Glutamatergic neurotransmission in schizophrenia: A systematic review and quantitative synthesis of proton magnetic resonance spectroscopy studies across schizophrenia spectrum disorders.

OBJECTIVE: Studies using proton magnetic resonance spectroscopy reveal substantial inconsistencies in the levels of brain glutamate, glutamine and glutamate + glutamine across schizophrenia spectrum disorders. This systematic review employs qualitative and quantitative methods to analyse the patterns and relationships between glutamatergic metabolites, schizophrenia spectrum disorders and brain regions. METHODS: A literature search was conducted using various databases with keywords including glutamate, glutamine, schizophrenia, psychosis and proton magnetic resonance spectroscopy. Inclusion criteria were limited to case-control studies that reported glutamatergic metabolite levels in adult patients with a schizophrenia spectrum disorder diagnosis - i.e. first-episode psychosis, schizophrenia, treatment-resistant schizophrenia and/or ultra-treatment-resistant schizophrenia - using proton magnetic resonance spectroscopy at 3 T or above. Pooled study data were synthesized and analysed. RESULTS: A total of 92 studies met the inclusion criteria, including 2721 healthy controls and 2822 schizophrenia spectrum disorder participants. Glu levels were higher in the basal ganglia, frontal cortex and medial prefrontal of first-episode psychosis participants, contrasting overall lower levels in schizophrenia participants. For Gln, strong differences in metabolite levels were evident in the basal ganglia, dorsolateral prefrontal cortex and frontal cortex, with first-episode psychosis showing significantly higher levels in the basal ganglia. In glutamate + glutamine, higher metabolite levels were found across schizophrenia spectrum disorder groups, particularly in the basal ganglia and dorsolateral prefrontal cortex of treatment-resistant schizophrenia participants. Significant relationships were found between metabolite levels and medication status, clinical measures and methodological variables. CONCLUSION: The review highlights abnormal glutamatergic metabolite levels throughout schizophrenia spectrum disorders and in specific brain regions. The review underscores the importance of standardized future research assessing glutamatergic metabolites using proton magnetic resonance spectroscopy due to considerable literature heterogeneity.

Exploring the cognitive profiles related to unimodal auditory versus multisensory hallucinations in schizophrenia-spectrum disorders.

INTRODUCTION: Hallucinations can be experienced across multiple sensory modalities, but psychiatric studies investigating the cognitive mechanisms of hallucinations have been somewhat restricted to the auditory domain. This study explored the cognitive profiles of individuals experiencing multisensory hallucinations (MH) in schizophrenia-spectrum disorders (SSD) and compared these to those experiencing unimodal auditory hallucinations (AH) or no hallucinations (NH). METHODS: Participants included SSD patients (n = 119) stratified by current hallucination status (NH, AH, MH) and nonclinical controls (NCs; n = 113). Group performance was compared across several cognitive domains: speed of processing, attention, working memory, verbal learning, visual learning, reasoning and problem-solving, social cognition, and inhibition. RESULTS: The clinical groups performed worse than NCs but differences between the clinical groups were not evident across most cognitive domains. Exploratory analyses revealed that the MH group was more impaired on the visual learning task compared to the NH (but not AH) group. CONCLUSIONS: Preliminary results suggest that impaired visual learning may be related to MH. This could be attributed to the presence of visual hallucinations (VH), or greater psychopathology, in this group. However, replication is needed, as well as the investigation of other potential cognitive mechanisms of MH.

A detailed examination of pitch discrimination deficits associated with auditory verbal hallucinations in schizophrenia.

Individuals with schizophrenia spectrum disorders (SSD) and a history of experiencing auditory verbal hallucinations (AVH) exhibit poor pitch discrimination relative to those with an SSD but no AVH history. The present study extended this research, asking if a lifetime history, and the current presence, of AVH exacerbated the pitch discrimination challenges that are seen in SSD. Participants completed a pitch discrimination task, where the tones presented differed in pitch by either 2 %, 5 %, 10 %, 25 % or 50 %. Pitch discrimination accuracy, sensitivity, reaction time (RT) and intra-individual RT variability (IIV) were examined in individuals with SSD and AVHs (AVH+; n = 46), or without AVHs (AVH-; n = 31), and healthy controls (HC; n = 131). Secondary analyses split the AVH+ group into state (i.e., actively experiencing AVH; n = 32) and trait hallucinators (i.e., a history of, but not actively experiencing, AVH; n = 16). Relative to HC, significantly poorer accuracy and sensitivity was detected in individuals with SSD at 2 % and 5 % pitch deviants, and in hallucinators at 10 %; however, no significant differences in accuracy, sensitivity, RT nor IIV were found between AVH+ and AVH- groups. No differences between state and trait hallucinators were observed. A general SSD deficit drove the current findings. The findings may inform future research into the auditory processing capabilities of AVH+ individuals.

