Cortisol and Cytokines in Chronic and Treatment-Resistant
Patients with Schizophrenia: Association with
Psychopathology and Response to Antipsychotics
Xiang Yang Zhang*,1,2,3, Dong Feng Zhou1, Lian Yuan Cao2, Gui Ying Wu2and Yu Cun Shen1
1Institute of Mental Health, Peking University, Beijing, PR China;2Beijing Hui-Long-Guan Hospital, Beijing, PR China;3Department of Psychiatry,
Yale University School of Medicine, New Haven, CT, USA
The bilateral communication between the immune and neuroendocrine systems plays an essential role in modulating the adequate
response of the hypothalamic–pituitary–adrenal (HPA) axis to the stimulatory influence of cytokines and stress-related mediators.
Growing evidence suggests that neuro-immune-endocrine crosstalk may be impaired in schizophrenia. We determined the relationship
between cortisol, cytokines interleukin-2 (IL-2) and interleukin-6 (IL-6), and symptoms in schizophrenia during treatment with typical and
atypical antipsychotic drugs. Subjects included 30 healthy controls (HC) and 78 schizophrenic (SCH) in-patients. SCH were randomly
assigned to 12-week treatment with 6mg/day of risperidone or 20mg/day of haloperidol using a double-blind design. Clinical efficacy
was determined using the Positive and Negative Syndrome Scale (PANSS). Serum cortisol and IL-2 levels were assayed by
radioimmunometric assay, and serum IL-6 levels by quantitative enzyme-linked immunosorbent assay. Following a 2-week washout
period, serum levels of cortisol, IL-2, and IL-6 were increased in patients with schizophrenia compared to HC. Elevations in cortisol were
associated with increase in both IL-2 and IL-6 in SCH. Moreover, elevations in cortisol were associated with negative symptoms and IL-2
with positive symptoms. In all, 12 weeks of risperidone treatment significantly decreased elevated cortisol and improved negative
symptoms, but produced similar effects on IL-2 and IL-6 as well as on positive symptoms compared to haloperidol. The improvement of
negative symptoms was related to the change in cortisol. Our results suggest that the imbalance in the HPA axis and cytokine system in
patients with SCH is implicated in clinical symptoms, and is improved with atypical antipsychotic treatment.
Neuropsychopharmacology (2005) 30, 1532–1538, advance online publication, 11 May 2005; doi:10.1038/sj.npp.1300756
Keywords: schizophrenia; immune; interleukin; cortisol; psychopathology; antipsychotic; hypothalamic–pituitary–adrenal (HPA) axis
There is a complex bidirectional communication between
the nervous, endocrine, and immune systems that can be
demonstrated by the presence of shared neurotransmitters,
hormones, and cytokines (Blalock, 1989; Haddad et al,
2002). Communication between these systems plays an
essential role in modulating the adequate response of the
hypothalamic–pituitary–adrenal (HPA) axis to the stimula-
tory influence of cytokines and stress-related mediators
(Spangelo et al, 1995). Growing evidence suggests that, in
addition to providing communication between immune
cells, specific cytokines play a role in signaling the brain to
produce neurochemical, neuroendocrine, neuroimmune,
and behavioral changes (Muller and Ackenheil, 1998;
Kronfol and Remick, 2000). Recently, studies have shown
that the interface between these complex systems is
impaired in schizophrenia (SCH, Altamura et al, 1999).
Specially, SCH has been associated with several immuno-
logical abnormalities, including decreased mitogen-induced
lymphocyte proliferation (Chengappa et al, 1995), altered
numbers of total T and T-helper cells (Muller et al, 1993),
the presence of antibrain antibodies in serum (Henneberg
et al, 1994), and changes in cytokines and cytokine
receptors in the blood and the cerebrospinal fluid (CSF)
(Licinio et al, 1993; Rapaport et al, 1994, 1997; Ganguli
et al, 1994, 1995; Maes et al, 1995, 1997, 2000, 2002; Lin
et al, 1998; Arolt et al, 2000; Zhang et al, 2002a,b).
