Psychiatric Quarterly

https://doi.org/10.1007/s11126-020-09731-8

ORIGINAL PAPER

Galectin-1 and Galectin-3 Levels in Patients

with Schizophrenia and their Unaffected Siblings

Rabia Nazik Yüksel 1 & Diğdem Göverti 2 & Aybeniz Civan Kahve 1 &
Işık Batuhan Çakmak 1 & Çiğdem Yüksel 3 & Erol Göka 1

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Many hypothesis suggest that inflammation plays an important role in schizophrenia.
Galectins can regulate inflammatory response in central nervous system. The relation
between galectins and neuropsyhchiatric diseases and schizophrenia is unclear. The
present study compared levels of Gal-1 and Gal-3 of patients with schizophrenia to that
of first-degree relatives without the disease and healthy controls in order to evaluate any
possible association. Sixty-two patients with schizophrenia, fifty-five unaffected siblings
and fifty-eight age- and sex-matched healthy controls enrolled. Serum Gal-1, Gal-3 and
CRP levels were measured. PANNS and CGI-S were used to evaluate the severity of
disease. There was a statistically significant difference in serum Gal-1 levels among the
patient, sibling, and control groups. There were no statistically significant correlations
between serum CRP and serum Gal-1 or Gal-3 levels. Gal-1 values were significantly
higher in the unaffected siblings compared to both the patient group and the healthy
control group. Gal-3 levels were elevated in the sibling group relative to the patient group.
In the literature, the relationship between galectins and schizophrenia is very limited and
appears to be a new field of study. Future studies are needed to evaluate the protective
roles of galectins.

Keywords Galectins . Schizophrenia . Galectin 1 . Galectin 3 . CRP . Psychosis

* Rabia Nazik Yüksel

rabianazik@gmail.com

1
Department of Psychiatry, University of Health Science, Ankara City Hospital, Ankara, Turkey
2
Department of Psychiatry, Elazığ Psychiatric Hospital, Elazığ, Turkey
3
Department of Biochemistry, University of Health Science, Ankara City Hospital, Ankara, Turkey
 Psychiatric Quarterly

Introduction

Schizophrenia is a serious neuropsychiatric disorder with a lifetime prevalence of approxi-

mately 0.7% [35]. The etiology and pathogenesis are uncertain, but infectious and inflamma-
tory processes have been identified as potential contributing factors [2, 30]. Inflammation is a
complex response to injury or tissue destruction, which involves the activation and recruitment
of immune cells with increases in blood supply and vascular permeability. Abnormal levels of
acute-phase inflammatory proteins have been observed in patients with schizophrenia [22, 25,
43], and numerous studies have shown increased blood concentrations of inflammatory
cytokines in people with schizophrenia [24]. Kirkpatrick and Miller emphasized two important
points about these studies [17]. First, inflammatory abnormalities were observed in subjects
with first-episode, drug-naive psychosis compared with controls, suggesting that the associa-
tion between schizophrenia and inflammation is independent of the effects of antipsychotic
medications. Second, the concentrations of some inflammatory molecules varied according to
the clinical situation of the patients, suggesting that there are separate groups of state and trait
markers [17]. Biomarkers currently play important roles in research to understand schizophre-
nia, including for diagnosing the disease, monitoring prognosis and treatment responses, and in
the early detection of disease in individuals prone to schizophrenia [19]. Various proteins have
been investigated as candidate biomarkers for studying the relationship between inflammation
and psychiatric disorders.
Galectins, a family of β-galactoside-binding lectins, play important roles in the regulation
of immune and inflammatory responses [3]. They have been implicated in various biological
processes, including cell adhesion, migration, proliferation, transformation, apoptosis, angio-
genesis, and immune responses [8]. The members of the galectin family differ in the roles they
play in mediating pathological processes in various inflammatory diseases ([21], Liu et al.
2005). In neuronal diseases, galectins can regulate the inflammatory response and confer
remodeling capacity to damaged central nervous system (CNS) tissues [31]. Galectins are
present both inside and outside cells: extracellular galectins interact with the cell surface and
extracellular matrix glycoproteins, whereas intracellular galectins interact with cytoplasmic
and nuclear proteins in a carbohydrate-independent manner [8, 10, 20, 28].
Galectin-1 and galectin-3 (Gal-1 and Gal-3, respectively) are the most ubiquitously
expressed members of the galectin family. Gal-1 is expressed in skeletal and cardiac myocytes,
hepatocytes, and prostate stromal cells, and Gal-3 is expressed in epithelial cells of the
digestive and respiratory tracts [16]. Several studies have reported the altered expression of
Gal-1 in neurological diseases and that this wascorrelated with neuroregeneration [23, 39].
Gal-1 is an important modulator of CNS homeostasis; depending on host environmental
factors, it can contribute to neuroinflammation or play a neuroprotective role [7]. Over recent
decades, there has been a rapid growth in the literature on Gal-3. Studies have found that Gal-3
plays diverse roles in inflammation of the CNS, combining a proinflammatory role with its
remodeling capacity in damaged neuronal tissues [31]. Studies of Gal-3-deficient mice have
provided evidence that Gal-3 plays a role in promoting inflammatory responses [1, 4, 11]. In
addition, an increasing numbers of studies have suggested that Gal-3 released by activated
microglia in response to proinflammatory stimuli participates in brain immune responses [31,
37, 44].
Few studies of inflammation of the CNS have evaluated the relationship between Gal-1 and
Gal-3. Sirko et al. reported that Gal-3 was highly expressed in reactive astrocytes and that Gal-
3 and Gal-1 together regulated the proliferative and neural stem cell potential of a subset of
Psychiatric Quarterly

