Dealing with heterogeneity of cognitive dysfunction in acute depression: a clustering approach

Abstract Background Heterogeneity in cognitive functioning among major depressive disorder (MDD) patients could have been the reason for the small-to-moderate differences reported so far when it is compared to other psychiatric conditions or to healthy controls. Additionally, most of these studies did not take into account clinical and sociodemographic characteristics that could have played a relevant role in cognitive variability. This study aims to identify empirical clusters based on cognitive, clinical and sociodemographic variables in a sample of acute MDD patients. Methods In a sample of 174 patients with an acute depressive episode, a two-step clustering analysis was applied considering potentially relevant cognitive, clinical and sociodemographic variables as indicators for grouping. Results Treatment resistance was the most important factor for clustering, closely followed by cognitive performance. Three empirical subgroups were obtained: cluster 1 was characterized by a sample of non-resistant patients with preserved cognitive functioning (n = 68, 39%); cluster 2 was formed by treatment-resistant patients with selective cognitive deficits (n = 66, 38%) and cluster 3 consisted of resistant (n = 23, 58%) and non-resistant (n = 17, 42%) acute patients with significant deficits in all neurocognitive domains (n = 40, 23%). Conclusions The findings provide evidence upon the existence of cognitive heterogeneity across patients in an acute depressive episode. Therefore, assessing cognition becomes an evident necessity for all patients diagnosed with MDD, and although treatment resistant is associated with greater cognitive dysfunction, non-resistant patients can also show significant cognitive deficits. By targeting not only mood but also cognition, patients are more likely to achieve full recovery and prevent new relapses.

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S62. COGNITIVE DEFICITS IN TREATMENT RESISTANT SCHIZOPHRENIA

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa031.128 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S56-S57

Author(s):

Edward Millgate ◽

Eugenia Kravariti ◽

James MacCabe ◽

Olga Hide

Keyword(s):

Executive Function ◽

Cognitive Deficits ◽

Verbal Memory ◽

Antipsychotic Drugs ◽

Treatment Resistance ◽

Antipsychotic Treatment ◽

Verbal Intelligence ◽

Treatment Resistant ◽

Domain Specific ◽

Visual Spatial

Abstract Background Schizophrenia (Sz) and other psychoses are complex mental disorders, characterised by sensory, cognitive and emotional symptoms, but mainly distinguished by positive and negative symptoms. Cognitive impairment is a core feature of schizophrenia, with research into cognitive deficits indicating that cognitive impairment precedes clinical disease onset and is still evident after positive symptoms are no longer present. The current mainstream treatment for Sz are first and second-generation antipsychotics, such as chlorpromazine and aripiprazole respectively. However, about a third of patients treated with antipsychotic drugs have no change in their symptoms despite adequate trials of several antipsychotic drugs. Treatment-resistant schizophrenia (TRS) refers to individuals with a F20-F29 diagnosis who have had at least two courses of antipsychotic treatment with little to no symptomatic relief. Emerging evidence into the factors associated with antipsychotic treatment response has investigated genetic, demographic and clinical factors and their relation to treatment response, with emerging evidence from cognitive data inferring a domain specific deficit in TRS populations for verbal, general cognition (IQ) and executive function tasks. Methods Publications were selected from a systematic search from four databases: PsycINFO, Ovid MEDLINE(R), Scopus and Web of Science. Following inclusion/exclusion criteria, cognitive test outcomes were extracted for each responder group (TRS/NTRS; treatment responders), as well as variables such as age of psychotic illness onset, average chlorpromazine equivalents and duration of illness. Neuropsychological tasks and subtests identified across publications were then grouped into one of seven exclusive cognitive domains (e.g. executive function) prior to analysis based on recommendations from existing literature. Following this, a random-effects model was adopted to test the differences between responder groups in each cognitive domain across publications. Results From the 17 publications identified, sample sizes ranged from 817 to 36, with the majority of publications using a sample size of ~65 TRS/NTRS cases, and a total sample size of N = 1,943 across studies. The random-effects model indicates that cases reaching treatment resistance criteria demonstrated marked neuropsychological performance generally across all domains (d = 0.372, 95CIs 0.29; 0.46], p< .001), with this being most marked in tasks of verbal memory and learning (d = 0.49, 95CIs [0.28; 0.70], p<. 001), verbal intelligence and processing (d = 0.38, 95CIs [0.17; 0.58], p< .001), IQ/general cognitive functioning (d = 0.46, 95CIs [0.17; 0.75], p = 0.002), attention, Working memory and Visual-motor/processing speed (d = 0.38, 95CIs [0.24; 0.51], p< 0.001) and executive function (d = 0.41, 95CIs [0.13; 0.68], p = 0.003), with these all demonstrating a close to medium effect size. There was no significant differences between responder groups in test performance for visual-spatial memory and learning (d = .16, 95CIs [-0.16; 0.48], p = 0.334) and visual-spatial intelligence and processing (d = .50, 95CIs [-0.05; 01.04], p = 0.074) tasks. Discussion In line with existing literature, treatment resistant schizophrenia appears to demonstrate domain specific marked performance on tasks relating to verbal memory, verbal intelligence, as well as tasks relating to executive function, attention and working memory in relation to responders. When considering the clinical importance of identification of treatment resistance in the early disease stages (i.e. at first episode) the use of domain specific cognitive testing could help improve prediction of future antipsychotic response/non-response.

