Corollary Discharge Dysfunction as a Possible Substrate of Anomalous Self-experiences in Schizophrenia.

BACKGROUND AND HYPOTHESIS: Corollary discharge mechanism suppresses the conscious auditory sensory perception of self-generated speech and attenuates electrophysiological markers such as the auditory N1 Event-Related Potential (ERP) during Electroencephalographic (EEG) recordings. This phenomenon contributes to self-identification and seems to be altered in people with schizophrenia. Therefore, its alteration could be related to the anomalous self-experiences (ASEs) frequently found in these patients. STUDY DESIGN: To analyze corollary discharge dysfunction as a possible substrate of ASEs, we recorded EEG ERP from 43 participants with schizophrenia and 43 healthy controls and scored ASEs with the 'Inventory of Psychotic-Like Anomalous Self-Experiences' (IPASE). Positive and negative symptoms were also scored with the 'Positive and Negative Syndrome Scale for Schizophrenia' (PANSS) and with the 'Brief Negative Symptom Scale' (BNSS) respectively. The N1 components were elicited by two task conditions: (1) concurrent listening to self-pronounced vowels (talk condition) and (2) subsequent non-concurrent listening to the same previously self-uttered vowels (listen condition). STUDY RESULTS: The amplitude of the N1 component elicited by the talk condition was lower compared to the listen condition in people with schizophrenia and healthy controls. However, the difference in N1 amplitude between both conditions was significantly higher in controls than in schizophrenia patients. The values of these differences in patients correlated significantly and negatively with the IPASE, PANSS, and BNSS scores. CONCLUSIONS: These results corroborate previous data relating auditory N1 ERP amplitude with altered corollary discharge mechanisms in schizophrenia and support corollary discharge dysfunction as a possible underpinning of ASEs in this illness.

Real-life outcomes in biotypes of psychotic disorders based on neurocognitive performance.

Aiming at discerning potential biotypes within the psychotic syndrome, we have recently reported the possible existence of two clusters or biotypes across schizophrenia and bipolar disorder characterized by their cognitive performance using the Brief Assessment of Cognition in Schizophrenia (BACS) instrument and validated with independent biological and clinical indexes (Fernández-Linsenbarth et al. in Schizophr Res 229:102-111, 2021). In this previous work, the group with larger cognitive deficits (N = 93, including 69 chronic schizophrenia, 17 first episodes (FE) of schizophrenia and 7 bipolar disorder patients) showed smaller thalamus and hippocampus volume and hyper-synchronic electroencephalogram than the group with milder deficits (N = 105, including 58 chronic schizophrenia, 25 FE and 22 bipolar disorder patients). We predicted that if these biotypes indeed corresponded to different cognitive and biological substrates, their adaptation to real life would be different. To this end, in the present work we have followed up the patients' population included in that work at 1st and 3rd years after the date of inclusion in the 2021 study and we report on the statistical comparisons of each clinical and real-life outcomes between them. The first cluster, with larger cognitive deficits and more severe biological alterations, showed during that period a decreased capacity for job tenure (1st and 3rd years), more admissions to a psychiatric ward (1st year) and a higher likelihood for quitting psychiatric follow-up (3rd year). Patients in the second cluster, with moderate cognitive deficits, were less compliant with prescribed treatment at the 3rd year. The differences in real-life outcomes may give additional external validity to that yielded by biological measurements to the described biotypes based on neurocognition.

Relation between EEG resting-state power and modulation of P300 task-related activity in theta band in schizophrenia.

