Jacqueline A. Hobbs, MD, PhD, DFAPA

This activity offers CE credits for:
1. Physicians (CME)
2. Other

To understand the pathogenic impact of viruses on mental illness.

At the end of this CME activity, participants should be able to:

• Name viruses that can infect the brain

• Discuss the neurodevelopmental hypothesis of schizophrenia

• Recognize genetic and environmental factors that may contribute to the pathogenesis of mental illness

• Describe possible mechanisms by which viruses may contribute to mental illness

This continuing medical education activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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Everyone has had a cold or flu, right? How does it feel? There is usually a sense of malaise or general discomfort. You may have felt sad or blue. You may have had a high fever associated with a viral infection that made you hallucinate (or have illusions) or at least wonder whether you were hallucinating. In fact, psychiatrists and scientists have wondered for well over 100 years whether viruses (and other infections) can actually cause mental disorders.

Association of viruses with schizophrenia and bipolar disorder

There are many theories about the causes of schizophrenia and bipolar disorder as well as other mental disorders. There is the question of nature versus nurture, or genes versus environment. There is much support for genetic factors as etiologies of schizophrenia and bipolar disorder, but no particular gene has been shown to be completely responsible. It is likely that many genes contribute small effects to the overall disease phenotype. Although the heritability of these disorders has in some studies been shown to be quite high, there is plenty of evidence for environmental factors as well.

Many people associate a viral infection such as a cold or flu with winter. We spend more time indoors because of the cold, which allows viruses to spread easily. Interestingly, birth in late winter or early spring-the period when many viral infections are at their height-has been found to increase the development of schizophrenia by approximately 10%.

 This finding along with other evidence has led to a theory of a viral etiology for schizophrenia and bipolar disorder.

Viruses that have been associated with schizophrenia and other chronic mental illnesses such as bipolar disorder, MDD, and autism include but are not limited to influenza viruses; human endogenous retroviruses; and the herpesviruses, such as cytomegalovirus, Epstein-Barr virus, and herpes simplex virus. Influenza as a contributor to schizophrenia pathogenesis has a large evidence base, both from older literature and more recent studies.

As we make breakthroughs in neuroscience and neurovirology, the possibilities for prevention, diagnosis, and treatment of mental illness seem limitless.

One might ask how so many different types of viruses with different infectious properties are involved in the pathogenesis of mental disorders. Can any one virus be truly accountable as a cause of one or several mental illnesses? The short answer is, we don’t know. But it is likely that many different viruses (and other infectious agents) have the ability to trigger certain immune and signaling pathways when they infect during a particular neurodevelopmental window of susceptibility, which ultimately leads to the brain disease process that ends in a mental disorder. Also, it is likely that viruses are just one hit in a multi-hit process that culminates in a major psychiatric disorder.

Possible mechanisms of virus-induced psychopathology

There are several proposed mechanisms by which viruses may contribute to psychopathology. The overarching theory for the development of major psychiatric disorders is the neurodevelopmental hypothesis, which states that psychiatric disorders (eg, schizophrenia) are the result of insults (eg, viral infection) on neuropathological processes that occur throughout neurodevelopment.

 These insults can start as early as the late first trimester and may continue during adolescence and early adulthood when processes such as cortical myelination are still in development. The insults may lead to pathological brain circuit function that results in mental disorder symptoms such as delusions or mood disturbances.

Moreover, viruses can be directly neurotoxic and induce apoptosis or programmed cell death in susceptible brain cells. Imagine if this were to happen in utero during early neurodevelopment. If too many or certain types of critical cells in certain brain circuits (or in areas that would ultimately become circuits) were killed, it could lead to long-term behavioral, cognitive, and emotional consequences. One might wonder why the effect would not be noted early on instead of later in life as occurs with many severe mental illnesses that manifest in the late teens and early 20s. It may be that the effects are subtle early on, and other cells/circuits compensate, but with further specialization, development, and demand-as well as additional insults to the brain (eg, cannabis use)-the disorder becomes manifest.