The relationship between cognitive clusters and telomere length in bipolar-schizophrenia spectrum disorders.

BACKGROUND: Schizophrenia and bipolar disorder are complex mental illnesses that are associated with cognitive deficits. There is considerable cognitive heterogeneity that exists within both disorders. Studies that cluster schizophrenia and bipolar patients into subgroups based on their cognitive profile increasingly demonstrate that, relative to healthy controls, there is a severely compromised subgroup and a relatively intact subgroup. There is emerging evidence that telomere shortening, a marker of cellular senescence, may be associated with cognitive impairments. The aim of this study was to explore the relationship between cognitive subgroups in bipolar-schizophrenia spectrum disorders and telomere length against a healthy control sample. METHODS: Participants included a transdiagnostic group diagnosed with bipolar, schizophrenia or schizoaffective disorder (n = 73) and healthy controls (n = 113). Cognitive clusters within the transdiagnostic patient group, were determined using K-means cluster analysis based on current cognitive functioning (MATRICS Consensus Cognitive Battery scores). Telomere length was determined using quantitative PCRs genomic DNA extracted from whole blood. Emergent clusters were then compared to the healthy control group on telomere length. RESULTS: Two clusters emerged within the patient group that were deemed to reflect a relatively intact cognitive group and a cognitively impaired subgroup. Telomere length was significantly shorter in the severely impaired cognitive subgroup compared to the healthy control group. CONCLUSIONS: This study replicates previous findings of transdiagnostic cognitive subgroups and associates shorter telomere length with the severely impaired cognitive subgroup. These findings support emerging literature associating cognitive impairments in psychiatric disorders to accelerated cellular aging as indexed by telomere length.

Brain Morphological Characteristics of Cognitive Subgroups of Schizophrenia-Spectrum Disorders and Bipolar Disorder: A Systematic Review with Narrative Synthesis.

Despite a growing body of research, there is yet to be a cohesive synthesis of studies examining differences in brain morphology according to patterns of cognitive function among both schizophrenia-spectrum disorder (SSD) and bipolar disorder (BD) individuals. We aimed to provide a systematic overview of the morphological differences-inclusive of grey and white matter volume, cortical thickness, and cortical surface area-between cognitive subgroups of these disorders and healthy controls, and between cognitive subgroups themselves. An initial search of PubMed and Scopus databases resulted in 1486 articles of which 20 met inclusion criteria and were reviewed in detail. The findings of this review do not provide strong evidence that cognitive subgroups of SSD or BD map to unique patterns of brain morphology. There is preliminary evidence to suggest that reductions in cortical thickness may be more strongly associated with cognitive impairment, whilst volumetric deficits may be largely tied to the presence of disease.

Speech processing in voice-hearers: Bridging the gap between empirical research and clinical implications.

Individuals who hear voices (i.e. auditory verbal hallucinations) have been reported to exhibit a range of difficulties when listening to and processing the speech of other people. These speech processing challenges are observed even in the absence of hearing voices; however, some appear to be exacerbated during periods of acute symptomology. In this advisory piece, key findings from pertinent empirical research into external speech processing in voice-hearers are presented with the intention of informing healthcare professionals. It is the view that through a better understanding of the speech processing deficits faced by individuals who hear voices, more effective communication with such patients can be had.

Assessing the dimensionality of scores derived from the Revised Formal Thought Disorder Self-Report Scale in schizotypy.

