Neuropsychological differences between treatment-resistant and treatment-responsive schizophrenia: a meta-analysis.

Antipsychotic treatment resistance affects up to a third of individuals with schizophrenia. Of those affected, 70-84% are reported to be treatment resistant from the outset. This raises the possibility that the neurobiological mechanisms of treatment resistance emerge before the onset of psychosis and have a neurodevelopmental origin. Neuropsychological investigations can offer important insights into the nature, origin and pathophysiology of treatment-resistant schizophrenia (TRS), but methodological limitations in a still emergent field of research have obscured the neuropsychological discriminability of TRS. We report on the first systematic review and meta-analysis to investigate neuropsychological differences between TRS patients and treatment-responsive controls across 17 published studies (1864 participants). Five meta-analyses were performed in relation to (1) executive function, (2) general cognitive function, (3) attention, working memory and processing speed, (4) verbal memory and learning, and (5) visual-spatial memory and learning. Small-to-moderate effect sizes emerged for all domains. Similarly to previous comparisons between unselected, drug-naïve and first-episode schizophrenia samples v. healthy controls in the literature, the largest effect size was observed in verbal memory and learning [dl = -0.53; 95% confidence interval (CI) -0.29 to -0.76; z = 4.42; p < 0.001]. A sub-analysis of language-related functions, extracted from across the primary domains, yielded a comparable effect size (dl = -0.53, 95% CI -0.82 to -0.23; z = 3.45; p < 0.001). Manipulating our sampling strategy to include or exclude samples selected for clozapine response did not affect the pattern of findings. Our findings are discussed in relation to possible aetiological contributions to TRS.

Demographic and clinical variables associated with response to clozapine in schizophrenia: a systematic review and meta-analysis.

Clozapine is the only licensed pharmacotherapy for treatment-resistant schizophrenia. However, response to clozapine is variable. Understanding the demographic and clinical features associated with response to clozapine may be useful for patient stratification for clinical trials or for identifying patients for earlier initiation of clozapine. We systematically reviewed the literature to investigate clinical and demographic factors associated with variation in clozapine response in treatment-resistant patients with schizophrenia spectrum disorders. Subsequently, we performed a random-effects meta-analysis to evaluate differences in duration of illness, age at clozapine initiation, age of illness onset, body weight and years of education between clozapine responders and non-responders. Thirty-one articles were eligible for qualitative review and 17 of these were quantitatively reviewed. Shorter duration of illness, later illness onset, younger age at clozapine initiation, fewer hospitalisations and fewer antipsychotic trials prior to clozapine initiation showed a trend to be significantly associated with a better response to clozapine. Meta-analysis of seven studies, totalling 313 subjects, found that clozapine responders had a significantly shorter duration of illness compared to clozapine non-responders [g = 0.31; 95% confidence interval (CI) 0.06-0.56; p = 0.01]. The results imply that a delay in clozapine treatment may result in a poorer response and that a focus on prompt treatment with clozapine is warranted.

PsyCog: A computerised mini battery for assessing cognition in psychosis.

Despite the functional impact of cognitive deficit in people with psychosis, objective cognitive assessment is not typically part of routine clinical care. This is partly due to the length of traditional assessments and the need for a highly trained administrator. Brief, automated computerised assessments could help to address this issue. We present data from an evaluation of PsyCog, a computerised, non-verbal, mini battery of cognitive tests. Healthy Control (HC) (N = 135), Clinical High Risk (CHR) (N = 233), and First Episode Psychosis (FEP) (N = 301) participants from a multi-centre prospective study were assessed at baseline, 6 months, and 12 months. PsyCog was used to assess cognitive performance at baseline and at up to two follow-up timepoints. Mean total testing time was 35.95 min (SD = 2.87). Relative to HCs, effect sizes of performance impairments were medium to large in FEP patients (composite score G = 1.21, subtest range = 0.52-0.88) and small to medium in CHR patients (composite score G = 0.59, subtest range = 0.18-0.49). Site effects were minimal, and test-retest reliability of the PsyCog composite was good (ICC = 0.82-0.89), though some practice effects and differences in data completion between groups were found. The present implementation of PsyCog shows it to be a useful tool for assessing cognitive function in people with psychosis. Computerised cognitive assessments have the potential to facilitate the evaluation of cognition in psychosis in both research and in clinical care, though caution should still be taken in terms of implementation and study design.