There is some consistency in previous EEG findings that patients with schizophrenia have increased resting-state cortical activity. Furthermore, in previous work, we have provided evidence that there is a deficit in the modulation of bioelectrical activity during the performance of a P300 task in schizophrenia. Our hypothesis here is that a basal hyperactivation would be related with altered ability to change or modulate cortical activity during a cognitive task. However, no study so far, to the best of our knowledge, has studied the association between resting-state activity and task-related modulation. With this aim, we used a dual EEG paradigm (resting state and oddball task for elicitation of the P300 evoked potential) in a sample of patients with schizophrenia (n = 100), which included a subgroup of patients with first episode psychosis (n = 30), as well as a group of healthy controls (n = 93). The study measures were absolute power for resting-state; and spectral entropy (SE) and connectivity strength (CS) for P300-task data, whose modulation had been previously found to be altered in schizophrenia. Following the literature on P300, we focused our study on the theta frequency band. As expected, our results showed an increase in resting state activity and altered task-related modulation. Moreover, we found an inverse relationship between the amount of resting-state activity and modulation of task-related activity. Our results confirm our hypothesis and support the idea that a greater amount of resting theta-band synchrony could hamper the modulation of signal regularity (quantified by SE) and activity density (measured by CS) during the P300 task performance. This association was found in both patients and controls, suggesting the existence of a common mechanism and a possible ceiling effect in schizophrenia patients in relation to a decreased inhibitory function that limits their cortical reactivity to the task.

Neurobiological underpinnings of cognitive subtypes in psychoses: A cross-diagnostic cluster analysis.

Schizophrenia and bipolar disorder include patients with different characteristics, which may hamper the definition of biomarkers. One of the dimensions with greater heterogeneity among these patients is cognition. Recent studies support the identification of different patients' subgroups along the cognitive domain using cluster analysis. Our aim was to validate clusters defined on the basis of patients' cognitive status and to assess its relation with demographic, clinical and biological measurements. We hypothesized that subgroups characterized by different cognitive profiles would show differences in an array of biological data. Cognitive data from 198 patients (127 with chronic schizophrenia, 42 first episodes of schizophrenia and 29 bipolar patients) were analyzed by a K-means cluster approach and were compared on several clinical and biological variables. We also included 155 healthy controls for further comparisons. A two-cluster solution was selected, including a severely impaired group and a moderately impaired group. The severely impaired group was associated with higher illness duration and symptoms scores, lower thalamus and hippocampus volume, lower frontal connectivity and basal hypersynchrony in comparison to controls and the moderately impaired group. Moreover, both patients' groups showed lower cortical thickness and smaller functional connectivity modulation than healthy controls. This study supports the existence of different cognitive subgroups within the psychoses with different neurobiological underpinnings.

Deficits of entropy modulation of the EEG: A biomarker for altered function in schizophrenia and bipolar disorder?

Background: The synchronized activity of distributed neural assemblies ­ reflected in the electroencephalogram (EEG) ­ underpins mental function. In schizophrenia, modulation deficits of EEG spectral content during a P300 task have been replicated. The effects of treatment, chronicity and specificity in these deficits and their possible relationship with anatomic connectivity remain to be explored. Methods: We assessed spectral entropy modulation of the EEG during a P300 task in 79 patients with schizophrenia (of those, 31 werein their first episode), 29 patients with bipolar disorder and 48 healthy controls. Spectral entropy values summarize EEG characteristics by quantifying the irregularity of spectral content. In a subsample, we calculated the network architecture of structural connectivity using diffusion tensor imaging and graph-theory parameters. Results: We found significant spectral entropy modulation deficits with task performance in patients with chronic or first-episode schizophrenia and in patients with bipolar disorder, without significant pre-stimulus spectral entropy differences. The deficits were unrelated to treatment doses, and spectral entropy modulation did not differ between patients taking or not taking antipsychotics, lithium, benzodiazepines or antidepressants. Structural connectivity values were unrelated to spectral entropy modulation. In patients with schizophrenia, spectral entropy modulation was inversely related to negative symptoms and directly related to verbal memory. Limitations: All patients were taking medication. Patients with bipolar disorder were euthymic and chronic. The cross-sectional nature of this study prevented a more thorough analysis of state versus trait criteria for spectral entropy changes. Conclusion: Spectral entropy modulation with task performance is decreased in patients with schizophrenia and bipolar disorder. This deficit was not an effect of psychopharmacological treatment or structural connectivity and might reflect a deficit in the synchronization of the neural assemblies that underlie cognitive activity.

