Orexinergic Receptor Antagonists as a New Therapeutic Target to Overcome Limitations of Current Pharmacological Treatment of Insomnia Disorder.

Insomnia disorder is a common condition that is considered a risk factor for multiple physical and mental disorders, contributing to reduced quality of life and increased healthcare expenditures. Although cognitive behavioral therapy (CBT) is typically recommended as the primary intervention, its accessibility is hindered by limited resources, prompting the prevalent use of pharmacological interventions as the primary treatment in clinical settings. This study reviews the benefits and risks of current pharmacological treatments for insomnia, with special reference to the orexinergic system as a novel therapeutic target for treatment. The prescription of GABAergic mechanism enhancers (benzodiazepine (BZD) and "Z drugs") has shown efficacy in short-term insomnia treatment (less than 4 weeks), however, concerns arise regarding their long-term effectiveness, unfavorable tolerability and safety profiles, including the potential for dependency. Drugs with antihistamine properties, including certain antidepressants and antipsychotics, exhibit short-term efficacy but have documented tolerability limitations, especially in the elderly. The use of melatonin, available in various formulations, lacks comprehensive long-term data. Dual orexin receptor antagonists (DORAs) such as daridorexant, lemborexant, and suvorexant, represent a novel approach to insomnia treatment by inhibiting wakefulness rather than enhancing sedation. As the only DORA approved for insomnia treatment by the European Medicines Agency (EMA) and Food and Drug Administration (FDA), daridorexant has demonstrated sustained efficacy over a 12-month period, improving nocturnal sleep parameters and daytime functionality, with a favorable safety and tolerability profile.

Orexinergic Receptor Antagonists as a New Therapeutic Target to Overcome Limitations of Current Pharmacological Treatment of Insomnia Disorder

Insomnia disorder is a common condition that is considered a risk factor for multiple physical and mental disorders, contributing to reduced quality of life and increased healthcare expenditures. Although cognitive behavioral therapy (CBT) is typically recommended as the primary intervention, its accessibility is hindered by limited resources, prompting the prevalent use of pharmacological interventions as the primary treatment in clinical settings. This study reviews the benefits and risks of current pharmacological treatments for insomnia, with special reference to the orexinergic system as a novel therapeutic target for treatment. The prescription of GABAergic mechanism enhancers (benzodiazepine (BZD) and “Z drugs”) has shown efficacy in short-term insomnia treatment (less than 4 weeks), however, concerns arise regarding their long-term effectiveness, unfavorable tolerability and safety profiles, including the potential for dependency. Drugs with antihistamine properties, including certain antidepressants and antipsychotics, exhibit short-term efficacy but have documented tolerability limitations, especially in the elderly. The use of melatonin, available in various formulations, lacks comprehensive long-term data. Dual orexin receptor antagonists (DORAs) such as daridorexant, lemborexant, and suvorexant, represent a novel approach to insomnia treatment by inhibiting wakefulness rather than enhancing sedation. As the only DORA approved for insomnia treatment by the European Medicines Agency (EMA) and Food and Drug Administration (FDA), daridorexant has demonstrated sustained efficacy over a 12-month period, improving nocturnal sleep parameters and daytime functionality, with a favorable safety and tolerability profile. (AU)

The polygenic basis of relapse after a first episode of schizophrenia.

Little is known about genetic predisposition to relapse. Previous studies have linked cognitive and psychopathological (mainly schizophrenia and bipolar disorder) polygenic risk scores (PRS) with clinical manifestations of the disease. This study aims to explore the potential role of PRS from major mental disorders and cognition on schizophrenia relapse. 114 patients recruited in the 2EPs Project were included (56 patients who had not experienced relapse after 3 years of enrollment and 58 patients who relapsed during the 3-year follow-up). PRS for schizophrenia (PRS-SZ), bipolar disorder (PRS-BD), education attainment (PRS-EA) and cognitive performance (PRS-CP) were used to assess the genetic risk of schizophrenia relapse.Patients with higher PRS-EA, showed both a lower risk (OR=0.29, 95% CI [0.11-0.73]) and a later onset of relapse (30.96± 1.74 vs. 23.12± 1.14 months, p=0.007. Our study provides evidence that the genetic burden of neurocognitive function is a potentially predictors of relapse that could be incorporated into future risk prediction models. Moreover, appropriate treatments for cognitive symptoms appear to be important for improving the long-term clinical outcome of relapse.

Exploration of cannabis use and polygenic risk scores on the psychotic symptom progression of a FEP cohort.

