A Preliminary Study of Cytokines in Suicidal
and Nonsuicidal Adolescents with Major Depression
Vilma Gabbay, M.D., M.S.,1,2Rachel G. Klein, Ph.D.,1Leah E. Guttman, B.A.,1
James S. Babb, Ph.D.,1Carmen M. Alonso, M.D.,1Melissa Nishawala, M.D.,1
Yisrael Katz, B.S.,1Marta R. Gaite, M.D.,1,3and Charles J. Gonzalez, M.D.1,4
Background: Increased systemic cytokine levels, modulators of the immune system, have been repeatedly docu-
the role of cytokines in suicidal symptomatology in adolescent MDD. Hypotheses were that acutely suicidal
depressed adolescents would have: (1) increased plasma levels of interferon-g (IFN-g), tumor necrosis factor-a
by plasma IFN-g=IL-4), compared to nonsuicidal depressed adolescents and healthy controls.
Methods: Twelve suicidal adolescents with MDD (7 females [58%]; 5 medication-free=naı ¨ve), 18 nonsuicidal ad-
olescents with MDD (12 females [67%]; 8 medication-free=naı ¨ve), and 15 controls (8 females [53%]) were enrolled.
MDD had to be of at least 6 weeks duration, with a minimum severity score of 40 on the Children’s Depression
Rating Scale–Revised. Plasma cytokines were examined using enzyme-linked immunosorbent assays. Nonpara-
metric tests were used to compare subject groups.
Results: Unexpectedly, suicidal adolescents with MDD had significantly decreased plasma TNF-a concentrations
compared to nonsuicidal adolescents with MDD (1.33?2.95pg=mL versus 30.9?110.9pg=mL; p¼0.03). IFN-g
was increased in both suicidal and nonsuicidal adolescents with MDD compared to controls (2.14?6.22 and
symptomatology in adolescent MDD. These findings should be replicated in larger samples with medication-free
risk factor for suicide in adolescence (Shaffer et al. 1996), most
depressed adolescents do not attempt or commit suicide. The
recent Food and Drug Administration (FDA) warnings link-
ing antidepressant treatment to suicide, specifically in chil-
dren and young adults, further highlight the need for specific
biological research in adolescent suicide to illuminate patient
vulnerability and improve risk assessment. However, to date,
little research has examined the biological correlates of sui-
cidal behavior in adolescents with MDD.
uicide is a leading cause of death among teenagers.
Although major depressive disorder (MDD) is a major
Mounting evidence, derived from epidemiological, clinical,
and basic science research, has linked immune system acti-
vation to a wide variety of neuropsychiatric illnesses, in-
cluding MDD (Cohen et al. 1998; Peterson et al. 2000; Dantzer
et al. 2008; Leslie et al. 2008). One possible pathway impli-
cating the immune system is through the action of cytokines,
signaling molecules that mediate key steps in cellular and
humoral immunity and that can cross the blood–brain barrier
and influence complex brain functions (Dantzer et al. 2008).
(Th1) cytokines induce cellular-mediated immunity and in-
clude interleukin-12 (IL-12) and interferon-g (IFN-g); (2) Th2
cytokines promote humoral immunity and include IL-4 and
1New York University School of Medicine, NYU Child Study Center, New York, New York.
2Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York.
3Harvard School of Public Health, Boston, Massachusetts.
4New York State Department of Health, AIDS Institute, New York, New York.
James S. Babb, Ph.D., New York University School of Medicine, Department of Radiology, Research served as statistical consultant.
This study was supported by grants from the National Institutes of Health (NIH) (AT002395, MH077072), the American Foundation for
Suicide Prevention, the NYU School of Medicine General Clinical Research Center grant (M01-RR00096), and generous gifts from the Leon
Levy Foundation, the Anita Saltz Foundation, and from Bruce and Claude Wasserstein.
JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY
Volume 19, Number 4, 2009
ª Mary Ann Liebert, Inc.
IL-10. Cytokines are also characterized as proinflammatory
(e.g., IFN g) or antiinflammatory (e.g., IL-4). Clinical case re-
ports worldwide have noted the emergence of depressive
symptoms and death by suicide in patients treated with cy-
Capuron et al. 2001; Maes et al. 2001; Bonaccorso et al. 2002;
Van Gool et al. 2003). In addition, studies in adult MDD
have reported increased plasma levels of cytokines, including
IFN-g, tumor necrosis factor-a (TNF-a), IL-6, IL-1b, and IL-12
(Maes et al. 1997; Song et al. 1998; Myint et al. 2005; Irwin and
Miller 2007; Kim et al. 2007; Simon et al. 2008).
