Can schizophrenia be affected or even caused by viral infections? Is it possible that common infections and viruses like herpes can trigger schizophrenia? Some epidemiological studies have indicated prenatal viral infection as one of the factors in the development of schizophrenia but which way the risk lies is not still well understood.

Background on schizophrenia

Symptoms and diagnosis

Schizophrenia is a chronic mental disorder that can cause disability and affects 1% of the world's population. It is characterized by recurring episodes of psychosis which can include hallucinations and misperception of reality. Early symptoms usually appear in late adolescence or early adulthood coinciding with the end of the development of the brain.¹

Cognitive functions like attention, verbal memory, reasoning, and processing speed are reduced in people who suffer from schizophrenia.² Also, they show deficits in social cognitive abilities, like identifying emotions, inferring people's thoughts, and reacting emotionally to others.³ These cognitive deficits associated with schizophrenia make affected Individuals likely to have a functional and social disability.⁴

Physiopathology of schizophrenia

It is believed that schizophrenia and psychotic disorders affect mainly the temporal lobe, one of the main regions of the cortex brain involved in processing sensory information into long-term memory. Brain CT (Computed tomography Scan) and MRI (magnetic resonance imaging) findings in patients have shown enlarged lateral cerebral ventricles (cavities of the human brain) and decreased volume of the cerebral cortex (part of the brain responsible for cognition), mainly in the frontal and temporal lobes, as well as reduced hippocampal volume which is common in neurodegenerative diseases like Alzheimer.⁵

Risk factors

The etiology of schizophrenia still remains unknown but it is believed to be a combination of genetic and environmental factors. The rate in monozygotic twins is 50% and is considered as strong evidence of environmental factors influence.⁶

Despite this, it is believed that schizophrenia can have a heritability of up to 80%.⁷ If one of the parents has schizophrenia, the risk of passing it to the offspring is 13%. If both parents are affected, the risk increases to more than 20%.⁸ Therefore, genetics has a strong influence on the development of schizophrenia environmental factors for Schizophrenia, the most important identified are:⁸ 

• Substance and drug abuse
• Pregnancy and birth complications
• Stress
• Infections

In this article, we are going to focus on the last factor, specifically, viral infections.

Background on virus infections

Viruses are infectious agents which only can reproduce by infecting a host cell. They are formed by a genomic particle inside a capsule. Our immune system can recognize proteins on viral capsids and this leads to the immune response.

The immune response involves proteins called cytokines. Cytokines are a wide group of proteins responsible for cell signalling during infection. They act as messengers indicating to the immune cells what to do. Some of these cytokines have proinflammatory effects and these are the ones believed to hurt brain development and increase the risk of schizophrenia.⁹

Evidence linking virus infections to schizophrenia

Many viruses have been associated with schizophrenia and mental disorders. Most of the studies have been conducted on neurotrophic and neuroinvasive viruses.⁹ A neurotropic virus is a virus that can infect nerves like poliovirus, rabies virus, or even the common herpes type 1, well known because it is responsible for cold sores.

For decades it has been known that viral infections can trigger psychiatric disorders, especially when they occur during the first and second trimester of pregnancy.¹⁰ Despite this, the molecular pathways are not fully known. 

Some studies have found a relationship between higher prenatal levels of inflammatory markers like cytokines and increased schizophrenia risk. These molecules are not indicators of infection themselves but their levels rise during the immune response. Many researchers have found an association between the levels of some cytokines. However, although levels of some inflammatory cytokines like TNF-α,  IL-8, and IL-10 seem to be related to a higher schizophrenia risk, other cytokines (IL-4, IL-5, and IL-13) have been associated with lower odds of psychosis.⁹ 

Studies of these markers can provide evidence regarding specific immune system pathways as potential mechanisms linking prenatal infection to schizophrenia risk in the offspring.

Specific viruses implicated in schizophrenia

Herpesviridae virus

Herpesviridae is a large family of common viruses, which typically infects through the mucosal surface and migrate to the nervous ganglia where they remain dormant and can be reactivated producing outbreaks.

• Herpes virus type 1 (HSV-1) which causes cold sores.
• Herpes virus type 2 (HSV-2) responsible for  genital herpes
• Herpes zoster (HHV-3), is well known for causing varicella in the first outbreak and shingles in the following outbreaks.
• Epstein Barr Virus (HHV-4) which causes infectious mononucleosis.
• Cytomegalovirus (HSV-5)

Herpes viruses are very common viruses. It is estimated that HSV-1 and HSV-2 affect 67% and 13% of the population respectively,¹¹ around one-third of the American population have Herpes Zoster,¹² 95% have been exposed to Epstein Barr Virus (EPV).¹³  and almost 60% to cytomegalovirus (CMV).¹⁴

Herpes simplex type 1 and 2

Probably the most well-known viruses of the herpes-viridae family, they are very similar. HSV-1 infects mainly oral mucosa and HSV-2 appears on the genitals but both of them can infect either face or genital and are considered STI (Sexual Transmitted Infections).

