Discrete and continuous approach in the conceptualization of psychoses

L’évaluation cognitive permet-elle de distinguer la schizophrénie du trouble bipolaire ?

Bipolar disorder is associated with deficits in cognitive functioning. The etiology of cognitive impairment in bipolar disorder may relate to both genetic and environmental factors. A valine/methionine polymorphism of the catechol O-methyltransferase gene at amino acid 158 (COMT Val158Met polymorphism) has been identified as a risk factor for cognitive impairment in schizophrenia. Serological evidence of infection with herpes simplex virus type 1 (HSV-1) has also been identified as a risk factor for cognitive impairment in bipolar disorder. We used Taqman technology to measure COMT Val158Met alleles in 107 individuals with bipolar disorder and in 95 controls. We also measured antibodies to HSV-1 in sera obtained from the same individuals. Cognitive functioning was assessed with the Repeatable Battery for the Assessment of Neuropsychological Status and the Letter-Number Sequencing Test. The effects of the COMT Val158Met polymorphism and antibodies to HSV-1 on cognitive functioning were analyzed with multinomial logistic regressions. The COMT Val158Val genotype and serological evidence of infection with HSV-1 are independent risk factors for cognitive impairment in individuals with bipolar disorder, particularly in the domains of immediate and delayed memory. Individuals with bipolar disorder with the COMT158 Val/Val genotype and serological evidence of HSV-1 infection were more than 85 times more likely to be in the lowest quintile of cognitive functioning when compared with the highest quintile when controlling for potential confounding variables such as symptom severity and education. Control individuals did not display this association. Both the COMT Val158Met polymorphism and serological evidence of HSV-1 infection affect cognitive functioning in individuals with bipolar disorder.

Richard Keefe outlines the reasons for including cognitive impairment as one of the criteria for the diagnosis of schizophrenia in future diagnostic manuals (DSM-V and ICD-11). First, he convincingly argues that cognitive impairment has a major impact on the lives of almost all individuals who meet DSM-IV and ICD-10 criteria for schizophrenia. He reminds the reader that even patients who obtain normal or almost normal psychometric scores might still be cognitively impaired, compared to their potential as predicted by their parents’ intelligence and their socioeconomic context. Than he presents the advantages and stumbling blocks associated with adding cognitive impairment to future diagnostic criteria, and suggests solutions. The first advantage Keefe identifies is help in defining a point of rarity between schizophrenia and other diagnostic entities, to reduce diagnostic overlap. The second advantage is the encouragement of the clinical, academic, regulatory, and pharmaceutical communities to develop treatments targeting cognitive impairment. The main impediment he identifies is lack of assessment instruments which on the one hand are brief and simple and on the other are sufficiently detailed and comprehensive to capture developmental and current information in a valid and reliable manner. He voices the concern that non-psychologist clinicians, who are not sensitized and trained in the assessment of cognition, might be unwilling to carve out the necessary time from the already-limited patient-clinician encounter. Since, even for the most comprehensive scales, much of the variance is accounted for by only a few items, the solution he advocates is the use of brief scales which can be quickly learned and applied by clinicians. Keefe is correct to point out that cognitive impairment in schizophrenia differs from cognitive impairment in mood disorders, which is the main overlapping diagnostic group, in terms of prevalence, severity and course. However, the differences are neither large nor consistent, and it is unclear by how much the inclusion of cognitive impairment as a criterion would reduce the diagnostic overlap. Furthermore, cognitive impairment is present in almost all psychiatric diagnostic categories, some of which overlap with schizophrenia in manifestations other than cognitive impairment (e.g., severe personality disorders, drug abuse, obsessive-compulsive disorder). Moreover, there is considerable overlap between schizophrenia with severe cognitive impairment and mild mental retardation with unusual ideation, and the inclusion of cognitive impairment as a criterion for schizophrenia might only enhance the overlap. There is little doubt that the inclusion of cognitive impairment as a diagnostic criterion would increase awareness and focus on it the attention of all stakeholders. Whether this would hasten the development of treatments targeting cognitive impairment is less certain. Increased awareness might help divert budgets and other resources to education and rehabilitation programs focused on cognitive enchantment. Since education and rehabilitation activities have a incremental and cumulative effect, more budgets and resources might benefit cognition. However, the development of a pharmacological intervention targeting cognitive impairment is an endeavor waiting for a conceptual breakthrough, rather than the incremental assigning of more funds which would result from increased awareness. Cognitive impairment in schizophrenia may have more in common with cognitive impairment occurring in most other mental disorders than with schizophrenic psychosis per se 1,2. Cognitive attributes and predisposition to psychosis are partially inherited traits in schizophrenia patients. However, whether these traits co-segregate and follow common pathophysiologic pathways is far from certain. The lack of correlation between the severity of cognitive impairment and psychosis, and the fact that cognitive impairment appears before and persists after psychosis, are consistent with the idea that they are independent. Conceptually, therefore, it would take the same breakthrough to treat cognitive impairment in schizophrenia as it would take to improve cognitive functioning in any individuals, mentally ill or not, whose performance is 1.5 to 2.5 SDs below norms or expected performance. This major scientific endeavor could hardly benefit from the inclusion of cognitive impairment as a criterion for schizophrenia. I would not be too concerned with the willingness of those who treat schizophrenia (psychiatrists, nurses, social workers, and others) to learn and devote time to the assessment of cognition. The relentless efforts of researchers like Keefe and others over the past 15 years have already sensitized clinicians to the issue of cognitive impairment in schizophrenia patients. Once they are convinced of the benefit of diagnosing it and the potential of treating it, they are likely to adjust their priorities and fit cognitive assessment into the clinical encounter. In spite of the above reservations, I hope that Richard Keefe’s suggestion to include cognitive impairment as a criterion for schizophrenia is accepted. A diagnostic classification that leaves out an aspect which is so prevalent among the affected individuals and so central to their daily life would be deficient.