The few studies that have examined systemic cytokines in
suicidal MDD have been conducted in adult patients. Men-
dlovic et al. (1999) found increased IFN-g plasma levels in
outpatient suicidal adults with MDD compared to controls,
and decreased IL-4 and IL-5 plasma levels compared to out-
patient nonsuicidal adults with MDD. Kim et al. (2008) found
decreased plasma IL-6 levels in suicidal patients with MDD
compared to nonsuicidal patients with MDD. Additionally,
the Th1=Th2 ratio, as indexed by IL-2=IL-4, was significantly
group and the control group (Kim et al. 2008). A parallel line
of research involving postmortem studies found increased
microglial density in specific brain regions in suicide victims
(Steiner et al. 2008) and increased mRNA expression of IL-4
and IL-13 in the orbitofrontal cortex of women and men, re-
spectively, who committed suicide (Tonelli et al. 2008). These
findings support the notion that immunological regulation
may differ between suicidal and nonsuicidal patients with
Cytokine research in adolescent MDD has been sparse.
Recently, we reported increased IFN-g and IFN-g=IL-4 in ado-
lescents with MDD relative to controls, suggesting the role
of immune system dysregulation with a proinflammatory=
antiinflammatory imbalance in this age group as well (Gabbay
et al. 2009). The aim of this study was to extend analyses in
the previously reported sample of adolescents with MDD
and controls (Gabbay et al. 2009) to test the hypothesis that
suicidal adolescents with MDD would have elevated IFN-g,
TNF-a, IL-6, and IL-1b plasma levels and a proinflammatory=
antiinflammatory cytokine imbalance shifted toward the pro-
inflammatory subset (indexed by plasma IFN-g=IL-4) com-
pared to nonsuicidal MDD adolescents and healthy controls.
Materials and Methods
Subjects are described in a previous report by our labora-
tory that focuses on immunological indicators of dysregula-
tion in adolescents with MDD (Gabbay et al. 2009). This study
extends those findings by examining specific cytokine differ-
ences between acutely suicidal adolescents with MDD, non-
suicidal adolescents with MDD, and healthy controls. Briefly,
three groups were compared: 12 adolescents with MDD
(7 female, 58%), ages 14–19 (mean¼16.6?2.0) with active
suicidality, defined as expressing a highly lethal plan for
committing suicide that was perceived by the clinician as
presenting an imminent risk to self. The second group con-
sisted of 18 nonsuicidal adolescents with MDD (12 female,
67%), ages 12–19 (mean¼16.0?2.0). MDD had to have a
minimum duration of 6 weeks and a minimum severity score
of 40 on the Children’s Depression Rating Scale–Revised
(CDRS-R). Adolescents with MDD (suicidal and nonsuicidal)
were enrolled from the New York University (NYU) Child
Study Center, the NYU Tisch inpatient psychiatric unit, and
the Bellevue Department of Psychiatry. The third group
consisted of 15 healthy comparison subjects (8 females, 53%),
ages 12–19 (mean¼15.5?3.0), recruited from families of
NYU staff. Participants ages 18 and 19 (n¼11) provided
signed informed consent; those under age 18 provided assent,
and a parent or guardian provided signed consent. Consent
included authorization for the results of the research to be
published. This study was approved by the NYU School of
Medicine Institutional Review Board.
A child psychiatrist interviewed all adolescents (patients
and controls) and a parent using the Schedule for Affective
Disorders and Schizophrenia–Present and Lifetime Version
for Children (K-SADS-PL) (Kaufman et al. 1997), a semi-
structured psychiatric interview. On the basis of interview,
the psychiatrist rated severity of depression on the CDRS-R,
and overall adjustment on the Children’s Global Assessment
Scale (CGAS). Participants completed the Beck Depression
Inventory, 2ndedition (BDI-II), and the Beck Scale for Suicidal
Ideation (BSS). Baseline medical assessments included medi-
cal history and laboratory tests, including complete blood
count, metabolic panel, liver, and thyroid function tests, urine
toxicology test, and a pregnancy test for females. For the
medical history assessment, both the parent and the adoles-
cent were interviewed by the clinician to assess for positive
indication of an infectious illness in the month prior to en-
rollment, including the common cold.
medications taken in the past 6 months, any immunological or
hematological disorder, chronic fatigue syndrome, any infec-
tion during the month prior to the blood draw (including the
common cold), significant medical or neurological disorders,
and, in females, a positive urine pregnancy test.
