Letters to Editor
Psychiatria Danubina, 2023; Vol. 35, No. 1, pp 136-140

some of these problems were tackled with changes in the new
training program starting from 2014, it seems that there is still ahigh level of dissatisfaction with academic opportunities.
Migration tendencies of junior psychiatrists in Croatia
present a worrying trend that could negatively impact theperformance of the healthcare system in Croatia. Taking into
account the overall decline of recruitment of psychiatry
trainees and positive migration trend towards high income
countries, it seems necessary to implement strategies toprevent brain drain, such as improvement of educational andprofessional opportunities followed with adequate financial
income (Andlauer et al. 2012, Nawka et al. 2015). As seen in
the recent COVID-19 pandemic, stable and functioning
medical system is of utmost importance. Our study provides
important data which could be used by medical stakeholders
to retain junior doctors in order to sustain quality of medical
service in Croatia. Existing shortage of healthcare personnel,
accompanied by increasing emigration tendencies of the juniordoctors who were to be the system's backbone in the future,might lead to insufficient service capabilities. Psychiatricpatients are already considered as a group with unmet service
needs whose unfavorable position could further decline with therise of the new global mental health challenges associated with
the COVID-19 pandemics (Moreno et al. 2020).

Acknowledgments:
The authors would like to thank the European Federation of
Psychiatric Trainees (EFPT) for their support to this research
project.

Conflict of interest: None to declare.

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DULOXETINE DOES NOT AFFECTVASCULAR ENDOTHELIAL GROWTH
FACTOR PLASMA LEVELS IN PATIENTSWITH FIRST-EPISODE, DRUG-NAÏVE
MAJOR DEPRESSION
Reiji Yoshimura1*, Naomichi Okamoto1 & Atsuko
Ikenouchi1,21Department of Psychiatry, School of Medicine, University ofOccupational and Environmental Health, Kitakyushu, Fukuoka,Japan, yoshi621@med.uoeh-u.ac.jp
2Medical Center for Dementia, University Hospital, University ofOccupational and Environmental Health, Kitakyushu, Fukuoka, Japan* correspondence author* * * * *Dear editor,According to the neurotrophic hypothesis of major depression (MD), impairment in growth factor signaling may beassociated with the pathology of this disorder. Current evidence demonstrates that impaired neuroplasticity induced byalterations in neurotrophic growth factors and related signaling
pathways may be underlying to the pathophysiology of MD(Boku et al. 2018). Stress induces alterations in the neuroplastic pathways in the emotional and cognitive processing
areas of the brain, leading to reduced neurogenesis and hippocampal volume, and predisposing an individual to depression.
A key factor in the neuroplastic pathways is the vascularendothelial growth factor (VEGF), which is known to possess
strong neurogenic effects. VEGF was first presented as aninducer of vascular permeability, but the understanding of its
actions has broadened to include stimulation of angiogenesis
and acetogenesis, and promotion of neurogenesis and neuroprotective mechanisms (Storkebaum et al. 2004). Novel
VEGF-related associations identified by MD genome-wide association studies (GWAS) suggest a role for this molecule in
MD development. This could help to promote personalized
medicine (Xie et al. 2017). We previously reported a genotype-diagnosis interaction for GWAS single nucleotide polymorphism (SNP) rs6921438 (G/G versus GA/AA genotype) in
the subiculum of the left hippocampus, but not for rs4416670,rs6993770, or rs10738760 (Nguyen et al. 2019).
Recent reports show that VEGF plays a crucial role in thepathogenesis of MD by increasing blood-brain barrier (BBB)
permeability, indicating that VEGF inhibition is a potential
therapeutic strategy for the MD subtype associated with BBB
dysfunction (Matsumoto et al. 2022). Our previous researchdemonstrated that neither paroxetine, a selective serotonin
reuptake inhibitor (SSRI), nor milnacipran, a serotonin andnoradrenaline reuptake inhibitor (SNRI), changed plasma VEGF
levels in patients with MD (Yoshimura et al. 2022). The present
study aimed to investigate the effect of duloxetine on plasma
VEGF levels in patients with first-episode, drug-naïve MD.
Twenty-eight patients who met MD criteria according to theDiagnostic and Statistical Manual of Mental Disorders 5 (DSM5) (American Psychiatric Association, 2013) were enrolled inthis study (age 47.5±13.1 years; male/female 14/14). Additionally, 20 age-, and sex-matched healthy control (HC) patients

139

Letters to Editor
Psychiatria Danubina, 2023; Vol. 35, No. 1, pp 136-140

Table 1. Difference of plasma VEGF between R- and NR- groupRNRPlasma VEGF (W4-W0) pg/ml-0.01±1.71
0.44 ±1.49(age 42.3±10.0 years; male/female 12/8) were enrolled. Patients were treated for four weeks using SNRI duloxetine. Themaximum dose of duloxetine at week 4 was 43.5±14.1 mg/day.
Depressive symptoms were evaluated pre- and post-treatmentusing the 17-item Hamilton Rating Scale for Depression (HAMD) (Hamilton 1960). Blood was drawn at 9:00 a.m.
Plasma VEGF levels were measured using a Quantikine®
HS Human IL-6 Immunoassay kit (R&D Systems, Minneapolis, USA). Plasma levels were analyzed in duplicate, andmean values were calculated for each data point. Plasma
level differences were determined for i) MD versus HC groupsat baseline, ii) MD patients at baseline versus at week 4, andiii) responder (RG; 50% or greater decrease in HAM-D score)versus non-responder (NR) groups.
This study was approved by the ethics committee of theUniversity of Occupational and Environmental Health, andwritten informed consent was obtained from all the participants.
HAM-D scores significantly decreased in the MD group after
duloxetine treatment (week 0, 25.4±3.0; week 4, 13.2±4.6;
p<0.001, paired t-test). No difference was found in baseline
plasma VEGF levels between the MD and HC groups (MD,18.3±3.1 pg/ml, HC, 18.3±2.7 pg/ml, p=0.89, multiple regression analysis). In the MD group, VEGF plasma levels were notsignificantly altered four weeks after duloxetine treatment (week0, 18.3±3.1 pg/ml; week 4, 18.6±3.5 pg/ml; p=0.41, paired ttest). Furthermore, no correlation was found between plasma
VEGF levels and HAM-D score changes (rho = -0.06, p=0.74,
Spearman rank correlation coefficient). Table 1 shows theanalysis of R group and NR groups. No difference was foundin plasma VEGF levels between these two groups.
The results of the present study showed that treatment withduloxetine for four weeks did not change plasma VEGF levels
and that plasma VEGF levels were not associated with theclinical response to duloxetine. Fornaro et al. (2013) reported
no significant difference in VEGF plasma levels compared tothose in health controls, whereas VEGF levels significantly
increased with clinical response to duloxetine in early
responders at week 6.

140p-value
0.46

Adjusted p-value
0.65

Acknowledgments: None.
Conflict of interest: None to declare.

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3.

4.
5.

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