Together, these studies show that SCH is associated with
significant immunological alterations, and activation of the
Online publication: 31 March 2005 at http://www.acnp.org/citations/
Received 30 November 2004; revised 22 February 2005; accepted 24
*Correspondence: Dr XY Zhang, Department of Psychiatry, Yale
University School of Medicine, Building 5, 3rd Floor, VA Connecticut
Healthcare System, 950 Campbell Ave, West Haven, CT 06516, USA,
Tel: þ1 203 932 5711 ext. 4133, Fax: þ1 203 974 7897,
Neuropsychopharmacology (2005) 30, 1532–1538
& 2005 Nature Publishing GroupAll rights reserved 0893-133X/05 $30.00
inflammatory response system (IRS) is mediated, in part, by
cytokines. Interestingly, these abnormalities are particularly
prominent in treatment-resistant SCH (Lin et al, 1998; Maes
et al, 2000, 2002).
Evidence also suggests dysfunction in the HPA axis in
SCH (Walker and Diforio, 1997; Marx and Lieberman,
1998). Abnormalities in the HPA axis of SCH have been
shown using the dexamethasone suppression test (DST).
Nonsuppression, due to the lack of glucocorticoid secretion
feedback mechanisms, occurs frequently in SCH, with
percentages varying between 11 and 55% (Sharma et al,
1988; Yeragani, 1990; Coryell and Tsuang, 1992). Moreover,
several studies showed that basal cortisol levels are
significantly higher in schizophrenic (SCH) patients com-
pared to normal controls (Walker and Diforio, 1997;
Lammers et al, 1995), although these findings have not
been consistent between studies (Jansen et al, 1998; Kaneda
et al, 2002). Studies also suggest a relationship between HPA
activity and symptomatology in SCH. Cortisol secretion has
been associated with more severe positive symptoms
(Kaneko et al, 1992; Walder et al, 2000), whereas in others
it was associated with higher ratings of negative symptoms
(Newcomer et al, 1991; Tandon et al, 1991). Some
investigators purport that in SCH, there is an association
of DST nonsuppression with negative symptoms (Altamura
et al, 1989; Newcomer et al, 1991; Tandon et al, 1991).
Taken together, these results suggest that HPA axis
dysregulation/activation and hypercortisolemia are frequent
present in SCH patients.
Wang and Dunn (1999) reported that HPA axis activation
can be elicited by exogenous cytokines, such as interleukin-
1 (IL-1), IL-6 when administered to rodents. Several
cytokines are also known to affect the release of anterior
pituitary hormones by an action on the hypothalamus and/
or the pituitary glands (Bumiller et al, 1999). Moreover, as
mentioned previously, SCH is associated with a hyper-
responsive IRS. Therefore, Altamura et al (1999) proposed
the hypothesis that hypercortisolemia observed in SCH
could be induced by cytokines. So far, however, this
association remains to be elucidated.
In view of the previously mentioned studies and the close
relationship between HPA axis and immune system, we
tested the hypothesis that alterations in neuroendocrine
systems may be related to changes in immune system in
SCH; changes that could be especially apparent in
treatment-resistant SCH. Also, we speculate that inap-
propriate interaction of HPA axis and cytokines might play
a role in the pathogenesis of some symptoms occurring in
SCH. Further, we wanted to determine if typical or atypical
antipsychotics-induced effects on HPA axis and IRS could
account for the differences in clinical response, which, to
our knowledge, has not been investigated so far. Therefore,
the purpose of the study was to investigate whether (1)
serum cortisol, IL-2, and IL-6 were increased simulta-
neously in chronic and treatment-resistant schizophrenic
patients; (2) there was a relation between cortisol and
cytokines, or between symptom severity and both cortisol
and cytokines; (3) there was a significant difference between
typical and atypical antipsychotic drugs in the influence on
the serum cortisol, IL-2, and IL-6; (4) there were any
relationships between the changes of serum cortisol, IL-2,
and IL-6 and the changes of psychopathological symptoms.
