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Bransfield, R.C.; Mao, C.; Greenberg, R. Microbes and Mental Illness: Past, Present, and Future. Encyclopedia. Available online: https://encyclopedia.pub/entry/53520 (accessed on 07 July 2024).
Bransfield RC, Mao C, Greenberg R. Microbes and Mental Illness: Past, Present, and Future. Encyclopedia. Available at: https://encyclopedia.pub/entry/53520. Accessed July 07, 2024.
Bransfield, Robert C., Charlotte Mao, Rosalie Greenberg. "Microbes and Mental Illness: Past, Present, and Future" Encyclopedia, https://encyclopedia.pub/entry/53520 (accessed July 07, 2024).
Bransfield, R.C., Mao, C., & Greenberg, R. (2024, January 08). Microbes and Mental Illness: Past, Present, and Future. In Encyclopedia. https://encyclopedia.pub/entry/53520
Bransfield, Robert C., et al. "Microbes and Mental Illness: Past, Present, and Future." Encyclopedia. Web. 08 January, 2024.
Microbes and Mental Illness: Past, Present, and Future
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This entry is adapted from the peer-reviewed paper 10.3390/healthcare12010083

Microbes are associated with a number of mental disorders, including autism, schizophrenia, bipolar disorder, depressive disorders, and anxiety disorders, as well as suicidality and aggressive or violent behaviors. Specific microbes that have been associated or potentially associated with at least one of these conditions include Aspergillus, Babesia, Bartonella, Borna disease virus, Borrelia burgdorferi (Lyme disease), Candida, Chlamydia, coronaviruses (e.g., SARS-CoV-2), Cryptococcus neoformans, cytomegalovirus, enteroviruses, Epstein–Barr virus, hepatitis C, herpes simplex virus, human endogenous retroviruses, human immunodeficiency virus, human herpesvirus-6 (HHV-6), human T-cell lymphotropic virus type 1, influenza viruses, measles virus, Mycoplasma, Plasmodium, rubella virus, Group A Streptococcus (PANDAS), Taenia solium, Toxoplasma gondii, Treponema pallidum (syphilis), Trypanosoma, and West Nile virus.

aggression anxiety autism bipolar depression immune

1. Introduction

As human beings, we are interdependent upon both the microbiota within us and those present within our environment. In 2007, the United States National Institutes of Health Human Microbiome Project was established to study the microbial communities that live in and on our bodies, with the goal of elucidating their role in human health and disease [1]. With advancing technology, there is greater recognition that infectious diseases contribute to not only acute but also chronic illness, both physical and mental. Research from the United States Centers for Disease Control and Prevention (CDC) has recognized “that non-communicable chronic diseases can stem from a variety of infectious agents” [2]. Identifying these relationships between pathogens and illnesses can significantly impact human health, both acutely and chronically. Knowledge of these processes creates opportunities for prevention or early invention. The end goal is to reduce or eliminate the impact of illness, especially chronic disease. Scientific evidence demonstrates more support for the role of infectious agents in cancers, immune-mediated syndromes, neurodevelopmental disorders, and other chronic conditions [2][3].
It is recognized that some infectious diseases can play a significant role in the etiology of neuropsychiatric disturbances. There is little debate that syphilis can cause the development of symptoms of various mental illnesses [4]. Some suspect and others recognize that the novel SARS-CoV-2 virus that is responsible for COVID-19 can contribute to mental illnesses [5]. There exists some uncertainty as to whether some other infections, such as Lyme borreliosis/tick-borne disease, are associated with neuropsychiatric disorders. However, there are over 500 journal articles supporting this association [6][7][8][9][10][11][12][13].

2. Definitions of Relevant Terms

2.1. Microbes and Related Terms

A microbe has traditionally been defined as a very small, living thing that can be seen only with the use of a microscope. There are a number of related terms. The human microbiota is the full array of microorganisms that live on and in humans. The human microbiome is the combined genetic material of the microorganisms that live in and on humans. The pathobiome is the set of human-host-associated organisms (crucially encompassing prokaryotes, eukaryotes, and viruses) associated with reduced (or potentially reduced) health status as a result of interactions between members of that set and the human host.

