Cognitive Symptoms In Major Depressive Disorder Research Articles

The role of ketamine in major depressive disorders: Effects on parvalbumin-positive interneurons in hippocampus.

Major depressive disorder (MDD) is a complex illness that is arising as a growing public health concern. Although several brain areas are related to this type of disorders, at the cellular level, the parvalbumin-positive cells of the hippocampus interplay a very relevant role. They control pyramidal cell bursts, neuronal networks, basic microcircuit functions, and other complex neuronal tasks involved in mood disorders. In resistant depressions, the efficacy of current antidepressant treatments drops dramatically, so the new rapid-acting antidepressants (RAADs) are being postulated as novel treatments. Ketamine at subanesthetic doses and its derivative metabolites have been proposed as RAADs due to their rapid and sustained action by blocking N-methyl-d-aspartate (NMDA) receptors, which in turn lead to the release of brain-derived neurotrophic factor (BDNF). This mechanism produces a rapid plasticity activation mediated by neurotransmitter homeostasis, synapse recovery, and increased dendritic spines and therefore, it is a promising therapeutic approach to improve cognitive symptoms in MDD.

Changes of anhedonia and cognitive symptoms in first episode of depression and recurrent depression, an analysis of data from NSSD

BackgroundAnhedonia and cognitive impairment are core features of major depressive disorder (MDD), and are essential to the treatment and prognosis. Here, we aimed to investigate anhedonia and its cognitive correlates between first episode of depression (FED) and recurrent depression (RD), which was part of the National Survey on Symptomatology of Depression. MethodsIn this study, 1400 drug naïve FED patients and 487 on medicine RD patients were included. Differences of anhedonia, cognitive symptoms and other clinical characteristics between groups were compared via Student's t-test, or the chi-square test as appropriate. Partial correlation analysis was used to analyze the correlations between anhedonia and cognitive symptoms after adjusting for potential confounders. A stepwise logistic regression analysis was performed to identify relapse risk factors among symptomatic variables, demographic factors, clinical characteristics and medication use. ResultsCompared to FED, RD patients displayed more comprehensive depressive, impaired cognitive and anhedonia symptoms. Cognitive symptoms were significantly related with the anhedonia symptoms with varying aspects. Patients taking emotional stabilizers displayed more abnormal cognitive symptoms, followed by benzodiazepines, and finally SSRIs, SNRIs and TCAs. The effect of drug use on anhedonia is not as extensive as that of cognitive symptoms. ConclusionCollectively, the results of this investigation advance the knowledge on changes in anhedonia and cognitive symptoms in MDD. LimitationsAs this is a cross sectional study, it is difficult to draw any causal conclusions between cognitive impairment and anhedonia in MDD, and to ascertain the worse cognitive performances identified here were induced by current drug use.

Non-REM sleep in major depressive disorder

Disturbed sleep is a key symptom in major depressive disorder (MDD). REM sleep alterations are well described in the current literature, but little is known about non-REM sleep alterations. Additionally, sleep disturbances relate to a variety of cognitive symptoms in MDD, but which features of non-REM sleep EEG contribute to this, remains unknown. We comprehensively analyzed non-REM sleep EEG features in two central channels in three independently collected datasets (N = 284 recordings of 216 participants). This exploratory and descriptive study included MDD patients with a broad age range, varying duration and severity of depression, unmedicated or medicated, age- and gender-matched to healthy controls. We explored changes in sleep architecture including sleep stages and cycles, spectral power, sleep spindles, slow waves (SW), and SW-spindle coupling. Next, we analyzed the association of these sleep features with acute measures of depression severity and overnight consolidation of procedural memory. Overall, no major systematic alterations in non-REM sleep architecture were found in patients compared to controls. For the microstructure of non-REM sleep, we observed a higher spindle amplitude in unmedicated patients compared to controls, and after the start of antidepressant medication longer SWs with lower amplitude and a more dispersed SW-spindle coupling. In addition, long-term, but not short-term medication seemed to lower spindle density. Overnight procedural memory consolidation was impaired in medicated patients and associated with lower sleep spindle density. Our results suggest that alterations of non-REM sleep EEG in MDD might be more subtle than previously reported. We discuss these findings in the context of antidepressant medication intake and age.

