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21
Infectious Diseases in Major Depressive
Disorder, Bipolar Disorder, and
Obsessive– Compulsive Disorder
Chris H. Miller, Liz Pritchard, Marisol Duran, Martin Shapiro,
Matthew D. Sacchet, and Ellen Woo
Introduction
Psychiatric disorders are highly prevalent and aect more than 16 percent of people
(> 1 billion people) globally each year and are responsible for about 6.8 percent of
all disease burden and 18.7 percent of all disability burden (the largest of all disease
categories) worldwide (Rehm & Shield, 2019). In addition, the estimated occurrence and impact of psychiatric disorders has been substantially increasing over
time throughout the world by about 48.1 percent over a roughly 30- year period,
with depressive disorders ranking the highest among most age groups and regions.
Unfortunately, the implementation of evidence- based interventions has not generated a detectable, systemic impact on disease burden at the global level (Ferrari
et al., 2022).
Some investigators have argued that this mental health crisis supports the need
for a paradigm shi that involves reconceptualizing our diagnostic systems to one
based on underlying neurobiological mechanisms rather than self- reported clinical
syndromes (Cuthbert & Insel, 2013). Given that patients diagnosed with the same
mental disorder can have heterogeneous presentations, identication of biomarkers
can help further dierentiate subgroups and enhance eorts for prevention, diagnosis, and treatment (García- Gutiérrez et al., 2020). Over the past several decades,
investigators have elucidated some of the infectious disease mechanisms that primarily or secondarily aect brain structure or function and thereby produce neuropsychiatric symptoms that can contribute to many major psychiatric disorders, as
detailed throughout this book. is chapter summarizes our present understanding
of the clinical importance of several of the most prevalent and well- studied bacterial,
parasitic, and viral infections that contribute to major depressive disorder (MDD),
bipolar disorder (BD), and obsessive– compulsive disorder (OCD). Insofar as possible, it also explains the biological mechanisms responsible for the linkage between
Chris H. Miller, Liz Pritchard, Marisol Duran, Martin Shapiro, Matthew D. Sacchet, and Ellen Woo, Infectious Diseases in Major Depressive
Disorder, Bipolar Disorder, and Obsessive– Compulsive Disorder In:
DOI: 10.1093/ oso/ 9780192870414.003.0022
Infectious Disease and Neurocognition
infectious diseases and these psychiatric disorders, particularly the mediating role of
immune responses, inammatory reactions, and cytokine signaling.
Major depressive disorder
MDD is a highly prevalent psychiatric disorder with a lifetime prevalence of approximately 20.6 percent (Hasin et al., 2018). It is now considered the leading cause of
disability worldwide (Friedrich, 2017) and is responsible for approximately $326.2
billion in economic burden in the United States alone. Its current Diagnostic and
Statistical Manual of Mental Disorders, h edition, diagnosis requires the presence
of at least ve symptoms within a 2- week period, including either low mood or anhedonia combined with altered appetite, weight changes, sleep diculty, fatigue,
suicidality, or diminished ability to think or concentrate (American Psychiatric
Association, 2022). MDD is highly comorbid with other psychiatric disorders, particularly anxiety disorders, and has a lifetime comorbidity rate as high as 60 percent
with generalized anxiety disorder (Kaufman & Charney, 2000).
Investigators also now increasingly recognize signicant relations between infectious diseases and MDD, which are oen mediated through mechanisms of inammation. e following sections provide examples of prevalent and well- studied
bacterial, parasitic, and viral infections that appear to contribute to the onset and
maintenance of depressive symptoms, with a particular emphasis on the currently
known epidemiology and biological mechanisms linking these infectious disease
and disorders.
Gram- negative enterobacteria
Gram- negative enterobacteria, which exist inside the human intestinal tract, have
been implicated in a number of diseases when these toxic bacteria escape gastrointestinal isolation, referred to as leaky gut syndrome. is condition appears to contribute to the onset and maintenance of MDD as well as ulcerative colitis and Crohn’s
disease, collectively referred to as inammatory bowel disease (IBD) (Yu et al., 2022).
Comorbidity and bidirectional associations between MDD and IBD are high, with
MDD and IBD each contributing substantial bidirectional risk, aer adjustment for
potential confounders, of an odds ratio of 1.87 (p < 0.028) and an odds ratio of 9.43
(p < 0.001) relative to controls, respectively (Zhang et al., 2022). In healthy individuals, the intestinal tract contains toxic enterobacteria containing liposaccharides
in the cellular walls that are mainly ingested through contaminated food or water.
e typical immune system does not show a response to these enterobacteria because the bacteria are quarantined within the gastrointestinal tract and isolated from
the rest of the body through selective mucosal barriers, tight junction proteins, and
mesenteric lymph nodes (Maes et al., 2012; Yu et al., 2022). However, if the barriers
Depressive and Bipolar Disorders and OCD 333
are compromised, the enterobacteria may escape the isolation of the gut and enter
the lamina propria and the bloodstream through bacterial translocation and, once
outside the outside the intestines, the liposaccharides in the cells walls of the Gramnegative bacteria activate the immune system (Yu et al., 2022).