METHODS AND SUBJECTS
Physically healthy Chinese in-patients were diagnosed as
meeting the Diagnostic and Statistical Manual of Mental
Disorders (DSM-III-R) criteria for SCH, using the Struc-
tured Clinical Interview for DSM-III-R (SCID). All patients
were considered resistant to treatment if meeting the
following criteria: no response to at least three antipsycho-
tics treated 3 months or over at full dose, equivalent to
chlorpromazine 800mg/day. Both patients and 30 normal
volunteers were recruited at the same period from Beijing
area. Normal controls were recruited from the community,
and matched for age and gender. Both patients and matched
normal subjects had similar socioeconomic status. Demo-
graphic data for patients and normal controls are summar-
ized in Table 1.
All subjects gave informed written consent to participate
in the study, which was approved by the Institutional
Review Board, the Institute of Mental Health, Peking
University. They were screened with a complete physical,
neurological, and psychiatric evaluation conducted by the
clinical physicians. None of the SCH patients nor control
subjects suffered from substance abuse/dependence or were
receiving immunosuppressive drugs.
Clinical Treatment and Clinical Ratings
Clinical treatment and ratings have been described in detail
in our earlier report (Zhang et al, 2001). Briefly, the clinical
trials consisted of a 2-week placebo lead-in followed by 12
weeks of double-blind treatment. Medications that patients
had been taking prior to the 2-week washout period were
either clozapine (n¼20), perphenazine (n¼17), chlorpro-
mazine (n¼16), haloperidol (n¼15), thioridazine (n¼6),
or sulpiride (n¼4). A total of 78 patients were randomized
into risperidone group (n¼41) and haloperidol group
(n¼37). The dose of risperidone was increased to 6mg/day
and the dose of haloperidol to 20mg/day during the first
week of blind administration, and the doses were main-
tained at those levels until the end of the trial.
The Positive and Negative Syndrome Scale (PANSS) (Kay
et al, 1987) was administered by four clinical psychiatrists
who were blind to the treatment. To ensure consistency and
Table 1 Demographics of Patients and Normal Control Subjects
Duration of illness
Smokers28 (68%)24 (65%)19 (63%)
All data were reported as mean7SD unless otherwise indicated. There were no
significant differences among risperidone, haloperidol and control groups on any
characteristic by w2test and analysis of variance (ANOVA), followed by post hoc
tests (Fisher’s LSD test).
Cortisol and cytokines in schizophrenia
XY Zhang et al
reliability of ratings across study, four psychiatrists
attended a training session in the proper use of the PANSS
before study began. After training, a correlation coefficient
greater than 0.8 was maintained for the PANSS total score
by repeated assessments.
Serum samples of patients were collected between 0700 and
0900h at the end of the 2-week washout period and after 12-
week treatment. Samples from healthy controls were
collected at the same period as that of the patients at the
end of washout period. The serum was separated via
centrifugation, aliquoted and stored at ?701C until assayed.
Serum cortisol was determined by radioimmunometric
assay (RIA). The assay was performed in accordance with
the manufacturer’s instructions (Tianjin DePu Inc., China).
Each sample was run in duplicate. The sensitivity was 1ng/
ml, intra- and inter-assay variation coefficients were 6 and
Measurement of Serum IL-2 and IL-6
IL-2 was assayed in serum by RIA (ChangZheng Inc.,
Chinese Second Military Medical University, Shanghai,
China). The assay was performed in accordance with the
manufacturer’s instructions. Each assay was run in dupli-
cate. The sensitivity was 0.2ng/ml, intra- and inter-assay
variation coefficients were 6 and 8%, respectively.
