Immuno-psychiatry

Last updated

Immuno-psychiatry, according to Pariante, is a discipline that studies the connection between the brain and the immune system. It differs from psychoneuroimmunology by postulating that behaviors and emotions are governed by peripheral immune mechanisms. Depression, for instance, is seen as malfunctioning of the immune system.

Contents

History

History Tying The Immune System to Psychosis

Since the late 1800’s scientists and physicians have noticed a possible link between the immune system and psychiatric disorders. [1] [2] [3] In 1876 Alexandar Rosenblum, and later in the 1880s Dr. Julius Wagner-Jauregg, observe patients with neurosyphilis, syphilis that had spread to the nervous system, have decreased symptoms of psychosis after contracting malaria. [3]   Then from the 1920s, Karl Menninger notices how many patients recovering or recovered from influenza have psychosis similar to that seen in patients with schizophrenia. [1]   Moritz Tramer then reports how schizophrenia is associated with a child being born in the winter or spring months (when influenza is most commonly contracted). [1]   Later in 1980s, much research is conducted associating increased rates of schizophrenia in patients with a history of prenatal, postnatal infection, and especially childhood central nervous system infections. [1] [4]

History: Tying Inflammatory States to Changes in Mood

In modern medicine, William Osler provides an early documentation of the association between inflammation and changes in mood and motivation. In his 1892 book, "The Principles and Practice of Medicine," he observed that clinical patients with progressive septicemia showed "early delirium and marked mental prostration and apathy." [2]

In 1988 while studying animals, Benjamin Hart coined the term "sickness behavior" to describe the "sleepy or depressed or inactive" state and decreased motivation to move about that sick animals displayed. [2] A previous study from 1979, by M.J. Murry, found increased mortality when animals were force-fed after reducing their food intake in response to bacterial infection, suggesting that these changes played an essential role in fighting off infection. [2]

Beginning in the mid 1990s, investigation into the similarity in these animal “sick behavior” and persons with depression led to more and more studies showing elevated levels of pro-inflammatory cytokines among persons with depression. Many of these early studies in sickness behavior showed significant differences in the many pro-inflammatory cytokines reviving interest into the role that the immune system played in psychiatric disorders. [2]

Modern immuno-psychiatry model

Modern immuno-psychiatry theory now focuses on some variation of this model of how the environment leads to biological changes which affect the peripheral immune system and later affect the mind, mood, behavior, and response to psychiatric treatment. [3] Stress leads to processing by the sympathetic nervous system which releases catecholamines (dopamine and norepinephrine) that increase the number of monocytes, which respond to inflammatory signals (DAMPS/MAMPs), which causes the release of pro-inflammatory cytokines, which then later reach the brain and lead to changes in neurotransmitter metabolism neuronal signaling, and ultimately behavior.

Support For The Role of The Immune System Affecting Mood and Behavior

How Cytokines Can Reach The Brain And Central Nervous System

  1. Passing through more leaky areas of the blood brain barrier, near the circumventricular organs. [5] [6]
  2. Active transport of cytokines in the blood to bypass the Blood Brain Barrier. [5] [6]
  3. Activation of endothelial cells lining the brain's vasculature which later release cytokines into the central nervous system. [5] [6]
  4. Cytokines binding receptors on peripheral afferent nerves which then conduct a message to the central nervous system in specialized regions of the brain which release their own cytokines. [5] [6]
  5. Recruitment of monocytes in the blood which then travel to the brain and release cytokines. [6]
Blood-brain barrier methods of transport. Given the large and charged size of cytokines, active transport is the only direct way for the same cytokine circulating in the blood to pass through an intact blood-brain barrier. Other methods, such as activation of the endothelial cells, cytokine signaling, recruitment of granulocyte cells, and activation of afferent neurons work indirectly and cause the creation or release cytokines. Blood-brain barrier transport en.png
Blood–brain barrier methods of transport. Given the large and charged size of cytokines, active transport is the only direct way for the same cytokine circulating in the blood to pass through an intact blood-brain barrier. Other methods, such as activation of the endothelial cells, cytokine signaling, recruitment of granulocyte cells, and activation of afferent neurons work indirectly and cause the creation or release cytokines.

