European Psychiatry 31 (2016) 8–12

Contents lists available at ScienceDirect

European Psychiatry
journal homepage: http://www.europsy-journal.com

Original article

Elevated C-reactive protein levels in schizophrenia inpatients is

associated with aggressive behavior
R. Barzilay a,b,*, T. Lobel a, A. Krivoy a, D. Shlosberg a, A. Weizman a, N. Katz a
a
Geha Mental Health Center, Sackler Faculty of Medicine, Tel Aviv University, 1 Helsinki St., 4910002 Petah-Tikva, Israel
b
Neurosciences laboratory, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Israel

A R T I C L E I N F O A B S T R A C T

Article history: Background: An association between inflammation and behavioral domains of mental disorders is of
Received 17 August 2015 growing interest. Recent studies reported an association between aggression and inflammation. In this
Received in revised form 28 September 2015 study, we investigated the association between aggressive behavior and inflammatory markers in
Accepted 29 September 2015
schizophrenia inpatients.
Available online 3 December 2015
Methods: Adult schizophrenia inpatients without affective symptoms (n = 213) were retrospectively
identified and categorized according to their C-reactive protein measurement at admission as either
Keywords:
elevated (CRP > 1 mg/dL; n = 57) or normal (CRP < 1 mg/dL; n = 156). The following indicators of
Schizophrenia
Inflammation
aggression were compared: PANSS excitement component (PANSS-EC), restraints and suicidal behavior
C-reactive protein during hospitalization. Univariate comparisons between elevated and normal CRP levels were
Aggression performed and multivariate analysis was conducted to control for relevant covariates.
Suicidal behavior Results: CRP levels significantly correlated with other laboratory markers indicating increased
Neutrophil to lymphocyte ratio inflammation including leukocyte count and neutrophil to lymphocyte ratio (r = 0.387,
P < 0.0001 and r = 0.356, P < 0.0001) respectively. Inpatients with elevated C-reactive protein displayed
increased aggressive behavior compared to patients with normal CRP levels (<1 mg/dL). This was
manifested by higher rates of restraint during hospitalization (x2 = 5.22, P = 0.031) and increased PANSS-
EC score (U = 5410.5, P = 0.012). Elevated CRP levels were not associated with suicidal behavior.
Multivariate analysis revealed that higher PANSS-EC score was associated with elevated CRP after
controlling for the covariates age, sex, BMI and smoking.
Conclusion: This study identified a potential biological correlate (inflammation) of a specific behavioral
endophenotype (aggression) in schizophrenia inpatients.
ß 2015 Elsevier Masson SAS. All rights reserved.

1. Introduction with psychiatric morbidity, has been recently investigated.

Schizophrenia inpatients often present with aggressive behav-
ior during hospitalization, partly due to the association between
positive symptoms and aggression [1,2]. Early identification and
treatment of aggressive tendencies upon admission to a psychiat-
ric facility may reduce the risk of patient and staff injury. Risk
factors for aggression in schizophrenia patients include active
psychosis, a history of aggressive behavior and illicit substance use
[3]. These risk factors, however, are non-specific and the pursuit of
other risk factors is an unmet need.
The role of inflammation in the underlying pathophysiology of
aggressive behavior, both in healthy individuals [4] and in patients
* Corresponding author. Ran Barzilay, Geha Mental Health Center, Sackler Faculty
of Medicine, Tel Aviv University, Israel. Tel.: +97 2523 020443;
fax: +97 2775 251518.
E-mail address: barzilyr@post.tau.ac.il (R. Barzilay).
Specifically, a positive correlation between aggression and serum
and cerebrospinal fluid levels of the inflammatory marker C-
reactive protein (CRP) was reported in patients with personality
disorders and intermittent explosive disorder [5–7]. Suicidal
behavior, as an expression of self-inflicted aggression, has also
been found to correlate with increased inflammatory markers,
both in cerebrospinal fluid [8] and in peripheral blood [9,10]. Ele-
vated blood CRP levels were also reported in schizophrenia
patients as compared to healthy controls [11], although studies
evaluating the association of CRP levels with schizophrenia
symptomatology have yielded inconclusive results, with some
studies reporting correlation between CRP levels and certain
clinical scales, while other report no such association [12–16].
To date, an association between aggressive behavior and
inflammation in schizophrenia has not been investigated. This
study, therefore, aimed to explore the relationship between
aggressive behavior and elevated CRP levels in schizophrenia