2.2. Health

A generally accepted definition of health is the ability to adapt and to self-manage in the face of social, physical, and emotional challenges [14].

2.3. Illness

Illness refers to an unhealthy condition of the body or mind: “The human experience of sickness” [15] and “The innately human experience of symptoms and suffering” [16].

2.4. Mental Health

According to the American Psychiatric Association, mental health is a state of mind characterized by emotional well-being, good behavioral adjustment, relative freedom from anxiety and disabling symptoms, and a capacity to establish constructive relationships and cope with the ordinary demands and stresses of life [17]. The World Health Organization defines mental health as “a state of well-being in which the individual realizes his or her own abilities, can cope with the normal stresses of life, can work productively and fruitfully, and is able to make a contribution to his or her community” [18]. In summary, mental health occurs when mental functioning (cognition, emotions, vegetative functioning) reflects the individual’s life situation and facilitates adaptation with the capacity to experience well-being, pleasure, fulfilling relationships, and productive activities; the ability to recognize and contend with adversity; and the mental flexibility to adapt to change.

2.5. Mental Illness

The American Psychiatric Association defines a mental disorder as a syndrome characterized by a clinically significant disturbance in an individual’s cognition, emotion regulation, or behavior that reflects a dysfunction in the psychological, biological, or developmental processes underlying mental functioning [17]. In a state of mental illness, mental functioning does not reflect the life situation, and there is an impairment of adaptive capabilities; an impaired capacity to experience well-being, pleasure, fulfilling relationships, and/or productive activities; a diminished ability to recognize and contend with adversity; and/or restricted mental flexibility to adapt to change.

2.6. Acute vs. Chronic Illness

Acute illnesses generally develop suddenly and last a short time, often only a few days or weeks. Chronic conditions, by contrast, are long-developing and may worsen over an extended period of time—months to years. Chronic diseases more often can be controlled but not cured. Some define chronic diseases as lasting at least 3 or 6 months. Chronic diseases are defined broadly by the CDC as “conditions that last 1 year or more and require ongoing medical attention or limit activities of daily living or both” [19]. Post-acute is a term that has more recently been used.

3. Models for Understanding Disease

Illness is caused by an underlying disease process. To better understand the underlying disease process, a variety of approaches can be used.

3.1. A Multisystem Approach to Understanding the Cause of Disease

A multisystem approach is useful when analyzing complex issues, such as the cause of disease. It allows for a complex model with many contributors. All systems are interconnected and affect other systems to varying degrees. Furthermore, they are constantly changing and in dynamic balance with each other. Time is a significant dimension, and different effects occur over time. Systems have evolved over the dimension of time.

3.2. An Evolutionary or Darwinian Approach to Understanding the Cause of Disease

An evolutionary or Darwinian approach applies the principles of evolutionary biology to help explain problems in medicine and public health and prevent human disease. It explains how disease occurs from the perspective of evolution. From this perspective, disease can be the result of genetic vulnerabilities from the unique path of evolution, design compromises, and competing organisms. Competing organisms can include microbes. “Core principles drawn from evolutionary biology include selection, drift, plasticity, mismatch, cultural practices, trade-offs, life history traits, antagonistic pleiotropy, heterozygote advantage, constraints, biologic defenses, co-evolution (i.e., microbiome), adaptation/maladaptation, novel environments, and the genome-phenome relationship” [20][21].

3.3. An Organismal Approach to Understanding Disease

Disease results from an interaction of host vulnerabilities and environmental contributors. Host vulnerabilities may be genetic or otherwise, and the environmental contributors may be of infectious or non-infectious origin. While acknowledging that there are many non-infectious contributors associated with mental illness, this specifically focuses upon the infectious contributors. The infectious and/or non-infectious contributors may then provoke immune activity that can result in the impairment of adaptive mechanisms, resulting in disease progression [22][23][24][25][26][27][28][29][30][31] (Figure 1).
Healthcare 12 00083 g001
Figure 1. Disease progression. Disease progression evolves over time. The unique path of evolution can create genetic vulnerabilities. Genetic and other vulnerabilities may then interact with pathogens and other disease contributors to begin a pathological process with regulatory dysfunction. The resulting pathological cascade may then lead to symptoms and syndromes (groups of symptoms). The symptoms, and syndromes (e.g., chronic stress, sleep deprivation, immune dysfunction) may further exacerbate disease progression.