The effects of viral infections from childhood to adulthood can range from benign to severe. For example, viral infections of the CNS can cause meningitis and encephalitis. These may be self-limited or have short- to long-term effects (eg, headache, seizure)-or they can lead to death. In the same way, one can imagine that a virus might produce a range of effects during in utero infection that could leave some intermediate and long-term effects on the brain that may ultimately result in a psychotic or other neuropsychiatric process.

Besides direct neurotoxicity, the immune response to viruses-both in the CNS and in the periphery-may play a role in the development of major mental disorders. A sense of malaise and other symptoms of viral infections result from the immune response. A particular response, and a major cause of the illness-related symptoms such as fever and muscle and joint aches, is the release of cytokines such as interferons and interleukins. Viruses that infect the brain or other organs such as the thyroid can affect brain development and function, consequently altering the expression of various cytokines and hormone receptors, including the thyroid hormone receptor.

 An overactive immune response such as occurs in inflammation and autoimmunity may be a mechanism by which viral infections cause changes in brain development, structure, and function, especially if it occurs during neurodevelopment.

Active investigation into the role of cytokines in mental illness has revealed that in a significant number of individuals with bipolar disorder, the cytokine profile in their immune cells is of an inflammatory nature.

 This knowledge may one day lead to biomarkers of the disorder to aid in diagnosis-something sorely needed for bipolar disorder, which can remain undiagnosed and untreated for many years.

In a significant number of individuals with bipolar disorder, the cytokine profile in their immune cells is of an inflammatory nature.

In addition to diagnosis, the role of cytokines in inflammation has also been investigated for treatment of mental disorders, in particular schizophrenia. The use of anti-inflammatory drugs such as aspirin and celecoxib for the treatment of schizophrenia has been investigated; however, this is controversial and cannot be recommended at this time.

 It is likely that much is still to be learned about the biology of inflammation in mental disorders. It is possible that the timing of treatment is important because the disease process may have started during very early neurodevelopment; thus, anti-inflammatory drugs may not be as helpful long after the initial insult.

The effects of viruses on the brain and mental disorders may not be of immediate clinical relevance for the practicing psychiatrist. However, it is important to understand that viruses can alter a person’s neurodevelopment and neurobiology. Awareness of past, current, and future research in this area can help in the psychoeducation of patients and their families. Understanding of the causes of mental illness can reduce stigma and help patients to see their disorders as brain diseases that are not unlike medical illnesses (eg, hypertension, cardiac disease) that require often long-term therapy. Effective treatment may take trial and error as well as a combination of interventions. It may also be helpful for patients to understand that, much like cancer, chronic mental illness likely results from multiple hits during neurodevelopment, beginning in utero and progressing to adolescence and early adulthood.

In addition, patients can be reassured that research continues in this area and will hopefully lead to innovative prevention and treatment strategies. For example, vaccines against known viruses such as influenza viruses as well as future vaccines for newly emerging viruses are likely key to preventing schizophrenia and other severe and chronic mental disorders.

For those who are involved in the education of medical students and psychiatric residents, having an understanding of potential causes of mental illnesses such as viruses can be a great way to capture the students’ attention and interest. The role of infectious agents in disease is often intriguing to those who have seen movies such as 

. It can be an exciting area that leads to an enhanced interest in mental disorders, their causes, and treatments.

As medical practitioners, psychiatrists cannot ignore viruses. Emerging viruses such as Zika 

 if infections occur in utero; such infections may lead to microcephaly and other severe brain defects.

Although we have made many strides, there is so much we do not know about the brain in general-and even less about the neuroscience of mental illness. Therefore, our understanding of viruses and their relationship to mental illness is extremely limited. As we make breakthroughs in neuroscience and neurovirology, the possibilities for prevention, diagnosis, and treatment of mental illness seem limitless.

Many questions remain. How many viruses infect the brain and when? How many latent viruses remain in brain cells at any one time? How many viruses can any one neuron or glial cell harbor at any given time? What effect do these viruses have on the brain, and what effect does a combination of viruses have on the brain? Much work lies ahead, but the possibilities for informing our clinical work are limitless.

Much like cancer, chronic mental illness likely results from multiple hits during neurodevelopment, beginning in utero and progressing to adolescence and early adulthood.

