Role of cyclin-dependent kinase 5 in psychosis and the modulatory effects of cannabinoids.

Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that has emerged as a key regulator of neurotransmission in complex cognitive processes. Its expression is altered in treated schizophrenia patients, and cannabinoids modulate CDK5 levels in the brain of rodents. However, the role of this kinase, and its interaction with cannabis use in first-episode psychosis (FEP) patients is still not known. Hence, we studied the expression changes of CDK5 and its signaling partner, postsynaptic density protein 95 (PSD95) in olfactory neuroepithelial (ON) cells of FEP patients with (FEP/c) and without (FEP/nc) prior cannabis use, and in a dual-hit mouse model of psychosis. In this model, adolescent mice were exposed to the cannabinoid receptor 1 agonist (CB1R) WIN-55,212-2 (WIN: 1 mg/kg) during 21 days, and to the N-methyl-d-aspartate receptor (NMDAR) blocker phencyclidine (PCP: 10 mg/kg) during 10 days. FEP/c showed less social functioning deficits, lower CDK5 and higher PSD95 levels than FEP/nc. These changes correlated with social skills, but not cognitive deficits. Consistently, exposure of ON cells from FEP/nc patients to WIN in vitro reduced CDK5 levels. Convergent results were obtained in mice, where PCP by itself induced more sociability deficits, and PSD95/CDK5 alterations in the prefrontal cortex and hippocampus than exposure to PCP-WIN. In addition, central blockade of CDK5 activity with roscovitine in PCP-treated mice restored both sociability impairments and PSD95 levels. We provide translational evidence that increased CDK5 could be an early indicator of psychosis associated with social deficits, and that this biomarker is modulated by prior cannabis use.

Obstetric complications and clinical presentation in first episode of psychosis.

OBJECTIVE: Psychotic disorders exhibit a complex aetiology that combines genetic and environmental factors. Among the latter, obstetric complications (OCs) have been widely studied as risk factors, but it is not yet well understood how OCs relate to the heterogeneous presentations of psychotic disorders. We assessed the clinical phenotypes of individuals with a first episode of psychosis (FEP) in relation to the presence of OCs. METHODS: Two-hundred seventy-seven patients with an FEP were assessed for OCs using the Lewis-Murray scale, with data stratified into three subscales depending on the timing and the characteristics of the obstetric event, namely: complications of pregnancy, abnormal foetal growth and development and difficulties in delivery. We also considered other two groups: any complications during the pregnancy period and all OCs taken altogether. Patients were clinically evaluated with the Positive and Negative Syndrome Scale for schizophrenia. RESULTS: Total OCs and difficulties in delivery were related to more severe psychopathology, and this remained significant after co-varying for age, sex, traumatic experiences, antipsychotic dosage and cannabis use. CONCLUSIONS: Our results highlight the relevance of OCs for the clinical presentation of psychosis. Describing the timing of the OCs is essential in understanding the heterogeneity of the clinical presentation.

Clozapine use in the first two years after first-episode psychosis in a real-world clinical sample.

BACKGROUND: Approximately 20-30% of patients with schizophrenia fail to respond to antipsychotic treatment and are considered treatment resistant (TR). Although clozapine is the treatment of choice in these patients, in real-world clinical settings, clinicians often delay clozapine initiation, especially in first-episode psychosis (FEP). AIM: The main aim of this study was to describe prescription patterns for clozapine in a sample of patients diagnosed with FEP and receiving specialized treatment at a university hospital. More specifically, we aimed to determine the following: (1) the proportion of patients who received clozapine within two years of disease onset, (2) baseline predictors of clozapine use, (3) time from starting the first antipsychotic to clozapine initiation, (4) concomitant medications, and (5) clozapine-related adverse effects. METHODS: All patients admitted to a specialized FEP treatment unit at our hospital between April 2013 and July 2020 were included and followed for two years. The following variables were assessed: baseline sociodemographic characteristics; medications prescribed during follow-up; clozapine-related adverse effects; and baseline predictors of clozapine use. We classified the sample into three groups: clozapine users, clozapine-eligible, and non-treatment resistant (TR). RESULTS: A total of 255 patients were consecutively included. Of these, 20 (7.8%) received clozapine, 57 (22.4%) were clozapine-eligible, and 178 (69.8%) were non-TR. The only significant variable associated with clozapine use at baseline was the Global Assessment of Functioning (GAF) score (R2=0.09, B=-0.07; OR=0.94; 95% CI: 0.88-0.99; p=0.019). The median time to clozapine initiation was 55.0 (93.3) days. The most common side effect was sedation. CONCLUSIONS: A significant proportion (30.2%) of patients in this cohort were treatment resistant and eligible for clozapine. However, only 7.8% of the sample received clozapine, indicating that this medication was underprescribed. A lower baseline GAF score was associated with clozapine use within two years, suggesting that it could be used to facilitate the early identification of patients who will need treatment with clozapine, which could in turn improve treatment outcomes.

