Toxoplasma gondii Infection

Abstract

Toxoplasma gondii (T. gondii), a protozoan parasite that persists in host tissues, including brain, has been associated with several psychiatric disorders and with suicidal behavior. We sought to test the hypothesis that latent T. gondii infection, as manifest by circulating immunoglobulin G (IgG) antibodies to T. gondii, is associated with both categorical and dimensional measures of aggression.IgG antibodies to T. gondii were collected between 1991 and 2008 from 358 adult subjects with DSM-5 intermittent explosive disorder (IED), non-IED psychiatric disorders (psychiatric controls), or no evidence of any psychiatric diagnosis (healthy controls). Assessments of aggression, anger, and impulsivity, as well as state/trait anger, depression, and anxiety were completed. T. gondii seropositive status (IgG > 12 IU) was the primary outcome measure for this study.T. gondii seropositive status (IgG > 12 IU) was associated with higher aggression (P = .022) and impulsivity (P = .05) scores. When both aggression and impulsivity scores were controlled for, however, only aggression scores were higher in seropositive subjects (P = .011). In addition, T. gondii seropositive status and marginal mean ± SE aggression scores increased from healthy controls (9.1% and -0.66 ± 0.05) to psychiatric controls (16.7% and -0.27 ± 0.05) to subjects with IED (21.8% and 1.15 ± 0.06; P ≤ .05). These findings were not accounted for by the presence of other syndromal/personality disorders or by states or traits related to depressed or anxious moods.These data are consistent with previous studies suggesting a relationship between T. gondii and self-directed aggression (ie, suicidal behavior) and further add to the biological complexity of impulsive aggression both from a categorical and a dimensional perspective.

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334 J Clin Psychiatry 77:3, March 2016
Original Research
Toxoplasma gondii Infection:
Relationship With Aggression in Psychiatric Subjects
Emil F. Coccaro,MDa,*; Royce Lee,MDa; Maureen W. Groer,PhDb; Adem Can,PhDc;
Mary Coussons-Read,PhDd; and Teodor T. Postolache,MDc,e
Toxoplasma gondii (T. gondii) is a highly successful neurotropic
protozoan parasite, infecting any warm-blooded animal
including approximately one-third of all humans.1 Within the
animal world, felids have been identified as the definitive host
of T. gondii that localizes only in the gastrointestinal tract of any
member of the cat family. Humans may be infected by T. gondii
via ingestion of the parasite’s oocysts, which can spread from
the feces of infected cats. Other routes of transmission include
consumption of undercooked meat that has been infected with
T. gondii cysts or ingestion of contaminated water2,3; congenital
infection, occurring if a mother has a primary infection during
pregnancy and transmits T. gondii to the fetus, is relatively rare.
Postnatal chronic “latent” infection is very common, minimally
symptomatic in the immune competent host, and with an
encephalitic picture in the immunocompromised.4 When
ingested by an intermediate host, the parasite uses leukocytes
to travel from the intestine to other organs, finally localizing
in muscle and brain. Once in the brain, T. gondii hides within
neurons and glial cells, forming characteristic cystic intracellular
structures under the pressure of the immune system.5 Although
it is thought to be relatively harmless in immunocompetent
adults, latent toxoplasmosis has been linked to several psychiatric
disorders (eg, schizophrenia,6,7 bipolar disorder,7–9 personality
disorders10) and with suicidal behavior.11–17
Given the strong relationship between suicidal behavior and
impulsive aggressive behavior,18 either as a dimension or as a
category, and in light of a recent study19 that reported that T.
gondii seropositivity status may be associated with high self-
reported trait aggression and impulsivity in mentally healthy
individuals, we hypothesized that the categorical presence of
immunoglobulin G (IgG) antibodies to T. gondii would (1) be
associated with higher aggression and impulsivity scores in a
sample of psychiatric and healthy control subjects and (2) be
more frequent in individuals with intermittent explosive disorder
(IED), a disorder of recurrent, problematic, and impulsive
aggressive behavior, compared with healthy controls. In this
study, we used psychometric assessments20–23 as the dimensional
representation of impulsive aggression and the presence of IED
as the categorical representation24 of impulsive aggression.
METHOD
Subjects
Three hundred fifty-eight physically healthy subjects
participated in this study. All subjects were systematically
evaluated in regard to aggressive, anxiety, and other behaviors
as part of a larger program that is designed to study correlates of
ABSTRACT
Objective: Toxoplasma gondii (T. gondii), a protozoan parasite
that persists in host tissues, including brain, has been
associated with several psychiatric disorders and with suicidal
behavior. We sought to test the hypothesis that latent T. gondii
infection, as manifest by circulating immunoglobulin G (IgG)
antibodies to T. gondii, is associated with both categorical and
dimensional measures of aggression.
