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BACKGROUND: Antipsychotic polypharmacy (APP) is frequently prescribed for schizophrenia-spectrum disorders. Despite the inconsistent findings on efficacy, APP may be beneficial for subgroups of psychotic patients. This meta-analysis of individual patient data investigated moderators of efficacy and tolerability of APP in adult patients with schizophrenia-spectrum disorders. DESIGN: We searched PubMed, EMBASE, and the Cochrane Central Register of Randomized Trials until September 1, 2022, for randomized controlled trials comparing APP with antipsychotic monotherapy. We estimated the effects with a one-stage approach for patient-level moderators and a two-stage approach for study-level moderators, using (generalized) linear mixed-effects models. Primary outcome was treatment response, defined as a reduction of 25 % or more in the Positive and Negative Syndrome Scale (PANSS) score. Secondary outcomes were study discontinuation, and changes from baseline on the PANSS total score, its positive and negative symptom subscale scores, the Clinical Global Impressions Scale (CGI), and adverse effects. RESULTS: We obtained individual patient data from 10 studies (602 patients; 31 % of all possible patients) and included 599 patients in our analysis. A higher baseline PANSS total score increased the chance of a response to APP (OR = 1.41, 95 % CI 1.02; 1.94, p = 0.037 per 10-point increase in baseline PANSS total), mainly driven by baseline positive symptoms. The same applied to changes on the PANSS positive symptom subscale and the CGI severity scale. Extrapyramidal side effects increased significantly where first and second-generation antipsychotics were co-prescribed. Study discontinuation was comparable between both treatment arms. CONCLUSIONS: APP was effective in severely psychotic patients with high baseline PANSS total scores and predominantly positive symptoms. This effect must be weighed against potential adverse effects.
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The risk of violence is higher in schizophrenia spectrum disorders (SSD) compared to the general population and it is a pressing and understudied issue. Several dispositional and environmental factors have been previously correlated with violence, however, there has been little success in assessing their ability to predict violence patterns across the life span. This study aims to assess violence prediction based on personality traits, psychological resilience, and life-course adversities in a non-forensic population of SSD patients. In a sample of 231 patients with SSD, we assessed violence using the Brown-Goodwin History of Lifetime Aggression Scale and conducted cross-sectional assessments of possible predictors such as childhood trauma, personality traits and resilience scores. We then utilized a logistic regression classification algorithm to predict different violence trajectories based on the proposed risk factors. Our model significantly predicted individuals with violence in both childhood and adulthood, as well as childhood-only violence (p < 0.001). However, the model did not show significance for adult-only violence (p = 0.604). In all given trajectories, female sex appeared to be protective against violence, while stressful life events appeared to contribute to it. These results suggest that distinct factors can better inform risk assessment of lifespan violence patterns for personalized interventions in SSD.
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Personalidade , Resiliência Psicológica , Esquizofrenia , Violência , Humanos , Masculino , Feminino , Adulto , Esquizofrenia/epidemiologia , Personalidade/fisiologia , Violência/psicologia , Violência/estatística & dados numéricos , Pessoa de Meia-Idade , Experiências Adversas da Infância/estatística & dados numéricos , Estudos Transversais , Fatores de Risco , Adulto Jovem , Psicologia do EsquizofrênicoRESUMO
Recent research suggests that neurocognitive deficits in patients with schizophrenia may increase the risk of developing cognitive biases. As such, we set out to determine this predictive relationship as it pertains to the development of a first-episode psychosis. We hypothesized that poorer performance in processing speed would be associated with jumping to conclusions and an externalizing bias. Poorer performance in working memory would be associated with belief inflexibility and jumping to conclusions, and poorer performance in attention would be associated with attention to threat. We hypothesized that all cognitive biases would be associated with subsyndromal positive symptoms, and schizotypal traits would moderate these relationships. Undergraduate students (N = 130) completed the Schizotypal Personality Questionnaire, DAVOS Assessment of Cognitive Biases, Community Assessment of Psychic Experiences, and a computerized neuropsychological assessment battery. Processing speed had a small effect on externalizing bias, which in turn affected subsyndromal positive symptoms. There was no moderating effect of schizotypal traits on externalizing bias, but it was significantly associated with subsyndromal positive symptoms. Only the externalizing bias was associated with subsyndromal positive symptomatology, which might be explained by a restricted range and reduced variance in performance as a result of using a university student sample. This is one of few studies that sought to explain the mechanism responsible for the development of subsyndromal positive symptoms in a healthy sample using self-report measures.
