April 14, 2021 | Sarah Reitz, PennNeuroKnow
Major depressive disorder, commonly called depression, is a disorder that affects more than 168 million people worldwide1,2. Symptoms include depressed mood, lack of energy, loss of interest/pleasure, sleep disturbances, significant weight changes, and thoughts of suicide3. While depression can occur on its own, which is known as primary depression, it can also be caused by other diseases or medical conditions. This form of depression, called secondary depression, is relatively common in patients diagnosed with chronic illnesses, and is one of the key factors resulting in an impaired quality of life experienced by patients with chronic diseases4.
Research has shown that patients with autoimmune diseases involving the brain and spinal cord, such as multiple sclerosis (MS), Hashimoto encephalopathy, and autoimmune encephalitis (AE), are at increased risk for depression and other mood disorders5,6. One study found that depressive symptoms occur in up to half of all patients with MS7, and another showed that prior hospitalization for an autoimmune disease increases the risk of developing a major mood disorder by 45%8. Some of this increase is likely a reaction to the diagnosis itself and the impairments caused by the disease. However, increased rates of depression are seen in MS patients up to 2 years before they are diagnosed with MS. These findings suggest that there is a biological link between autoimmune disease and depression that increases the risk of developing depression, independent of any reaction to the diagnosis or resulting lifestyle changes. 9,10. Research over the last 2 decades supports this idea, with increasing evidence linking the immune system and inflammation to a number of psychiatric disorders, including depression.
A link between the immune system and depression?
One indicator that the immune system can affect mood and behavior is the phenomenon of cytokine-induced sickness behavior. During an illness, cells in the immune system release small proteins called cytokines to help regulate and synchronize the immune system’s response to an invading bacteria or virus. Some examples of cytokines include interleukins (IL), tumor necrosis factors (TNF), and interferons (IFN). This increase in cytokines leads to specific behaviors many of us have experienced before while sick, including decreased activity, loss of energy, and even depressed mood11.
Based on the observation that increased cytokines during sickness can lead to depression-like symptoms, researchers began to examine cytokine levels in patients diagnosed with depression and other psychiatric disorders. Many studies have found that patients with depression, who were otherwise medically healthy, showed signs of immune system activation, with increased levels of IL-6 and, in some cases, TNF-alpha12. Another study examined brain tissue from patients diagnosed with depression and found increased levels of many types of interleukins as well as IFN-gamma13. Additionally, mice treated with cytokines or drugs that increase levels of cytokines show depression-like behaviors, further linking the immune system and inflammatory response to depression14. This effect is also seen in humans, with one study finding that 17% of patients treated with IFN-alpha developed psychiatric side effects, including depression, and that these side effects improve once the cytokine treatment is stopped15.
Just as increases in cytokine levels are linked to an increased risk of depression, research suggests that decreasing cytokines and inflammation can improve depression symptoms. A number of antidepressant therapies, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and even psychotherapy have anti-inflammatory effects, lowering levels of certain pro-inflammatory cytokines16-19. Taking this even further, there is evidence that anti-inflammatory drugs can improve depression symptoms20. However, anti-inflammatory treatments can sometimes interfere with the anti-depressant effects of SSRIs, so adding an anti-inflammatory drug (including drugs such as aspirin or ibuprofen) to a depression treatment plan should only be done after careful discussion with your doctor21.
Depression in autoimmune encephalitis
Given this link between immune system activation and depression, it is not altogether surprising that depression and other psychiatric symptoms are common in AE and other autoimmune disorders. For reasons that are still not understood, patients with autoimmune encephalitis with antibodies directed against cell surface antigens (especially anti-NMDA receptor encephalitis) are more likely to experience psychiatric symptoms compared to patients with antibodies directed against intracellular antigens (such as anti-Hu or anti-Ma encephalitis)22. In fact, between 65-80% of patients with anti-NMDA receptor encephalitis experience psychiatric symptoms, with depression being among the most common23,24. This has also been demonstrated in a mouse model of AE, where mice received infusions of cerebrospinal fluid into their brains containing antibodies from patients with NMDA receptor encephalitis. As the anti-NMDA receptor antibodies attacked their NMDA receptors, the mice developed depressive-like behaviors and lost interest in things they had previously found pleasurable (in this case, a sugary drink). Once the infusions stopped and the NMDA receptor levels returned to normal, these depressive-like behaviors improved25.
In NMDA receptor encephalitis, psychiatric symptoms often appear before any neurologic symptoms26. As a result, it can be difficult to distinguish the initial phases of the disease from psychiatric disorders such as depression or schizophrenia. This leads many patients to assume they have a purely psychiatric disorder and to seek help from a psychiatrist first. One study found that this occurred in 76% of patients ultimately diagnosed with NMDA receptor encephalitis27!
This becomes problematic when psychiatrists are not aware that early stages of autoimmune encephalitis can mimic psychiatric disorders. Rather than ordering antibody tests to examine a potential autoimmune disorder, they may assume the patient has major depressive disorder or another psychiatric disorder. Based on this assumption, they may attempt to treat the patient with anti-depressant therapies rather than treatments aimed at the underlying autoimmune condition. This is unfortunately not a hypothetical scenario. In a study examining a group of 464 people with NMDA receptor encephalitis, nearly 10% were initially diagnosed with a psychiatric disorder, including depression, before the correct diagnosis of NMDA receptor encephalitis was reached6.