Interestingly, patients with chronic MDD have higher levels of immunoglobin
antibodies targeting Gram- negative bacterial liposaccharides relative to healthy
controls, which suggests higher rates of bacterial translocation (Maes et al., 2012).
Moreover, injection of liposaccharides into animal models induces depressive symptoms, including anhedonia, reduced exploratory behavior, fatigue, and reduced
social interactions (Arling et al., 2009; Dantzer et al., 2008; Maes et al., 2012). In
addition, these depressive symptoms have been shown to be ameliorated by immunosuppressant treatment of IBD (Guloksuz et al., 2013; Horst et al., 2015), and treatment of Crohn’s disease with anti- tumor necrosis factor alpha (TNF- α) antibodies
reduces depressive symptoms (Rook & Lowry, 2008).
A leaky gut may be a primary trigger of depression for individuals at risk or could
be a secondary reaction to existing depressive symptoms (Leonard & Maes, 2012;
Maes et al., 2012). If a leaky gut is a primary trigger of depression, the underlying
mechanism responsible may involve inammation of brain tissue following a sustained immune response to leaking enterobacteria that causes elevation of cytokine
levels in the body. In particular, cytokines, which are released by immune cells such
as macrophages in the body or microglia in the central nervous system (CNS), promote an inammatory response to intracellular pathogens, including Gram- negative
bacteria liposaccharides (Beurel et al., 2020; Chen & Gotlib, 2015; Kim et al., 2016).
Proinammatory cytokines are depressogenic molecules inducing sickness behaviors such as fatigue, weight loss, and disrupted sleep patterns (Dantzer et al., 2008;
Maes et al., 2012). Indeed, a large- scale meta- analysis found elevated TNF- α and
interleukin (IL)- 6 cytokine concentrations in depressed individuals, though other
cytokine levels were not signicantly dierent in MDD individuals (Dowlati et al.,
2010), and there is much heterogeneity among individual studies on the relationship
between cytokine levels and depression (Köhler et al., 2017).
In addition, clinical studies show that elevated levels of cytokines in physically ill
patients can induce MDD (Dantzer et al., 2008), that elevated cytokine levels have
been observed in MDD patients and suicide victims (Canli, 2019), and that treatment of hepatitis and cancer patients with proinammatory cytokines such as IL2 and interferon alpha can induce depression (Beurel et al., 2020; Rook & Lowry,
2008). Basic science studies also show that production of proinammatory cytokines
by microglia, which are critical for neuroplasticity, learning, and memory (Beurel
et al., 2020; Kim et al., 2016) at normal basal levels, becomes harmful when produced at chronically high levels and negatively impacts neurotransmitter signaling
as well as the synthesis, reuptake, and release of neurotransmitters (Beurel et al.,
2020). Other investigators have found that high concentrations of IL- 6 and TNF- α
followed by microglial activation decreases neurogenesis within the hippocampus
and is associated with reductions in hippocampal volume, including in rst- episode
Infectious Disease and Neurocognition
and drug- naïve patients with MDD (Kakeda et al., 2018), and likely contribute to the
onset and maintenance of depression (Kim et al., 2016; Roohi et al., 2021).
Alternatively, if a leaky gut is a secondary symptom of depression, the inammatory factors associated with depression may cause damage to the mucosal barriers
and tight junctions of the gut, thereby triggering bacterial translocation (Maes et al.,
2012). Stressful or negative life events have been shown to increase proinammatory
cytokine production in humans (Maes et al., 2008), and this response is exaggerated
in depressed individuals (Rook & Lowry, 2008). Furthermore, depression is associated with increased production of corticotropin- releasing hormone and glucocorticoids, which are both involved in the permeability of the mucosal barrier in
the gut (Maes et al., 2012). Hence, leaky gut symptoms may be a primary trigger or a
secondary complication of depression— or, most likely, these two complex disorders
and their underlying mechanisms may exert reciprocal inuences on each other.