http://dx.doi.org/10.1016/j.eurpsy.2015.09.461
0924-9338/ß 2015 Elsevier Masson SAS. All rights reserved.
 R. Barzilay et al. / European Psychiatry 31 (2016) 8–12 9

inpatients. The association between clinical measures of aggres- Table 1

Demographic and clinical characteristics of the study subjects.
sion and suicidal behavior with CRP, a general laboratory marker
of immune activation and inflammation, was retrospectively n = 213
studied in schizophrenia patients admitted to a single closed Age in years, mean (SD) 42.2 (14.09)
ward. Sex
Male, n (%) 133 (62.4)
2. Methods Female, n (%) 80 (37.6)
BMI [kg/m2]–mean (SD) 25.01 (5.17)
Smoking status
2.1. Design Yes, n (%) 156 (73.2)
No, n (%) 57 (26.8)
The study utilized a retrospective cross-sectional patients’ Illicit substance use
Cannabis use only, n (%) 21 (9.9)
records study design. Data was retrieved from the electronic
Multiple substance use, n (%) 13 (6.1)
medical records of all hospitalized patients between October No illicit substance use, n (%) 179 (84)
2010 and December 2013 in a single adult closed ward with a Antipsychotics at admission
catchment area of approximately 300,000 inhabitants, at the Geha Typicals, n (%) 99 (46.5)
Atypicals, n (%) 95 (44.6)
Mental Health Center (GMHC), a regional mental health center. The
No pharmacotherapy, n (%) 19 (8.9)
GMHC review board approved the study and waived the need for Clinical measures
informed consent due to the retrospective nature of the study. PANSS total – mean (SD) 82.76 (22.8)
PANSS positive – mean (SD) 20.69 (6.89)
2.2. Subjects PANSS negative – mean (SD) 21.49 (7.46)
PANSS depression – mean (SD) 8.77 (3.79)