Improving cognitive functioning in major depressive disorder with psychedelics: A dimensional approach

The high symptomatic and biological heterogeneity of major depressive disorder (MDD) makes it very difficult to find broadly efficacious treatments that work against all symptoms. Concentrating on single core symptoms that are biologically well understood might consist of a more viable approach. The Research Domain Criteria (RDoC) framework is a trans-diagnostic dimensional approach that focuses on symptoms and their underlying neurobiology. Evidence is accumulating that psychedelics may possess antidepressant activity, and this can potentially be explained through a multi-level (psychobiological, circuitry, (sub)cellular and molecular) analysis of the cognitive systems RDoC domain. Cognitive deficits, such as negative emotional processing and negativity bias, often lead to depressive rumination. Psychedelics can increase long-term cognitive flexibility, leading to normalization of negativity bias and reduction in rumination. We propose a theoretical model that explains how psychedelics can reduce the negativity bias in depressed patients. At the psychobiological level, we hypothesize that the negativity bias in MDD is due to impaired pattern separation and that psychedelics such as psilocybin help in depression because they enhance pattern separation and hence reduce negativity bias. Pattern separation is a mnemonic process that relies on adult hippocampal neurogenesis, where similar inputs are made more distinct, which is essential for optimal encoding of contextual information. Impairment in this process may underlie the negative cognitive bias in MDD by, for example, increased pattern separation of cues with a negative valence that can lead to excessive deliberation on aversive outcomes. On the (sub) cellular level, psychedelics stimulate hippocampal neurogenesis as well as synaptogenesis, spinogenesis and dendritogenesis in the prefrontal cortex. Together, these effects help restoring resilience to chronic stress and lead to modulation of the major connectivity hubs of the prefrontal cortex, hippocampus, and amygdala. Based on these observations, we propose a new translational framework to guide the development of a novel generation of therapeutics to treat the cognitive symptoms in MDD.

Age at illness onset and physical activity are associated with cognitive impairment in patients with current diagnosis of major depressive disorder

Background. Cognitive impairment has been reported in patients with Major Depressive Disorder (MDD). This study aims to explore the association between lifestyle habits and health-related factors and the presence of cognitive symptoms in MDD patients.Methods. Demographic, clinical, health-related variables and cognitive scores measured with the Cambridge Neuropsychological Test Automated Battery (CANTAB) were compared between 74 patients with current MDD and 68 healthy controls (HC). To test the hypothesis of associated factors to cognitive symptoms, multivariate backward stepwise linear regression models were run.Results. Significant neuropsychological deficits were evident in MDD compared with HC in the global cognitive index (F=8.29; df=1, 140; p=0.005). In the regression analysis performed on MDD and HC, years of schooling (β=˗0.11; p=<0.001), job status (β=˗0.50; p=0.016), physical activity (β=˗0.25; p=0.04) and age at illness onset (β=0.17; p=0.017) were statistically significant factors associated to cognitive impairment. The regression model ran in HC showed that only years of schooling were significant (β=-0.07; p=<0.001) in this group.Limitations. Sample size was relatively small. Everyday cognitive skills were not evaluated.Conclusions. MDD patients have cognitive deficits. These deficits are linked with the years of education, job status, age of onset of the disease and the performance of physical activity. These results support the importance of the implementation of interventions targeting the cognitive reserve and lifestyle habits of MDD patients, in addition to the conventional therapeutic approach focused on symptoms control.

Patient Perspective of Cognitive Symptoms in Major Depressive Disorder: Retrospective Database and Prospective Survey Analyses.

BackgroundMajor depressive disorder (MDD) is a common and burdensome condition. The clinical understanding of MDD is shaped by current research, which lacks insight into the patient perspective.ObjectiveThis two-part study aimed to generate data from PatientsLikeMe, an online patient network, on the perception of cognitive symptoms and their prioritization in MDD.MethodsA retrospective data analysis (study 1) was used to analyze data from the PatientsLikeMe community with self-reported MDD. Information on patient demographics, comorbidities, self-rated severity of MDD, treatment effectiveness, and specific symptoms of MDD was analyzed. A prospective electronic survey (study 2) was emailed to longstanding and recently active members of the PatientsLikeMe MDD community. Study 1 analysis informed the objectives of the study 2 survey, which were to determine symptom perception and prioritization, cognitive symptoms of MDD, residual symptoms, and medication effectiveness.ResultsIn study 1 (N=17,166), cognitive symptoms were frequently reported, including “severe” difficulty in concentrating (28%). Difficulty in concentrating was reported even among patients with no/mild depression (80%) and those who considered their treatment successful (17%). In study 2 (N=2525), 23% (118/508) of patients cited cognitive symptoms as a treatment priority. Cognitive symptoms correlated with depression severity, including difficulty in making decisions, concentrating, and thinking clearly (rs=0.32, 0.36, and 0.34, respectively). Cognitive symptoms interfered with meaningful relationships and daily life tasks and had a profound impact on patients’ ability to work and recover from depression.ConclusionsPatients acknowledge that cognitive dysfunction in MDD limits their ability to recover fully and return to a normal level of social and occupational functioning. Further clinical understanding and characterization of MDD for symptom prioritization and relapse risk due to residual cognitive impairment are required to help patients return to normal cognitive function and aid their overall recovery.

