High S100B Levels Predict Antidepressant Response in Patients With Major Depression Even When Considering Inflammatory and Metabolic Markers.

BACKGROUND: The relationship between antidepressant response and glial, inflammatory, and metabolic markers is poorly understood in depression. This study assessed the ability of biological markers to predict antidepressant response in major depressive disorder (MDD). METHODS: We included 31 MDD outpatients treated with escitalopram or sertraline for 8 consecutive weeks. The Montgomery-Åsberg Depression Rating Scale (MADRS) was administered at baseline and at week 4 and 8 of treatment. Concomitantly, blood samples were collected for the determination of serum S100B, C-reactive protein (CRP), and high-density lipoprotein cholesterol (HDL)-C levels. Treatment response was defined as ≥50% improvement in the MADRS score from baseline to either week 4 or 8. Variables associated with treatment response were included in a linear regression model as predictors of treatment response. RESULTS: Twenty-seven patients (87%) completed 8 weeks of treatment; 74% and 63% were responders at week 4 and 8, respectively. High S100B and low HDL-C levels at baseline were associated with better treatment response at both time points. Low CRP levels were correlated with better response at week 4. Multivariate analysis showed that high baseline S100B levels and low baseline HDL-C levels were good predictors of treatment response at week 4 (R2 = 0.457, P = .001), while S100B was at week 8 (R2 = 0.239, P = .011). Importantly, baseline S100B and HDL-C levels were not associated with depression severity and did not change over time with clinical improvement. CONCLUSIONS: Serum S100B levels appear to be a useful biomarker of antidepressant response in MDD even when considering inflammatory and metabolic markers.

Cannabis use selectively modulates circulating biomarkers in the blood of schizophrenia patients.

Cannabis use disorder is frequent in schizophrenia patients, and it is associated with an earlier age of onset and poor schizophrenia prognosis. Serotonin 2A receptors (5-HT2AR) have been involved in psychosis and, like Akt kinase, are known to be modulated by THC. Likewise, endocannabinoid system dysregulation has been suggested in schizophrenia. The presence of these molecules in blood makes them interesting targets, as they can be evaluated in patients by a minimally invasive technique. The aim of the present study was to evaluate 5-HT2AR protein expression and the Akt functional status in platelet homogenates of subjects diagnosed with schizophrenia, cannabis use disorder, or both conditions, compared with age- and sex-matched control subjects. Additionally, endocannabinoids and pro-inflammatory interleukin-6 (IL-6) levels were also measured in the plasma of these subjects. Results showed that both platelet 5-HT2AR and the active phospho (Ser473)Akt protein expression were significantly increased in schizophrenia subjects, whereas patients with a dual diagnosis of schizophrenia and cannabis use disorder did not show significant changes. Similarly, plasma concentrations of anandamide and other lipid mediators such as PEA and DEA, as well as the pro-inflammatory IL-6, were significantly increased in schizophrenia, but not in dual subjects. Results demonstrate that schizophrenia subjects show different circulating markers pattern depending on the associated diagnosis of cannabis use disorder, supporting the hypothesis that there could be different underlying mechanisms that may explain clinical differences among these groups. Moreover, they provide the first preliminary evidence of peripherally measurable molecules of interest for bigger prospective studies in these subpopulations.

Ligand bias and inverse agonism on 5-HT2A receptor-mediated modulation of G protein activity in post-mortem human brain.