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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.
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Antipsicóticos , Astrócitos , Clozapina , Espectroscopia de Prótons por Ressonância Magnética , Esquizofrenia Resistente ao Tratamento , Clozapina/farmacologia , Humanos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Antipsicóticos/farmacologia , Adulto , Masculino , Feminino , Pessoa de Meia-Idade , Esquizofrenia Resistente ao Tratamento/tratamento farmacológico , Esquizofrenia Resistente ao Tratamento/metabolismo , Inositol/metabolismo , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/patologiaRESUMO
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.
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Antipsicóticos , Córtex Cerebral , Clozapina , Imageamento por Ressonância Magnética , Esquizofrenia Resistente ao Tratamento , Humanos , Feminino , Masculino , Adulto , Antipsicóticos/farmacologia , Clozapina/farmacologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Esquizofrenia Resistente ao Tratamento/tratamento farmacológico , Esquizofrenia Resistente ao Tratamento/patologia , Esquizofrenia Resistente ao Tratamento/fisiopatologia , Esquizofrenia Resistente ao Tratamento/diagnóstico por imagem , Pessoa de Meia-Idade , Adulto Jovem , Esquizofrenia/tratamento farmacológico , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/fisiopatologia , Esquizofrenia/patologiaRESUMO
OBJECTIVES: The pathology of Tardive Dyskinesia (TD) has yet to be fully understood, but there have been proposed hypotheses for the cause of this condition. Our team previously reported a possible association of TD with the Complement Component C4 gene in the HLA region. In this study, we explored the HLA region further by examining two previously identified schizophrenia-associated HLA-region single-nucleotide polymorphisms (SNPs), namely rs13194504 and rs210133. METHODS: The SNPs rs13194504 and rs210133 were tested for association with the occurrence and severity of TD in a sample of 172 schizophrenia patients who were recruited for four studies from three different clinical sites in Canada and USA. RESULTS: The rs13194504 AA genotype was associated with decreased severity for TD as measured by Abnormal Involuntary Movement Scale (AIMS) scores (p = 0.047) but not for TD occurrence. SNP rs210133 was not significantly associated with either TD occurrence or AIMS scores. CONCLUSION: Our findings suggest that the rs13194504 AA genotype may play a role in TD severity, while SNP rs210133 may not have a major role in the risk or severity of TD.
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Polimorfismo de Nucleotídeo Único , Esquizofrenia , Discinesia Tardia , Humanos , Esquizofrenia/genética , Discinesia Tardia/genética , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Fatores de Risco , Marcadores Genéticos , Índice de Gravidade de Doença , Genótipo , Predisposição Genética para Doença , Canadá , Antipsicóticos/efeitos adversosRESUMO
Assessing the number of past suicide attempts is vital in clinical and research settings, as it is a significant variable in assessing suicide risk. This study sought to compare the accuracy of the C-SSRS and the BSS in reporting past suicide attempts in schizophrenia spectrum disorders . Six hundred participants were recruited from the Centre for Addiction and Mental Health in Toronto, and completed the BSS and C-SSRS. A medical chart review was performed to determine the number of past suicide attempts. In addition, receiver operating characteristic curves were generated to compare the accuracy of both tests under various stratifications. Based on our findings, there were no significant differences (P = 0.8977) between the BSS and CSSRS in detecting a history of past suicide attempts. The BSS exhibited a sensitivity of 0.847 and a specificity of 0.841, while the C-SSRS had a slightly lower sensitivity of 0.795 and a slightly higher specificity of 0.889. Additionally, repeating the analysis to determine the accuracy of detecting multiple past suicide attempts, the BSS demonstrated a sensitivity of 0.704 and a specificity of 0.959, whereas the C-SSRS had a sensitivity of 0.787 and a specificity of 0.927. We further contrasted the two scales, stratified by different demographic variables such as age and sex. The accuracy of both tools, which is defined as the ability to identify true positive cases while minimizing false positives, increased as age increased, but these differences were not statistically significant. Therefore, both tools show a high level of accuracy in reporting past suicide attempt history and should be utilized to fit the specific needs of the research or clinical teams. These findings can inform clinical practice and future research, highlighting the importance of selecting assessment tools that fit the population's needs and context.