Factors associated with suicide attempts in first-episode psychosis during the first two years after onset.

The risk of suicide in first-episode psychosis (FEP) is high. However, there are many unknowns about this phenomenon and the risk factors associated with higher risk are not well-understood. Therefore, we aimed to determine the baseline sociodemographic and clinical factors associated with suicide attempts in FEP patients over two-years after psychosis onset. Univariate and logistic regression analyses were performed. Between April 2013 and July 2020, 279 patients treated at the FEP Intervention Program at our hospital (Hospital del Mar, Spain) were enrolled and 267 completed the follow-up. Of these, 30 patients (11.2%) made at least one suicide attempt, mostly during the untreated psychosis period (17 patients, 48.6%). Several variables-prior history of suicide attempts and low functionality, depression, and feelings of guilt at baseline-were all significantly associated with suicide attempts. These findings suggest that targeted interventions, especially in prodromal stages, could play a key role in identifying and treating FEP patients with a high suicide risk.

A multicenter, observational study of pain and functional impairment in individuals with major depressive disorder in partial remission: the DESIRE study.

BACKGROUND: The study explores the association between pain and functional impairment in patients with partially remitted MDD, considering both clinician and patient reported outcomes. METHODS: Multicenter, observational, and cross-sectional study, with 583 outpatients with partially remitted MDD. Measures of pain intensity (VAS), functional impairment (SOFAS), depressive symptomatology (HAM-D6), and remission from MDD and functional status from a patient-centered perspective (RDQ) were collected. VAS scores (cut-off: 30) were used to divide the sample in two groups: no pain (n = 274) and pain (n = 309). Descriptive data, correlation and regression analyses were obtained. RESULTS: Functional impairment (SOFAS) and pain (VAS) were negatively and significantly correlated in the total sample, and in the group with pain. Lower pain predicted higher functioning. The pain sub-sample was older, less educated, with higher medical comorbidities, higher HAM-D6 scores, and lower functionality (SOFAS). In the RDQ, the pain group showed significantly higher scores in the symptom-related subscales, and lower scores in the subscales related to positive mental health, functioning and wellbeing. LIMITATIONS: Correlational and observational design. The criteria and instruments used to measure pain and to define a threshold might limit the generalizability of findings. CONCLUSIONS: Pain and functionality should be assessed and treated in patients with MDD in partial remission. Our results indicate that functionality should be assessed with a broader perspective, that also considers positive mental health features.

Síntomas maníacos en encefalitis autoinmune por anticuerpos contra mGluR5: a propósito de un caso / Maniac symptoms in autoimmune encephalitis due to mGluR5 antibodies: Presentation of a case

La encefalitis autoinmune es una entidad heterogénea en cuanto a su presentación clínica y pronóstico. Es frecuente que este cuadro presente síntomas psiquiátricos por lo que es habitual la intervención de los servicios de psiquiatría tanto en el proceso diagnóstico como en el manejo sintomático. El curso de la enfermedad suele ser agudo o rápidamente progresivo motivo por el cual es esencial la detección precoz de esta enfermedad con el fin de realizar las exploraciones complementarias y el tratamiento etiológico. Describimos el caso de un varón de 49 años, sin antecedentes psiquiátricos que presenta sintomatología maniforme en urgencias pero que a las pocas horas de ingresar en la unidad de agudos presenta disminución del nivel de consciencia y fiebre. Las exploraciones complementarias permiten orientarlo como encefalitis autoinmune por anticuerpos contra el receptor metabotrópico de glutamato 5. La psiquiatría de interconsulta participa en el manejo sintomático del paciente

Autoimmune encephalitis is a heterogeneous entity in terms of its symptoms and prognosis. As the clinical presentation frequently includes psychiatric symptoms, the intervention of psychiatric services is usual in the diagnostic process, as well as in the management of the symptoms. The course of the disease is usually acute or rapidly progressive, making the early detection of this disease essential in patients in order to perform the complementary tests and to treat the origin. The case is presented of a 49 year-old man, with no psychiatric history, who presents with maniac symptoms in the emergency room. A few hours after being admitted to the inpatient unit he presents with decrease in consciousness level and fever. Complementary tests led to the diagnosis of autoimmune encephalitis with antibodies against the metabotropic receptor of glutamate 5. The psychiatric approach for symptomatic treatment was made by joint consultation