Association of Polymorphic Variants in Argonaute Genes with Depression Risk in a Polish Population.

Argonaute (AGO) proteins, through their key role in the regulation of gene expression, participate in many biological processes, including cell differentiation, proliferation, death and DNA repair. Accurate regulation of gene expression appears to be important for the proper development of complex neural circuits. Loss of AGO proteins is known to lead to early embryonic mortality in mice with various malformations, including anomalies of the central nervous system. Single-nucleotide polymorphisms (SNPs) of AGO genes can lead to deregulation of the processes in which AGO proteins are involved. The contribution of different SNPs in depression has been extensively studied. However, there are hardly any studies on the contribution of AGO genes. The aim of our research was to assess the relationship between the occurrence of depression and the presence of SNPs in genes AGO1 (rs636882) and AGO2 (rs4961280; rs2292779; rs2977490) in a Polish population. One hundred and one subjects in the study group were diagnosed with recurrent depressive disorder by a psychiatrist. The control group comprised 117 healthy subjects. Study participants performed the HDRS (Hamilton Depression Scale) test to confirm or exclude depression and assess severity. The frequency of polymorphic variants of genes AGO1 (rs636882) and AGO2 (rs4961280; rs2292779; rs2977490) was determined using TaqMan SNP genotyping assays and the TaqMan universal PCR master mix, no AmpErase UNG. The rs4961280/AGO2 polymorphism was associated with a decrease in depression occurrence in the codominant (OR = 0.51, p = 0.034), dominant (OR = 0.49, p = 0.01), and overdominant (OR = 0.58, p = 0.049) models. Based on the obtained results, we found that the studied patients demonstrated a lower risk of depression with the presence of the polymorphic variant of the rs4961280/AGO2 gene-genotype C/A and C/A-A/A.

Preliminary Study of the Impact of Single-Nucleotide Polymorphisms of IL-1α, IL-1ß and TNF-α Genes on the Occurrence, Severity and Treatment Effectiveness of the Major Depressive Disorder.

The purpose of the preliminary study was to determine whether the occurrence of certain SNPs of genes encoding IL-1α, IL-1ß, and TNF-α is associated with the development of depression. Five polymorphisms were selected: i.e. c.-1560G > C-IL-1ß (rs1143623), c. -118 C > T-IL-1ß (rs1143627), c.340G > T-IL-1α (rs17561), c.-1211T > C-TNF-α (rs1799964) and c.-488G > A-TNF-α (rs1800629). These were analyzed using TaqMan probes. The genotypes of the analyzed polymorphisms were found to be associated with disease severity and may affect the effectiveness of antidepressant therapy. In addition, the gene-gene analysis confirmed that combined genotypes of investigated SNPs may modulate the risk of depression.

Interleukin 1 level, cognitive performance, and severity of depressive symptoms in patients treated with systemic anticancer therapy: a prospective study.

AIM: To assess the relationship between cognitive functions, severity of depressive symptoms, and expression of interleukin 1 (IL)-1 in patients treated with systemic anticancer therapy. METHODS: This prospective study, conducted in 2017-2018, involved 55 patients (56% men) subjected to systemic anticancer therapy. Forty-one patients had lung cancer (74.55%) and 14 had breast cancer (25.45%). Patients' mean age was 55.5±9.3 (from 26 to 65 years). Neuropsychological tests were conducted twice: on the day of qualifying for the study before the start of chemotherapy and after the end of the full treatment cycle. We assessed patients' cognitive functioning using Trail Making Test A&B (TMT), Stroop Color-Word Interference Test, and Verbal Fluency Test (VFT). Severity of depressive symptoms and the level of IL-1 expression were also examined. RESULTS: After chemotherapy, patients had significantly lower expression of IL-1α (P<0.005) and IL-1ß (P<0.001) at the protein level. They also had lower severity of depressive symptoms (borderline significant, P=0.063), needed more time to complete the first part of the Stroop test (P=0.03), and had worse score on the first part of the VFT (P<0.001). Before chemotherapy there was a significant negative correlation between IL-1ß expression and the speed at which the first part of the TMT test was completed. CONCLUSIONS: The severity of depressive symptoms after chemotherapy was lower than before chemotherapy. Patients' cognitive performance did not significantly deteriorate after chemotherapy, except the performance at the first part of the Stroop test and the first part of the VFT.