The current work explored the dimensionality and convergent validity of responses to Barrera et al.'s (2015) 29-item Formal Thought Disorder-Self Scale (FTD-SS) obtained in two non-clinical samples. Exploratory factor analyses were conducted in Sample 1 (n = 324), yielding evidence of three correlated factors, although simple structure was not achieved until nine items were removed. Support for the correlated three factors model of responses to the revised 20-item scale (FTD-SS-R) was replicated when a confirmatory factor analysis was conducted in Sample 2 (n = 610). Finally, convergent associations were found between FTD-SS-R scores and scores from other schizotypy measures across both samples, though these measures only explained half of the variance in FTD-SS-R scores. Additional research is needed to evaluate the appropriateness of the items and incremental validity of the scale in non-clinical samples.

Evidence that a working memory cognitive phenotype within schizophrenia has a unique underlying biology.

It is suggested studying phenotypes within the syndrome of schizophrenia will accelerate understanding the complex molecular pathology of the disorder. Supporting this hypothesis, we have identified a sub-group within schizophrenia with impaired working memory (WM) and have used Affymetrix™ Human Exon 1.0 ST Arrays to compare their blood RNA levels (n=16) to a group of with intact WM (n=18). Levels of 72 RNAs were higher in blood from patients with impaired WM, 11 of which have proven links to the maintenance of different aspects of working memory (cognition). Overall, changed gene expression in those with impaired WM could be linked to cognition through glutamatergic activity, olfaction, immunity, inflammation as well as energy and metabolism. Our data gives preliminary support to the hypotheses that there is a working memory deficit phenotype within the syndrome of schizophrenia with has a biological underpinning. In addition, our data raises the possibility that a larger study could show that the specific changes in gene expression we have identified could prove to be the biomarkers needed to develop a blood test to identify those with impaired WM; a significant step toward allowing the use of personalised medicine directed toward improving their impaired working memory.

No influence of sex on the relationship between schizotypy factors and executive control across the schizophrenia spectrum.

Sex differences in symptoms and executive control across schizophrenia spectrum disorders (SSD) are consistently reported. Similarly, these findings of sex differences are also observed in schizotypy, that is, schizophrenia-like features occurring in healthy individuals in the absence of a clinical diagnosis. This study aimed to examine the relationships between performance on three major domains of executive control: performance monitoring, response inhibition, and cognitive set-shifting, and schizotypy factor scores in both SSD patients and healthy controls (HCs), and whether sex moderated any relationships observed. A total of 111 (67 males and 44 females) patients with SSD and 258 (129 males and 129 females) HCs were included in this study. Schizotypal personality traits (in both SSD and HC) was assessed using the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE). Executive control performance was assessed using seven tasks. Stepwise linear regressions revealed that performance on cognitive set-shifting tasks was significantly associated with the introvertive anhedonia, cognitive disorganisation, and unusual experiences subscales of the O-LIFE. When sex was examined as a moderator, it was not a significant moderator of any of the relationships between cognitive set-shifting tasks and schizotypy factors. The results suggest that independent of sex, cognitive set-shifting ability is associated to an increased vulnerability to schizotypal personality traits, although performance monitoring and response inhibition did not.

Psychosis and Hopelessness Mediate the Relationship Between Reduced Sleep and Suicidal Ideation in Schizophrenia Spectrum Disorders.

OBJECTIVE: Suicide is a major cause of death amongst individuals with schizophrenia spectrum disorders (SSD). Despite numerous risk factors being identified, accurate prediction of suicidality and provision of tailored and effective treatment is difficult. One factor that may warrant particular attention as a contributor to increased psychopathology and suicidality in SSD is disturbed sleep. Sleep disturbances have been reliably linked to greater levels of suicidal ideation and are highly prevalent amongst individuals with SSD. This study aimed to examine if reduced sleep duration and psychopathology are associated with increased suicidal ideation. METHOD: One-hundred and eighteen adults with chronic SSD living within the community participated in this cross-sectional study. Psychosis symptoms were assessed using the Positive and Negative Syndrome Scale. Items 4 and 10 from the Montgomery-Asperg Depression Rating Scale and Item 2 from the Calgary Depression Scale for Schizophrenia were used to assess reduced sleep duration, current suicidal ideation, and hopelessness, respectively. All measures were rated concurrently. RESULTS: A hierarchical logistic regression revealed that greater acute sleep disturbances were associated with increased suicidal ideation and this relationship was found to be uniquely mediated by both positive symptom severity and hopelessness. CONCLUSION: These results suggest that individuals with SSD who exhibited disrupted or disordered sleep, positive symptoms and/or hopelessness should be routinely screened for suicidal thinking. Furthermore, interventions that effectively target sleep disruptions may provide much-needed action against suicidal ideation.HIGHLIGHTSReduced sleep found to be associated with increased suicidal ideationThis was uniquely mediated by both hopelessness and positive symptomsMore regular screening of sleep problems in schizophrenia is needed.