The following psychiatric disorders were exclusionary for
subjects with MDD: (1) bipolar disorder, (2) schizophrenia, (3)
pervasive developmental disorder, (4) posttraumatic stress
disorder, (5) obsessive-compulsive disorder, (6) Tourette’s
disorder, (7) eating disorder, and (8) a substance-related dis-
order in the past 12 months (based on history and urine tox-
icology test). Control subjects could not meet criteria for any
Disorders, 4thedition (DSM-IV) (American Psychiatric Asso-
ciation 1994) diagnosis, and could not be taking psychotropic
To address diurnal variability of cytokine production,
all blood samples (10mL) were drawn between 08:00 and
09:00a.m. after an overnight fast; the EDTA blood was pro-
cessed within 20 minutes of collection. Aliquots of the plasma
samples were stored at ?808C for appropriate serial immu-
The quantitative determination of the plasma levels of
IFN-g, TNF-a, IL-6, IL-1b, and IL-4 was performed in dupli-
cate for each of the serial aliquots by commercial enzyme-
linked immunosorbent assays (ELISA) in accordance with the
manufacturer’s instructions. All thawed samples for the re-
spective cytokines were run simultaneously. The IFN-g assay
424 GABBAY ET AL.
(GE-Biosciences, Piscataway, NJ). For TNF-a, also known as
cachectin and TNFSF1A, the Quantikine Human TNF-a=
TNFSF1A assay (R&D Systems, Minneapolis, MN) was used;
IL-6 was assayed with High Sensitivity Human Quantikine IL-6
(R&D Systems, Minneapolis, MN); for IL-1b, also known as
IL-1F2, the Quantikine HS Human IL-1b=ILF2 immunoassay
(R&D Systems, Minneapolis, MN) was used; and for IL-4, the
Quantikine High Sensitivity Human IL-4 assay (R&D Systems,
Minneapolis, MN) was used. According to the manufacturers,
the lower limits of detection of the assays are: 0.1pg=mL,
0.038pg=mL, 0.039pg=mL, 0.057pg=mL, and 0.11pg=mL, re-
spectively. The intraassay variability was less than 10%. The
mean of the duplicate sample values was used. All assays were
performed by CG, who was blind to the subjects’ clinical status.
Because data were not normally distributed, the nonpara-
metric Mann–Whitney test was used to compare subject
groups. Additionally, to control for possible covariates,
analysis of covariance based on ranks was used to compare
the groups while adjusting for age and gender. For each
outcome measure, the observed levels were converted to
ranks, which were then used as the dependent variable.
Spearman rank correlation coefficients were used to charac-
terize the association of cytokine levels with the number of
past suicide attempts, CDRS-R, BDI-II,and BSS scores, as well
as duration of depressive illness.
All reported p values are exact two-sided significance lev-
els. Statistical significance was defined as p?0.05. SAS ver-
sion 9.0 (SAS Institute, Cary, NC) was used for all statistical
Demographics, diagnoses, and treatment profiles are
compiled in Table 1.
Suicidal MDD group.
who had attempted suicide in the previous week, were ac-
tively suicidal and were perceived by the clinician as pre-
senting an imminent risk to self at the time of the blood draw.
Suicidal plan=methods included medication overdose (pre-
scription and over-the-counter), jumping from the roof, run-
ning into a train, hanging, cutting the carotid artery, cutting
wrists, and drinking cleaning agents.
Five patients in the suicidal MDD group (42%) were med-
ication free for at least 1 year, 3 of whom were medication
naı ¨ve. Two patients (17%) had recently initiated psychotropic
medications (4 and 7 days prior to the study), and 5 patients
(42%) had been treated with medications for periods ranging
from 1 month to 2 years. Medications included fluoxetine,
sertraline, citalopram, mirtazapine, lithium, lamotrigine, and
All 12 patients, including 6 patients
Nonsuicidal MDD group.
were medication-free for at least 1 year, 7 of whom were
patients on medication had failed to respond to treatment.
Medications included fluoxetine, sertraline, bupropion, la-
motrigine, lithium, risperidone, methylphenidate, and mixed
Eight of the 18 patients (44%)
Means and standard deviations of plasma cytokine levels
are summarized in Table 2.
adolescents with MDD.
had significantly decreased plasma levels of TNF-a compared
to nonsuicidal adolescents with MDD (1.33?2.95pg=mL
versus 30.90?110.9pg=mL, rank statistic¼136; p¼0.03).
Findings remained evident when analysis was adjusted for
age and gender (t¼2.29, degrees of freedom [df]¼40;
Suicidal adolescents with MDD
MDD versus nonsuicidal
Table 1. Demographic and Clinical Characteristics of Suicidal Adolescents with MDD,
Nonsuicidal Adolescents with MDD, and Healthy Controls
with MDD n¼12
with MDD n¼18
Duration of Illness (months)
History of suicide attempts
Any anxiety disorder
aRespective percentages (may not add up to 100% due to rounding).