HSV-1, HSV-2, and also cytomegalovirus (CMV) exposure has been linked with lower levels of working memory in patients with schizophrenia and a control group of healthy patients. One study with 423 participants of which 105 had schizophrenia found that seropositivity and antibody levels of HSV, HSV-2, and CMV viruses were associated with lower scores on working memory.¹⁵ Other studies with 45 schizophrenia patients and a control of 45 healthy people showed that antibody levels were higher in HSV-1, HSV-2, and CMV.¹⁶ More studies have found a correlation between maternal exposure to HSV-2 and the risk of schizophrenia. However, the relationship between exposure to HSV-1 and HSV-2 remains controversial because at least two studies have not found a correlation between them.⁹

Epstein barr virus (EPV)

EPV causes 90% of the syndrome commonly named infectious mononucleosis. However, only 15–20% of teenagers and about 40% of adults exposed to the virus develop infectious mononucleosis.¹⁷

Some studies have associated the presence of antibodies to different EBV proteins with a higher risk for schizophrenia and depressive disorders.^{18 19} Antibodies to different EBV proteins could be associated with differential levels and domains of cognitive functioning in individuals with schizophrenia. 

Cytomegalovirus

Cytomegalovirus (CMV) are common viruses that usually do not cause any symptoms. CMV can be transmitted from the mother to the fetus. Some studies have found a relationship between CMV infection and schizophrenia. One of them measured an immunoglobulin (IgG) in two groups, one control of healthy people and another one with schizophrenia patients. The researchers found that the percentage of people with IgG positivity was higher in the patient group diagnosed with schizophrenia (81.3%) than in the psychiatrically healthy control group (48.6%). On the other hand, in a review of 14 similar studies, there was no difference in CMV IgG levels between the schizophrenia patient and control groups. However, these studies were conducted a few decades ago (1973–1992), CMV IgG was investigated using methods with low sensitivity (so it could be not detected in some individuals) and the schizophrenia group was not sufficiently structured according to current information. This may be the reason why no relationship was found between schizophrenia and CMV IgG.²⁰

Instead, more recent studies have reported that CMV infection is related to schizophrenia, affective disorder, a decrease in cognitive functions, and suicide risk. A study with 81,912 cases carried out in Denmark in 2019 found that CMV was statistically related to the state of having any psychiatric illness.²¹

Influenza viruses

Influenza viruses cause the flu and several authors have related them with schizophrenia. Statistically, the schizophrenia rate is higher in people born at the end of winter and beginning of spring. As winter is the high season for flu this is considered evidence that prenatal exposure to influenza can trigger schizophrenia in the offspring.^8,9 Several epidemiological studies have been conducted to determine the relationship between influenza virus infection and schizophrenia. Some of them have studied the influence of flu epidemics on the population. One of these studies, conducted in Helsinki with 1781 patients showed an increased risk of schizophrenia among individuals whose second trimester of fetal life coincided with the flu epidemic that occurred in 1957, compared to those whose fetal life coincided with the first or third trimester.²²

Another study with 973 schizophrenic patients compared with their non-schizophrenic brothers found an association between exposure to the influenza virus, especially during the second trimester of pregnancy, and the manifestation of schizophrenia.²³

Despite these findings, a big study was carried out with 43,778 people with schizophrenia and compared it to 10,496,686 births between 1950 and 1959 in the USA. They studied the schizophrenia rate just before, during, or after the 1957 flu epidemic and they did not find any significant increase in the schizophrenic birth rate.²⁴

In conclusion, the association between the influenza virus and schizophrenia is still a controversial subject among the scientific community.

Other viruses

Other viruses such as COVID-19, retroviruses, or parvovirus have been studied as possible triggers of schizophrenia. However, in many of them, there is still not much evidence available to see a correlation.

Summary

Schizophrenia is a multifactorial disorder, which can be caused by both genetic and environmental factors. The influence of viral infections remains uncertain. Given that a large part of the population has been exposed to many of the viruses mentioned above and schizophrenia only affects 1% of the population, viruses can likely be a trigger along with other factors. More research is necessary to determine this association and also help to prevent and predict Schizophrenia onset.