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Escalas de Graduação Psiquiátrica , Esquizofrenia , Ideação Suicida , Tentativa de Suicídio , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Esquizofrenia/diagnóstico , Tentativa de Suicídio/estatística & dados numéricos , Adulto Jovem , Escalas de Graduação Psiquiátrica/normas , Adolescente , Psicologia do Esquizofrênico , Idoso , Sensibilidade e Especificidade , Curva ROC , Transtornos Psicóticos/diagnósticoRESUMO
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.
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Antipsicóticos , Clozapina , Neutropenia , Humanos , Clozapina/efeitos adversos , Antipsicóticos/efeitos adversos , Estudos Retrospectivos , Canadá , Neutropenia/induzido quimicamenteRESUMO
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.
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Esquizofrenia , Feminino , Humanos , Cuidadores/psicologia , Depressão/epidemiologia , Saúde Mental , Esquizofrenia/epidemiologia , Esquizofrenia/terapia , Estigma SocialRESUMO
BACKGROUND AND HYPOTHESIS: Given the heterogeneity and possible disease progression in schizophrenia, identifying the neurobiological subtypes and progression patterns in each patient may lead to novel biomarkers. Here, we adopted data-driven machine-learning techniques to identify the progression patterns of brain morphological changes in schizophrenia and investigate the association with treatment resistance. STUDY DESIGN: In this cross-sectional multicenter study, we included 177 patients with schizophrenia, characterized by treatment response or resistance, with 3D T1-weighted magnetic resonance imaging. Cortical thickness and subcortical volumes calculated by FreeSurfer were converted into z scores using 73 healthy controls data. The Subtype and Stage Inference (SuStaIn) algorithm was used for unsupervised machine-learning analysis. STUDY RESULTS: SuStaIn identified 3 different subtypes: (1) subcortical volume reduction (SC) type (73 patients), in which volume reduction of subcortical structures occurs first and moderate cortical thinning follows, (2) globus pallidus hypertrophy and cortical thinning (GP-CX) type (42 patients), in which globus pallidus hypertrophy initially occurs followed by progressive cortical thinning, and (3) cortical thinning (pure CX) type (39 patients), in which thinning of the insular and lateral temporal lobe cortices primarily happens. The remaining 23 patients were assigned to baseline stage of progression (no change). SuStaIn also found 84 stages of progression, and treatment-resistant schizophrenia showed significantly more progressed stages than treatment-responsive cases (Pâ =â .001). The GP-CX type presented earlier stages than the pure CX type (Pâ =â .009). CONCLUSIONS: The brain morphological progressions in schizophrenia can be classified into 3 subtypes, and treatment resistance was associated with more progressed stages, which may suggest a novel biomarker.
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Esquizofrenia , Humanos , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/tratamento farmacológico , Esquizofrenia/complicações , Estudos Transversais , Afinamento Cortical Cerebral/patologia , Imageamento por Ressonância Magnética , Lobo Temporal/patologia , Progressão da Doença , Hipertrofia/complicações , Hipertrofia/patologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologiaRESUMO
Antipsychotics (APs) are the cornerstone of treatment for schizophrenia (SCZ) spectrum disorders. Previous research suggests that there may be a positive association between AP-induced weight gain and/or dyslipidemia and improvement in psychiatric symptoms, often referred to as a "metabolic threshold". To determine whether a similar relationship exists for glucose parameters, we conducted a systematic search in six databases from inception to June 2022 for all longitudinal studies that directly examined the relationship between changes in glucose-related outcomes and changes in psychopathology among patients with SCZ treated with APs. We identified 10 relevant studies and one additional study that considered cognition. In most cases, we found that increased levels of fasting glucose and insulin following treatment were associated with clinical improvement. These findings contribute to existing literature that could suggest a common mechanism between AP action and metabolic side effects and support a need for additional work aimed at exploring the validity of a glucose-psychopathology relation in SCZ.
