Peripheral Lipid Signatures, Metabolic Dysfunction, and Pathophysiology in Schizophrenia Spectrum Disorders.

Metabolic dysfunction is commonly observed in schizophrenia spectrum disorders (SSDs). The causes of metabolic comorbidity in SSDs are complex and include intrinsic or biological factors linked to the disorder, which are compounded by antipsychotic (AP) medications. The exact mechanisms underlying SSD pathophysiology and AP-induced metabolic dysfunction are unknown, but dysregulated lipid metabolism may play a role. Lipidomics, which detects lipid metabolites in a biological sample, represents an analytical tool to examine lipid metabolism. This systematic review aims to determine peripheral lipid signatures that are dysregulated among individuals with SSDs (1) with minimal exposure to APs and (2) during AP treatment. To accomplish this goal, we searched MEDLINE, Embase, and PsychINFO databases in February 2024 to identify all full-text articles written in English where the authors conducted lipidomics in SSDs. Lipid signatures reported to significantly differ in SSDs compared to controls or in relation to AP treatment and the direction of dysregulation were extracted as outcomes. We identified 46 studies that met our inclusion criteria. Most of the lipid metabolites that significantly differed in minimally AP-treated patients vs. controls comprised glycerophospholipids, which were mostly downregulated. In the AP-treated group vs. controls, the significantly different metabolites were primarily fatty acyls, which were dysregulated in conflicting directions between studies. In the pre-to-post AP-treated patients, the most impacted metabolites were glycerophospholipids and fatty acyls, which were found to be primarily upregulated and conflicting, respectively. These lipid metabolites may contribute to SSD pathophysiology and metabolic dysfunction through various mechanisms, including the modulation of inflammation, cellular membrane permeability, and metabolic signaling pathways.

The impact of weight gain on antipsychotic nonadherence or discontinuation: A systematic review and meta-analysis.

BACKGROUND: Nonadherence/discontinuation of antipsychotic (AP) medications represents an important clinical issue in patients across psychiatric disorders, including schizophrenia spectrum disorders (SSDs). While antipsychotic-induced weight gain (AIWG) is a reported contributor to nonadherence, a systematic review of the association between AIWG and medication nonadherence/discontinuation has not been explored previously. METHOD: A systematic search was conducted in MEDLINE, EMBASE, PsychINFO, CINAHL, and CENTRAL databases, among others, to help identify all studies which explored adherence, study dropouts, AP switching and/or discontinuations attributable to AIWG among individuals with severe mental illness. A meta-analysis was also completed where applicable. RESULTS: We identified two categories of studies for the meta-analysis. Category 1 included three studies, which compared measures of AP adherence or discontinuation across BMI classes/degrees of self-reported weight gain. When compared to normal weight individuals receiving APs or those who did not report AIWG, individuals who were either overweight or obese or reported weight gain in relation to AP use had an increased odds of AP nonadherence (OR 2.37; 95% CI 1.51-3.73; p = 0.0002). Category 2 had 14 studies which compared measures of discontinuation related to weight gain reported as an adverse effect across different APs. Olanzapine was associated with a 3.32 times (95% CI 2.32-4.74; p < 0.00001) increased likelihood of nonadherence or discontinuation when compared to other APs with lower weight gain liabilities. Similarly, APs with moderate weight gain liability (paliperidone, risperidone, and quetiapine) increased the odds of nonadherence or discontinuation by 2.25 (95% CI 1.31-3.87; p = 0.003) when compared to APs considered to have lower weight gain liability (i.e. haloperidol and aripiprazole). The qualitative summary also confirmed these findings. CONCLUSION: This review and meta-analysis suggests that AIWG influences medication nonadherence/discontinuation, whereby APs with higher weight gain liability are associated with nonadherence/discontinuation. Additional studies are needed to confirm these findings.

The neuromuscular basis of functional impairment in schizophrenia: A scoping review.

