Alexithymia and its relationships with C-reactive protein and serum lipid levels
among drug naïve adult outpatients with major depression
Domenico De Berardisa,b,⁎, Nicola Serronib, Daniela Campanellaa,b, Alessandro Caranoa,c,
Francesco Gambia, Alessandro Valcherad, Chiara Contia, Gianna Sepedea, Marco Scalic,
Mario Fulcherie, Rosa Maria Salernoa, Filippo Maria Ferroa
aDepartment of Oncology and Neurosciences, Institute of Psychiatry, University “G. d'Annunzio” of Chieti, Italy
bDepartment of Mental Health, Teramo, Italy
cDepartment of Mental Health, ASUR Marche 8, Civitanova Marche, Italy
d“San Giuseppe” Clinic, Ascoli Piceno, Italy
eClinical Psychology, University “G. d'Annunzio” of Chieti, Italy
a b s t r a c ta r t i c l ei n f o
Received 27 March 2008
Received in revised form 27 September 2008
Accepted 29 September 2008
Available online 7 October 2008
Serum lipid levels
Several studies have investigated the relationship between C-reactive protein (CRP) and serum lipid levels in
Major Depression (MD), but no study has, to date, evaluated the impact of alexithymia on these parameters.
Therefore, the aim of the present cross-sectional study was to evaluate the relationship between alexithymia,
a DSM-IV diagnosis of MD. Alexithymia was measured with the 20-item Toronto Alexithymia Scale (TAS-20),
depression severity was evaluated with the 17-item Hamilton Depression Rating Scale (HAM-D) and suicide risk
was determined using the Scale of Suicide Ideation (SSI). Alexithymics showed altered serum lipid levels and
Identifying Feelings” dimension of TAS-20were significantlyassociatedwithdepressionseverity,whereas lower
associated with higher suicide risk. Authors discuss study limitations and future research needs.
© 2008 Elsevier Inc. All rights reserved.
The role of acute phase proteins and lipid levels in neuropsychia-
tric disorders has been widely investigated (Papakostas et al., 2004;
Kuo et al., 2005; Sagud et al., 2007). The relationship between
depressive symptoms and C-reactive protein (CRP) have been
extensively and consistently examined. Results indicate a possible
association between CRP, severityof depressive symptoms and suicide
risk (Liukkonen et al., 2006; Kling et al., 2007). Concerning lipid levels,
there have been some data that suggest that changes in serum lipid
composition may be related to MD, suicide risk and immune-
inflammatory activation (Huang and Chen, 2005; Zhang et al., 2005;
Jowet al., 2006). However, todate, findings areinconsistent. Increases,
decreases or no change at all in CRP and/or serum lipid levels have
been reported in patients with MD and/or suicide attempts (Huang,
2005; Fiedorowicz and Coryell, 2007; Huang and Lin, 2007).
Coined by Sifneos (1973), the term “alexithymia” was introduced to
designate a cluster of cognitive and affective characteristics that were
observed among patients suffering from psychosomatic diseases. The
alexithymia construct, formulated from clinical investigations, is multi-
faceted and includes four different characteristics: (a) difficulty in
identifying and describing feelings, (b) difficulty in distinguishing
feelings from body sensations, (c) reduction in fantasy, and (d) concrete
and poor introspective thinking (Taylor et al., 1991). Alexithymic
individuals also suffer from affective dysregulation, the inability to self
soothe and manage emotions because of a lack of emotional awareness
(Taylor et al.,1997). Thus, the adaptive informational value of emotions,
whichis essentialforemotion regulation, ofteneludestheseindividuals
et al.,2001, 2006).Its presence in majordepressionhas alsobeenlinked
Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1982–1986
Abbreviations: ANCOVA, analysis of covariance; ANOVA, analysis of variance; BMI,
Body Mass Index; CRP, C-reactive protein; DDF, Difficulty in Describing Feelings; DIF,
Difficulty in Identifying Feelings; DSM-IV, Diagnostic and Statistical Manual of Mental
Disorders, 4th edition; EOT, externally-oriented thinking; HAM-D, Hamilton Depression
Rating Scale; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MD, major
depression; SCID-P, Structured Clinical Interview for DSM-IV—Patient Edition; SD,
Standard Deviation; SSI, Scale of Suicide Ideation; TAS-20, Toronto Alexithymia Scale;
TC, total cholesterol; TG, triglyceridaemia; VLDL, very-low-density lipoprotein; WAIS-R,
Wechsler Adult Intelligence Scale—Revised.