A timely diagnosis is critical in treating autoimmune encephalitis, since earlier administration of immunotherapies is associated with better patient outcomes28. A delay in a correct diagnosis and treatment plan can be especially harmful given that an estimated 10% of patients with NMDA receptor encephalitis experience suicidal thoughts29. Luckily, as more is learned about AE, psychiatrists are becoming increasingly educated and aware of the psychiatric symptoms of the disease. An improved awareness of AE will allow for faster and more accurate diagnoses, leading to faster treatment and improved outcomes for patients suffering from this disease.
- Kessler RC, Bromet EJ. The epidemiology of depression across cultures. Annu Rev Public Health. (2013) 34:119–38. doi: 10.1146/annurev-publhealth-031912-114409
- Abajobir AA, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. (2017) 390:1211–59. doi: 10.1016/S0140-6736(17)32154-2
- American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th ed.) (2013). doi: 10.1176/appi.books.9780890425596
- Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V, Ustun B. Depression, chronic diseases, and decrements in health: results from the World Health Surveys. Lancet. (2007) 370:851–8. doi: 10.1016/S0140-6736(07)61415-9
- Pape K, Tamouza R, Leboyer M, Zipp F. Immunoneuropsychiatry – novel perspectives on brain disorders. Nat Rev Neurol (2019) 15(6):317–28. doi: 10.1038/s41582-019-0174-4
- Al-Diwani A et al. The psychopathology of NMDAR-antibody encephalitis in adults: a systematic review and phenotypic analysis of individual patient data. Lancet Psychiatry (2019) 6(3):235–46. doi: 10.1016/S2215-0366(19)30001
- Patten SB, Marrie RA, Carta MG. Depression in multiple sclerosis. Int Rev Psychiatry (2017) 29(5):463–72. doi: 10.1080/09540261.2017.1322555
- Benros, M. E. et al. Autoimmune diseases and severe infections as risk factors for schizophrenia: a 30-year population-based register study. Am. J. Psychiatry (2011)168, 1303–1310.
- Hoang H, Laursen B, Stenager EN, Stenager E. Psychiatric co-morbidity in multiple sclerosis: The risk of depression and anxiety before and after MS diagnosis. Mult Scler J. (2016) 22:347–53. doi: 10.1177/1352458515588973
- Marrie RA et al. Rising incidence of psychiatric disorders before diagnosis of immune-mediated inflammatory disease. Epidemiol Psychiatr Sci. (2017) 28:333–42. doi: 10.1017/S2045796017000579
- Kelley, K. W. et al. Cytokine-induced sickness behavior. Brain Behav. Immun. (2003) 17(Suppl. 1):112–118
- Haapakoski, R., Mathieu, J., Ebmeier, K. P., Alenius, H. & Kivimaki, M. Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain Behav. Immun. (2015) 49, 206–215
- Shelton RC, Claiborne J, Sidoryk-Wegrzynowicz M, Reddy R, Aschner M, Lewis DA, Mirnics K. Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Mol Psychiatry (2011) 16:751–762
- Fu X, Zunich SM, O’Connor JC, Kavelaars A, Dantzer R, Kelley KW. Central administration of lipopolysaccharide induces depressive-like behavior in vivo and activates brain indoleamine 2,3 dioxygenase in murine organotypic hippocampal slice cultures. J Neuroinflammation(2010) 7(43):1–12
- Renault PF et al. Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med. (1987) 147:1577–80. doi: 10.1001/archinte.1987.00370090055011
- Mohr DC, Goodkin DE, Islar J, Hauser SL, Genain CP. Treatment of depression is associated with suppression of nonspecific and antigen-specific TH1 responses in multiple sclerosis. Arch Neurol. (2001) 58:1081. doi: 10.1001/archneur.58.7.1081
- Ohgi Y, Futamura T, Kikuchi T, Hashimoto K. Effects of antidepressants on alternations in serum cytokines and depressive-like behavior in mice after lipopolysaccharide administration. Pharmacol Biochem Behav. (2013) 103:853–9. doi: 10.1016/j.pbb.2012.12.003
- Hannestad J, Dellagioia N, Bloch M. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology. (2011) 36:2452–9. doi: 10.1038/npp.2011.132
- Ramirez K, Shea DT, Mckim DB, Reader BF, Sheridan JF. Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance. Brain Behav Immun. (2015) 46:212–20. doi: 10.1016/j.bbi.2015.01.016
- Kohler, O. et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry (2014) 71:1381–1391
- Warner-Schmidt JL, Vanover KE, Chen EY, Marshall JJ, Greengard P. Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc Natl Acad Sci USA. (2011) 108:9262–7. doi: 10.1073/pnas.1104836108
- Hansen N and Timaus C. Autoimmune encephalitis with psychiatric features in adults: historical evolution and prospective challenge. J. Neural Transm. (2021) 128:1-14
- Kruse JL et al. Psychiatric autoimmunity: N-methyl-D-aspartate receptor IgG and beyond. Psychosomatics. (2015) 56(3)227-241
- Wang W, Zhang L, Chi XS, He L, Zhou D, Li JM. Psychiatric symptoms of patients with anti-NMDA receptor encephalitis. Front in Neurol.(2020) doi: 10.3389/fneur.2019.01330
- Planaguma J et al. Human N-methyl-D-aspartate receptor antibodies alter memory and behaviour in mice. Brain 138(1):94-109
- Dalmau J, Armangué T, Planagumà J, Radosevic M, Mannara F, Leypoldt F, Geis C, Lancaster E, Titulaer MJ, Rosenfeld MR, Graus F (2019) An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol 18:1045–1057
- Dalmau J et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol., (2008) 1091-1098.
- Titulaer MJ, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol (2013)12:157-165.
- Zhang L et al. Suicidality is a common and serious feature of anti-N-methyl-D-aspartate receptor encephalitis. J Neurol. (2017) 264(12):2378-2386.
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