Background: Bipolar disorder is a chronic mental disorder characterized by mania and depression with intervening periods of euthymia. Although cognitive impairments are associated with acute episodes, these do seem to persist in lower degree during periods of euthymia. Aim: The objective was to study cognitive functions and psychosocial functioning among euthymic patients with bipolar mood disorder, to correlate the same with sociodemographic and clinical characteristics, and finally, to compare cognitive function disorder with those of apparently healthy controls. Settings and Design: A cross-sectional comparative study was conducted among patients in the department of psychiatry of a tertiary care center in Karnataka, India. Materials and Methods: Thirty euthymic patients with bipolar mood disorder were selected using the Young Mania Rating Scale and Hamilton Depression Rating Scale screening and compared with 30 healthy controls who were screened using the General Health Questionnaire-12 for cognitive function and psychosocial functioning. Sociodemographic and clinical data were collected using a standard questionnaire. Trail making test, digit symbol substitution test, visual memory test, and digit span test were used to assess cognitive function. Functioning assessment short test was used to assess psychosocial functioning. Chi-square test, “t”- test, and Pearson’s correlation were used to analyze the data. Results: Compared to controls, cases took significantly more time for visual attention and task switching (P = 0.001), had poorer psychological functioning and speed (P = 0.001), and had poorer memory (P = 0.001). The number of episodes (depression/mania) was negatively correlated with psychomotor speed (P = 0.001), verbal working memory/attention (P = 0.049), and visual memory test (P = 0.031), respectively, and positively correlated with time taken for psychomotor functioning of cases (P = 0.001). Age of onset and reduction of psychomotor speed (P = 0.031) were positively correlated. Conclusions: Patients with bipolar disorder exhibited cognitive and psychosocial impairments during euthymic period. These impairments were correlated with number of episodes and age of onset.