Method: IgG antibodies to T. gondii were collected between
1991 and 2008 from 358 adult subjects with DSM-5
intermittent explosive disorder (IED), non-IED psychiatric
disorders (psychiatric controls), or no evidence of any
psychiatric diagnosis (healthy controls). Assessments of
aggression, anger, and impulsivity, as well as state/trait anger,
depression, and anxiety were completed. T. gondii seropositive
status (IgG > 12 IU) was the primary outcome measure for this
study.
Results: T. gondii seropositive status (IgG > 12 IU) was
associated with higher aggression (P = .022) and impulsivity
(P = .05) scores. When both aggression and impulsivity scores
were controlled for, however, only aggression scores were
higher in seropositive subjects (P = .011). In addition, T. gondii
seropositive status and marginal mean ± SE aggression scores
increased from healthy controls (9.1% and −0.66 ± 0.05) to
psychiatric controls (16.7% and −0.27 ± 0.05) to subjects with
IED (21.8% and 1.15 ± 0.06; P ≤ .05). These findings were not
accounted for by the presence of other syndromal/personality
disorders or by states or traits related to depressed or anxious
moods.
Conclusions: These data are consistent with previous studies
suggesting a relationship between T. gondii and self-directed
aggression (ie, suicidal behavior) and further add to the
biological complexity of impulsive aggression both from a
categorical and a dimensional perspective.
J Clin Psychiatry 2016;77(3):334–341
dx.doi.org/10.4088/JCP.14m09621
© Copyright 2016 Physicians Postgraduate Press, Inc.
aClinical Neuroscience Research Unit, Department of Psychiatry and
Behavioral N euroscience, Pritzker School of Medicine, Universit y of
Chicago, Illinois
bCollege of Nur sing, University of South Florida, Tampa
cDepartment of Psychiatr y, University of Maryland College of
Medicine, Baltimore
dDepartment of Psychology, University of Denver, Colorado Springs,
Colorado
eVeterans Integrated S ervice Network 19, Mental Illness Research
Education and Clinical Center, Denver, Colora do, and Veterans
Integrated Service Net work 5, Mental Illness Research Education and
Clinical Center, Baltimore, Maryland
*Corresponding author: Emil F. Coccaro, MD, Depar tment of Psychiatry
and Behavioral Neuroscience, Universit y of Chicago, 5841 South
Maryland Ave, Chicago, IL 60637 (ecoccaro@yoda.bsd.uchicago.edu).

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335J Clin Psychiatry 77:3, March 2016
T. gondii Infection and Aggression
impulsive aggressive and other personality-related behaviors
in human subjects. Subjects were recruited through public
service, newspaper, and other media announcements
seeking individuals who (1) reported psychosocial difficulty
related to syndromal psychiatric and/or personality disorder
conditions or (2) had little evidence of any psychopathology.
All subjects gave informed consent and signed the informed
consent document approved by the first author’s (E.F.C.)
Institutional Review Board.
Diagnostic Assessment
Syndromal and personality disorder diagnoses were
made according to DSM-5 criteria.25 Diagnoses were
made using information from (1) the Structured Clinical
Interview for DSM-IV Axis I disorders (SCID-I)26 for
syndromal disorders and the Structured Interview for
DSM-IV Personality (SIDP-IV)27 for personality disorders,
(2) a clinical interview by a research psychiatrist, and (3)
the review of all other available clinical data. The research
diagnostic interviews were conducted by individuals with a
master’s or doctor’s degree in clinical psychology, blinded
to the study hypothesis. All diagnostic raters went through
a rigorous training program that included lectures on
DSM diagnoses and rating systems, videos of expert raters
conducting SCID-I/SIDP-IV interviews, and practice
interviews and ratings until the raters were deemed reliable
by the trainer. This process resulted in good to excellent
interrater reliabilities (mean ± SE κ = 0.84 ± 0.05; range,
0.79 to 0.93) across anxiety, mood, substance use, impulse
control, and personality disorders. Final diagnoses were
assigned by team best-estimate consensus procedures28,29
involving research psychiatrists and clinical psychologists
as previously described.30 This methodology has been shown
to enhance the accuracy of diagnosis over direct interview
alone.31 Subjects with a current history of a substance use
disorder or a life history of bipolar disorder, schizophrenia
(or other psychotic disorder), or mental retardation were
excluded from study.
