Ethanol and illicit drugs acute use and abuse as risk factors for suicide: A case-control study based on forensic autopsies in the Basque Country, Spain.

INTRODUCTION: Abuse/dependence and acute use of ethanol and illicit drug are considered risk factors for suicide. The risk is also influenced by demographic conditions and/or psychiatric comorbidity. The aim of the study was to test the association between presence of ethanol, illicit substances and prescribed drugs in suicide decedents and controls. MATERIALS AND METHODS: Case-control study of autopsies performed in the Biscay Forensic Pathology Service, Basque Country, Spain from 01/01/2010 to 30/06/2021 in subjects between 15 and 55 years old. Suicide deaths (n=481) with completed autopsy were evaluated. Concurrent natural deaths were chosen as controls (n=330). The risk for suicide according to demographic, toxicological and psychiatric variables was analyzed using logistic regression. RESULTS: Ethanol was present in 21% and illicit drugs, mainly cannabis, cocaine and amphetamine, in 27% of suicide deaths. Illicit drugs were more frequent among males. In 63% of suicide cases, prescribed psychotropic drugs were detected. In a multivariate analysis, the main risk factors for suicide were psychiatric diagnosis of illicit drug abuse/dependence (OR=5.56, 95% CI 2.74-11.30) or another mental disease as mood or psychotic disorders (OR=13.05, 95% CI 8.79-19.37). Acute presence of ethanol (OR=4.22, 95% CI 2.52-7.08), recent use of cocaine (OR=2.52, 95% CI 1.05-6.07) and age <35 years (OR=2.50, 95% CI 1.62-3.87) were also associated with suicide deaths. CONCLUSIONS: The presence of drugs of abuse in suicide deaths of people ≤55 years old is high. Recent use of ethanol and cocaine is significantly associated with an increased suicide risk. Specific prevention strategies against exposition to substances of abuse should be promoted, especially in psychiatric patients.

Subcellular distribution of membrane-bound aminopeptidases in the human and rat brain.

We evaluated the subcellular distribution of four membrane-bound aminopeptidases in the human and rat brain cortex. The particulate enzymes under study--puromycin-sensitive aminopeptidase (PSA), aminopeptidase N (APN), pyroglutamyl-peptidase I (PG I) and aspartyl-aminopeptidase (Asp-AP)--were fluorometrically measured using beta-naphthylamide derivatives. Membrane-bound aminopeptidase activity was found in all the studied subcellular fractions (myelinic, synaptosomal, mitochondrial, microsomal and nuclear fractions), although not homogenously. Human PSA showed highest activity in the microsomal fraction. APN was significantly higher in the nuclear fraction of both species, while PG I showed highest activity in the synaptosomal and myelinic fractions of the human and rat brain. The present results suggest that in addition to inactivating neuropeptides at the synaptic cleft, these enzymes may participate in other physiological processes. Moreover, these peptidases may play specific roles depending on their activity levels at the different subcellular structures where they are localized.

Additive effect of rimonabant and citalopram on extracellular serotonin levels monitored with in vivo microdialysis in rat brain.

Current pharmacological therapies for depression, including selective serotonin reuptake inhibitors (SSRI), are far from ideal. The cannabinoid system has been implicated in control of mood and neural processing of emotional information, and the modulation of serotonin (5-HT) release in the synaptic clefts. The aim of the present study was to evaluate whether the combination of a selective SSRI (citalopram) with a selective cannabinoid CB1 receptor antagonist (rimonabant) represents a more effective strategy than the antidepressant alone to enhance serotonergic transmission. For this purpose extracellular 5-HT levels were monitored with microdialysis in forebrain (prefrontal cortex, PFC) and mesencephalic (locus coeruleus, LC) serotonergic terminal areas in freely awake rats. Rimonabant at 10 mg/kg, i.p., but not at 3mg/kg i.p. increased 5-HT in both areas. Citalopram at 3, 5 and 10 mg/kg i.p. increased 5-HT both in PFC and LC in a dose-dependent manner. The effect of citalopram (5mg/kg, i.p.) on 5-HT levels was significantly enhanced by rimonabant at 10 mg/kg, i.p. but not at 3 mg/kg i.p. in both areas. The present results demonstrate that the cannabinoid CB1 receptor antagonist rimonabant is able to enhance in an additive manner the citalopram-induced increase of 5-HT concentrations in serotonergic terminal areas. The combination of a cannabinoid antagonist and a SSRI may provide a novel strategy to increase 5-HT availability, reducing the dose of SSRIs, and potentially decreasing the time lag for the clinical onset of the antidepressant effect.

El sistema noradrenérgico en la neurobiología de la depresión / The noradrenergic system in the neurobiology of depression

Introducción: Los tratamientos antidepresivos delos que se dispone en la actualidad se encuentran aún muy lejos de ser óptimos. Por un lado hay un porcentaje de pacientes que no responden a los tratamientos y además hay un período de retraso de unas 3-4 semanas entre el inicio del tratamiento y la aparición del efecto terapéutico. El conocimiento dela neurobiología de la enfermedad resulta imprescindible para el desarrollo de nuevos tratamientos. Objetivo: Revisar las bases neurobiológicas de uno de los sistemas diana de los fármacos antidepresivos, el sistema noradrenérgico. Desarrollo: se describe la anatomía y la función del núcleo noradrenérgico más importante, el locus coeruleus, su interacción con los demás sistemas de neurotransmisión, así como el papel de los receptores adrenérgicos alfa2 en el mecanismo de acción de los fármacos antidepresivos. Conclusiones: El estudio profundo de los sistemas de neurotransmisión diana de los antidepresivos es el mejor abordaje como fuente de conocimiento para el diseño de nuevas estrategias antidepresivas. Los receptores adrenérgicos alfa2 parecen tener un papel muy relevante en el mecanismo de acción de estos fármacos. Además, los antidepresivos tanto de perfil noradrenérgico como serotoninérgico son capaces de modular el sistema noradrenérgico, lo que evidencia que ambos sistemas son modulados conjuntamente en el SNC (AU)

Introduction: Currently available antidepressant drugs are far from optimal. On the one hand, approximately 30% patients are treatment-resistant, while on the other, there is a 3-4 week delay between the start of treatment and the onset of therapeutic effects. Knowledge of the neurobiology of depression is essential for the development of new therapeutic strategies. Objective: The present article aims to review the neurobiological bases of the noradrenergic system, one of the main targets of antidepressant drugs. Development: we describe current knowledge of the anatomy and function of the most important noradrenergic nucleus, the locus coeruleus, and its interaction with different neurotransmission systems, as well as of the role of alfa2-adrenoceptors in the mechanism of action of antidepressant drugs. Conclusions: Study of neurotransmission targets for antidepressants seems to be the most effective approach for the design of new antidepressant drugs. In this context, the alfa2-adrenoceptors play a major role in the mechanism of action of these agents. In addition, antidepressants, whether with a noradrenergic or a serotonergic profile, are able to modulate the noradrenergic system, demonstrating that both systems are modulated at the same time in the central nervous system (AU)