these astrocytes [33]. In a study of 36 patients with schizophrenia, Kajitani et al. observed high
levels of Gal-3, with levels of Gal-1 equal to those of healthy controls [15]. However, that
study evaluated Gal-1 and Gal-3 together in patients with schizophreni the sample was limited.
Further research on this subject is needed.
Another inflammation marker studied in the etiology of schizophrenia is C-reactive protein
(CRP), an acute-phase protein produced by hepatocytes. Measuring CRP levels is useful for
diagnosing and monitoring many acute and chronic inflammatory conditions, including
infections, periodontal disease, chronic lung disease, obesity, and metabolic syndrome [42].
Studies have examined levels of CRP in schizophrenia [24, 26]. In their updated meta-analysis,
Wang et al. reported that higher CRP levels were associated with an increased risk of
schizophrenia, especially for adult patients younger than 30 years [41]. In another meta-
analysis, significant increases in CRP levels were found in patients with schizophrenia and
related disorders [25].
The present study compared the inflammation status of patients with schizophrenia to that
of first-degree relatives without the disease. We therefore recruited genetically similar siblings
with and without schizophrenia and measured levels of Gal-1, Gal-3,and CRP. We previously
reported low-grade inflammation in patients with schizophrenia [45]. To obtain a better
understanding of the effect of this, we evaluated CRP levels in the patients; and we measured
galectin levels to establish whether these could act as a biomarker in schizophrenia. We
established our sample from patients with schizophrenia at a similar period in the disease,
their unaffected siblings, and healthy controls.
The aim of this study was to evaluate the relationship between schizophrenia and inflam-
mation by measuring blood CRP, Gal-1, and Gal-3 levels in patients with schizophrenia at a
similar period in the disease, their unaffected siblings, and healthy controls. The intention for
including genetically similar siblings in the study in addition to healthy controls was to provide
a better idea of whether galectins could be a biomarker in schizophrenia. Levels of CRP, a
marker of low-grade inflammation reported previously in schizophrenia, were also evaluated.
To the best of our knowledge, this was the first study to investigate Gal-1 and Gal-3 levels in
patients with schizophrenia and their unaffected siblings.

Methods

Participants

This study was conducted in the Psychiatry Clinic of SBU Ankara Numune Training and
Research Hospital between December 2018 and April 2019. In total, 90 consecutive patients
who met the DSM-5 diagnostic criteria for schizophrenia were invited to enroll in the study
with their unaffected siblings. To confirm the schizophrenia diagnosis, each patient was
interviewed by two psychiatrists based on the Structured Clinical Interview for DSM-5
Disorders, Clinical Version. The Non-patient Editionof this was used to determine whether
the siblings were affected by schizophrenia and whether they and the healthy controls had any
psychiatric disorders. The following exclusion criteria were applied: dementia, alcohol and
drug dependency, mental retardation, and the presence of other comorbid psychiatric or
neurological disorders. Finally, 62 patients and 55 siblings who met the criteria were included
in the study, with 58 age- and sex-matched volunteers with no known psychiatric or neuro-
logical disease enrolled as healthy controls.
 Psychiatric Quarterly

Two clinicians completed sociodemographic data forms for the participants. The clinical
status of the patients was assessed using the Positive and Negative Syndrome Scale (PANSS)
and the Clinical Global Impression–Severity scale (CGI-S).
The study was approved by SBU Ankara Numune Training and Research Hospital Clinical
Research Ethics Committee. All the participants were informed about the study and gave their
written informed consent.

