Speech markers to predict and prevent recurrent episodes of psychosis: A narrative overview and emerging opportunities.

Preventing relapse in schizophrenia improves long-term health outcomes. Repeated episodes of psychotic symptoms shape the trajectory of this illness and can be a detriment to functional recovery. Despite early intervention programs, high relapse rates persist, calling for alternative approaches in relapse prevention. Predicting imminent relapse at an individual level is critical for effective intervention. While clinical profiles are often used to foresee relapse, they lack the specificity and sensitivity needed for timely prediction. Here, we review the use of speech through Natural Language Processing (NLP) to predict a recurrent psychotic episode. Recent advancements in NLP of speech have shown the ability to detect linguistic markers related to thought disorder and other language disruptions within 2-4 weeks preceding a relapse. This approach has shown to be able to capture individual speech patterns, showing promise in its use as a prediction tool. We outline current developments in remote monitoring for psychotic relapses, discuss the challenges and limitations and present the speech-NLP based approach as an alternative to detect relapses with sufficient accuracy, construct validity and lead time to generate clinical actions towards prevention.

The functional and structural associations of aberrant microglial activity in major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is a debilitating mental illness that has been linked to increases in markers of inflammation, as well as to changes in brain functional and structural connectivity, particularly between the insula and the subgenual anterior cingulate cortex (sgACC). In this study, we directly related inflammation and dysconnectivity in treatment-resistant MDD by concurrently measuring the following: microglial activity with [18F]N-2-(fluoroethoxyl)benzyl-N-(4phenoxypyridin-3-yl)acetamide ([18F]FEPPA) positron emission tomography (PET); the severity of MDD; and functional or structural connectivity among insula or sgACC nodes. METHODS: Twelve patients with treatment-resistant MDD (8 female, 4 male; mean age ± standard deviation 54.9 ± 4.5 years and 23 healthy controls (11 female, 12 male; 60.3 ± 8.5 years) completed a hybrid [18F]FEPPA PET and MRI acquisition. From these, we extracted relative standardized uptake values for [18F]FEPPA activity and Pearson r-to-z scores representing functional connectivity from our regions of interest. We extracted diffusion tensor imaging metrics from the cingulum bundle, a key white matter bundle in MDD. We performed regressions to relate microglial activity with functional connectivity, structural connectivity and scores on the 17-item Hamilton Depression Rating Scale. RESULTS: We found significantly increased [18F]FEPPA uptake in the left sgACC in patients with treatment-resistant MDD compared to healthy controls. Patients with MDD also had a reduction in connectivity between the sgACC and the insula. The [18F]FEPPA uptake in the left sgACC was significantly related to functional connectivity with the insula, and to the structural connectivity of the cingulum bundle. [18F]FEPPA uptake also predicted scores on the Hamilton Depression Rating Scale.Limitations: A relatively small sample size, lack of functional task data and concomitant medication use may have affected our findings. CONCLUSION: We present preliminary evidence linking a network-level dysfunction relevant to the pathophysiology of depression and related to increased microglial activity in MDD.

Assessment of treatment resistance criteria in non-invasive brain stimulation studies of schizophrenia.

Novel treatment modalities, such as non-invasive brain stimulation (NIBS), typically focus on patient groups that have failed multiple treatment interventions. Despite its promise, the clinical translation of NIBS in schizophrenia has been limited. One important obstacle to implementation is the inconsistent reporting of treatment resistance in the clinical trial literature contributing to heterogeneity in reported effects. In response, we develop a numerical approach to synthesize quality of assessment of Treatment-Resistant Schizophrenia (TRS) and apply this to studies investigating therapeutic response to NIBS in patients with schizophrenia. Literature search conducted through PubMed database identified 119 studies investigating Transcranial Magnetic Stimulation and Transcranial Electrical Stimulation in treating resistant schizophrenia symptoms. A quality score out of 11 was assigned to each study based on adherence to the international consensus guidelines for TRS developed by the Treatment Response and Resistance in Psychosis (TRRIP) group. Results revealed an overall paucity of studies with thorough assessment and/or reporting of TRS phenomenon, as evidenced by a mean quality score of 3.38/11 (SD: 1.01) for trials and 5.16/11 (SD: 1.57) for case reports, though this improved minimally since the publication of consensus criteria. Most studies considered treatment-resistance as a single dimensional construct by reporting resistance of a single symptom, and failed to establish treatment adherence, resistance time course and functional impairment. We conclude that the current NIBS literature in schizophrenia do not reflect its true effects on treatment-resistance. There is an urgent need to improve assessment and reporting standards of clinical trials that target TRS.

Schizophrenia Increases Variability of the Central Antioxidant System: A Meta-Analysis of Variance From MRS Studies of Glutathione.