Recognition and Treatment of Cognitive Dysfunction in Major Depressive Disorder.

Major Depressive Disorder (MDD) is a prevalent, chronic, disabling, and multidimensional mental disorder. Cognitive dysfunction represents a core diagnostic and symptomatic criterion of MDD, and is a principal determinant of functional non-recovery. Cognitive impairment has been observed to persist despite remission of mood symptoms, suggesting dissociability of mood and cognitive symptoms in MDD. Recurrent impairments in several domains including, but not limited to, executive function, learning and memory, processing speed, and attention and concentration, are associated with poor psychosocial and occupational outcomes. Attempts to restore premorbid functioning in individuals with MDD requires regular screenings and assessment of objective and subjective measures of cognition by clinicians. Easily accessible and cost-effective tools such as the THINC-integrated tool (THINC-it) are suitable for use in a busy clinical environment and appear to be promising for routine usage in clinical settings. However, antidepressant treatments targeting specific cognitive domains in MDD have been insufficiently studied. While select antidepressants, e.g., vortioxetine, have been demonstrated to have direct and independent pro-cognitive effects in adults with MDD, research on additional agents remains nascent. A comprehensive clinical approach to cognitive impairments in MDD is required. The current narrative review aims to delineate the importance and relevance of cognitive dysfunction as a symptomatic target for prevention and treatment in the phenomenology of MDD.

Long-Term Stress Disrupts the Structural and Functional Integrity of GABAergic Neuronal Networks in the Medial Prefrontal Cortex of Rats.

Clinical and experimental data suggest that fronto-cortical GABAergic deficits contribute to the pathophysiology of major depressive disorder (MDD). To further test this hypothesis, we used a well characterized rat model for depression and examined the effect of stress on GABAergic neuron numbers and GABA-mediated synaptic transmission in the medial prefrontal cortex (mPFC) of rats. Adult male Wistar rats were subjected to 9-weeks of chronic mild stress (CMS) and based on their hedonic-anhedonic behavior they were behaviorally phenotyped as being stress-susceptible (anhedonic) or stress-resilient. Post mortem quantitative histopathology was used to examine the effect of stress on parvalbumin (PV)-, calretinin- (CR), calbindin- (CB), cholecystokinin- (CCK), somatostatin-(SST) and neuropeptide Y-positive (NPY+) GABAergic neuron numbers in all cortical subareas of the mPFC (anterior cingulate (Cg1), prelimbic (PrL) and infralimbic (IL) cortexes). In vitro, whole-cell patch-clamp recordings from layer II–III pyramidal neurons of the ventral mPFC was used to examine GABAergic neurotransmission. The cognitive performance of the animals was assessed in a hippocampal-prefrontal-cortical circuit dependent learning task. Stress exposure reduced the number of CCK-, CR- and PV-positive GABAergic neurons in the mPFC, most prominently in the IL cortex. Interestingly, in the stress-resilient animals, we found higher number of neuropeptide Y-positive neurons in the entire mPFC. The electrophysiological analysis revealed reduced frequencies of spontaneous and miniature IPSCs in the anhedonic rats and decreased release probability of perisomatic-targeting GABAergic synapses and alterations in GABAB receptor mediated signaling. In turn, pyramidal neurons showed higher excitability. Anhedonic rats were also significantly impaired in the object-place paired-associate learning task. These data demonstrate that long-term stress results in functional and structural deficits of prefrontal GABAergic networks. Our findings support the concept that fronto-limbic GABAergic dysfunctions may contribute to emotional and cognitive symptoms of MDD.

Cognitive dysfunction in major depressive disorder.