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More about Jacqueline A. Hobbs, MD, PhD, DFAPA

Neurovirology, the study of viral infection of the nervous system, is what truly got me interested in pursuing psychiatry as a career. 

It all began when I was an MD-PhD student at Indiana University. After the first 2 years of medical school, I pursued my PhD studies in microbiology and immunology. My thesis and later postdoctoral studies were focused on the effects of viral infections on the immune system. When I returned to medical school, I saw myself as a virologist and thought I would become an infectious disease specialist. However, clinically, I was intrigued by patients with severe psychotic disorders, and I was torn about how I would combine these interests. They just did not seem to fit together. That was when I started learning about theories of infectious causes of schizophrenia such as influenza. That was it-I was hooked!

During my residency, I received funding from the Stanley Medical Research Institute to study the potential role of parvoviruses in schizophrenia. I went on to study parvovirus infection of both the brain and thyroid at the University of Florida. Parvoviruses are small DNA viruses, some of which cause human disease (possibly brain disease). I published the largest study of parvovirus detection in the brain, including in schizophrenia and bipolar disorder. Parvoviruses can be detected in the thyroid gland, the disease of which can influence mood and cognition. And, parvoviruses can affect the immune system.

At this point, there is still much to learn. We cannot definitively prove cause and effect of viruses and mental disorders. However, there is so much we do not understand about the brain and the interplay with the immune system. We still have so much to learn about mental disorders. We know viruses infect the brain. We know that viruses activate/alter the immune system. We are learning much more about immune-brain interactions.

I’m excited to keep learning the neurobiology of mental disorders and take a very holistic view of how other body systems such as the immune and endocrine systems may influence the brain and mental disorders. I hope that one day we psychiatrists, as well as the patients we serve, will have a broad view of mental disorders based on neurobiological, endocrine, immune, psychological, and infectious factors, and that this will lead to further breakthroughs in treatments.

Dr. Hobbs is Vice Chair for Education, Director, Residency Training Program, University of Florida College of Medicine, Department of Psychiatry, Gainesville, FL.

 Mortensen PB, Pedersen CB, Westergaard T, et al. Effects of family history and place and season of birth on the risk of schizophrenia. 

 Yolken RH, Torrey EF. Viruses, schizophrenia, and bipolar disorder. 

 Mednick SA, Machon RA, Huttunen MO, Bonett D. Adult schizophrenia following prenatal exposure to an influenza epidemic. 

 Parboosing R, Bao Y, Shen L, et al. Gestational influenza and bipolar disorder in adult offspring. 

 Giovanoli S, Engler H, Engler A, et al. Preventive effects of minocycline in a neurodevelopmental two-hit model with relevance to schizophrenia. 

 Keshavan MS. Development, disease and degeneration in schizophrenia: a unitary pathophysiological model. 

 Fatemi SH, Folsom TD. The neurodevelopmental hypothesis of schizophrenia, revisited. 

 Hobbs JA. Detection of adeno-associated virus 2 and parvovirus B19 in the human dorsolateral prefrontal cortex. 

 Adamson-Small LA, Ignatovich IV, Laemmerhirt MG, Hobbs JA. Persistent parvovirus B19 infection in non-erythroid tissues: possible role in the inflammatory and disease process. 

 Polcz ME, Adamson LA, Lu X, et al. Increased IL-6 detection in adult and pediatric lymphoid tissue harboring parvovirus B19.

 Ignatovich IV, Hobbs JA. Human parvovirus B19 infection leads to downregulation of thyroid, estrogen, and retinoid hormone receptor expression. 

 Padmos RC, Hillegers MH, Knijff EM, et al. A discriminating messenger RNA signature for bipolar disorder formed by an aberrant expression of inflammatory genes in monocytes. 

 Andrade C. Anti-inflammatory strategies in the treatment of schizophrenia. 

 Centers for Disease Control. Zika virus. 

http://www.cdc.gov/zika/pregnancy/index.html

Articles

Here's a deep dive into possible mechanisms by which viruses may contribute to mental illness. 

Jacqueline A. Hobbs, MD, PhD, DFAPA

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The Virus Connection: How Viruses Affect Psychiatric Pathologies