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S67. TREATMENT-RESISTANCE AFFECTS LONG-TERM COGNITIVE TRAJECTORIES IN SCHIZOPHRENIA: A LONGITUDINAL STUDY

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa031.133 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S59-S59

Author(s):

Marco Spangaro ◽

Marta Bosia ◽

Margherita Bechi ◽

Mariachiara Buonocore ◽

Francesca Martini ◽

...

Keyword(s):

Cognitive Impairment ◽

Cognitive Decline ◽

Cognitive Functioning ◽

Effect Size ◽

Treatment Resistance ◽

Cognitive Outcome ◽

Treatment Resistant ◽

First Line ◽

Index Effect

Abstract Background Schizophrenia is a highly heterogeneous disorder, and despite extensive research progress approximately 30% of patients with schizophrenia show poor response to first-line antipsychotics, denoted as treatment-resistant schizophrenia (TRS). Meta-analytic evidence showed that clozapine is the most effective antipsychotic for TRS, although 40% of TRS patients do not respond even to clozapine (ultra-treatment-resistant schizophrenia -UTR). Recent studies indicated that TRS is neurobiologically and categorically distinct from treatment-responsive schizophrenia, being associated with elevated glutamate levels in the anterior cingulate cortex and unaltered striatal dopamine synthesis. Moreover, the striking majority of TRS patients do not respond to first-line antipsychotic therapy since disease onset and present more severe cognitive deficits since first episode of psychosis, further suggesting the presence of a distinct and more disrupted neurobiological substrate. It is widely known that cognitive impairment is a core feature of schizophrenia and determines a significant detrimental impact on long-term functional outcome, which represents the ultimate treatment goal. However, despite the central role of cognition in schizophrenia, to date no study has investigated longitudinal cognitive outcome among TRS patients. Based on these evidences, the aim of this study is to evaluate longitudinal cognitive trajectories in a sample of clinically stabilized patients with schizophrenia, stratified according to antipsychotic response. We hypothesized that treatment-resistance is associated with a more severe long-term cognitive decline. Methods We enrolled 93 patients with schizophrenia (DSM-V), stratified as follows: 32 first-line responders (FLR), 42 TRS and 19 UTR. Cognition was longitudinally assessed at baseline and at least after 6 years of follow-up (mean: 9.3±2.8 years) using the Brief Assessment of Cognition in Schizophrenia (BACS). From BACS subscores we calculated for each patient a Cognitive Index, as a measure of overall cognitive functioning. In order to quantify global cognitive functioning changes during the course of illness, we estimated effect size score for Cognitive Index using Cohen’s d. Finally, General linear Models (GLM) were performed with overall cognitive index effect size as dependent variable, treatment (FLR/TRS/UTR) as categorical variable and age, duration of illness and education as covariates. Results The first GLM (FLR vs TRS+UTR) showed a significant main effect of treatment (F=7.34, p=0.01), with worse cognitive outcome between resistant patients. Consistently, the second GLM (FLR/TRS/UTR) resulted significant as well (F=17.90, p<0.001), with UTR group showing worse cognitive trajectory (Fisher’s post-hoc: p<0.001, UTR Cognitive Index effect size = -0.7). Discussion This is the first study to longitudinally evaluate cognitive trajectories of patients with schizophrenia according to their antipsychotic response. We showed that treatment resistance is associated with a more severe cognitive decline, with worse outcome among UTR patients. These data suggest that greater severity of treatment resistance in schizophrenia is associated with greater cognitive impairment, possibly due to the presence of a distinct and more disrupted neurobiological substrate that affects both cognition and antipsychotic response. These findings further highlight the necessity of early individuation and tailored pharmacological treatment for TRS patients, in order to improve long-term clinical, cognitive and functional outcome.