In any case, bacterial translocation should be of increasing concern for human
health. Rates of IBD are curiously much greater in industrialized, Western countries
than in developing countries (Molodecky et al., 2012), which is likely due in part to
the increased sterilization of the environment in industrialized nations that has reduced human exposure to many microorganisms, including the symbiotic bacteria
that form our healthy gut microbiota. Evolutionary exposure to these tolerogenic
bacteria may have previously served to calibrate our immune system to respond appropriately to diering pathogen threat levels. With signicantly reduced exposure
to these “old friend” microorganisms, the human immune system may now overreact when exposed to leaking enterobacteria, which may contribute to the rising
incidence of chronic inammatory disorders and MDD in industrialized nations
(Raison et al., 2010).
Toxoplasma gondii
e parasite Toxoplasma gondii is an obligate intracellular protozoan parasite and
lives primarily in the feline intestinal tract (X. Wang et al., 2014). T. gondii oen
infects humans through undercooked meat or exposure to water, garden soil, or
a child’s sandbox that has been contaminated by cat feces (Montoya & Liesenfeld,
2004) and is estimated to have infected approximately one- third of the human population worldwide. When rats encounter the T. gondii eggs in cat excrement, the par-
asite forms cysts within the rats’ amygdala, which reduces corticosterone levels and
activates sexual arousal pathways and decreases capacity for memory and learning
(Arling et al., 2009). Some studies have found that T. gondii infection is associated
with behavioral changes and various diseases as well as psychiatric disorders in humans, including MDD and suicidality (Bak et al., 2018; Soleymani et al., 2020); however, other studies have not found a signicant link between T. gondii infection and
MDD (Gale et al., 2021).
Depressive and Bipolar Disorders and OCD 335
Investigators have identied multiple mechanisms through which T. gondii may
contribute to depressive symptoms. First, humans typically experience an acute initial reaction to T. gondii infection, which can be followed by a chronic latent intracellular infection in the form of cysts in various brain regions (McConkey et al.,
2013) that may contribute directly to depressive symptoms. Typically, this chronic
cyst infection is suppressed by T helper () and natural killer (NK) cells that allow
the host to remain immunocompetent. However, if these cysts are not contained,
parasitic T. gondii cells may be released back into circulation in the body, and the
metabolites from within the broken cyst may directly alter neurotransmitter concentrations (Groer et al., 2011).
Alternatively, infection by T. gondii may indirectly inuence human depressive
symptoms via a prolonged immune response by the host. Humans infected with
T. gondii have higher concentrations of cytokine proteins, due to the long- term efforts by cells to suppress T. gondii cysts (Canli, 2014). ese cytokine proteins are
necessary to ght o the original infection by T. gondii but have depressogenic side
eects, as discussed previously.
T. gondii may also indirectly inuence depressive symptoms of its host through
tryptophan withdrawals. Tryptophan, which is an essential amino acid for human
hosts (and for T. gondii), is ingested through dietary proteins (Mittal et al., 2017).
e human immune response to T. gondii infection includes increasing the enzy-
matic activity of indoleamine 2,3- dioxygenase (IDO), which degrades tryptophan
in the body and starves the parasite. However, tryptophan is also used to synthesize
serotonin in humans (Chen & Gotlib, 2015); without the building block of tryptophan, serotonin levels would presumably decrease, which some investigators have
argued could induce depressive symptoms (Beurel et al., 2020; Dantzer et al., 2008;
Leonard & Maes, 2012). Notably, the activation of IDO also creates other neurotoxic
metabolites through the kynurenine pathway, which may contribute to depressive
symptoms. In particular, the degradation of tryptophan by IDO forms quinolinic
acid, which is an N- methyl- D- aspartate (NMDA) receptor agonist, and kynurenic
acid, which is an NMDA receptor antagonist (Dantzer et al., 2008). Some evidence
indicates that the ratio between these metabolites of tryptophan, which have opposing functional roles, is associated with depression (Dantzer et al., 2008; Guloksuz
et al., 2013; Leonard & Maes, 2012; Mittal et al., 2017).
Borna disease virus
Borna disease virus (BDV), which is well known for inducing fatal encephalitis
in infected sheep and horses, also infects the nervous system of humans (Murray,
2021) and appears to be linked to higher rates of psychiatric disorders such as MDD.
Indeed, a meta- analysis of infectious agents and depression found a statistically signicant correlation (p = 0.026) between BDV infection and depression and an odds
Infectious Disease and Neurocognition
ratio of 3.25 for exposure to BDV among MDD patients compared to healthy controls (X. Wang et al., 2014).
