioral changes, such as depression. Thus, it can be concluded that
because of the increased levels of pro-inflammatory cytokines and the effects
on the synthesis of serotonin, diseases causing a prolonged immune response
(such as tuberculosis) can lead to behavioral changes, such as depression.
Clinical Applications:
1. Probiotics as modulators of cytokine production
Probiotics: microorganisms
that have a favorable influence on physiological and pathological processes of
the host by their effect on the intestinal flora. Probiotics may play a role in
improving human health. The most intriguing aspect of probiotic modulation of
immune response is believe to work through its effects on cytokine production
Studies
have shown that probiotics—which by regulating cytokine levels in the gut, can
influence infection and inflammation throughout the body, and even help balance
brain function and mood.
The
Three Steps to Successful Use of Probiotics in Depression
•
Establish that your patient is suffering from atypical depression (inflammation
driven)
•
Examine their levels of SIgA by salivary analysis and correcting if required.
•
Use the most effective human derived strains of probiotics to suppress excess
inflammatory cytokines by induction of IL-10 and regulate immune response
systemicall
Beneficial effects
exerted by probiotic bacteria in the treatment of human disease may be broadly
classified as those effects that arise due to activity in the large
intestine and are related to colonization or inhibition of pathogen growth. These
effects, which arise in both the small and large
intestine, are related to enhancement of the host immune response and
intestinal barrier function. In a strain dependent fashion, probiotic bacteria
can enhance intestinal barrier function and modulate signal
transduction pathways and gene expression in epithelial and immune cells. Oral
administration of live probiotics and bacterial structural components can also
differentially modulate dendritic cells resulting
in an increased production of IL-10
and regulatory T cells. Probiotic bacteria can modulate both innate and
adaptive immune responses. The use of probiotics can modulate the amount of
cytokine produced, and therefore, decrease the levels of pro-inflammatory
factors; this will prevent the depression seen with increased concentration of
cytokines.
2. Multiple Sclerosis
and Depression
Depression
is very common in people with multiple sclerosis (MS). In fact, symptoms of depression severe enough to require medical intervention affect
up to half of all people with MS at some point during their illness.
· Why Do People With Multiple Sclerosis Also Have Depression
-Depression may be the result of a difficult
situation or stress. It is easy to understand how
patients with MS, which has its potential for progressing to permanent
disability, can bring on depression. In addition, MS has the capability to
destroy the insulating myelin that surrounds nerves that transmit signals
affecting mood. Lastly, drugs used to treat MS have proven to have depression
has a potential side effect.
· What Are the Symptoms of Depression?
Depression
is differentiated from normal every day feelings of sad or blue, because of its
long lasting period. Depression can last for years and cause much suffering in
the individual. More importantly, this condition eventually becomes too intense
and prevents an individual from living a normal life. Depression has several
key symptoms that physicians should be conscious of. Below is a list of typical
symptoms seen in patients with depression.
-Sadness
-Loss of
energy
-Feelings
of hopelessness or worthlessness
-Loss of
enjoyment from things that were once pleasurable
-Difficulty
concentrating
-Uncontrollable
crying
-Difficulty
making decisions
-Irritability
-Increased
need for sleep
-Inability
to fall or stay asleep at night (insomnia)
-Unexplained
aches and pains
-Stomachache
and digestive problems
-Decreased
sex drive
-Sexual
problems
-Headache
-A change
in appetite causing weight loss or gain
-Thoughts
of death or suicide
-Attempting
suicide
Questions:
1.
Are there any immunological explanations for
the patient’s symptoms?
Taking into
consideration the list of symptoms presented in the case, it can be concluded
that the women presents with depression. As of late, there has been new
research giving evidence of immunological factors playing a role in the
exhibition of depression. The relationship between depression and the
immunological response has been found to involve cytokines. Within the immune
system cytokines are signaling peptides used by a diverse group of cells within
the body to communicate. When the body is immunologically compromised the body
releases a myriad of cytokines, which all work together to have multiple
effects throughout the human body. These effects include neuropsychiatric
symptoms, more specifically, INF-alpha, which is responsible for, causing
fever, fatigue and lack of appetite.
