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Pharmacotherapy is an effective treatment modality across psychiatric disorders. Nevertheless, many patients discontinue their medication at some point. Evidence-based guidance for patients, clinicians, and policymakers on rational discontinuation strategies is vital to enable the best, personalized treatment for any given patient. Nonetheless, there is a scarcity of guidelines on discontinuation strategies. In this perspective, we therefore summarize and critically appraise the evidence on discontinuation of six major psychotropic medication classes: antidepressants, antipsychotics, benzodiazepines, mood stabilizers, opioids, and stimulants. For each medication class, a wide range of topics pertaining to each of the following questions are discussed: (1) Who can discontinue (e.g., what are risk factors for relapse?); (2) When to discontinue (e.g., after 1 year or several years of antidepressant use?); and (3) How to discontinue (e.g., what's the efficacy of dose reduction compared to full cessation and interventions to mitigate relapse risk?). We thus highlight how comparing the evidence across medication classes can identify knowledge gaps, which may pave the way for more integrated research on discontinuation.
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In the context of COVID-19 concerns related to the potential interactions between clozapine and vaccination arose. With the ultimate goal of deriving recommendations for clinical practice, we systematically reviewed the current evidence regarding altered vaccine effectiveness in clozapine-treated patients and safety aspects of vaccination, such as haematological changes and the impact of vaccines on clozapine blood levels, in clozapine-treated patients. A systematic PRISMA-conform literature search of four databases (PubMed, PsycINFO, EMBASE and Cochrane Library) complemented by a case-by-case analysis of the Vaccine Adverse Event Reporting System (VAERS) database was performed. We then systematically appraised the joint evidence and tried to derive recommendations for clinical practice. 14 records were included in this analysis. These records consisted of 5 original articles and 9 case reports. Among the original articles, two studies provided data on the association between clozapine use and antibody responses to vaccination, both indicating that clozapine use in schizophrenia may be associated with reduced levels of immunoglobulins. Additionally, three studies examined vaccine safety in clozapine-treated patients, with no clinically significant adverse effects directly attributable to the interplay between vaccinations and clozapine. VAERS Analysis encompassed 137 reports and showed no consistent evidence of an increased risk for clozapine blood level increases or adverse events. We found no evidence indicating that clozapine impairs the effectiveness of vaccines. Moreover, no serious safety concerns seem to apply when patients on clozapine are receiving vaccines. However, it is crucial to acknowledge that data on the interaction between clozapine and vaccines remain limited.
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Obsessive-compulsive symptoms (OCS) are frequently observed in individuals with schizophrenia (SCZ) treated with clozapine (CLZ). This study aimed to analyze prevalence of OCS and obsessive-compulsive disorder (OCD) in this subgroup and find possible correlations with different phenotypes. Additionally, this is the first study to examine polygenetic risk scores (PRS) in individuals with SCZ and OCS. A multicenter cohort of 91 individuals with SCZ who were treated with CLZ was recruited and clinically and genetically assessed. Symptom severity was examined using the Positive and Negative Symptom Scale (PANSS), Clinical Global Impression Scale (CGI), the Calgary Depression Scale for Schizophrenia (CDSS), Global Assessment of Functioning Scale (GAF) and Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Participants were divided into subgroups based on phenotypic OCS or OCD using Y-BOCS scores. Genomic-wide data were generated, and PRS analyses were performed to evaluate the association between either phenotypic OCD or OCS severity and genotype-predicted predisposition for OCD, SCZ, cross-disorder, and CLZ/norclozapine (NorCLZ) ratio, CLZ metabolism and NorCLZ metabolism. OCS and OCD were frequent comorbidities in our sample of CLZ-treated SCZ individuals, with a prevalence of 39.6% and 27.5%, respectively. Furthermore, the Y-BOCS total score correlated positively with the duration of CLZ treatment in years (r = 0.28; p = 0.008) and the PANSS general psychopathology subscale score (r = 0.23; p = 0.028). A significant correlation was found between OCD occurrence and PRS for CLZ metabolism. We found no correlation between OCS severity and PRS for CLZ metabolism. We found no correlation for either OCD or OCS and PRS for OCD, cross-disorder, SCZ, CLZ/NorCLZ ratio or NorCLZ metabolism. Our study was able to replicate previous findings on clinical characteristics of CLZ-treated SCZ individuals. OCS is a frequent comorbidity in this cohort and is correlated with CLZ treatment duration in years and PANSS general psychopathology subscale score. We found a correlation between OCD and PRS for CLZ metabolism, which should be interpreted as incidental for now. Future research is necessary to replicate significant findings and to assess possible genetic predisposition of CLZ-treated individuals with SCZ to OCS/OCD. Limitations attributed to the small sample size or the inclusion of subjects on co-medication must be considered. If the association between OCD and PRS for CLZ metabolism can be replicated, it should be further evaluated if CYP1A2 alteration, respectively lower CLZ plasma level, is relevant for OCD development.
