scholarly journals Serotonin Heteroreceptor Complexes and Their Integration of Signals in Neurons and Astroglia—Relevance for Mental Diseases

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1902
Author(s):  
Dasiel O. Borroto-Escuela ◽  
Patrizia Ambrogini ◽  
Manuel Narvaez ◽  
Valentina Di Liberto ◽  
Sarah Beggiato ◽  
...  
Keyword(s):  
Mental Disease ◽  
Antidepressant Drug ◽  
Antidepressant Drugs ◽  
Positive Effects ◽  
Heteroreceptor Complexes ◽  
Receptor Interactions ◽  
Mental Diseases ◽  
Biological Principle ◽  
Serotonin Neurons ◽  
Allosteric Mechanisms

The heteroreceptor complexes present a novel biological principle for signal integration. These complexes and their allosteric receptor–receptor interactions are bidirectional and novel targets for treatment of CNS diseases including mental diseases. The existence of D2R-5-HT2AR heterocomplexes can help explain the anti-schizophrenic effects of atypical antipsychotic drugs not only based on blockade of 5-HT2AR and of D2R in higher doses but also based on blocking the allosteric enhancement of D2R protomer signaling by 5-HT2AR protomer activation. This research opens a new understanding of the integration of DA and 5-HT signals released from DA and 5-HT nerve terminal networks. The biological principle of forming 5-HT and other heteroreceptor complexes in the brain also help understand the mechanism of action for especially the 5-HT hallucinogens, including putative positive effects of e.g., psilocybin and the indicated prosocial and anti-stress actions of MDMA (ecstasy). The GalR1-GalR2 heterodimer and the putative GalR1-GalR2-5-HT1 heteroreceptor complexes are targets for Galanin N-terminal fragment Gal (1–15), a major modulator of emotional networks in models of mental disease. GPCR-receptor tyrosine kinase (RTK) heteroreceptor complexes can operate through transactivation of FGFR1 via allosteric mechanisms and indirect interactions over GPCR intracellular pathways involving protein kinase Src which produces tyrosine phosphorylation of the RTK. The exciting discovery was made that several antidepressant drugs such as TCAs and SSRIs as well as the fast-acting antidepressant drug ketamine can directly bind to the TrkB receptor and provide a novel mechanism for their antidepressant actions. Understanding the role of astrocytes and their allosteric receptor–receptor interactions in modulating forebrain glutamate synapses with impact on dorsal raphe-forebrain serotonin neurons is also of high relevance for research on major depressive disorder.

scholarly journals The Role of Central Serotonin Neurons and 5-HT Heteroreceptor Complexes in the Pathophysiology of Depression: A Historical Perspective and Future Prospects

2021 ◽  
Vol 22 (4) ◽  
pp. 1927
Author(s):  
Dasiel O. Borroto-Escuela ◽  
Patrizia Ambrogini ◽  
Barbara Chruścicka ◽  
Maria Lindskog ◽  
Minerva Crespo-Ramirez ◽  
...  
Keyword(s):  
Major Depression ◽  
Convection Flow ◽  
Target Cells ◽  
Volume Transmission ◽  
Heteroreceptor Complexes ◽  
Oxytocin Receptors ◽  
Receptor Interactions ◽  
Serotonin Neurons ◽  
Novel Targets

Serotonin communication operates mainly in the extracellular space and cerebrospinal fluid (CSF), using volume transmission with serotonin moving from source to target cells (neurons and astroglia) via energy gradients, leading to the diffusion and convection (flow) of serotonin. One emerging concept in depression is that disturbances in the integrative allosteric receptor–receptor interactions in highly vulnerable 5-HT1A heteroreceptor complexes can contribute to causing major depression and become novel targets for the treatment of major depression (MD) and anxiety. For instance, a disruption and/or dysfunction in the 5-HT1A-FGFR1 heteroreceptor complexes in the raphe-hippocampal serotonin neuron systems can contribute to the development of MD. It leads inter alia to reduced neuroplasticity and potential atrophy in the raphe-cortical and raphe-striatal 5-HT pathways and in all its forebrain networks. Reduced 5-HT1A auto-receptor function, increased plasticity and trophic activity in the midbrain raphe 5-HT neurons can develop via agonist activation of allosteric receptor–receptor interactions in the 5-HT1A-FGFR1 heterocomplex. Additionally, the inhibitory allosteric receptor–receptor interactions in the 5-HT1AR-5-HT2AR isoreceptor complex therefore likely have a significant role in modulating mood, involving a reduction of postjunctional 5-HT1AR protomer signaling in the forebrain upon activation of the 5-HT2AR protomer. In addition, oxytocin receptors (OXTRs) play a significant and impressive role in modulating social and cognitive related behaviors like bonding and attachment, reward and motivation. Pathological blunting of the OXTR protomers in 5-HT2AR and especially in 5-HT2CR heteroreceptor complexes can contribute to the development of depression and other types of psychiatric diseases involving disturbances in social behaviors. The 5-HTR heterocomplexes are novel targets for the treatment of MD.