Expression of SIR1-SIR7 genes in the course of recurrent depressive disorders.

BACKGROUND: The role of sirtuins as a pathogenetic element of some mental disorders is becoming increasingly more common. They participate in many cellular processes, such as ageing, transcription, apoptosis, inflammatory processes, post-translational modification of proteins, gene transcription silencing, activation of DNA repair mechanisms, and regulation of many metabolic processes. The aim of this paper is to verify the statistical hypothesis assuming the difference in expression at the level of mRNA in genes for sirtuins 1-7 between patients with recurrent depressive disorders (rDD) and patients from the control group, and the hypothesis assuming the relation between the expression at the level of mRNA for these genes and clinical variables in the course of recurrent depressive disorders. SUBJECTS AND METHODS: A total of 198 individuals took part in the study (rDD gropup, N=99; control group, N=99). RESULTS: SIR-1 and SIR-6 expression at the mRNA level was significantly higher among the people with rDD as compared to the subjects from the control group. A reversed relationship was observed for SIR-2, SIR-3, SIR-4 and SIR-5. Statistically significant correlations were observed only in the case of SIR-1 and the number of depression episodes (negative relationship), as well as SIR-5 and the severity of depression measured by the Hamilton Depression Rating Scale (positive relationship). CONCLUSIONS: Expression at the mRNA level for selected sirtuins is a factor that significantly differentiates people with depressive episodes from healthy ones. SIR-1 and SIR-6 expression at the mRNA level was significantly higher among the people with depression as compared to the subjects from the control group. A reversed relationship (also statistically significant) was observed for SIR-2, SIR-3, SIR-4 and SIR-5.

Expression of ESR1 and ESR2 oestrogen receptor encoding gene and personality traits - preliminary study.

INTRODUCTION: The main objective of the study is to examine the hypothesis claiming a correlation between personality traits measured with the use of the Minnesota Multiphasic Personality Inventory (MMPI-2) personality questionnaire and the expression of the ERα (ESR1) and ERß (ESR2) encoding gene in patients suffering from depression. MATERIAL AND METHODS: The experiment was carried out on a group of 44 individuals with depression. The Polish variant of the MMPI-2 was applied with the aim of assessing personality traits. Furthermore, the authors evaluated the expression of the genes encoding the oestrogen receptors (ERα and ERß) at the mRNA level and protein level in the studied population. RESULTS: No significant differences in the expression of ERα and ERß encoding genes were found and confirmed in the patients with the first episode of depression and those suffering from subsequent episodes of the disease. No differences were found between women and men, either. In women a positive relationship was found between the scale of psychopathy (p = 0.04), paranoia (p = 0.01), and mania (p = 0.03) and expression for the ERα encoding gene at the mRNA level. A negative relationship was found between the mania scale and ERß encoding gene expression at mRNA (p = 0.03) and protein (p = 0.04) levels. In males a positive relationship between anxiety as a personality trait and expression of the ERß receptor encoding gene at mRNA level (p = 0.03) and protein level (p = 0.03) was found. CONCLUSIONS: Personality traits may be linked with the expression of genes encoding oestrogen receptors (ERα and ERß) among patients with depressive disorders.

Association between single nucleotide polymorphisms of TPH1 and TPH2 genes, and depressive disorders.

Tryptophan catabolites pathway disorders are observed in patients with depression. Moreover, single nucleotide polymorphisms of tryptophan hydroxylase genes may modulate the risk of depression occurrence. The objective of our study was to confirm the association between the presence of polymorphic variants of TPH1 and TPH2 genes, and the development of depressive disorders. Six polymorphisms were selected: c.804-7C>A (rs10488682), c.-1668T>A (rs623580), c.803+221C>A (rs1800532), c.-173A>T (rs1799913)-TPH1, c.-1449C>A (rs7963803), and c.-844G>T (rs4570625)-TPH2. A total of 510 DNA samples (230 controls and 280 patients) were genotyped using TaqMan probes. Among the studied polymoorphisms, the G/G genotype and G allele of c.804-7C>A-TPH1, the T/T homozygote of c.803+221C>A-TPH1, the A/A genotype and A allele of c.1668T>A-TPH1, the G/G homozygote and G allele of c.-844G>T-TPH2, and the C/A heterozygote and A allele of c.-1449C>A-TPH2 were associated with the occurrence of depression. However, the T/T homozygote of c.-1668T>A-TPH1, the G/T heterozygote and T allele of c.-844G>T-TPH2, and the C/C homozygote and C allele of c.-1449C>A-TPH2 decreased the risk of development of depressive disorders. Each of the studied polymorphisms modulated the risk of depression for selected genotypes and alleles. These results support the hypothesis regarding the involvement of the pathway in the pathogenesis of depression.