Cannabis use is highly prevalent in first-episode psychosis (FEP) and plays a critical role in its onset and prognosis, but the genetic underpinnings promoting both conditions are poorly understood. Current treatment strategies for cannabis cessation in FEP are clearly inefficacious. Here, we aimed to characterize the association between cannabis-related polygenic risk scores (PRS) on cannabis use and clinical course after a FEP. A cohort of 249 FEP individuals were evaluated during 12 months. Symptom severity was measured with the Positive and Negative Severity Scale and cannabis use with the EuropASI scale. Individual PRS for lifetime cannabis initiation (PRSCI) and cannabis use disorder (PRSCUD) were constructed. Current cannabis use was associated with increased positive symptoms. Cannabis initiation at younger ages conditioned the 12-month symptom progression. FEP patients with higher cannabis PRSCUD reported increased baseline cannabis use. PRSCI was associated with the course of negative and general symptomatology over follow-up. Cannabis use and symptom progression after a FEP were modulated by cannabis PRS, suggesting that lifetime initiation and use disorders may have partially independent genetic factors. These exploratory results may be the first step to identify those FEP patients more vulnerable to cannabis use and worse outcomes to ultimately develop tailored treatments.

The black hole of the transition process: dropout of care before transition age in adolescents.

Recent evidence confirms the risks of discontinuity of care when young people make a transition from child and adolescent mental health services (CAMHS) to adult mental health services (AMHS), although robust data are still sparse. We aimed to identify when and how patients get lost to care during transition by tracking care pathways and identifying factors which influence dropping out of care during transition. This is a retrospective observational study of 760 patients who reached the transition age boundary within 12 months before transition time and being treated at CAMHS for at least during preceding 18 months. Data were collected at two time points: last visit to CAHMS and first visit to AHMS. Socio-demographic, clinical and service utilization variables on CAMHS treatment were collected. In the 12 months leading up to the transition boundary, 46.8% of subjects (n = 356) withdrew from CAHMS without further contact with AHMS, 9.3% withdrew from CAHMS but were referred to AHMS by other services, 29% were transferred from CAHMS to AHMS, 10% remained at CAHMS and 5% patients were transferred to alternative services. Fifty-six percent of subjects experience cessation of care before the transition age. The risk of dropout increases with shorter contact time in CAMHS, is greater in subjects without pharmacological treatment, and decreases in subjects with psychosis, bipolar disorder, eating disorders, mental retardation, and neurodevelopmental disorders. This study confirms that a large number of people drop out of care as they approach the CAMHS transition and experience discontinuity of care during this critical period.

The prescriber's guide to classic MAO inhibitors (phenelzine, tranylcypromine, isocarboxazid) for treatment-resistant depression.

This article is a clinical guide which discusses the "state-of-the-art" usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion-this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy-while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward "bridging" methods that may be used to transition simply and safely from other antidepressants to MAOIs.

Identification of EP300 as a Key Gene Involved in Antipsychotic-Induced Metabolic Dysregulation Based on Integrative Bioinformatics Analysis of Multi-Tissue Gene Expression Data.

Antipsychotics (APs) are associated with weight gain and other metabolic abnormalities such as hyperglycemia, dyslipidemia and metabolic syndrome. This translational study aimed to uncover the underlying molecular mechanisms and identify the key genes involved in AP-induced metabolic effects. An integrative gene expression analysis was performed in four different mouse tissues (striatum, liver, pancreas and adipose) after risperidone or olanzapine treatment. The analytical approach combined the identification of the gene co-expression modules related to AP treatment, gene set enrichment analysis and protein-protein interaction network construction. We found several co-expression modules of genes involved in glucose and lipid homeostasis, hormone regulation and other processes related to metabolic impairment. Among these genes, EP300, which encodes an acetyltransferase involved in transcriptional regulation, was identified as the most important hub gene overlapping the networks of both APs. Then, we explored the genetically predicted EP300 expression levels in a cohort of 226 patients with first-episode psychosis who were being treated with APs to further assess the association of this gene with metabolic alterations. The EP300 expression levels were significantly associated with increases in body weight, body mass index, total cholesterol levels, low-density lipoprotein cholesterol levels and triglyceride concentrations after 6 months of AP treatment. Taken together, our analysis identified EP300 as a key gene in AP-induced metabolic abnormalities, indicating that the dysregulation of EP300 function could be important in the development of these side effects. However, more studies are needed to disentangle the role of this gene in the mechanism of action of APs.

Suicide. The post-COVID era: a time for action / Suicidio. La era post-COVID: tiempo para la acción

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Identifying key transcription factors for pharmacogenetic studies of antipsychotics induced extrapyramidal symptoms.