3.4. Infections Associated with Mental Illness

A myriad of journal articles address different aspects of the possible connection between infections and mental illnesses. Some mental illness symptoms, such as those associated with delirium, are generally, although not exclusively, associated with the acute phase of infection [32][33]. Viruses and vector-borne diseases have drawn some of the greatest attention. There are at least 320,000 different species of viruses in mammals [34]. Vector-borne diseases are mostly zoonotic, i.e., diseases that are transmitted between species, from animals to humans, or from humans to animals. It appears that vector-borne diseases are increasing, and possible explanations include heightened awareness, climate change, changing ecosystems, globalization, human population growth, and toxic warfare environments [35][36].

3.5. What Mental Illnesses Are Associated with Specific Microbes?

A systematic review and meta-analysis was previously conducted on mental illnesses associated with SARS-CoV-2 infection [37], and a prior PRISMA analysis was performed on mental illnesses associated with Lyme borreliosis [7].
A search was conducted for specific microbes associated with five mental illnesses with the greatest psychiatric disability and two behaviors of particular concern in psychiatric patients.
The microbes identified with these conditions collectively included Aspergillus, Babesia, Bartonella, relapsing fever group Borrelia, Borrelia burgdorferi, Borna disease virus, Candida, Chlamydia, SARS-CoV-2 (COVID-19) and other coronaviruses, cytomegalovirus, enterovirus, Epstein–Barr virus, hepatitis C virus, herpes simplex virus, human endogenous retroviruses, human herpesvirus-6, human immunodeficiency virus (HIV), human T-cell lymphotropic virus type 1 (HTLV-1), influenza viruses, measles virus, Mycoplasma, Plasmodium, rubella virus (congenital), Shigella, group A Streptococcus, Taenia solium, Toxoplasma gondii, Treponema pallidum (syphilis), varicella zoster virus, and changes in intestinal microbiota composition.