Anterior cingulate glutamate metabolites as a predictor of antipsychotic response in first episode psychosis: data from the STRATA collaboration.

Elevated brain glutamate has been implicated in non-response to antipsychotic medication in schizophrenia. Biomarkers that can accurately predict antipsychotic non-response from the first episode of psychosis (FEP) could allow stratification of patients; for example, patients predicted not to respond to standard antipsychotics could be fast-tracked to clozapine. Using proton magnetic resonance spectroscopy (1H-MRS), we examined the ability of glutamate and Glx (glutamate plus glutamine) in the anterior cingulate cortex (ACC) and caudate to predict response to antipsychotic treatment. A total of 89 minimally medicated patients with FEP not meeting symptomatic criteria for remission were recruited across two study sites. 1H-MRS and clinical data were acquired at baseline, 2 and 6 weeks. Response was defined as >20% reduction in Positive and Negative Syndrome Scale (PANSS) Total score from baseline to 6 weeks. In the ACC, baseline glutamate and Glx were higher in Non-Responders and significantly predicted response (P < 0.02; n = 42). Overall accuracy was greatest for ACC Glx (69%) and increased to 75% when symptom severity at baseline was included in the model. Glutamate metabolites in the caudate were not associated with response, and there was no significant change in glutamate metabolites over time in either region. These results add to the evidence linking elevations in ACC glutamate metabolites to a poor antipsychotic response. They indicate that glutamate may have utility in predicting response during early treatment of first episode psychosis. Improvements in accuracy may be made by combining glutamate measures with other response biomarkers.

Cognitive performance at first episode of psychosis and the relationship with future treatment resistance: Evidence from an international prospective cohort study.

BACKGROUND: Antipsychotic treatment resistance affects up to a third of individuals with schizophrenia, with recent research finding systematic biological differences between antipsychotic resistant and responsive patients. Our aim was to determine whether cognitive impairment at first episode significantly differs between future antipsychotic responders and resistant cases. METHODS: Analysis of data from seven international cohorts of first-episode psychosis (FEP) with cognitive data at baseline (N = 683) and follow-up data on antipsychotic treatment response: 605 treatment responsive and 78 treatment resistant cases. Cognitive measures were grouped into seven cognitive domains based on the pre-existing literature. We ran multiple imputation for missing data and used logistic regression to test for associations between cognitive performance at FEP and treatment resistant status at follow-up. RESULTS: On average patients who were future classified as treatment resistant reported poorer performance across most cognitive domains at baseline. Univariate logistic regressions showed that antipsychotic treatment resistance cases had significantly poorer IQ/general cognitive functioning at FEP (OR = 0.70, p = .003). These findings remained significant after adjusting for additional variables in multivariable analyses (OR = 0.76, p = .049). CONCLUSIONS: Although replication in larger studies is required, it appears that deficits in IQ/general cognitive functioning at first episode are associated with future treatment resistance. Cognitive variables may be able to provide further insight into neurodevelopmental factors associated with treatment resistance or act as early predictors of treatment resistance, which could allow prompt identification of refractory illness and timely interventions.

Cognitive function and treatment response trajectories in first-episode schizophrenia: evidence from a prospective cohort study.

OBJECTIVES: This prospective cohort study tested for associations between baseline cognitive performance in individuals early within their first episode and antipsychotic treatment of psychosis. We hypothesised that poorer cognitive functioning at the initial assessment would be associated with poorer antipsychotic response following the subsequent 6 weeks. DESIGN: Prospective cohort . SETTING: National Health Service users with a first-episode schizophrenia diagnosis, recently starting antipsychotic medication, recruited from two UK sites (King's College London, UK and University of Manchester, UK). Participants attended three study visits following screening. PARTICIPANTS: Eighty-nine participants were recruited, with 46 included in the main analysis. Participants required to be within the first 2 years of illness onset, had received minimal antipsychotic treatment, have the capacity to provide consent, and be able to read and write in English. Participants were excluded if they met remission criteria or showed mild to no symptoms. PRIMARY AND SECONDARY OUTCOME MEASURES: Antipsychotic response was determined at 6 weeks using the Positive and Negative Syndrome Scale (PANSS), with cognitive performance assessed at each visit using the Brief Assessment of Cognition in Schizophrenia (BACS). The groups identified (responders and non-responders) from trajectory analyses, as well as from >20% PANSS criteria, were compared on baseline BACS performance. RESULTS: Trajectory analyses identified 84.78% of the sample as treatment responsive, and the remaining 15.22% as treatment non-responsive. Unadjusted and adjusted logistic regressions observed no significant relationship between baseline BACS on subscale and total performance (BACS t-score: OR=0.98, p=0.620, Cohen's d=0.218) and antipsychotic response at 6 weeks. CONCLUSIONS: This investigation identified two clear trajectories of treatment response in the first 6 weeks of antipsychotic treatment. Responder and non-responder groups did not significantly differ on performance on the BACS, suggesting that larger samples may be required or that an association between cognitive performance and antipsychotic response is not observable in the first 2 years of illness onset. TRIAL REGISTRATION NUMBER: REC: 17/NI/0209.