BACKGROUND AND PURPOSE: Whereas biased agonism on the 5-HT2A receptor has been ascribed to hallucinogenic properties of psychedelics, no information about biased inverse agonism on this receptor is available. In schizophrenia, increased 5-HT2A receptor constitutive activity has been suggested, highlighting the therapeutic relevance of inverse agonism. This study characterized the modulation of G protein activity promoted by different drugs, commonly considered as 5-HT2A receptor antagonists, in post-mortem human brain cortex. EXPERIMENTAL APPROACH: Modulation of [35S]GTPγS binding to different subtypes of Gα proteins exerted by different 5-HT2A receptor drugs was determined by scintillation proximity assays in brain from human, WT and 5-HT2A receptor KO mice. KEY RESULTS: MDL-11,939 was the only drug having no effect on the basal activity of 5-HT2A receptor. Altanserin and pimavanserin decreased basal activation of Gi1, but not Gq/11 proteins. This effect was blocked by MDL-11,939 and absent in 5-HT2A receptor KO mice. Volinanserin showed 5-HT2A receptor-mediated inverse agonism both on Gi1 and Gq/11 proteins. Ketanserin exhibited 5-HT2A receptor partial agonism exclusively on Gq/11 proteins. On the other hand, eplivanserin and nelotanserin displayed inverse agonism on Gq/11 and/or Gi1 proteins, which was insensitive to MDL-11,939 and was present in KO mice suggesting a role for another receptor. CONCLUSION AND IMPLICATIONS: The results reveal the existence of constitutively active 5-HT2A receptors in human pre-frontal cortex and demonstrate different pharmacological profiles of various 5-HT2A receptor drugs previously considered antagonists. These findings indicate that altanserin and pimavanserin possess biased inverse agonist profile towards 5-HT2A receptor activation of Gi1 proteins.

Isolation and Differentiation of Neurons and Glial Cells from Olfactory Epithelium in Living Subjects.

The study of psychiatric and neurological diseases requires the substrate in which the disorders occur, that is, the nervous tissue. Currently, several types of human bio-specimens are being used for research, including postmortem brains, cerebrospinal fluid, induced pluripotent stem (iPS) cells, and induced neuronal (iN) cells. However, these samples are far from providing a useful predictive, diagnostic, or prognostic biomarker. The olfactory epithelium is a region close to the brain that has received increased interest as a research tool for the study of brain mechanisms in complex neuropsychiatric and neurological diseases. The olfactory sensory neurons are replaced by neurogenesis throughout adult life from stem cells on the basement membrane. These stem cells are multipotent and can be propagated in neurospheres, proliferated in vitro and differentiated into multiple cell types including neurons and glia. For all these reasons, olfactory epithelium provides a unique resource for investigating neuronal molecular markers of neuropsychiatric and neurological diseases. Here, we describe the isolation and culture of human differentiated neurons and glial cells from olfactory epithelium of living subjects by an easy and non-invasive exfoliation method that may serve as a useful tool for the research in brain diseases.

Pimavanserin exhibits serotonin 5-HT2A receptor inverse agonism for Gαi1- and neutral antagonism for Gαq/11-proteins in human brain cortex.

Pimavanserin is claimed as the first antipsychotic drug that shows selectivity for serotonin 5-HT2 receptors (5-HT2Rs) and lacks of affinity for dopamine D2 receptors (D2Rs). Cell-based functional assays suggest that pimavanserin and antipsychotics with D2R/5-HT2R affinity could act as inverse agonists of 5-HT2ARs. However, there is not evidence of such pharmacological profile in native brain tissue. 5-HT2ARs are able to engage both canonical Gαq/11- and non-canonical Gαi1-proteins. In the present study, the response to pimavanserin of the 5-HT2AR coupling to Gαq/11- and Gαi1-proteins was measured in membranes of postmortem human prefrontal cortex by antibody-capture [35S]GTPγS binding scintillation proximity assays. Pimavanserin promoted a concentration-dependant inhibition of the 5-HT2AR coupling to Gαi1-proteins whereas the response of Gαq/11-proteins was unaltered, suggesting inverse agonism and neutral antagonism properties, respectively. The inhibition was abolished in the presence of the selective 5-HT2AR antagonist MDL-11,939 and was absent in brain cortex of 5-HT2AR knock-out mice when compared to respective 5-HT2AR wild-type animals. In conclusion, the results demonstrate the existence of constitutive 5-HT2AR activity in human brain for the signalling pathway mediated by Gαi1-proteins. Pimavanserin demonstrates 5-HT2AR functional selectivity and exhibits inverse agonist profile towards Gαi1-proteins, which is considered the effector pathway promoting hallucinogenic responses. In contrast, pimavanserin behaves as neutral antagonist on the 5-HT2AR coupling to the canonical Gαq/11-protein pathway. The results strengthen the relevance of inverse agonism as potential mechanism of antipsychotic activity. Moreover, the existence of functional selectivity of 5-HT2ARs for different Gα-proteins could contribute to better design of 5-HT2AR-related antipsychotic drugs.

