Delineating classical schizophrenia: quantifying disorganization and the core deficit in classical schizophrenia and exploring their neural correlates

Despite the moderate efficacy of antipsychotic medication, many patients with psychotic illnesses continue to experience persisting symptoms and disability. The classical descriptions of schizophrenia by Kraepelin and Bleuler emphasize disorganization and impoverishment of mental activity together with impairment of cognition and role function. In this thesis, we examine the core classical features of disorganization, impoverishment, and cognitive dysfunction, along with impairment in role-function in psychotic illnesses. In addition, we examine the relationship between these classical features and reality distortion, the characteristic feature of florid episodes of psychosis. Methods of quantifying disorganization and impoverishment using systematic review of three common symptom scales is presented in Chapter1, along with methods to quantify formal thought disorder (FTD) using speech and language manifestations. Cognition as a core feature is presented with supporting evidence in Chapter 2 along with rationale for neural investigation tools that we employed. Chapter 3 presents confirmatory factor analysis (CFA) investigation of core features to identify a single latent variable of shared variance (classicality), termed putative core deficit, along with cluster analysis to try to seek the answer for dimensionality versus categorical nature of classicality. Chapter 4 presents maximum likelihood factor analysis (EFA) and cluster analysis in an independent sample with stable psychosis illness, but with advantage of availability of persistent measures of disorganization and impoverishment, in addition to current measures. Chapter 5 presents delineation of core deficit from a heterogenous multi-centre mix sample of recent onset and established schizophrenia. Chapter 6 presents neural correlates of classicality in the sample described in chapter 5. Relationship of core deficit with reality distortion and FTD is explored in all three independent samples, in addition to neural correlates. Our results demonstrate that a single latent variable of core deficit is derived from each of the three independent samples, and we further demonstrate in two samples that core deficit predicts reality distortion as well as positive correlation with FTD measure. We argue for core deficit to be a valid and replicable marker of classicality which can be targeted with focussed interventions to potentially ameliorate the burden of psychosis and to improve outcome. Through our cluster analysis, we demonstrate that classicality data fits into dimensional nature rather than discrete categories. Our results provide evidence for post-movement beta rebound (PMBR), an electrophysiology neural marker, to be diminished in proportion to the severity of core deficit. Limitations include small sample size, cross-sectional nature of data and potential confounding effect from variables such as medication exposure. We recommend for future large-scale research and clinical efforts towards potential development of a new scale utilising severity of core deficit, along with trials of focussed psychopharmacology and neuromodulation interventions to ameliorate the severity of core deficit

Small for gestational age babies and depressive symptoms of mothers during pregnancy: Results from a birth cohort in India

Background: Annually, more than a million Low birthweight (LBW) are born in India, often afflicting disadvantaged families. Several studies have undertaken association of poverty, nutritional status, and obstetric factors with LBW. Through our study, we aimed to examine the possibility of any relation between Edinburgh Postnatal Depression Scale (EPDS) score measured during pregnancy with incidence of babies born Small for Gestational Age (SGA). Moreover, we explored if there is any utility for identifying a cut-off point of EPDS for predicting SGA.Methods: Pregnant women attending the antenatal clinic at a public hospital between 14 to 32 weeks were recruited from April 2016 to Oct 2017. The EPDS was administered to assess depression through face-to-face interviews. Newborn anthropometry was performed post-delivery. For analysis, birth weight 90th percentile as Large for Gestational Age (LGA).Results: Prevalence of depressive symptoms (EPDS score >11) was 16.5% (n=108/654) in antenatal mothers. These women delivered a higher proportion of SGA babies (21.3 v/s 15.8) and LGA (9.3 v/s 3.3) compared to women with no symptoms. The odds of women giving birth to a child with SGA were twice as high for women with EPDS scores >11 (adjusted OR = 2.03; 95% CI = 1.12 – 3.70) compared to the women with EPDS scores of ≤11. In terms of Area under curve (AUC), EPDS 11 cut off (AUC: 0.757, CI 0.707- 0.806) was same as EPDS 12 cut-off (AUC: 0.757, CI 0.708- 0.807), which was slightly lower than EPDS 13 cut off (AUC: 0.759 CI 0.709- 0.809).Conclusions: We found a strong association of antenatal depressive symptoms during pregnancy with SGA measured by EPDS. Thus, we recommend implementation of timely and effective screening, diagnostic services, and evidence-based antenatal mental health services in order to combat SGA, and further associated-metabolic syndromes