Patrón de uso de la terapia electroconvulsiva en España: propuestas para una práctica óptima y un acceso equitativo / Pattern of electroconvulsive therapy use in Spain: Proposals for an optimal practice and equitable access

Objetivos. Analizar en términos cuantitativos y cualitativos la situación del uso de la terapia electroconvulsiva (TEC) en España en la actualidad, así como explorar aquellos aspectos que pudieran condicionar su utilización. Metodología. Encuesta transversal en todas las unidades psiquiátricas existentes en España a fecha 31/12/2012. Resultados. El 54,9% de las unidades estudiadas aplicaban TEC, resultando en una tasa de aplicación de 0,66 por 10.000 habitantes. Existen amplias variaciones en las tasas de aplicación entre comunidades autónomas (0,00-1,39) y provincias (0,00-3,90). La TEC se indicó en el período estudiado a una media de 25,5 pacientes en los centros que disponían de la técnica, y a 4,5 en los centros que remitían a otros para aplicarla (p=0,000), pero con amplias diferencias entre centros. Conclusiones. El número de centros que disponen de TEC en España es uno de los más elevados entre los países occidentales, pero la tasa de aplicación de esta técnica continúa siendo una de las más bajas, existiendo además marcadas diferencias entre las distintas comunidades autónomas, e incluso entre provincias y centros hospitalarios de una misma comunidad autónoma. Parece preciso implementar estrategias de planificación sanitaria y de formación para reducir la heterogeneidad observada en la prescripción y aplicación de la TEC en España (AU)

Objectives. The main aims of our study were to estimate the current rates and pattern of electroconvulsive therapy (ECT) use in Spain, as well as exploring the causes that may be limiting its use in our country. Methods. A cross-sectional survey was conducted covering every psychiatric unit in Spain as of 31 December 2012. Results. More than half (54.9%) of the psychiatric units applied ECT at a rate of 0.66 patients per 10,000 inhabitants. There are wide variations with regard to ECT application rates between the different autonomous communities (0.00-1.39) and provinces (0.00-3.90). ECT was prescribed to a mean of 25.5 patients per hospital that used the technique and 4.5 in referral centre (P=.000), but wide differences were reported in the number of patients who were prescribed ECT from hospital to hospital. Conclusions. Although the percentage of psychiatric units applying ECT in our country is among the highest in the world, the ECT application rate in Spain is among the lowest within western countries. Large differences in ECT use have been reported across the various autonomous communities, provinces and hospitals. Thus, health planning strategies need to be implemented, as well as promoting training in ECT among health professionals, if these differences in ECT use are to be reduced (AU)

Pattern of electroconvulsive therapy use in Spain: Proposals for an optimal practice and equitable access. / Patrón de uso de la terapia electroconvulsiva en España: propuestas para una práctica óptima y un acceso equitativo.

OBJECTIVES: The main aims of our study were to estimate the current rates and pattern of electroconvulsive therapy (ECT) use in Spain, as well as exploring the causes that may be limiting its use in our country. METHODS: A cross-sectional survey was conducted covering every psychiatric unit in Spain as of 31 December 2012. RESULTS: More than half (54.9%) of the psychiatric units applied ECT at a rate of 0.66 patients per 10,000 inhabitants. There are wide variations with regard to ECT application rates between the different autonomous communities (0.00-1.39) and provinces (0.00-3.90). ECT was prescribed to a mean of 25.5 patients per hospital that used the technique and 4.5 in referral centre (P=.000), but wide differences were reported in the number of patients who were prescribed ECT from hospital to hospital. CONCLUSIONS: Although the percentage of psychiatric units applying ECT in our country is among the highest in the world, the ECT application rate in Spain is among the lowest within western countries. Large differences in ECT use have been reported across the various autonomous communities, provinces and hospitals. Thus, health planning strategies need to be implemented, as well as promoting training in ECT among health professionals, if these differences in ECT use are to be reduced.

Electroconvulsive Therapy Practice in Spain: A National Survey.