Included in the study were all adult patients (n = 213, age 19–
89) who were discharged with the primary psychiatric diagnosis of
schizophrenia, based on the Diagnostic and Statistical Manual of
Mental Disorders, 4th Edition (DSM-IV-TR) criteria. Patients
diagnosed with a major affective disease (i.e. schizoaffective,
bipolar disorder, major depression and mania) were excluded. We
also excluded patients suffering from any acute physical illness,
patients with fever (>37.90C) or those who were treated with
antibiotics, steroids, antipyretics or anti-inflammatory medica-
tions.
2.3. Variables
Laboratory data associated with inflammation included blood
tests routinely performed upon admission: white blood cells
(WBC), platelets count, albumin levels and neutrophil to lympho-
cyte ratio [17]. CRP levels were determined in the ward as part of
the routine laboratory tests conducted upon admission. Blood for
CRP levels was drawn from all patients at 8 a.m within the first day
after admission. Serum CRP levels were measured using Beckman
Coulter AU 2700 analyzer (Brea, CA), by a particle enhanced
immunoturbidimetric method, using latex particles coated with
monoclonal anti-CRP antibodies (Roche CRPL3 reagent, Indiana-
polis, IN). The test is linear within a concentration range of 0.008–
8 mg/dl. A level of >1 mg/dL was considered as elevated according
to the classification of the American Heart Association and levels
under 1 mg/dL were considered as normal [18]. All CRP levels were
below 11 mg/dL, reducing the chance of an acute physical illness as
a cause for the inflammatory state.
The clinical data retrieved included body mass index (BMI),
smoking status (smoker or non-smoker, as documented at each
admission following an interview by the admitting nurse), illicit
substance use and treatment with antipsychotics as recorded
upon admission. Psychiatric scales including the positive and
negative syndrome scale (PANSS) [19] are routinely completed in
GMHC. PANSS score was determined by the patient’s treating
psychiatrist following an interview that was conducted within
72 hours from admission as a routine practice of the inpatient
unit. PANSS excitement component (PANSS-EC) was used as a
measure of aggression and agitation [20–22]. The need for
physical restraint during hospitalization and the presence of
suicide ideation and/or suicide attempt at admission were
recorded according to the evaluation of the medical records.
Demographic and clinical characteristics of the sample are
presented in Table 1.
2.4. Statistical analysis
We used SPSS ver. 21 (SPSS Inc., Chicago, IL) for statistical
analysis. Descriptive statistics are expressed as mean  SD, or rate
(%). Two groups of patients were compared by levels of CRP at the
cutoff of 1 mg/dL (elevated vs. normal). For univariate analyses, we
used 2-tailed Student’s t-tests, Mann-Whitney U test or Chi-squared
test as appropriate. Multivariate analysis was performed using binary
logistic regression analyses with CRP levels (elevated or normal) as a
dependent variable controlling for age, sex, BMI, smoking status and
illicit substance use as covariates. A P-value < 0.05 was considered to
indicate statistical significance.
3. Results
3.1. Increased CRP correlates with known laboratory inflammatory
markers
CRP measurements were distributed in a non-normal manner
with the majority of patients (156 from 213, 73.2%) below the
mean (1.068 mg/dL, Fig. 1A). To validate the assumption that
patients with an elevated CRP level (>1 mg/dL) present a sub-
population with increased inflammatory state, a correlation
analyses was performed between CRP levels and other laboratory
indices indicative of inflammation. We found that the following
parameters significantly correlated with logCRP: albumin levels
(Fig. 1B), platelets count (Fig. 1C), leukocytes count (Fig. 1D) and
the neutrophil to lymphocyte ratio (Fig. 1E).
3.2. Elevated CRP is associated with increased aggressiveness
Clinical variables indicative of aggressive behavior, general
measures based on the PANSS score, and evaluation of suicidal
behavior, were compared between inpatients with normal and
elevated levels of CRP. Covariates that could affect aggression and
CRP levels including gender, age, BMI, illicit substance use and
smoking status were compared. The results show that patients with
elevated CRP levels are more aggressive during hospitalization as
detected by statistically significant higher scores of irritability and
aggressive behavior (PANSS-EC score), and by increased rates of
physical restraint during hospitalization (Table 2). Noteworthy, we
found no statistically significant differences in the other clinical
measures, including suicidal behavior.
10 R. Barzilay et al. / European Psychiatry 31 (2016) 8–12
Fig. 1. CRP measurements (A, dotted line represents the cutoff 1 mg/dL, full line
represents the mean CRP measurement) and correlation with inflammatory indices
including albumin (B), platelet count (PLT) (C), white blood cells (WBC) (D) and
neutrophil to lymphocyte ratio (E).
3.3. The effect of covariates on the association between elevated CRP
and aggression
Multivariate analysis was performed to assess the effect of
covariates on the association between CRP levels upon admission
and aggression in hospitalization (represented by PANSS-EC score).
A binary logistic regression with normal or elevated CRP levels as a
dependent variable was applied. The model contained PANSS-EC
score, age, sex, BMI, smoking status, and illicit substance use as
independent variables. The logistic regression model was statisti-
cally significant (x2 (6) = 13.349, P = 0.038). The model explained
9.6% (Nagelkerke R2) of the variance in CRP status and correctly
classified 75.9% of cases. From the independent variables, after
controlling for all other factors in the model, PANSS-EC score made
a statistically significant contribution to the model (b = 0.1,
P = 0.013), whereas age (b = 0.001, P = 0.917), sex (b = –0.643,
P = 0.105), BMI (b = 0.064, P = 0.051), illicit substance use
(b = 0.238, P = 0.438) and smoking (b = 0.274, P = 0.517) did not.
4. Discussion
This study tested whether schizophrenia patients with elevated
serum CRP were more aggressive during hospitalization. The
results show an association between elevated CRP levels and
aggressive behavior, suggesting a possible link between inflam-
mation and aggression in these patients. This is consistent with
data demonstrating a similar correlation between aggressive
behavior and CRP levels in non-schizophrenia population [4–7].
In our study, we chose three clinical variables as indicators of
aggression:
 PANSS-EC score;
 rate of restraints during hospitalization;
 presence of suicidal thoughts or acts in the index admission.
We found that increases in the first two parameters are
associated with elevated inflammatory indices (i.e. CRP > 1 mg/
dL). The difference in PANSS-EC score was <2 points between
patients with elevated and normal CRP, raising a question of its
clinical significance. However, as the sample population was not
chosen based on high aggression (the PANSS-EC score of the
normal CRP patients was lower than 10), the ordinary change in the
score may be better expressed as a 16% higher score in the PANSS-
EC in elevated CRP patients compared to those with normal CRP.
Furthermore, the increased rate of restraints of elevated CRP
patients concurs with the larger PANSS-EC scores in elevated CRP
patients. Patients with elevated CRP had 2.48-fold chance of being
restrained during hospitalization compared to normal CRP patients
(27.8% versus 11.2% of patients, respectively). Though multiple
factors affect the need for restraint during hospitalization, this
finding is highly suggestive that the larger PANSS-EC score
represents clinically significant aggressive phenotype in the
elevated CRP patients, which is not fully expressed in the 2 point
or 16% difference in the PANSS-EC score.
We did not find an association between elevated CRP and
suicidality in our cohort. Previous studies pointed to association
between increased inflammation in suicidal patients as manifested
by elevated inflammatory markers in plasma [9] and in cerebro-
spinal fluid [8]. As inflammation is associated with affective
symptomatology [23], which often underlies suicidal thoughts and
actions, it is plausible that the exclusion of patients with mood
disorder in our cohort (major depression, bipolar or schizoaffective
disorders) may account for the lack of association between
elevated CRP and suicidality. In addition, the fact that suicidal
thoughts and acts were not specifically evaluated by designated
 R. Barzilay et al. / European Psychiatry 31 (2016) 8–12 11