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Schizophrenia spectrum disorders (SSDs) are associated with significant functional impairments, disability, and low rates of personal recovery, along with tremendous economic costs linked primarily to lost productivity and premature mortality. Efforts to delineate the contributors to disability in SSDs have highlighted prominent roles for a diverse range of symptoms, physical health conditions, substance use disorders, neurobiological changes, and social factors. These findings have provided valuable advances in knowledge and helped define broad patterns of illness and outcomes across SSDs. Unsurprisingly, there have also been conflicting findings for many of these determinants that reflect the heterogeneous population of individuals with SSDs and the challenges of conceptualizing and treating SSDs as a unitary categorical construct. Presently it is not possible to identify the functional course on an individual level that would enable a personalized approach to treatment to alter the individual's functional trajectory and mitigate the ensuing disability they would otherwise experience. To address this ongoing challenge, this study aims to conduct a longitudinal multimodal investigation of a large cohort of individuals with SSDs in order to establish discrete trajectories of personal recovery, disability, and community functioning, as well as the antecedents and predictors of these trajectories. This investigation will also provide the foundation for the co-design and testing of personalized interventions that alter these functional trajectories and improve outcomes for people with SSDs.
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Esquizofrenia , Humanos , Esquizofrenia/terapia , Conhecimento , Mortalidade Prematura , Neurobiologia , Exame FísicoRESUMO
Suicide is a significant public health crisis, with 800,000 people dying annually. Most people completing suicide have previous psychiatric conditions, and those with psychotic and mood disorders are particularly vulnerable. Unfortunately, there are currently no biomarkers available for accurately detecting suicidal ideation. Given the genetic and environmental factors that play a role in suicidal ideation, we attempted to determine epigenetic modifications, specifically DNA methylation, in response to changes in suicidal ideation. Using a longitudinal study design, 31 participants with schizophrenia spectrum disorders were interviewed at a baseline visit and again at a follow-up visit 3-12 months later. Current suicidal ideation was recorded at both visits with the Columbia Suicide Severity Rating Scale and the Beck Scale for Suicide Ideation, and whole blood was collected for methylation analysis. Our analysis shows a significant negative correlation between cg26910920 methylation and increasing Columbia Suicide Severity Rating Scale scores and a positive correlation between cg13673029 methylation and increasing Beck Scale for Suicide Ideation scores. This pilot study indicates that there is the possibility that DNA methylation can respond to changes in suicidal ideation over time and potentially be used as a biomarker of suicidal ideation in the future.
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Esquizofrenia , Humanos , Esquizofrenia/genética , Ideação Suicida , Tentativa de Suicídio/psicologia , Estudos Longitudinais , Metilação , Projetos Piloto , Biomarcadores , Escalas de Graduação PsiquiátricaRESUMO
Schizophrenia (SCZ) is a severe psychotic disorder associated with premature mortality and aging. Moreover, the symptoms and progression of psychiatric disorders in general are associated with decreased lifespan, biological aging, and poorer medical outcomes. In this study, we investigated the relationship between several epigenetic clocks and scanned the entire genome for association in a cohort of SCZ individuals (n = 107). Biological age was computed from blood DNA methylation (DNAm) and tested for association against common variants across the genome using general linear models. Genes affecting epigenetic age acceleration in our cohort were found mainly when using the telomeric length clock rather than the other biological clocks. These findings pair with existing evidence that there are some genes associated with longevity and suggest further investigations of putative biological mechanisms for morbidity and premature mortality, not only in patients with SCZ but also in the general population.