Birth Month and Course of Recurrent Depressive Disorders in a Polish Population.

BACKGROUND The aim of this study was to determine whether the specific season of the year during which the first trimester of pregnancy takes place is significantly associated with the course (intensification and frequency of occurrence) of an episode of recurrent depressive disorder in adult life. MATERIAL AND METHODS We enrolled 184 patients treated for recurrent depressive disorders. RESULTS An analysis of the results obtained indicates that the greatest number of people suffering from a major depressive episode were born in the spring and summer (from April to September), meaning that the first trimester of pregnancy occurred between October and March. However, our results were not statistically significant, perhaps due to the small size of the examined group. CONCLUSIONS The results obtained indicate that birth month may be significantly associated with the course of recurrent depressive disorders. In patients from Central Europe, the first trimester of pregnancy falling in autumn and winter seems to be significant. These results need to be interpreted with caution due to the small size of the examined group.

[The importance of the kynurenine pathway in depressive disorders]. / Znaczenie szlaku kynureninowego w zaburzeniach depresyjnych.

Depressive disorders are the most frequently diagnosed mental disorder. It is assumed that the etiology of depression is multifactorial and the individual theories complement each other. Referring to the neurochemical hypothesis of the underlying depressive disorder, the relationship between lowering levels of serotonin, norepinephrine, dopamine and a change in mood is suggested. Particular attention has been given to serotonin, called the happiness hormone, which is synthesized from the exogenous amino acid tryptophan. The main methods of antidepressant treatment, in particular the use of serotonin reuptake inhibitors (SSRIs), take into account the concept of monoamine deficiency in patients with depression. However, an insufficient response in some patients to antidepressants (the existence of a refractory depression), indicates the importance of looking for other possible causes for the development of this disease and thus alternative treatment methods. It is indicated that in patients with depression there are disorders of tryptophan metabolism, ie the redirection of tryptophan from the serotonin synthesis pathway to the kynurenine pathway, which is the source of neuroactive compounds in the central nervous system, so-called. kynurenin m.in. kynurenic acid, 3-hydroxycinurenine, quinoline acid. It has been proved that certain metabolites of this cycle of transformations have neuroprotective and other neurotoxic properties. For this reason, it seems reasonable to summarize the research published so far on this subject.

[The emotional intelligence in major depressive disorders]. / Inteligencja emocjonalna w zaburzeniach depresyjnych nawracajacych.

The term emotional intelligence was introduced by Salovey & Mayer. It is the individual's ability to perceive, evaluate and express emotions. It is also a set of abilities which enable an individual to function effectively and they are an important factor affecting the quality of life. The literature also has a synonymous concept of emotional competence which is a collection of already acquired skills used in specific social situations. Major depressive disorder represents an affective disorder having an impact on a human being's ability to regulate emotions. In their course, there are difficulties with adequate recognition of one's emotional states as well as emotional states of other people. Research indicates, among others, the relationship between emotional intelligence and the occurrence of suicidal thoughts and tendencies, prognosis of therapeutic interactions in patients. A high level of emotional intelligence is a protective factor in the occurrence of mental disorders, including depression, affects the treatment process and influences the creation of effective strategies for coping with stress. The paper presents reports on the level of emotional intelligence and its impact on the functioning of patients with major depressive disorders.

[The level of experienced stress and personality traits in health professionals - the Polish study]. / Poziom odczuwanego stresu a cechy osobowosci u pracowników sluzby zdrowia ­ badania polskie.