Serum IL-6 levels were measured in duplicate by sand-
wich ELISA using a commercially available kit (BanDing
Biological Inc., Chinese Academy of Sciences, Beijing,
China). The sensitivities were 0.2ng/ml, and intra- and
inter-assay variation coefficients were 7 and 9%, respec-
All samples were assayed by the same investigator who
was blind to the treatment condition.
Since the majority of the interleukin variables were not
normally distributed in patients (Kolmogorov–Smirnov
one-sample test), and although all these variables were
normally distributed in normal controls, the principal
analysis consisted of nonparametric tests for comparison
between groups of patient and normal control (Mann–
Whitney). Since serum cortisol was normally distributed in
both patients and normal controls, analysis of variance
(ANOVA) was used. Analysis of covariance (ANCOVA) was
also performed, using age, duration of illness, baseline
cortisol level, baseline PANSS score as covariates, followed
by Fisher’s least significant difference (LSD) test to compare
the differences in cortisol levels between the groups.
Correlation among cortisol, IL-2, and IL-6 levels and
clinical ratings were examined by bivariate correlation
(Spearman or Pearson correlation coefficients). Where there
was a significance, the Bonferroni correction was used if
necessary. Total PANSS scores and its subscores, cortisol,
IL-2, and IL-6 levels were examined by multivariate
regression analyses. All statistical tests were two-tailed
and were considered to be statistically significant at po0.05.
Table 1 shows characteristics of the patients and normal
controls. No significant relationships between age or sex
and serum IL-2, IL-6, or cortisol were noted either for the
whole group, or when the normal controls and patients were
examined separately. Age of onset of psychosis, duration of
illness, and hospitalization did not significantly correlate
with IL-2, IL-6, and cortisol levels in the patient group.
Table 2 showed statistically significant differences between
baseline and after 12 weeks of treatment with either
risperidone or haloperidol. Both drugs improved PANSS
total scores and all subscore measures (po0.01–0.001).
Further comparison between risperidone and haloperidol
show that risperidone showed greater improvement on
PANSS total score (p¼0.03) and the general psychopatho-
logy subscore (p¼0.01).
Changes of Serum IL-2, IL-6, and Cortisol before and
IL-2 was detected in 72 patients (92.3%) and 26 controls
(86.7%), and IL-6 in 55 patients (70.5%) and 16 controls
(53.3%). IL-2 and IL-6 not detected in patients or normal
control subjects were not included in the analysis.
Serum cortisol was significantly lower in healthy con-
trols (72.2724.7ng/ml) compared to patients at baseline
Table 2 Comparison of Scores at Baseline and Week 12 on the
Total and Subscores of PANSS in Risperidone and Haloperidol
Baseline Week 12Fa
PANSS total score
PASS, Positive and Negative Syndrome Scale; P-subscore, positive symptom
subscore; N-subscore, negative symptoms subscore; G-subscore, general
aF values and p are related to comparison between risperidone and haloperidol
groups at week 12.
*Comparison between pre- and post-treatment. **po0.01, ***po0.001.
Cortisol and cytokines in schizophrenia
XY Zhang et al
concentrations (103.2742.3ng/ml; ANOVA) and at post-
treatment (77.9730.7ng/ml; w2¼22.69, df¼2, po0.01).
Serum cortisol concentrations in SCH patients were
significantly lower after treatment compared to before
treatment (Wilcoxon’s test, Z¼?10.45, po0.01). Baseline
levels of IL-2 in healthy controls (3.371.4ng/ml) were
significantly lower compared to SCH subjects (9.675.2
ng/ml) even at post-treatment (6.774.6ng/ml; w2¼11.89,
df¼2, po0.01). Finally, serum IL-2 concentrations in SCH
patients were significantly lower after treatment (Wilcox-
on’s test, Z¼?4.33, po0.01).
Table 3 shows a significantly lower cortisol level at post-
treatment in risperidone group compared to the haloperidol
group (Z¼?2.46, po0.05). In addition, no significant
difference in IL-6 concentrations was noted between before
and after treatment for both groups (all p40.05). Both
risperidone and haloperidol significantly decreased cortisol
and IL-2 levels compared to baseline (see Table 3).