Patients with schizophrenia exhibit functional impairments in their locomotory tasks, which decreases their quality of life. Due to the limited current research, the neuromuscular mechanisms behind the functional impairments in patients is not fully understood. Thus, this review aims to summarize the neuromuscular mechanisms that underlie these deficits in daily functioning. These deficits are speculated to stem from abnormalities at various levels from neurons through to the skeletal muscles. The neurological abnormalities are exhibited as lower motor neuron dysfunction whereas the skeletal muscle pathology is shown as increased muscle fibre (type 1 and type 2) atrophy, reduction in maximal force generation, and increased strength loss per decade. Although antipsychotics effectively reduce positive symptoms, functional impairments remain unresolved. Both endurance and resistance training have shown potential benefits in alleviating deficits in daily functioning by increasing muscular strength, increasing fat-free mass, and preserving neuromuscular properties from degradation. In summary, the review elucidates various possible mechanisms for the onset of functional impairment experienced by patients with schizophrenia and highlights the potential utility of endurance and resistance training to alleviate these deficits in daily functioning.

Semaglutide in Psychiatry-Opportunities and Challenges.

This Viewpoint discusses clinical trial results of glucagon-like peptide 1 receptor agonists for treating the weight gain and cardiovascular disease risk of psychiatric medications.

Protocol for the hyperinsulinemic euglycemic clamp to measure glucose kinetics in rats.

In rats, cannulation of the jugular vein and the carotid artery precedes the use of the hyperinsulinemic euglycemic clamp to determine insulin sensitivity in vivo. Here, we present a vascular surgery protocol to allow the infusion of substances via the vein and the collection of blood samples from the artery on the day of the hyperinsulinemic euglycemic clamp. We describe steps for preparing for and performing catheterization surgery. We then detail procedures for clamp preparation and its use. For complete details on the use and execution of this protocol, please refer to Pereira et al.1,2,3.

Clozapine treatment and astrocyte activity in treatment resistant schizophrenia: A proton magnetic resonance spectroscopy study.

Clozapine is the only antipsychotic approved for treating treatment-resistant schizophrenia (TRS), characterized by persistent positive symptoms despite adequate antipsychotic treatment. Unfortunately, clozapine demonstrates clinical efficacy in only ~30-60 % of patients with TRS (clozapine-responders; ClzR+), while the remaining ~40-70 % are left with no pharmacological recourse for improvement (clozapine-resistant; ClzR-). Mechanism(s) underlying clozapine's superior efficacy remain unclear. However, in vitro evidence suggests clozapine may mitigate glutamatergic dysregulations observed in TRS, by modulating astrocyte activity in ClzR+, but not ClzR-. A factor that if proven correct, may help the assessment of treatment response and development of more effective antipsychotics. To explore the presence of clozapine-astrocyte interaction and clinical improvement, we used 3 T proton-magnetic resonance spectroscopy to quantify levels of myo-Inositol, surrogate biomarker of astrocyte activity, in regions related to schizophrenia neurobiology: Dorsal-anterior-cingulate-cortex (dACC), left-dorsolateral-prefrontal-cortex (left-DLPFC), and left-striatum (left-striatum) of 157 participants (ClzR- = 30; ClzR+ = 37; responders = 38; controls = 52). Clozapine treatment was assessed using clozapine to norclozapine plasma levels, 11-12 h after last clozapine dose. Measures for symptom severity (i.e., Positive and Negative Symptoms Scale) and cognition (i.e., Mini-Mental State Examination) were also recorded. Higher levels of myo-Inositol were observed in TRS groups versus responders and controls (dACC (p < 0.001); left-striatum (p = 0.036); left-DLPFC (p = 0.023)). In ClzR+, but not ClzR-, clozapine to norclozapine ratios were positively associated with myo-Inositol levels (dACC (p = 0.004); left-DLPFC (p < 0.001)), and lower positive symptom severity (p < 0.001). Our results support growing in vitro evidence of clozapine-astrocyte interaction in clozapine-responders. Further research may determine the viability of clozapine-astrocyte interactions as an early marker of clozapine response.

The effect of second-generation antipsychotics on anxiety/depression in patients with schizophrenia: A systematic review and meta-analysis.

