Robert Yolken, MD

The association between infection and psychiatric disorders was one of the milestones of early 20th century medicine. The identification of 

 in the brains of individuals with “general paresis of the insane” by Noguchi and Moore in 1913 established the role of tertiary syphilis and showed that bacterial infections can cause long-term changes in both neurological and psychiatric functioning. The eventual development of treatments for syphilis and the subsequent curing of individuals with general paresis also showed that the discovery of an infectious cause of a neuropsychiatric disorder could be followed by effective treatment. The association between infection and some cases of psychiatric disorders was further solidified by the identification of an increased rate of encephalitis lethargica following the influenza epidemic of 1918-1919. Influenza control measures might be partially credited for the rarity of encephalitis lethargica in the modern era.

Since that time and until recently, the association between infection and psychiatric disorders has received less attention than other causes of psychiatric disorders such as emotional stress and genomics. However, there has been a resurgence of interest in the role of infections in psychiatric disorders because of a number of scientific advances in the understanding of how infectious agents and the immune response can alter brain functioning and affect human behavior.

One advance that has rekindled interest in a role for infectious agents is an increased understanding of the mechanisms by which a range of microorganisms can enter the central nervous system and establish long-terms persistence within the human brain. It had been previously thought that infection of the brain would lead to characteristic signs of inflammation such as white cell infiltration, granulomas, and tissue destruction.

Postmortem examination revealed that these features are uncommon in the brains of individuals with serious psychiatric disorders, thus suggesting that infection is uncommon in persons with these disorders.

 However recent discoveries have shown that many neuropathic infectious agents have complex mechanisms that allow them to lie dormant within the brain for extensive periods with little evidence of classical inflammatory reactions.

 This concept is consistent with recent studies indicating that there is substantial immune activity in the brains and systemic circulation of individual with psychiatric disorders.

Microorganisms capable of his latency include a diverse range of taxa including viruses such as the herpesviruses herpes simplex virus types 1 and 2, cytomegalovirus, and Epstein Barr virus as well as retroviruses such as human immunodeficiency virus, measles virus, bacteria such as 

There has been an increased understanding of the workings of the immune system within the CNS. It is now clear that the immune system in the brain utilizes specialized cells and mechanisms not found in other parts of the body. This difference is best exemplified by the microglia, which are specialized cells within the brain that form during fetal development and are present from birth. While microglia have multiple biological activities, their main function is the monitoring of infections agents and the generation of a controlled immune response.

Microglia are activated following infection with viral, bacterial, fungal, and protozoan agents through a complex and highly refined process of signaling that is mediated by pattern recognition molecules called toll-like receptors. Microglial activation has been documented in a wide range of psychiatric disorders including schizophrenia, bipolar disorder, and autism. Because the pattern of response to infectious agents is similar, microorganisms from widely diverse taxa can cause similar activation of immune processes and, hence, similar clinical pictures.

The list of infectious agents with neuropsychiatric potential includes a diverse set of taxonomic kingdoms including viruses, bacteria, and protozoa, largely overlapping with the microorganisms capable of establishing latency within the brain. The concept that different microorganisms can cause similar clinical disorders represents a divergence from the usual conceptualization of infectious diseases: that each disorder is caused by a specific infectious agent and that each agent has an identifiable clinical effect.

This understanding, derived from Koch’s famous postulates, is useful for the study of many infectious disease. However, this concept has been less useful for the study of complex brain disorders due to the substantial overlap in the immune response to infectious agents within the brain. The role of the immune system also opens the possibility of immune-based therapies for psychiatric disorders, although these are mostly in the stages of development and evaluation.

Microglial activation can be measured in patients using neuroimaging techniques such as PET scanning. However, the optimal method for employing these scans and their sensitivity and specificity in clinical practice have not yet been defined.

 The pharmacological targeting of microglial activation remains a promising approach in terms of novel therapeutic interventions for a range of psychiatric disorders.

Another advance in understanding the potential role of infections and inflammation in brain disorders are research findings that suggest the brain does not exist as an isolated organ but rather interacts with many other organ systems in the body. The gastrointestinal tract is the best characterized brain-interacting organ system. Numerous studies indicate that the gastrointestinal tract and the brain interact with each other by means of a series of networks categorized as the gut-brain-axis.

Clinical manifestations of the gut-brain axis have been long noted by clinicians who observed a high rate of gastrointestinal symptoms in individuals with psychiatric disorders and a correspondingly high rate of psychiatric symptoms in individuals with gastrointestinal disorders, particularly immune-based gastrointestinal disorders such as inflammatory bowel diseases. Alterations in gut-based immune markers have been found in several psychiatric disorders including schizophrenia, bipolar disorder, and major depressive disorder as well as in individuals who had a recent suicide attempt.

Recent studies have also shown that genetic differences can modulate the individual response to infectious agents. Many components of the immune system display individual variation based on genetic elements that comprise the human leukocyte antigen (HLA) and other immune networks. This immune variation is likely to explain much of the individual variation in response to infectious agents. For example, not every person who is exposed to the protozoan 

 is at an increased risk for a psychiatric disorder-some of the variation apparently results from genetic differences.

In the case of Epstein Barr virus, increased risk of schizophrenia appears to be associated with an altered immune response to viral proteins, some of which is likely to be under genetic control. Furthermore, many microbial agents also have their own genomes, which can vary and define differing degrees of pathogenicity. For example, some strains of 

 appear to be more associated with psychiatric disorders than others.

