Cognitive Dysfunction In Depression Research Articles

Chronic inflammation is associated with worsening working memory performance: Preliminary evidence from a diverse, longitudinal cohort of adolescents and young adults

Many depressed individuals experience cognitive difficulties that persist when depression is in remission. Inflammation is hypothesized to play a role in cognitive dysfunction in depression; however, many aspects of this relationship are not well characterized. The current study examined whether inflammation is associated with specific cognitive deficits in individuals with a history of depression and with progressively worsening working memory over time. Adolescents who participated in a prospective, longitudinal study of adolescent-onset depression were recruited to complete a follow-up cognitive assessment. The sample was comprised of 82 participants (52.4% female; 37.8% white; 42.7% low socioeconomic status) who were aged 22.61 years (SD = 1.50) at the time of the follow-up cognitive assessment. Prior to the follow-up cognitive assessment, they had completed an average of 6.24 (SD = 1.80) prior annual assessments over 6.24 years (SD = 2.08) as part of the parent longitudinal study in which C-reactive protein (CRP), depressive symptoms, and working memory were assessed repeatedly. First, using linear regression, we tested whether individuals exhibiting inflammation (CRP ≥3 mg/L) at multiple timepoints and a history of likely depression (Children’s Depression Inventory ≥19) exhibited differentially worse executive functioning, episodic memory, or psychomotor speed. Second, using hierarchical linear modeling, we tested whether the combination of inflammation and likely past depression was associated with poorer working memory over time. Chronic inflammation was associated with worsening working memory over time, but no significant associations were observed in cross-sectional analyses. These preliminary data indicate that chronic inflammation may lead to progressive decline in working memory over time.

Perceived antidepressant efficacy associated with reduced negative and enhanced neutral mnemonic discrimination.

While antidepressants are one of the first-line treatments for depression, the mechanisms underlying antidepressant action are unclear. Furthermore, the extent to which antidepressants impact emotional and cognitive dysfunction in depression requires more fine-grained approaches toward measuring these impacts in humans. Depression is associated with emotion and mood dysregulation in addition to cognitive deficits. Depressed individuals experience general memory impairment as well as a negativity bias in episodic memory, where negative events are better remembered than positive or neutral events. One potential mechanism hypothesized to underlie the negativity bias in memory is dysfunctional hippocampal pattern separation, in which depressed individuals tend to show impaired general pattern separation but enhanced negative pattern separation. Mnemonic discrimination tasks have been designed to tax hippocampal pattern separation in humans and provide a powerful approach to develop a mechanistic account for cognitive dysfunction in depression. While antidepressants have been examined primarily in rodent models in the context of hippocampal pattern separation, this has yet to be examined in humans. Here, we investigated how antidepressant usage and their perceived efficacy was associated with emotional mnemonic discrimination, given our prior work indicating a negativity bias for mnemonic discrimination in individuals with greater depressive symptoms. We found that individuals who reported a greater improvement in their depressive symptoms after taking antidepressants (responders) showed reduced negative and enhanced neutral mnemonic discrimination compared to those with little to no improvement (non-responders). Perceived antidepressant efficacy was the strongest predictor of a reduction in the negativity bias for mnemonic discrimination, even when controlling for current depressive symptoms, antidepressant type, and other relevant factors. These results suggest that antidepressants, when effective, can shift memory dynamics toward healthy function.

Epigenetic modification related to cognitive changes during a cognitive training intervention in depression