Table 2
Comparison of clinical parameters between patients with normal (<1 mg/dL) and elevated (>1 mg/dL) serum CRP levels at admission (*P < 0.05).

CRP < 1 CRP > 1 Test t/U/Pearson x2 P-values

n = 156 n = 57

Aggression measures
PANSS-excitement component, mean (SD) 9.98 (4.36) 11.6 (4.16) Mann-Whitney 5410.5 0.012*
Restrained during hospitalization, % 11.2% 27.8% Chi-square 5.219 0.031*
Suicide ideation and/or suicide attempt 18.6% 14% Chi-square 0.603 0.542
Other clinical measures
Total PANSS, mean (SD) 82.01 (22.77) 84.79 (22.96) t-test 0.785 0.434
PANSS positive, mean (SD) 20.37 (7) 21.58 (6.58) t-test 1.135 0.258
PANSS negative, mean (SD) 21.48 (7.4) 21.53 (7.69) t-test 0.42 0.966
PANSS depression, mean (SD) 8.81 (3.77) 8.65 (3.88) Mann-Whitney 4241 0.706
Priori covariates
Age, mean (SD) 42.17 (14.24) 42.28 (13.76) Mann-Whitney 4483.5 0.925
Gender male, % 59.6% 70.2% Chi-square 1.985 0.201
BMI [kg/m2] , mean (SD) 24.61 (4.82) 26.25 (6.02) Mann-Whitney 4254.5 0.115
Smoking, % 71.8% 77.2% Chi-square 0.621 0.488
Illicit substance use, % 15.4% 17.5% Chi-square 0.145 0.678