How Cytokines Can Cause Changes To Neurotransmitter levels Which Can Sometimes Be Reversed.

Pro-inflammatory cytokines alter the metabolism of neurotransmitters and has been documented to effect decrease levels of serotonin, increase indolamine-2,3-dioxygenase (IDO) activity(which normally catabolizes tryptophan and consequentially decrease serotonin synthesis), increased levels of kynurenine (leading to decreased glutamate and dopamine release), decrease dopamine as well as decreased levels of expression of tyrosine hydroxylase (which is required to make dopamine),  increased levels of quinolinic acid, leading to more NMDA receptor activation and oxidative stress leading to excitotoxicity and neurodegeneration. [6]

Additionally, cytokines interferon-alpha and IL-6 can cause reversible reductions in brain levels of tetrahydrobiopterin (used in the serotonin, dopamine, and norepinephrine synthesis pathways).  However, inhibition of nitric oxide synthase, one of the down stream effects of interferon-alpha, can lead to a reversal of this decrease in tetrahydrobiopterin. [6]

How Cytokines Can Cause Molecular And Cellular Changes Similar to Those Seen In Patients With Mood Disorders

Microglia make the most cytokines of all cells in the brain, respond to stress, and are likely important in the stress response as they are found to be increased in density (yet decreased in overall number) in different parts of the brain of persons who had killed themselves with major depressive disorder, bipolar disorder, and schizophrenia. [6]

On a molecular level, cytokines effect the glutamate metabolism of the nervous system and can lead to structural changes involving microglia similar to those seen in depressed patients. [6] TNF-alpha and IL-1, through oxidative stress via increased release of reactive oxygen and nitrogen species, impair re-uptake and transport of glutamate by glial cells, increasing release of glutamate by astrocytes and microglia, leading to an excitotoxic state. This loss of oligodendrocytes (the astrocytes and microglia mentioned before) are a key marker in structural analysis of the brains of depressed patient populations. [6]

How Inflammatory Cytokines Can Disrupt Cortisol Signaling And The HPA-axis Seen in Psychopathologies

The hippocampus helps regulate the HPA-axis' secretion of cortisol and has the largest number of glucocorticoid receptors in the brain. [8] This makes it making it especially sensitive to stress and stress related increases to cortisol. Additionally, the neuroendocrine response by the HPA-axis is effected by the regulation of glucocorticoid receptor expression in the different regions of the brain. And multiple studies have shown that “altered HPA stress responsivity being associated with increased risk of psychopathology” such as in the study of human brain cell, gathered post-mortem, mRNA was harvested in patients who had killed themselves with either a history or a lack of a history of early childhood stresses revealed significant epigenetic changes in glucocorticoid receptor expression.

Patients with elevated levels chronic inflammatory cytokines, (such as those with chronic hepatitis C and others undergoing injections of interferon-alpha, cause changes in glucocorticoid receptors and cortisol release similar to patients with major depression.  Both exhibit a loss of the normal cortisol rhythm of secretion throughout the day, and both show a loss of functional glucocorticoid receptors which would otherwise decrease the inflammation in the body. [6]

Associated findings in Major Depressive Disorder

Following studies of patients with significant chronic inflammation, like those undergoing interferon-alpha therapy for hepatitis C showing an association with depressive symptoms, not unlike Osler's "sickness behavior", more studies into major depressive disorder and its link to inflammation have been done. [2] There have been many studies inferring a link between inflammation and major depressive disorder from correlating levels of cytokines in the blood, correlating genes linked to inflammation to treatment response, and changes in cytokines to antidepressant therapy.