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Clozapina , Trastorno Obsesivo Compulsivo , Esquizofrenia , Humanos , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Esquizofrenia/diagnóstico , Clozapina/uso terapéutico , Psicología del Esquizofrénico , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Trastorno Obsesivo Compulsivo/epidemiología , Trastorno Obsesivo Compulsivo/genética , Comorbilidad , Puntuación de Riesgo Genético , FenotipoRESUMEN
BACKGROUND: Currently, guidance on the most effective treatment for patients with clozapine-resistant schizophrenia-spectrum disorders (SSD) is lacking. While augmentation strategies to clozapine with aripiprazole and electroconvulsive therapy (ECT) have been demonstrated to be effective in patients with clozapine-resistant schizophrenia spectrum disorders (CRS), head-to-head comparisons between these addition strategies are unavailable. We therefore aim to examine the feasibility of a larger randomized, single-blind trial comparing the effectiveness, cost-effectiveness, and safety of aripiprazole addition vs. ECT addition in CRS. METHODS: In this multi-center, randomized, single-blind feasibility study, the feasibility of recruiting 20 participants with CRS who will be randomized to either aripiprazole or bilateral ECT addition will be assessed. The main endpoint is the number of patients willing to be randomized. The number of screened individuals and reasons to decline participation will be recorded. Effects will be estimated for the benefit of the foreseen larger trial. To that end, differences between both arms in symptom severity will be assessed using blinded video assessments. In addition, tolerability (e. g., cognitive functioning), safety, quality of life, recovery, and all-cause discontinuation will be compared. The follow-up period is 16 weeks, after which non-responders will be given the option to switch to the other treatment. DISCUSSION: Strengths of this feasibility trial include maintaining blinding with video assessment, a possibility to switch groups in case of non-response, and a broad set of outcome measures. Identification of factors contributing to non-participation and drop-out will generate valuable information on trial feasibility and may enhance recruitment strategies in a follow-up RCT. TRIAL REGISTRATION: The study has been approved by the Medical Research Ethics Committee of the Amsterdam University Medical Center, location AMC, and was registered on 1 May 2022 in the EU Clinical Trials Register (EudraCT) under the trial name 'EMECLO' (2021-006333-19).
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The current study was conducted to provide a general guidance for model specifications in polygenic risk score (PRS) analyses of the UK Biobank, such as adjusting for covariates (i.e. age, sex, recruitment centers, and genetic batch) and the number of principal components (PCs) that need to be included. To cover behavioral, physical and mental health outcomes, we evaluated three continuous outcomes (BMI, smoking, drinking) and two binary outcomes (Major Depressive Disorder and educational attainment). We applied 3280 (656 per phenotype) different models including different sets of covariates. We evaluated these different model specifications by comparing regression parameters such as R2, coefficients, and P values, as well as ANOVA tests. Findings suggest that only up to three PCs appears to be sufficient for controlling population stratification for most outcomes, whereas including other covariates (particularly age and sex) appears to be more essential for model performance.