Impaired verbal memory function is related to anterior cingulate glutamate levels in schizophrenia: findings from the STRATA study.

Impaired cognition is associated with lower quality of life and poor outcomes in schizophrenia. Brain glutamate may contribute to both clinical outcomes and cognition, but these relationships are not well-understood. We studied a multicentre cohort of 85 participants with non-affective psychosis using proton magnetic resonance spectroscopy. Glutamate neurometabolites were measured in the anterior cingulate cortex (ACC). Cognition was assessed using the Brief Assessment for Cognition in Schizophrenia (BACS). Patients were categorised as antipsychotic responders or non-responders based on treatment history and current symptom severity. Inverted U-shaped associations between glutamate or Glx (glutamate + glutamine) with BACS subscale and total scores were examined with regression analyses. We then tested for an interaction effect of the antipsychotic response group on the relationship between glutamate and cognition. ACC glutamate and Glx had a positive linear association with verbal memory after adjusting for age, sex and chlorpromazine equivalent dose (glutamate, ß = 3.73, 95% CI = 1.26-6.20, P = 0.004; Glx, ß = 3.38, 95% CI = 0.84-5.91, P = 0.01). This association did not differ between good and poor antipsychotic response groups. ACC glutamate was also positively associated with total BACS score (ß = 3.12, 95% CI = 0.01-6.23, P = 0.046), but this was not significant after controlling for antipsychotic dose. Lower glutamatergic metabolites in the ACC were associated with worse verbal memory, and this relationship was independent of antipsychotic response. Further research on relationships between glutamate and cognition in antipsychotic responsive and non-responsive illness could aid the stratification of patient groups for targeted treatment interventions.

The relationship between alexithymia and theory of mind: A systematic review.

Theory of Mind (ToM), the ability to represent the mental states of oneself and others, is an essential social skill disrupted across many psychiatric conditions. The transdiagnostic nature of ToM impairment means it is plausible that ToM impairment is related to alexithymia (difficulties identifying and describing one's own emotions), as alexithymia is seen across psychiatric conditions. Whilst many studies have examined links between alexithymia and ToM, results are mixed. Therefore, the purpose of this systematic review is to provide a taxonomy of ToM tests and assess their relationship with alexithymia. Tests are grouped according to whether they assess propensity to engage spontaneously in ToM or accuracy of ToM inferences, with tests further subdivided into those that do, and do not, require emotion recognition. A review of 63 suitable studies suggests that alexithymia is often associated with reduced ToM, and inaccurate ToM when tasks require emotion recognition. This latter finding appears due to impaired emotion recognition, rather than ToM impairment per se. Further directions and considerations for future research are discussed.

Cross-sectional study comparing cognitive function in treatment responsive versus treatment non-responsive schizophrenia: evidence from the STRATA study.

