Monika Talarowska

Nitric oxide plasma concentration associated with cognitive impairment in patients with recurrent depressive disorder

BACKGROUND/AIM Depressive disorders are multifactorial diseases, in which cognitive impairment is one of the characteristic feature. One of the molecules that regulate of various cognitive, emotional and behavioural processes is nitric oxide (NO), synthesized from l-arginine by a family of isoformic enzymes known as nitric oxide synthases (NOS). NO is a gaseous compounds that acts as a biological second messenger in a number of organ system. In addition, NO is a ubiquitous free radical (NO) that affects many normal physiologic functions but is also implicated in the etiology and progression of many diseases. The aim of the study was to determine the concentration of NO in patients with recurrent depressive disorder (rDD) and to define relationship between plasma NO levels and the cognitive performance. METHODS The study comprised 78 subjects: patients with rDD (n=45), healthy controls (CG, n=33). Cognitive function assessment was based on: TMT, The Stroop Test, VFT, AVLT. RESULTS Statistically significant differences were found among patients with rDD in the intensity of depression symptoms, measured by the HDRS on therapy onset vs. the examination results after 8 weeks of treatment (p<0.001). The level of NO was substantially higher in patients with rDD compared to CG. For all examined subjects (p<0.001), elevated levels of NO in blood plasma adversely affect the efficiency of visual-spatial and auditory-verbal working memory as well as short-term declarative memory. For rDD patients, elevated NO levels were associated with worse cognitive test performance. The higher was the concentration of plasma NO, the greater was the severity of depressive symptoms measured by HDRS (p=0.03). CONCLUSIONS (1) Higher concentration of plasma NO in rDD patients is associated with the severity of depressive symptoms. (2) Elevated levels of plasma NO are related to impairment of visual-spatial and auditory-verbal working memory as well as to impairment of short-term declarative memory.

Mechanisms Underlying Neurocognitive Dysfunctions in Recurrent Major Depression

Recent work shows that depression is intimately associated with changes in cognitive functioning, including memory, attention, verbal fluency, and other aspects of higher-order cognitive processing. Changes in cognitive functioning are more likely to occur when depressive episodes are recurrent and to abate to some degree during periods of remission. However, with accumulating frequency and duration of depressive episodes, cognitive deficits can become enduring, being evident even when mood improves. Such changes in cognitive functioning give depression links to mild cognitive impairment and thereby with neurodegenerative conditions, including Alzheimer’s disease, Parkinson’s disease, schizophrenia, and multiple sclerosis. Depression may then be conceptualized on a dimension of depression – mild cognitive impairment – dementia. The biological underpinnings of depression have substantial overlaps with those of neurodegenerative conditions, including reduced neurogenesis, increased apoptosis, reactive oxygen species, tryptophan catabolites, autoimmunity, and immune-inflammatory processes, as well as decreased antioxidant defenses. These evolving changes over the course of depressive episodes drive the association of depression with neurodegenerative conditions. As such, the changes in cognitive functioning in depression have important consequences for the treatment of depression and in reconceptualizing the role of depression in wider neuroprogressive conditions. Here we review the data on changes in cognitive functioning in recurrent major depression and their association with other central conditions.

Elevated Level of DNA Damage and Impaired Repair of Oxidative DNA Damage in Patients with Recurrent Depressive Disorder

Background Depressive disorder (DD), including recurrent DD (rDD), is a severe psychological disease, which affects a large percentage of the world population. Although pathogenesis of the disease is not known, a growing body of evidence shows that inflammation together with oxidative stress may contribute to development of DD. Since reactive oxygen species produced during stress may damage DNA, we wanted to evaluate the extent of DNA damage and efficiency of DNA repair in patients with depression. Material/Methods We measured and compared the extent of endogenous DNA damage – single- and double-strand breaks, alkali-labile sites, and oxidative damage of the pyrimidines and purines – in peripheral blood mononuclear cells isolated from rDD patients (n=40) and healthy controls (n=46) using comet assay. We also measured DNA damage evoked by hydrogen peroxide and monitored changes in DNA damage during repair incubation. Results We found an increased number DNA breaks, alkali-labile sites, and oxidative modification of DNA bases in the patients compared to the controls. Exposure to hydrogen peroxide evoked the same increased damage in both groups. Examination of the repair kinetics of both groups revealed that the lesions were more efficiently repaired in the controls than in the patients. Conclusions For the first time we showed that patients with depression, compared with non-depresses individuals, had more DNA breaks, alkali-labile sites, and oxidative DNA damage, and that those lesions may be accumulated by impairments of the DNA repair systems. More studies must be conducted to elucidate the role of DNA damage and repair in depression.

Auditory-verbal declarative and operating memory among patients suffering from depressive disorders - preliminary study.