Serum ß-endorphin levels are associated with addiction to suicidal behavior: A pilot study.

The literature provides partial support for the hypothesis that some suicide attempters develop a behavioral addiction to suicidal behavior (SB). We hypothesized that major suicide repeaters (MR) (≥5 lifetime suicide attempts) are addicted to suicide attempts as measured by modified DSM-IV criteria for substance dependence. In this cross-sectional study with 13 psychiatric controls (PC), 55 non-major suicide attempters (NMR), and 9 MR we found that MR are characterized by emotional abuse and neglect, as well as higher scores on the Personality and Life Event scale (short version). The levels of 8 AM serum ACTH, cortisol and ß-endorphin were elevated in all three groups. Serum ß-endorphin (pg/mL) was particularly high in PC diagnosed with schizophrenia 220.34 (±56.30). The level of 8 AM serum ß-endorphin rose with increased numbers of criteria met for addiction to SB from 130.31 (±88.16) (≥ 3 criteria met for addiction to SB) to 174.84 (±114.93) (≥ 6 criteria met for addiction to SB) whereas serum ACTH and cortisol did not change. SB addicts (≥ 6 criteria) displayed higher serum ß-endorphin concentrations than non-addicts (174.84 ± 114.93 vs. 116.93 ± 61.70, FET p = 0.09). The present study brings some support to the addictive hypothesis of SB. Our results delineate ß-endorphin as a promising biomarker of SB addiction, and offer a good basis for future studies that test whether buprenorphine can be used to prevent repetitive suicide attempts, non-suicidal-self-injury (NSSI), and the development of an addiction to SB.

Chronic fluoxetine reverses the effects of chronic corticosterone treatment on α2-adrenoceptors in the rat frontal cortex but not locus coeruleus.

Disruption of the hypothalamic-pituitary-adrenal axis is an established finding in patients with anxiety and/or depression. Chronic corticosterone administration in animals has been proposed as a model for the study of these stress-related disorders and the antidepressant action. Alterations of the central noradrenergic system and specifically of inhibitory α2-adrenoceptors seem to be part of the pathophysiology of depression and contribute to the antidepressant activity. The present study evaluates in male rats the effect of chronic corticosterone treatment during 35 days (16-20 mg kg-1 day-1) on the sensitivity of α2-adrenoceptors expressed in the somatodendritic and terminal noradrenergic areas locus coeruleus (LC) and prefrontal cortex (PFC), respectively. Further, the effect of chronic fluoxetine treatment (5 mg kg-1, i.p., since the 15th day) on the sensitivity of α2-adrenoceptors was examined under control conditions and in corticosterone-treated rats. The α2-adrenoceptor functionality was analysed in vitro by agonist-mediated [35S]GTPγS binding stimulation and in vivo through the modulation of noradrenaline (NA) release evaluated by dual-probe microdialysis. The concentration-effect curves of the [35S]GTPγS binding stimulation by the agonist UK14304 (5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine) demonstrated a desensitization of cortical α2-adrenoceptors induced by corticosterone (-logEC50 = 6.7 ±â€¯0.2 vs 8.2 ±â€¯0.3 in controls) that was reverted by fluoxetine treatment (-logEC50 = 7.5 ±â€¯0.3). Local administration of the α2-adrenoceptor antagonist RS79948 ((8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-methoxy-12-(ethylsulfonyl)-6H-isoquino[2,1-g][1,6]naphthyridine) (0.1-100 µmol L-1) into the LC induced a concentration-dependent NA increase in the PFC of the control group (Emax = 191 ±â€¯30%) but non-significant effect was observed in corticosterone-treated rats (Emax = 133 ±â€¯46%), reflecting a desensitization of α2-adrenoceptors that control the firing of noradrenergic neurons. Fluoxetine treatment did not alter the corticosterone-induced desensitization in this area (Emax = 136 ±â€¯19%). No effect of fluoxetine on α2-adrenoceptor functionality was observed in control animals (Emax = 223 ±â€¯30%). In PFC, the local administration of RS79948 increased NA in controls (Emax = 226 ±â€¯27%) without effect in the corticosterone group (Emax = 115 ±â€¯26%), suggesting a corticosterone-induced desensitization of terminal α2-adrenoceptors. Fluoxetine administration prevented the desensitization induced by corticosterone in the PFC (Emax = 233 ±â€¯33%) whereas desensitized α2-adrenoceptors in control animals (Emax = -24 ±â€¯10%). These data indicate that chronic corticosterone increases noradrenergic activity by acting at different α2-adrenoceptor subpopulations. Treatment with the antidepressant fluoxetine seems to counteract these changes by acting mainly on presynaptic α2-adrenoceptors expressed in terminal areas.