OBJECTIVE: Despite the high prevalence of anxiety in schizophrenia, no established guideline exists for the management of these symptoms. We aimed to synthesize evidence on the effect of second-generation antipsychotics (SGAs) on anxiety in patients with schizophrenia. METHODS: We systematically searched Medline, Embase, PsycInfo, Web of Science, PubMed, and Cochrane library to identify randomized controlled trials of SGAs that reporting anxiety measures in schizophrenia. The search was limited to English-language articles published before February 2024. Data were pooled using a random-effects model. RESULTS: Among 48 eligible studies, 29 (n = 7712) were included in the meta-analyses comparing SGAs to placebo, haloperidol, or another SGAs for their effect on anxiety/depression. SGAs had a small effect on anxiety/depression versus placebo (SMD = -0.28 (95 % CI [-0.34, -0.21], p < .00001, I2 = 47 %, n = 5576)) associated with efficacy for positive (z = 5.679, p < .001) and negative symptoms (z = 4.490, p < .001). Furthermore, SGAs were superior to haloperidol (SMD = -0.44, 95 % CI [-0.75, -0.13], p = .005, n = 1068) with substantial study-level heterogeneity (I2 = 85 %). Excluding one study of quetiapine in first-episode patients (SMD = -3.05, n = 73), SGAs showed a small effect on anxiety/depression versus haloperidol without heterogeneity (SMD = -0.23, 95 % CI [-0.35, -0.12], p = 01; I2 = %0). Risperidone's effect on anxiety/depression was comparable to olanzapine (SMD = -0.02, 95 % CI [-0.24,0.20], p = .87, I2 = 45 %, n = 753) and amisulpride (SMD = 0.27, 95 % CI [-1.08,0.61], p = .13, I2 = 50 %, n = 315). CONCLUSION: While SGAs showed a small effect on anxiety/depression, the findings are inconclusive due to scarcity of research on comorbid anxiety in schizophrenia, heterogeneity of anxiety symptoms, and the scales used to measure anxiety. Further studies employing specific anxiety scales are required to explore antipsychotics, considering their receptor affinity and augmentation with serotonin/norepinephrine reuptake inhibitors or benzodiazepines for managing anxiety in schizophrenia.

Metformin co-commencement at time of antipsychotic initiation for attenuation of weight gain: a systematic review and meta-analysis.

Background: Antipsychotic medications are associated with weight gain and metabolic derangement. However, comprehensive evidence for the efficacy of co-commenced pharmacological treatments to mitigate initial weight gain is limited. Metformin has been shown to be effective in reducing weight among people on antipsychotic medications who are already overweight, but the potential benefits of metformin co-commencement in mitigating antipsychotic-induced weight gain has not been systematically reviewed. Method: We conducted a systematic review of PubMed, EMBASE, PsychInfo, CINAHL, the Cochrane database, and China National Knowledge Infrastructure from inception to 18 November 2023. We undertook a meta-analysis of concomitant commencement of metformin versus placebo for attenuation of weight gain and metabolic syndrome for people with schizophrenia commencing a new antipsychotic. Results: Fourteen studies from Australia, United States, Venezuela, and China with 1126 participants were included. We found that metformin was superior to placebo in terms of attenuating weight gain (-3.12 kg, 95% CI -4.22 to -2.01 kg). Metformin also significantly attenuated derangement of fasting glucose levels, total cholesterol, and total triglyceride levels. Sensitivity analysis on study quality, duration, and antipsychotic agent did not impact the results. Meta-analysis was also conducted on adverse drug reactions (ADR) reported in each study which showed no significant difference in ADR incidence between metformin and placebo groups. Subgroup analysis on antipsychotic-naïve participants and participants switching to new antipsychotic did not impact the results. Conclusion: Metformin led to statistically significant and clinically meaningful attenuation of weight gain as well as attenuation of several other metabolic parameters when commenced concomitantly with antipsychotic medications. Co-commencement of metformin with antipsychotic medications, where tolerated, should be considered in the clinical setting with aim to improve long-term cardiometabolic outcomes for patients with long-term need of antipsychotic treatments.