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Trastorno Depresivo Mayor , Humanos , Trastorno Depresivo Mayor/genética , Bancos de Muestras Biológicas , Factores de Riesgo , Fenotipo , Reino Unido/epidemiología , Estudio de Asociación del Genoma Completo , Herencia Multifactorial/genéticaRESUMEN
BACKGROUND: There is evidence for a polygenic contribution to psychosis. One targetable mechanism through which polygenic variation may impact on individuals and interact with the social environment is stress sensitization, characterized by elevated reactivity to minor stressors in daily life. The current study aimed to investigate whether stress reactivity is modified by polygenic risk score for schizophrenia (PRS) in cases with enduring non-affective psychotic disorder, first-degree relatives of cases, and controls. METHODS: We used the experience sampling method to assess minor stressors, negative affect, positive affect and psychotic experiences in 96 cases, 79 first-degree relatives, i.e. siblings, and 73 controls at wave 3 of the Dutch Genetic Risk and Outcome of Psychosis (GROUP) study. Genome-wide data were collected at baseline to calculate PRS. RESULTS: We found that associations of momentary stress with psychotic experiences, but not with negative and positive affect, were modified by PRS and group (all pFWE<0.001). In contrast to our hypotheses, siblings with high PRS reported less intense psychotic experiences in response to momentary stress compared to siblings with low PRS. No differences in magnitude of these associations were observed in cases with high v. low level of PRS. By contrast, controls with high PRS showed more intense psychotic experiences in response to stress compared to those with low PRS. CONCLUSIONS: This tentatively suggests that polygenic risk may operate in different ways than previously assumed and amplify reactivity to stress in unaffected individuals but operate as a resilience factor in relatives by attenuating their stress reactivity.
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Trastornos Psicóticos , Esquizofrenia , Humanos , Evaluación Ecológica Momentánea , Trastornos Psicóticos/genética , Trastornos Psicóticos/psicología , Esquizofrenia/genética , Factores de Riesgo , Herencia Multifactorial , Estrés Psicológico/genéticaRESUMEN
BACKGROUND: A transdiagnostic and contextual framework of 'clinical characterization', combining clinical, psychopathological, sociodemographic, etiological, and other personal contextual data, may add clinical value over and above categorical algorithm-based diagnosis. METHODS: Prediction of need for care and health care outcomes was examined prospectively as a function of the contextual clinical characterization diagnostic framework in a prospective general population cohort (n = 6646 at baseline), interviewed four times between 2007 and 2018 (NEMESIS-2). Measures of need, service use, and use of medication were predicted as a function of any of 13 DSM-IV diagnoses, both separately and in combination with clinical characterization across multiple domains: social circumstances/demographics, symptom dimensions, physical health, clinical/etiological factors, staging, and polygenic risk scores (PRS). Effect sizes were expressed as population attributable fractions. RESULTS: Any prediction of DSM-diagnosis in relation to need and outcome in separate models was entirely reducible to components of contextual clinical characterization in joint models, particularly the component of transdiagnostic symptom dimensions (a simple score of the number of anxiety, depression, mania, and psychosis symptoms) and staging (subthreshold, incidence, persistence), and to a lesser degree clinical factors (early adversity, family history, suicidality, slowness at interview, neuroticism, and extraversion), and sociodemographic factors. Clinical characterization components in combination predicted more than any component in isolation. PRS did not meaningfully contribute to any clinical characterization model. CONCLUSION: A transdiagnostic framework of contextual clinical characterization is of more value to patients than a categorical system of algorithmic ordering of psychopathology.