Effect of subchronic corticosterone administration on α2-adrenoceptor functionality in rat brain: an in vivo and in vitro study.

RATIONALE: Noradrenergic system plays a critical role in the hypothalamic-pituitary-adrenal (HPA) axis regulation and the stress response. A dysregulated HPA axis may be indicative of an increased biological vulnerability for depression. In addition, a variety of studies have focused on specific alterations of α2-adrenoceptors as a mechanism involved in the pathogenesis of mood disorders and antidepressant response. OBJECTIVES: This study aimed to evaluate the effect of subchronic corticosterone administration on rat brain α2-adrenoceptor functionality by in vitro [35S]GTPγS binding stimulation assays and in vivo dual-probe microdialysis determination of extracellular noradrenaline concentrations. RESULTS: Implantation of a time release corticosterone pellet during 14 days induced sustained changes in endocrine function. However, there were no differences in α2-adrenoceptor agonist UK14304-induced stimulation of [35S]GTPγS binding in prefrontal cortex (PFC) between corticosterone-treated and control rats. In the same way, the in vivo evaluation of α2-adrenoceptor-mediated noradrenaline release responses to the α2-adrenoceptor agonist clonidine local administration into the locus coeruleus (LC), and the PFC did not show differences between the groups. CONCLUSIONS: The present results show that subchronic corticosterone administration does not induce changes on functionality of α2-adrenoceptors neither in the LC nor in noradrenergic cortical terminal areas.

Chronic pain leads to concomitant noradrenergic impairment and mood disorders.

BACKGROUND: Patients suffering chronic pain are at high risk of suffering long-lasting emotional disturbances characterized by persistent low mood and anxiety. We propose that this might be the result of a functional impairment in noradrenergic circuits associated with locus coeruleus (LC) and prefrontal cortex, where emotional and sensorial pain processes overlap. METHODS: We used a chronic constriction injury of sciatic nerve as a model of neuropathic pain in male Sprague-Dawley rats to assess the time-dependent changes that might potentially precipitate mood disorders (2, 7, 14, and 28 days after injury). This was measured through a combination of behavioral, electrophysiological, microdialysis, immunohistochemical, and Western blot assays. RESULTS: As expected, nerve injury produced an early and stable decrease in sensorial pain threshold over the testing period. By contrast, long-term neuropathic pain (28 days after injury) resulted in an inability to cope with stressful situations, provoking depressive and anxiogenic-like behaviors, even more intense than the aversiveness associated with pain perception. The onset of these behavioral changes coincided with irruption of noradrenergic dysfunction, evident as: an increase in LC bursting activity; in tyrosine hydroxylase expression and that of the noradrenaline transporter; and enhanced expression and sensitivity of α2-adrenoceptors in the LC. CONCLUSIONS: Long-term neuropathic pain leads to anxio-depressive-like behaviors that are more predominant than the aversion of a painful experience. These changes are consistent with the impairment of noradrenergic system described in depressive disorders.

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.

Long lasting effects of early-life stress on glutamatergic/GABAergic circuitry in the rat hippocampus.