After diagnostic assignment, 110 subjects had no evidence
of any psychiatric diagnosis (healthy controls); 138 subjects
met criteria for a lifetime diagnosis of a syndromal psychiatric
or personality disorder, but not for a lifetime diagnosis of
IED (psychiatric controls); and 110 subjects met criteria for
a lifetime diagnosis of IED. Of the 248 subjects with any
DSM-5 diagnosis, most (72.4%) reported (1) a history of
formal psychiatric evaluation and/or treatment (46.3%) or
(2) a history of behavioral disturbance during which the
subjects, or others, thought they should have sought mental
health services but did not (26.1%). Syndromal psychiatric
and personality disorder diagnoses are listed in Table 1.
Psychometric Measures of Aggression,
Impulsivity, and Related Behaviors
Aggression was assessed with the Aggression score from
the Life History of Aggression (LHA)20 assessment and the
Aggression (Physical and Verbal) score from the Buss-Perry
Aggression Questionnaire (BPAQ).21 The LHA assesses the
history of actual aggressive behavior and the BPAQ assesses
aggressive tendencies as a personality trait. Impulsivity
was assessed with the Barratt Impulsiveness Scale, version
11 (BIS-11)22 and the Impulsivity scale from the Eysenck
Personality Inventory-2 (EPQ-2).23 Both BIS-11 and EPQ-2
Impulsivity assess a person’s disposition to act impulsively as
a personality trait. Life history of suicidal and self-injurious
behavior was assessed during the diagnostic interviews. An
act was considered a suicide attempt if it involved behavior
with the conscious (even if ambivalent) intent to die by
means that the subject believed could end his or her life;
an act was considered self-injurious if it involved behavior
with the conscious (even if ambivalent) intent by the subject
to physically harm, but not kill, himself or herself. Other
assessments included the State-Trait Anger Expression
Inventory-2 (STAXI-2)32 for state and trait anger, Beck
Depression Inventory-II (BDI-II)33 for state depression,
Depression scale from the General Behavior Inventory
(GBI)34 for trait depression, Beck Anxiety Inventory (BAI)35
for state anxiety, and State-Trait Anxiety Inventory (STAI)36
for trait anxiety. The Global Assessment of Functioning
(GAF)37 scale served as the variable for psychosocial
functioning. Racial data, collected by diagnostic assessors,
reflected self-identified racial characteristics of subjects.
Socioeconomic status was assessed by the Hollingshead
method (A. B. Hollingshead, Four Factor Index of Social
Status, unpublished dissertation, 1975).
Table 1. Psychiatric and Personality Disorder Diagnoses
in Psychiatric Controls and in Subjects With Intermittent
Explosive Disordera
Diagnosis
Psychiatric
Controls
(n = 138)
Intermittent
Explosive
Disorder
(n = 110) P Value
Lifetime syndromal disorders 108 (78.3) 109 (99.1) < .001*
Any depressive disorder 49 (35.5) 69 (62.7) < .001*
Any anxiety disorder 32 (23.2) 33 (30.0) .226
Any substance use disorder 37 (26.8) 57 (51.8) < .001*
Intermittent explosive disorder 0 (0.0) 109 (99.1) < .001
Stress and trauma disorders 20 (14.5) 21 (19.1) .333
Eating disorders 3 (2.2) 12 (10.9) .004
Obsessive-compulsive disorders 3 (2.2) 3 (2.7) .778
Other impulse-control disorders 0 (0.0) 4 (3.6) .226
Any personality disorder 89 (64.5) 109 (99.1) < .001*
Cluster A 12 (8.7) 27 (24.5) .001*
Cluster B 19 (13.8) 63 (57.3) < .001*
Cluster C 22 (15.9) 33 (30.0) .008
Personality disorder, not
otherwise specified
46 (33.3) 31 (28.2) .384
aAll values are n (%). Subjects may have more than 1 disorder.
*Significant after Bonferroni correction for 14 comparisons (P < .003).
 While limited information exists on the causes of human
aggression, new research is pointing to inflammatory or
infectious processes as a possible etiology.
 Patients with significant histories of aggression (ie,
intermittent explosive disorder) may have a latent
infection with T. gondii, a common protozoan, that often
goes undetected but is treatable.