Mismatch Negativity in Schizophrenia, Unaffected First-degree Relatives, and Healthy Controls.

BACKGROUND: Mismatch negativity (MMN) amplitude is attenuated in schizophrenia patients (SZ). However, variability in illness course among SZ samples and types of deviant stimuli used in MMN paradigms have contributed to inconsistent findings across studies. Though MMN is suggested to be impaired in schizotypy, the potential link between the two is yet to be systematically examined in unaffected first-degree relatives of schizophrenia patients (FDR). METHODS: The SZ sample had twenty-two drug-naïve or drug-free patients (dSZ) and thirty chronic/medicated patients (cSZ). dSZ and cSZ patients were compared with thirty-six unaffected FDR and thirty-two healthy controls (HC) using a two-tone passive auditory oddball MMN paradigm in an event-related potential experiment with two conditions (presented as separate blocks)-duration-deviant (duration-MMN) and frequency-deviant (frequency-MMN). Schizotypy scores and MMN indices were examined for correlation in FDR. RESULTS: Duration-MMN amplitude was significantly attenuated in both dSZ and cSZ compared to other groups. dSZ and cSZ did not differ on MMN indices. Psychopathology scores and features of illness (illness duration, medication dosage, etc.) did not correlate with MMN indices. In FDR, Schizotypal trait measures did not correlate with MMN indices. CONCLUSIONS: Duration-MMN emerged as a more robust indicator of prediction error signalling deficit in SZ. Frequency-MMN amplitude did not significantly differ among the groups, and MMN indices did not correlate with state and trait measures of schizophrenia-related psychopathology. These findings reiterates that auditory sensory processing captured by MMN is likely reflective of dynamic cognitive functions at the point of testing, and is unlikely to be an expression of enduring symptomatology.

Glucagon-like-peptide 1 receptor agonism and attempted suicide: A Mendelian randomisation study to assess a potential causal association.

Glucagon-like-peptide 1 receptor agonists (GLP-1RA) have transformed type 2 diabetes (T2D) and obesity management. Multiple regulatory agencies are investigating reported associations between GLP1-RA and increased suicide attempts (SA), but observational data may be prone to confounding. Randomised control trials (RCT) of GLP-1RA were largely undertaken in people at lower risk of SA. Real-world data suggest semaglutide use associates with reduced suicidal ideation and depression but was under-powered to statistically assess risk of SA. Mendelian randomisation (MR) leverages genetic instrument(s) to infer potential causal association between an exposure and an outcome. We undertook MR using missense variants in the gene encoding GLP1R that improve glycemia, lower T2D risk and/or lower BMI, to investigate potential causal association between GLP-1RA and SA. In people of European ancestry, MR did not find evidence genetically proxied GLP1RA increased SA in a general population cohort: (rs10305492, exposure: HbA1c, odds ratio [OR] and 95% confidence interval [CI]: 1.38, 0.41-4.62, p = .60), (rs10305492, exposure: FG, OR 1.27, 0.52-3.13, p = .60) and (rs1042044, exposure BMI, OR 0.30, 0.06-1.48) with concordant results in a multi-ancestry SA case-control cohort. In conclusion, we did not find MR evidence that increased GLP-1RA impacts SA. This awaits confirmation with RCT and real-world data.

Evaluation of the Glymphatic System in Schizophrenia Spectrum Disorder Using Proton Magnetic Resonance Spectroscopy Measurement of Brain Macromolecule and Diffusion Tensor Image Analysis Along the Perivascular Space Index.