3.6. Disease Models

  • Acute vs. chronic infections
As noted earlier, the CDC defines a chronic illness as lasting one year or more [19]. The nomenclature regarding acute vs. chronic infections and acute vs. chronic manifestations of infectious diseases can be confusing. Some acute infections can be “hit and run” and cause residual injury that leads to dysfunction and chronic disease, with the illness continuing and sometimes progressing long after the infection is clearly eradicated. Developing mitral valve stenosis following a streptococcal infection is an example of this. On the other hand, infections can also be recognized as being chronic with ongoing symptoms and often disease progression as the pathogen persists. An example of this is seen with syphilis. Not all infections are easily placed into these two categories. Some infections may be acute, then be latent, and then be reactivated at a later time. An example of this is varicella zoster (chicken pox), which can be reactivated as shingles decades later when the patient is in an immunocompromised state. Some infections may suppress and/or evade the immune system, which results in difficulty detecting them by commonly used immune-based testing. These immune-evasive, persistent infections can cause symptoms that are chronically progressive or chronically relapsing and remitting. An example is Borrelia burgdorferi [38][39][40][41][42][43]. Persistent or progressive symptoms after commonly used treatment for Borrelia burgdorferi infection are viewed by some researchers as caused by a self-perpetuating immune process in the absence of ongoing active infection [44].
  • Complex interactive infections
Koch’s initial view of infectious disease is that many human diseases are caused by microbes that exert their effects independently of other microbes, environmental factors, or genes. However, most common human diseases are caused by the interaction of environmental insults and susceptibility genes [45]. Many of the susceptibility genes are diverse determinants of human responses to environmental factors, e.g., infection.
Informative laboratory methods for complex disorders must address both genetic and environmental factors [46].
Some infection-associated symptom presentations are not the result of single pathogens but instead the result of complex interactive infections with multiple infectious agents. These infections could be compared to a foxhunt, in which three different species (humans, horses, and dogs) participate. In this case, the foxhunt would have a very different effect than if only one species were involved. Human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) is one example in which a pathogen (virus) causes immunodeficiency, allowing other microbes to become more pathogenic to the host. This pattern can also be seen with tick-borne diseases, as multiple tick-borne pathogens such as Borrelia, Babesia, Anaplasma, Ehrlichia, other Rickettsia, Nematodes, etc., may be present at the same time [47]. Additional unidentified, non-testable pathogens may also be contributory. The Borrelia bacterium has the capacity to cause immunosuppression and immune evasion [38][39][40][41][42][43]. This can result in previously asymptomatic latent infections becoming symptomatic. These previously acquired latent infections may not have been transmitted via tick bites and may include viruses and Bartonella and Mycoplasma species [48][49][50]. In addition, tick-borne polymicrobial coinfections can have an interactive effect upon the Borrelia infection [51][52][53]. SARS-CoV-2 viral infections have also been associated with complex interactive infections. There is anecdotal evidence that COVID-19 infections have resulted in the re-activation of latent Borrelia infections [54]. Increased levels of Borrelia-specific IgG antibodies strongly correlated with SARS-CoV-2 viral severity and the risk of hospitalization [55]. The human microbiota has been implicated in the development of a variety of mental illnesses, including Alzheimer’s disease, attention-deficit/hyperactivity disorder, anorexia nervosa, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and substance use disorders [56]. The human gut microbiome is recognized to have a significant impact upon both health and disease, as well as human metabolism, nutrition, physiology, and immune functioning. An altered gut microbiome is associated with different disease states [57][58]. The human microbiome is not just located in the gut. It can also be located in other parts of the body [56]. Some of the human microbiota can be located deep in connective tissue, where they may be protected from the immune system and attempts at antibiotic treatment [59][60][61].
When there is a complex interactive infection, it is sometimes possible to say that 1 + 1 does not = 2, but instead, 1 + 1 = 11.
  • Total load theory
Microbes may also interact with other non-infectious environmental contributors. The initial foundation of this view is based upon the disease triangle, which is a conceptual model showing the interactions between the environment, the host, and an infectious (or abiotic) agent [62]. This concept is addressed in the total load theory. Here, the focus is on how the presence of multiple stressors can result in an increasing number of developmental delays, cognitive problems, behavioral and emotional issues, and other impairments that have been seen in children in recent years. The approach views groups of symptoms as being the result of reaching a tipping point where development is stressed beyond the capacity for healthy adaptation. At that point, the youth shows signs of overload. This state is then manifested as attentional difficulties, developmental delays, mood issues, autoimmune problems, failure to thrive, repeated ear infections, etc. Some of the elements that can lead to developmental issues include birth trauma, pregnancy complications, nutritional deficiencies, frequent ear infections, etc. [63].