Clinical Points

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336 J Clin Psychiatry 77:3, March 2016
Coccaro et al
Statistical Analysis
Comparisons of between-group variables were
performed by χ2, univariate (ANOVA/ANCOVA),
and multivariate analysis of variance/covariance
(MANOVA/MANCOVA), followed by Tukey honestly
significant difference post hoc testing. Other analyses
included binary logistic regression using age as a
covariate. The primary biological variable in this
study was T. gondii seropositive status as in previous
studies.19 The primary dimensional variables included
composite scores for aggression and impulsivity; these
variables were created by z-transforming each of the 2
sets of aggression (LHA/BPAQ) and impulsivity (BIS-
11/EPQ-2) variables and taking the mean z score of
the source variables. The primary categorical variables
included diagnostic status (healthy controls/psychiatric
controls/subjects with IED), positive history of
suicide attempt, and positive history of self-injurious
behavior. A 2-tailed α value of .05 was used to denote
statistical significance for all analyses. The primary
analysis tested the relationship between T. gondii
seropositive status and composite aggression scores,
composite impulsivity scores, and history of self-
directed aggression in all subjects. This was followed
by analyses to determine if (1) T. gondii seropositive
status was more frequent among IED subjects (subjects
characterized by high levels of impulsive aggressive and
suicidal behaviors), (2) T. gondii seropositive status
was greater among subjects with other psychiatric and
personality disorders, and (3) T. gondii seropositive
individuals had higher levels of state and/or trait
depression, anxiety, or anger.
RESULTS
Demographic Characteristics of the Sample
Healthy controls, psychiatric controls, and IED
subjects differed only in age, with a less than 5-year age
difference between IED subjects and healthy controls
and a less than 3-year age difference between IED
subjects and psychiatric controls. T. gondii seropositive
status did not differ as a function of sex, race, or
socioeconomic status (Table 2). As expected, the groups
differed as a function of aggression, impulsivity, and
history of suicidal and self-injurious behavior (Table
2). The rate of T. gondii seropositive subjects in this
study was 15.9%, which is comparable with the most
recent estimate of 14.1% for the United States.9
T. gondii Seropositive Status as a Function of
Aggression and Impulsivity
One-way ANCOVA, with age as a covariate, revealed
that Composite Aggression scores were significantly
higher in T. gondii seropositive subjects (F1,342 = 5.32,
P = .022; Figure 1, left). Composite Impulsivity scores
were also higher in T. gondii seropositive subjects
(F1,325 = 3.83, P = .05; Figure 1, right). Composite
Table 2. Demographic, Psychometric, and Clinical Characteristics
of Sample
Variable
Healthy
Controls
(n = 110)
Psychiatric
Controls
(n = 138)
Intermittent
Explosive
Disorder
(n = 110) P Value
Demographic variables
Age, mean ± SD, y 31.3 ± 8.7 33.7 ± 8.1 36.1 ± 8.3 < .001a
Male, % 58 59 64b.748b
Race (white/African
American/other), %
64/26/10 66/30/4 65/28/7 .379b
SES score, mean ± SD 37.0 ± 12.8 36.5 ± 14.5 35.6 ± 12.2 .719a
Psychometric variables,
mean ± SD
Aggression (LHA) 4.5 ± 3.6 7.2 ± 5.2 18.3 ± 5.3 < .001a
Aggression (BPAQ) 40.8 ± 13.4 47.7 ± 14.8 74.8 ± 19.7 < .001a
Impulsivity (BIS-11) 56.3 ± 8.4 62.0 ± 9.7 69.3 ± 12.0 < .001a
Impulsivity (EPQ-2) 3.4 ± 3.1 4.4 ± 3.8 8.5 ± 4.4 < .001a
State anger (STAXI-2) 15.2 ± 1.0 16.3 ± 1.4 22.7 ± 1.1 < .001a
Trait anger (STAXI-2) 13.2 ± 2.5 16.3 ± 5.4 26.6 ± 7.2 < .001a
State depression (BDI-II) 2.4 ± 7.4 6.7 ± 7.7 16.5 ± 11.9 < .001a
Trait depression (GBI) 0.1 ± 0.5 8.8 ± 13.6 14.0 ± 11.5 < .001a
State anxiety (BAI) 22.6 ± 2.2 27.9 ± 8.6 32.3 ± 9.4 < .001a
Trait anxiety (STAI) 29.7 ± 6.9 38.5 ± 11.6 47.1 ± 10.2 < .001a
Clinical variables, mean ± SD
GAF score 84.0 ± 4.9 65.1 ± 10.6 54.6 ± 8.6 < .001a
Suicide attempt history NA 3.6% 26.4% < .001c
Self-injurious behavior
history
NA 6.5% 15.5% .023c
Suicidal or self-injury
history
NA 7.2% 36.4% < .001c
aBy analysis of variance.
bBy χ2.
cBy Fisher exact test.
Abbreviations: BAI = Beck Anxiety Inventory; BDI-II = Beck Depression Inventory-II;
BIS-11 = Barratt Impulsivity Scale, version 11; BPAQ = Buss-Perry Aggression
Questionnaire; EPQ-2 = Eysenck Personality Inventory-2; GAF = Global
Assessment of Functioning; GBI = General Behavior Inventory; LHA = Life History
of Aggression; SES = socioeconomic status; STAXI-2 = State-Trait Anger Expression
Inventory-2; STAI = State-Trait Anxiety Inventory.