Quantifying the core deficit in classical schizophrenia

In the classical descriptions of schizophrenia, Kraepelin and Bleuler recognised disorganization and impoverishment of mental activity as fundamental symptoms. Their classical descriptions also included a tendency to persisting disability. The psychopathological processes underlying persisting disability in schizophrenia remain poorly understood. The delineation of a core deficit underlying persisting disability would be of value in predicting outcome and enhancing treatment. We tested the hypothesis that mental disorganization and impoverishment are associated with persisting impairments of cognition and role-function, and together reflect a latent core deficit that is discernible in cases diagnosed by modern criteria. We used Confirmatory Factor Analysis to determine whether measures of disorganisation, mental impoverishment, impaired cognition and role functioning in 40 patients with schizophrenia represent a single latent variable. Disorganization scores were computed from the variance shared between disorganization measures from three commonly used symptom scales. Mental impoverishment scores were computed similarly. A single factor model exhibited a good fit, supporting the hypothesis that these measures reflect a core deficit.Persisting brain disorders are associated with a reduction in Post Motor Beta Rebound (PMBR), the characteristic increase in electrophysiological beta amplitude that follows a motor response. Patients had significantly reduced PMBR compared with healthy controls. PMBR was negatively correlated with core deficit score.While the symptoms constituting impoverished and disorganised mental activity are dissociable in schizophrenia, nonetheless, the variance that these two symptom domains share with impaired cognition and role function, appears to reflect a pathophysiological process that might be described as the core deficit of classical schizophrenia

Defining the disturbance in cortical glutamate and GABA function in psychosis and its origins and consequences

It is widely thought that the onset of psychotic symptoms in schizophrenia may arise from an early neurotoxic phase, possibly related to oxidative stress or inflammation, and a late residual damage phase associated with persistent negative symptoms. We tested this hypothesis in a 3-centre study using magnetic resonance spectroscopy (MRS) to determine whether abnormalities in glutamate, glutamine and GABA content in anterior cingulate cortex (ACC) differed between people with minimally treated ‘Recent’ onset schizophrenia and an ‘Established’ group with > 10 years of treatment. We tested whether neurochemical abnormalities were i) mediated by raised circulating inflammatory cytokine concentrations, c-reactive protein (CRP) and interleukin-6 (IL-6), or depletion of glutathione and ii) associated with ratings of positive and negative symptoms. Relative to age-matched controls, the Established group showed significantly greater reduction in ACC glutamate than the Recent group, which did not differ from controls. This effect was not attributable to antipsychotic drug exposure. Patient ACC glutathione was negatively correlated with age. IL-6 was increased in both clinical groups, while increases in CRP were greater in the Established than Recent group. Elevated CRP was entirely accounted for by greater antipsychotic drug exposure and BMI, while residual elevation in IL-6 in the Established group did not account for their lower ACC glutamate. GABA was reduced relative to controls across ACC and occipital voxels. This reduction was not associated with drug treatment, BMI or cytokine levels. Only ACC GABA content correlated significantly with symptoms, lower content with greater positive and negative symptoms across both groups

Delineating classical schizophrenia: quantifying disorganization and the core deficit in classical schizophrenia and exploring their neural correlates