INTRODUCTION: We explore the transcription factors involved in the molecular mechanism of antipsychotic (AP)-induced acute extrapyramidalsymptoms (EPS) in order to identify new candidate genes for pharmacogenetic studies. METHODS: Protein-protein interaction (PPI) networks previously created from three pharmacogenomic models (in vitro, animal, and peripheral blood inhumans) were used to, by means of several bioinformatic tools; identify key transcription factors (TFs) that regulate each network. Once the TFs wereidentified, SNPs disrupting the binding sites (TFBS) of these TFs in the genes of each network were selected for genotyping. Finally, SNP-basedassociations with EPS were analyzed in a sample of 356 psychiatric patients receiving AP. RESULTS: Our analysis identified 33 TFs expressed in the striatum, and 125 SNPs disrupting TFBS in 50 genes of our initial networks. Two SNPs (rs938112,rs2987902) in two genes (LSMAP and ABL1) were significantly associated with AP induced EPS (p < 0.001). These SNPs disrupt TFBS regulated byPOU2F1. CONCLUSION: Our results highlight the possible role of the disruption of TFBS by SNPs in the pharmacological response to AP.

Essential fatty acids and Barratt impulsivity in gambling disorder.

BACKGROUND: Polyunsaturated fatty acids (PUFA) have been long implicated in the etiopathogenesis of mental illnesses, including disorders characterized by high impulsivity. The objective of most of the studies in this field is to determine the effect of omega-3 supplementation on the impulsive symptoms. In contrast, studies analyzing basal PUFA composition in patients with impulsive behaviors are very scarce, results are not yet conclusive, and to date, no publication has specifically evaluated this in gambling disorder. Therefore, the main purpose of this research is to examine the relationship between basal PUFA composition of plasma and erythrocyte membrane and impulsivity in subjects with gambling disorder. METHODS: It is an observational and cross-sectional study. The sample consisted of fifty-five men with gambling disorder, who voluntarily accepted to participate. Basal composition of PUFA in plasma and erythrocyte membrane was assessed by gas chromatography and mass spectrometry. Trait impulsivity was measured by the Barratt Impulsiveness Scale version 11 (BIS-11). RESULTS: Arachidonic acid (AA)/eicosapentaenoic acid (EPA) ratio in the erythrocyte membrane was negatively correlated with total scores in BIS-11. It was also observed that impulsive gamblers had a higher proportion of EPA and a lower value of AA/EPA and AA/docosahexaenoic acid (DHA) ratio in erythrocyte membrane than non-impulsive gamblers. CONCLUSIONS: These results support the hypothesis that alteration of basal PUFA composition exists in disorders characterized by high impulsivity, although the direction of this is still unknown. Unfortunately, the empirical literature on this field is non-existent at the time and we have no direct means to support or refute these outcomes. Further research is needed to determine the relationship between essential fatty acids and disorders characterized by high impulsivity.

Examining Gene-Environment Interactions Using Aggregate Scores in a First-Episode Psychosis Cohort.

Gene-environment (GxE) interactions have been related to psychosis spectrum disorders, involving multiple common genetic variants in multiple genes with very small effect sizes, and several environmental factors that constitute a dense network of exposures named the exposome. Here, we aimed to analyze GxE in a cohort of 310 first-episode psychotic (FEP) and 236 healthy controls, by using aggregate scores estimated in large populations such as the polygenic risk score for schizophrenia and (PRS-SCZ) and the Maudsley environmental risk score (ERS). In contrast to previous findings, in our study, the PRS-SCZ did not discriminate cases from controls, but the ERS score explained a similar percentage of the variance as in other studies using similar approaches. Our study supports a positive additive interaction, indicating synergy between genetic susceptibility to schizophrenia (PRS-SCZ dichotomized according to the highest quartile distribution of the control population) and the exposome (ERS > 75% of the controls). This additive interaction showed genetic and environmental dose dependence. Our study shows that the use of aggregate scores derived from large and powered studies instead of statistics derived from specific sample characteristics is a powerful tool for the study of the effects of GxE on the risk of psychotic spectrum disorders. In conclusion, by using a genetic risk score and an ERS we have provided further evidence for the role of GxE in psychosis.

Initial and relapse prodromes in adult patients with episodes of bipolar disorder: A systematic review.