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Algoritmos , Ansiedad , Humanos , Estudios Prospectivos , Trastornos de Ansiedad/diagnóstico , Manual Diagnóstico y Estadístico de los Trastornos MentalesRESUMEN
Posttraumatic stress disorder (PTSD) is a heritable (h2 = 24-71%) psychiatric illness. Copy number variation (CNV) is a form of rare genetic variation that has been implicated in the etiology of psychiatric disorders, but no large-scale investigation of CNV in PTSD has been performed. We present an association study of CNV burden and PTSD symptoms in a sample of 114,383 participants (13,036 cases and 101,347 controls) of European ancestry. CNVs were called using two calling algorithms and intersected to a consensus set. Quality control was performed to remove strong outlier samples. CNVs were examined for association with PTSD within each cohort using linear or logistic regression analysis adjusted for population structure and CNV quality metrics, then inverse variance weighted meta-analyzed across cohorts. We examined the genome-wide total span of CNVs, enrichment of CNVs within specified gene-sets, and CNVs overlapping individual genes and implicated neurodevelopmental regions. The total distance covered by deletions crossing over known neurodevelopmental CNV regions was significant (beta = 0.029, SE = 0.005, P = 6.3 × 10-8). The genome-wide neurodevelopmental CNV burden identified explains 0.034% of the variation in PTSD symptoms. The 15q11.2 BP1-BP2 microdeletion region was significantly associated with PTSD (beta = 0.0206, SE = 0.0056, P = 0.0002). No individual significant genes interrupted by CNV were identified. 22 gene pathways related to the function of the nervous system and brain were significant in pathway analysis (FDR q < 0.05), but these associations were not significant once NDD regions were removed. A larger sample size, better detection methods, and annotated resources of CNV are needed to explore this relationship further.
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Variaciones en el Número de Copia de ADN , Trastornos por Estrés Postraumático , Humanos , Trastornos por Estrés Postraumático/genética , Genoma , Encéfalo , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Predisposición Genética a la EnfermedadRESUMEN
PURPOSE: The health correlates of polygenic risk (PRS-SCZ) and exposome (ES-SCZ) scores for schizophrenia may vary depending on age and sex. We aimed to examine age- and sex-specific associations of PRS-SCZ and ES-SCZ with self-reported health in the general population. METHODS: Participants were from the population-based Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2). Mental and physical health were measured with the 36-item Short Form Survey 4 times between 2007 and 2018. The PRS-SCZ and ES-SCZ were respectively calculated from common genetic variants and exposures (cannabis use, winter birth, hearing impairment, and five childhood adversity categories). Moderation by age and sex was examined in linear mixed models. RESULTS: For PRS-SCZ and ES-SCZ analyses, we included 3099 and 6264 participants, respectively (age range 18-65 years; 55.7-56.1% female). Age and sex did not interact with PRS-SCZ. Age moderated the association between ES-SCZ and mental (interaction: p = 0.02) and physical health (p = 0.0007): at age 18, + 1.00 of ES-SCZ was associated with - 0.10 of mental health and - 0.08 of physical health, whereas at age 65, it was associated with - 0.21 and - 0.23, respectively (all units in standard deviations). Sex moderated the association between ES-SCZ and physical health (p < .0001): + 1.00 of ES-SCZ was associated with - 0.19 of physical health among female and - 0.11 among male individuals. CONCLUSION: There were larger associations between higher ES-SCZ and poorer health among female and older individuals. Accounting for these interactions may increase ES-SCZ precision and help uncover populational determinants of environmental influences on health.
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Esquizofrenia , Humanos , Masculino , Femenino , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Esquizofrenia/epidemiología , Autoinforme , Predisposición Genética a la Enfermedad , Factores de Riesgo , Estudios de CohortesRESUMEN
INTRODUCTION: Program directors dismiss a small percentage of residents from residency training programs, presumably due to underperformance or lack of progress. Whether underperformance in competency domains differs by residents' specialty is unknown. METHODS: In 2021, we analysed the case law of Dutch residents who were dismissed from training by the program director, and who challenged this dismissal before the national conciliation board between 2011 and 2020. Across medical specialties we compared which of the CanMEDS competency domains these residents failed to meet. RESULTS: We found 116 cases of residents dismissed from their training programmes who challenged the decision of the program director before the board. In general, most residents were unable to meet the requirements of several CanMEDS competency domains (usually: medical expert, communicator, and professional). In surgery, all dismissed residents failed to meet the competency domain of the medical expert, while most of the dismissed psychiatry residents met this domain. In specialties with a primarily diagnostic task, more dismissed residents failed to meet the competency domain of the scholar, while dismissed general medicine residents (for example family medicine and nursing homecare) were less likely to do so. Residents in general medicine, more often than other specialties, however, failed to meet the competency domain of the professional. CONCLUSION: Residents dismissed from training, who challenged their dismissal, failed to meet the requirements of multiple CanMEDS competency domains. Competency domain failures differ by specialty.