Despite the moderate efficacy of antipsychotic medication, many patients with psychotic illnesses continue to experience persisting symptoms and disability. The classical descriptions of schizophrenia by Kraepelin and Bleuler emphasize disorganization and impoverishment of mental activity together with impairment of cognition and role function. In this thesis, we examine the core classical features of disorganization, impoverishment, and cognitive dysfunction, along with impairment in role-function in psychotic illnesses. In addition, we examine the relationship between these classical features and reality distortion, the characteristic feature of florid episodes of psychosis. Methods of quantifying disorganization and impoverishment using systematic review of three common symptom scales is presented in Chapter1, along with methods to quantify formal thought disorder (FTD) using speech and language manifestations. Cognition as a core feature is presented with supporting evidence in Chapter 2 along with rationale for neural investigation tools that we employed. Chapter 3 presents confirmatory factor analysis (CFA) investigation of core features to identify a single latent variable of shared variance (classicality), termed putative core deficit, along with cluster analysis to try to seek the answer for dimensionality versus categorical nature of classicality. Chapter 4 presents maximum likelihood factor analysis (EFA) and cluster analysis in an independent sample with stable psychosis illness, but with advantage of availability of persistent measures of disorganization and impoverishment, in addition to current measures. Chapter 5 presents delineation of core deficit from a heterogenous multi-centre mix sample of recent onset and established schizophrenia. Chapter 6 presents neural correlates of classicality in the sample described in chapter 5. Relationship of core deficit with reality distortion and FTD is explored in all three independent samples, in addition to neural correlates. Our results demonstrate that a single latent variable of core deficit is derived from each of the three independent samples, and we further demonstrate in two samples that core deficit predicts reality distortion as well as positive correlation with FTD measure. We argue for core deficit to be a valid and replicable marker of classicality which can be targeted with focussed interventions to potentially ameliorate the burden of psychosis and to improve outcome. Through our cluster analysis, we demonstrate that classicality data fits into dimensional nature rather than discrete categories. Our results provide evidence for post-movement beta rebound (PMBR), an electrophysiology neural marker, to be diminished in proportion to the severity of core deficit. Limitations include small sample size, cross-sectional nature of data and potential confounding effect from variables such as medication exposure. We recommend for future large-scale research and clinical efforts towards potential development of a new scale utilising severity of core deficit, along with trials of focussed psychopharmacology and neuromodulation interventions to ameliorate the severity of core deficit

The Prevalence of Attention-Deficit Hyperactivity Disorder in Functional Neurological Disorder: An Integrative Literature Review

Aims Functional Neurological Disorders (FNDs) affect motor or sensory functions without a detectable underlying disease. FNDs encompass a range of presentations including non-epileptic seizures, cognitive changes, weakness, and sensory symptoms. The prevalence of FND as a diagnosis is increasing rapidly. Following our clinical observations of a high prevalence of Attention-Deficit Hyperactivity Disorder (ADHD) in people referred with a previous diagnosis of FND to our tertiary Neuropsychiatry pilot service in Derbyshire, we conducted an integrative literature review with the aim to investigate the prevalence of ADHD in people diagnosed with FND. Methods We conducted an integrative literature review using a systematic approach. A literature search was performed on two databases, PubMed and ScienceDirect. The keywords ‘Functional Neurological Disorder’, ‘Attention-Deficit Hyperactivity Disorder’, ‘Non-Epileptic Seizures’, ‘Functional’ were used. Databases were searched for initial search on 31 November 2023 and the search was repeated on 31 January 2024. Only articles in English language were included. Studies were eligible if reporting the prevalence of ADHD in FND populations. Studies involving adults and children were included. A further search was conducted on reference lists from the selected articles. Results Database searches on PubMed and ScienceDirect had 298 and 11,837 results, respectively. Only seven studies were identified that explored the prevalence of ADHD in individuals diagnosed with a FND and were included. In the adult population an association between a FND diagnosis, and ADHD traits identified on screening, or a final ADHD diagnosis was identified. The findings also demonstrate an increased incidence of comorbid ADHD and FND with the presence of another co-existing neurodevelopmental disorder such as Autism Spectrum Disorder. Furthermore, results indicated that the prevalence of an ADHD diagnosis in children with a FND was higher compared with adults. The literature suggests that, in both adults and children with FND-related functional seizures there is an increased prevalence of comorbid ADHD. Conclusion In conclusion, the findings from this review demonstrate a lack of evidence looking into the prevalence of Attention-Deficit Hyperactivity Disorder in complex presentations being labelled as Functional Neurological Disorder. However, the existing literature indicates there is an association between FND and ADHD. These findings highlight the importance of considering potential ADHD comorbidity in the assessment and management of FND, potentially informing targeted treatment approaches for affected individuals. Further research could explore the efficacy of ADHD medication and similar dopamine modulating molecules in treating sub-cohort of people with FND

Quantifying the Core Deficit in Classical Schizophrenia From Three Independent Samples of Psychosis Spectrum Patients