Depression, as well as other behavioral changes, has been linked to
pro-inflammatory cytokines. It is thought that these pro-inflammatory cytokines
are responsible for causing the symptoms associated with depression in patients
who do not have prior mental disorders. This is because pro-inflammatory
cytokines have been shown to produce psychiatric mood disruptions in those
patients that did not have former mood disorders. Below, a summarized chart for
the basis of this phenomenon is shown:
Autoimmunity is used
to describe when an organism fails to recognize proper cells as “self” cells;
this eventually leads to an immune response in which the own body attacks its
“self” cells. This disrupts the normal function of the human body and puts the
individual at risk for potential complications. This autoimmunity can be quite
detrimental in the brain and central nervous system (CNS) because the antibody
production will cause further damage to neurons, as well as other types of
brain cells. These autoimmunities have the potential of affecting different
features of the brain and CNS. One example would be changes in memory, behavior
and mood, all of which stem from auto antigens for synaptic receptors on cell
surface proteins. Disruptions such as these eventually produce a decrease in
the synthesis of neurotransmitters that are important in the activity of many
regions of the brain (this could include regions such as the
hypothalamus-pituitary axis or parts of the limbic system). Because of the role
of these regions with conduct, a change in the neurotransmitters will lead to
presentation of behavioral changes, such as depression, mood swings, loss of
ability to concentrate and loss of interest in activities which were once
pleasurable. These areas are at risk to be affected by an autoimmune disorder.
3.
What are the main structures of the CNS
involved in normal mood?
One of the major CNS
systems involved in normal mood is the limbic system. The components of this
system include the hippocampus and amygdala. Other key players involved in
normal mood include the prefrontal cortex, nucleus accumbens and hypothalamus.
The roles of each structure is described below:
References:
Siegel A, Sapru H. Essentials of Neuroscience. 2nd
ed.Baltimore, MD:Lippincott, Williams
and Wilkins; 2011.
Smith R. Cytokines
and Depression : How your immune system causes depression.Gilroy
California;1997.
Dantzer R. From
inflammation to sickness and depression: when the
immune system
subjugates the brain. NIH
Public Access. Available
at: http://ecourses.sanjuanbautista.edu/file.php/4/Immunoblog_2012/Case_1_Group_1.pdf.
Accessed May 7, 2013.
C. A. Opitz, W. Wick,
L. Steinman, M. Platten.Tryptophan
degradation in autoimmune diseases. Cell Mol Life Sci. 2007
October; 64(19-20): 2542–2563. doi: 10.1007/s00018-007-7140-9
Billiau, A. ; Vanderbroeck, K. INF Gamma. Rega Intitute,
University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Year
2000
Matsuda, T. ; Hirano, T; IL-6. Department of Immunology,
Toyama Medical and Pharmaceutical University, Toyama, Japan. Year 2000
Aggarwal, B.; Samanta, A.; Feldman, M. ; TNF Alpha.
Cytokine Research Laboratory, Department of Biotherapy, The University of Texas
M.D. Anderson Cancer Center, Houston, Texas, USA 2000
Cytokine Reference, A compendium of cytokines and other
mediators of host defense, Vol 1: Ligands, Acadmeic Press, 2001
Michael E. Ash; A
Novel Approach to Treating Depression, How probiotics Can Shift Mood by
Modulating Cytokines, B.S.c. (Hons) D.O.N.D. F. Dip ION, September 2009
Brunilda Nazario M.D.; Multiple Sclerosis and Depression, Web MD Medical Reference, @2011WebMD, LCC, Available at: http://www.webmd.com/multiple-sclerosis/guide/ms-depression
This was my favorite case. It is very interesting to acknowledge the fact that everything is connected in the body. Referring to this case, one can profoundly understand the effect of an immune response and its effect in the nervous system. Studying its effect on mental health is an important aspect needed to be taken into consideration. It amazes me to know that cytokines can provoke symptoms of mental illness such as depression and schizofrenia. Taking into consideration that cytokines can pass through the blood brain barrier brings up an interesting point because they can also bind to receptors located in the brain. In fact, they are also synthesized by immune cells that reside in the brain. What makes this topic my favorite one is knowing the fact that cytokines do have an impact on the activity of neurotransmitters that have to do with depression and schizophrenia, such as norepinephrine, serotonin and dopamine. To me this is an amazing point that shows how the human body works as an integrated system.
ResponderBorrarI think this is very interesting. You always hear that the "mind over matter" is what can make us overcome depression. I never knew or thought that cytokines released in response to autoimmunity could be a major reason for depression. I would think, as mentioned in the MS portion of this research, that these patients are depressed simply because they have the disease. I didn't think the microbial and biochemical disease processes itself would be the causes of diseases. That's why I find immunology so interesting. We have adapted over thousands of years to maintain homeostasis with a very complicated immune system. When something with it goes wrong, as in auto-immune processes, we see how it can have long- ranging effects, not only with disease, but also mental problems. I also think the pro-biotic portion of this essay is very interesting and I have recently begun seeing commercials promoting them. I would like to know more about them and know which ones we should consider taking in particular to help improve our moods.