Among professions of social services the highest level of stress is connected with health care and saving lives. This work demands making decisions, rapid changes, coordination of unforeseen requirements, moreover abounds in critical situations. One of the important factors affecting an ability of managing stressful situations are personality traits. AIM: The aim of this study was to verify hypothesis if there is a connection between personality traits (extraversion, neuroticism, psychoticism) and level of perceived stress among health care workers. MATERIALS AND METHODS: 180 participants of training (Certificated Partner of the Mental Health Center conducted in Poland) were selected to the analysis: psychologists, paramedics, nureses and doctors. Research was conducted using the Perceived Stress Scale (PSS-10) and Eysenck Personality Questionnaire (EPQ-R). RESULTS: Statistically significant corellation was observed in relation to subjectively experienced tension and results in scale of Psychoticism and Neuroticism (positive relationship). In case of extraversion scale corellation has negative character, but is not statistically important. CONCLUSIONS: Neuroticism as a state feature of character dominate among helath care workers. Both neuroticism and psychoticism conduce to negative effects of experienced stress.

The Evolutionary Theory of Depression.

The evolutionary success of Homo sapiens is attributed to the following two factors: the upright body posture (which freed our hands and allowed unconstrained operation of various objects) and intensive development of the frontal lobes, mainly the Broca area of the brain. Underlining the uniqueness of the human brain, we often forget about the fact that the frontal lobes - the most developed part of the brain - are at the same time our greatest weakness, exposed to the action of damaging factors in our evolving environment. Is depression the cost of evolution?

Human neuropsin gene in depression.

BACKGROUND: Neuropsin (NP, kallikrein 8, KLK8) - a kallikrein gene-related (KLK) endoprotease - plays a key role in neuroplasticity processes, since intracellular signal cascades and regulation of gene expression are engaged in long-term synaptic plasticity. The main aim of this paper is to compare expression of the human neuropsin gene on the mRNA level in a group of patients diagnosed with depression and in a group of healthy subjects who have never been treated psychiatrically. SUBJECTS AND METHODS: 291 people, aged 18-67, were qualified to participate in the experiment: major recurrent depression group (MRD) and the control group (CG). Designations were carried out for the human NP gene (hNP). RESULTS: For hNP gene expression at the mRNA level was higher in patients with depression than in the CG (p<0.005). A Spearman's rank correlation analysis did not reveal any statistically significant relationship between the intensity of the disease measured using the HDRS scale and expression on the mRNA level for the hNP gene. Expression for the hNP gene in the entire group analysed increased with age of the examined individuals (p<0.005). CONCLUSION: Expression of the hNP gene on the mRNA level, evaluated based on peripheral blood, is significantly higher in the patients with MRD than in the healthy subjects.

[Autobiographical memory in depressive disorders]. / Pamiec autobiograficzna w zaburzeniach depresyjnych.

Contemporary research studies regarding autobiographical memory (AM) indicate that its deficits have a significant impact on the development of mental disorders. We find particularly many reports regarding the comorbidity of AM deficits and depressive disorders. The characteristic feature of AM in the people suffering from depressive disorders is the presence of overgeneral autobiographical memory (OGM), i.e. the reminiscences which contain a summary of many emotion-laden situations, yet without significant detail. This type of reminiscences is observed in the patients with depressive disorders and the ones susceptible to the disease but not experiencing presently an episode of depression, as well as the ones being in the phase of disease remission. In recent years, the interest in the significance of negative thinking processes, such as ruminations, as risk factors in the development of depression has been growing. It is emphasized that they are significantly associated with the occurrence of OGM. Research shows that people suffering from OGM and characterised by a rumination-based style of processing experience a greater number of depressive episodes. There are also research studies which confirm that the activities aimed at reducing the number of ruminations influence an improvement of the detail level of reminiscences. These data may serve as valuable therapeutic advice in depression disorders. The aim of the paper is to present results of contemporary research regarding mutual interrelations between autobiographical memory dysfunctions and the occurrence of symptoms of depression and its course.

Serum KIBRA mRNA and Protein Expression and Cognitive Functions in Depression.