⁎ Corresponding author. Department of Oncology and Neurosciences, Institute of
Psychiatry, University “G. D'Annunzio” of Chieti, Palazzina SE.BI., Scuole di Specializzazione,
via dei Vestini, 31, 66013 Chieti Scalo, Italy. Tel.: +39 08713556750; fax: +39 08713556721.
E-mail address: firstname.lastname@example.org (D. De Berardis).
0278-5846/$ – see front matter © 2008 Elsevier Inc. All rights reserved.
Contents lists available at ScienceDirect
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journal homepage: www.elsevier.com/locate/pnpbp
to severityof depressionand suicide risk(Bankier et al., 2001; Saarijarvi
et al., 2006).
So far it is not clear whether alexithymia is a personality trait, a
state-dependent phenomenon or both. Some have observed that
alexithymia, as measured by the 20-item Toronto Alexithymia Scale
(TAS-20), tends to stay stable even with improvement in the
symptoms of depression, implying that it is a personality trait
(Luminet et al., 2001; Taylor and Bagby, 2004). Others have, however,
suggested that alexithymia is a reaction to cope with the distress of
depressive symptoms like emotional pain, aversive memories and
psychological arousal (Marchesi et al., 2008). This concept of
“secondary alexithymia” is strengthened by the findings of Saarijarvi
et al. (2001), who showed that alexithymia features resolve in most
individuals after successful treatment of depression, and patients
resume their capability to recognize and communicate their feelings.
The only study (Corcos et al., 2004), to our knowledge, that has
investigated a possible association between alexithymia and inflam-
matory markers found a positive relationship between interleukin-4
serum levels and TAS scores. Any possible association between
alexithymia in patients with MD and other inflammatory markers or
serum lipid profiles has not yet been studied.
Moreover, many studies have evaluated MD patients with a
relatively long history of illness, which may lead to potential biases
because of current or previous pharmacological treatments that may,
on their own, influence CRP and serum lipid levels (Lanquillon et al.,
2000; Tuglu et al., 2003; McIntyre et al., 2006). Therefore, in the
present exploratory study, we evaluated only drug naïve patients with
MD. Specifically, and the aims of this study were to: 1) evaluate
possible clinical and laboratory differences between patients positive
or not for alexithymia, 2) study whether alexithymia and clinical and
laboratory data are correlated, and 3) investigate which variables are
associated with MD and suicidal ideation severity.
Patients between18 and 45 years withfirstepisodeof MD whohad
never received pharmacological or psychotherapeutic treatment were
considered eligible for this study. Diagnoses were made by clinical
assessment, following the Structured Clinical Interview for DSM-IV—
Patient Edition (SCID-P) (First et al.,1995). All participants had to have
met criteria for moderate-to-severe Major Depressive Episode with a
score of at least 16 on Hamilton Depression Rating Scale, 17-item
version (HAM-D) (Hamilton, 1960). In our sample, the inter-rater
reliability for the total HAM-D score was 0.93 (pb0.001).
Exclusion criteria included: mild depression (HAM-Db16), history
of a manic or hypomanic episode, comorbidity with schizophrenia or
other psychotic disorders, comorbidity with any eating disorder,
history or current drug or alcohol dependence, organic mental
disorders, pregnant or nursing women, current treatment with anti-
inflammatory or immunosuppressant drugs (such as non-steroidal
anti-inflammatory drugs, steroids, paracetamol), known familial
hypercholesterolemia and obesity. Subjects with diabetes, other
endocrinological disorders, hypertension, liver dysfunction or other
conditions necessitating any chronic pharmacotherapy were
excluded. Patients who received medication for cholesterol dysregu-
lation such as statins and fibrates in the last 6 months and those
whose body mass changed substantially within the last 4 weeks prior
to screening were also excluded from the study.
We recruited 183 never-medicated, drug-naïve adult outpatients
with a diagnosis of MD, according to Diagnostic and Statistical Manual
of Mental Disorders, 4th ed. (DSM-IV) criteria, from referrals to the
Institute of Psychiatry, University of Chieti. Subjects with an IQ≤70 as
(Wechsler, 1981) were excluded from the study in order to avoid
potential biases in interpreting results of the TAS-20. Abnormal serum
concentrations of triiodothyronine, thyroxine, alanine aminotransfer-
ase, aspartate aminotransferase or proteinogram results were also
considered as exclusion criteria. Of the 183 recruited patients, 27
(14.8%) subjects meet exclusion criteria and 11 (6.0%) refused to par-
ticipate. Therefore a total of 145 drug-naïve adult outpatients were
included in the analysis (79.2% retention rate). Patients included in
the study had no serious medical conditions in their history that
required anti-inflammatory treatment for more than one week (mean
8.3 weeks and mean duration of last use: 1.2 days).
