Alteration of Serum Levels of Interlukin 1 and Tumor Necrosis Factor in Depression Independentof Treatment or Overdose of Tricyclic Antidepressants
The aim of this study was to evaluate the status of serum IL-1b and TNF-α
in depressed patients who treated or non-treated or poisoned with tricyclic
antidepressants (TCAs) in comparison to healthy subjects. In this prospective
comparative study, patients were selected from those admitted at Loghman-Hakim
Hospital from August 2007 to January 2008. Serum level of IL-1b and TNF-α
were compared among group of subjects (10 in each) of healthy subjects,
TCA-poisoned patients, TCA-treated depressed patients and non-treated
depressed patients. Demographic and clinical data were collected by a
questioner filled out by a trained practitioner in daily clinical management.
Blood was tested for liver function, blood cells, electrocardiography
and arterial blood gases. Complete blood analysis and demographic data
did now show significant change between groups. IL-1b level was higher
among females. The group of depressed patients non-treated with TCAs showed
higher serum levels of IL-1b and TNF-α than other groups. No significant
difference was observed in IL-1b and TNF-α values among healthy control,
depressed TCA-treated and TCA-poisoned groups. It is concluded that depression
and gender may influence the production of cytokines while neither TCAs
treatment nor its overdose affect IL-1b and TNF-α.
to cite this article:
Haleh Talaie, Abdolkarim Pajoumand, Reyhaneh Panahandeh, Behjat Barari, Maryam Baeeri and Mohammad Abdollahi, 2008. Alteration of Serum Levels of Interlukin 1 and Tumor Necrosis Factor in Depression Independentof Treatment or Overdose of Tricyclic Antidepressants
. Journal of Medical Sciences, 8: 287-292.
Tricyclic antidepressants (TCAs) are pharmacological agents widely
prescribed in treatment of depressive disorders and other forms of psychiatric
These antidepressants continue to be a leading cause of both non-fatal/fatal
morbidity and mortality in overdoses cases worldwide (Eizadi-Mood et
al., 2005; Singh et al., 2002; Abdollahi et al., 1997;
Shadnia et al., 2007; Talaie et al., 2007; Moghadamnia and
Abdollahi, 2002). Most of TCAs have been registered in Iran and are available
in Iran (Nikfar et al., 2005). In 2004, data of a US. poison center
revealed 12,000 exposures to TCAs (Woolf et al., 2007). Previous
studies have demonstrated various immunomodulatory effects of antidepressants
dependent on the immune status of the depressed patients at the initiation
of the treatment. It is believed that inflammatory-response system is
activated in depression and proinflammatory cytokines play a role in the
etiology of depression. Thus, it is not surprising to expect positive
immunomodulating effects by antidepressants as already reported by some
researchers (Peng et al., 2008; Maes, 2001; Kubera et al.,
2001a, b ). A spontaneous suppression of lipopolysacharide (LPS)-induced
secretion of pro-inflammatory cytokines such as IL-1b and TNF-α from
monocytes by TCAs has been reported by Xia et al. (1996) and Kubera
et al. (1996). There is evidence that TCA-induced reduction of
pro-inflammatory cytokines is usually accompanied with a rise in the production
of the anti-inflammatory cytokine such as IL-10 (Castanon et al.,
2002; Dredge et al., 1999). On the other hand, study of depressed
patients exhibiting immune suppression before treatment has shown that
the TCA (clomipramine) increases the production of IL-1b, IL-2 and IL-3
(Weizman et al., 1994). It is worthy to note that cytokines specially
IL-1b and TNF-α have important role in pathogenesis of various disease
in human (Rahimi et al., 2007a,b; Kajbaf et al., 2007; Vazin
et al., 2005; Rezaie et al., 2007). One of the problems
in overdose cases or those who use TCAs is lack of satisfactory biomarkers
to estimate the severity of clinical conditions of patients. Present hypothesis
is that determination of blood levels of cytokines can be suitable and
convincing when blood TCA levels are not easily available.
Regarding above-mentioned reports we aimed to investigate whether depression
or exposure to TCAs at normal doses or at overdosage might influences
serum concentrations of IL-1b and TNF-α.