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Medicina General , Internado y Residencia , Humanos , Competencia Clínica , Educación de Postgrado en Medicina , Evaluación EducacionalRESUMEN
BACKGROUND: Research on the effectiveness of pharmacotherapies for schizophrenia and comorbid substance use disorder (SUD) is very sparse, and non-existent on the prevention of the development of SUDs in patients with schizophrenia. AIMS: To compare the real-world effectiveness of antipsychotics in schizophrenia in decreasing risk of developing an initial SUD, and psychiatric hospital admission and SUD-related hospital admission among patients with an SUD. METHOD: Two independent national cohorts including all persons diagnosed with schizophrenia (N = 45 476) were followed up for 22 (Finland: 1996-2017) and 11 (Sweden: 2006-2016) years. Risk of developing an SUD was calculated with between-individual models, and risks of psychiatric and SUD-related hospital admission were calculated with within-individual models, using Cox regression and adjusted hazard ratios (aHRs) for using versus not using certain antipsychotics. RESULTS: For patients with schizophrenia without an SUD, clozapine use (Finland: aHR 0.20, 95% CI 0.16-0.24, P < 0.001; Sweden: aHR 0.35, 95% CI 0.24-0.50, P < 0.001) was associated with lowest risk of developing an initial SUD in both countries. Antipsychotic polytherapy was associated with second lowest risk (aHR 0.54, 95% CI 0.44-0.66) in Sweden, and third lowest risk (aHR 0.47, 95% CI 0.42-0.53) in Finland. Risk of relapse (psychiatric hospital admission and SUD-related hospital admission) were lowest for clozapine, antipsychotic polytherapy and long-acting injectables in both countries. Results were consistent across both countries. CONCLUSIONS: Clozapine and antipsychotic polytherapy are most strongly associated with reduced risk of developing SUDs among patients with schizophrenia, and with lower relapse rates among patients with both diagnoses.
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Antipsicóticos , Clozapina , Esquizofrenia , Trastornos Relacionados con Sustancias , Humanos , Antipsicóticos/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/epidemiología , Clozapina/uso terapéutico , Trastornos Relacionados con Sustancias/epidemiología , Enfermedad Crónica , RecurrenciaRESUMEN
BACKGROUND: The prevalence of psychotic experiences (PEs) is higher in low-and-middle-income-countries (LAMIC) than in high-income countries (HIC). Here, we examine whether this effect is explicable by measurement bias. METHODS: A community sample from 13 countries (N = 7141) was used to examine the measurement invariance (MI) of a frequently used self-report measure of PEs, the Community Assessment of Psychic Experiences (CAPE), in LAMIC (n = 2472) and HIC (n = 4669). The CAPE measures positive (e.g. hallucinations), negative (e.g. avolition) and depressive symptoms. MI analyses were conducted with multiple-group confirmatory factor analyses. RESULTS: MI analyses showed similarities in the structure and understanding of the CAPE factors between LAMIC and HIC. Partial scalar invariance was found, allowing for latent score comparisons. Residual invariance was not found, indicating that sum score comparisons are biased. A comparison of latent scores before and after MI adjustment showed both overestimation (e.g. avolition, d = 0.03 into d = -0.42) and underestimation (e.g. magical thinking, d = -0.03 into d = 0.33) of PE in LAMIC relative to HIC. After adjusting the CAPE for MI, participants from LAMIC reported significantly higher levels on most CAPE factors but a significantly lower level of avolition. CONCLUSION: Previous studies using sum scores to compare differences across countries are likely to be biased. The direction of the bias involves both over- and underestimation of PEs in LAMIC compared to HIC. Nevertheless, the study confirms the basic finding that PEs are more frequent in LAMIC than in HIC.