Asessment of T. gondii Seropositivity Status
Subjects were free of all medications for at least 4 weeks. Whole
blood, anticoagulated with EDTA (ethylenediaminetetraacetic
acid), was obtained between 9  and 11  through venipuncture
of a forearm vein. Plasma was processed after centrifugation,
placed in a polypropylene tube, and stored at −80°C until assay.
These frozen plasma samples were collected between 1991 and
2008 and were tested for IgG antibodies to T. gondii in 2014
by solid-phase enzyme-linked immunosorbent assay (ELISA)
with kits from IBL (Hamburg, Germany). All samples were run
in duplicate, and quality controls were used. The coefficient of
intra-assay variation was less than 10%. A subject with plasma T.
gondii IgG antibodies > 12 IU was considered to be seropositive
for T. gondii. Equivocal samples (8–12 IUs) were reanalyzed to
accurately classify them as negative or positive. The laboratory
technician was not aware of the diagnostic status of the subject.
T. gondii seropositive status, rather than serointensity, was used
because the latter cannot be measured in seronegative subjects.
Despite the 18-year duration of sample collection, no association
was observed between T. gondii seropositive status and time from
the first to last study year (Spearman ρ = 0.08, P = .12). Fina lly,
plasma levels for the proinflammatory cytokine interleukin 6
(IL-6) were available in 176 of these subjects as part of a previously
published study.38

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337J Clin Psychiatry 77:3, March 2016
T. gondii Infection and Aggression
(B = 1.05 ± 0.47, Wald1 = 5.06, P = .025), compared with healthy
controls. Adding Composite Aggression scores to the models
eliminated these relationships for lifetime depressive disorder
(B = 0.56 ± 0.50, Wald1 = 1.26, P = .263) and lifetime anxiety
disorder (B = 0.76 ± 0.5.21, Wald1 = 2.13, P = .144).
T. gondii Seropositive Status as a
Function of Personality Disorder
A significant difference in T. gondii seropositive status was
also noted as a function of the presence of borderline and/or
antisocial personality disorder compared with healthy controls
(healthy controls, 9.1%; psychiatric controls, 18.2%; borderline
and/or antisocial personality disorder, 20.9%; linear by linear
association: χ21 = 5.10, P = .024); the difference with psychiatric
controls was not significant. Binary logistic regression, with age
as covariate, yielded a similar result that approached, but did not
*
†
**
Marginal Mean Composite
± SEM Scores
Aggression
Impulsivity
Healthy
Controls
Psychiatric
Controls
Intermittent
Explosive Disorder
0
Perecentage T.gondii Seropositive
25
16.7%
21.8%
9.1%
% T. gondii +
2.00
2.50
1.50
0.00
1.00
0.50
−0.50
−1.00
Figure 2. Percentage of T. gondii Seropositive (+) Subjects
and Composite Aggression and Composite Impulsivity Scores
(adjusted for age) as a Function of Healthy Controls, Psychiatric
Controls, and Intermittent Explosive Disorder Status
*P < .05, based on χ2.
**P < .025, based on analysis of covariance (ANCOVA).
†P = .051, based on ANCOVA.
Figure 1.Composite Aggression and Impulsivity (age as covariate)
in Subjects Seropositive (+) and Seronegative (–) for T. gondiia
aAggression (impulsivity) refers to Composite Aggression scores with Composite
Impulsivity scores as a covariate; impulsivity (aggression) refers to Composite
Impulsivity scores with Composite Aggression scores as a covariate.
*P ≤ .05.
Abbreviation: NS = not significant.
*
*
*
NS
Aggression Aggression
(Impulsivity)
Impulsivity Impulsivity
(Aggression)
Marginal Means ± SEM for Composite Scores
T. gondii +
T. gondii −
0.50
0.60
0.40
0.10
0.30
0.20
−0.30
0.00
−0.10
−0.20
Aggression scores adjusted for Composite Impulsivity
scores continued to be higher among T. gondii
seropositive subjects (P = .011; Figure 1, left), although
the reverse was not true for Composite Impulsivity
scores adjusted for Composite Aggression scores
(P = .984; Figure 1, right). Similarly, when placed in the
same binary logistic regression, with age as covariate,
Composite Aggression (B = 0.44 ± 0.20, Wald1 = 4.77,
Exp(B) = 1.55, P = .029), but not Composite Impulsivity
(B = 0.02 ± 0.20, Wald1 = 0.08, Exp(B) = 1.06, P = .773),
scores were associated with T. gondii seropositive status.