OBJECTIVES: The use of electroconvulsive therapy (ECT) in Spain has not been systematically evaluated since 2000 to 2001. The aim of this study is to assess the current use of ECT in Spain. METHODS: A cross-sectional survey was conducted covering every psychiatric unit in Spain as of December 31, 2012. RESULTS: About 93.2% of the centers answered the questionnaire. About 54.9% of the psychiatric units applied ECT at a rate of 0.66 patients per 10,000 inhabitants. Wide variations existed among the different autonomous communities and provinces. Written informed consent was obtained in all the facilities. About 38.2% of ECT-treated patients were 65 years or older. About 55.7% were women. Depressive episodes were the main indication for ECT (80.2%). All the facilities applied modified ECT. No sine wave current devices are currently used in Spain. Bifrontotemporal ECT was elective in 85% of the hospitals, bifrontal in 13.3%, and unilateral in 1.8%. Stimulus titration methods were elective in 8.6% of the centers. The decision to end ECT relied on the psychiatrist's clinical impression in 89.4% of the centers and on rating scales in 10.6%. The ECT training was mandatory in 56.5% of the centers. CONCLUSIONS: The ECT practice has significantly improved in Spain in recent years. Overall, Spanish facilities seem to comply with established clinical guidelines; however, specific concerns were identified, meaning there is still further scope for improvement.

Quo Vadis Clozapine? A Bibliometric Study of 45 Years of Research in International Context.

We have carried out a bibliometric study about the international scientific publications on clozapine. We have used the EMBASE and MEDLINE databases, and we applied bibliometric indicators of production, as Price's Law on the increase of scientific literature. We also calculated the participation index (PI) of the different countries. The bibliometric data have also been correlated with some social and health data from the 12 most productive countries in biomedicine and health sciences. In addition, 5607 original documents dealing with clozapine, published between 1970 and 2013, were downloaded. Our results state non-fulfilment of Price's Law, with scientific production on clozapine showing linear growth (r=0.8691, vs. r=0.8478 after exponential adjustment). Seven of the 12 journals with the highest numbers of publications on clozapine have an Impact Factor>2. Among the countries generating clozapine research, the most prominent is the USA (PI=24.32), followed by the UK (PI=6.27) and Germany (PI=5.40). The differences among countries on clozapine research are significantly related to economic variables linked to research. The scientific interest in clozapine remains remarkable, although after the application of bibliometric indicators of production, a saturation point is evident in the growth of scientific literature on this topic.

Greater clinical and cognitive improvement with clozapine and risperidone associated with a thinner cortex at baseline in first-episode schizophrenia.

Cortical thickness may be useful as a treatment response predictor in first-episode (FE) patients with schizophrenia, although this possibility has been scarcely assessed. In this study we assessed the possible relation between cortical thickness in regions of interest selected because of previously reported structural alterations in schizophrenia and clinical and cognitive changes after two years of treatment with risperidone or clozapine in 31 neuroleptic-naïve FE patients with schizophrenia (16 of them treated with clozapine and 15 with risperidone). Using the last-observation-carried-forward (LOCF), a larger improvement in positive, negative and total symptoms was predicted by the amount of baseline cortical thinning in the right prefrontal cortex (pars orbitalis). After two years of treatment, cognitive status was reassessed in the 17 patients (11 on clozapine) who had not dropped out. Working memory improvement after reassessment was associated with a greater baseline cortical thinning in the left prefrontal cortex (pars orbitalis), and verbal memory improvement with a greater baseline cortical thinning in the left pars triangularis. Significant but weak cortical thickness decrease from baseline to follow-up was observed in patients in comparison to controls (left pars triangularis and opercularis, and left caudal middle frontal areas). These results may support a positive predictive role for cortical thinning in the frontal region with regard to clinical and cognitive improvement with clozapine and risperidone in FE patients with schizophrenia.

Randomized trial of clozapine vs. risperidone in treatment-naïve first-episode schizophrenia: results after one year.