Aims In schizophrenia, disorganisation and impoverished mental activity (as described in the classical descriptions by Kraepelin and Bleuler) together with impaired cognitive function, predict persisting functional impairment (Liddle, 2019). We propose that in schizophrenia, four ‘classical’ features (disorganisation, impoverished mental activity, cognitive dysfunction, and impaired role-functioning) arise from a shared pathophysiological process that increases risk of persisting functional impairment. We also propose that this shared process creates a risk of subsequent episodic reality distortion (delusions and hallucinations). In the current work, we investigate whether a single latent variable accounts for the shared variance in the four ‘classical’ features. We also investigate whether the severity of this latent variable based on assessment of long-standing classical symptoms predicts severity of current reality distortion. Methods We performed maximum likelihood factor analysis of disorganisation, impoverishment, cognition and role-function in three separate samples of patients (n = 54, n = 128, n = 64) with DSM diagnosed schizophrenia, schizo-affective disorder or bipolar disorder. In the first two samples, we quantified current disorganisation and impoverished mental activity using the Positive and Negative Syndrome Scale (PANSS). In the third, we scored persistent disorganisation and impoverished mental activity according to Symptoms & Signs of Psychosis Illness (SSPI) based on systematic examination of case records. We assessed cognition using the Digit Symbol Substitution Test (DSST) and role-function using the Social & Occupational functioning scale (in two studies) and the Personal & Social Performance scale (in one study). We quantified current reality distortion by summing SSPI scores for current delusions and hallucinations. Results In each of the three studies, a single latent variable accounted for more than 50% of variance. Loadings were similar whether current or persistent symptoms were used. The latent variable derived from persistent symptom scores correlated significantly with current reality distortion. Conclusion This series of studies provide further evidence that disorganisation, impoverished mental activity, cognitive impairment and impaired role function share substantial variance, consistent with the proposal that they reflect a core pathophysiological process underlying ‘classical’ schizophrenia. Furthermore, our findings are consistent with the hypothesis that over time, this pathophysiological process increases the risk of episodic reality distortion. However, these were all cross-sectional studies, and need to be confirmed using longitudinal data. Our findings have potential clinical and research implications including development of a custom-made clinical tool to quantify the core deficit as well as investigating targeted interventions employing medication or neuromodulation

Data_Sheet_1_Sociodemographic and Medical Risk Factors Associated With Antepartum Depression.PDF

Background<p>The increasing recognition of antenatal depression is an emerging area of concern in developing countries. We conducted a study to estimate the prevalence of antenatal mental distress and its relation with sociodemographic factors, obstetric factors, and physiological wellbeing in pregnant women attending public health facilities in Bengaluru, South India.</p>Methods<p>Nested within a cohort study, we assessed the mental status in 823 pregnant women in two public referral hospitals. Kessler Psychological Distress Scale (K-10 scale) was used to assess maternal depression. We collected information related to social-demographic characteristics and recent medical complaints. Descriptive statistics and odds ratios were calculated using SPSS version 20.</p>Results<p>Results show that 8.7% of the women exhibited symptoms of antenatal depression. Sociodemographic characteristics, such as respondent occupation, husband education, husband’s occupation, total family income showed significance. First time pregnancy, anemia, and high blood pressure were also associated with mental distress.</p>Conclusion<p>Our study has demonstrated feasibility of screening for mental health problems in public hospitals. Early detection of mental distress during pregnancy is crucial as it has a direct impact on the fetus. The public health facilities in low- and middle-income countries such as India should consider piloting and scaling up screening services for mental health conditions for pregnant women.</p

Data_Sheet_2_Sociodemographic and Medical Risk Factors Associated With Antepartum Depression.PDF

Background<p>The increasing recognition of antenatal depression is an emerging area of concern in developing countries. We conducted a study to estimate the prevalence of antenatal mental distress and its relation with sociodemographic factors, obstetric factors, and physiological wellbeing in pregnant women attending public health facilities in Bengaluru, South India.</p>Methods<p>Nested within a cohort study, we assessed the mental status in 823 pregnant women in two public referral hospitals. Kessler Psychological Distress Scale (K-10 scale) was used to assess maternal depression. We collected information related to social-demographic characteristics and recent medical complaints. Descriptive statistics and odds ratios were calculated using SPSS version 20.</p>Results<p>Results show that 8.7% of the women exhibited symptoms of antenatal depression. Sociodemographic characteristics, such as respondent occupation, husband education, husband’s occupation, total family income showed significance. First time pregnancy, anemia, and high blood pressure were also associated with mental distress.</p>Conclusion<p>Our study has demonstrated feasibility of screening for mental health problems in public hospitals. Early detection of mental distress during pregnancy is crucial as it has a direct impact on the fetus. The public health facilities in low- and middle-income countries such as India should consider piloting and scaling up screening services for mental health conditions for pregnant women.</p