T. gondii Seropositive Status as a
Function of Self-Directed Aggression
Binary logistic regression, with age as covariate,
revealed that T. gondii seropositive status did not
predict history of suicide attempt (20.6% vs 15.4%
T. gondii seropositive: B = −0.26 ± 0.46, Wald1 = 0.31,
P = .577), history of self-injurious behavior (26.9%
vs 15.1% T. gondii seropositive: B = −0.75 ± 0.47,
Wald 1 = 2.48, P = .116), or history of either type of self-
directed aggressive behavior (24.0% vs 14.6% T. gondii
seropositive: B = −0.58 ± 0.37, Wald1 = 2.42, P = .119).
T. gondii Seropositive Status as a Function of IED
Next, we examined the relationship between
T. gondii seropositive status as a function of IED,
a disorder of recurrent, problematic, impulsive
aggressive behavior, compared with healthy controls
and psychiatric controls. A significant difference in
T. gondii seropositive status was noted among the
groups (linear by linear association χ21 = 6.06, P = .014;
Figure 2). Binary logistic regression, with age as a
covariate, yielded the same result with IED subjects
(B = 0.89 ± 0.41, Wa ld1 = 4.68, P = .030) signif icantly
associated with T. gondii seropositive status compared
with healthy controls. Psychiatric controls were not
significantly associated with T. gondii seropositive
status compared with healthy controls (B = −0.63 ± 0.41,
Wald 1 = 2.42, P = .120). Increasing T. gondii seropositive
status paralleled mean Composite Aggression (and
Composite Impulsivity) scores, adjusted for age, across
the groups (Figure 2). Adding Composite Aggression
scores to the model eliminated the relationship for T.
gondii seropositive status for IED subjects, compared
with healthy controls (B = 0.26 ± 0.63, Wald1 = 0.18,
P = .675).
T. gondii Seropositive Status as a
Function of Non-IED Syndromal Disorders
A significant difference in T. gondii seropositive
status was also noted as a function of lifetime depressive
disorder and lifetime anxiety disorder, but not lifetime
substance use disorder. Binary logistic regression, with
age as covariate, yielded similar results for subjects
with depressive disorder (B = 0.79 ± 0.42, Wald1 = 3.51,
P = .061) and subjects with anxiety disorder

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338 J Clin Psychiatry 77:3, March 2016
Coccaro et al
reach, statistical significance (B = 0.85 ± 0.45, Wald1 = 3.47,
P = .062). Adding Composite Aggression scores to the model
eliminated this relationship (B = 0.32 ± 0.60, Wald1 = 0.29,
P = .592). Expanding this analysis to include all personality
disorders resulted in the same observation with respect
to psychiatric controls having a higher rate of T. gondii
seropositive status compared with healthy controls; this
finding was nonsignificant after the addition of Composite
Aggression scores to the model.
T. gondii Seropositive Status as a Function
of State and Trait Dysphoric Moods: Anger,
Depression, and Anxiety
ANCOVA, with age as covariate, revealed higher state
and trait anger scores as a function of T. gondii seropositive
status (Figure 3, left). Similar analysis using state and
trait depression and anxiety scores, however, revealed no
significant differences as a function of T. gondii seropositive
status (Figure 3, center and right).
Circulating IL-6 Levels as a
Function of T. gondii Seropositive Status
ANCOVA, with age as covariate, revealed no difference in
circulating levels of IL-6 as a function of T. gondii seropositive
status in the subgroup in which these data were available
(T. gondii seropositive: 0.98 ± 1.64 pg/mL vs T. gondii
seronegative: 1.41 ± 1.67 pg/mL; F1,172 = 1.27, P = .262). As
previously reported, IL-6 (log IL-6: r = –0.39, P < .001) levels
were inversely correlated with Composite Aggression scores
in the subjects in this study.39
DISCUSSION
The results of this study suggest a relationship between
latent infection with T. gondii and impulsive aggression from
both a dimensional and categorical perspective. Specifically,
T. gondii seropositive status was associated with higher
scores on the psychometric measures for both Aggression
and Impulsivity. Between aggression and impulsivity,
these data suggest that T. gondii seropositive status is
primarily related to aggression than to impulsivity in that
the variance associated with impulsivity overlaps with the
variance associated with aggression. In addition, the rate
of T. gondii seropositivity in IED subjects was significantly
greater than that in healthy controls, though not significantly
greater than that in psychiatric controls without IED. The
nonsignificant difference in seropositivity rate between
IED subjects and psychiatric controls may be due to the
fact that Aggression scores in psychiatric controls were
intermediate between healthy controls and IED subjects, that
this sample did not have the power to detect this difference
to a statistically significant degree, or that other behaviors,
such as depression or anxiety, are also associated with latent
toxoplasmosis. These results are supported by findings from
animal studies39 that showed a relationship between T. gondii
infection and elevated aggression-related behaviors and a
recent study19 of 1,000 psychiatrically healthy subjects that
documented elevated trait aggression and impulsivity as a
function of T. gondii seropositivity.