MATERIALS AND METHODS
The study conducted in poison center and psychology clinic of Loghman-Hakim
Hospital during August 2007 to January 2008. In this prospective comparative
study 40 subjects were included in four groups with 10 in each. Group
1 included 10 cases of TCA-poisoned patients diagnosed on the basis of
history, clinical manifestations and confirmation by urine analysis for
TCA by thin layer chromatography (TLC) by routine laboratory analysis.
Group 2 included 10 age- and sex-matched controls who were recruited from
healthy individuals of the hospital. Those with any history of psychiatric
illness, substance or alcohol abuse, infectious diseases, chronic renal
or liver diseases and malignancy were excluded. The psychopathological
status of the patients was assessed by a trained psychiatric through an
interview. Group 3 included 10 outpatients with depressive disorder and
previous history of TCA treatment who were recruited from psychology clinic
of the Hospital. Depressive disorder was diagnosed by trained psychiatric
specialists using DSM-IV criteria (American Psychiatric Association, 2000).
Group 4 included 10 outpatients who were first diagnosed for depressive
disorder and not having previous history of TCA usage recruited from psychology
Ten milliliter venous blood was obtained from all subjects, serum was
separated and frozen at -70°C until analysis. Serum concentrations
of the IL-1b and TNF-α were assayed using enzyme-linked immunosorbent
assay (ELISA) by BioSource kits (Belgium). The detection limits for IL-1b
and TNF-α were 0-1400 and 0-1500 pg mL-1, respectively.
Results were expressed as pg IL-1b and TNF-α per milliliter of serum.
The demographic (age, sex, history of underlying disease) and clinical
data (pulse rate, respiratory rate, blood pressure, body temperature)
were collected via a questioner filled out by a trained practitioner in
daily clinical management. Tests for liver function, blood cells, electrocardiography
(ECG) and Arterial Blood Gases (ABG) were performed. Patients who had
history of any concomitant drug poisoning, substance or alcohol abuse,
infectious diseases, chronic renal or liver diseases, malignancy, autoimmune
disease, leukocytosis and fever were excluded.
The study protocol was approved by review board of Pharmaceutical Sciences
Research Center of TUMS and Toxicological Research Center of SBUMS.
Statistical analysis of data: Data were analyzed by one-way ANOVA
followed by Newman-Keul`s test. p-value less than 0.05 was considered
statistically significant. Data are mean±SD unless otherwise stated.
Mean age of study population was 32.7±9.9 ranged from 17
to 56 years. Of 40 cases, 16 patients (40%) were male, while females were
24 (60%). Only in one case,
||Demographic data of study subjects
|There was one case with positive history of hyperlipidemia
||Paraclinical data of study subjects
|WBC was significantly (p = 0.00) higher in TCA-poisoned
patients as compared to other groups. Depressed patients without previous
history of TCA treatment had significantly (p<0.01) higher IL-1b
and TNF-α values than other groups. No other significant difference
was observed among groups. Data are Mean±SD
positive history of hyperlipidemia was reported (Table
1). Mean body temperature was 37±0.3°C. Mean systolic pressure
in the study population was 112.7 mmHg. Mean pulse rate was 84.3 per minute
ranged from 57 to 120. Airway support and incubations were performed in
9 patients (22.5%). Majority of patients had normal arterial blood gas
while acidosis was seen in 2 (5%) patients. ECG of 3 (7.5%) patients showed
bradycardia, 2 (5%) tachycardia, 1 (2.5%) T wave changes, whereas 34 patients
(85%) had no abnormal ECG findings. Liver function tests showed mean ALT
(28.5 U L-1) and AST (27.9 U L-1) within normal
ranges. Moreover, subjects` WBC count was within the normal range with
mean of 7637 per microliter while they were lower than that of controls
There was no significant difference in serum concentration of IL-1b and
TNF-α between controls and TCA poisoned patients. Also no significant
difference was found in serum concentrations of IL-1b and TNF-α among
cases with TCA poisoning and those in other groups. The group of depressed
patients non-treated with TCAs showed higher serum concentrations of IL-1b
and TNF-α than other groups. No significant difference was observed
in IL-1b and TNF-α values among healthy control, depressed TCA-treated
and depressed non-TCA-treated groups (Table 2). Results
revealed gender differences in IL-1b values with female predominance while
no gender difference for TNF-α value was observed.