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BACKGROUND: Aberrant brain insulin signaling has been posited to lie at the crossroads of several metabolic and cognitive disorders. Intranasal insulin (INI) is a non-invasive approach that allows investigation and modulation of insulin signaling in the brain while limiting peripheral side effects. OBJECTIVES: The objective of this systematic review and meta-analysis is to evaluate the effects of INI on cognition in diverse patient populations and healthy individuals. METHODS: MEDLINE, EMBASE, PsycINFO, and Cochrane CENTRAL were systematically searched from 2000 to July 2021. Eligible studies were randomized controlled trials that studied the effects of INI on cognition. Two independent reviewers determined study eligibility and extracted relevant descriptive and outcome data. RESULTS: Twenty-nine studies (pooled N = 1,726) in healthy individuals as well as those with Alzheimer's disease (AD)/mild cognitive impairment (MCI), mental health disorders, metabolic disorders, among others, were included in the quantitative meta-analysis. Patients with AD/MCI treated with INI were more likely to show an improvement in global cognition (SMD = 0.22, 95% CI: 0.05-0.38 p = <0.00001, N = 12 studies). Among studies with healthy individuals and other patient populations, no significant effects of INI were found for global cognition. CONCLUSIONS: This review demonstrates that INI may be associated with pro-cognitive benefits for global cognition, specifically for individuals with AD/MCI. Further studies are required to better understand the neurobiological mechanisms and differences in etiology to dissect the intrinsic and extrinsic factors contributing to the treatment response of INI.
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Doença de Alzheimer , Transtornos Cognitivos , Disfunção Cognitiva , Humanos , Insulina/uso terapêutico , Disfunção Cognitiva/complicações , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/complicações , Cognição , Transtornos Cognitivos/etiologiaRESUMO
BACKGROUND: A critical facet of motivation is effort-based decision making, which refers to the mental processes involved in deciding whether a potential reward is worth the effort. To advance understanding of how individuals with schizophrenia and major depressive disorder utilize cost-benefit information to guide choice behavior, this study aimed to characterize individual differences in the computations associated with effort-based decision making. METHODS: One hundred forty-five participants (51 with schizophrenia, 43 with depression, and 51 healthy control participants) completed the Effort Expenditure for Rewards Task, with mixed effects modeling conducted to estimate the predictors of decision making. These model-derived, subject-specific coefficients were then clustered using k-means to test for the presence of discrete transdiagnostic subgroups with different profiles of reward, probability, and cost information utilization during effort-based decision making. RESULTS: An optimal 2-cluster solution was identified, with no significant differences in the distribution of diagnostic groups between clusters. Cluster 1 (n = 76) was characterized by overall lower information utilization during decision making than cluster 2 (n = 61). Participants in this low information utilization cluster were also significantly older and more cognitively impaired, and their utilization of reward, probability, and cost was significantly correlated with clinical amotivation, depressive symptoms, and cognitive functioning. CONCLUSIONS: Our findings revealed meaningful individual differences among participants with schizophrenia, depression, and healthy control participants in their utilization of cost-benefit information in the context of effortful decision making. These findings may provide insight into different processes associated with aberrant choice behavior and may potentially guide the identification of more individualized treatment targets for effort-based motivation deficits across disorders.
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Transtorno Depressivo Maior , Esquizofrenia , Humanos , Transtorno Depressivo Maior/psicologia , Esquizofrenia/complicações , Individualidade , Tomada de Decisões , CogniçãoRESUMO
Psychosis spectrum disorders (PSDs), as well as other severe mental illnesses where psychotic features may be present, like bipolar disorder, are associated with intrinsic metabolic abnormalities. Antipsychotics (APs), the cornerstone of treatment for PSDs, incur additional metabolic adversities including weight gain. Currently, major gaps exist in understanding psychosis illness biomarkers, as well as risk factors and mechanisms for AP-induced weight gain. Metabolomic profiles may identify biomarkers and provide insight into the mechanistic underpinnings of PSDs and antipsychotic-induced weight gain. In this 12-week prospective naturalistic study, we compared serum metabolomic profiles of 25 cases within approximately 1 week of starting an AP to 6 healthy controls at baseline to examine biomarkers of intrinsic metabolic dysfunction in PSDs. In 17 of the case participants with baseline and week 12 samples, we then examined changes in metabolomic profiles over 12 weeks of AP treatment to identify metabolites that may associate with AP-induced weight gain. In the cohort with pre-post data (n = 17), we also compared baseline metabolomes of participants who gained ≥5% baseline body weight to those who gained <5% to identify potential biomarkers of antipsychotic-induced weight gain. Minimally AP-exposed cases were distinguished from controls by six fatty acids when compared at baseline, namely reduced levels of palmitoleic acid, lauric acid, and heneicosylic acid, as well as elevated levels of behenic acid, arachidonic acid, and myristoleic acid (FDR < 0.05). Baseline levels of the fatty acid adrenic acid was increased in 11 individuals who experienced a clinically significant body weight gain (≥5%) following 12 weeks of AP exposure as compared to those who did not (FDR = 0.0408). Fatty acids may represent illness biomarkers of PSDs and early predictors of AP-induced weight gain. The findings may hold important clinical implications for early identification of individuals who could benefit from prevention strategies to reduce future cardiometabolic risk, and may lead to novel, targeted treatments to counteract metabolic dysfunction in PSDs.