BACKGROUND: Genes participating in synaptic signalling or plasticity in brain regions such as the prefrontal cortex (PFC) and the hippocampus have been implicated in cognition. Recently, a new gene (KIBRA, WWC1) has been added to this group due to its impact on memory performance. Recurrent depressive disorder (rDD) is a multifactorial disease, that one of the typical features is cognitive impairment. The main objective of this study was to perform an analysis of the KIBRA gene on both mRNA and protein levels in patients suffering from rDD and to investigate the relationship between KIBRA expression and cognitive performance. MATERIAL/METHODS: The study comprised 236 subjects: patients with rDD (n=131) and healthy subjects (n=105, HS). Cognitive function assessment was based on: Trail Making Test, The Stroop Test, Verbal Fluency Test and Auditory Verbal Learning Test. RESULTS: Both mRNA and protein expression levels of KIBRA gene were significantly higher in healthy subjects when compared to rDD. The presented relationship is clear even after taking age, education and sex of the examined subjects into consideration. No statistically significant relationship was found in the experiments between any of the conducted tests and KIBRA gene expression on mRNA level for both the rDD and HS groups. The presented study has limitations related to the fact that patients were being treated with antidepressant. This is relevant due to the fact that some antidepressants may affect mRNA expression. Number of patients and healthy subjects may result in the lack of statistical significance in some cases. CONCLUSIONS: 1. The results of our study show decreased expression of the KIBRA gene on both mRNA and protein levels in depression. 2. We did not find any significant relationship between KIBRA gene expression and cognitive functions in case of both the healthy subjects and the patients affected by rDD.

Autobiographical memory dysfunctions in depressive disorders.

Autobiographical memory (AM) is a ubiquitous human experience that belongs to long-term declarative memory. It plays interpersonal and intrapsychic functions. The main aim of this study is to present results of contemporary research on AM in recurrent depressive disorders. The available research literature suggests that AM dysfunctions are a precursor and risk factor for recurrent depressive disorders and that they also appear to be a consequence of depressive symptoms in a bidirectional and interacting manner. These data suggest that AM might be a viable therapeutic target for cognitive remediation strategies, given the impact of cognition on diverse clinical outcomes.

The role of MMP genes in recurrent depressive disorders and cognitive functions.

OBJECTIVE: Among the 28 metalloproteinases described so far, 23 can be found in the human organism, but only few are expressed in the human brain. The main objective of this study was to analyse the relationship between MMP-2, MMP-9 and TIMP-2 gene expression and cognitive performance. METHODS: The study comprised 234 subjects: patients suffering from recurrent depressive disorder (rDD, n=139) and healthy subjects (HS, n=95). The cognitive function assessment was carried out with the help of the following tests: Trail Making Test, The Stroop Test, Verbal Fluency Test and Auditory Verbal Learning Test. Gene expression on the mRNA and protein level was evaluated for MMP-2, MMP-9 and TIMP-2 in both groups using RNA extraction, reverse transcription and enzyme-linked immunosorbent assay. RESULTS: Both mRNA and protein expression levels of all the genes were significantly lower in rDD subjects as compared with HS. Having analysed the entire experimental group (N=234), significant interrelations were found between the expression of the analysed genes and the results of the tests used to measure cognitive functions. Increased expression on both the mRNA and the protein level was associated in each case with better performance of all the tests conducted. After carrying out a separate analysis on the people from the rDD group and the HS group, similar dependencies were still observed. CONCLUSIONS: The results of our study show decreased expression of MMP-2, MMP-9 and TIMP-2 genes on both mRNA and protein levels in depression. Elevated expression of MMP-2, MMP-9, TIMP-2 positively affects cognitive efficiency: working memory, executive functions, attention functions, direct and delayed auditory-verbal memory, the effectiveness of learning processes and verbal fluency. The study highlights the important role of peripheral matrix metalloproteinases genes in depression and cognitive functions.

Variants of Base Excision Repair Genes MUTYH , PARP1 and XRCC1 in Alzheimer's Disease Risk.