Characterization and interrelationships of theory of mind, socially competitive emotions and affective empathy in bipolar disorder.

OBJECTIVE: Evidence shows impaired theory of mind (ToM) in patients with bipolar disorder (BD), yet research examining its cognitive and affective components simultaneously is sparse. Moreover, recognition of socially competitive 'fortune of others' emotions (e.g. envy/gloat) may be related to ToM, but has not been assessed in BD. Finally, if and how ToM and 'fortune of others' emotions relate to affective empathy in BD is currently unclear. This study aimed to address these points. METHODS: 64 BD patients and 34 healthy controls completed the Yoni task, a visual task assessing first- and second-order cognitive and affective ToM as well as 'fortune of others' emotions. The Toronto Empathy Questionnaire was used to assess self-reported affective empathy. RESULTS: Patients with BD showed no deficits in cognitive and affective ToM or recognition of 'fortune of others' emotions. The ability to infer 'fortune of others' emotions correlated with several ToM measures, indicating that these functions are part of the same system. Patients with BD reported similar levels of affective empathy to healthy controls, and this was not related to ToM or 'fortune of others' emotions, suggesting that affective empathy represents a separate social domain. CONCLUSIONS: These findings highlight areas of spared social functioning in BD, which may be utilized in therapeutic strategies. PRACTITIONER POINTS: Our results suggest theory of mind and empathy may represent areas of potentially spared cognitive functioning in BD. As many BD patients have experienced adversity during developmental periods in which theory of mind and empathy develop, our findings suggest that these abilities may be markers of resilience in the disorder. Our findings are important for the formulation of therapeutic interventions for BD, which may include considering practical ways that a patients' knowledge of intact ToM and empathy could be utilized to reduce self-stigma and promote self-efficacy, improved well-being and functioning.

Mindfulness, mood symptom tendencies and quality of life in bipolar disorder: An examination of the mediating influence of emotion regulation difficulties.

BACKGROUND: The aim of this cross-sectional study was to investigate dispositional mindfulness and its association with depression and manic tendencies, and subjective life quality in bipolar disorder (BD). Furthermore, this study sought to examine the potential mediating effects of emotion regulation difficulties on these relationships. METHOD: Twenty-eight healthy controls (HC) and 66 clinically stable outpatients with a DSM-IV-TR diagnosis of BD completed the Mindfulness Attention Awareness Scale (MAAS), Difficulties in Emotion Regulation Scale (DERS), Seven Up (7 Up) Seven Down (7 Down) and the Quality of Life in Bipolar Disorder Questionnaire (QoL.BD). These variables were compared between groups and entered into a series of mediation analyzes using PROCESS in the BD group only. RESULTS: Lower MAAS scores were detected amongst the BD patients compared to HCs. Lower MAAS scores in BD patients predicted higher 7 Up, 7 Down and lower QoL.BD scores. For the 7 Down and QoL.BD, the associations were completely mediated by DERS scores, with difficulties in strategy use and emotional clarity mediating the association between mindfulness and depressive tendencies and quality of life, respectively. No significant direct or indirect effects were detected for the 7 Up model. LIMITATIONS: The cross-sectional design precludes causal inference. The MAAS conceptualises mindfulness as unidimensional. Self-report scales of depressive and manic tendencies utilised. CONCLUSIONS: This study detected a significant association between dispositional mindfulness and depressive tendencies and life quality in BD, and found that these associations were influenced by emotion regulation difficulties. These findings encourage further investigation of mindfulness-based interventions in BD.

Characterising Demographic, Clinical and Functional Features of Cognitive Subgroups in Schizophrenia Spectrum Disorders: A Systematic Review.