BackgroundDNA methylation as a biomarker is well suited to investigate dynamic processes, such as symptom improvement. For this study we focus on epigenomic state or trait markers as early signatures of cognitive improvement in individuals receiving a cognitive intervention. We performed a first epigenome-wide association study (EWAS) on patients with cognitive dysfunction in depression comparing those with vs without cognitive dysfunction and those cognitively improving vs non-improving following a cognitive intervention. MethodData from a randomized controlled trial (RCT) were used for this analysis, where cognitive function of 112 patients randomly assigned to a personalized cognitive intervention was compared to standard cognitive treatment. Cognition was measured for this study using the four cognitive tasks from the THINC-it battery. We compared individuals with cognitive impairment with individuals without cognitive impairment at baseline and after a cognitive intervention of 8 weeks. Blood for DNA methylation analysis (Illumina Infinium MethylationEPIC 850 k BeadChip) was collected at baseline and 8 weeks into the treatment. For the baseline analysis, after quality control, the final sample comprised 90 individuals, and analyses at week 8 were performed on 84 individuals. Data cleaning, quality control, and differential methylation analysis of DNA methylation data was performed using the RnBeads package (R). Analyses were corrected for gender, age, depression score (MADRS), reported years of education, height and weight, as well as surrogate variables estimated by the pipeline used. The within-individual paired longitudinal analysis was performed using Welch's t-test. ResultsAnalyses at baseline and at week 8 did not show any genome-wide significant CpGs (p < 5 × 10−8) comparing patients with and without cognitive impairment. The most significant result in the baseline analysis comparing the groups with and without cognitive impairment at baseline is located in an open Sea region with predominantly regulatory qualities (cg10962945; 6.61 × 10−7). The most significant CpG at 8 weeks was also located in open sea, though in exon 13 of the NTRK2-gene, linked to the BDNF pathway (cg13620631, 5.56 × 10−7). Finally, a within-individual paired longitudinal analysis with only patients that show improved cognitive function over time was performed, showing 65 CpGs that overlapped between the 1% most significant of this analysis and the 1% most significant CpGs from the cross-sectional analysis at 8 weeks. ConclusionOur result suggest that DNA methylation can be suitable to capture early signs of treatment response of a cognitive intervention in depression. In our layered approach we could capture dynamics that can help differentiate between biological trait and state markers of cognitive function in depression. Despite not being genome-wide significant, the CpG locations returned by our analysis comparing patients with and without cognitive impairment, are in line with prior knowledge on pathways and genes relevant for depression treatment and cognition.

Immune gene co-expression signatures implicated in occurence and persistence of cognitive dysfunction in depression

Cognitive dysfunction contributes significantly to the burden caused by Major Depressive Disorder (MDD). Yet, while compelling evidence suggests that different biological processes play a part in both MDD aetiology and the development of cognitive decline more generally, we only begin to understand the molecular underpinnings of depression-related cognitive impairment. Developments in psychometric assessments, molecular high-throughput methods and systems biology derived analysis strategies advance this endeavour.Here, we aim to identify gene expression signatures associated with cognitive dysfunction and cognitive improvement following therapy using RNA sequencing to analyze the whole blood-derived transcriptome of altogether 101 MDD patients who enrolled in the CERT-D study. The mRNA(Nova)Seq based transcriptome was analyzed from whole blood taken at baseline assessment, and patients' cognitive performance was measured twice at baseline and following eight weeks of therapy by means of the THINC integrated tool. Thirty-six patients showed comparatively low cognitive performance at baseline assessment, and 32 patients showed comparatively strong cognitive improvement following therapy. Differential gene expression analysis was performed using limma to a significance threshold of 0.05 and a logFC cutoff of |1.2|. Although we observed some indications for expression differences related to low cognitive performance and cognitive therapy response, signals did not withstand adjustment for multiple testing. Applying WGCNA, we retrieved altogether 25 modules of co-expressed genes and we used a combination of correlational and linear analyses to identify modules related to baseline cognitive performance and cognitive improvement following therapy. Three immune modules reflected distinct but interrelated immune processes (the yellow module: neutrophil-mediated immunity, the darkorange module: interferon signaling, the tan module: platelet activation), and higher expression of the yellow (r = −0.21, p < .05), the dark orange (r = 0.2, p < .05), and the tan (r = −0.23, p < .05) module correlated significantly negatively with patients' cognitive baseline performance. Patients' cognitive baseline performance was a significant predictor of the darkorange module (b = −0.039, p < .05) and the tan module's expression (b = 0.02, p < .05) and was close to becoming a significant predictor of the yellow module's expression (b = −0.02, p = .05). Furthermore, patients characterized by comparatively low cognitive performance at baseline showed significantly higher expression of the tan module when compared to all other patients F(1,97) = 4.32, p < .05, η= 0.04. Following eight weeks of treatment, we observed altogether significant improvement in patients' cognitive performance (b = 0.30, p < .001), and patients with comparatively high cognitive gain showed noticeably lower, but not significantly lower F(1,98) = 3.76, p = .058, expression of a dark turquoise module, which reflects complement and B-cell-associated immune processes. Noteworthy, the relation between cognitive performance and module expression remained observable after controlling for symptom severity and BMI, which partly accounted for variance in module expression. As such, our findings provide further evidence for the involvement of immune processes in MDD related cognitive dysfunction and they suggest that different immune processes contribute to the development and long-term persistence of cognitive dysfunction in the context of depression.