BACKGROUND AND HYPOTHESIS: The glymphatic system (GS), a brain waste clearance pathway, is disrupted in various neurodegenerative and vascular diseases. As schizophrenia shares clinical characteristics with these conditions, we hypothesized GS disruptions in patients with schizophrenia spectrum disorder (SCZ-SD), reflected in increased brain macromolecule (MM) and decreased diffusion-tensor-image-analysis along the perivascular space (DTI-ALPS) index. STUDY DESIGN: Forty-seven healthy controls (HCs) and 103 patients with SCZ-SD were studied. Data included 135 proton magnetic resonance spectroscopy (1H-MRS) sets, 96 DTI sets, with 79 participants contributing both. MM levels were quantified in the dorsal-anterior cingulate cortex (dACC), dorsolateral prefrontal cortex, and dorsal caudate (point resolved spectroscopy, echo-time = 35ms). Diffusivities in the projection and association fibers near the lateral ventricle were measured to calculate DTI-ALPS indices. General linear models were performed, adjusting for age, sex, and smoking. Correlation analyses examined relationships with age, illness duration, and symptoms severity. STUDY RESULTS: MM levels were not different between patients and HCs. However, left, right, and bilateral DTI-ALPS indices were lower in patients compared with HCs (P < .001). In HCs, age was positively correlated with dACC MM and negatively correlated with left, right, and bilateral DTI-ALPS indices (P < .001). In patients, illness duration was positively correlated with dACC MM and negatively correlated with the right DTI-ALPS index (P < .05). In the entire population, dACC MM and DTI-ALPS indices showed an inverse correlation (P < .01). CONCLUSIONS: Our results suggest potential disruptions in the GS of patients with SCZ-SD. Improving brain's waste clearance may offer a potential therapeutic approach for patients with SCZ-SD.

Elevated intrinsic cortical curvature in treatment-resistant schizophrenia: Evidence of structural deformation in functional connectivity areas and comparison with alternate indices of structure.

BACKGROUND: Research suggests structural and connectivity abnormalities in patients with treatment-resistant schizophrenia (TRS) compared to first-line responders and healthy-controls. However, measures of these abnormalities are often influenced by external factors like nicotine and antipsychotics, limiting their clinical utility. Intrinsic-cortical-curvature (ICC) presents a millimetre-scale measure of brain gyrification, highly sensitive to schizophrenia differences, and associated with TRS-like traits in early stages of the disorder. Despite this evidence, ICC in TRS remains unexplored. This study investigates ICC as a marker for treatment resistance in TRS, alongside structural indices for comparison. METHODS: We assessed ICC in anterior cingulate, dorsolateral prefrontal, temporal, and parietal cortices of 38 first-line responders, 30 clozapine-resistant TRS, 37 clozapine-responsive TRS, and 52 healthy-controls. For comparative purposes, Fold and Curvature indices were also analyzed. RESULTS: Adjusting for age, sex, nicotine-use, and chlorpromazine equivalence, principal findings indicate ICC elevations in the left hemisphere dorsolateral prefrontal (p < 0.001, η2partial = 0.142) and temporal cortices (LH p = 0.007, η2partial = 0.060; RH p = 0.011, η2partial = 0.076) of both TRS groups, and left anterior cingulate cortex of clozapine-resistant TRS (p = 0.026, η2partial = 0.065), compared to healthy-controls. Elevations that correlated with reduced cognition (p = 0.001) and negative symptomology (p < 0.034) in clozapine-resistant TRS. Fold and Curvature indices only detected group differences in the right parietal cortex, showing interactions with age, sex, and nicotine use. ICC showed interactions with age. CONCLUSION: ICC elevations were found among patients with TRS, and correlated with symptom severity. ICCs relative independence from sex, nicotine-use, and antipsychotics, may support ICC's potential as a viable marker for TRS, though age interactions should be considered.

Neurocognitive correlates of metabolic dysregulation in individuals with mood disorders: a systematic review and meta-analysis.