Therapy and prevention for mental health: What if mental diseases are mostly not brain disorders?

2019 ◽  
Vol 42 ◽  
Author(s):  
John P. A. Ioannidis
Keyword(s):  
Mental Health ◽  
Mental Disease ◽  
Brain Disorders ◽  
Social Stressors ◽  
Labor Education ◽  
Mental Diseases ◽  
Long Term Follow Up ◽  
Political Decisions

AbstractNeurobiology-based interventions for mental diseases and searches for useful biomarkers of treatment response have largely failed. Clinical trials should assess interventions related to environmental and social stressors, with long-term follow-up; social rather than biological endpoints; personalized outcomes; and suitable cluster, adaptive, and n-of-1 designs. Labor, education, financial, and other social/political decisions should be evaluated for their impacts on mental disease.

scholarly journals Examining the impact of mental disease on type 2 diabetes outcomes: results from the EpiChron Cohort

2020 ◽  
Vol 30 (Supplement_5) ◽  
Author(s):  
I Guerrero Fernández de Alba ◽  
A Gimeno-Miguel ◽  
B Poblador Plou ◽  
K Bliek Bueno ◽  
J Carmona Pirez ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Substance Abuse ◽  
Early Detection ◽  
Health Outcomes ◽  
Emergency Room ◽  
Mental Disease ◽  
Emergency Room Visits ◽  
Mental Diseases ◽  
The Impact

Abstract Background Type 2 diabetes mellitus (T2D) is often accompanied by other chronic diseases, including mental diseases (MD). This work aimed at studying MD prevalence in T2D patients and analyse its impact on T2D health outcomes. Methods Retrospective, observational study of individuals of the EpiChron Cohort aged 18 and over with prevalent T2D at baseline (2011) in Aragón, Spain (n = 63,365). Participants were categorized by the existence or absence of MD, defined as the presence of depression, anxiety, schizophrenia or substance abuse. MD prevalence was calculated, and a logistic regression model was performed to analyse the likelihood of the four studied health outcomes (4-year all-cause mortality, all-cause hospitalization, T2D-hospitalization, and emergency room visits) based on the presence of each type of MD, after adjusting by age, sex and number of comorbidities. Results Mental diseases were observed in 19% of T2D patients, with depression being the most frequent condition, especially in women (20.7% vs. 7.57%). Mortality risk was significantly higher in patients with MD (odds ratio -OR- 1.24; 95% confidence interval -CI- 1.16-1.31), especially in those with substance abuse (OR 2.18; 95% CI 1.84-2.57) and schizophrenia (OR 1.82; 95% CI 1.50-2.21). The presence of MD also increased the risk of T2D-hospitalization (OR 1.51; 95% CI 1.18-1.93), emergency room visits (OR 1.26; 95% CI 1.21-1.32) and all-cause hospitalization (OR 1.16; 95% CI 1.10-1.23). Conclusions The high prevalence of MD among T2D patients, and its association with health outcomes, underscores the importance of providing integrated, person-centred care and early detection of comorbid mental diseases in T2D patients to improve disease management and health outcomes. Key messages Comprehensive care of T2D should include specific strategies for prevention, early detection, and management of comorbidities, especially mental disorders, in order to reduce their impact on health. Substance abuse was the mental disease with the highest risk of T2D-hospitalization, emergency room visits and all-cause hospitalization.

scholarly journals EPID-36. ANTIDEPRESSANT DRUG USE IN GLIOBLASTOMA PATIENTS: AN EPIDEMIOLOGICAL VIEW

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii86-ii86
Author(s):  
Dorothee Gramatzki ◽  
James Rogers ◽  
Marian Neidert ◽  
Caroline Hertler ◽  
Emilie Le Rhun ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Drug Use ◽  
Survival Data ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Methylation Status ◽  
Antidepressant Drug ◽  
Antidepressant Drugs ◽  
Population Level ◽  
Disease Course