ResponderBorrarI was surprised to learn that cytokines can be responsible for causing depression. And, further, that it stems from a bacterial infection. It's actually kind of scary to know that a mentally healthy person can end up acquiring depression from getting sick!
ResponderBorrarMore interesting to me was the mechanism that the above happens: how microglia take in the cytokine and once it is exposed in the brain, causes breakdown of the tryptophan precursor to Serotonin. I always understood how Serotonin was the neurotransmitter involved in psychiatric depression, but it was fascinating to learn that this is one of the ways that Serotonin levels can become abnormal.
¿Entonces esto funciona así? Se desencadena una respuesta inmune que eventualmente degrada triptófano, disminuyendo así la cantidad disponible del mismo para la síntesis de serotonina. Jamás imaginé que las citoquinas estuvieran relacionadas a la depresión. Honestamente aunque sabía que el sistema inmune estaba ligado a la parte emocional del individuo me parece muy interesante comprender como es capaz de causar depresión en ciertos casos. Me pregunto si estos pacientes serán tratados con inhibidores de la receptación de serotonina tales como Prozac y Paxil o con inhibidores de MAO.
ResponderBorrarEl hecho de que existen interleukinas que influyen en la síntesis de serotonina es muy interesante. Esto ayuda grandemente al tratamiento de enfermedades inmune ya que no solo va a ser importante tratar la condición como la tuberculosis por ejemplo también hay que evaluar el aspecto neurológico como el efecto que tiene la misma en los neurotransmisores y que efecto tendrá en los diferentes tractos que llevan a la depresion . Solo cabe preguntar si las interleukinas también tienen algún efecto sobre otros neurotransmisores y si afectan como a otros estados de animo.
ResponderBorrarI find the findings of this paper curious considering how depression is treated today. I am not aware of any FDA approved pharmacological agents that treat depression via the immune system. All FDA approved products available on the market today treat idiopathic depression, not cytokine induced depression. If recent research is trending more towards linking Cytokines and depression, then where are the advances in treatment of depression targeting cytokines as the mechanism of action? Why haven’t any products been fast-tracked through the FDA’s approval process considering how crowded the market is for anti-depressants?
ResponderBorrarMore interesting is the American Psychiatric Association on this topic.
The Diagnostic And Statistical Manual Of Mental Disorders-IV, Text Revision, never mentions the immune system as to having a correlation to depression. Additionally, the DSM-IV TR mentions the word “immune” only six times in its entire text, and the circumstances are particularly broad: Dementia, Personality Changes, Opioid-Related Disorder, Other Substance Related Disorders, Psychotic Disorder due to General Medical Condition, and Mood Disorder due to General Medical Condition. Apparently the DSM-IV TR and the APA are not convinced that depression and cytokines are related. Should we? Interestingly enough, the DSM-IV TR never mentions the word “cytokine” in its text. However, it does mention numerous times other physiological phenomena including serotonin, norepinephrine, dopamine, acetylcholine, and gamma-aminobutyric acid. Is the DSM-IV TR obsolete? It’s last revision was in the year 2000. The DSM-V is projected to be published in May 2013. Will it reflect findings on Cytokines and depression or is more research necessary before making this paradigm shift?
Este comentario ha sido eliminado por el autor.
ResponderBorrarUnknown12 de mayo de 2013 15:37
ResponderBorrarEste caso fue mi favorito ya que me asombra continuar aprendiendo como todo se conecta y funciona en el cuerpo. La física me enseñó que toda causa tiene un efecto pero jamás se me hubiera ocurrido que respuestas inflamatorias pudieran causar síntomas que afectan la personalidad del paciente. Además es bien interesante saber que otras alternativas naturales se están identificando para mediar la depresión. Dentro de las aplicaciones que el grupo nos presenta me encantó aprender como los pro bióticos funcionan y su efecto en mediar la producción de citokinas. Ahora entiendo porque Yogen Fruz tiene tanto éxito :P
Desireé Franceschi
Estos son detalles que definitivamente debemos conocer antes de salir a la practica con pacientes reales porque entendiendo como funciona el organismo en la enfermedad y como esto repercude en su conducta (en este caso un paciente enfermo, que sin opción va a estar deprimido)aprendemos a ser mas empáticos y tolerantes. Cualidades que en mi opinión, deben formar parte de cada uno de nosotros como doctores que somos.