Blood Collection and Quantification

Venous blood samples were collected from the participants after 8–12 h of fasting. The blood
samples were centrifuged at 4000 rpm for 10 min, and the separated sera were aliquoted into
Eppendorf tubes and stored at −80 °C until the time of analysis. Serum Gal-1 and Gal-3 levels
were measured with double-antibody sandwich enzyme-linked immunosorbent assay kits
(BosterBio, Pleasanton, CA, USA),according to the manufacturer’s instructions. Values of
Gal-1 and Gal-3 are expressed in ng/mL.

Statistical Analysis

The sociodemographic data and clinical scale measures are reported using descriptive statistics
and expressed as mean ± SD and median (range) for continuous variables and number and
percentage for categorical variables. The Kolmogorov–Smirnov test was used to compare the
distributions of Gal-1 and Gal-3 levels among the groups. Comparisons of sex and smoking
status between the groups were evaluated using the chi-squared test, andcomparisons of
continuous variables were evaluated using one-way ANOVA, Mann–Whitney U tests,or
Kruskal–Wallis tests, as appropriate. The relationships between groups of variables were
examined using Spearman’s correlation coefficients. The statistical analyses were performed
using SPSS version 22.0. Statistical significance was defined as p < 0.05.

Results

In total, 63 patients with schizophrenia, 55 siblings, and 58 healthy controls participated in the
study. Of these, 60.8% were male and 39.2% were female; the mean age was 40 ± 10 (18–60)
years, the mean body mass index (BMI) was 25.88 ± 4.36 (17.01–43.66) kg/m2 and the
smoking ratewas 43.1%. The characteristics of the three groups are compared in Table 1.
Additional characteristics and the clinical measures of the patient group are summarized in
Table 2.
There were no significant differences in age, sex, smoking status, or BMI between the three
groups. The duration of illness of the patients with schizophrenia ranged from 0.5 to 36 years.
There were no significant differences in Gal-1 and Gal-3 levels between the patients who had
been newly diagnosed with schizophrenia and those who had already received treatment. (p =
0.608 and p = 0.351, respectively).
There was a statistically significant difference in serum Gal-1 levels among the patient,
sibling, and control groups(19.31 ± 5.92 ng/mL, 23.96 ± 11.21 ng/mL, and 17.43 ± 4.57 ng/
mL, respectively; p < 0.001). Post hoc pairwise comparisons with the Bonferroni correction
showed that serum Gal-1 levels were significantly lower in the healthy control group compared
to the sibling group (p < 0.001), and significantly lower in the patient group compared to the
Psychiatric Quarterly

Table 1 Characteristics of the patients with schizophrenia, their unaffected siblings, and the healthy control
group

Characteristic Patients (n = 63) Siblings (n = 55) Control (n = 58) p

Age (years)
Mean ± SD 37.21 ± 10.36 39.25 ± 11.54 37.60 ± 8.76 0.527a
Median (range) 36.00 (19.00–59.00) 39.00 (18.00–59.00) 37.00 (19.00–60.00)
Sex
Male, n (%) 39 (36.4) 31 (29.0) 37 (34.6) 0.703b
Female, n (%) 24 (34.8) 24 (34.8) 21 (30.4)
Smoking (y/n) 25/38 23/32 28/30 0.616b
BMI (kg/m2) 0.913c
Mean ± SD 26.11 ± 5.30 25.89 ± 3.96 25.62 ± 3.60
Median (range) 24.69 (18.07–43.66) 25.71 (17.0–35.94) 25.43 (19.03–34.11)
a One-way ANOVA. b Chi-square test. c Kruskall–Wallis test. BMI, body mass index

sibling group (p = 0.044), but there was no significant difference between the control and
patient groups (p = 0.289) (Fig. 1 ).
There was a statistically significant difference in serum Gal-3 levels among the patient,
sibling, and control groups (5.13 ± 2.27 ng/mL, 6.75 ± 3.22 ng/mL, and 6.00 ± 1.85 ng/mL,
respectively; p = 0.009). Post hoc pairwise comparisons with the Bonferroni correction showed
that serum Gal-3 levels were significantly lower in the patient group compared to the sibling
group (p = 0.009), but there wereno statistically significant differencesbetween the patient and

Table 2 Characteristics and clinical scale measures of the patient group (n = 63)

Antipsychoticuse (y/n)a 13/50

Duration of illness (years)