Relationship among Cortisol, IL-2, and IL-6
Table 4 demonstrates a positive correlation between cortisol
and IL-2 (r¼0.36, df¼75, po0.01) and IL-6 (r¼0.41,
df¼75, po0.01) in the SCH group. Serum IL-2 and IL-6
(r¼0.42, df¼30, po0.05) and serum IL-6 and cortisol were
also positively corrected in healthy controls (r¼0.38,
Relation between Cortisol, IL-2, or IL-6 and Clinical
Symptoms at Pre- and Post-Treatment
The results from Table 5 suggest that cortisol levels were
indeed associated with negative symptomology. In addition,
IL-2 levels were negatively correlated with PANSS positive
subscore (r¼?0.31, df¼71, po0.01) at pretreatment.
Relation of Cortisol and Cytokines with Clinical
Reduction in PANSS total score and its subscores after
treatment determined the efficacy of antipsychotic drugs.
The change of IL-2, IL-6, and of cortisol refers to the values
of these parameters before treatment minus their respective
values after treatment.
The results showed that there was a significant correlation
between the reduction of PANSS total score and the change
of IL-2 before and after treatment (r¼0.38, df¼65,
po0.01) or cortisol levels at post-treatment (r¼?0.36,
df¼67, po0.01). Reduction in PANSS positive subscore
was negatively correlated with serum IL-2 at baseline
(r¼?0.36, df¼67, po0.01). Moreover, the reduction of
PANSS negative subscore was associated with decrease in
serum cortisol between pre- and post-treatment (r¼0.34,
df¼69, po0.01). No correlations were observed between
the change of IL-6 before and after treatment and the
reduction of the PANSS total score and its subscores (all
A set of regression analyses was conducted in order to
identify the possible contribution of the cortisol, IL-2, and
IL-6 to clinical outcome (as defined by the reduction of
PANSS total score). A simultaneous entry regression
analysis was conducted first, with age, sex, duration of
illness, and measures of cortisol, IL-2, and IL-6 at both pre-
and post-treatment, as well as the changes in cortisol, IL-2,
and IL-6 between pre- and post-treatment as dependents.
The overall analysis was statistically significant (R¼0.707,
R2¼0.50, F¼3.77, p¼0.002). When this analysis was
repeated with a forward entry stepwise regression analysis,
sex was entered into the regression equation first (b¼0.45,
t¼3.26, p¼0.002), and accounted for 18.3% of the
variance, followed by IL-2 levels at baseline (b¼?0.33,
t¼?2.56, p¼0.014) and the change in cortisol between
pre- and post-treatment (b¼0.26, t¼2.04, p¼0.048),
which accounted for 9.5 and 5.2%, respectively.
Elevated levels of cortisol in SCH found in the present study
are in agreement with some previous studies (Newcomer
et al, 1991; Tandon et al, 1991; Lammers et al, 1995; Meltzer
et al, 2001), but not with others (Jansen et al, 1998; Kaneda
et al, 2002). Our finding of positive correlation between
cortisol and negative symptoms is consistent with some
previous studies (Newcomer et al, 1991; Tandon et al, 1991;
Shirayama et al, 2002). In contrast, some other studies
Table 3 Comparison of Serum Cortisol, IL-2 and IL-6 Levels
at Baseline and Week 12 in Risperidone and Haloperidol Groups
Note: * indicates comparison between risperidone vs haloperidol, *p¼0.014.