Individuals with mood disorders are predisposed to metabolic dysfunction, while those with metabolic dysregulation such as diabetes and obesity experience more severe depressive symptoms. Both metabolic dysfunction and mood disorders are independently associated with cognitive deficits. Therefore, given their close association, this study aimed to explore the association between metabolic dysfunction in individuals with mood disorders in relation to cognitive outcomes. A comprehensive search comprised of these three domains was carried out; a random-effects meta-analysis pooling mean cognitive outcomes was conducted (PROSPERO ID: CRD42022295765). Sixty-three studies were included in this review; 26 were synthesized in a quantitative meta-analysis. Comorbid metabolic dysregulation was associated with significantly lower global cognition among individuals with mood disorders. These trends were significant within each mood disorder subgroup, including major depressive disorder, bipolar disorder, and self-report depression/depressive symptoms. Type 2 diabetes was associated with the lowest cognitive performance in individuals with mood disorders, followed by peripheral insulin resistance, body mass index ⩾25 kg/m2, and metabolic syndrome. Significant reduction in scores was also observed among individual cognitive domains (in descending order) of working memory, attention, executive function, processing speed, verbal memory, and visual memory. These findings demonstrate the detrimental effects of comorbid metabolic dysfunction in individuals with mood disorders. Further research is required to understand the underlying mechanisms connecting mood disorders, metabolism, and cognition.

Olanzapine's effects on hypothalamic transcriptomics and kinase activity.

Olanzapine is a second-generation antipsychotic that disrupts metabolism and is associated with an increased risk of type 2 diabetes. The hypothalamus is a key region in the control of whole-body metabolic homeostasis. The objective of the current study was to determine how acute peripheral olanzapine administration affects transcription and serine/threonine kinase activity in the hypothalamus. Hypothalamus samples from rats were collected following the pancreatic euglycemic clamp, thereby allowing us to study endpoints under steady state conditions for plasma glucose and insulin. Olanzapine stimulated pathways associated with inflammation, but diminished pathways associated with the capacity to combat endoplasmic reticulum stress and G protein-coupled receptor activity. These pathways represent potential targets to reduce the incidence of type 2 diabetes in patients taking antipsychotics.

Glucose dysregulation in antipsychotic-naive first-episode psychosis: in silico exploration of gene expression signatures.

Antipsychotic (AP)-naive first-episode psychosis (FEP) patients display early dysglycemia, including insulin resistance and prediabetes. Metabolic dysregulation may therefore be intrinsic to psychosis spectrum disorders (PSDs), independent of the metabolic effects of APs. However, the potential biological pathways that overlap between PSDs and dysglycemic states remain to be identified. Using meta-analytic approaches of transcriptomic datasets, we investigated whether AP-naive FEP patients share overlapping gene expression signatures with non-psychiatrically ill early dysglycemia individuals. We meta-analyzed peripheral transcriptomic datasets of AP-naive FEP patients and non-psychiatrically ill early dysglycemia subjects to identify common gene expression signatures. Common signatures underwent pathway enrichment analysis and were then used to identify potential new pharmacological compounds via Integrative Library of Integrated Network-Based Cellular Signatures (iLINCS). Our search results yielded 5 AP-naive FEP studies and 4 early dysglycemia studies which met inclusion criteria. We discovered that AP-naive FEP and non-psychiatrically ill subjects exhibiting early dysglycemia shared 221 common signatures, which were enriched for pathways related to endoplasmic reticulum stress and abnormal brain energetics. Nine FDA-approved drugs were identified as potential drug treatments, of which the antidiabetic metformin, the first-line treatment for type 2 diabetes, has evidence to attenuate metabolic dysfunction in PSDs. Taken together, our findings support shared gene expression changes and biological pathways associating PSDs with dysglycemic disorders. These data suggest that the pathobiology of PSDs overlaps and potentially contributes to dysglycemia. Finally, we find that metformin may be a potential treatment for early metabolic dysfunction intrinsic to PSDs.

Safety of BEN guidelines in clozapine treatment: A Canadian perspective.