Typically, other-directed aggression is strongly associated
with self-directed aggressive behavior in psychiatric
subjects,18 and greater rates of T. gondii seropositive status
have been reported among those with a history of suicidal
be hav ior.11–15 Despite these previous findings, we did not
find an association between T. gondii seropositive status and
self-directed aggression in our sample. The proportion of
subjects with lifetime histories of suicidal or self-injurious
behavior was small, however, and the present study had
limited statistical power to detect relationships reported
from previous, and larger, samples. It is also possible that the
psychiatric diagnostic composition of the sample (psychiatric
controls) and tendency to direct aggression outward (IED)
reduced an association with suicidal self-directed aggression.
Consistently, in the largest study14 on T. gondii seropositive
status and suicidal self-directed violence, performed on a
cohort of Danish women, the association was significantly
weaker in those women who had a concurrent diagnosis of
mood disorder, psychotic disorder, or personality disorder.
Individuals with a lifetime history of depressive
and anxiety disorder also had higher rates of T. gondii
seropositive status compared with healthy controls. While
higher depression and anxiety scores should be observed
as a function of T. gondii seropositive status, no significant
differences in state or trait scores for depression or anxiety
were observed. The observed effect size for depression
or anxiety scores was modest (d = 0.10 to 0.20), and it is
possible that a larger sample would have yielded different
results. However, studies in much larger samples report no
significant association between T. gondii seropositive status
and unipolar major depression or dysthymia,9 generalized
anxiety disorder, panic disorder, or posttraumatic stress
disorder,39 suggesting that mood and anxiety disorders are
not accounting for the findings in our study. In contrast,
composite aggression and state and trait anger scores were
aTo place all symptom measures on the same scale, z scores were used.
*P < .05.
†P < .10.
Abbreviation: NS = not significant.
Figure 3. State and Trait Anger, Depression, and Anxiety
(z) Scores (age as covariate) as a Function of T. gondii
Seropositive (+) and Seronegative (–) Subjectsa
*
†
NS NS
NS NS
State
Marginal Means
± SEM for Scale z Scores
Trait
Anger
State Trait
Depression
State Trait
Anxiety
T. gondii +
T. gondii −
0.8
1.0
0.6
0.0
0.4
0.2
−0.2

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339J Clin Psychiatry 77:3, March 2016
T. gondii Infection and Aggression
significantly elevated as a function of T. gondii seropositive
status and, in every case, eliminated all differences as a
function of T. gondii seropositive status. Thus, we posit
that the higher T. gondii seropositive rates observed in
individuals with depressive/anxiety disorder, compared with
healthy controls, were due to their comorbidity with IED or
a correlation between aggression, depression, and anxiety
scores. In the current sample, IED was highly comorbid
with lifetime depressive disorder (64% vs 35%, P < .001),
and aggression scores correlated with both trait depression
(r = 0.38, P = .001) and anxiety (r = 0.52, P < .001) scores,
though not as strongly as depression correlated with anxiety
(r = 0.74, P < .001).
Several factors may account for these findings. First,
chronic latent infection with T. gondii may lead to a low-
grade chronic immune activation within the brain, with
(or without) downstream effects on neurotransmitter
systems involved in aggressive behavior.40 Second, chronic
T. gondii infection may alter the structure and function
of corticolimbic circuits that are known to modulate
impulsive aggressive behavior.41 Specifically, persistent T.
gondii infection in mice is associated with neuronal tissue
lesions, altered neuronal function, ventricular dilation,
and neuroinflammation.42 In addition, several, though not
all, studies suggest that T. gondii–containing cysts localize
primarily in the prefrontal cortex and amygdala43,44 and that
latent infection with T. gondii induces dendritic retraction in
the basolateral amygdala.45 Third, as shown experimentally
in rats,46 T. gondii infection increases testicular expression
of genes involved in the production of testosterone. In
addition, there is evidence that T. gondii–infected males,
though not females, have higher circulating levels of
testosterone compared with controls.47 However, while a
number of studies report a relationship between elevated
levels of testosterone and aggression,48 the magnitude of this
relationship is small. Thus, it is unlikely that testosterone
plays any more than a modest role in this regard.