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Trastornos Psicóticos , Análisis Factorial , Alucinaciones , Humanos , Renta , Trastornos Psicóticos/diagnóstico , Trastornos Psicóticos/epidemiología , AutoinformeRESUMEN
BACKGROUND: This study attempted to replicate whether a bias in probabilistic reasoning, or 'jumping to conclusions'(JTC) bias is associated with being a sibling of a patient with schizophrenia spectrum disorder; and if so, whether this association is contingent on subthreshold delusional ideation. METHODS: Data were derived from the EUGEI project, a 25-centre, 15-country effort to study psychosis spectrum disorder. The current analyses included 1261 patients with schizophrenia spectrum disorder, 1282 siblings of patients and 1525 healthy comparison subjects, recruited in Spain (five centres), Turkey (three centres) and Serbia (one centre). The beads task was used to assess JTC bias. Lifetime experience of delusional ideation and hallucinatory experiences was assessed using the Community Assessment of Psychic Experiences. General cognitive abilities were taken into account in the analyses. RESULTS: JTC bias was positively associated not only with patient status but also with sibling status [adjusted relative risk (aRR) ratio : 4.23 CI 95% 3.46-5.17 for siblings and aRR: 5.07 CI 95% 4.13-6.23 for patients]. The association between JTC bias and sibling status was stronger in those with higher levels of delusional ideation (aRR interaction in siblings: 3.77 CI 95% 1.67-8.51, and in patients: 2.15 CI 95% 0.94-4.92). The association between JTC bias and sibling status was not stronger in those with higher levels of hallucinatory experiences. CONCLUSIONS: These findings replicate earlier findings that JTC bias is associated with familial liability for psychosis and that this is contingent on the degree of delusional ideation but not hallucinations.
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Trastornos Psicóticos , Esquizofrenia , Sesgo , Toma de Decisiones , Deluciones/psicología , Alucinaciones , Humanos , Trastornos Psicóticos/psicología , Esquizofrenia/genéticaRESUMEN
BACKGROUND: There is evidence that environmental and genetic risk factors for schizophrenia spectrum disorders are transdiagnostic and mediated in part through a generic pathway of affective dysregulation. METHODS: We analysed to what degree the impact of schizophrenia polygenic risk (PRS-SZ) and childhood adversity (CA) on psychosis outcomes was contingent on co-presence of affective dysregulation, defined as significant depressive symptoms, in (i) NEMESIS-2 (n = 6646), a representative general population sample, interviewed four times over nine years and (ii) EUGEI (n = 4068) a sample of patients with schizophrenia spectrum disorder, the siblings of these patients and controls. RESULTS: The impact of PRS-SZ on psychosis showed significant dependence on co-presence of affective dysregulation in NEMESIS-2 [relative excess risk due to interaction (RERI): 1.01, p = 0.037] and in EUGEI (RERI = 3.39, p = 0.048). This was particularly evident for delusional ideation (NEMESIS-2: RERI = 1.74, p = 0.003; EUGEI: RERI = 4.16, p = 0.019) and not for hallucinatory experiences (NEMESIS-2: RERI = 0.65, p = 0.284; EUGEI: -0.37, p = 0.547). A similar and stronger pattern of results was evident for CA (RERI delusions and hallucinations: NEMESIS-2: 3.02, p < 0.001; EUGEI: 6.44, p < 0.001; RERI delusional ideation: NEMESIS-2: 3.79, p < 0.001; EUGEI: 5.43, p = 0.001; RERI hallucinatory experiences: NEMESIS-2: 2.46, p < 0.001; EUGEI: 0.54, p = 0.465). CONCLUSIONS: The results, and internal replication, suggest that the effects of known genetic and non-genetic risk factors for psychosis are mediated in part through an affective pathway, from which early states of delusional meaning may arise.
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Trastornos Psicóticos , Esquizofrenia , Humanos , Trastornos Psicóticos/etiología , Trastornos Psicóticos/genética , Alucinaciones/etiología , Alucinaciones/genética , Esquizofrenia/etiología , Esquizofrenia/genética , Herencia Multifactorial , Riesgo , Deluciones/diagnósticoRESUMEN
The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.