In first-episode patients with psychosis, clozapine may be potentially valuable as an initial treatment seeking to limit early on clinical and cognitive deterioration. Nevertheless, until recently its restricted use has limited the study of this possibility. Our research group is developing a non-commercial, multicentric and open label study on the differential efficacy between clozapine and risperidone in first-episode schizophrenia. In this paper, we present the results related to clinical variables after a one-year follow-up. So far, we have recruited 30 patients diagnosed with schizophrenia or schizophreniform disorder with illness duration of less than two years. The patients had not received any previous treatment and they were randomized to treatment with clozapine or risperidone. Our results indicate that on average, patients on clozapine adhered to their original treatment for a longer time period than patients on risperidone. By last observation carried forward (LOCF) analysis, patients on clozapine and risperidone displayed similar clinical improvements, although marginally greater improvements in positive and total symptoms scores were found in the clozapine group. At the 12-month point we observed a marginal improvement in negative symptom scores in patients on clozapine. Subjective secondary effects, as measured with the Udvalg for KliniskeUndersøgelser (UKU) scale, correlated negatively with negative symptoms at follow-up. Our data, although preliminary, suggest that clozapine may have a slightly superior efficacy in the initial year of treatment of first-episode treatment-naïve patients with schizophrenia, and this can be explained for the most part by greater adherence to this treatment.

Clozapine as treatment of first choice in first psychotic episodes. What do we know?

Schizophrenia is currently conceptualized as a neurodevelopmental disorder with progressive clinical, neurophysiological and neurostructural deterioration mostly occurring at early stages of the disease. During the last years, several early intervention programs have tried to modify the natural history of the disease. The choice of antipsychotic treatment adapted to the specific needs of the patient would make it possible to optimize the results of the intervention programs in first psychotic episodes. Clozapine has become a keystone in the treatment of psychosis, with multiple contributions to the treatment of schizophrenia. Clozapine has been proven superior to other antipsychotics in efficacy and effectiveness with comparable cost-effectiveness to that accepted for many medical interventions. On the other hand, recent studies indicate that the incidence and mortality of clozapine-induced agranulocytosis could be lower than previously estimated and that all-cause mortality due to clozapine is less than that associated to other antipsychotic drugs. However, in spite of clinical guideline recommendations, clozapine is used less and later than recommended. There is a lack of studies comparing clozapine with other antipsychotics in first episode psychosis patients. The aim of our paper is to review the current medical evidence about the use of clozapine as a first-line treatment for naive first episode psychosis patients.

Clozapina como tratamiento de primera elección en primeros episodios psicóticos ¿qué sabemos? / Clozapine as treatment of first choice in first psychotic episodes. What do we know?

La esquizofrenia se conceptualiza, en la actualidad, como una enfermedad del neurodesarrollo con un deterioro clínico, neurofisiológico y neuroestructural, especialmente notorio en las etapas iniciales de la enfermedad. En los últimos años, los programas de intervención precoz buscan tratar de modificar el curso natural de la enfermedad. La elección de un tratamiento antipsicótico ajustado a las necesidades específicas del paciente permitiría optimizar los resultados de los programas de intervención en primeros episodios psicóticos. La clozapina ha sido un fármaco clave en la historia del tratamiento de la psicosis y sus aportaciones en el tratamiento de la esquizofrenia han sido múltiples. Ha demostrado su superioridad sobre otros antipsicóticos en términos de eficacia y efectividad con un costo efectividad comparable al aceptado para numerosas intervenciones médicas. Por otro lado, estudios recientes indican que la incidencia y mortalidad asociadas a la agranulocitosis por clozapina serían inferiores a las estimadas en estudios previos y la mortalidad global por clozapina inferior a la asociada a otros antipsicóticos. A pesar de las recomendaciones de las guías clínicas, la clozapina se emplea con mucha menor frecuencia y más tardíamente de lo recomendado y los ensayos clínicos comparando la eficacia y efectividad de la clozapina frente a otros antipsicóticos en primeros episodios psicóticos son prácticamente inexistentes. En el presente artículo de revisión selectiva pretendemos revisar la evidencia clínica existente acerca del empleo de clozapina en primeros episodios psicóticos que nunca han recibido tratamiento farmacológico (AU)