Many studies investigating the role of the immune system in patients with major depressive disorder found that such patients had decreased immune cell activity of natural killer cells and lymphocytes despite reliably having elevated levels of pro-inflammatory cytokines(IL-6, TNF-alpha, and C-reactive protein). [2] [6] Depression is also associated with a decrease in regulatory T cells which secrete anti-inflammatory IL-10 and TGF-beta. [6]   Different studies have shown the that persons with depression also have lower circulating levels of IL-10, TGF-beta, in addition to the mentioned elevated levels of pro-inflammatory IL-6 in their blood stream. [6]

Antidepressants have been used to infer a link between inflammation and major depressive disorder. In human studies associating the link between inflammation and depression found that giving antidepressants prior to an expected inflammatory insult decreased observed severity of depression. For example, giving paroxetine prior to treatment for malignant melanoma and hepatitis C was found to decrease depressive symptoms compared to persons not given paroxetine (an antidepressant).  Additional experimental support of giving an antidepressant prior to injection of endotoxin, a substance known to cause systemic inflammation) was also found to reduce self-reported symptoms of depression. [6] In studies of antidepressant use, some persons show return to normal cytokine levels with depression treatment.  Patients with major depressive disorder treated with antidepressants have an increase in regulatory T cells and a decrease in inflammatory IL-1 beta. [6] And even more strongly replicated, patients with increased levels of pro-inflammatory cytokines, or even genes tied to increased pro-inflammatory activity, are more likely to have antidepressant resistant depression. [6] [9]

Through all these studies there seems to be a slight difference in symptoms of major depressive disorder with and without inflammation. Inflammation related depression tends to have less guilt/self negativity and increased slowness and lack of appetite compared to depression in persons without increased levels of systemic inflammation. [6]

Proposed roles of the immune system in Schizophrenia and Psychotic Disorders

There are ties to episodes of psychosis, and persons at risk for schizophrenia, severity of schizophrenia, and with antipsychotic therapy especially with levels of IL-6 in the blood as well as the cerebrospinal fluid of patients with schizophrenia. [1]

Following studies revealing kynurenic acid's uniqueness as being the NMDA receptor's only endogenous (naturally found in the body) antagonist, and the fact that psychosis can be elicited from NMDA receptor antagonism, multiple studies investigated and confirmed change levels of this kynurenic acid may be related to psychosis.  Later drug studies have found that COX1 inhibition, which increases kynurenic acid,  has been reported to cause psychotic symptoms.  COX2 selective inhibitors like celecoxib, which reduce kynurenic acid, were found to reduce clinical severity of schizophrenia in non-randomized, unblinded clinical trials. [1] [10] While encouraging, these results remain to be confirmed in randomized clinical trials with confirmatory results before they are even considered for off-label usage.

Recent research has shown that patients with OCD have six times the amount of a protein called Immuno-moodulin, or Imood, compared to individuals who do not contend with OCD. In addition to OCD, Imood was also found to increase symptoms of anxiety and stress, both mental health areas that have already been linked to OCD. [11]

Overall impact for clinical medicine

The overall results for the many clinical trials of combinations of NSAIDS and antidepressants, proposed to more thoroughly treat standard major depressive disorder and treatment-resistant major depressive disorder, shows that the current degree of importance of addressing the inflammatory component of mood disorders is unclear. Mixed results of some or no improvement in such studies, and the relative lack of studies recruiting sufficient numbers of patients with treatment resistant depression, a lack of studies of patients with chronic inflammation and treatment depression, and a lack of a standardized definition of an elevated chronic inflammatory state leaves more studies to be desired in pursuing the understanding of inflammation and psychiatric disorders. [3]

Related Research Articles

<span class="mw-page-title-main">Major depressive disorder</span> Mood disorder

Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Introduced by a group of US clinicians in the mid-1970s, the term was adopted by the American Psychiatric Association for this symptom cluster under mood disorders in the 1980 version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III), and has become widely used since. The disorder causes the second-most years lived with disability, after lower back pain.