Abstract PURPOSE Antidepressant drugs have shown anti-tumor activity in preclinical glioblastoma studies. Antidepressant drug use, as well as its association with survival, in glioblastoma patients has not been well characterized on a population level. METHODS Patient characteristics, including the frequency of antidepressant drug use, were assessed in a glioblastoma cohort diagnosed in a 10-year time-frame between 2005 and 2014 in the Canton of Zurich, Switzerland. Cox proportional hazards regression models were applied for multivariate analysis. Kaplan-Meier survival curves were used to estimate overall survival data and the log-rank test was performed for comparisons. RESULTS Four hundred four patients with isocitrate dehydrogenase (IDH) wildtype glioblastoma were included in this study. Sixty-five patients (16.1%) took antidepressant drugs at some point during the disease course. Patients were most commonly prescribed selective serotonin reuptake inhibitors at any time (N=46, 70.8%). Nineteen patients (29.2%) were on antidepressant drugs at the time of their tumor diagnosis. No differences were observed in overall survival between those patients who had taken antidepressants at some point in their disease course and those who had not (p=0.356). These data were confirmed in a multivariate analysis including age, Karnofsky performance status, gender, extent of resection, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, and first-line treatment as cofounders (p=0.315). Also, there was no association of use of drugs modulating voltage-dependent potassium channels (citalopram; escitalopram) with survival (p=0.639). CONCLUSIONS This signal-seeking study does not support the hypothesis that antidepressants have antitumor efficacy in glioblastoma on a population level.

scholarly journals The Antidepressant Desipramine Is an Arrestin-biased Ligand at the α2A-Adrenergic Receptor Driving Receptor Down-regulation in Vitro and in Vivo

2011 ◽  
Vol 286 (41) ◽  
pp. 36063-36075 ◽  
Author(s):  
Christopher Cottingham ◽  
Yunjia Chen ◽  
Kai Jiao ◽  
Qin Wang
Keyword(s):  
Adrenergic Receptor ◽  
Antidepressant Drug ◽  
Antidepressant Drugs ◽  
Direct Interaction ◽  
Receptor Expression ◽  
Receptor Internalization ◽  
Down Regulation ◽  
Altered Expression

The neurobiological mechanisms of action underlying antidepressant drugs remain poorly understood. Desipramine (DMI) is an antidepressant classically characterized as an inhibitor of norepinephrine reuptake. Available evidence, however, suggests a mechanism more complex than simple reuptake inhibition. In the present study, we have characterized the direct interaction between DMI and the α2A-adrenergic receptor (α2AAR), a key regulator of noradrenergic neurotransmission with altered expression and function in depression. DMI alone was found to be sufficient to drive receptor internalization acutely and a robust down-regulation of α2AAR expression and signaling following prolonged stimulation in vitro. These effects are achieved through arrestin-biased regulation of the receptor, as DMI selectively induces recruitment of arrestin but not activation of heterotrimeric G proteins. Meanwhile, a physiologically relevant concentration of endogenous agonist (norepinephrine) was unable to sustain a down-regulation response. Prolonged in vivo administration of DMI resulted in significant down-regulation of synaptic α2AAR expression, a response that was lost in arrestin3-null animals. We contend that direct DMI-driven arrestin-mediated α2AAR down-regulation accounts for the therapeutically desirable but mechanistically unexplained adaptive alterations in receptor expression associated with this antidepressant. Our results provide novel insight into both the pharmacology of this antidepressant drug and the targeting of the α2AAR in depression.

Adverse Drug Reaction Monitoring of Antidepressant Drugs in a Mental Health Institute in Odisha

2021 ◽  
pp. 6479-6483
Author(s):  
Priti Das ◽  
Jyotiranjan Nayak ◽  
Sarada Prasanna Swain
Keyword(s):  
Mental Health ◽  
Causality Assessment ◽  
Antidepressant Drug ◽  
Antidepressant Drugs ◽  
Cross Sectional ◽  
Adverse Drug Reaction Monitoring ◽  
Health Institute ◽  
Medical College ◽  
Centre Of Excellence ◽  
Mental Health Institute

Introduction: Antidepressants are used primarily in the management of depressive and anxiety disorders. The occurrence of adverse drug reactions (ADRs) to antidepressants is a major challenge as it influences patient compliance. Aim: The aim of this study was to find out the ADR profile of antidepressant drugs in a mental health institute in Odisha. Materials and Methods: This is a cross sectional observational study conducted in Department of Pharmacology in collaboration with Mental Health Institute (Centre of Excellence) S.C.B Medical College and Hospital, Cuttack from September 2017 to September 2019. Patients who received at least one antidepressant drug were included in the study irrespective of age and sex. Data were collected by interviewing the patients or attendants and on detection of ADR, it was recorded on suspected ADR reporting form designed by PvPI. Causality, severity and preventability of ADRs were assessed by, WHO-UMC causality assessment, modified Hartwig-Siegel Scale and modified Schumock-Thornton criteria respectively. Results: Out of 180 patients taking antidepressants, ADRs were reported in 24% of patients, with either possible or probable causality. None were labelled as certain. ADRs were observed in 50% of patients who received TCAs and among 34.5% who received polytherapy. Insomnia (27%), fatigue (17%) and agitation (13%) were most common ADRs. Most of the ADRs were of mild severity (91%) and not preventable (84%). Conclusion: Insomnia, fatigue and agitation were among most common ADRs. There was increased chance of ADRs with polytherapy and use of TCAs. Most ADRs were mild and not preventable.

