Lithium decreases VEGF mRNA expression in leukocytes of healthy subjects and patients with bipolar disorder

Department of Psychiatry, Course of Integrated Brain Sciences, University of Tokushima School of Medicine, Tokushima, Japan
Human Psychopharmacology Clinical and Experimental (Impact Factor: 2.19). 06/2011; 26(4-5):358 - 363. DOI: 10.1002/hup.1215


Vascular endothelial growth factor (VEGF) is thought to be involved in the pathophysiology of mood disorders and the target of antidepressants. The aim of this study was to elucidate molecular effects of lithium on VEGF expression by using leukocytes of healthy subjects and patients with bipolar disorder.Methods
Eight healthy male subjects participated in the first study. Lithium was prescribed for 2 weeks, enough to reach therapeutic serum concentration. Leukocyte counts and serum lithium concentrations were determined at baseline, at 1- and 2-week medication, and at 2 weeks after stopping medication. VEGF mRNA levels were also examined in nine lithium-treated bipolar patients and healthy controls in the second study.ResultsIn the first study, leukocyte counts were significantly increased at 2 weeks compared with those at baseline and were normalized after 2 weeks. VEGF mRNA levels were significantly decreased at 2 weeks and after 2 weeks compared with those at baseline. Consistent with the first study, VEGF mRNA levels were significantly decreased in the lithium-treated bipolar patients compared with healthy controls.Conclusions
Our investigation suggests that VEGF mRNA expression may be useful as a peripheral marker of the effects of lithium. Copyright © 2011 John Wiley & Sons, Ltd.

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    • "Kikuchi et al. [69] identified the gene expression of VEGFA (vascular endothelial growth factor A) to be downregulated by lithium in BD subjects using whole blood RNA and qRT-PCR; this observation corroborates previous findings of reduced VEGFA expression in lymphoblastoid cell lines treated with lithium [70]. These studies focused on the drug effects of lithium on expression, while Lowthert and collaborators (2012) [71] investigated gene expression associated to lithium response by performing a peripheral gene expression study with 20 depressed BD patients treated with lithium for 8 weeks. "
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    ABSTRACT: Mood disorders and schizophrenia are common and complex disorders with consistent evidence of genetic and environmental influences on predisposition. It is generally believed that the consequences of disease, gene expression, and allelic heterogeneity may be partly the explanation for the variability observed in treatment response. Correspondingly, while effective treatments are available for some patients, approximately half of the patients fail to respond to current neuropsychiatric treatments. A number of peripheral gene expression studies have been conducted to understand these brain-based disorders and mechanisms of treatment response with the aim of identifying suitable biomarkers and perhaps subgroups of patients based upon molecular fingerprint. In this review, we summarize the results from blood-derived gene expression studies implemented with the aim of discovering biomarkers for treatment response and classification of disorders. We include data from a biomarker study conducted in first-episode subjects with schizophrenia, where the results provide insight into possible individual biological differences that predict antipsychotic response. It is concluded that, while peripheral studies of expression are generating valuable results in pathways involving immune regulation and response, larger studies are required which hopefully will lead to robust biomarkers for treatment response and perhaps underlying variations relevant to these complex disorders.
    Full-text · Article · Jul 2013 · Disease markers
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    • "Paroxetine appears to decrease VEGF mRNA levels in peripheral leukocytes of depressed patients (predominantly at their first episode) after 8-weeks treatment in significant correlation with clinical improvement (Iga et al., 2007), while escitalopram did not alter VEGF plasma levels in depressed patients (predominantly characterized by recurrent depressive episodes and a history of treatment with antidepressants) during 12-weeks of treatment (Ventriglia et al., 2009). Finally, VEGF levels appear to be increased by electroconvulsive therapy, haloperidol, olanzapine, sleep deprivation and lamotrigine; VEGF mRNA expression in leucocytes appear to be decreased by lithium (Elfving and Wegener, 2012; Ibrahim et al., 2011; Kikuchi et al., 2011; Minelli et al., 2011; Pillai and Mahadik, 2006; Segi-Nishida et al., 2008; Sun et al., 2011). "
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    ABSTRACT: The vascular endothelial growth factor (VEGF) signaling, which modulates angiogenesis and neurogenesis within the neurovascular unit, might play an important role in the neuro-endocrine-immune (NEI) stress-adaptation system. Recent evidence suggests that VEGF is involved in the pathophysiology of a number of diseases including major depressive disorder (MDD) and is affected by some treatments, including antidepressants. The objective of the study was to investigate the VEGF level variations in MDD patients during antidepressant treatment with duloxetine, a relatively new SNRI. A total of 30 MDD patients and 32 healthy controls were assessed using the Hamilton Depression Scale (HAM-D) and monitored for VEGF plasma levels at baseline, week 6 and week 12 of duloxetine treatment (60mg/day) and at baseline, respectively. According to early clinical response to duloxetine (defined at week 6 by reduction>50% of baseline HAM-D score), the MDD patients were divided into early responders (ER) and early non-responders (ENR). During duloxetine treatment, we found an opposite trend in the VEGF levels between ER and ENR: in ER the VEGF levels significantly increased in association with clinical response at W6, while in ENR the VEGF levels significantly decreased in association with an overall clinical response at W12. Small sample size. The opposite trends in VEGF levels, increasing in ER and decreasing in ENR, might reflect differential Norepinephrine/Serotonin effects of duloxetine on differential neurobiological backgrounds of depressive syndromes. Overall, the modulation of VEGF signaling within the neurovascular unit during antidepressant treatment could hypothetically favor the remodeling of neural circuitry, contributing to adaptive adjustment of the NEI stress-adaptation system.
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    ABSTRACT: The capacity of lithium to induce neutrophilia and increase circulating CD34(+) cells of marrow origin has long been known. Lithium has been the object of hematological investigations for many years, but no definitive use in hematology has yet emerged. We review the evidence that lithium increases granulocyte colony-stimulating factor (G-CSF) and augments G-CSF effects, showing its potential use in stem cell mobilization and engraftment of stem cell transplantation. We suggest possible therapeutic uses of lithium in neutropenia. In bone marrow transplantation, preharvest lithium-assisted hematopoietic stem cell mobilization may be useful as well.
    No preview · Article · Nov 2011 · Current opinion in hematology
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