PURPOSE Dysfunctions of auditory-verbal declarative and working memory are observed in patients with depressive disorders (DD). The authors wanted to see, whether antidepressive therapy improved the efficiency of cognitive processes among patients suffering from DD and determine possible associations between auditory-verbal declarative and working memory performance, evaluated before treatment vs. remission degree after treatment. MATERIAL AND METHODS The study was carried out in 87 subjects, patients with depressive disorders (n=30, DD) and healthy subjects (n=57, CG, control group). The AVLT (Auditory Verbal Learning Test) and the Stroop Test were used. RESULTS CG obtained higher results vs. DD-I (the evaluation started on the therapy onset) in the Stroop Test-RCNb (Reading Colour Names in Black)/time, NCWd (Naming Colour of Word - Different)/time, NCWd/errors, AVLT: the number of words after 30 minutes. CG demonstrated higher results than DD-II (following eight weeks of pharmacological treatment) in RCNb/time, NCWd/time, AVLT: the number of words in the first trial, the number of words after 30 minutes. Compared to DD-I, DD-II achieved better results in NCWd/errors. No statistically significant differences were observed in both tests between the patients with remission and without remission. Statistical analysis revealed the lack of significant dependences among HDRS after treatment and cognitive functions before treatment. CONCLUSIONS Depressive disorders are associated with deteriorated efficiency of auditory-verbal declarative and working memory. No improvement was observed in the efficiency of auditory-verbal declarative or working memory after 8-week therapy. The performance level of cognitive processes before pharmacotherapy has no effect on the intensity of depression symptoms after therapy.

Impact of oxidative/nitrosative stress and inflammation on cognitive functions in patients with recurrent depressive disorders.

Data show that up to 38.2% of the European population have a mental disorder and that recurrent depressive disorder (rDD) is among the most commonly diagnosed disabling diseases. Over the last few years, neurocognitive impairments in rDD have become a new research front focusing on the role of cognitive decline during the course of rDD and in relation to its clinical presentation and prognosis. Both immune-inflammatory and oxidative and nitrosative stress (O&NS) processes potentially play a role in development of cognitive dysfunction in rDD. New evidence shows that chronic inflammatory and O&NS reactions occur in the brains of patients with neurodegenerative disorders and those with rDD. This narrative review presents the current state of knowledge on the possible impact of selected inflammatory and O&NS enzymes on cognitive functioning in patients with rDD. We focus on manganese superoxide dismutase (MnSOD), inducible nitric oxide synthase (iNOS), and myeloperoxidase (MPO).

Normalization of the Verbal Fluency Test on the basis of results for healthy subjects, patients with schizophrenia, patients with organic lesions of the chronic nervous system and patients with type 1 and 2 diabetes

Introduction Verbal fluency is the ability to form and express words compatible with required criteria. Verbal fluency is necessary for optimal communication and for normal social and occupational functioning. The Verbal Fluency Test is a good indicator of frontal lobe dysfunction, particularly of the left frontal cortex. Material and methods The aim of the study was to compare verbal fluency in healthy subjects (n = 50), patients with paranoid schizophrenia (n = 36), patients with organic lesions of the central nervous system (CNS) (n = 33), and patients with diabetes (n = 62) – type 1 diabetes (n = 31) and type 2 diabetes (n = 31). Results Healthy subjects and patients with diabetes achieved the highest results in all categories of the Verbal Fluency Test. Patients with paranoid schizophrenia achieved significantly lower results. Sten norms of the Verbal Fluency Test were developed for the general population. Using these norms it was found that subjects with schizophrenia or with organic lesions of the CNS had very poor results more often and very high results less frequently compared to healthy subjects and also to patients with diabetes. Conclusions This observation is consistent with the neurodevelopmental hypothesis of schizophrenia, in which cognitive functions of the frontal lobe (e.g. verbal fluency) play a major role in the psychopathological picture. We have also demonstrated that in patients with type 1 and 2 diabetes verbal fluency is comparable with healthy subjects.

Depression and ways of coping with stress: A preliminary study

Background Coping with stress is defined as all activities undertaken by a human in a stressful situation. The effect of stress on depression, its role in triggering the subsequent phases of the disease, and the factors that mediate the stress-depression relationship become more and more often subjects of research in psychiatry and psychology. Factors important for the formation of depressive symptoms and disease progression are significantly associated with coping strategies used in the face of stress. The main aim of the study was to evaluate the most popular strategies of coping with stress in people with depression in comparison to healthy subjects. Material/Methods Initial research was carried on 80 patients aged from 20 to 66 years with a diagnosis of depression. The control group consisted of 30 healthy subjects aged 22 to 57 years. Analysis of the most popular strategies of coping with stress was performed with the Multiphasic Inventory for Measuring Coping (COPE) by Carver, Scheier, and Weintraub. Results In contrast with healthy people, patients with depression in stressful situations more often use strategies based on avoidance and denial and have more difficulties in finding positive aspects of stressful events. Conclusions Depression may be an important factor in the negative assessment of one’s own ability to cope with difficult situations and can aggravate a tendency to perceive stressful events as overwhelming.