Abbreviations: MDD¼major depressive disorder; CDRS-R¼children’s depression rating scale–revised; BDI-II¼Beck Depression
Inventory-II; BSS¼Beck Scale for Suicidal Ideation; ADHD¼attention-deficit=hyperactivity disorder; ODD¼oppositional defiant disorder.
CYTOKINES AND SUICIDALITY425
p<0.03). The groups did not differ significantly on any other
cytokine measure (Fig. 1 and Table 2).
Suicidal adolescents with MDD versus controls.
was significantly increased in the suicidal MDD group com-
pared to the control group (2.14?6.22pg=mL versus
0.37?0.64pg=mL, rank statistic¼218; p<0.02). Findings re-
mained evident when analysis was adjusted for age and
gender (t¼?2.31, df¼40; p<0.03). No other significant
group differences were found.
was significantly increased in the nonsuicidal MDD group
compared to the control group (4.20?14.48pg=mL versus
0.37?0.64pg=mL, rank statistic¼180; p¼0.005), even when
controlled for age and gender (t¼?2.94, df¼40; p¼0.005).
The IFN-g=IL-4 ratio was also significantly elevated in the
nonsuicidal MDD group compared to the control group
even when controlled for age and gender (t¼?2.83, df¼40;
significantly between unmedicated and medicated adoles-
cents with MDD (p¼0.5, 0.4, 0.9, respectively).
IFN-g, TNF-a, and IFN-g=IL-4 levels did not differ
Correlations of MDD features and cytokine measures
No significant correlations were found between MDD
clinical features and cytokine plasma levels.
Plasma levels of TNF-a were significantly decreased in
suicidal adolescents with MDD compared to the nonsuicidal
MDD group. IFN-g was significantly elevated in the suicidal
and nonsuicidal groups compared to controls. Findings re-
mained evident when controlled for age and gender.
Our finding of decreased TNF-a in suicidal adolescents
compared to controls was unexpected. TNF-a is produced by
macrophages and circulating monocytes and plays an im-
portant role in a wide range of immune reactions, including
autoimmune conditions (Vassalli 1992). TNF-a has been
shown toaffect central processes through stimulation ofvagal
afferents and acts as a central nervous system modulator
(Rothwell and Hopkins 1995). Most studies in adult MDD
have reported increased TNF-a compared to controls (Tuglu
et al. 2003; Leo et al. 2006; Pavon et al. 2006; Kim et al. 2007).
By contrast, many studies have reported decreased TNF-a in
adults with obsessive compulsive disorder (OCD) (Brambilla
et al. 1997; Monteleone et al. 1998; Denys et al. 2004). The
interpretation of the similarity between our finding of de-
creased TNF-a in suicidal adolescents with MDD and parallel
findings in adult OCD will require further study.
With respect to the effect on monoamines, systemic ad-
ministration of TNF-a was shown to result in increased
serotonin (5-HT) levels in the prefrontal cortex (PFC) and
decreased 5-HT levels in the paraventricular nucleus (Breb-
ner et al. 2000). Relatedly, multiple postmortem studies have
implicated the PFC serotonergic system in suicide in ado-
lescents and adults (Mann et al. 1989; Pandey et al. 2002),
providing a possible pathway linking decreased TNF-a to
suicidality. It is important to note that, to date, cytokine
studies have not included assessment of TNF-a, excluding
examination of its influence on brain function in suicidal
adults (Mendlovic et al. 1999; Kim et al. 2008). Also con-
tributing to the interpretation of the TNF-a finding is the
observation that TNF-a knockout mice exhibit increased
emotional responses when exposed to stressful conditions
(which respond to benzodiazepine treatment), andincreased
grooming activity compared to wild-type mice (Yamada
et al. 2000).
Our second finding of increased plasma IFN-g in suicidal
adolescents with MDD compared to controls is consistent
with one prior study of cytokines in suicidal adult patients
compared to controls (Mendlovic et al. 1999). However, be-
cause we found IFN-g to be elevated in nonsuicidal MDD
patients as well, consistent with many adult MDD studies
2006; Simon et al. 2008), it seems that elevated plasma IFN-g
may be related to major depression rather than to active sui-
cidality. One possible link between IFN-g, MDD, and suicide
is the enzyme indoleamine 2,3-dioxygenase (IDO), the rate-
limiting enzyme in the tryptophan-kynurenine pathway that
converts tryptophan (TRP) to kynurenine (KYN), and is
mainly induced by IFN-g (Carlin et al. 1989; Takikawa et al.