Introduction Bipolar disorder (BD) has a lifetime prevalence of approximately 2% and is one of the 17 most disabling diseases worldwide. Multiple factors, beyond the impact of acute mood episodes, contribute to the burden of the disease. BD is also characterized by cognitive impairment (CI), which affects between 30% and 57% of patients during euthymic phases [1]. The most impacted cognitive domains are memory, attention, processing speed, and executive function [1]. CI plays a critical role in the diminished psychosocial functioning observed in BD patients [2, 3]. However, cognitive profiles in BD are heterogeneous, and the underlying causes of CI are likely multifactorial, involving more than just the effects of acute mood episodes. In recent years, growing evidence on the biomarkers associated with BD has expanded our understanding of various molecular pathways—such as inflammatory, oxidative stress, and dysmetabolic pathways—which have been linked to CI. These pathways not only affect cognitive function but also contribute to an increased risk of metabolic and inflammatory comorbidities, further exacerbating CI and the overall burden of the illness [4, 5]. As a result, further research into biomarkers of CI is essential, as it may enhance our knowledge of the molecular mechanisms involved and help identify potential pharmaceutical targets. Despite recent systematic reviews on the topic, most have focused on individual pathways [2, 6], and there is a need for a more comprehensive review of the current evidence regarding biomarkers linked to CI in BD. Objectives The goal of the present review is to examine the relationship between peripheral biomarkers (e.g., blood, saliva, urine) and impairments across specific cognitive domains in individuals with BD in euthymic state. Methods Inclusion/exclusion criteria: we included studies that assessed patients in euthymic states at the time of both cognitive evaluation and biomarker collection, and we excluded studies employing more invasive techniques (e.g., spinal puncture). Study quality will be assessed using the Joanna Briggs Institute Critical Appraisal tools. Results A database search (PubMed, Scopus, PsychInfo) identified 6,767 records after duplicate removal. Following title, abstract, and full-text screening, as well as manual reference list checks, a total of 52 studies were included. Data extraction is currently ongoing and includes publication year, country of origin, study design, sample size, sociodemographic and clinical characteristics, cognitive assessment tools, biomarkers investigated, and study outcomes. Conclusions Conclusions will be drawn at the end of the systematic review process. Further research into biomarkers of CI in BD is essential, as it may enhance our knowledge of the molecular mechanisms involved and help identify potential pharmaceutical targets. Disclosure of Interest None Declared

Bipolar disorder (BD) is commonly associated with cognitive impairments, that directly contribute to patients' functional disability. However, there is no effective treatment targeting cognition in BD. A key reason for the lack of pro-cognitive interventions is the limited insight into the brain correlates of cognitive impairments in these patients. This is the first study investigating the resting-state neural underpinnings of cognitive impairments in different neurocognitive subgroups of patients with BD. Patients with BD in full or partial remission and healthy controls (final sample of n = 144 and n = 50, respectively) underwent neuropsychological assessment and resting-state functional magnetic resonance imaging. We classified the patients into cognitively impaired (n = 83) and cognitively normal (n = 61) subgroups using hierarchical cluster analysis of the four cognitive domains. We used independent component analysis (ICA) to investigate the differences between the neurocognitive subgroups and healthy controls in resting-state functional connectivity (rsFC) in the default mode network (DMN), executive central network (ECN), and frontoparietal network (FPN). Cognitively impaired patients displayed greater positive rsFC within the DMN and less negative rsFC within the ECN than healthy controls. Across cognitively impaired patients, lower positive connectivity within DMN and lower negative rsFC within ECN correlated with worse global cognitive performance. Cognitive impairments in BD seem to be associated with a hyper-connectivity within the DMN, which may explain the failure to suppress task-irrelevant DMN activity during the cognitive performance, and blunted anticorrelation in the ECN. Thus, aberrant connectivity within the DMN and ECN may serve as brain targets for pro-cognitive interventions.

Cognitive impairment is a core feature of schizophrenia. These deficits can also serve as an endophenotype for the illness in genetic studies. There is evidence that suggests that cognition can be considered a reasonable target for intervention in both schizophrenia and bipolar disorder. One of the most studied genetic phenotypes for psychosis is brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms. BDNF has an established role in neuronal development and cell survival in response to stress and is abnormally expressed in schizophrenia. Studies have shown that childhood trauma is associated with poor prognosis of schizophrenic patients. BDNF-Val66Met polymorphism has been shown to moderate the impact of childhood adversity on later expression of affective symptoms, suggesting the possibility of gene environment interactions. Considering the recent advances of neuroscience an up to date review of relevant literature is warranted in this field. This article reviews the current literature available regarding associations between the Val66Met polymorphism, childhood trauma and cognitive dysfunction in schizophrenia.