OBJECTIVE: Unidentified benign ethnic neutropenia (BEN) has been recognized as a factor contributing to clozapine underutilization and discontinuation. Guidelines were implemented to accommodate BEN in Canada, and our main objective was to evaluate clozapine's safety in a sample of Canadian psychiatric patients with BEN. METHOD: A retrospective chart review was conducted at the Centre for Addiction and Mental Health, Toronto, Canada. Through the clozapine clinic registry, participants were identified who (i) received clozapine using the approved BEN guidelines for hematological monitoring, and (ii) had at least one complete blood count pre- and post-clozapine initiation. RESULTS: Our sample population was comprised of 41 BEN patients who were African-Caribbean (49 %), African (34 %), African-North American (12 %), Middle Eastern (2 %), and Indian-Caribbean (2 %). There was a significant reduction in hematological alerts for these patients while monitored under BEN guidelines (p < 0.001). The mean within-patient ANC value was not significantly different one year after clozapine initiation compared to the pre-clozapine baseline (p = 0.069). None of the patients discontinued clozapine for hematological reasons. CONCLUSIONS: Findings demonstrated that patients monitored under the modified hematological guidelines for BEN can be safely treated with clozapine. These findings have important clinical ramifications as increased implementation of BEN guidelines may allow for broader use of clozapine.

Depression in caregivers of patients with schizophrenia: a scoping review.

PURPOSE: Caregivers play a vitally important role in the lives of people with schizophrenia. However, their mental health can often be overlooked. In recent years, with increasing attention to mental health and wellness, common mental illness such as depression in caregivers of people with schizophrenia has received renewed attention. The purpose of this review was to consolidate and synthesize recent literature on (1) the prevalence of depression in caregivers of people with schizophrenia, (2) factors associated with depression in caregivers of people with schizophrenia, and (3) interventions that target depression in caregivers of people with schizophrenia. METHODS: A systematic search focusing on literature published between 2010 and 2022 was done to retrieve relevant articles from the following databases: Ovid MEDLINE, Ovid EMBASE, and Ovid Psych INFO. RESULTS: Twenty-four studies met inclusion criteria and were included in the review. Nine evaluated the prevalence of depression, 18 evaluated factors associated with depression in caregivers, and 6 examined interventions targeting depression. The prevalence of depression and depressive symptoms in samples of caregivers ranged between 12 and 40% across the studies. Females, especially mothers of people with schizophrenia, were more likely to experience depression, followed by younger caregivers. Several factors, including gender, interpersonal relationships, social support, stigma, literacy, and financial constraints, were identified as factors associated with depression in caregivers. Several interventions like yoga, emotional training, and psychoeducation were evaluated, and they showed a significant reduction in the level of depression and depressive symptoms experienced by the caregiver population. CONCLUSIONS: Depression in caregivers in this clinical population may be widespread and warrants further study. There are promising interventions that can target depression in caregivers. Well-designed longitudinal studies may help identify caregivers at risk of developing depression and further inform targets for intervention.

Central insulin dysregulation in antipsychotic-naïve first-episode psychosis: In silico exploration of gene expression signatures.

Antipsychotic drug (AP)-naïve first-episode psychosis (FEP) patients display premorbid cognitive dysfunctions and dysglycemia. Brain insulin resistance may link metabolic and cognitive disorders in humans. This suggests that central insulin dysregulation represents a component of the pathophysiology of psychosis spectrum disorders (PSDs). Nonetheless, the links between central insulin dysregulation, dysglycemia, and cognitive deficits in PSDs are poorly understood. We investigated whether AP-naïve FEP patients share overlapping brain gene expression signatures with central insulin perturbation (CIP) in rodent models. We systematically compiled and meta-analyzed peripheral transcriptomic datasets of AP-naïve FEP patients along with hypothalamic and hippocampal datasets of CIP rodent models to identify common transcriptomic signatures. The common signatures were used for pathway analysis and to identify potential drug treatments with discordant (reverse) signatures. AP-naïve FEP and CIP (hypothalamus and hippocampus) shared 111 and 346 common signatures respectively, which were associated with pathways related to inflammation, endoplasmic reticulum stress, and neuroplasticity. Twenty-two potential drug treatments were identified, including antidiabetic agents. The pathobiology of PSDs may include central insulin dysregulation, which contribute to dysglycemia and cognitive dysfunction independently of AP treatment. The identified treatments may be tested in early psychosis patients to determine if dysglycemia and cognitive deficits can be mitigated.