Alexithymia was evaluated by the Italian version of the 20-item
Toronto Alexithymia Scale (TAS-20), the patient-rated scale most
widely used for measuring alexithymia (Bressi et al.,1996). A score of
61 or higher was considered indicative of alexithymia as stated by
Taylor et al. (1997). The TAS-20 has a three-factor structure: Factor l
assesses the capacity to identify feelings and to distinguish between
the feelings and bodily sensations of emotional arousal (Difficulty in
Identifying Feelings [DIF]); Factor 2 reflects the inability to commu-
nicate feelings to other people (Difficulty in Describing Feelings
[DDF]); Factor 3 assesses Externally-Oriented Thinking (EOT). In our
sample, the reliability for TAS-20 was 0.87 (Cronbach's α).
et al.,1979), a 3 point clinician-rated scale with statements of suicidal
intentions, were evaluated. In our sample, Cronbach's α was 0.91.
Weight was measured (in light indoor clothing with shoes
removed) using a balance beam scale, and height was measured
using a stadiometer. Weight and height were used to calculate Body
Mass Index (BMI) (kg/m2).
Forall patients the following determinations were performed: CRP,
triglyceridaemia (TG), total cholesterol (TC), high-density lipoprotein
(HDL), very-low-density lipoprotein (VLDL) and low-density lipopro-
tein levels (LDL). Serum CRP was measured using a highly sensitive
nephelometric assay [BN-II Nephelometer; Dade Behring, Deerfield,
IL], which is able to detect a minimal CRP concentration of 0.22 mg/dl.
All blood samples for lipid studies were collected in tubes containing
EDTA (1 mg/ml) and separated within 1 h after sampling. Serum lipid
concentrations were determined by enzymatic methods with an
Abbott ABA-100 Biochromatic analyser (USA). Cholesterol and serum
triglycerides were also measured using enzymatic methods (choles-
terol: Boehringer Mannheim, Germany; serum triglycerides: Abbott).
HDL cholesterol was measured after phosphotungstic acid/MgCl2
precipitation on fresh plasma. Inter-assayand intra-assay variations of
all measurements were less than 10%.
The ratios of TC/HDL and LDL/HDL were also evaluated. Blood
samples were taken between 7:30 and 8:30 a.m. after the patients had
fasted for at least 10 h and after a psychiatric evaluation (mean time
between psychiatric evaluation and blood sampling 17.5±3.1 h).
The study was approved by the local ethical committee of the
University of Chieti. Each patient had to understand the nature of the
study and sign an informed consent document prior to WAIS
administration and laboratory testing.
Descriptive statistics and percentages for the study sample were
computed on demographic variables and all psychometric-scales. All
checked for deviations from the Gaussian distribution using the
Kolmogorov–Smirnov test. Given the normal distribution of the
variables, a one-way analysis of variance (ANOVA) was used to analyze
gender differences. The differences between individuals with and
with TAS-20 positivity/negativity as a factor, and age, gender, BMI and
to obtain effect sizes for a better evaluation of the magnitude of group
differences on the continuous study measures. Partial correlations
D. De Berardis et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1982–1986
correlationsthat were statisticallysignificantatpb0.01 were examined.
Finally, two block-wise linear regression analyses were performed to
determine which variables were associated with the severity of MD
(Model 1: HAM-D as dependent variable) or suicidal ideation (Model 2:
were entered. In the second block, laboratory data were added to the
model. The DIF, DDF, and EOT subscales of the TAS-20 were entered in
the last step. The quality of the regression model was also tested using
the Durbin–Watson statistic (a value between 0 and 4, indicating the
amount of autocorrelation within the model with an optimum value
of 2.0). p values≤0.05 were deemed statistically significant. All statis-
tical testing was two-sided. Statistical analyses were performed using
Standard Deviation (SD).
The sample consisted of 69 men and 76 womenwith a mean age of
28.5 years (SD=5.7) (age range: 19–45 years) and a mean duration of
illness of 0.78 years (SD=0.8) (range 0.4–1.0). The mean BMI was
22.5 kg/m2(SD=2.4) (range 15.4–29.1) and the mean HAM-D score
was 27.9 (SD=9.4) (range 17–39). Gender comparisons between all
demographic and clinical variables showed no significant differences
on any of the variables. The mean TAS-20 total score was 51.7
(SD=14.1); 33.8% (n=49) of 145 patients who scored 61 or more were
considered positive for alexithymia. Descriptive statistics of the whole
sample and a comparison between patients positive and negative for
alexithymia is reported in Table 1.