Interestingly, many of the genetic regions associated with increased risk of psychiatric disorders have been shown to encode components of the immune system and other immune active proteins. This finding suggests that some of the genetic risk of psychiatric disorders lies in variations in the immune response to infectious agents. In this scenario, many cases of psychiatric disorders represent an environmental exposure occurring in a genetically susceptible individual in a manner characterized as representing gene-environmental interactions.

Microbes can also interact with each other within the gastrointestinal tract and other mucosal sites. This combination of microbes within the gastrointestinal tract has been characterized as the microbiome. Each person’s microbiome is established in early life and is determined by genetic and environmental factors. Environmental factors that shape the microbiome include exposure to microbial agents through breast feeding and household contacts, exposure to viruses and other agents that infect the gastrointestinal tract, exposure to allergens and diet.

The microbiome can also be altered by antibiotics and other pharmacological agents including many medications that are used to treat psychiatric disorders. Numerous studies have documented altered microbial composition in samples from individuals with a range of psychiatric disorders including schizophrenia, recent onset psychosis, bipolar disorder, and autism.

The microbiome can also affect the metabolism and pharmacokinetics of orally administered therapeutic agents. Person to person differences in the microbiome might thus explain some of the individual variation noted in the response to orally administered psychotherapeutic agents.

Another intriguing aspect of the microbiome is that is can be manipulated therapeutically by low-toxicity modalities. One type of intervention involves the administration of non-pathogenic microorganisms that can colonize the gastrointestinal tract, generally termed probiotics. Another intervention involves the administration of substances, generally non-digestible sugars called oligosaccharides that are nutrients for non-pathogenic bacteria in the diet and hence can indirectly alter the microbiome. Such prebiotics can also be combined with probiotics to generate what has been characterized as synbioti preparations.

The potential role of probiotic agents in psychiatric disorders is evidenced by some recent research. One study documented that the administration of a probiotic preparation administered with standard medications prevented relapse in individuals discharged after hospitalization for acute mania.

 Another study showed that a similar probiotic preparation improved gastrointestinal symptoms and decreased markers of inflammation in individuals with schizophrenia, although psychiatric symptoms were not significantly altered.

Additional studies are needed to define the optimal dosage and composition of probiotic regimens as well as optimal treatment regimens. In addition, methods for documenting potency and shelf life of different commercially available preparations are needed. For these reasons, probiotic or previous preparations are not currently recommended for general use in the prevention or treatment of psychiatric disorders.

Antibiotics have been shown to increase the incidence of psychiatric disorders when administered in childhood, and the administration of antibiotics has been shown to be increased before hospital admission for a psychiatric disorder.10 These studies suggest that alterations in the microbiome might also have adverse effects and that the judicious use of antibiotics and the normalization of the microbiome following antibiotic use might be way to prevent some cases of psychiatric disorders.

The resurgence of interest in the role of infections and inflammation in serious psychiatric disorders provides exciting opportunities in terms of novel diagnostic methods and therapeutic interventions. Most of these innovations remain in the future, although there may be individual patients who can benefit from immunological evaluations and immune-based therapies. However, blanket recommendations concerning specific diagnostic tests cannot be made at this time but should be evaluated on a case-by-case basis. The number of patients who might respond to immune or infectious disease-based therapies is unknown.

To make further advances clinical research studies are needed. In the meantime, we need to focus on the development of additional methods for the detection of infection and inflammation in the brain, improved pharmacological control of brain infection and inflammation, and clinicians who are alert to the possible occurrence of infectious and inflammatory disorders in each patient.

Dr Yolken is Theodore and Vada Stanley Distinguished Professor of Neurovirology in Pediatrics, Johns Hopkins University, Baltimore, MD; Ms Shwartz is a Psychiatric-Mental Health Nurse Practitioner, Telecare Corporation, Alameda County, CA; and Dr Quanbeck is Associate Medical Director, Cordilleras Mental Health Rehabilitation Center, San Mateo County Health, Redwood City, CA.

 Bakhshi K, Chance SA. The neuropathology of schizophrenia: a selective review of past studies and emerging themes in brain structure and cytoarchitecture. 

 Severance EG, Xiao J, Jones-Brando L, et al.Toxoplasma gondii-A gastrointestinal pathogen associated with human brain diseases. 

 Khandaker GM, Cousins L, Deakin J, et al. Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. 

 MÃ¼ller N. Immunological aspects of the treatment of depression and schizophrenia. Dial Clin Neurosci. 2017;19:55-63.

 Tronel C, Largeau B, Santiago Ribeiro MJ, et al. Molecular targets for PET imaging of activated microglia: the current situation and future expectations. 

 Wang AW, Avramopoulos D, Lori A, et al. Genome-wide association study in two populations to determine genetic variants associated with Toxoplasma gondii infection and relationship to schizophrenia risk. 

Prog Neuropsychopharmacol Biol Psychiatry

 Dickerson F, Adamos M, Katsafanas E, et al. Adjunctive probiotic microorganisms to prevent rehospitalization in patients with acute mania: a randomized controlled trial. 

 Dickerson FB, Stallings C, Origoni A, et al. Effect of probiotic supplementation on schizophrenia symptoms and association with gastrointestinal functioning: a randomized, placebo-controlled trial. 

 KÃ¶hler-Forsberg O, Petersen L, Gasse C, et al. A nationwide study in Denmark of the association between treated infections and the subsequent risk of treated mental disorders in children and adolescents. 

Articles

Ongoing research has identified multiple infectious diseases that may play a role in the development of neuropsychiatric disorders, particularly in people predisposed to genetic and environmental factors.

Author | Robert Yolken, MD

Articles

Psychiatric Disorders: Are Infectious Agents to Blame?