The principal aim of this review is to highlight recent advances in our understanding of cognitive dysfunction in major depressive disorder (MDD). We review new assessment and treatment approaches, in which cognition and associated psychosocial dysfunction are considered primary outcomes. Current work suggests that cognitive dysfunction reduces occupational productivity, and interferes broadly with domains of day-to-day and social functioning. These findings imply that cognitive dysfunction interacts with emotional and social factors relevant to MDD. Recent advances in screening instruments enable standardized detection of cognitive symptoms in MDD. Clinical trials suggest that cognitive symptoms are suitable targets and primary outcomes of psychological and pharmacological treatments. A growing interest in cognitive dysfunction in MDD has improved our ability to assess and treat MDD. Future research will be strengthened by the use of consistent terminology, standardized cognitive screening, and treatments that target cognitive dysfunction in MDD. Integration of emotional and social treatment strategies may further advance clinical efficacy.

Efficacy of Ziprasidone Augmentation of Escitalopram for Cognitive Symptoms of Major Depressive Disorder.

To examine the efficacy of adjunctive ziprasidone for cognitive symptoms in adult patients with major depressive disorder (MDD) experiencing persistent symptoms after 8 weeks of open-label escitalopram. This post hoc analysis was conducted on a database derived from a previously published study. The parent study was a multicenter, parallel, randomized, double-blind, placebo-controlled trial conducted at 3 academic medical centers in the United States from July 2008 to October 2013. The participant pool consisted of 139 outpatients with persistent symptoms of MDD, according to DSM-IV criteria, following an 8-week open label, flexible-dose trial of escitalopram. Subjects were randomly assigned (1:1, N = 139) to adjunctive fixed-dose ziprasidone (escitalopram + ziprasidone, n = 71) or adjunctive placebo (escitalopram + placebo, n = 68) with 8 weekly follow-up assessments. Primary outcome was clinical response according to the 17-item Hamilton Depression Rating Scale, which was defined as a 50% or greater reduction in scale scores. The Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) was used to measure cognitive and executive dysfunction at each study visit. All statistical testing was conducted at the nominal, 2-sided, 0.05 level of significance. Adjunctive ziprasidone therapy did not result in significantly greater improvement in CPFQ scores compared to adjunctive placebo (P > .05). Residual cognitive symptoms were reported in a substantial number of patients who were considered responders to either adjunctive ziprasidone or placebo. In the present study, ziprasidone used adjunctively with the selective serotonin reuptake inhibitor escitalopram did not demonstrate a greater efficacy for cognitive symptoms in patients with MDD compared with adjunctive placebo. Future, well-designed studies examining the role of atypical antipsychotics or other augmentation versus switch strategies for cognitive symptoms in MDD are warranted.

Selective Serotonin Reuptake Inhibitors and Serotonin and Noradrenaline Reuptake Inhibitors Improve Cognitive Function in Partial Responders Depressed Patients: Results from a Prospective Observational Cohort Study.

Major Depressive disorder (MDD) is often accompanied by cognitive deficits, involving attention, learning, memory and executive functioning. Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs) show efficacy on affective symptoms, but it is unclear whether or not they improve cognitive symptoms. We carried out a 12 week-prospective observational study in two cohorts of recurrent moderate-severe partial responder MDD patients, to test the hypothesis that SSRIs and/or SNRIs may affect cognitive symptoms and assess whether or not such an effect was correlated to their effect on affective symptoms. All patients underwent cognitive and neuropsychiatric assessment at baseline, 4- and 12-week follow-up. Thirty-three patients in the SSRI- and sixteen patients in the SNRI-cohort completed the follow-up. Both SSRIs and SNRIs reduced affective symptoms and improved global cognitive function. Both SSRIs and SNRIs improved executive function and verbal memory. Global cognitive function, verbal memory and executive function improved both in full and partial responder patients. Finally, there was no correlation between baseline Mini Mental State Examination, Montreal Cognitive Assessment and Frontal Assessment Battery scores and the mean change in Hamilton Psychiatric Rating scale for Depression or Beck Depression Inventory at the end of the 12 weeks of treatment. Present data show that SSRIs and SNRIs improve cognitive symptoms in MDD independently from their efficacy on affective symptoms. Affective and cognitive symptoms may represent distinct psychopathological dimensions of MDD with different response to antidepressant drugs.