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Impaired insight into illness is a common element of schizophrenia that contributes to treatment nonadherence and negative clinical outcomes. Previous studies suggest that impaired insight may arise from brain abnormalities. However, interpretations of these findings are limited due to small sample sizes and inclusion of patients with a narrow range of illness severity and insight deficits. In a large sample of patients with schizophrenia, the majority of which were designated as treatment-resistant, we investigated the associations between impaired insight and cortical thickness and subcortical volumes. A total of 94 adult participants with a schizophrenia spectrum disorder were included. Fifty-six patients (60%) had treatment-resistant schizophrenia. The core domains of insight were assessed with the VAGUS insight into psychosis scale. We obtained 3T MRI T1-weighted images, which were analysed using CIVET and MAGeT-Brain. Whole-brain vertex-wise analyses revealed impaired insight, as measured by VAGUS average scores, was related to cortical thinning in left frontotemporoparietal regions. The same analysis in treatment-resistant patients showed thinning in the same regions, even after controlling for age, sex, illness severity, and chlorpromazine antipsychotic dose equivalents. No association was found in non-treatment-resistant patients. Region-of-interest analyses revealed impaired general illness awareness was associated with cortical thinning in the left supramarginal gyrus when controlling for covariates. Reduced right and left thalamic volumes were associated with VAGUS symptom attribution and awareness of negative consequences subscale scores, respectively, but not after correction for multiple testing. Our results suggest impaired insight into illness is related to cortical thinning in left frontotemporoparietal regions in patients with schizophrenia, particularly those with treatment resistance where insight deficits may be more chronic.
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Metformin is the currently accepted first-line treatment for antipsychotic-associated weight gain (AAWG). However, not all patients benefit from metformin. Glucagon-like peptide-1 receptor agonists (GLP1-RA) have shown promise in the management of obesity in the general population, with preliminary evidence supporting efficacy in AAWG. Semaglutide is a weekly injectable GLP-1RA which received recent approval for obesity management and noted superiority over other GLP-1RAs. This study explored the efficacy and tolerability of semaglutide in AAWG among individuals with severe mental illness. A retrospective chart review of patients treated with semaglutide in the Metabolic Clinic at the Center for Addiction and Mental Health (CAMH) between 2019 and 2021 was conducted. Patients failing a trial of metformin (<5% weight loss or continuing to meet criteria for metabolic syndrome) after 3 months at the maximum tolerated dose (1500-2000 mg/day) were initiated on semaglutide up to 2 mg/week. The primary outcome measure was a change in weight at 3, 6, and 12 months. Twelve patients on weekly semaglutide injections of 0.71 ± 0.47 mg/week were included in the analysis. About 50% were female; the average age was 36.09 ± 13.32 years. At baseline, mean weight was 111.4 ± 31.7 kg, BMI was 36.7 ± 8.2 kg/m2, with a mean waist circumference of 118.1 ± 19.3 cm. A weight loss of 4.56 ± 3.15 kg (p < 0.001), 5.16 ± 6.27 kg (p = 0.04) and 8.67 ± 9 kg (p = 0.04) was seen at 3, 6, and 12 months, respectively, after initiation of semaglutide with relatively well-tolerated side-effects. Initial evidence from our real-world clinical setting suggests that semaglutide may be effective in reducing AAWG in patients not responding to metformin. Randomized control trials investigating semaglutide for AAWG are needed to corroborate these findings.