5-hydroxytryptamine6 receptor (5-HT6R) antagonists have shown efficacy in animal models for cognitive impairment in multiple cognitive domains relevant for schizophrenia. Improvements were found with 5-HT6R antagonists in preclinical tests for episodic memory, social cognition, executive function, working memory and several other tests for both learning and memory. In contrast, there is little evidence for efficacy on attention. It will be interesting to further investigate 5-HT6R antagonists in neurodevelopmental animal models which are based on prenatal exposure to specific environmental insults, and are characterized by a high level of face, construct and predictive validity for cognitive impairments associated with schizophrenia. It is also important to do more add-on preclinical studies of 5-HT6 antagonists with antipsychotics. Possible mechanisms of action to improve cognition have been described. 5-HT6R antagonists decrease GABA release and GABAergic interneuron excitability, which subsequently disinhibits glutamate and/or acetylcholine release and results in enhancement of synaptic plasticity. Furthermore, cognition could be improved by 5-HT6R antagonists, because these compounds increase the number of NCAM PSA-immunoreactive neurons in the dendate gyrus, inhibit mTOR and Fyn-tyrosine kinase and interact with DARPP-32. Interestingly, there is increasing preclinical evidence that could support additional benefits of 5-HT6R ligandson comorbid conditions in schizophrenia such as drug abuse, depression, anxiety, obesity andantipsychotic-induced EPS. Finally, we briefly give an overview of the 5-HT6R compounds that are currently in clinical development for the treatment of cognitive impairment in both schizophrenia and Alzheimer's disease.

Neurological soft signs (NSS) and cognitive impairment in chronic schizophrenia

Prevalence and correlates of cognitive impairment in euthymic adults with bipolar disorder: A systematic review

Background: Cognitive impairments are common in bipolar disorder, which can negatively impact patients' psychological and psychosocial functioning, but there are no tools for assessing cognitive deficits, especially in patients with bipolar disorder in Iran. Objectives: This study assessed the psychometric properties of the Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA) scale in Iranian patients with bipolar disorder (BD). Methods: Eighty patients diagnosed with bipolar spectrum disorder were selected from Tehran's major psychiatric facilities: Razi Psychiatric Hospital and Taleghani Hospital. A purposive sampling method was followed to select 80 non-patient control individuals from the general population in Tehran. Participants were evaluated using the Beck Depression Inventory-II (BDI-II), the Bech-Rafaelsen Mania Rating Scale (BRMAS), the Mini-Mental State Examination (MMSE), and the COBRA. The data were analyzed using SPSS-24 to evaluate convergent and discriminant validity, test-retest reliability, and internal consistency. Results: The convergent validity was examined by calculating the correlation between the scores on the COBRA and those on the MMSE; the results were significant (r = - 0.63, P < 0.001). Discriminant validity was assessed by comparing the COBRA total scores between the patients with BD and the control group; the results indicated a significant difference between the two groups (t = 6.413, P = 0.001). The CFA and EFA showed that the one-factor structure of COBRA was the best model. The Cronbach's alpha of 0.72 indicated an internal consistency. A test-retest reliability estimate of 0.84 indicated the high reliability of the scale. The current investigation suggested a cutoff score of 28, with 0.72 sensitivity and 0.69 specificity. Conclusions: Our translated version of the COBRA in Persian in this study showed adequate psychometric properties. This test can be considered an applicable instrument in investigating cognitive complaints in patients with bipolar disorder in Iran.

To review the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of ziprasidone as a treatment for schizophrenia. Information was selected from a MEDLINE search (July 2000-October 2001) of English-language medical literature using ziprasidone as the search term. Manual searches of pertinent journal article references, request for medical information from Pfizer, and access of the Web site of the Food and Drug Administration were also performed. All available published information regarding the pertinent characteristics of ziprasidone were considered for selection. Pharmacology and pharmacokinetic studies were selected to provide a comprehensive description of these characteristics. Clinical investigations were evaluated for design, sample size, diagnosis, duration, and outcome. Data from all investigations were selected by 1 author and reviewed by both authors. Ziprasidone is a benzisothiazolyl piperazine-type atypical antipsychotic that shares the serotonin(2A)/dopamine(2) (5-HT(2A)/D(2)) profile of the available atypical antipsychotics. Ziprasidone has demonstrated in vitro activity as a 5-HT(1A) receptor agonist and as a very weak inhibitor of serotonin and norepinephrine reuptake. These data do not support ziprasidone as being a clinically meaningful inhibitor of serotonin/norepinephrine reuptake. Oral bioavailability of ziprasidone taken with food is approximately 60%, half-life is approximately 6-7 hours, and protein binding is extensive at >99%. Twelve metabolites have been identified, yet only 4 of these are considered to be primary metabolites. Metabolism of ziprasidone by aldehyde oxidase produces its only metabolite with potential pharmacologic activity; CYP3A4 also contributes to the metabolism of ziprasidone. Clinical studies support ziprasidone as efficacious for the treatment of patients with acute exacerbations of schizophrenia or schizoaffective disorder. Daily doses permitted in these clinical trials ranged from 40 to 160 mg, but only doses between 120 and 160 mg/d have been superior to placebo. Future research efforts should be directed toward refractory schizophrenia, cognitive impairment in schizophrenia, affective and anxiety symptoms associated with schizoaffective disorder, and bipolar disorder. Adverse effect characteristics of ziprasidone commonly include headache, nausea, and somnolence; infrequent effects include extrapyramidal symptoms and weight gain. Ziprasidone has been reported to cause an average QTc prolongation of approximately 20 msec; there have only been 2 patients (0.06%) reported by the manufacturer to have a measured QTc interval >500 msec. Ziprasidone is a safe and efficacious atypical antipsychotic for the acute management of schizophrenia. Efficacy data and most safety data for ziprasidone support its use as a first-line treatment for schizophrenia; however, its potential effects on ventricular repolarization relegate it to second-line status in patients with comorbid cardiovascular risks.