4. Pathophysiology

4.1. Is Trauma from Infection or from the Host’s Immune Reaction to the Infection?

Symptoms associated with infectious disease are a result of both the direct effects of the pathogen upon the host and the indirect effects caused by host immune activation. In an acute infection, the early inflammatory (innate immune) response evolves into a humoral (adaptive immune) response. In a chronic infection, there may instead be a persistence of the inflammatory state without effective adaptive immunity, and sometimes with an autoimmune response. This interaction between pathogen and host contributors results in trauma to the host. Microbial contributors to pathophysiology include toxin release, cell penetration, the effects of bacterial lipoproteins, and the incorporation of pathogen genes into the host genome. Host response contributors can include cytokine release, inflammation, inflammation-causing metabolic changes, the effects of bacterial lipoproteins and other pathogen-associated molecular patterns (PAMPs) such as toll-like receptor signaling, the interaction of heat shock proteins with the immune system, oxidative stress, the action of nitric oxide, other cellular responses, and autoimmune reactions [9][12][64][65][66]. Oxidative stress and changes in nitric oxide are also well recognized as being a part of the stress response and the pathogenesis of depression and other mental illnesses [67][68][69].
In addition, infections outside the central nervous system (CNS) can have immune and toxic effects upon the CNS, with molecular mimicry leading to autoantibody formation and cellular immune responses against host neuronal structures, oxidative stress, glutamate excitotoxicity, changes in homocysteine metabolism, mitochondrial dysfunction, and altered metabolism of tryptophan with decreased production of the neurotransmitter serotonin and increased production of neurotoxic and excitotoxic quinolinic acid and kynurenine metabolites [70][71][72][73][74].
The glymphatic system is important in healthy brain functioning and the prevention of the accumulation of neurotoxic cellular waste products [75][76]. A common neuropsychiatric symptom with a microbial infection is some form of insomnia [77]. During sleep, the glymphatic system expands, and brain contracts as immune system attempts to eliminate waste and cleanse itself [78]. If a bacterial toxin released by living organisms or perhaps dead remnants of microbes is not cleared, destructive secretions or ongoing immune stimulation can result in neuroinflammation and neural degeneration. This then has the potential to contribute to cognitive, behavioral, and emotional difficulties.
These pathophysiological processes are hypothesized to result in neuropsychiatric symptoms [12][71][72][73][79][80][81][82]. Bacterial infections are associated with many autoimmune diseases involving chronic inflammation and demyelination [83]. The pathophysiology of how these mechanisms impact the brain is addressed in the field of psychoneuroimmunology [84].

4.2. Psychoneuroimmunology or Psychoimmunology

Psychoneuroimmunology (formerly known as psychoimmunology) is the study of the connections between the brain and the immune system. There are basically two major communication networks in the brain—the neurotransmitter system and the immune system. Although the blood–brain barrier is a barrier to some things, it is not an absolute barrier to the immune system. Immune activity in the body releases cytokines, chemokines, antibodies, and other substances that impact immune activity in the brain [85][86].
Infections can have several biochemical effects. One of the most significant effects relevant to mental illness is the effect of inflammation upon the kynurenine pathway. This is a pathway that converts tryptophan into serotonin and melatonin. Chronic infections that do not result in adaptive immunity can instead provoke persistent inflammation. When the brain is exposed to an inflammatory state, there is an increase in an enzyme, indoleamine 2,3-dioxygenase (IDO), that shifts the conversion of tryptophan away from serotonin, melatonin, and kynurenic acid (a neuroprotective compound) and instead pushes the conversion to quinolinic acid, which is a neurotoxin and an N-methyl-D-aspartate (NMDA) agonist [87]. Therefore, ongoing chronic inflammation switches the brain from making necessary neurotransmitters, neurohormones, and neuroprotective substances toward self-destructive activity.
Infections in the body can therefore have immune-mediated effects upon the brain through cytokine and biochemical effects. These changes can result in the dysfunction of limbic and paralimbic brain circuits, impairing emotional functioning and contributing to psychiatric symptoms and illnesses [88][89][90][91][92][93][94].

4.3. Clinical Presentation Variability

It is clear from clinical observations of all infectious diseases that the same infection can have a very different presentation in different individuals. This is the result of a combination of different host and pathogen considerations. There are many genetic and other susceptibility and resistance contributors. Microbial variables can include the load of organisms, pathogen strain variability, and coinfections. Host variables include age, genetic, and other susceptibilities.