Table 2. Mean (SD) Levels of Plasma Cytokines in Suicidal Adolescents with MDD,
Nonsuicidal Adolescents with MDD, and Controls
Adolescents with MDD
Cytokine measureHealthy controls (n¼15)
Tumor necrosis factor-a (TNF-a)
Analysis of covariance is based on ranks adjusting for age and gender.
aIFN-g: suicidal versus controls (Mann–Whitney, p<0.02; ANCOVA, p<0.03).
bIFN-g: nonsuicidal versus controls (Mann–Whitney, p¼0.005; ANCOVA, p¼0.005).
cTNF-a: suicidal versus nonsuicidal (Mann–Whitney, p¼0.03; ANCOVA, p<0.03).
dIFN-g=IL-4: nonsuicidal versus controls (Mann–Whitney, p¼0.005; ANCOVA, p¼0.007).
Abbreviations: SD¼standard deviation; MDD¼major depressive disorder; ANCOVA¼analysis of covariance.
426GABBAY ET AL.
(A) Actual plasma cytokine levels (in pg=mL) for control, nonsuicidal major depressive disorder (MDD), and suicidal adolescents (þ, medicated; ^, medication
free=naı ¨ve); outliers were deleted to enhance resolution, which did not affect results because a nonparametric test was used for analysis. (B) Ranks of plasma cytokine levels
for control, nonsuicidal MDD, and suicidal adolescents (þ, medicated; ^, medication free=naı ¨ve) including all data points, with no outliers deleted. (C) Box plots displaying
the 25thand 75thpercentiles (box), median (line within box), 95% range (whiskers), and moderate outliers (asterisks) of the cytokine data in control, nonsuicidal MDD, and
suicidal adolescents; Interferon-g (IFN-g) (top), IFN-g=interleukin-4 (IL-4) ratio (middle), and tumor necrosis factor-a (TNF-a (bottom).
CYTOKINES AND SUICIDALITY 427
1991; Taylor and Feng 1991; Daubener and MacKenzie 1999;
Currier et al. 2000; Fujigaki et al. 2001). In cases of overstim-
ulation, induction of this pathway may lead to lower TRP
concentrations (serotonin substrate), which have been impli-
cated in MDD (Maes et al. 1993; Wirleitner et al. 2003). Of
relevance to suicide, low peripheral levels of tryptophan were
found in children who had made a recent suicide attempt
(Pfeffer et al. 1998). KYN itself can be further metabolized to
N-methyl-D-aspartate (NMDA) receptor agonist and antag-
onist (Stone and Darlington 2002), and alterations in NMDA
receptors have also been noted in the PFC of suicide victims
(Nowak et al. 1995). However, while IDO is mainly activated
by IFN-g, TNF-a can also synergistically increase IDO tran-
scriptional activation in response to IFN-g (Robinson et al.
2005), suggesting that IDO activation may be linked to the
depressive state rather than to the suicidal state of the patient
Our findings of immune system dysregulation in suicidal
adolescents with MDD should be considered preliminary in
light of several limiting factors: (1) the cohort size was rela-
tively modest; (2) a substantial proportion of patients (57%)
were receiving psychotropic medications, which have been
reported to induce negative immunoregulatory effects in
adults with MDD. This possible confound may have limited
our ability to discern other group differences between cyto-
kines and contributed to a Type II error (false negative). Im-
portantly, there were no statistical differences between
medicated and nonmedicated patients with MDD. Further-
more, due to the small sample, we did not apply a multiple
comparison correction in order to preserve statistical power.
As such, our significant findings may include Type I errors
(false positive). Additionally, it would be important to collect
data on a larger number of cytokines and to measure cytokine
activity across multiple time points.
In summary, our results support the notion that sui-
cidal behavior in the context of adolescent MDD entails im-
TNF-a is suggested. These findings require replication in a
larger sample of medication-free adolescents.
Drs. Vilma Gabbay, Rachel G. Klein, Carmen M. Alonso,
Melissa Nishawala, Marta R. Gaite, and Charles J. Gonzalez
have no conflicts of interest or financial ties to report. Leah E.
Guttman and Yisrael Katz have no conflicts of interest or
financial ties to report. At the time of the data collection,
Dr. James S. Babb had consulting contracts with E-Z-EM, Inc.
and Applied NeuroSolutions, Inc.
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Address correspondence to:
Vilma Gabbay, M.D., M.S.
Leon Levy Assistant Professor of Psychiatry
New York University School of Medicine
Department of Child & Adolescent Psychiatry
NYU Child Study Center
577 First Avenue
New York, NY 10016
430 GABBAY ET AL.