Table 4 Intercorrelations between Cortisol, IL-2 and IL-6 in
Patients with Schizophrenia before and after 12-Week Treatment
COR T1 COR T2 IL-2 T1IL-2 T2 IL-6 T1IL-6 T2
COR T20.12 __
**Correlation is significant at the 0.01 level.
Note: T1 and T2 indicate the cortisol and interleukin levels at baseline and at
Cortisol and cytokines in schizophrenia
XY Zhang et al
found a correlation between cortisol and positive symptoms
(Kaneko et al, 1992; Walder et al, 2000). Differences in
experimental methodology between studies may explain
divergent studies. These include: differences in tested
material (serum vs plasma), sampling of patients in
different stages of disease progression (acute vs chronic or
active phase vs remission), exposure to a variety and
duration of neuroleptic treatments and different disease
progression. Nevertheless, our results clearly show that
cortisol is elevated in patients with SCH and this elevation is
positively correlated with negative symptoms.
Some previous study found abnormalities in the cytokine
system in treatment-refractory SCH patients (Lin et al, 1998;
Maes et al, 2000). In our present study, we also found that
levels of IL-2 and IL-6 were elevated in patients with
treatment-refractory SCH, suggesting again activation of the
IRS. Moreover, serum IL-2 or IL-6 and cortisol were
positively correlated in our SCH population providing
support for the hypothesis that hypercortisolemia observed
in SCH could be induced by proinflammatory cytokines
(Altamura et al, 1999).
Cytokine IL-2 exerts numerous effects within the immune
as well as the central nervous system and is thought to
serve as a humoral signal in their communication. IL-2
plays a major role in regulating HPA axis action, which
may occur at different levels of regulation (Haddad et al,
2002). For example, Hanisch et al (1994) found that IL-2
caused a significant increase in ACTH levels during the
later portion of the dark phase of the cycle, and plasma
corticosterone concentrations were significantly elevated
over almost the entire diurnal cycle (Hanisch et al, 1994).
An additional study showed that HPA axis activation can
be elicited by exogenous cytokines (IL-1, IL-6, TNF-a) when
administered to rodents (Wang and Dunn, 1999). Injection
of IL-6 into humans increases plasma adrenocorticotropic
hormone and plasma cortisol (Bethin et al, 2000; Steensberg
et al, 2003). Moreover, both the pituitary corticotrophs
and adrenocortical cells express IL-6 receptors, and IL-6
increases cortisol both directly and indirectly (Bethin et al,
2000). Taken together, the data indicate that IL-2 and IL-6
are potent activators of the HPA axis, which provide
additional evidence to support the hypothesis that hyper-
cortisolemia in SCH may be mediated by the elevated
Risperidone, which is more effective on negative symp-
toms, decreased cortisol serum levels more to a greater
degree than haloperidol in the present study. Furthermore,
the significant reduction of PANSS negative subscore and
the change of cortisol level before and after treatment
suggests that the improvement in negative symptoms is
associated with the changes in serum cortisol levels. Taken
together, these findings suggest that different clinical
responses to atypical vs typical neuroleptics, paralleled with
their different effects on hypercortisolism, could offer an
explanation of the additional efficacy on negative symptoms
for the former drugs. In addition, it is worthy of mentioning
that the effects of antipsychotic drugs on cortisol levels and/
or the negative symptoms may be not directly related to the
changes in IL-2 or IL-6, because no significant relationships
were found among these variables during treatment.