4.4. Infections Early in Life with Later Consequences

Accumulating evidence supports the concept that infections early in life may play a role in the later development of mental disorders. Infections with herpes simplex virus, cytomegalovirus, rubella, and Toxoplasma gondii during the prenatal period are examples of infections that can result in fetal neurodevelopmental abnormalities. These can include structural abnormalities, such as hypoplasia of different areas of the brain, as well as functional problems. The resultant cerebral dysfunction can manifest as behavioral issues, learning problems, autistic spectrum disorders, or mental retardation [9][95].
One population-based cohort study utilizing a large, well-documented Australian database looked at the relationship between early exposure to infection between birth and 4 years and the subsequent development of mental disorders in children aged 5–13 years. The authors found that there was a positive correlation between the rates of childhood mental disorders and infection in the first four years of life. The authors found a moderate association of infection during this time period with autistic spectrum disorder and other developmental disorders, as well as externalizing disorders. In addition, there was a smaller but significant association with internalizing disorders [96].
A review of a nationwide Danish register-based cohort of over one million children born between 1995 and 2012 attempted to determine whether there was any association between hospitalization for infection and the later development of mental illness. The investigators found that youths who were medically hospitalized with infectious illnesses have an 84% increased risk of later developing a mental disorder. The most common mental disorders found included schizophrenia, obsessive–compulsive disorder, tics, attention-deficit hyperactivity disorder, oppositional defiant behavior, conduct disorder, personality and behavior disorders, autism, and mental retardation [97].
In another study, children with autism were found to have substantially greater odds of neonatal and early childhood infections when compared to children with other developmental disorders and healthy controls [98].
In summary, there is increasing evidence that the impact of infections early in life may be an important contributor to the later development of a mental illness. The various mechanisms by which this occurs require further study.

5. Clinical Considerations: Assessment

The standard of care in medicine has always been the detailed clinical evaluation. Like other illnesses, the search for the diagnosis and cause of a condition may be initiated by using a screening assessment followed by a thorough history, a review of systems, a comprehensive psychiatric clinical exam, a mental status exam, a neurological exam, and a physical exam relevant to the patient’s complaints. Laboratory or other testing may be ordered based upon the clinical assessment. The diagnosis and the cause of the condition are determined based on a knowledge of the medical literature, clinical judgment, pattern recognition, and a knowledgeable interpretation of all clinical findings [10][99].

5.1. Clinical Assessment

The nature of the clinical assessment to determine whether microbes may be causing mental illness is an emerging field. Since infections that contribute to mental illness often cause multisystem illness, a comprehensive multisystem assessment can be helpful in determining the diagnosis and the pathophysiology. It can be challenging to differentiate between psychosomatic, somatopsychic, and multisystem illnesses and medical uncertainty [100]. Two assessments were previously developed for Lyme disease [101][102]. The General Symptom Questionnaire (GSQ-30) was developed and validated to fill the need for a brief patient-reported measure of multisystem symptom burden, and it can be useful in both clinical and research settings [103]. A multisystem assessment has been developed for Lyme borreliosis with a particular emphasis upon neuropsychiatric symptoms, which could be adapted for the assessment of any infection(s) causing mental illness. This assessment is readily available and includes screening questions, three clinical assessment forms (24-item, 61-item, full assessment), and a coinfection screen [10] (Supplementary S2 and S3).

5.2. Laboratory and Other Diagnostic Testing

In addition to a thorough history and physical exam, a number of diagnostic tools can assist the assessment. This includes laboratory testing, structural and functional brain imaging, and neuropsychological testing. The sensitivity and specificity of laboratory testing of body fluids (blood, cerebrospinal fluid, urine) and tissue for the myriad of microbes that are associated with mental illness vary over a wide spectrum. Some are generally considered very accurate and extremely helpful in determining the presence or absence of a pathogen. On the other hand, laboratory assays are presently available only for some microbes, and their interpretative criteria have significant limitations. While serologic testing is commonly used for the lab diagnosis of microbes associated with mental illness, the detection of an antibody response to a pathogen can provide evidence of past exposure and infection but does not necessarily indicate an active, ongoing infection. At the same time, the presence of an infection does not alone prove that an infectious agent caused or contributed to any given psychiatric symptom. Psychiatric and other late-stage manifestations of an infection are more likely to occur when an infection is not adequately diagnosed and/or treated in the earlier stages of infection. A common error contributing to a lack of diagnosis or late diagnosis is confusing public health surveillance criteria with diagnostic criteria. As emphasized by the US CDC, “surveillance definitions are designed to study and identify trends in a population… Alternatively, clinical diagnoses are patient specific. Unlike surveillance definitions, ALL available diagnostic data are considered in a clinical diagnosis, including additional clinical, epidemiological and laboratory data not used for national health system surveillance. Therefore, a clinical diagnosis may be made even when a surveillance definition may not be met and vice versa is also true. Failure to meet a surveillance definition should never impede or override clinical judgment during diagnosis, management, or treatment of patents [sic]” [104]. Future testing may be more dependent upon metabolomics, the measuring and assessing of metabolites to provide specific metabolic profiling of biological fluids to help identify biomarkers for infectious disease diagnosis [105] as well as other “-omics” testing, such as proteomics, transcriptomics and metagenomic next-generation sequencing.