suicide assessment tools, due to the retrospective nature of the
study, may further limit the capacity of the current study to
elucidate such association, due to the complexity of defining
suicidal thoughts or actions as a distinct behavioral phenotype
[24].
The neurobiological mechanisms underpinning aggressive
behavior are largely unknown but recent research sheds light on
possible mechanisms including the serotonergic system and
gonadal hormones, specifically testosterone [25]. In schizophrenia
patients, aggressive behavior has been recently linked to the
‘‘urgency’’ construct, which may be defined as s impulsivity in the
context of strong emotion, which often occurs during hospitaliza-
tion [26]. The association between aggression and inflammation
was reported in a few studies [5–7], however no specific biological
mechanism was demonstrated. One study pointed to a possible
involvement of oxidative stress as mediating a neuromodulatory
effect on aggression, but with a weak association with inflamma-
tion [27]. Beurel and Jope recently suggested that lithium, one of
the only established anti-aggressive compounds, at least in bipolar
disorder, exerts its therapeutic effect in part through inhibition of
the glycogen synthase kinase-3 pathway, which promotes
inflammation, and is thought to be activated following stress
[28]. Interestingly, recent literature suggests that there is a long
lasting low-grade inflammation following exposure to adversities
in childhood [29]. Since exposure to childhood adversities is a risk
factor for aggressive and violent behavior in adulthood in
schizophrenia patients [30], it is possible that the disruptive effect
of early life stress on the immune system is partly involved in brain
mechanisms that regulate aggressive behavior in schizophrenia
patients.
A possible moderator for increased aggression may be a more
severe psychotic presentation. Prior studies that explored the
association between CRP levels and severity of psychiatric
symptomatology in schizophrenia patients, yielded inconsistent
results. In a small sample of 26 schizophrenia and schizoaffective
inpatients, patients with CRP levels >0.5 mg/dL presented with
higher total and negative PANSS score in [13], while another study
of 30 schizophrenia inpatients did not find an association between
CRP and symptom severity [15]. Another study reported a
correlation of CRP with the severity of symptoms as reflected by
PANSS scores, specifically negative symptoms, in a population of
drug naive schizophrenia outpatients [16]. Dickerson et al. showed
that elevated CRP correlates with cognitive impairments, but not
with total, positive or negative scales of the PANSS, in a sample of
schizophrenia and schizoaffective patients [12,31]. In the current
study, patients with elevated CRP levels did not present with
higher total, positive or negative PANSS scores. Considering the
current results and those of prior studies, it is less likely therefore,
that increased CRP levels are associated with a more severe state of
psychosis.
Although an association between elevated CRP and depressive
symptoms has been described [23], this study found no correlation
between the elevated CRP levels and PANSS-depression scores. In
addition, although some studies suggest that suicidal behavior in
depressed patients is associated with inflammation [8–10], such an
association was not found in our study. This discrepancy may be
explained by the fact that affective symptoms do not correlate with
inflammation in schizophrenia patients as was previously showed,
in contrast to bipolar patients [32]. Additionally, in schizophrenia
patients, the PANSS-depression scale might reflect the occurrence
of negative symptoms or antipsychotic-induced side effects rather
than depressive symptoms [33].
Clinical psychiatry is in a continuous attempt to identify
relevant biological correlates of human behaviors that may serve
as biomarkers for mental disorder state, trait and prognosis
[34]. Inflammation, as a moderator or a biomarker for psycho-
pathological symptoms, is of growing interest due to the
accumulating preclinical and clinical evidence suggesting a link
of clinical significance. Our study expands the awareness of the
possible association between aggression and inflammation in