Schizophrenia is currently conceptualized as a neurodevelopmental disorder with progressive clinical, neurophysiological and neurostructural deterioration mostly occurring at early stages of the disease. During the last years, several early intervention programs have tried to modify the natural history of the disease. The choice of antipsychotic treatment adapted to the specific needs of the patient would make it possible to optimize the results of the intervention programs in first psychotic episodes. Clozapine has become a keystone in the treatment of psychosis, with multiple contributions to the treatment of schizophrenia. Clozapine has been proven superior to other antipsychotics in efficacy and effectiveness with comparable cost-effectiveness to that accepted for many medical interventions. On the other hand, recent studies indicate that the incidence and mortality of clozapine-induced agranulocytosis could be lower than previously estimated and that all-cause mortality due toclozapine is less than that associated to other antipsychotic drugs. However, in spite of clinical guideline recommendations, clozapine is used less and later than recommended. There is a lack of studies comparing clozapine with other antipsychotics in first episode psychosis patients. The aim of our paper is to review the current medical evidence about the use of clozapine as a first-line treatment for naive first episode psychosis patients (AU)

Monitorización de niveles plasma de antipsicóticos atípicos / Atypical antipsychotics plasma level monitoring

Introducción: El estudio de la concentración de psicofármaco en sangre o en suero permite individualizar el perfil farmacocinético del sujeto tratado. Esto se conoce como monitorización de fármacos. Actualmente se pueden analizar antidepresivos, antipsicóticos, estabilizadores del ánimo, fármacos sustitutivos de los opioides, ansiolíticos e hipnóticos. Objetivos: Revisar el estado actual del conocimiento sobre monitorización de antipsicóticos, de utilidad tanto para evaluar la adherencia terapéutica como para conocer la concentración del fármaco en plasma. Metodología: Se revisaron los trabajos publicados sobre monitorización de antipsicóticos desde 1975 hasta 2010. Como fuente de información se empleó:Embase, Medline y Pubmed. Conclusiones: La monitorización de antipsicóticos, así como de otros psicofármacos, es una práctica establecida que debe conocerse y ser objeto de actualización por parte del psiquiatra interesado en un ejercicio terapéutico basado en datos objetivos(AU)

Introduction: Analysis of psychotropic drug concentration in blood or serum is a mean to ascertain the pharmacokinetic profile of the treated subject. This is known as drug monitoring. Currently plasma antidepressants, antipsychotics, mood stabilizers, drugs substitutes for opioids, anxiolytics and hypnotics can be monitorized. Methodology: We reviewed all published articles on monitoring of psychotropic drugs in general from 1975 to 2010. As a source of information used: Embase, Medline and Pubmed. Objetive: To review the current state of science in relation to the monitoring of atypical antipsychotics. Antipsychotic plasma level monitoring is crucial both to assess adherence and to determine the plasma drug concentration. Conclusions: The monitoring of antipsychotics and other psychotropic drugs, is an established practice must be known and be maintained by a psychiatrist, like other aspects of psychopharmacology, for a therapeutic exercise based on the current state of science(AU)

Electroconvulsive therapy as treatment for malignant neuroleptic syndrome.

In the era of new antipsychotic drugs the severe symptomatology known by the name of neuroleptic malignant syndrome (NMS) continues to have a high incidence and mortality. We review its origin, pathophysiology, diagnostic criteria and staging, particularly with electroconvulsive therapy (ECT), and proposing a less restrictive use and more adjusted to the updated knowledge of this technique. In particular, we consider the justified use of bilateral lead placement, a frequency of three sessions per week, and loads calculated for age, which would ensure effective seizures with an early response, thus avoiding the use of repeated sub-seizure stimuli to calculate the threshold by titration. We believe there is little evidence on the fear of the risk of increasing malignant hyperthermia in NMS due to the substances used in anaesthesia, but is justified to use non-depolarising relaxants due to the risk of hyperkalaemia on being exposed to succinylcholine. Finally we believe it is essential to familiarise the other specialists involved in the treatment with ECT, to increase the availability of the technique and our training in this to the currently available complexity.