ResponderBorrarI always thought that the reason for depression during sickness was purely psychological with no physiological changes. In other words, just the believe that one is ill, changes one's mood. Interesting connection between immunology (INF) and depression.
ResponderBorrarThis case is certainly the most interesting to me for a variety of reasons. First, inducing depression during a pro-inflammatory immune response causes one to ask what is the evolutionary benefit or how was this selected for. The symptoms presented by the patient are contradictory from an evolutionary point of view. The patient presented with fatigue and loss of interest in general activities. Functionally, the withdrawal from daily activities and a feeling of fatigue is beneficial to the patient as the reduced activity level may direct valuable caloric resources to fight the infection. It is well established in the literature that mounting an immune response is costly, and the conservation of caloric resources caused by the onset on fatigue would be beneficial to the patient and possibly selected for during the course of evolution. However, the patient also presented with loss of appetite. Again noting that the mounting of an immune response is costly, the reduction of caloric intake is counter to what one might except from a selection point of view. Further, the insomnia experienced by the patient may aggravate the infection because a lack of sleep is known to increase a person’s risk of disease. Overall however, I found this case interesting to read although somewhat contradictory.
ResponderBorrarThis is very interesting. I think that this is the kind of evidence that really supports the link between Neurology, and Immunology. More importantly it allows us to begin a dialog about behavior and psychology and its role in the human body. Too often do we see the "typical medical student" ignoring psychological symptoms in favor of more concrete and objective physiological presentations. As representatives of the new generation of doctors we must attempt to understand these very-real psychological symptoms. They should not be consider less important than any other type. And so i call on all of you to assist me in Objectifying the subjective Psychology with the very-objective Neurology. This blog is evidence that my point of view is shared with Biology.
ResponderBorrarThis case is pretty interesting, talk about ‘integration of systems’. I would have never guessed that cytokines have a direct effect on depression. We get sick and our body works overtime to fight an infection, bring down the inflammation and as a ‘side effect’ we get depressed. So is it safe to say that changing the lifestyle of depressed individuals to an anti-inflammatory diet will also improve their mood? (Instead of using opposed to using anti-depressants.) Or maybe even use anti-inflammatory drugs to treat depression?
ResponderBorrarKassia Silva
This case brings us full circle from of our first course in medical school (Biochemistry) to our last two courses of the year (Immunology and Neuroscience). It is also a great transition into our second year of medical school, as it allows us to see the integration of all our courses and the inevitable connections found in medicine. In biochemistry, we learned how tryptophan undergoes a reaction catalyzed by tryptophan hydroxylase to form 5 – Hydroxy Tryptophan followed by serotonin. This reaction not only produced serotonin, but it also produced a by - product, BH4 (Tetrahydrobiopterin), which is necessary for the metabolism of phenylalanine. In fact, deficiencies of BH4 caused by a lack of production from Tyrosine, Catecholamines and Serotonin synthesis, resulted in Phenylketonuria, a very well known metabolic disorder which causes mental retardation in children who are not diagnosed in a timely manner.
ResponderBorrarWhile studying the synthesis of serotonin and its role in depression I always thought that the reason why this neurotransmitter was low in the CNS of depressive patients was due to an enzyme deficiency, in this case Tryptophan hydroxylase; and that the only way to treat this deficiency was with pharmacological agents. I was pleasantly surprised to learn via this case presentation that decreases in serotonin may not only be due to enzyme deficiencies, but also to cytokine increase post – inflammation. I am interested in seeing how the clinical application presented by this group (the use of probiotics to stimulate the release of IL – 10 which will inhibit Thelper1 cells and the cytokines it produces) may alter the treatment plan of patients who suffer from depression. Will the use of probiotics replace highly prescribed anti-depressive drugs such as Lexapro, Cymbalta and Prozac? Can changes in a patients diet free them from a lifelong intake of these medications and its side effects?
Alanna Guzman
Este caso me llamo mucho la atencion ya que contesta una inquietud que muchos de nosotros tenemos, como es que una sola persona es capaz de padecer tantos problemas de salud. Es muy interesante ver que INF-alpha es uno de los responsables de causar fiebre, fatiga, y falta de apetito. No solamente eso si no que también IL-6 como otros antiinflamatorios causan depresión. Entonces todas estas conexiones nos dejan conectar los puntos vacíos que nosotros teníamos a todos los otros síntomas, y esto me llamo mucho la atención y me abrió el conocimiento de conectar los dos sistemas y no solo pensar que su función es solo erradicar infecciones.Pero como podemos ver como el sistema inmune esta relacionado e interactúan con el sistema nervioso. Este caso me llamo mucho la atención al ver que INF-alpha es uno de los responsables de causar fiebre, fatiga, y falta de apetito. No solamente eso si no que también IL-6 como otros antiinflamatorios causan depresión. Entonces todas estas conexiones no dejan conectar los puntos vacíos que nosotros teníamos a todos los otros síntomas, y esto me llamo mucho la atención y me abrió el conocimiento de conectar los dos sistemas y no solo pensar que su función es solo erradicar infecciones.