Patients with schizophrenia diverge in their clinical trajectories. Such diverge outcomes may result from the resilience provided by antioxidant response system centered on glutathione (GSH). Proton Magnetic Resonance Spectroscopy (1H-MRS) has enabled the precise in vivo measurement of intracortical GSH; but individual studies report highly variable results even when GSH levels are measured from the same brain region. This inconsistency could be due to the presence of distinct subgroups of schizophrenia with varying GSH-levels. At present, we do not know if schizophrenia increases the interindividual variability of intracortical GSH relative to matched healthy individuals. We reviewed all 1H-MRS GSH studies in schizophrenia focused on the Anterior Cingulate Cortex published until August 2021. We estimated the relative variability of ACC GSH levels in patients compared to control groups using the variability ratio (VR) and coefficient of variation ratio (CVR). The presence of schizophrenia significantly increases the variability of intracortical GSH in the ACC (logVR = 0.12; 95% CI: 0.03-0.21; log CVR = 0.15; 95% CI = 0.06-0.23). Insofar as increased within-group variability (heterogeneity) could result from the existence of subtypes, our results call for a careful examination of intracortical GSH distribution in schizophrenia to seek redox-deficient and redox-sufficient subgroups. An increase in GSH variability among patients also indicate that the within-group predictability of adaptive response to oxidative stress may be lower in schizophrenia. Uncovering the origins of this illness-related reduction in the redox system stability may provide novel treatment targets in schizophrenia.

Treatment Resistance: A Time-Based Approach for Early Identification in First Episode Psychosis.

Although approximately 1/3 of individuals with schizophrenia are Treatment Resistant (TR), identifying these subjects prospectively remains challenging. The Treatment Response and Resistance in Psychosis working group defines <20% improvement as an indicator of TR, though its utility in First Episode Schizophrenia (FES) remains unknown. In a prospective cohort of FES (n = 129) followed up for 5 years, we evaluated two improvement thresholds for 'probable TR'; <20% and <50% based on positive, negative, and total symptoms. We ascertained (1) the ecological validity (i.e., the ability to identify an expected subgroup of 1/3rd of patients); (2) the predictive validity (i.e., ability to predict poor global functioning) and (3) the clinical utility (association with clozapine use at the 5th year). Using the criteria of a total symptom reduction of <50% or negative symptom reduction of <20% resulted in 'probable TR' rates of 37% and 33%, respectively. Using <20% positive or total symptoms criteria resulted in very low rates, indicating minimal utility in FES. <50% total symptom criterion best predicted the global functioning over 5 years. Clozapine use was only predicted by positive symptom criterion. Prospective characterization of TRS is possible at 6 months after FES through a time-based approach using a 50% threshold for symptom change in treatment-adherent patients.

Deviant cortical sulcation related to schizophrenia and cognitive deficits in the second trimester.

OBJECTIVES: Aberrant cortical development, inferred from cortical folding, is linked to the risk of schizophrenia. Cortical folds develop in a time-locked fashion during fetal growth. We leveraged this temporal specificity of sulcation to investigate the timing of the prenatal insult linked to schizophrenia and the cognitive impairment seen in this illness. METHODS: Anatomical MRI scans from 68 patients with schizophrenia and 72 controls were used to evaluate the sulcal depth of five major invariable primary sulci representing lobar development (calcarine sulcus, superior temporal sulcus, superior frontal sulcus, intraparietal sulcus and inferior frontal sulcus) with formation representing the distinct developmental periods. RESULTS: A repeated-measure ANOVA with five sulci and two hemispheres as the within-subject factors and gender, age and intracranial volume as covariates revealed a significant effect of diagnosis (F[1,134] = 14.8, p = 0.0002). Control subjects had deeper bilateral superior temporal, right inferior frontal and left calcarine sulci. A deeper superior frontal sulcus predicted better cognitive scores among patients. CONCLUSION: Our results suggest that the gestational disruption underlying schizophrenia is likely to predate, if not coincide with the appearance of calcarine sulcus (early second trimester). Nevertheless, the burden of cognitive deficits may relate specifically to the aberrant superior frontal development apparent in late second trimester.

Neurovascular Uncoupling in Schizophrenia: A Bimodal Meta-Analysis of Brain Perfusion and Glucose Metabolism.

The use of modern neuroimaging approaches has demonstrated resting-state regional cerebral blood flow (rCBF) to be tightly coupled to resting cerebral glucose metabolism (rCMRglu) in healthy brains. In schizophrenia, several lines of evidence point toward aberrant neurovascular coupling, especially in the prefrontal regions. To investigate this, we used Signed Differential Mapping to undertake a voxel-based bimodal meta-analysis examining the relationship between rCBF and rCMRglu in schizophrenia, as measured by arterial spin labeling (ASL) and 18Flurodeoxyglucose positron emission tomography (FDG-PET) respectively. We used 19 studies comprised of data from 557 patients and 584 controls. Our results suggest that several key regions implicated in the pathophysiology of schizophrenia such as the frontoinsular cortex, dorsal ACC, putamen, and temporal pole show conjoint metabolic and perfusion abnormalities in patients. In contrast, discordance between metabolism and perfusion were seen in superior frontal gyrus and cerebellum, indicating that factors contributing to neurovascular uncoupling (e.g. inflammation, mitochondrial dysfunction, oxidative stress) are likely operates at these loci. Studies enrolling patients on high doses of antipsychotics had showed larger rCBF/rCMRglu effects in patients in the left dorsal striatum. Hybrid ASL-PET studies focusing on these regions could confirm our proposition regarding neurovascular uncoupling at superior frontal gyrus in schizophrenia.