Individuals with attention-deficit/hyperactivity disorder (AD/HD) and autism spectrum disorders (ASD) often display symptoms from other diagnostic categories. Exclusion criteria in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the International Statistical Classification of Diseases and Related Health Problems (ICD-10) impede the use of categorical diagnoses to describe the particular problem constellation in a patient. In this study, we describe the prevalence and patterns of comorbid bipolar and psychotic disorders in 241 consecutively referred adult patients with AD/HD and/or ASD. Thirty per cent of patients with AD/HD had comorbid ASD and 38% of patients with ASD had comorbid AD/HD. Of the subjects with ASD, 7% had bipolar disorder with psychotic features, and 7.8% had schizophrenia or another psychotic disorder. The corresponding figures for the patients with AD/HD were 5.0% and 5.0%, respectively. Current diagnostic criteria have to be revised to acknowledge the comorbidity of bipolar and/or psychotic disorders in AD/HD and ASD.

Purpose of the article Synaptic plasticity is known to play role in pathogenesis of schizophrenia. Cognitive impairment is one of the complications of schizophrenia, leading to poor quality of life. Matrix metalloprotease-9 (MMP-9) and neurotrophin-3 (NT-3) are markers of synaptic plasticity, widely investigated in neuropsychiatric disorders. The objective of the study was to investigate the levels of MMP-9 and NT-3 and their association with cognitive impairment in schizophrenia. Material and methods 124 schizophrenia patients and 124 controls were enrolled in the study. MMP-9 and NT-3 were estimated in both the groups using ELISA. Cognition was assessed using Addenbrooke cognitive examination-III (ACE-III) and disease severity was assessed using PANSS. Results MMP-9 (p = .003) and NT −3 (p < .001) were found to be elevated in schizophrenia cases compared to controls. There was significant association of MMP-9 with fluency (r = −0.195, p = .030), language (r = −0.196, p = .029) and total ACE-III scores (r = −0.197, p = .029). Also we observed that MMP-9 increases the risk of cognitive impairment in schizophrenia patients (OR = 2.509, CI= 1.215 − 5.18, p = .013). Conclusion MMP-9 and NT-3 are elevated in schizophrenia. MMP-9 was associated with fluency and language component of cognition and increases the risk of cognitive impairment in schizophrenia.

This study examined the criterion and construct validity of a brief computerized cognitive test battery (CogState Schizophrenia Battery) compared to a conventional cognitive test battery recommended by the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) consensus. The CogState and MATRICS batteries yielded comparable effect sizes in comparing patients with schizophrenia to healthy controls (Cohen's ds = −1.50 for both batteries). Moderate to large correlations were observed between CogState and MATRICS measures of processing speed, attention/vigilance, working memory, verbal and visual learning, reasoning/problem solving, and social cognition (rs = .56–.79). CogState and MATRICS composite scores also correlated strongly with scores on the University of California at San Diego (UCSD) Performance-Based Skills Assessment (UPSA; rs = .76 and .79, respectively) in patients with schizophrenia. Results of this study suggest that the CogState Schizophrenia Battery provides valid measurement of the cognitive domains nominated by the MATRICS consensus group as being important to consider in the context of pharmacological treatments for cognitive impairment in schizophrenia.