BACKGROUND: Distinguishing prodromes of bipolar disorder (BD) specific to children/adolescents, adults, and elderly patients is essential. The primary objective of this systematic review was to determine initial and relapse prodromes identifying adult patients with BD. METHODS: PubMed, PsycINFO, and Web of Science databases were searched using a predetermined strategy. A controlled process of study selection and data extraction was performed. RESULTS: The 22 articles selected included 1,809 adult patients with BD. Initial prodromes cited most frequently in these studies showed low specificity. Among relapse prodromes cited most frequently, more talkative than usual, increased energy/more goal-directed behavior, thoughts start to race, increased self-esteem, strong interest in sex, increase in activity, and spending too much were identified exclusively before a manic/hypomanic episode, while loss of interest and hypersomnia were detected only before a depressive episode. Initial prodromal phases lasted longer than prodromal relapse phases. In the selected studies, the most used prodrome identification procedure was the clinical interview. CONCLUSIONS: For adult patients with BD, initial and relapse prodromes of manic, hypomanic, and depressive episodes were identified. It is proposed that the most frequent prodromes found in this review be incorporated into a smartphone app that monitors the functioning of people at risk of BD and patients who have already been diagnosed. Data from this app would constitute a relevant source of big data.

Association study of candidate genes with obesity and metabolic traits in antipsychotic-treated patients with first-episode psychosis over a 2-year period.

AIMS: Patients with a first episode of psychosis (FEP) often display different metabolic disturbances even independently of drug therapy. However, antipsychotic (AP) treatment, especially with second-generation APs, is strongly linked to weight gain, which increases patients' risk of developing obesity and other metabolic diseases. There is an important genetic risk component that can contribute to the appearance of these disturbances. The aim of the present study was to evaluate the effect of polymorphisms in selected candidate genes on obesity and other anthropometric and metabolic traits in 320 AP-treated FEP patients over the course of a 2-year follow-up. METHODS: These patients were recruited in the multicentre PEPs study (Phenotype-genotype and environmental interaction; Application of a predictive model in first psychotic episodes). A total of 127 validated single nucleotide polymorphisms (SNPs) in 18 candidate genes were included in the genetic analysis. RESULTS: After Bonferroni correction, SNPs in ADRA2A, FTO, CNR1, DRD2, DRD3, LEPR and BDNF were associated with obesity, abdominal circumference, triglycerides, HDL cholesterol, and/or percentage of glycated haemoglobin. CONCLUSIONS: Although our results should be interpreted as exploratory, they support previous evidence of the impact of these candidate genes on obesity and metabolic status. Further research is required to gain a better knowledge of the genetic variants that can be considered relevant metabolic risk factors. The ability to identify FEP patients at higher risk for these metabolic disturbances would enable clinicians to better select and control their AP treatment.

Una década del proyecto de primeros episodios psicóticos (PEPs): avanzando hacia una psiquiatría de precisión / One decade of the first episodes project (PEPs): Advancing towards a precision psychiatry

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Barreras para la recuperación completa en la depresión mayor: estudio transversal multicéntrico en la práctica clínica. Estudio RECORD / Barriers to complete recovery of major depression: cross-sectional, multi-centre study on clinical practice. RECORD study

Introducción: El objetivo de este estudio fue identificar las barreras para lograr una recuperación completa en pacientes con depresión mayor. Métodos: Un total de 461 psiquiatras participaron en un estudio cualitativo, no randomizado, transversal y multicéntrico basado en una encuesta. El cuestionario incluía 42 ítems relacionados con el tratamiento, prevalencia, perfil del paciente, impacto de los síntomas residuales, barreras y estrategias para aumentar la recuperación completa. Resultados: Un 86% de participantes definieron recuperación completa como la remisión completa de síntomas más recuperación funcional. Un 83,4% consideraron que las bajas laborales se suelen prolongar más de 4 meses. Un 75% que los síntomas residuales eran el principal motivo de esta prolongación de las bajas, y un 62% que un 26-50% de pacientes tenían síntomas residuales. La falta de adherencia al tratamiento fue la barrera más importante para la recuperación completa, seguida de falta de colaboración del paciente, inicio tardío el tratamiento, respuesta parcial y bajas dosis de antidepresivos. En caso de respuesta parcial, el 71,8% de los participantes aumentaría la dosis del tratamiento actual, y en caso de falta de respuesta, el 72,7% cambiaría a otro antidepresivo. Un 22,8% usaría la combinación de dos antidepresivos, en cuyo caso el 85,2% elegiría fármacos con mecanismos de acción complementarios. Un 49% recomendaría la psicoterapia cognitivo-conductual en pacientes sin respuesta completa. Conclusiones: En un 50% de los pacientes no se logra la recuperación completa, con frecuencia por la presencia de síntomas residuales. Lograr la recuperación completa debe ser un objetivo imprescindible