Present data demonstrated that serum concentrations of pro-inflammatory
cytokines such as IL-1b and TNF-α did not statistically differ among
TCA-poisoned patients and depressed patients with or without previous
history of TCA treatment meaning that TCA does not influence cytokine
levels even in over dosage. Interestingly, results indicated higher serum
concentrations of IL-1b and TNF-α in patients with depression. Some
previous studies have reported higher levels of pro-inflammatory cytokines
in depressed patients. They suggested that elevated cytokines might be
considered as etiology of depression. To explain changes, they claimed
that TCAs suppress immune system (Peng et al., 2008; Myint et
al., 2005; Maes, 2001; Kubera et al., 2001a,b). In contrast,
another study in depressed patients in 2007 reported no significant differences
in plasma concentration of TNF-α between patients and healthy controls
(Farid-Hosseini et al., 2007). In addition, a linear relationship
between intensity of depression and indicators of cellular immunity and
serum IL-1b has been shown (Herbert et al., 1993). As reported,
over-stimulated production of cytokines is seen in melancholic and treatment-resistant
depressions than in minor cases (Meas, 1999). In the present study, blood
cytokines were measured without considering severity of depression and
thus this can be numbered as a limitation to this work. On the other hand,
most of animal studies support TCA-induced changes in cytokine levels.
In vitro incubation of activated monocytes with TCAs inhibited
production of inflammatory cytokines such as IL-1b and TNF-α (Xia
et al., 1996). Furthermore, TCAs attenuated monocytic pro-inflammatory
cytokine release in microglial cell cultures (Obuchowicz et al.,
2006). Likewise, in another repot, 14-day treatment of rats with desipramine
(75 mg kg-1) impaired TNF-α secretion following an in
vivo challenge by LPS (Shen et al., 1999). Similarly in rats
subjected to a chronic mild stress model of depression, daily administration
of imipramine for 8 weeks, accompanied by a decrease in the ability of
splenocytes to produce IL-1b while administration of imipramine alone
did not alter splenocytes activity (Kubera et al., 1996). Imipramine
also inhibited LPS-induced increases in serum concentrations of TNF-α
both 3 and 6 hours following administration. However, LPS-induced interleukin
IL-1b secretion was not significantly altered following imipramine treatment
at either of the time points examined (Dredge et al., 1999). On
the contrary, increased rat hippocampus TNF-α was observed after
14 days administration of desipramine (Ignatowski et al., 1994).
The controversy in different animal studies might also result from different
sample sizes, in vivo or in vitro procedures, duration of
treatment and methods of cytokine assays used in various studies.
In the present study, gender difference with female predominance was
observed for serum IL-1b but not for TNF-α. In contrast, previous
study, significantly lower TNF-α levels in female than male patients
was reported. This difference was diminished after antidepressant treatment
(Kim et al., 2007). In females, higher prevalence of Th2-mediated
autoimmune diseases such as systemic lupus erythematosus has been shown
(Rider and Abdou, 2001). There is also evidence that in systemic inflammatory
conditions mediated by monocytic pro-inflammatory cytokines, females show
better outcomes (De Maio et al., 2005). Meanwhile, reduced T cell
proliferative responses and the pro-inflammatory cytokines production
in women with depressive disorders have been reported by Miller et
al. (1999) and Cyranowski et al. (2007). Moreover, female hormones
such as estrogen may influence the immune response in women (Beagley and
Gockel, 2003; Cutolo et al., 2004) and thus menstrual phase and
consumption of oral contraceptive should be considered for any conclusion.
Taking collectively, there are many controversial reports on the cytokine
levels and TCA treatment. In human studies, blood cytokines have not been
measured in relation to severity of depression that is a limitation. In
animal studies, source of controversy seems to be different sample sizes,
in vivo or in vitro procedures, duration of treatment and
methods of cytokine assays used in various studies. However, the present
results show that depression and gender may influence production of cytokines
while neither TCA treatment nor its overdose affect cytokine levels.
This study was supported by Toxicological Research Center of SBUMS
and Pharmaceutical Sciences Research Center of TUMS. Special
thanks are given to psychiatrics cooperating in poison ward and ICU of
Loghman Hakim Hospital Dr. M. Zarei, Dr. F. Nazemi and Dr. M. Karimi.
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