Bridging the Gap From a Clinician's Perspective to Patient-Oriented Remission: Focusing on Cognitive Dysfunction in Depression

Cognitive problems in depression are a major factor affecting functional recovery, improvement of quality of life, therapeutic response, and overall prognosis. Cognitive dysfunction tends to be persistently observed during the active episode of depression and after remission. To achieve functional recovery, cognitive dysfunction is an essential target for depression treatment. To improve cognitive function in treatment of depression, early recognition and assessment with personalized management are necessary. In this review, the importance of cognitive dysfunction in the treatment of depression and potential pathophysiological mechanisms are summarized. The monoamine system, systematic inflammation, and hypothalamic–pituitary–adrenal axis are all related to the pathogenesis of cognitive dysfunction in depression. Clinicians should consider individualized factors that can affect cognitive problem, including age, duration of illness, the number of episodes, previous treatment response, baseline cognitive reservoir, subtype of depression, and presence of childhood trauma. Comorbid physical and psychiatric conditions also need to be evaluated. [ Psychiatr Ann . 2022;52(3):95–99.]

Cognitive Dysfunction in Mood Disorder: Similarities and Differences Between Depression Subtypes

Cognitive dysfunction is common in depression. Depression is heterogeneous conditions that comprise biologically diverse subtypes. This manuscript reviewed the similarities and differences in cognitive function between major depressive disorder (MDD) and bipolar disorder (BD). Relatively few studies have compared the cognitive function in BD and MDD; furthermore, the differences might exist between BD types I and II. The neurobiological background of cognitive impairment in MDD and BD involves structural and functional disturbances in neural circuits, as well as disturbances in the connectivity of cognitive networks. Several clinical factors such as symptom severity, onset age, premorbid IQ, psychotic features, and illness course may influence cognitive dysfunction in depression. To understand the differences between the cognitive dysfunctions of MDD and BD, the aforementioned features should be controlled. Setting a standard of evaluating cognitive functions in various mood disorders will be a critical step for future studies. [ Psychiatr Ann . 2022;52(3):100–104.]

Is the Therapeutic Mechanism of Repetitive Transcranial Magnetic Stimulation in Cognitive Dysfunctions of Depression Related to the Neuroinflammatory Processes in Depression?

The lifetime prevalence of depression is reported to be >10%, and it is an important illness that causes various disabilities over a long period of life. Neuroinflammation process is often reported to be closely linked to the pathophysiology of depression. Approximately one-third of depression is known to be treatment-resistant depression (TRD), in which the symptoms are refractory to adequate treatment. Cognitive dysfunction is one of the most important symptoms of depression that impedes the rehabilitation of patients with depression. Repetitive transcranial magnetic stimulation (rTMS) is a minimally invasive and effective treatment for TRD and is also known to be effective in cognitive dysfunction in depression. Since the details of the therapeutic mechanism of rTMS are still unknown, we have been conducting studies to clarify the therapeutic mechanism of rTMS, especially focusing on cognitive dysfunction in depression. In the present review, we present our latest results and discuss them from the standpoint of the neuroinflammation hypothesis of depression, while citing relevant literature.

Neurocognitive Performance in Depressed Patients with low-grade inflammation and somatic symptoms