Introduction: To identify barriers to complete recovery in patients suffering from major depressive disorder. Methods: A total of 461 psychiatrists participated in a cross-sectional, non-randomised, qualitative and multi-centre study based on a survey. The study questionnaire included 42 ítems related to management, prevalence, patient profile, impact of residual symptoms, barriers to full recovery, and strategies to increase complete recovery. Results: Complete recovery was defined by 86% of participants as complete remission of symptoms plus functional recovery. A total of 83.4% of participants considered that sick leave usually lasted more than 4 months. Seventy-five percent stated that residual symptoms were the main reason for prolongation of sick leave, and 62% that between 26%-50% of patients complained of residual symptoms. Poor compliance with treatment was the most important barrier to complete recovery, followed by a lack of patient cooperation, late beginning of treatment, partial response to antidepressants, and low doses of antidepressant medication. In the case of partial response, 71.8% of participants chose to increase the dose of current treatment, and in the case of lack of response, 72.7% would switch to another antidepressant, and 22.8% would use the combination of two antidepressants, in which case 85.2% would choose agents with complementary mechanisms of action. Forty-nine percent of participants would recommend standard cognitive-behavioural psychotherapy for patients without complete response. Conclusions: Some 50% of patients did not achieve complete remission, frequently related to persistence of residual symptoms. Achievement of complete recovery should be an essential objective

Tratamiento farmacológico del trastorno obsesivo-compulsivo en adultos: una guía de práctica clínica basada en el método ADAPTE / Pharmacological treatment of obsessive compulsive disorder in adults: a clinical practice guideline based on the ADAPTE methodology

A pesar de la existencia de tratamientos efectivos basados en la evidencia para el tratamiento del trastorno obsesivo-compulsivo (TOC), el abordaje de esta enfermedad sigue siendo subóptimo. Disponer de una guía terapéutica farmacológica del TOC puede ayudar a mejorar el manejo de la enfermedad en nuestro entorno y contribuir a reducir la carga de la enfermedad para el paciente. Con el patrocinio de la Sociedad Española de Psiquiatría un grupo de expertos ha desarrollado una guía para el tratamiento farmacológico del TOC a partir de algunas guías existentes siguiendo la metodología de la ADAPTE Collaboration. En este artículo se resume el proceso de elaboración de esta guía y las recomendaciones adoptadas por consenso por el grupo elaborador de las guías agrupadas en 5 áreas de interés: tratamiento agudo, duración del tratamiento, predictores de respuesta y síntomas especiales, respuesta parcial a falta de respuesta al tratamiento y poblaciones especiales

Despite the existence of effective evidence-based treatments for the management of obsessive-compulsive disorder (OCD), the therapeutic approach to this disease remains suboptimal. The availability of a therapeutic pharmacological guideline for OCD could help to improve the management of the disease in our setting and to reduce the burden of disease for the patient. With the sponsorship of the Spanish Society of Psychiatry, a group of experts has developed a guideline for the pharmacological treatment of OCD based on the recommendations of existing guidelines and following the methodology of the ADAPTE Collaboration. This article summarises the process of preparing this guideline and the recommendations adopted by consensus by a guideline panel grouped into five areas of interest: acute treatment, duration of treatment, predictors of response and special symptoms, partial response to lack of response to treatment, and special populations

Author Correction: Improving pharmacogenetic prediction of extrapyramidal symptoms induced by antipsychotics.

One of the funding sources (FEDER-Unión Europea) was not previously acknowledged in this Article. This study was supported by the Spanish Ministry of Health, Instituto de Salud Carlos III (FIS, Fondo de Investigacion Sanitaria PI13/00812, PI16/0122) and FEDER-Unión Europea.

Pharmacological treatment of obsessive compulsive disorder in adults: A clinical practice guideline based on the ADAPTE methodology. / Tratamiento farmacológico del trastorno obsesivo-compulsivo en adultos: una guía de práctica clínica basada en el método ADAPTE.

Despite the existence of effective evidence-based treatments for the management of obsessive-compulsive disorder (OCD), the therapeutic approach to this disease remains suboptimal. The availability of a therapeutic pharmacological guideline for OCD could help to improve the management of the disease in our setting and to reduce the burden of disease for the patient. With the sponsorship of the Spanish Society of Psychiatry, a group of experts has developed a guideline for the pharmacological treatment of OCD based on the recommendations of existing guidelines and following the methodology of the ADAPTE Collaboration. This article summarises the process of preparing this guideline and the recommendations adopted by consensus by a guideline panel grouped into five areas of interest: acute treatment, duration of treatment, predictors of response and special symptoms, partial response to lack of response to treatment, and special populations.