Considerable cognitive heterogeneity is present within the schizophrenia spectrum disorder (SSD) population. Several subgroups characterised by more homogenous cognitive profiles have been identified. It is not yet clear however, whether these subgroups represent different points along a continuum of cognitive symptom severity, or whether they reflect unique profiles of the disorder. One way to determine this is by comparing subgroups on their non-cognitive characteristics. The aim of the present review was to systematically summarise our current understanding of the non-cognitive features of the cognitive subgroups of schizophrenia spectrum disorder (SSD). Thirty-five relevant studies were identified from January 1980 to March 2020. Cognitive subgroups were consistently compared on age, sex, education, age of illness onset, illness duration, positive, negative and disorganised symptoms, depression and psychosocial functioning. It was revealed that subgroups were consistently distinguished by education, negative symptom severity and degree of functional impairment; with subgroups characterised by worse cognitive functioning performing/rated worse on these characteristics. The lack of consistent subgroup differences for the majority of the non-cognitive characteristics provides partial support for the notion that cognitive subgrouping in SSD is not simply reflecting a rehash of previously identified clinical subtypes. However, as subgroups were consistently distinguished by three characteristics known to be associated with cognition, our understanding of the extent to which the cognitive subgrouping approach is representing separate subtypes versus subdivisions along a continuum of symptom severity is still not definitive.

External speech processing and auditory verbal hallucinations: A systematic review of functional neuroimaging studies.

It has been documented that individuals who hear auditory verbal hallucinations (AVH) exhibit diminished capabilities in processing external speech. While functional neuroimaging studies have attempted to characterise the cortical regions and networks facilitating these deficits in a bid to understand AVH, considerable methodological heterogeneity has prevented a consensus being reached. The current systematic review investigated the neurobiological underpinnings of external speech processing deficits in voice-hearers in 38 studies published between January 1990 to June 2020. AVH-specific deviations in the activity and lateralisation of the temporal auditory regions were apparent when processing speech sounds, words and sentences. During active or affective listening tasks, functional connectivity changes arose within the language, limbic and default mode networks. However, poor study quality and lack of replicable results plague the field. A detailed list of recommendations has been provided to improve the quality of future research on this topic.

A Systematic Review of Cognition-Brain Morphology Relationships on the Schizophrenia-Bipolar Disorder Spectrum.

The nature of the relationship between cognition and brain morphology in schizophrenia-spectrum disorders (SSD) and bipolar disorder (BD) is uncertain. This review aimed to address this, by providing a comprehensive systematic investigation of links between several cognitive domains and brain volume, cortical thickness, and cortical surface area in SSD and BD patients across early and established illness stages. An initial search of PubMed and Scopus databases resulted in 1486 articles, of which 124 met inclusion criteria and were reviewed in detail. The majority of studies focused on SSD, while those of BD were scarce. Replicated evidence for specific regions associated with indices of cognition was minimal, however for several cognitive domains, the frontal and temporal regions were broadly implicated across both recent-onset and established SSD, and to a lesser extent BD. Collectively, the findings of this review emphasize the significance of both frontal and temporal regions for some domains of cognition in SSD, while highlighting the need for future BD-related studies on this topic.

Sleep disturbances and cognitive impairment in schizophrenia spectrum disorders: a systematic review and narrative synthesis.

Individuals with schizophrenia spectrum disorders (SSD) experience frequent sleep disturbances in addition to enduring cognitive impairments. The purpose of the present review was to systematically summarise our current understanding of the association between sleep disturbances and cognition in SSD. Through this, it was aimed to identify features of disturbed sleep that are reliably associated with cognitive deficits in SSD and identify the gaps within the current literature that require future investigation. Eighteen relevant studies were identified following a two-stage screening process. Following a structured narrative synthesis of key study components, no clear and consistent pattern emerged. Considerable methodological variability was present amongst the reviewed studies. Although some broad consistencies were identified, such as associations between sleep spindle density and sleep-dependent memory consolidation, the overall pattern of results lacked a cohesive composition due to the diverse list of sleep parameters and cognitive domains investigated, as well as a lack of replication. Additional research is needed before more definitive remarks can be made regarding the influence of sleep disturbances on cognitive function in SSD.

Brain morphology does not clearly map to cognition in individuals on the bipolar-schizophrenia-spectrum: a cross-diagnostic study of cognitive subgroups.