BackgroundThe link between inflammation and depression has been investigated extensively. Cognitive dysfunction in depression is an unmet treatment need. A better understanding of possible links between inflammation and cognition in people with depression may help to identify new treatment targets. MethodsWe report findings from a study comparing a range of cognitive functions between 80 depressed patients with (C-reactive protein ≥3 ​mg/L; n ​= ​37) and without (CRP<3 ​mg/L; n ​= ​43) evidence of inflammation. All participants met the International Classification of Diseases 10th Revision criteria for current depressive episode and had somatic symptoms of depression. All participants completed cognitive testing and clinical assessment and were screened for acute infection. ResultsPatients with evidence of inflammation, compared to those without, had slower psychomotor speed as measured by symbol coding task (mean difference ​= ​0.06, 95% CI ​= ​0.003–0.11) and slower reaction time, as measured by a simple movement time task (mean difference ​= ​26.56, 95% CI ​= ​-48.92 to −4.20). These effects were fully explained after controlling for age, sex, and body mass index. Measures of emotional processing, memory, and planning were comparable between two groups. ConclusionsCertain cognitive domains, particularly processing speed and reaction time may be more affected in depressed patients with evidence of low-grade inflammation and somatic symptoms. Further studies with larger samples are required for a clearer understanding of the association between inflammation and cognitive dysfunction in depression.

Investigating the Link Between Depression, Cognition, and Motivation in Late Childhood.

Research has revealed broad cognitive deficits (e.g., memory, learning) in depression, and that motivation may account for this link. We tested the state (i.e., only present during depression), trait (i.e., underlying vulnerability) and scar (i.e., lasting corollary) hypotheses of cognitive dysfunction in depression. We additionally tested subjective motivation as a mediator of the concurrent depression-cognition link. In a longitudinal sample of 11,878 children ages 9-11, we found no evidence of a concurrent state or longitudinal trait or scar relationship between depression and cognition. The pattern of depression-cognition relationships-which precluded a mediator analysis-in our childhood sample is a departure from previous studies. Our findings indicate that cognitive deficits are not strongly associated with depression in childhood, in contrast with the impairment commonly seen in older individuals with depression.

The role of prepotent response inhibition and interference control in depression

ABSTRACT Introduction The ability to suppress inappropriate prepotent response and to overcome the interference of irrelevant information are two important components of inhibitory control. Little is known, however, about the relevant contributions in these two components of inhibitory control to depression. The aim of the present study was to assess the prepotent response inhibition and interference control simultaneously in a group of patients diagnosed with major depression disorder (MDD). Methods A clinical group of patients with MDD (n = 41) and a control group of healthy volunteers (n = 39) were recruited and assessed using the stop-signal task and the Flanker task respectively. Results The results showed longer stop-signal reaction time in patients with MDD in the stop-signal task. Regarding the interference control function, the analysis showed the response accuracy under the incongruent condition was significantly lower in patients with MDD than healthy individuals. Conclusions In conclusion, patients with MDD showed impairments both in prepotent response inhibition and interference control. The present findings provide a better understanding of the mechanism of depression-related deficits in inhibition and have great implications for the development of cognitive training programmes to remediate cognitive dysfunction in depression.

Inflammation and depression: Research designs to better understand the mechanistic relationships between depression, inflammation, cognitive dysfunction, and their shared risk factors

There is convergent evidence that the immune system is dysregulated in some depressed individuals. A psychoneuroimmunology-based understanding of depression is advancing rapidly; however, a question of fundamental importance is poorly understood: does inflammation play a causal role in the etiology of depression or are elevated inflammatory biomarkers a downstream effect of depressive behaviors? Although longitudinal studies suggest that the relationship between depression and inflammation is characterized by complex bidirectional associations, existing prospective, longitudinal research designs are poorly equipped to investigate the dynamic interplay of depression and inflammation that unfolds over a relatively short time period. In addition, the precise role played by multiple, shared, and overlapping risk factors (e.g., diet, adiposity, stress, sleep dysregulation) in the etiology of depression and a pro-inflammatory phenotype (or both) is poorly understood. In this manuscript, I highlight the benefits of research designs that (i) manipulate constructs of interest (depression/inflammation) using intervention or treatment designs and (ii) use intensive sampling approaches with an ultimate goal of better understanding the temporal sequence and causal relationships of depression, inflammation, cognitive dysfunction, and their shared risk factors. For instance, are improved depressive symptoms a downstream effect of changes in inflammatory activity caused by increases in exercise or, alternatively, are changes in inflammatory activity and depression sequelae of improvements in sleep quality caused by increases in exercise? Potential benefits of these research designs are discussed in terms of their contribution to a better understanding of the etiology of depression and a pro-inflammatory phenotype, their relevance to structural health inequalities, and better characterizing the heterogeneous clinical presentation of depression, particularly relating to the etiology of cognitive dysfunction in depression.