BACKGROUND: 70%-84% of individuals with antipsychotic treatment resistance show non-response from the first episode. Emerging cross-sectional evidence comparing cognitive profiles in treatment resistant schizophrenia to treatment-responsive schizophrenia has indicated that verbal memory and language functions may be more impaired in treatment resistance. We sought to confirm this finding by comparing cognitive performance between antipsychotic non-responders (NR) and responders (R) using a brief cognitive battery for schizophrenia, with a primary focus on verbal tasks compared against other measures of cognition. DESIGN: Cross-sectional. SETTING: This cross-sectional study recruited antipsychotic treatment R and antipsychotic NR across four UK sites. Cognitive performance was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS). PARTICIPANTS: One hundred and six participants aged 18-65 years with a diagnosis of schizophrenia or schizophreniform disorder were recruited according to their treatment response, with 52 NR and 54 R cases. OUTCOMES: Composite and subscale scores of cognitive performance on the BACS. Group (R vs NR) differences in cognitive scores were investigated using univariable and multivariable linear regressions adjusted for age, gender and illness duration. RESULTS: Univariable regression models observed no significant differences between R and NR groups on any measure of the BACS, including verbal memory (ß=-1.99, 95% CI -6.63 to 2.66, p=0.398) and verbal fluency (ß=1.23, 95% CI -2.46 to 4.91, p=0.510). This pattern of findings was consistent in multivariable models. CONCLUSIONS: The lack of group difference in cognition in our sample is likely due to a lack of clinical distinction between our groups. Future investigations should aim to use machine learning methods using longitudinal first episode samples to identify responder subtypes within schizophrenia, and how cognitive factors may interact within this. TRAIL REGISTRATION NUMBER: REC: 15/LO/0038.

No effect of age on emotion recognition after accounting for cognitive factors and depression.

A decline in emotion recognition ability across the lifespan has been well documented. However, whether age predicts emotion recognition difficulties after accounting for potentially confounding factors which covary with age remains unclear. Although previous research suggested that age-related decline in emotion recognition ability may be partly a consequence of cognitive (fluid intelligence, processing speed) and affective (e.g., depression) factors, recent theories highlight a potential role for alexithymia (difficulty identifying and describing one's emotions) and interoception (perception of the body's internal state). This study therefore aimed to examine the recognition of anger and disgust across the adult lifespan in a group of 140 20-90-year-olds to see whether an effect of age would remain after controlling for a number of cognitive and affective factors potentially impacted by age. In addition, using an identity recognition control task, the study aimed to determine whether the factors accounting for the effects of age on emotion discrimination also contribute towards generalised face processing difficulties. Results revealed that discrimination of disgust and anger across the lifespan was predicted by processing speed and fluid intelligence, and negatively by depression. No effect of age was found after these factors were accounted for. Importantly, these effects were specific to emotion discrimination; only crystallised intelligence accounted for unique variance in identity discrimination. Contrary to expectations, although interoception and alexithymia were correlated with emotion discrimination abilities, these factors did not explain unique variance after accounting for other variables.

Direct and indirect effects of age on interoceptive accuracy and awareness across the adult lifespan.

Various aspects of physical and mental health have been linked to an individual's ability to perceive the physical condition of their body ('interoception'). In addition, numerous studies have demonstrated a role for interoception in higher-order cognitive abilities such as decision-making and emotion processing. The importance of interoception for health and typical cognitive functioning has prompted interest in how interoception varies over the lifespan. However, few studies have investigated interoception into older adulthood, and no studies account for the set of physiological changes that may influence task performance. The present study examined interoception from young to very late adulthood (until 90 years of age) utilising a self-report measure of interoception (Study One) and an objective measure of cardiac interoception (Study Two). Across both studies, interoception decreased with age, and changes in interoceptive accuracy were observed which were not explained by accompanying physiological changes. In addition to a direct effect of age on interoception, an indirect effect of ageing on cardiac interoceptive accuracy mediated by body mass index (BMI) was found, such that ageing was associated with increased BMI which was, in turn, associated with reduced interoceptive accuracy. Such findings support and extend previous research demonstrating interoceptive decline with advancing age, and highlight the importance of assessing whether decreasing interoceptive ability is responsible for some aspects of age-related ill-health and cognitive impairment.

Knowledge of resting heart rate mediates the relationship between intelligence and the heartbeat counting task.

Evidence suggests that intelligence is positively associated with performance on the heartbeat counting task (HCT). The HCT is often employed as measure of interoception - the ability to perceive the internal state of one's body - however it's use remains controversial as performance on the HCT is strongly influenced by knowledge of resting heart rate. This raises the possibility that heart rate knowledge may mediate the previously-observed association between intelligence and HCT performance. Study One demonstrates an association between intelligence and HCT performance (N = 94), and Study Two demonstrates that this relationship is mediated by knowledge of the average resting heart rate (N = 134). These data underscore the need to account for the influence of prior knowledge and beliefs when examining individual differences in cardiac interoceptive accuracy using the HCT.