Comparison between individuals with or without alexithymia
(n=96, 66.2%) controlling for age, gender, BMI and smoking status,
revealed that subjects positive for alexithymia showed higher HAM-D
and SSI scores than non-alexithymics (Table 1). Moreover, subjects
positive for alexithymia showed higher CRP and VLDL and lower TC,
HDL and TG levels than non-alexithymics. Finally, TC/HDL and LDL/
HDL ratios were higher in subjects positive for alexithymia compared
to non-alexithymics. Levels of LDL were not significantly different
between groups. Effect size calculation showed that the magnitude of
the group effect for HAM-D, SSI, CRP, TC, HDL, VLDL, TG and TC/HDL
was large, whereas the effect for LDL/HDL was medium.
In our sample, we found positive partial correlations (controlling for
DIF and DDF) and almost all considered variables except LDL and the
correlation between DDF and TG, whereas the EOT subscale did not
correlate with any variable (to reduce alpha inflation, only correlations
statistically significant at pb0.01 were examined) (Table 2).
In the linear regression models (Table 3), higher SSI scores, lower TC
levels and DIF/DDF dimensions of TAS-20 were significantly associated
with depression severity (HAM-D as dependent variable), whereas
HAM-D, lower HDL levels and DIF dimension of TAS-20 were associated
with higher suicide risk (SSI as dependent variable). In the current
analyses, the R2values accounted for 71% of the variance in HAM-D and
and 1.88, respectively for model 1 and 2 (near to the optimum of 2.0). A
scatter plot of residuals and a plot of regression-standardized residuals
indicated a near normal distribution.
To our knowledge, this is the first study to evaluate the relation-
ships between alexithymia, CRP and serum lipid levels in a sample of
drug-naïve adult outpatients with MD.
We found that alexithymics showed higher CRP than non-
alexithymics even if CRP was not associated with depression severity
in the linear regression model. The finding of higher CRP levels among
alexithymics may be consistent with the stress-alexithymia hypoth-
esis (Martin and Pihl, 1985): patients with more alexithymic features
may be suffering from chronic stress reaction that, on its own, can
promote transient and often subclinical increases in inflammatory
factors such as CRP and interleukins (Black, 2002; Jeanmonod et al.,
2004). Moreover, alexithymia is related to high cortisol levels due
to short-term stress reactions (Finset et al., 2006), and cortisol may
enhance the release of interleukin-6, the major inducer of CRP
Comparison of HAM-D, SSI,CRP and serum lipid levels between individuals with (patients
with a TAS-20 score≥61) and without alexithymia (patients with a TAS-20 score≤61)
controlling for age, gender, BMI and smoking status
VLDL (mg/dl) 106.2±16.8
F=35.5 pb0.001 1.29
F=64.5 pb0.001 1.65
F=125.1 pb0.001 2.35
F=28.5 pb0.001 1.25
F=39.7 pb0.001 1.62
F=76.6 pb0.001 2.06
F=31.8 pb0.001 1.34
Partial correlations between TAS-20 total scores (and subscales) and clinical (HAM-D
and SSI) and laboratory data among whole sample (n=145) controlling for age, gender,
BMI and smoking status (to control for alpha inflation, only the correlations that were
statistically significant at pb0.01 were examined)
Results of two linear regression analyses with HAM-D as the dependentvariable (Model 1),
SSI as dependent variables (Model 2) and other variables as independent
interval for B
Model 1 Dependent variable: HAM-D⁎
Model 2 Dependent variable: SSI⁎⁎
Only statistically significant variables are shown.
⁎ R2=0.71; F=13.79 df=12 pb0.001.
⁎⁎ R2=0.69; F=14.42 df=12 pb0.001.
D. De Berardis et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 32 (2008) 1982–1986
production by liver (Baumann and Gauldie, 1994). Together, this may
further explain the higher CRP levels among individuals with
According to our results, the serum TC levels among alexithymic
depressed patients were significantly lower than those among non-
alexithymic depressed patients and was associated with an increased
MD severity in the linear regression. Moreover, the DIF and DDF
dimensions of the TAS-20 were noticeably associated with depression
severity, as shown also in previous studies (Marchesi et al., 2000; De
Gennaro et al., 2004). It is possible to hypothesize that individuals
with higher difficulty in identifying and describing feelings (even if
not necessarily categorized as alexithymics) may have higher depres-
sion severity, as has been demonstrated in previous studies (Saarijarvi
et al., 2001, 2006). Thus, in these patients, lower serum TC may be
related to depression severity.