<span class="mw-page-title-main">Hypothalamic–pituitary–adrenal axis</span> Set of physiological feedback interactions

The hypothalamic–pituitary–adrenal axis is a complex set of direct influences and feedback interactions among three components: the hypothalamus, the pituitary gland, and the adrenal glands. These organs and their interactions constitute the HPS axis.

<span class="mw-page-title-main">Duloxetine</span> Antidepressant medication used also for treatment of anxiety and chronic pain

Duloxetine, sold under the brand name Cymbalta among others, is a medication used to treat major depressive disorder, generalized anxiety disorder, obsessive-compulsive disorder, fibromyalgia, neuropathic pain and central sensitization. It is taken by mouth.

<span class="mw-page-title-main">Serotonin–norepinephrine reuptake inhibitor</span> Class of antidepressant medication

Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant medications used to treat major depressive disorder (MDD), anxiety disorders, social phobia, chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopausal symptoms. Off-label uses include treatments for attention-deficit hyperactivity disorder (ADHD), obsessive–compulsive disorder (OCD), and migraine prevention. SNRIs are monoamine reuptake inhibitors; specifically, they inhibit the reuptake of serotonin and norepinephrine. These neurotransmitters are thought to play an important role in mood regulation. SNRIs can be contrasted with the selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (NRIs), which act upon single neurotransmitters.

Psychoneuroimmunology (PNI), also referred to as psychoendoneuroimmunology (PENI) or psychoneuroendocrinoimmunology (PNEI), is the study of the interaction between psychological processes and the nervous and immune systems of the human body. It is a subfield of psychosomatic medicine. PNI takes an interdisciplinary approach, incorporating psychology, neuroscience, immunology, physiology, genetics, pharmacology, molecular biology, psychiatry, behavioral medicine, infectious diseases, endocrinology, and rheumatology.

<span class="mw-page-title-main">Interleukin 6</span> Cytokine protein

Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the IL6 gene.

Neuroimmunology is a field combining neuroscience, the study of the nervous system, and immunology, the study of the immune system. Neuroimmunologists seek to better understand the interactions of these two complex systems during development, homeostasis, and response to injuries. A long-term goal of this rapidly developing research area is to further develop our understanding of the pathology of certain neurological diseases, some of which have no clear etiology. In doing so, neuroimmunology contributes to development of new pharmacological treatments for several neurological conditions. Many types of interactions involve both the nervous and immune systems including the physiological functioning of the two systems in health and disease, malfunction of either and or both systems that leads to disorders, and the physical, chemical, and environmental stressors that affect the two systems on a daily basis.

<span class="mw-page-title-main">Kynurenine</span> Chemical compound

l-Kynurenine is a metabolite of the amino acid l-tryptophan used in the production of niacin.

<span class="mw-page-title-main">Kynurenic acid</span> Chemical compound

Kynurenic acid is a product of the normal metabolism of amino acid L-tryptophan. It has been shown that kynurenic acid possesses neuroactive activity. It acts as an antiexcitotoxic and anticonvulsant, most likely through acting as an antagonist at excitatory amino acid receptors. Because of this activity, it may influence important neurophysiological and neuropathological processes. As a result, kynurenic acid has been considered for use in therapy in certain neurobiological disorders. Conversely, increased levels of kynurenic acid have also been linked to certain pathological conditions.

<span class="mw-page-title-main">Quinolinic acid</span> Dicarboxylic acid with pyridine backbone

Quinolinic acid, also known as pyridine-2,3-dicarboxylic acid, is a dicarboxylic acid with a pyridine backbone. It is a colorless solid. It is the biosynthetic precursor to niacin.