Disfunção Cognitiva na Depressão: O Triste Esquecimento

INTRODUÇÃO: Aproximadamente 30% a 40% dos idosos com depressão apresentam sintomas cognitivos reversíveis, vulgarmente denominada de pseudodemência, que corresponde à condição tratável mais vezes confundida com demência.O nosso objetivo foi rever a evidência existente sobre a disfunção cognitiva na depressão e as principais diferenças no diagnóstico, abordagem e prognóstico, comparativamente à demência.METODOLOGIA: Revisão da literatura usando os seguintes termos MeSH: “Depressive Disorder”, “Cognitive Dysfunction” e “Dementia”.RESULTADOS E CONCLUSÃO: Diversas situações podem cursar com défices cognitivos, sendo essencial colher uma história clínica completa e avaliar o estado funcional basal do doente. O exame neurológico deve ser sempre realizado, assim como excluídas as principais causas orgânicas de défice cognitivo. O papel do médico de família é importante na orientação do doente com queixas mnésicas e sintomatologia depressiva, podendo implicar, em alguns casos, uma abordagem multidisciplinar entre a Medicina Geral e Familiar, a Psiquiatria e a Neurologia.

Cognitive dysfunctions in depression - significance, description and treatment prospects.

Cognitive dysfunctions are part of the symptomatology of depressive disorders but they may persist even after the patient reaches symptomatic remission. As persistent symptoms of depression, cognitive dysfunctions may inhibit and restrict the patient's functioning in many spheres and significantly impair its quality. In addition, they increase the risk of somatic diseases and contribute to the increase of benefits disbursed from state aid. Furthermore, it is a factor negatively affecting the prognosis of depressive disorders because it increases the risk of recurrence of depression and reduces the susceptibility to pharmacotherapy. Neural network dysfunctions and changes in morphometry in particular areas of the brain are responsible for the persistence of cognitive deficits after MDD treatment. Most of currently used thymoleptics facilitate remission of depressive disorders but do not lead to reversal of cognitive deficits. There is growing evidence that antidepressants used in clinical practice can improve cognitive functions regardless of their impact on the affective component. The aim of the present study is to discuss the neurobiological mechanisms of cognitive dysfunctions and their clinical symptoms, and to present therapeutic prospects for patients with persistent cognitive dysfunctions in depressive disorders.

Altered GABA-mediated information processing and cognitive dysfunctions in depression and other brain disorders.

Cognitive dysfunctions, including impaired attention, learning, memory, planning and problem solving, occur in depressive episodes, often persist during remission, predict relapse, worsen with recurrent episodes, and are not treated by current antidepressants or other medications. Cognitive symptoms are also present in other psychiatric disorders, are a hallmark of aging, and define several late-life disorders, including Alzheimer's disease. This pervasive occurrence suggests either a non-specific outcome of a diseased brain, or a shared underlying pathology contributing to this symptom dimension. Recent findings suggest a role for altered GABAergic inhibition in cognitive symptoms. Cellular, molecular and biochemical studies in human subjects report changes affecting the gamma-amino butyric acid (GABA) system, specifically somatostatin-expressing (SST+) GABAergic interneurons, across brain disorders and during aging. SST+ neurons gate excitatory input onto pyramidal neurons within cortical microcircuits. Experimentally reducing the function of these neurons affects excitatory signal-to-noise ratio, reduces synchronized cellular and neural activity, and leads to cognitive dysfunctions. Conversely, augmenting SST+ cell post-synaptic α5-GABA-A receptor activity has pro-cognitive efficacy in stress and aging models. Together, this suggests that reduced signaling of the SST+ neuron/α5-GABA-A receptor pathway contributes to cognitive dysfunctions, and that it represents a novel therapeutic target for remediating mood and cognitive symptoms in depression, other psychiatric disorders and during aging.

Long-term Sustained Cognitive Benefits of Vagus Nerve Stimulation in Refractory Depression.