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Do cognitive deficits play a role in treatment-resistant depression? Characterizing resistance from cognitive perspective

10.26226/morressier.5b681760b56e9b005965c675 ◽

2018 ◽

Author(s):

Clara Lopez-Sola ◽

Muriel Vicent-Gil ◽

Guillem Navarra Ventura ◽

Diego Jose Palao Vidal

Keyword(s):

Cognitive Deficits ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Cognitive Perspective ◽

Resistant Depression

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Molecular and Functional Links between Neurodevelopmental Processes and Treatment-Induced Neuroendocrine Plasticity in Prostate Cancer Progression

Cancers ◽

10.3390/cancers13040692 ◽

2021 ◽

Vol 13 (4) ◽

pp. 692

Author(s):

Roosa Kaarijärvi ◽

Heidi Kaljunen ◽

Kirsi Ketola

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Treatment Resistance ◽

Research Field ◽

Phenotypic Change ◽

Prostate Cancer Progression ◽

Castration Resistant Prostate Cancer ◽

Treatment Resistant ◽

Molecular Features ◽

Neuroendocrine Prostate Cancer

Neuroendocrine plasticity and treatment-induced neuroendocrine phenotypes have recently been proposed as important resistance mechanisms underlying prostate cancer progression. Treatment-induced neuroendocrine prostate cancer (t-NEPC) is highly aggressive subtype of castration-resistant prostate cancer which develops for one fifth of patients under prolonged androgen deprivation. In recent years, understanding of molecular features and phenotypic changes in neuroendocrine plasticity has been grown. However, there are still fundamental questions to be answered in this emerging research field, for example, why and how do the prostate cancer treatment-resistant cells acquire neuron-like phenotype. The advantages of the phenotypic change and the role of tumor microenvironment in controlling cellular plasticity and in the emergence of treatment-resistant aggressive forms of prostate cancer is mostly unknown. Here, we discuss the molecular and functional links between neurodevelopmental processes and treatment-induced neuroendocrine plasticity in prostate cancer progression and treatment resistance. We provide an overview of the emergence of neurite-like cells in neuroendocrine prostate cancer cells and whether the reported t-NEPC pathways and proteins relate to neurodevelopmental processes like neurogenesis and axonogenesis during the development of treatment resistance. We also discuss emerging novel therapeutic targets modulating neuroendocrine plasticity.

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Cognitive Functioning and Late-Life Depression

Journal of the International Neuropsychological Society ◽

10.1017/s1355617714000198 ◽

2014 ◽

Vol 20 (5) ◽

pp. 461-467 ◽

Cited By ~ 47

Author(s):

Aaron M. Koenig ◽

Rishi K. Bhalla ◽

Meryl A. Butters

Keyword(s):

Older Adults ◽

Depressive Symptoms ◽

Cognitive Functioning ◽

Neuropsychological Assessment ◽

Cognitive Deficits ◽

Late Life ◽

Cognitive Outcomes ◽

Review Of The Literature ◽

Late Life Depression ◽

The Relationship

AbstractThis brief report provides an introduction to the topic of cognitive functioning in late-life depression (LLD). In addition to providing a review of the literature, we present a framework for understanding the heterogeneity of cognitive outcomes in this highly prevalent disorder. In addition, we discuss the relationship between LLD and dementia, and highlight the importance of regularly assessing cognitive functioning in older adults who present with depressive symptoms. If cognitive deficits are discovered during a neuropsychological assessment, we recommend referral to a geriatric psychiatrist or cognitive neurologist, for evaluation and treatment of the patient’s symptoms. (JINS, 2014, 20, 1–7)