schizophrenia. It is plausible that evaluation of inflammation in
routine practice using simple and relatively inexpensive laboratory
tools (i.e. blood count and CRP measurement), could help to stratify
patient population on the basis of their risk for or tendency
towards aggressive behavior during hospitalization.
Limitations of this study include its retrospective cross-
sectional design that did not allow a longitudinal assessment in
recurrent hospitalizations, and the fact that it assessed inpatients
from a single ward. To conclude, our data indicates an association
between inflammation and aggression in schizophrenia inpatients.
Further investigation should address the pathophysiological
mechanisms and the therapeutic potential of anti-inflammatory
agents in schizophrenia associated with elevated CRP levels.
Disclosure of interest
The authors declare that they have no competing interest.
Acknowledgements
None.
12 R. Barzilay et al. / European Psychiatry 31 (2016) 8–12
References
[1] Dack C, Ross J, Papadopoulos C, Stewart D, Bowers L. A review and meta-
analysis of the patient factors associated with psychiatric in-patient aggres-
sion. Acta Psychiatr Scand 2013;127:255–68. http://dx.doi.org/10.1111/
acps.12053.
[2] Krakowski M, Czobor P, Chou JCY. Course of violence in patients with schizo-
phrenia: relationship to clinical symptoms. Schizophr Bull 1999;25:505–17.
[3] Barlow K, Grenyer B, Ilkiw-Lavalle O. Prevalence and precipitants of aggression
in psychiatric inpatient units. Aust New Zeal J Psychiatry 2000;34:967–74.
http://dx.doi.org/10.1080/000486700271.
[4] Marsland AL, Prather AA, Petersen KL, Cohen S, Manuck SB. Antagonistic
characteristics are positively associated with inflammatory markers indepen-
dently of trait negative emotionality. Brain Behav Immun 2008;22:753–61.
http://dx.doi.org/10.1016/j.bbi.2007.11.008.
[5] Coccaro EF. Association of C-reactive protein elevation with trait aggression
and hostility in personality disordered subjects: a pilot study. J Psychiatr Res
2006;40:460–5. http://dx.doi.org/10.1016/j.jpsychires.2005.04.005.
[6] Coccaro EF, Lee R, Coussons-Read M. Elevated plasma inflammatory markers in
individuals with intermittent explosive disorder and correlation with aggres-
sion in humans. JAMA Psychiatry 2014;71:158–65. http://dx.doi.org/10.1001/
jamapsychiatry.2013.3297.
[7] Coccaro EF, Lee R, Coussons-Read M. Cerebrospinal fluid and plasma C-reactive
protein and aggression in personality-disordered subjects: a pilot study. J
Neural Transm 2015;122:321–6. http://dx.doi.org/10.1007/s00702-014-
1263-6.
[8] Lindqvist D, Janelidze S, Hagell P, Erhardt S, Samuelsson M, Minthon L, et al.
Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and
related to symptom severity. Biol Psychiatry 2009;66:287–92. http://
dx.doi.org/10.1016/j.biopsych.2009.01.030.
[9] Janelidze S, Mattei D, Westrin Å, Träskman-Bendz L, Brundin L. Cytokine levels
in the blood may distinguish suicide attempters from depressed patients.
Brain Behav Immun 2011;25:335–9. http://dx.doi.org/10.1016/
j.bbi.2010.10.010.
[10] O’Donovan A, Rush G, Hoatam G, Hughes BM, McCrohan A, Kelleher C, et al.
Suicidal ideation is associated with elevated inflammation in patients with
major depressive disorder. Depress Anxiety 2013;30:307–14. http://
dx.doi.org/10.1002/da.22087.
[11] Dickerson F, Stallings C, Origoni A, Vaughan C, Khushalani S, Yang S, et al. C-
reactive protein is elevated in schizophrenia. Schizophr Res 2013;143:198–
202. http://dx.doi.org/10.1016/j.schres.2012.10.041.
[12] Dickerson F, Stallings C, Origoni A, Boronow J, Yolken R. C-reactive protein is
associated with the severity of cognitive impairment but not of psychiatric
symptoms in individuals with schizophrenia. Schizophr Res 2007;93:261–5.
http://dx.doi.org/10.1016/j.schres.2007.03.022.
[13] Fan X, Pristach C, Liu EY, Freudenreich O, Henderson DC, Goff DC. Elevated
serum levels of C-reactive protein are associated with more severe psychopa-
thology in a subgroup of patients with schizophrenia. Psychiatry Res
2007;149:267–71. http://dx.doi.org/10.1016/j.psychres.2006.07.011.
[14] Akanji AO, Ohaeri JU, Al-Shammri S, Fatania HR. Association of blood levels of
C-reactive protein with clinical phenotypes in Arab schizophrenic patients.
Psychiatry Res 2009;169:56–61. http://dx.doi.org/10.1016/j.psychres.
2008.06.010.