Treatment-resistant depression (TRD) is a serious chronic condition disabling patients functionally and cognitively. Chronic vagus nerve stimulation (VNS) is recognized for the management of TRD, but few studies have examined its long-term effects on cognitive dysfunction in unipolar and bipolar resistant depression. The purpose of this study was to assess the course of cognitive functions and clinical symptoms in a cohort of patients treated with VNS for TRD. In 14 TRD patients with VNS, standardized clinical and neuropsychological measures covering memory, attention/executive functions, and psychomotor speed were analyzed prestimulation and up to 2 years poststimulation. Vagus nerve stimulation patients significantly improved on cognitive and clinical measures. Learning and memory improved rapidly after 1 month of stimulation, and other cognitive functions improved gradually over time. Cognitive improvements were sustained up to 2 years of treatment. At 1 month, improvement in Montgomery-Åsberg Depression Rating Scale scores was not correlated with changes in any of the cognitive scores, whereas at 12 months, the change in Montgomery-Åsberg Depression Rating Scale score was significantly correlated with several measures (Stroop interference, verbal fluency, and Rey-Osterrieth Complex Figure delayed recall). In recent years, a growing interest in cognitive dysfunction in depression has emerged. Our results suggest that chronic VNS produces sustained clinical and cognitive improvements in TRD patients, with some mental functions improving as soon as 1 month after the initiation of the VNS therapy. Vagus nerve stimulation seems a very promising adjunctive therapy for TRD patients with cognitive impairment.

5-HT6 receptor agonist and memory-enhancing properties of hypidone hydrochloride (YL-0919), a novel 5-HT1A receptor partial agonist and SSRI

Most current antidepressants are lacking a pro-cognition effect or even impair cognition as a side effect, and there are few effective psychopharmacological options that improve cognitive dysfunction in depression. Our previous studies revealed that hypidone hydrochloride (YL-0919), a novel 5-HT1A receptor partial agonist and SSRI, has antidepressant- and anxiolytic-like effects. Here, further studies found that YL-0919, but not vilazodone (a 5-HT1A receptor partial agonist and SSRI), exerted a significant memory-enhancing effect in the Morris water maze, object recognition test and step-down passive avoidance task. Because the 5-HT6 receptor has emerged as an interesting drug target to improve cognition, we investigated the target profile of YL-0919 using radioligand binding assays, [35S]-GTPγS binding and cAMP stimulation assays. YL-0919 was found to act as a highly effective, full agonist of 5-HT6 receptors. Finally, we observed that the memory-enhancing activities of YL-0919 were completely reversed after co-administration of SB271046 (a selective 5-HT6 receptor antagonist) at a dose that does not alter cognition. In summary, the findings of the current study suggest that YL-0919 has clear memory-enhancing effects, which might be at least partially mediated by 5-HT6 receptor activation.

Cognitive Control in Depression: Toward Clinical Models Informed by Cognitive Neuroscience

Cognitive control dysfunctions are thought to contribute to the onset and maintenance of depression. However, the causes and nature of these dysfunctions remain unknown. Here, we critically review contemporary research on cognitive control in depression. We identify three main conceptual issues in this field: (a) uncritical use of the tripartite model, (b) reliance on descriptive explanations, and (c) lack of integration with emotional and motivational impairments. Recent advances in cognitive neuroscience offer possibilities to resolve these issues. We review this progress focusing on the ability to detect the need for control, the role of motivation, and the flexibility-stability balance. We propose that depression-related dysfunctions arise from issues in detecting when, how, and for how long to engage in goal-oriented processing. In conclusion, we argue that integrating advances in cognitive neuroscience into clinical research can help to move from a descriptive toward a more mechanistic understanding of cognitive dysfunctions in depression.

Effects of adolescent social stress and antidepressant treatment on cognitive inflexibility and Bdnf epigenetic modifications in the mPFC of adult mice