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Resting State fMRI: A Valuable Tool for Studying Cognitive Dysfunction in PD

Parkinson s Disease ◽

10.1155/2018/6278649 ◽

2018 ◽

Vol 2018 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Kai Li ◽

Wen Su ◽

Shu-Hua Li ◽

Ying Jin ◽

Hai-Bo Chen

Keyword(s):

Cognitive Impairment ◽

Cognitive Dysfunction ◽

Cognitive Deficits ◽

Resting State ◽

Lewy Bodies ◽

Resting State Fmri ◽

Underlying Mechanism ◽

Research Field ◽

Functional Magnetic Resonance ◽

Positron Emission

Cognitive impairment is a common disabling symptom in PD. Unlike motor symptoms, the mechanism underlying cognitive dysfunction in Parkinson’s disease (PD) remains unclear and may involve multiple pathophysiological processes. Resting state functional magnetic resonance imaging (rs-fMRI) is a fast-developing research field, and its application in cognitive impairments in PD is rapidly growing. In this review, we summarize rs-fMRI studies on cognitive function in PD and discuss the strong potential of rs-fMRI in this area. rs-fMRI can help reveal the pathophysiology of cognitive symptoms in PD, facilitate early identification of PD patients with cognitive impairment, distinguish PD dementia from dementia with Lewy bodies, and monitor and guide treatment for cognitive impairment in PD. In particular, ongoing and future longitudinal studies would enhance the ability of rs-fMRI in predicting PD dementia. In combination with other modalities such as positron emission tomography, rs-fMRI could give us more information on the underlying mechanism of cognitive deficits in PD.

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P.2.b.001 Cognitive functioning after deep brain stimulation in subcallosal cingulate gyrus for treatment-resistant depression

European Neuropsychopharmacology ◽

10.1016/s0924-977x(13)70500-5 ◽

2013 ◽

Vol 23 ◽

pp. S318-S319

Author(s):

M. Serra-Blasco ◽

S. De Vita ◽

M. Rivas ◽

J. De Diego ◽

D. Puigdemont ◽

...

Keyword(s):

Deep Brain Stimulation ◽

Cognitive Functioning ◽

Brain Stimulation ◽

Cingulate Gyrus ◽

Treatment Resistant Depression ◽

Treatment Resistant ◽

Resistant Depression ◽

Deep Brain

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Cognitive Dysfunction as a Symptom Dimension Across Major Psychiatric Disorders

Cognitive Dimensions of Major Depressive Disorder ◽

10.1093/med/9780198810940.003.0004 ◽

2019 ◽

pp. 35-44

Author(s):

Zihang Pan ◽

Roger S. McIntyre

Keyword(s):

Bipolar Disorder ◽

Major Depressive Disorder ◽

Psychiatric Disorders ◽

Cognitive Dysfunction ◽

Cognitive Deficits ◽

Functional Disability ◽

Cognitive Symptoms ◽

Compelling Evidence ◽

Psychiatric Illnesses ◽

Neurobiological Substrates

Cognitive dysfunction is a symptom domain across multiple psychiatric disorders. Cognitive deficits in individuals with major depressive disorder (MDD) and bipolar disorder (BD) are significant contributors to global occupational and functional disability. The subdomains of learning and memory, executive function, processing speed, and attention and concentration are significantly impaired in individuals with MDD and BD. Treatment outcomes of cognitive symptoms with first-line agents have been suboptimal. Neuroinflammatory pathways are hypothesized to play key roles in the pathoaetiology of cognitive symptoms in MDD and BD. There is compelling evidence to suggest that elevation of systemic proinflammatory cytokines is involved in neurotoxicity, apoptosis, and aberrant neurocircuit function. These substrates offer opportunities to identify relevant biomarkers, refine treatment targets, and manage cognitive deficits across major psychiatric illnesses. This chapter provides an overview of cognitive symptoms across MDD and BD and discusses potential neurobiological substrates contributing to cognitive dysfunction.

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