ResponderBorrarOtro punto fascinante de este caso fue la degradación de tryptophan, cual es el precursor de serotonina, y serotonina va a la glándula pineal y hacen melatonina que es el nos produce el sueno. Y al mismo tiempo serotonina esta relacionada con depresión cuando hay una respuesta inmune prolongada.
También el tema de los pro bióticos estuvo muy interesante porque uno solo sabe o escucha de la flora intestinal. Al leer este caso me llamo mucho la atención que ellos baja o modula el nivel de IL-10; bajando el nivel de factores pro-inflamatorios ayudando al cuerpo que entre en depresión. También lei una caso los probioticos streptococcus thermophilus and lactobacillus bilgaricus son conocidos hace miles de anos atrás. Pero hay que tener cuidado con enfermedades autoinmune ya que pueden causar problemas de sepsis.
Jose Barrientos
As other have mentioned, I found this case to be the most interesting for many reasons. My grandma has had a very debilitating rheumatoid arthritis for over ten years now. Although it has gotten to the point where not only her joints are swollen, but also every part of her body including her feet is, I have not noticed a huge change in her mood over the years. Reading this case made me realize how strong she is because it is undeniable science that the cytokines have the ability to cross the blood-brain barrier to reach the CNS and cause neuropsychiatric symptoms by affecting neurotransmitter release and the hypothalamus-pituitary-adrenal axis. Despite her ability to keep her spirits up, I have also noticed that she has shown loss of interest in many previous activities she enjoyed, but I always had assumed it had to do with her getting older.
ResponderBorrarI also found two questions Kassie Silva brought up very interesting and decided to look into if there in fact have been attempts to use anti-inflammatory drugs in the treatment of depression. This in fact has been proven to be effective as reported in an article in cited below. Additional connections between the immune system and depression have been found in evidence of increased salivary prostaglandins and plasma acute phase proteins in depressed patients. This study used celecoxib as adjuncts to SSRIs (serotonin selective reuptake inhibitors) – generally used for depression- and found a significant decrease in depressive symptoms compared to subjects taking only SSRIs alone.
Davis A, Gilhooley M, Agius M. Using non-steroidal anti-inflammatory drugs in the treatment of depression. Psychiatr Danub. 2010 Nov;22 Suppl 1:S49-52. PubMed PMID: 21057403.
Sin lugar a dudas, este ha sido uno de los blogs más interesantes. La manera en que nuestro cuerpo esta intrínseca y mecánicamente regulado no deja de sorprenderme. No parecería extraño ver a un paciente con alguna condición crónica o degenerativa deprimirse. Pero la fisiología detrás de esto acaba de ser, tras la lectura y estudio de este caso, una gran duda aclarada. En resumen, citoquinas pro-inflamatorias, las mismas encargadas de mediar los signos de inflamación en estos pacientes (por ej., tuberculosis, esclerosis múltiple, etc.) causan una disrupción en el sistema nervioso central que resulta en la disminución del aminoácido triptófano y por ende, de serotonina. Un sinnúmero de estudios han vinculado la disminución en los niveles de serotonina con síntomas de depresión. He aquí entonces la ciencia y lógica detrás del comportamiento de estos pacientes.
ResponderBorrarPero si interesante fue la explicación por los cambios en conducta en pacientes con enfermedades inflamatorias, más interesante aún es ver las terapias que han surgido para contrarrestar o al menos mitigar estos daños. Es aquí donde se presenta el uso de probióticos. El uso de estos de manera oral pudiera conducir a una producción de la citoquina anti-inflamatoria IL-10. Una idea brillante por demás y sobre todo ventajosa en términos de que evita los daños colaterales resultado de tratamientos farmacológicos más agresivos. No me parecería extraño predecir que nuestra flora bacteriana aún guarda muchos secretos que con el tiempo serán dilucidados para nuestro asombro. Por el momento, no lo pensaré dos veces para incluir en mi dieta productos lácteos (por ej., quesos, yogurt, etc.) o suplementos que incluyan probióticos.