Mean ± SD 9.17 ± 8.02
Median (range) 7.08 (0.50 ± 36.00)
Newly diagnosis(y/n)a 16/47
Number of hospitalizations
Mean ± SD 2.77 ± 1.78
Median (range) 3.00 (1.00–10.00)
PANSS Total Score
Mean ± SD 82.98 ± 16.77
Median (range) 78 (58–134)
PANSS PositiveSymptoms
Mean ± SD 29.00 ± 6.14
Median (range) 30 (11–40)
PANSS NegativeSymptoms
Mean ± SD 21.32 ± 7.39
Median (range) 21 (7–44)
PANSS General Psychopathology
Mean ± SD 32.66 ± 10.89
Median (range) 32 (13–60)
CGI-S
Mean ± SD 6.11 ± 0.69
Median (range) 6 (4.00–7.00)

PANSS, Positive and Negative Syndrome Scale; CGI-S, Clinical Global Impression–Severity scale
 Psychiatric Quarterly

Fig. 1 Box plot of the galectin-1 (GAL1) serum levels in patients with schizophrenia (Patient), their siblings
(Sibling) and healthy controls (Control)

control groups or between the control and sibling groups (p = 0.117 and p = 1.000, respec-
tively) (Fig. 2).
Table 3 summarizes the correlations between serum galectin levels and clinical variables.
Serum Gal-1 levels showed statistically significant negative correlations with the total PANSS
scores (ρ = −0.311; p = 0.013) and the negative PANSS scores(ρ = −0.321; p = 0.010). In
addition, serum Gal-3 level showed a significant positive correlation with the PANSS general
psychopathology score (ρ = 0.263; p = 0.037). No significant correlations were found between

Fig. 2 Box plot of the galectin-3(GAL3) serum levels in patients with schizophrenia (Patient), their siblings
(Sibling) and healthycontrols (Control)
Psychiatric Quarterly

serum galectin levels and CGI-S scores (Gal-1: ρ = 0.058, p = 0.652; Gal-3: ρ = −0.192, p =
0.131).
Across all three groups combined, there was a statistically significant positive correlation
between serum Gal-1 and Gal-3 levels (ρ = 0.359, p < 0.001). When the groups were consid-
ered individually, serum Gal-1 and Gal-3 levels showed significant correlationsonly in the
sibling and control groups (ρ = 0.517, p < 0.001 and ρ = 0.462, p < 0.001, respectively).
There were no statistically significant correlations between serum CRP and serum Gal-1 or
Gal-3 levels (Gal-1:ρ = 0.075, p = 0.561; Gal-3:ρ = 0.001, p = 0.991). In the patient group,
there were significant positive correlations between age and serum CRP levels (ρ = 0.345, p =
0.006),and between disease duration and serum CRP levels (ρ = 0.272, p = 0.031).

Discussion

The underlying mechanisms for the pathogenesis of schizophrenia remain unknown, but clues
to this have been provided by many different methods, including brain imaging, genetic tests,
and analyses of patient sera. One result of these investigations is that inflammatory processes
have been identified as a potential contributing factor to the etiology and pathogenesis of
schizophrenia [2, 30]. Several members of the galectin family expressed by CNS cells are
thought to be important modulators of CNS homeostasis and neuroinflammation (Chen 2014;
[27, 34]). Galectins act in signaling pathways to regulate microglial activation, reducing
neurodegeneration and promoting neuroprotection.
As an initial step in this issue, we measured serum Gal-1 and Gal-3 levels in patients with
schizophrenia and evaluated their associations with the clinical features of the disease. Given
that Gal-1 plays a neuroprotective role against the increased CNS inflammatory response in
schizophrenia, it would be expected that patients with schizophrenia would have higher levels
of Gal-1 than healthy controls. In this study, Gal-1 values were significantly higher in the
unaffected siblings compared to both the patient group and the healthy control group. It might
be supposed that the unaffected siblings had effective neuroprotective mechanisms against the
burden of genetic disease and that this may be provided by Gal-1. Gal-3 levels were also
elevated in the sibling group relative to the patient group; Gal-3 may therefore be acting as a
protective agent against the inflammation. Dong et al. evaluated the functional results of 233
patients who had suffered acute ischemic attacks for one year and reported that higher Gal-3
serum levels were associated with lower disease severity and better functional recovery [6]. In
a study of patients with Alzheimer’s disease, those with mild cognitive impairment, and
healthy controls, Wang et al. reported that Gal-3 levels were higher in the patients with

Table 3 Correlation coefficients between serum galectin levels and clinical variables