Scientific studies have found that different brain areas show altered activity in humans with major depressive disorder (MDD), and this has encouraged advocates of various theories that seek to identify a biochemical origin of the disease, as opposed to theories that emphasize psychological or situational causes. Factors spanning these causative groups include nutritional deficiencies in magnesium, vitamin D, and tryptophan with situational origin but biological impact. Several theories concerning the biologically based cause of depression have been suggested over the years, including theories revolving around monoamine neurotransmitters, neuroplasticity, neurogenesis, inflammation and the circadian rhythm. Physical illnesses, including hypothyroidism and mitochondrial disease, can also trigger depressive symptoms.

<span class="mw-page-title-main">Kynurenine pathway</span> Metabolic pathway that produces the NAD coenzyme

The kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD+). Metabolites involved in the kynurenine pathway include tryptophan, kynurenine, kynurenic acid, xanthurenic acid, quinolinic acid, and 3-hydroxykynurenine. The kynurenine pathway is responsible for about 95% of total tryptophan catabolism. Disruption in the pathway is associated with certain genetic and psychiatric disorders.

<span class="mw-page-title-main">Selective serotonin reuptake inhibitor</span> Class of antidepressant medication

Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions.

The evolution of schizophrenia refers to the theory of natural selection working in favor of selecting traits that are characteristic of the disorder. Positive symptoms are features that are not present in healthy individuals but appear as a result of the disease process. These include visual and/or auditory hallucinations, delusions, paranoia, and major thought disorders. Negative symptoms refer to features that are normally present but are reduced or absent as a result of the disease process, including social withdrawal, apathy, anhedonia, alogia, and behavioral perseveration. Cognitive symptoms of schizophrenia involve disturbances in executive functions, working memory impairment, and inability to sustain attention.

The pharmacology of antidepressants is not entirely clear. The earliest and probably most widely accepted scientific theory of antidepressant action is the monoamine hypothesis, which states that depression is due to an imbalance of the monoamine neurotransmitters. It was originally proposed based on the observation that certain hydrazine anti-tuberculosis agents produce antidepressant effects, which was later linked to their inhibitory effects on monoamine oxidase, the enzyme that catalyses the breakdown of the monoamine neurotransmitters. All currently marketed antidepressants have the monoamine hypothesis as their theoretical basis, with the possible exception of agomelatine which acts on a dual melatonergic-serotonergic pathway. Despite the success of the monoamine hypothesis it has a number of limitations: for one, all monoaminergic antidepressants have a delayed onset of action of at least a week; and secondly, there are a sizeable portion (>40%) of depressed patients that do not adequately respond to monoaminergic antidepressants. Further evidence to the contrary of the monoamine hypothesis are the recent findings that a single intravenous infusion with ketamine, an antagonist of the NMDA receptor — a type of glutamate receptor — produces rapid, robust and sustained antidepressant effects. Monoamine precursor depletion also fails to alter mood. To overcome these flaws with the monoamine hypothesis a number of alternative hypotheses have been proposed, including the glutamate, neurogenic, epigenetic, cortisol hypersecretion and inflammatory hypotheses. Another hypothesis that has been proposed which would explain the delay is the hypothesis that monoamines don't directly influence mood, but influence emotional perception biases.

<span class="mw-page-title-main">Raz Yirmiya</span>

Raz Yirmiya is an Israeli behavioral neuroscientist and director of the Laboratory for Psychoneuroimmunology at the Hebrew University of Jerusalem in Israel. He is best known for providing the first experimental evidence for the role of immune system activation in depression, for discovering that disturbances in brain microglia cells underlie some forms of depression, and for elucidating the involvement of inflammatory cytokines in regulation of cognitive and emotional processes.

Epigenetics of depression is the study of how epigenetics contribute to depression.

Major depression is often associated or correlated with immune function dysregulation, and the two are thought to share similar physiological pathways and risk factors. Primarily seen through increased inflammation, this relationship is bidirectional with depression often resulting in increased immune response and illness resulting in prolonged sadness and lack of activity. This association is seen both long-term and short-term, with the presence of one often being accompanied by the other and both inflammation and depression often being co-morbid with other conditions.