BACKGROUND: Characterisation of brain morphological features common to cognitively similar individuals with bipolar disorder (BD) and schizophrenia spectrum disorders (SSD) may be key to understanding their shared neurobiological deficits. In the current study we examined whether three previously characterised cross-diagnostic cognitive subgroups differed among themselves and in comparison to healthy controls across measures of brain morphology. METHOD: T1-weighted structural magnetic resonance imaging scans were obtained for 143 individuals; 65 healthy controls and 78 patients (SSD, n = 40; BD I, n = 38) classified into three cross-diagnostic cognitive subgroups: Globally Impaired (n = 24), Selectively Impaired (n = 32), and Superior/Near-Normal (n = 22). Cognitive subgroups were compared to each other and healthy controls on three separate analyses investigating (1) global, (2) regional, and (3) vertex-wise comparisons of brain volume, thickness, and surface area. RESULTS: No significant subgroup differences were evident in global measures of brain morphology. In region of interest analyses, the Selectively Impaired subgroup had greater right accumbens volume than those Superior/Near-Normal subgroup and healthy controls, and the Superior/Near-Normal subgroup had reduced volume of the left entorhinal region compared to all other groups. In vertex-wise comparisons, the Globally Impaired subgroup had greater right precentral volume than the Selectively Impaired subgroup, and thicker cortex in the postcentral region relative to the Superior/Near-Normal subgroup. LIMITATIONS: Exploration of medication effects was limited in our data. CONCLUSIONS: Although some differences were evident in this sample, generally cross-diagnostic cognitive subgroups of individuals with SSD and BD did not appear to be clearly distinguished by patterns in brain morphology.

The Relationship between Negative Symptoms and Both Emotion Management and Non-social Cognition in Schizophrenia Spectrum Disorders.

OBJECTIVE: There is ongoing debate regarding the relationship between clinical symptoms and cognition in schizophrenia spectrum disorders (SSD). The present study aimed to explore the potential relationships between symptoms, with an emphasis on negative symptoms, and social and non-social cognition. METHOD: Hierarchical cluster analysis with k-means optimisation was conducted to characterise clinical subgroups using the Scale for the Assessment of Negative Symptoms and Scale for the Assessment of Positive Symptoms in n = 130 SSD participants. Emergent clusters were compared on the MATRICS Consensus Cognitive Battery, which measures non-social cognition and emotion management as well as demographic and clinical variables. Spearman's correlations were then used to investigate potential relationships between specific negative symptoms and emotion management and non-social cognition. RESULTS: Four distinct clinical subgroups were identified: 1. high hallucinations, 2. mixed symptoms, 3. high negative symptoms, and 4. relatively asymptomatic. The high negative symptom subgroup was found to have significantly poorer emotion management than the high hallucination and relatively asymptomatic subgroups. No further differences between subgroups were observed. Correlation analyses revealed avolition-apathy and anhedonia-asociality were negatively correlated with emotion management, but not non-social cognition. Affective flattening and alogia were not associated with either emotion management or non-social cognition. CONCLUSIONS: The present study identified associations between negative symptoms and emotion management within social cognition, but no domains of non-social cognition. This relationship may be specific to motivation, anhedonia and apathy, but not expressive deficits. This suggests that targeted interventions for social cognition may also result in parallel improvement in some specific negative symptoms.

Examining Self-Reported Thought Disorder: Continuous Variation, Convergence with Schizotypy, and Cognitive Correlates.

When measured from the perspective of a clinician, the severity of 'objective' thought disorder (TD) has been found to vary continuously between people with and without psychosis-related diagnoses, and has been linked with semantic and executive dysfunctions in people with psychosis. Measures of 'subjective' TD that are derived from a first-person perspective have also been produced, but their relationships with objective TD and cognition are unclear. The aims of the current study were: to determine whether responses on a self-report TD questionnaire correspond with responses to a self-report measure of schizotypal disorganization; and to explore the association between these self-reported subjective TD severities and cognitive performance. Data was collected from a sample of 33 people without psychiatric diagnoses and 38 people diagnosed with schizophrenia or schizoaffective disorder evincing mild symptomatology, and this data was pooled for analysis in accordance with the continuum model. Self-reported TD frequencies were associated with the endorsement of disorganized schizotypal experiences. Moreover, self-reported TD frequencies showed relationships with measures of semantic and executive functioning. Thus, at mild severities, self-reported TD shows continuous variation and is associated with altered cognitive function.