Interestingly, when MDD patients infected with BDV are treated with the antiviral
drug amantadine, both their BDV symptoms and depression symptoms improve
(Canli, 2019; Dietrich & Bode, 2008) One study found a response rate of 68 percent
in depressive symptoms in treating BDV- infected MDD patients with amantadine
aer an average of 2.9 weeks (Dietrich et al., 2000). e success of amantadine in
treating both BDV and MDD symptoms may provide insight into the biological
mechanism linking BDV and depression. As discussed above, the activation of IDO
in MDD patients increases quinolinic acid levels, which increases glutamate production (Müeller & Schwarz, 2007). Amantadine is an antagonist of the NMDA receptor,
which suggests it may counteract the imbalance in MDD between quinolinic acid
and kynurenic acid and serve as a link between depression and glutaminergic receptor activity (Dantzer et al., 2008; Guloksuz et al., 2013; Müeller & Schwarz, 2007).
Herpes simplex virus type 1
Herpes simplex virus type 1 (HSV- 1) is extremely common, with an estimated global
prevalence of approximately 66.6 percent for individuals 0– 49 years of age (James
et al., 2020). A large- scale meta- analysis found a signicant association between depression and HSV- 1 based on a pooled analysis of 28 primary studies (X. Wang et al.,
2014). In addition, a recent analysis of the UK Biobank, a vast biomedical database,
found higher HSV- 1 antibody serum concentrations were associated with an increased occurrence of depression (Ye et al., 2020).
Aer initial infection, HSV- 1 oen becomes a chronic latent infection in nerve
ganglia of human hosts, with sporadic reactivation most commonly in the form of
cold sores or genital herpes (Curanovic & Enquist, 2009). is chronic latent infection may cause prolonged cytokinetic inammation (Ye et al., 2020), which may contribute to depressive symptomatology, as discussed above. e UK Biobank study
also suggested several potential single nucleotide polymorphisms involved in nerve
development and immune function, which may serve as genetic vulnerabilities for
developing MDD following HSV- 1 infection (Ye et al., 2020). Nerve development
is particularly relevant to herpes viral infection, as HSV- 1 can enter the CNS of the
host and subsequently spread transneuronally (Curanovic & Enquist, 2009).
Epstein– Barr virus
Epstein– Barr virus (EBV) is another member of the herpesvirus family (HHV- 4)
and frequently manifests as infectious mononucleosis in human hosts. It is also very
common, with an estimated 90 percent of adults being exposed to the virus before
the age of 30 years (Vindegaard et al., 2021). Despite its broad distribution, EBV
Depressive and Bipolar Disorders and OCD 337
infection has been found to be nearly twice as prevalent among individuals with
MDD as in the general population (X. Wang et al., 2014), and individuals aicted
with infectious mononucleosis have a 40 percent increased risk of depression more
than 1 year following the initial EBV infection (Vindegaard et al., 2021). During viral
replication, EBV produces the protein EBV- encoded deoxyuridine triphosphate
nucleotidohydrolase, which induces the production of proinammatory cytokines,
including TNF- α and IL- 6, which can induce depressive symptoms (Vindegaard
et al., 2021).
Human immunodeficiency virus
Human immunodeciency virus type 1 (HIV- 1) is a retrovirus that causes acquired immunodeciency syndrome (AIDS) in humans. Approximately 1.2 million people in the United States (U.S. Department of Health & Human Services,
2022b) and 38.4 million people worldwide (U.S. Department of Health & Human
Services, 2022a) are infected with HIV- 1. e chronic activation of the immune
system from the presence of HIV- 1 increases enzymatic activity of IDO and reduces
tryptophan levels (Moreau et al., 2005). As discussed above, chronic activation of
IDO is associated with human depressive behavior, and this link between IDO activation and depressive behavior has been demonstrated experimentally in animal
models (Dantzer et al., 2008). Similarly, the chronic activation of the immune system
in response to HIV- 1 is also thought to activate microglia in the brain and cause
neuroinammation (Beurel et al., 2020), both of which have been identied as signicant correlates of depression (Yu et al., 2022).
Bipolar disorder
Bipolar I disorder (BD- I) is a common psychiatric disorder with a lifetime prevalence of approximately 4.4 percent (Harvard Medical School, 2007). It involves alternating episodes of major depression and mania, or distinct periods of elevated,
expansive, or irritable mood along with abnormal and persistent goal- directed behavior and energy as well as three or more symptoms such as inated self- esteem,
decreased need for sleep, increased talkativeness, ight of ideas, distractibility, psychomotor agitation, and high- risk behavior for at least 1 week (American Psychiatric
Association, 2022). BD- I has high comorbidity with multiple other disorders, including lifetime prevalence of 61.0 percent with substance- use disorder, the highest
comorbidity rate within any psychiatric disorder, and 52.8 percent with anxiety disorders (Simon et al., 2004).
e neural basis of BD closely resembles that of MDD in many ways, though
structural and functional imaging studies have found subtle dierences between the
two disorders in brain regions such as the caudate, anterior cingulate, and habenula