[15] Solanki RK, Singh P, Singh M, Sinha M, Swami MK, Saini S. C-reactive protein
(CRP) in patients with schizophrenia: are they related with symptomatology? J
Ment Heal Hum Behav 2010;6:1–5.
[16] Fawzi MH, Fawzi MM, Fawzi MM, Said NS. C-reactive protein serum level in
drug-free male Egyptian patients with schizophrenia. Psychiatry Res
2011;190:91–7. http://dx.doi.org/10.1016/j.psychres.2011.05.010.
[17] Zahorec R. Ratio of neutrophil to lymphocyte counts – rapid and simple
parameter of systemic inflammation and stress in critically ill. Bratisl Lek
Listy 2001;102:5–14.
[18] Ridker PM. Cardiology patient page. C-reactive protein: a simple test to help
predict risk of heart attack and stroke. Circulation 2003;108:e81–5. http://
dx.doi.org/10.1161/01.CIR.0000093381.57779.67.
[19] Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS)
for schizophrenia. Schizophr Bull 1987;13:261–76.
[20] Lindenmayer J-P, Brown E, Baker RW, Schuh LM, Shao L, Tohen M, et al. An
excitement subscale of the Positive and Negative Syndrome Scale. Schizophr
Res 2004;68:331–7. http://dx.doi.org/10.1016/S0920-9964(03)00087-2.
[21] Huber CG, Lambert M, Naber D, Schacht A, Hundemer H-P, Wagner TT, et al.
Validation of a Clinical Global Impression Scale for Aggression (CGI-A) in a
sample of 558 psychiatric patients. Schizophr Res 2008;100:342–8. http://
dx.doi.org/10.1016/j.schres.2007.12.480.
[22] Montoya A, Valladares A, Lizán L, San L, Escobar R, Paz S. Validation of the
Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC)
in a naturalistic sample of 278 patients with acute psychosis and agitation in a
psychiatric emergency room. Health Qual Life Outcomes 2011;9:18. http://
dx.doi.org/10.1186/1477-7525-9-18.
[23] Valkanova V, Ebmeier KP, Allan CL. CRP, IL-6 and depression: a systematic
review and meta-analysis of longitudinal studies. J Affect Disord
2013;150:736–44. http://dx.doi.org/10.1016/j.jad.2013.06.004.
[24] Gassmann-Mayer C, Jiang K, McSorley P, Arani R, Dubrava S, Suryawanshi S,
et al. Clinical and statistical assessment of suicidal ideation and behavior in
pharmaceutical trials. Clin Pharmacol Ther 2011;90:554–60. http://
dx.doi.org/10.1038/clpt.2011.144.
[25] Rosell DR, Siever LJ. The neurobiology of aggression and violence. CNS Spectr
2015;20:254–79. http://dx.doi.org/10.1017/S109285291500019X.
[26] Hoptman MJ. Impulsivity and aggression in schizophrenia: a neural circuitry
perspective with implications for treatment. CNS Spectr 2015;20:280–6.
http://dx.doi.org/10.1017/S1092852915000206.
[27] Coccaro EF, Lee R, Gozal D. Elevated plasma oxidative stress markers in
individuals with intermittent explosive disorder and correlation with aggres-
sion in humans. Biol Psychiatry 2014. http://dx.doi.org/10.1016/j.biop-
sych.2014.01.014.
[28] Beurel E, Jope RS. Inflammation and lithium: clues to mechanisms contribut-
ing to suicide-linked traits. Transl Psychiatry 2014;4:e488. http://dx.doi.org/
10.1038/tp.2014.129.
[29] Baumeister D, Akhtar R, Ciufolini S, Pariante CM, Mondelli V. Childhood
trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive
protein, interleukin-6 and tumour necrosis factor-a. Mol Psychiatry 2015.
http://dx.doi.org/10.1038/mp.2015.67.
[30] Swanson JW, Swartz MS, Van Dorn RA, Elbogen EB, Wagner HR, Rosenheck RA,
et al. A national study of violent behavior in persons with schizophrenia. Arch
Gen Psychiatry 2006;63:490–9. http://dx.doi.org/10.1001/archpsyc.63.5.490.
[31] Dickerson F, Stallings C, Origoni A, Vaughan C, Khushalani S, Yolken R. Additive
effects of elevated C-reactive protein and exposure to herpes simplex virus
type 1 on cognitive impairment in individuals with schizophrenia. Schizophr
Res 2012;134:83–8. http://dx.doi.org/10.1016/j.schres.2011.10.003.
[32] Hope S, Dieset I, Agartz I, Steen NE, Ueland T, Melle I, et al. Affective symptoms
are associated with markers of inflammation and immune activation in
bipolar disorders but not in schizophrenia. J Psychiatr Res 2011;45:1608–
16. http://dx.doi.org/10.1016/j.jpsychires.2011.08.003.
[33] Collins AA, Remington G, Coulter K, Birkett K. Depression in schizophrenia: a
comparison of three measures. Schizophr Res 1996;20:205–9.
[34] Kalia M, Costa E, Silva J. Biomarkers of psychiatric diseases: current status and
future prospects. Metabolism 2015;64:S11–5. http://dx.doi.org/10.1016/
j.metabol.2014.10.026.