BACKGROUND: Many clinical studies have shown that oxidative stress pathways and the efficiency of the oxidative DNA damage base excision repair (BER) system are associated with the pathogenesis of Alzheimer's disease (AD). Reduced BER efficiency may result from polymorphisms of BER-related genes. In the present study, we examine whether single nucleotide polymorphisms (SNPs) of BER genes are associated with increased risk of AD. METHODS: SNP genotyping was carried out on DNA isolated from peripheral blood mononuclear cells obtained from 120 patients with AD and 110 healthy volunteers. Samples were genotyped for the presence of BER-related SNPs, i.e. XRCC1-rs1799782, rs25487; MUTYH-rs3219489, and PARP1-rs1136410. RESULTS: We found a positive association between AD risk and the presence of G/A genotype variant of the XRCC1 rs25487 polymorphism [odds ratio (OR) = 3.762, 95% CI: 1.793-7.891]. The presence of the A/A genotype of this polymorphism reduced the risk of AD (OR = 0.485, 95% CI: 0.271-0.870). In cases of the PARP1 gene rs1136410 polymorphism, we observed that the T/C variant increases (OR = 4.159, 95% CI: 1.978-8.745) while the T/T variant reduces risk (OR = 0.240, 95% CI: 0.114-0.556) of AD. CONCLUSIONS: We conclude that BER gene polymorphisms may play an important role in the etiology of AD. Diagnosing the presence or absence of particular genetic variants may be an important marker of AD. Further research on a larger population is needed. There is also a need to examine polymorphisms of other BER in the context of AD risk.

Oxidant/antioxidant imbalance is an inherent feature of depression.

BACKGROUND: 50% to 60% of the people who have recovered from the first episode of depression experience a relapse. The immune system of the people suffering from depression is in a permanent state of pathological pro-inflammatory readiness. There are some reports that depressive episodes cause sensitization of immune-inflammatory pathways and that staing of depression (e.g. number of depressive episodes) is correlated with immune-inflammatory markers. The main objective of the study was to delineate whether recurrent major depression (rDD) is characterized by alterations in selected immune-inflammatory biomarkers as compared with first episode of depression (ED-I), i.e. expression of mRNA and enzymatic activity of manganese superoxide dismutase (MnSOD, SOD-2), myeloperoxidase (MPO), inducible nitric oxide synthase (iNOS, NOS-2), and cyclooxygenase-2 (COX-2). METHODS: The study was carried out in a group of 131 patients: ED-I group - 42 patients, rDD group - 89 patients. Depression severity was assessed with the 17-item Hamilton Depression Rating Scale (HDRS). The number of depression episodes and the disease duration periods were recorded in each patient. For the patients, HDRS was administered at admission during the symptomatic phase, which would generally be either before or shortly after modification of the previous antidepressant drug regimen. Reassessment of the mental condition was conducted after 8 weeks of the pharmacological treatment also with the use of the HDRS scale. RESULTS: No significant statistical differences were found between the analysed groups as regards the intensity of depressive disorders. No differences in the expression of MnSOD, MPO, COX-2 and i-NOS genes on the level of both mRNA and protein were observed between both groups. No significant interrelation was noticed between the number of depression episodes experienced and the expression of selected genes on the mRNA level and protein level. CONCLUSIONS: There is no significant difference in MnSOD, MPO, COX-2 and i-NOS between patients with recurrent depressive disorders and those in a first episode of depression. These findings suggest that these enzymes are trait markers of depression and are not related to staging of depression.

The Influence of C3435T Polymorphism of the ABCB1 Gene on Genetic Susceptibility to Depression and Treatment Response in Polish Population - Preliminary Report.

BACKGROUND: Despite the high prevalence of depression, the mechanism of the origin of this disease as well as the causes of resistance to therapy in some patients are still not fully understood. Increasingly, the possible role of genetic factors is considered. One of them is polymorphisms in the ABCB1 (MDR1) gene which encodes P-glycoprotein, responsible for the transport of xenobiotics, including antidepressant drugs, through the blood-brain barrier. METHODS: C3435T was evaluated in 90 patients with recurrent depressive disorders (rDD). Genotyping was performed using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). RESULTS: The obtained results indicate that the TT genotype occurred more frequently among patients with rDD than in healthy volunteers (p=0.0441). Also, at least one C allele was present significantly less frequent in the study group than in healthy individuals (p=0.0300). The severity of depressive symptoms was higher among patient with the CC genotype in comparison with the other genotypes (p=0.0106) but treatment response to antidepressants was better in this group than among patients with CT or TT genotypes (p=0.0301). Likewise, patients with the T allele have a significantly lower severity of symptoms (p=0.0026) and decreased therapy effectiveness (p=0.0142) than C allele carriers. CONCLUSIONS: This study suggests that C3435T polymorphisms in the ABCB1 gene are strongly associated with a predisposition to depression development, the severity of depressive symptoms and the effectiveness of therapy with using different groups of antidepressant agents.

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.