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Trastornos Psicóticos , Esquizofrenia , Cognición , Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Humanos , Trastornos Psicóticos/genética , Esquizofrenia/genéticaRESUMEN
OBJECTIVE: Paroxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations. METHODS: Confounding factors, including the heterogeneous etiology of epilepsies and medication effects, hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a genome-wide association study (GWAS) on epilepsy (n = 12 803 people with epilepsy and 24 218 controls) with that from a GWAS on background EEG (n = 8425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta, and theta. We replicated our findings in an independent epilepsy replication dataset (n = 4851 people with epilepsy and 20 428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores, and Mendelian randomization analyses. RESULTS: Our analyses show strong genetic correlations of genetic generalized epilepsy (GGE) with background EEG oscillations, primarily in the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations. SIGNIFICANCE: Our results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic workup of epilepsy.
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Electroencefalografía , Epilepsia Generalizada/genética , Epilepsia Generalizada/fisiopatología , Adulto , Algoritmos , Ritmo beta/genética , Estudios de Cohortes , Bases de Datos Factuales , Epilepsia Generalizada/diagnóstico , Estudio de Asociación del Genoma Completo , Humanos , Desequilibrio de Ligamiento , Análisis de la Aleatorización Mendeliana , Medición de Riesgo , Ritmo Teta/genéticaRESUMEN
OBJECTIVE: Schizophrenia is highly comorbid with substance use disorders (SUD) but large epidemiological cohorts exploring the prevalence and prognostic significance of SUD are lacking. Here, we investigated the prevalence of SUD in patients with schizophrenia in Finland and Sweden, and the effect of these co-occurring disorders on risks of psychiatric hospitalization and mortality. METHODS: 45,476 individuals with schizophrenia from two independent national cohort studies, aged <46 years at cohort entry, were followed during 22 (1996-2017, Finland) and 11 years (2006-2016, Sweden). We first assessed SUD prevalence (excluding smoking). Then, we performed Cox regression on risk of psychiatric hospitalization and all-cause and cause-specific mortality in SUD compared with those without SUD. RESULTS: The prevalence of SUD ranged from 26% (Finland) to 31% (Sweden). Multiple drug use (n = 4164, 48%, Finland; n = 3268, 67%, Sweden) and alcohol use disorders (n = 3846, 45%, Finland; n = 1002, 21%, Sweden) were the most prevalent SUD, followed by cannabis. Any SUD comorbidity, and particularly multiple drug use and alcohol use, were associated with 50% to 100% increase in hospitalization (aHR any SUD: 1.53, 95% CI = 1.46-1.61, Finland; 1.83, 1.72-1.96, Sweden) and mortality (aHR all-cause mortality: 1.65, 95% CI = 1.50-1.81, Finland; 2.17, 1.74-2.70, Sweden) compared to individuals without SUD. Elevated mortality risks were observed especially for suicides and other external causes. All results were similar across countries. CONCLUSION: Co-occurring SUD, and particularly alcohol and multiple drug use, are associated with high rates of hospitalization and mortality in schizophrenia. Preventive interventions should prioritize detection and tailored treatments for these comorbidities, which often remain underdiagnosed and untreated.