Neurotransmitter mechanisms by which T. gondii
may affect behavior include effects on serotonergic and
glutaminergic transmission, both of which have been shown
to play a role in aggressive behavior in human studies.49,50
Relevant to serotonin, conversion of tryptophan to
kynurenine is controlled by indoleamine 2,3-dioxygenase
([IDO]; IDO-1 and IDO-2).51 Since IDO can be activated by
inflammatory cytokines, levels of kynurenine can rise while
levels of serotonin decline. In addition, increased levels of
kynurenine lead to increased levels of its active metabolite
quinolinic acid, a potent N-methyl--aspartate receptor
agonist, which may increase the risk for aggressive behavior
in humans.50 While this hypothesis is partially supported by
reported elevations of kynurenine and quinolinic acid levels
in mice with chronic T. gondii infection,52 we did not find
differences in circulating levels of proinflammatory cytokines
(ie, IL-6) as a function of T. gondii seropositivity. It is possible
that the proinflammatory processes that keep T. gondii in a
latent state are confined to the brain and are not reflected in
the periphery. It is also possible that impulsively aggressive
individuals engage in behaviors that increase their own
risk of infection with T. gondii or that latent toxoplasmosis
changes behavior, as in felids,1 so that the expression of
aggression is increased. In addition, T. gondii is known to
increase risk-taking behavior in rodents, evolutionarily
benefiting the parasite (ie, transforming natural aversion
in cats to attraction).53,54 This is an example of the general
phenomenon of host manipulation by parasites, documented
in nature,55 and proposed as a model with some explanatory
potential for alterations in human behavior associated with
parasitic infections.56,57
The strengths of this hypothesis-driven study include
a well-characterized sample of healthy and psychiatric
controls as well as validated measures of aggression,
impulsivity, depression, and anxiety. Limitations to our study
are present, as well. First, we used a cross-sectional design,
and no causal, or directional, conclusions can be made from
these analyses. Second, ascertainment of subjects may limit
the generalizability of these findings in that these involved
subjects who volunteered for a research study, rather than
for clinical treatment. However, nearly three-quarters of the
psychiatric subjects reported a past history of psychiatric
treatment (or of having episodes of behavioral disturbance
for which they, or others, thought they should have sought
mental health services but did not), and, thus, most of these
subjects are likely similar to individuals who would have been
recruited from a clinical setting. Third, it is possible that the
presented associations are nonspecific and, instead, due to
other common latency-establishing neurotropic pathogens
such as herpes viruses or cytomegalovirus. However, recent
studies have documented that associations between T. gondii
and self-directed58 and other-directed19 aggression in human
subjects are not due to the presence of these other potential
pathogens. Finally, because immunoglobulin M antibodies
to T. gondii were not assessed, there is a possibility that a
small number of seropositive subjects had an acute, rather
than a chronic latent, infection at time of study.
In summary, we report a greater rate of T. gondii
seropositive status in subjects with DSM-5 IED compared
with healthy controls and a positive relationship with
aggression and anger, but not with depression or anxiety.
These findings are consistent with previous T. gondii
seropositive status data, suggesting a relationship with self-
directed aggression (ie, suicidal behavior) and a relationship
involving schizophrenia or mania—disorders in which many
individuals are often aggressive.59,60 Our results further add
to the biological complexity of impulsive aggression, from
both a categorical and a dimensional perspective.
Submitted: October 29, 2014; accepted Februar y 26, 2015.
Potentia l conicts of in terest: Dr Coccaro reports b eing a consultant
and on the Scientic Advisor y Board of and having stock options from
Azevan Pharmaceuticals. D r Lee reports being the recipient of a research
grant from Azevan Pharmaceuticals. Drs Groer, Can, Coussons-Read, and
Postolache have no potential conicts of interest.
Funding/support: This work was supported, in part, by grants from
the National Institute of Mental Health: RO1 MH60836, RO1 MH63262,
RO1 MH66984 (Dr Coccaro), a Project Pilot Grant from the University of

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340 J Clin Psychiatry 77:3, March 2016
Coccaro et al
Colorado, Denver (Dr Coussons-Read), and the
Distinguished Investigator Award from the
American Foundation for Suicide Prevention
(Dr Postolache). Dr Postolache’s contribution
was additionally suppor ted by the Veterans
Integrated Service Net work 19 Mental Illness
Research, Educ ation and Clinical Center, Denver,
Colorado.
Role of the sponsor: The funding agencies
had no role in the design and conduct of t he
study; collection, management, analysis, and
interpretation of the data; or preparation,
review, and approval of the manuscript.
Disclaimer: The views, opinions, and ndings
contained in this article are those of t he authors
and do not necessarily represent the ocial
policy or p osition of the Dep artment of Veterans
Aairs or the US Government.
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