Adolescent social stress (ASS) can increase susceptibility to depression in adulthood. However, the underlying psychological and neural mechanisms remain unclear. Cortically mediated cognitive dysfunctions are increasingly recognized as an independent and important risk factor of depression. Using social defeat stress, a classical animal model of depression, our previous studies found that mice subjected to this form of stress during early adolescence displayed cognitive inflexibility (CI) in adulthood. This change was accompanied by a down-regulation of Bdnf gene expression in the medial prefrontal cortex (mPFC); this gene encodes a key molecule involved in depression and antidepressant action. In the present paper, we identified epigenetic modification of Bdnf as a possible mechanism underlying the behavioral and molecular changes. ASS induced a set of depressive phenotypes, including increased social avoidance and CI, as well as reduced levels of total Bdnf and isoform IV but not isoform I or VI transcripts in the mPFC. In parallel with changes in Bdnf gene expression, previously stressed adult mice showed increased levels of dimethylation of histone H3 at lysine K9 (H3K9me2) immediately downstream of the Bdnf IV promoter. On the other hand, no differences were found in trimethylation of histone H3 at lysine K4 (H3K4me3) or in acetylation of histone H3 at lysine K9 (H3K9ac) or at K4 (H3K4ac) in the Bdnf IV promoter. Likewise, no alterations were found in DNA methylation of the Bdnf IV promoter. Additionally, treatment with the chronic antidepressant tranylcypromine reversed Bdnf epigenetic changes and related gene transcription while also reversing CI, but not social avoidance, in previously stressed adult mice. These results suggest that epigenetic changes to the Bdnf gene in the mPFC after adolescent social adversity may be involved in the regulation of cognitive dysfunction in depression and antidepressant action in adulthood.

P.1.i.045 - The effects of long-term psychosocial adversity on dopaminergic function and the acute stress response

Most current antidepressants are lacking a pro-cognition effect or even impair cognition as a side effect, and there are few effective psychopharmacological options that improve cognitive dysfunction in depression. Our previous studies revealed that hypidone hydrochloride (YL-0919), a novel 5-HT1A receptor partial agonist and SSRI, has antidepressant- and anxiolytic-like effects. Here, further studies found that YL-0919, but not vilazodone (a 5-HT1A receptor partial agonist and SSRI), exerted a significant memory-enhancing effect in the Morris water maze, object recognition test and step-down passive avoidance task. Because the 5-HT6 receptor has emerged as an interesting drug target to improve cognition, we investigated the target profile of YL-0919 using radioligand binding assays, [35S]-GTPγS binding and cAMP stimulation assays. YL-0919 was found to act as a highly effective, full agonist of 5-HT6 receptors. Finally, we observed that the memory-enhancing activities of YL-0919 were completely reversed after co-administration of SB271046 (a selective 5-HT6 receptor antagonist) at a dose that does not alter cognition. In summary, the findings of the current study suggest that YL-0919 has clear memory-enhancing effects, which might be at least partially mediated by 5-HT6 receptor activation.

Cognitive dysfunction in depression. Is it well detected?

IntroductionMajor depression cognitive impairments lasts in remission periods, have an impact on treatment outcome and hamper psychosocial functioning. Thus, its accurate detection and specific treatment has become a crucial step.ObjectivesIn order to assess objective cognitive functioning (OCF), a neuropsychological battery was administered. For subjective cognitive functioning (SCF), cognitive perception was evaluated by clinicians and patients.AimsTo determine the concordance between OCF and SCF.MethodsOne hundred and two patients were grouped according to Hamilton Depressive Rating Scale (HDRS−17): 18 remitters (RE &lt; 7), 40 partly remitters (PR, 7–18) and 44 acutely depressed (AD &gt; 18). OCF was computed combining T-scores of digit symbol substitution test (WAIS-IV) with two RAVLT subtests (learning and memory). SCF was assessed with a CGI adaptation for cognitive disturbances severity.ResultsThe OFC was 41.21(8.49) for all patients and 45.54(6.8), 41.93(6.8) and 38.7 (9.7) for RE, PR, and AD, respectively. Psychiatrist and patients’ SCF had a poor agreement (α=0.518), with Cronbach's alpha for RE, PR and AD of −0.607, 0.518 and 0.404. Concordance between OCF and SCF was calculated for all patients (psychiatrist, r = −0.317, P = 0.002; patient, r = −0.310, P = 0.002), for RE (r = −0.535, P = 0.022; r = 0.395, P = 0.105) for PR (r = −0.013, P = 0.94; r = −0.328, P = 0.045) and for AD (r = −0.252, P = 0.122; r = −0.333, P = 0.033). Patients rated their SFC as more impaired than did clinicians.ConclusionsConcordance between clinicians and patients regarding SCF is very poor, worsening in AD group and being null in remission. This study also points out that CF is best detected by patients in acute episodes and by psychiatrists when patients are in clinical remission.Disclosure of interestThe authors have not supplied their declaration of competing interest.