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Alcoholismo , Esquizofrenia , Trastornos Relacionados con Sustancias , Suicidio , Comorbilidad , Humanos , Prevalencia , Esquizofrenia/epidemiología , Trastornos Relacionados con Sustancias/epidemiologíaRESUMEN
BACKGROUND: Antipsychotic-induced Weight Gain (AiWG) is a debilitating and common adverse effect of antipsychotics. AiWG negatively impacts life expectancy, quality of life, treatment adherence, likelihood of developing type-2 diabetes and readmission. Treatment of AiWG is currently challenging, and there is no consensus on the optimal management strategy. In this study, we aim to evaluate the use of metformin for the treatment of AiWG by comparing metformin with placebo in those receiving treatment as usual, which includes a lifestyle intervention. METHODS: In this randomized, double-blind, multicenter, placebo-controlled, pragmatic trial with a follow-up of 52 weeks, we aim to include 256 overweight participants (Body Mass Index (BMI) > 25 kg/m2) of at least 16 years of age. Patients are eligible if they have been diagnosed with schizophrenia spectrum disorder and if they have been using an antipsychotic for at least three months. Participants will be randomized with a 1:1 allocation to placebo or metformin, and will be treated for a total of 26 weeks. Metformin will be started at 500 mg b.i.d. and escalated to 1000 mg b.i.d. 2 weeks thereafter (up to a maximum of 2000 mg daily). In addition, all participants will undergo a lifestyle intervention as part of the usual treatment consisting of a combination of an exercise program and dietary consultations. The primary outcome measure is difference in body weight as a continuous trait between the two arms from treatment inception until 26 weeks of treatment, compared to baseline. Secondary outcome measures include: 1) Any element of metabolic syndrome (MetS); 2) Response, defined as ≥5% body weight loss at 26 weeks relative to treatment inception; 3) Quality of life; 4) General mental and physical health; and 5) Cost-effectiveness. Finally, we aim to assess whether genetic liability to BMI and MetS may help estimate the amount of weight reduction following initiation of metformin treatment. DISCUSSION: The pragmatic design of the current trial allows for a comparison of the efficacy and safety of metformin in combination with a lifestyle intervention in the treatment of AiWG, facilitating the development of guidelines on the interventions for this major health problem. TRIAL REGISTRATION: This trial was registered in the Netherlands Trial Register (NTR) at https://www.trialregister.nl/trial/8440 as NTR NL8840 on March 8, 2020.
Asunto(s)
Antipsicóticos , Melia , Metformina , Antipsicóticos/efectos adversos , Método Doble Ciego , Humanos , Estilo de Vida , Metformina/uso terapéutico , Estudios Multicéntricos como Asunto , Países Bajos , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Aumento de PesoRESUMEN
BACKGROUND: Although clozapine is often discontinued, there is a paucity of guidelines and evidence on treatment options after clozapine discontinuation. Moreover, it is currently unknown whether reinstating clozapine in patients formerly using clozapine should be avoided. AIMS: To compare the real-world effectiveness of antipsychotics after clozapine cessation. METHOD: From Finnish registry data (1995-2017), we identified 2250 patients with schizophrenia who had been using clozapine for ≥1 year before treatment cessation. The primary analysis consisted of adjusted within-individual analyses of psychiatric ward readmission owing to psychosis and treatment failure. Secondary analyses concerned between-individual mortality differences. RESULTS: Compared with no use of antipsychotics, risk of psychiatric ward readmission was lowest for reinitiation of clozapine (adjusted hazard ratio (aHR) 0.49; 95% CI 0.40-0.61; P < 0.0001), oral olanzapine (aHR 0.58; 95% CI 0.48-0.71; P < 0.0001) and antipsychotic polypharmacy (aHR 0.62; 95% CI 0.53-0.72; P < 0.0001). Risk of treatment failure was lowest for aripiprazole long acting injectable (aHR 0.42; 95% CI 0.27-0.65; P < 0.0001), reinitiation of clozapine (aHR 0.49; 95% CI 0.43-0.57; P < 0.0001) and oral olanzapine (aHR 0.69; 95% CI 0.61-0.77; P < 0.0001). Mortality risk was lowest for reinitiation of clozapine (aHR 0.18; 95% CI 0.09-0.36; P < 0.0001) and oral olanzapine (aHR 0.26; 95% CI 0.17-0.40; P < 0.0001). CONCLUSIONS: Clozapine and olanzapine are the most effective and safest treatment options in those discontinuing clozapine for undefined reasons. Clozapine should therefore be reconsidered in patients with schizophrenia who previously discontinued this compound.
Asunto(s)
Antipsicóticos , Clozapina , Esquizofrenia , Antipsicóticos/efectos adversos , Benzodiazepinas/uso terapéutico , Clozapina/efectos adversos , Finlandia , Humanos , Olanzapina/uso terapéutico , Esquizofrenia/tratamiento farmacológicoRESUMEN
Genome-wide association studies have uncovered hundreds of loci associated with psychiatric disorders. Cross-disorder studies are among the prime ramifications of such research. Here, we discuss the methodology of the most widespread methods and their clinical utility with regard to diagnosis, prediction, disease aetiology and treatment in psychiatry.