Moreover, suicide risk seems associated with lower HDL levels as
well as DIF dimension of TAS-20. It has been reported that patients
with high risk of suicide may have lower serum HDL concentrations
(Zhang et al., 2005; Marcinko et al., 2008), which also seems to apply
to our observations. In addition, it has been previously demonstrated
that the DIF dimension of the TAS-20 is related to suicidal ideation
(Sakuraba et al., 2005). Thus, a combination of these factors may
account for the increased risk of suicide among MD patients in our
sample, even if further studies are needed.
All things considered, the results of our study support the notion
that alexithymic individuals with MD may show a cholesterol
dyregulation linked in an unclear way to suicide risk. In addition,
even if alexithymia can be considered a relatively stable personality
trait (Luminet et al., 2001; Saarijarvi et al., 2006), our overall results
may support Freyberger's concept (1977) of acute “secondary
alexithymia” as a reaction to stressful situations. Acute secondary
alexithymia is described as a transitory, state-dependent phenom-
enon that results as a consequence of personal distress, and which
may decrease once an acute disease episode has resolved. Through
such a perspective, it is possible that serum lipid alterations may
reflect a state-dependent phenomenon as we found a positive
correlation between TAS-20 and HAM-D/SSI. Also, as subjects positive
for alexithymia showed higher HAM-D scores than non-alexithymics
it is possible that cholesterol dysregulation may be due to both
depression and alexithymia, but further prospective studies are
needed in order to clarify this topic.
Between serum cholesterol and depression severity, it is rather
difficult to elucidate which is the cause and which the effect. Some
researchers have hypothesized that low serum cholesterol might
influence serotonin transmission and lead to depression (Engelberg,
1992; Vevera et al., 2005; De Berardis et al., 2008). In addition, poor
appetite, a common symptom of depression, might significantly
influence cholesterol levels. In any case, it was reported that low
cholesterol levels might impair neuronal membrane fluidity and
consequently the availability of serotonergic receptors (Heron et al.,
1980). This impairment may result in reduced presynaptic and
postsynaptic 5-HT neuronal activity and, consequently, low central
5-HT activity may explain depressive symptoms, impulsiveness and
suicidal behavior (Brown et al.,1982; Coccaro et al.,1989). However, to
6. Study limitations
This study has several limitations, and results should therefore be
interpreted with caution. The first limitation of our study is the
absence of controls. Including controls in our analysis would have
afforded us the opportunity to compare levels of serum cholesterol
betweendepressed andnot depressedalexithymic or non-alexithymic
subjects, controlling forage,genderandBMI. Moreover, this study was
performed in a population with a relatively narrow age range (19–
45 years old) and results may not be generalized to other age groups,
including elderly or adolescent patients with MD.
The cross-sectional nature of our study and the inclusion of
relatively young subjects with MD imply that our sample may be
considered heterogeneous in terms of further course. Therefore, to
date, we cannot exclude that a major depressive episode may be a
precursor of a bipolar or psychotic disorder. Moreover, even if
exclusion of individuals receiving medications for cholesterol dysre-
gulation was obviously one of the sample selection criteria, it implies
that subjects with MD and prominent dyslipidemia were excluded
from the study. In addition, as MD is associated with appetite changes
and subsequent weight changes (that were not measured), exclusion
of individuals whose body weight had changed substantially within
the last four weeks prior to screening would have potentially resulted
in exclusion of individuals with significant depression. Finally,
individuals with mild depression (HAM-Db16) were excluded.
Taken together, these limitations may limit the generalization of our
results to all patients with MD.
Moreover, even if severity of depression and suicidal ideationwere
analysed using clinician-rated rating scales, alexithymia was assessed
bya self-rated scale, with possible biases due to the inherent nature of
self-rating scales. Finally, our study lacks of follow-up data. Definitive
assessments of CRP, serum lipid levels, mood states and alexithymia
require that patients should be followed longitudinally, with serial
cholesterol sampling as well after clinical remission and pharmaco-
The authors would like to extend their sincere gratitude to Dr.
Alessandro D'Albenzio, Department of Oncology and Neurosciences,
Institute of Psychiatry, University of Chieti, for his most helpful advice
and review on this manuscript and to Dr. Marilde Cavuto, Istituto
Musicale “G. Braga” Teramo, for helping in literature searches.
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