The objective of the present work was to study the effects of an early-life stress (maternal separation, MS) in the excitatory/inhibitory ratio as a potential factor contributing to the ageing process, and the purported normalizing effects of chronic treatment with the antidepressant venlafaxine. MS induced depressive-like behaviour in the Porsolt forced swimming test that was reversed by venlafaxine, and that persisted until senescence. Aged MS rats showed a downregulation of vesicular glutamate transporter 1 and 2 (VGlut1 and VGlut2) and GABA transporter (VGAT) and increased expression of excitatory amino acid transporter 2 (EAAT2) in the hippocampus. Aged rats showed decreased expression of glutamic acid decarboxylase 65 (GAD65), while the excitatory amino acid transporter 1 (EAAT1) was affected only by stress. Glutamate receptor subunits NR1 and NR2A and GluR4 were upregulated in stressed rats, and this effect was reversed by venlafaxine. NR2B, GluR1 and GluR2/3 were not affected by either stress or age. MS, both in young and aged rats, induced an increase in the circulating levels of corticosterone. Corticosterone induced an increase glutamate and a decrease in GABA release in hippocampal slices, which was reversed by venlafaxine. Chronic treatment with corticosterone recapitulated the main biochemical findings observed in MS. The different effects that chronic stress exerts in young and adult animals on expression of proteins responsible for glutamate/GABA cycling may explain the involvement of glucocorticoids in ageing-related diseases. Modulation of glutamate/GABA release may be a relevant component of the therapeutic action of antidepressants, such as venlafaxine.

The function of alpha-2-adrenoceptors in the rat locus coeruleus is preserved in the chronic constriction injury model of neuropathic pain.

RATIONALE: Peripheral neuropathic pain is a chronic condition that may produce plastic changes in several brain regions. The noradrenergic locus coeruleus (LC) is a crucial component of ascending and descending pain pathways, both of which are frequently compromised after nerve injury. OBJECTIVES: The objective of the study was to examine whether chronic constriction injury (CCI), a model of neuropathic pain, alters noradrenergic activity in the rat LC. METHODS: Activity in the LC was assessed by electrophysiology and microdialysis, while protein expression was monitored in western blots and by immunohistochemistry. RESULTS: The pain threshold had dropped in injured rats 7 days after inducing neuropathy. While alpha-2-adrenoceptors mediate activity in the LC and in its terminal areas, no alterations in either spontaneous neuronal activity or extracellular noradrenaline levels were observed following CCI. Moreover, alpha-2-adrenoceptor activity in the LC of CCI rats remained unchanged after systemic administration of UK14,304, RX821002 or desipramine. Accordingly, extracellular noradrenaline levels in the LC were similar in CCI and control animals following local administration of clonidine or RX821002. In addition, there were no changes in the expression of the alpha-2-adrenoceptors, Gαi/z subunits or the regulators of G-protein signaling. However, pERK1/2 (phosphorylated extracellular signal-regulated kinases 1/2) expression augmented in the spinal cord, paragigantocellularis nucleus (PGi) and dorsal raphe nucleus (DRN) following CCI. CONCLUSIONS: Neuropathic pain is not accompanied by modifications in tonic LC activity after the onset of pain. This may indicate that the signals from the PGi and DRN, the excitatory and inhibitory afferents of the LC, cancel one another out.

Bases neurobiológicas de la depresión / Neurobiology of depression

La depresión es uno de los trastornos mentales que presenta una gran prevalencia, ya que afecta a cerca del 16% de la población general. Actualmente, la mayoría de los estudios coinciden en que este trastorno se produce por una interacción entre algún tipo de predisponente genético y diversos factores ambientales. Es por ello que la investigación de los mecanismos que median dicha interacción cobra vital importancia para conseguir avanzar en la comprensión de los mecanismos etiopatogénicos que originan el trastorno depresivo, y por ende para lograr herramientas más eficaces para su tratamiento y prevención. Durante las últimas décadas gran parte de los estudios sobre las bases neurobiológicas de la depresión evolucionaron a partir de dos grandes hipótesis, la teoría monoaminérgica y la teoría neurotrófica. El objeto del presente artículo es hacer una revisión de los hallazgos científicos que avalan ambas teorías.