Thymoquinone lipid nanoparticles cut the Gordian knots of depression via neuroprotective BDNF and downregulation of neuro-inflammatory NF-κB, IL-6, and TNF-α in LPS treated rats

2021 ◽  
Vol 22 ◽  
Author(s):  
Mahtab Alam ◽  
Md Noushad Javed ◽  
Abul Kalam Najmi ◽  
Farhan Jalees Ahmad ◽  
Syed Sarim Imam ◽  
...  
Keyword(s):  
Symptomatic Relief ◽  
Antidepressant Drug ◽  
Antidepressant Drugs ◽  
Tail Suspension Test ◽  
Signaling Mechanism ◽  
Force Swimming Test ◽  
Immobility Time ◽  
Rest Time ◽  
Horizontal Activity ◽  
Total Movement

Background: In over 300 million clinical cases, antidepressant drugs seem to provide only symptomatic relief and limited protection in life-threatening depressive events. Objective: To compare neuronal-signaling mechanism and neuroprotective roles of Thymoquinone (TQ) suspension and its SLN (TQSLN) against standard antidepressant drug fluoxetine. Results: As compared to fluoxetine, TQ reporteda significantly better docking score (-6.83 v/s -6.22) and a better lower free binding energy of (-34.715 Kcal/mol v/s -28.537 Kcal/mol). While poorly oral bioavailable and P-gp substrate TQ reported approximately 250% higher gut permeation if delivered as TQSLN formulation. In locomotor studies, as compared to TQS, TQSLN favored more prominent (p < 0.010) elevation in average time, horizontal-activity, average-velocity, and total-movement with reduced rest time LPS treated groups. However, in the tail suspension test, TQSLN significantly reduced immobility time (p<0.010). Similarly, In the modified force swimming test, TQSLN also significantly reduced immobility time (p<0.010), but swimming time (p<0.010) and climbing time (p<0.050) were significantly elevated. Conclusion: Despite the poor bioavailability of TQ, TQSLN potentially attenuates neuroinflammatory transmitters and favors BDNF to modulate depressive neurobehavioral states.

Pharmacokinetic factors affecting antidepressant drug clearance and clinical effect: evaluation of doxepin and imipramine--new data and review.

1988 ◽  
Vol 34 (5) ◽  
pp. 863-880 ◽  
Author(s):  
L Ereshefsky ◽  
T Tran-Johnson ◽  
C M Davis ◽  
A LeRoy
Keyword(s):  
Dietary Habits ◽  
Antidepressant Drug ◽  
Antidepressant Drugs ◽  
Drug Clearance ◽  
Metabolic Phenotype ◽  
Therapeutic Monitoring ◽  
Fixed Dose ◽  
Oral Clearance ◽  
Clearance Rates ◽  
Factors Affecting

Abstract The selection of a starting dose for an antidepressant, and subsequent clinical titration to an appropriate therapeutic dosage, should be based on pharmacokinetic and pharmacodynamic principles. In the past decade, therapeutic monitoring of antidepressant drugs and use of pharmacokinetic principles have been shown to be an improvement over the dose-response approach. Endogenous (e.g., genetic metabolic phenotype, hepatic blood flow, and protein binding) and exogenous factors (e.g., smoking, dietary habits, concurrent medications) are capable of influencing physiological and pharmacokinetic variables in patients, accounting for the marked interindividual differences in the clearance rates of cyclic antidepressants. Interpatient variability for steady-state concentrations in plasma (Cpss) greater than 20-fold are observed at a fixed dose of imipramine (r2 = 0.525, df = 346, t = 19.541, P less than 0.0001) or doxepin (r2 = 0.506, df = 128, t = 11.403, P less than 0.0001). Analysis of doxepin in plasma vs estimated in oral clearance for 61 patients demonstrates a significant decline in oral clearance as a function of Cpss. At doses approaching the upper range recommended for the treatment of depression, Cpss appear to approach, in at least a few individuals, the maximum metabolic capacity of the patient (Vmax), leading to greater-than-expected increases in concentrations for a given dosage increment. Significant alterations in oral clearance are observed when medications are administered concomitantly. A greater-than-threefold difference in mean oral doxepin clearance rates is observed between two groups of patients receiving additional medications that are either inducers or inhibitors (P less than 0.0001, df = 32, t = 6.687). Pharmacokinetic principles defining and explaining the determinants of oral clearance can provide the clinician with a greater insight into the reasons for therapeutic failure and toxicity.

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