Cognitive effects of transcranial direct current stimulation in depression: Results from the SELECT-TDCS trial and insights for further clinical trials

BackgroundCognitive dysfunction treatment remains an unmet clinical need in major depressive disorder (MDD). Transcranial direct current stimulation (tDCS) may improve cognitive symptoms in MDD. Our aim was to investigate the cognitive effects of tDCS in the Sertraline vs. Electric Current Therapy for Treating Depression Clinical Study (SELECT-TDCS). We also explored whether tDCS could have mood-independent cognitive effects. MethodsOne hundred twenty MDD patients aged from 18 to 65 years received 12 sessions of active/sham tDCS (2mA for 30min) and real/placebo 50mg/d sertraline over 6 weeks in a factorial trial. We analyzed whether changes in performance of neuropsychological tests (Trail Making, Digit Span, Stroop Task, Mini-Mental Status Exam and Montreal Cognitive Assessment) occurred over time, according to treatment group and depression improvement. Exploratory analyses were carried out to verify the influence of clinical and demographic variables on the outcomes. ResultsCognitive improvement was showed in most tests used, although they occurred regardless of intervention type and depression improvement. Further exploratory analyses revealed that clinical response and education level could have mediated pro-cognitive tDCS effects on some of the tests used. LimitationsThe neuropsychological battery used might not have been sensitive to detect tDCS-induced effects on cognition. Lack of simultaneous cognitive training during application may have also limited its cognitive effects. ConclusionsWe found no evidence of beneficial or deleterious cognitive effects of tDCS as a treatment for depression. We discussed clinical trial design considerations for further tDCS studies assessing cognitive effects, including sample and outcomes considerations.

Italian neurologists' perception on cognitive symptoms in major depressive disorder.

The assessment of cognition is an important part of major depressive disorder (MDD) evaluation and a crucial issue is the physicians' perception of cognitive dysfunction in MDD that remains nowadays a little known matter. The present study aims at investigating the understanding of neurologists' perception about cognitive dysfunction in MDD. An on-line survey addressed to 85 Italian neurologists in the period between May and June 2015 was performed. The questionnaire comprised three sections: the first section collecting information on neurologists' socio-demographic profile, the second investigating cognitive symptoms relevance in relation with different aspects and the third one explicitly focusing on cognitive symptoms in MDD. Cognitive symptoms are considered most significant among DSM-5 symptoms to define the presence of a Major Depressive Episode in a MDD, to improve antidepressant therapy adherence, patients' functionality and concurrent neurological condition, once resolved. Furthermore, an incongruity came to light from this survey: the neurologists considered cognitive symptoms a not relevant aspect to choose the antidepressant treatment in comparison with the other DSM-5 symptoms on one side, but they declared the opposite in the third part of the questionnaire focused on cognitive symptoms. Cognitive symptoms appeared to be a relevant aspect in MDD and neurologists have a clear understanding of this issue. Nevertheless, the discrepancy between neurologists' perception on cognitive symptoms and the antidepressant treatment highlights the feeling of an unmet need that could be filled increasing the awareness of existing drugs with pro-cognitive effects.

Italian psychiatrists’ perception on cognitive symptoms in major depressive disorder

Objective: Differently than Schizophrenia, the investigation of cognitive impairment in bipolar disorder and major depressive disorder (MDD) attracted the interest of research only recently. Therefore, it is worth understanding clinicians’ perception about cognitive dysfunction in MDD and raising awareness about this issue. Methods: Between December 2014 and January 2015, 128 Italian psychiatrists participated in an on-line survey aiming at understanding psychiatrists’ perception about cognitive symptoms in MDD. The questionnaire comprised three sections: the first investigating psychiatrists’ socio-demographic profile, the second assessing cognitive symptoms relevance without mentioning that they represented the study focus and the third explicitly investigating cognitive symptoms. Results: Cognitive symptoms were considered as a relevant dimension of MDD and appeared among the most frequently cited residual symptoms influencing patients’ work and relapse risk. About 70% of psychiatrists declared that cognitive symptoms significantly influence antidepressant choice. However, in the second questionnaire section cognitive symptoms appeared less frequently considered for antidepressant choice. Conclusions: Results revealed a clear understanding of cognitive symptoms relevance in MDD. Nevertheless, the discrepancy between psychiatrists’ perception and their therapeutical choices underlines the presence of an unmet-need that should be addressed increasing the awareness about the positive effects on cognitive symptoms of existing drugs, which could allow a more symptom-oriented therapeutical intervention.Key pointsMajor depressive disorder (MDD) is a common mental disorder often associated with deficits in cognitive function.Psychiatrists considered cognitive symptoms among the most relevant residual symptoms in MDD patients that compromise patients working and influence the relapse risk.The importance given to residual cognitive symptoms seemed not to be reflected by psychiatrists’ therapeutical choice.There is a gap between what psychiatrists know and what psychiatrists apply to their clinical practice reflecting the feeling of a therapeutical unmet need.