Risperidone is a relatively new atypical antipsychotic
agent, with potent serotonin-5-HT2A and dopamine-D2
receptor blocking properties (Janssen et al, 1988). The
superiority of risperidone over haloperidol on negative
symptoms may be related to its antagonism of 5-HT2 in
different brain areas (Wirshing et al, 1999; Geddes et al,
2000; Zhang et al, 2001). On the other hand, there is an
increasing evidence that 5-HT promotes HPA axis activity
at the hypothalamic, pituitary, and adrenal levels (Chaoul-
off, 1993; Dinan, 1996). Pharmacological stimulation of
different 5-HT receptor subtypes as well as stress-induced
5-HT release promote activation of the HPA axis and
subsequent release of CRH, ACTH, and glucocorticoids
(Chaouloff, 1993). In relation to the present study, Muck-
Seler et al (1999) showed that SCH patients have a HPA axis
dyregulation and that this may be related to abnormalities
in the 5-HT system (Muck-Seler et al, 1999). Thus,
risperidone’s action at 5HT2 receptors may explain its
greater efficacy on negative symptoms and its ability to
decrease cortisol serum levels compared to the typical
Several points concerning the reliability of measuring
IL-2 levels should be noted. Many researchers are not able
to detect IL-2 levels in serum which is most likely due
to the assay employed. We utilized radioimmuno-assay
which detects pico-gram quantities of the target protein in
question. This highly sensitive assay may be the reason we
were able to detect IL-2 in SCH patients and in normal
Table 5 Intercorrelations between Cortisol, IL-2 and IL-6 and Clinical Variables in Patients with Schizophrenia before and after 12-Week
COR T1CORT2 IL-2T1IL-2T2 IL-6T1IL-6T2
0.13 (0.36)0.04 (0.78) 0.06 (0.66)0.02 (0.87)0.02 (0.88)
Duration of illness
0.02 (0.91) 0.13 (0.34)0.15 (0.31)
PANSS total score (T1)0.17 (0.17)
PANSS positive (T1) 0.05 (0.69)
PANSS negative (T1)0.28 (0.02)*
PANSS total score (T2)0.03 (0.78) 0.30 (0.01)*
0.08 (0.49)0.07 (0.53)
PANSS positive (T2)0.14 (0.24)0.03 (0.84) 0.01 (0.93)0.01 (0.92)
PANSS negative (T2)
?0.08 (0.49)0.34 (0.005)**
?0.12 (0.32) 0.01 (0.99)0.01 (0.93)
Note: T1 and T2 indicate the cortisol, interleukin levels, or PANSS scores at baseline and at post-treatment. The numbers in the parentheses indicate the p-value.
Cortisol and cytokines in schizophrenia
XY Zhang et al
controls with significantly higher levels in patients. Another
possible explanation is that there are significant differences
in IL-2 genotype frequencies observed in different popula-
tions. Recent studies have shown that inheritance of
polymorphic cytokine gene alleles is dramatically influ-
enced by ethnicity (Cox et al, 2001; Hoffmann et al, 2002).
Moreover, a statistically significant ethnicity-based varia-
bility in the allelic frequency and genotype inheritance
patterns for IL-2 and IL-6 has been reported (Cox et al,
2001), suggesting that polymorphisms within these cytokine
genes may be responsible for the ethnic-based differences in
IL-2 or IL-6 levels. Unfortunately, there is no comparison
study on the IL-2 genotype between Chinese and Cauca-
sians. In regards to the present study, the possible effects of
antipsychotic treatment before the washout period may play
a role. Our patients had undergone chronic long-term
treatment with antipsychotics. Studies have shown that
typical and atypical antipsychotic drugs exert immunosup-
pressive effects on the production of cytokine (Maes et al,
1995; Song et al, 2000). IL-2 and IL-6 levels were measured
after patients underwent a 2-week washout period, thus it is
possible that elevated levels is a rebound effect following
drug withdrawal. To answer this question, future research
should examine the effects of antipsychotics on cytokine
levels in naive, first-episode SCH patients.
In summary, our results suggest that dysregulation in
neuro-immune-endocrine systems exist and are linked to
clinical symptoms of SCH. The differential effects of typical
vs atypical antipsychotics on the HPA axis and IRS in SCH
could account, at least in part, for the better clinical
outcome, especially for negative symptoms achieved in
patients treated with the latter drugs compared to those
receiving conventional neuroleptics.
We are grateful to Zhen Quan Guan and Li Sun for their
technical assistance. Appreciation is also owed to the
patients, clinical psychiatrists, and nursing staff of the
Wards 1, 2, 4, 7, and 17, Beijing Hui-Long-Guan Hospital
for their participation and collaboration. In addition, We
thank Dr Colin Haile for his helpful revision on the
manuscript. This study was supported by the Beijing
Scientific and Technological New Stars Fund, Beijing, China
(Dr XY Zhang).
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