Antioxidant defense in schizophrenia and bipolar disorder: A meta-analysis of MRS studies of anterior cingulate glutathione.

BACKGROUND: Glutathione [GSH] is a major intracellular antioxidant that disposes peroxides and protects neurons and glial cells from oxidative stress. In both schizophrenia and bipolar disorder, atypical levels of GSH have been demonstrated, particularly in the anterior cingulate cortex (ACC), though no consistent results have emerged due to limitations in sample size. Our objective was to evaluate if GSH levels in the ACC are abnormal in these 2 disorder, when compared to healthy controls. METHODS: We reviewed all 1H-MRS studies reporting GSH values for patients satisfying DSM or ICD based criteria for (1) the psychotic disorders - schizophrenia or schizoaffective disorder or (2) bipolar disorder in comparison to a healthy controls (HC) group in the Anterior Cingulate Cortex (ACC) published until June 2018. A random-effects model was used to calculate the pooled effect size. A meta-regression analysis of moderator variables was also undertaken. RESULTS: The literature search identified 18 studies with a total sample size of 581 controls, 578 patients with schizophrenia or bipolar disorder. There is a small but significant reduction in ACC GSH in patients with schizophrenia compared to HC (N = 13; RFX SMD =0.26; 95% CI [0.07 to 0.44]; p = 0.008; heterogeneity p = 0.11). There is a significant increase in the ACC GSH concentration in bipolar disorder compared to HC (N = 6; RFX SMD = -0.28, 95% CI [-0.09 to -0.47]; p = 0.003; heterogeneity p = 0.95). CONCLUSIONS: We report a small, but significant reduction in GSH concentration in the ACC in schizophrenia, and a similar sized increase in bipolar disorder. A notable limitation is the lack of sufficient data to examine the moderating effect of the symptom profile. Schizophrenia and bipolar disorder have notably different patterns of redox abnormalities in the ACC. Reduced ACC GSH may confer a schizophrenia-like clinical phenotype, while an excess favouring a bipolar disorder-like profile.

Putative Astroglial Dysfunction in Schizophrenia: A Meta-Analysis of 1H-MRS Studies of Medial Prefrontal Myo-Inositol.

Background: Several lines of evidence support a role for astroglial pathology in schizophrenia. Myo-inositol is particularly abundant in astroglia. Many small sized studies have reported on myo-inositol concentration in schizophrenia, but to date these have not been pooled to estimate a collective effect size. Methods: We reviewed all proton magnetic resonance spectroscopy (1H-MRS) studies reporting myo-inositol values for patients satisfying DSM or ICD based criteria for schizophrenia in comparison to a healthy controls group in the medial prefrontal cortex published until February 2018. A random-effects model was used to calculate the pooled effect size using metafor package. A meta-regression analysis of moderator variables was also undertaken. Results: The literature search identified 19 studies published with a total sample size of 585 controls, 561 patients with schizophrenia. Patients with schizophrenia had significantly reduced medial prefrontal myo-inositol compared to controls (RFX standardized mean difference = 0.19, 95% CI [0.05-0.32], z = 2.72, p = 0.0067; heterogeneity p = 0.09). Studies with more female patients reported more notable schizophrenia-related reduction in myo-inositol (z = 2.53, p = 0.011). Discussion: We report a small, but significant reduction in myo-inositol concentration in the medial prefrontal cortex in schizophrenia. The size of the reported effect indicates that the biological pathways affecting the astroglia are likely to operate only in a subset of patients with schizophrenia. MRS myo-inositol could be a useful tool to stratify and investigate such patients.

Transcranial magnetic stimulation for geriatric depression: Promises and pitfalls.

As the global population gets older, depression in the elderly is emerging as an important health issue. A major challenge in treating geriatric depression is the lack of robust efficacy for many treatments that are of significant benefit to depressed working age adults. Repetitive transcranial magnetic stimulation (rTMS) is a novel physical treatment approach used mostly in working age adults with depression. Many TMS trials and clinics continue to exclude the elderly from treatment citing lack of evidence in this age group. In this review, we appraise the evidence regarding the safety and efficacy of rTMS in the elderly. A consistent observation supporting a high degree of tolerability and safety among the elderly patients emerged across the Randomised Controlled Trials and the uncontrolled trials. Further, there is no reliable evidence negating the utility of rTMS in the elderly with depression. We also identified several factors other than age that moderate the observed variations in the efficacy of rTMS in the elderly. These factors include but not limited to: (1) brain atrophy; (2) intensity and number of pulses (dose-response relationship); and (3) clinical profile of patients. On the basis of the current evidence, the practice of excluding elderly patients from TMS clinics and trials cannot be supported.