Impaired Recognition of Communicative Interactions from Biological Motion in Schizophrenia

Background Patients with schizophrenia are deficient in multiple aspects of social cognition, including biological motion perception. In the present study we investigated the ability to read social information from point-light stimuli in schizophrenia. Methodology/Principal Findings Participants with paranoid schizophrenia and healthy controls were presented with a biological motion task depicting point-light actions of two agents either engaged in a communicative interaction, or acting independently of each other. For each stimulus, participants were asked to decide whether the two agents were communicating vs. acting independently of each other (task A), and to select the correct action description among five response alternatives (task B). Participants were also presented with a mental rotation task to assess their visuospatial abilities, and with a facial emotion recognition task tapping social cognition. Results revealed that participants with schizophrenia performed overall worse than controls both in discriminating communicative from non-communicative actions (task A) and in selecting which of the 5 response alternatives best described the observed actions (task B). Interestingly, the impaired performance of schizophrenic participants was mainly due to misclassification of non-communicative stimuli as communicative actions. Correlation analysis revealed that visuospatial abilities predicted performance in task A but not in task B, while facial emotion recognition abilities was correlated with performance in both task A and task B. Conclusions/Significance These findings are consistent with theories of “overmentalizing” (excessive attribution of intentionality) in schizophrenia, and suggest that processing social information from biological motion does rely on social cognition abilities.

Vascular endothelial growth factor gene (VEGFA) polymorphisms may serve as prognostic factors for recurrent depressive disorder development.

Recurrent depressive disorder (rDD) is a multifactorial disease. Vascular endothelial growth factor (VEGF) is one of the factors that have been suggested to play a role in the etiology and/or development of this disease. Limited information related to the role of VEGFA gene polymorphism in depressive disorder is available. The aim of the study was to analyze the association between VEGFA gene polymorphisms (+405G/C; rs2010963, +936C/T; rs 3025039), VEGFA gene expression, and its serum protein levels in rDD in the Caucasian population. In the current study, 268 patients and 200 healthy controls of the Caucasian origin were involved. Genotyping and gene expression were performed using polymerase chain reaction (PCR)-based methods. Enzyme-linked immunosorbent assay (ELISA) was used for detection of circulating serum VEGF levels. The distribution of VEGFA polymorphism +405G/C differed significantly between rDD patients and healthy subjects. The results of this study indicated that the C allele and CC genotype of VEGFA are risk factors for rDD. Haplotypes CC and TG are the important factors for depression development. Further, VEGFA mRNA expression and VEGF levels were higher in rDD patients than in controls. The VEGFA gene polymorphism may serve as a prognostic factor for rDD development. Our study showed higher levels of both VEGFA mRNA in the peripheral blood cells and serum VEGF in patients diagnosed with rDD than in healthy controls. The obtained results suggest VEGF and the gene encoding the molecule play a role in the etiology of the disease and should be further investigated.

Association between single nucleotide polymorphisms of MUTYH, hOGG1 and NEIL1 genes, and depression

BACKGROUND An elevated levels oxidative modified DNA bases and a decreased efficiency of oxidative DNA damage repair were found in patients with depression disorders, including recurrent type (rDD). The glycosylases are involved in base excision repair (BER), which eliminates oxidative DNA damage. Therefore, we genotyped the single nucleotide polymorphisms (SNPs) of genes encoding three glycosylases: hOGG1, MUTYH and NEIL1. METHODS We selected three polymorphisms: c.977C > G - hOGG1 (rs1052133), c.972G > C - MUTYH (rs3219489) and c.*589G > C - NEIL1 (rs4462560). A total of 555 DNA samples (257 cases and 298 controls) were genotyped using TaqMan probes. RESULTS The C/C genotype and allele C of the c.*589G > C decreased the risk of rDD occurrence, while the G/G genotype and allele G of the same SNP increased the risk. This polymorphism had a stronger association with early-onset depression (patients with first episode <35 years of age) than with late-onset depression (first episode ≥ 35 years of age). We did not find any significant differences in distribution of alleles and genotypes of other SNPs; however, the G/G genotype of the c.972G > C increased the risk of late-onset rDD. We also found that combined genotype C/C-C/C of c.977C > G and c.*589G > C significantly reduced the risk of rDD. LIMITATIONS Limited sample size and ethnic homogeneity of the studied population. CONCLUSION This is the first study to show that SNPs of genes involved in DNA repair, particularly in BER pathway, may modulate the risk of rDD. These results further support the hypothesis on the involvement of DNA repair mechanisms in pathogenesis of depression.