6. Treatment Options

Treatment must be individualized, and multidisciplinary approaches are often beneficial. Treatment can be divided into three basic areas—treatment of the infection(s) or other contributor(s), immune interventions, and treatment of the resulting symptoms and any other potential contributor(s). Initial subsequent interventions are dependent upon an understanding of the pathophysiological process, how the disease contributors interact, and the primary driver of disease perpetuation and progression.
When a patient has an inadequate response to psychotropics and infection is a possibility, antimicrobials are a consideration. When directly treating an infection, the choice of antimicrobial(s) is dependent on the microorganism, its expected or laboratory-obtained antimicrobial sensitivities, the location of the infection (e.g., CNS vs. non-CNS infection), and the medication’s adverse effect profile. It is important to note that many psychiatric conditions in which microbes may play an etiologic role are considered to be due not to a direct CNS infection but rather to a non-CNS infection that generates a pathogenic immune response with deleterious CNS effects. Antimicrobial treatment may be associated with a Jarisch–Herxheimer reaction, in which there may be a transient exacerbation of symptoms associated with the infection, including neuropsychiatric symptoms [12]. If there is a plausible mechanism for a non-infection environmental contributor, e.g., environmental toxin exposure, the mitigation of ongoing exposure, if any, to the environmental toxin and other measures to limit toxin exposure must be considered.
When immune-mediated symptoms are present from an active infection, a prior infection, or some non-infection immune provocation, consider immune-modulating interventions. With immune interventions, the choice of treatment is dependent upon whether or not there is immune suppression, excessive inflammation, autoimmunity, and/or a failure of adaptive immunity.
When symptoms such as chronic stress and sleep deprivation contribute to compromised immunity, consider symptomatic treatment. Regarding symptomatic treatment, it is necessary to perform a comprehensive clinical examination and then make a list with the patient, ranking which symptoms are the most severe and which symptoms most impede recovery. It is important to consider how symptoms interact with each other. This can help determine which symptoms are the most critical in contributing to disease perpetuation and progression. This type of reflection will help determine which symptoms to treat and in which order.
When a patient has a relapse, treatments that have been effective in the past are a consideration. When a patient is treatment-resistant, treatments that have not been used in the past are a consideration. Constant treatment revisions are needed depending upon whether the patient is improving or showing further disease progression. What has initially caused a condition may be different from what perpetuates that same condition.
From treating thousands of patients over decades, the authors (RB, RG) have found that the symptoms that usually need to be treated first are non-restorative sleep and the symptom(s) that cause the greatest chronic stress in the patient. Non-restorative sleep is often associated with fatigue and cognitive impairments, sometimes called “the terrible triad” [9][106]. A lack of restorative sleep is particularly significant in causing immune dysfunction, the failure of adaptive immunity, and disease progression [78][107][108]. In addition to non-restorative sleep, other symptoms frequently causing chronic stress in the patient include emotional symptoms (depression, anxiety, depersonalization, mood swings, psychosis, intrusive symptoms), chronic pain (headaches, neuropathy, radiculopathy, musculoskeletal pain), multisystem somatic symptoms (neurological, gastrointestinal, dysautonomia, cardiac, genitourinary, etc.), and addictive disorders [10].
Education to help the patient, the caregivers, and those in the support circle better understand the condition is always a critical component of treatment.

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