Galectin Duration of thedisease PANSS Scores

Gal-1 Positive Negative General Total

ρ 0.064 −0.157 −0.321 −0.164 −0.311

p 0.617 0.219 0.010* 0.198 0.013*
Gal-3
ρ −0.092 −0.207 −0.088 0.263 0.023
p 0.473 0.103 0.491 0.037* 0.861
 Psychiatric Quarterly

Alzheimer’s disease compared to the healthy controls, with a positive correlation between Gal-
3 levels and Mini-Mental State Examination scores [40].
Gal-1 and Gal-3 levels may be candidates as a biomarker in relatives of schizophrenia
patients of protection against the genetic burden and disease development. A previous study of
patients with schizophrenia reported a positive correlation between Gal-3 levels and positive
symptoms and a negative correlation with negative symptoms, whereas Gal-1 levels were not
associated with disease severity [15]. In contrast to those results, our studyshowed that the
severity of the disease decreased as Gal-1 levels increased and found no correlation between
Gal-3 levels and the severity of the disease. This finding expands the current knowledge about
Gal-1 and Gal-3 in schizophrenia. However, the available data are limited and further research
is needed before Gal-1 and Gal-3 levels can be used for predicting the course of the disease.
Given that levels of Gal-1 and Gal-3 increase as the inflammation persists, we evaluated
whether there was a difference in serum Gal-1 and Gal-3 levels between patients that had been
newly diagnosed and patients with a previous diagnosis. No difference was found between
these two groups, perhaps because of the limitednumber of newly diagnosed patients in this
study. A search of the literature found no studies that had evaluated the disease duration and
galectin levels in schizophrenia. The findings of the present study could be discussed in the
light of future studies.
A meta-analysis by Inoshita et al. examined the relationship between serum CRP levels and
schizophrenia, taking into account the effects of genetic variants associated with CRP levels,
and reported that serum CRP levels were significantly increased in patients with schizophrenia
compared to healthy controls [13](35). The reason for high CRP levels in the pathogenesis of
schizophrenia remains unclear. CRP has been reported to have proinflammatory effects, and
the paracellular permeability of the blood–brain barrier increases at elevated CRP levels [12].
Thus, chronic elevated CRP levels in disease development can affect blood–brain barrier
functions and cause neuroinflammation in the CNS. Elevated CRP levels may also affect
neurotransmitter synthesis and neurotransmission in the disrupted microvascular bed [9, 13,
18, 32]. Accordingly, inflammation and serum CRP values would be expected to increase with
age and disease duration. Consistent with this, the present studyfound that serum CRP levels
increased with age and disease duration; however, different results have previously been
reported. Interestingly, one study reported no relationship between CRP levels and age or
disease duration [14], whereas another study reported that CRP levels increased significantly
with age in patients with schizophrenia but that the age of onset did not affect CRP levels [5].
Several methodological differences between the studies may account for the inconsistent
results. For example, the measured CRP levels may be affected by the number of patients
included in the study, the selection of outpatients or inpatients, antipsychotic drug use, and the
metabolic status of the patients (such as BMI and cardiovascular risk factors). In particular,
several studies have reported that increased BMI was associated with increased CRP levels
[29, 36, 38]. For this reason, we investigated the relationship between BMI and CRP levels in
the patient group, showing a significant correlation. The prolongation of the disease duration
and the increase in CRP levels in patients with schizophrenia suggest that inflammatory
processes play a role in the etiopathogenesis of the disease.
This study had three main limitations. The first was that the sample size was relatively
small, and our findings may not be generalizable to broader communities of different races.
Second, CRP levels could not be measured for the healthy controls or the siblings group and so
could not be compared with the levels in the patient group. Third, the use of antipsychotic
drugs in the patient group, including the first episode, may have affected the results. In future
Psychiatric Quarterly

studies, comparison of galectin levels in drug-naive first-episode patients and patients with
chronic schizophrenia may provide more useful information about the etiopathogenesis of the
disease.

Conclusion

The role of Gal-1 and Gal-3 in schizophrenia is an important research topic. In this study, Gal-
1 and Gal-3 levels were found to be higher in the unaffected siblings of patients with
schizophrenia than in the patients themselves. The siblings would be expected to have genetic
susceptibility to schizophrenia, and the high galectin levels may have a protective role against
the neuroinflammatory process. A negative correlation was found between Gal-1 levels and
disease severity. After further studies, Gal-1, in particular, could be a potential prognostic
biomarker of the course of schizophrenia.

Compliance with Ethical Standards

Conflict of Interest The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards
of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later
amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.

Declaration of Interest No potential conflict of interest was reported by the authors.

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