Epigenetics of anxiety and stress–related disorders is the field studying the relationship between epigenetic modifications of genes and anxiety and stress-related disorders, including mental health disorders such as generalized anxiety disorder (GAD), post-traumatic stress disorder, obsessive-compulsive disorder (OCD), and more. These changes can lead to transgenerational stress inheritance.

Epigenetics of bipolar disorder is the effect that epigenetics has on triggering and maintaining bipolar disorder.

References

  1. 1 2 3 4 5 6 Khandaker, Golam M; Cousins, Lesley; Deakin, Julia; Lennox, Belinda R; Yolken, Robert; Jones, Peter B (March 2015). "Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment". The Lancet Psychiatry. 2 (3): 258–270. doi:10.1016/s2215-0366(14)00122-9. ISSN   2215-0366. PMC   4595998 . PMID   26359903.
  2. 1 2 3 4 5 6 7 Konsman, Jan Pieter (March 2019). "Inflammation and Depression: A Nervous Plea for Psychiatry to Not Become Immune to Interpretation". Pharmaceuticals. 12 (1): 29. doi: 10.3390/ph12010029 . PMC   6469164 . PMID   30769887.
  3. 1 2 3 4 Jones, Brett D. M.; Daskalakis, Zafiris J.; Carvalho, Andre F.; Strawbridge, Rebecca; Young, Allan H.; Mulsant, Benoit H.; Husain, M. Ishrat (July 2020). "Inflammation as a treatment target in mood disorders: review". BJPsych Open. 6 (4): e60. doi:10.1192/bjo.2020.43. ISSN   2056-4724. PMC   7345526 . PMID   32498754.
  4. ↑ Khandaker, G. M.; Dantzer, R.; Jones, P. B. (October 2017). "Immunopsychiatry: important facts". Psychological Medicine. 47 (13): 2229–2237. doi: 10.1017/S0033291717000745 . ISSN   0033-2917. PMC   5817424 . PMID   28418288.
  5. 1 2 3 4 Irwin, Michael R. (2011-09-01). "Inflammation at the Intersection of Behavior and Somatic Symptoms". Psychiatric Clinics of North America. Psychosomatic Medicine. 34 (3): 605–620. doi:10.1016/j.psc.2011.05.005. ISSN   0193-953X. PMC   3820277 . PMID   21889682.
  6. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Haroon, Ebrahim; Raison, Charles L.; Miller, Andrew H. (January 2012). "Psychoneuroimmunology Meets Neuropsychopharmacology: Translational Implications of the Impact of Inflammation on Behavior". Neuropsychopharmacology. 37 (1): 137–162. doi:10.1038/npp.2011.205. ISSN   1740-634X. PMC   3238082 . PMID   21918508.
  7. ↑ "File:Blood-brain barrier transport en.png", Wikipedia, retrieved 2020-11-17
  8. ↑ Mathews, Herbert L.; Janusek, Linda Witek (2011-01-01). "Epigenetics and psychoneuroimmunology: Mechanisms and models". Brain, Behavior, and Immunity. 25 (1): 25–39. doi:10.1016/j.bbi.2010.08.009. ISSN   0889-1591. PMC   2991515 . PMID   20832468.
  9. ↑ Irwin, Michael R.; Cole, Steven W. (September 2011). "Reciprocal regulation of the neural and innate immune systems". Nature Reviews Immunology. 11 (9): 625–632. doi:10.1038/nri3042. ISSN   1474-1741. PMC   3597082 . PMID   21818124.
  10. ↑ Khandaker, G. M.; Dantzer, R.; Jones, P. B. (October 2017). "Immunopsychiatry: important facts". Psychological Medicine. 47 (13): 2229–2237. doi:10.1017/S0033291717000745. ISSN   0033-2917. PMC   5817424 . PMID   28418288.
  11. ↑ Daze, Gilad (2021-08-19). "OCD Treatment Breakthroughs, New Therapy for OCD". BrainsWay. Retrieved 2024-08-16.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.