Mechanisms and molecular targets surrounding the potential therapeutic effects of psychedelics.

Psychedelics, also known as classical hallucinogens, have been investigated for decades due to their potential therapeutic effects in the treatment of neuropsychiatric and substance use disorders. The results from clinical trials have shown promise for the use of psychedelics to alleviate symptoms of depression and anxiety, as well as to promote substantial decreases in the use of nicotine and alcohol. While these studies provide compelling evidence for the powerful subjective experience and prolonged therapeutic adaptations, the underlying molecular reasons for these robust and clinically meaningful improvements are still poorly understood. Preclinical studies assessing the targets and circuitry of the post-acute effects of classical psychedelics are ongoing. Current literature is split between a serotonin 5-HT2A receptor (5-HT2AR)-dependent or -independent signaling pathway, as researchers are attempting to harness the mechanisms behind the sustained post-acute therapeutically relevant effects. A combination of molecular, behavioral, and genetic techniques in neuropharmacology has begun to show promise for elucidating these mechanisms. As the field progresses, increasing evidence points towards the importance of the subjective experience induced by psychedelic-assisted therapy, but without further cross validation between clinical and preclinical research, the why behind the experience and its translational validity may be lost.

Brilaroxazine lipogel displays antipsoriatic activity in imiquimod-induced mouse model.

BACKGROUND: Dopamine (D) and serotonin (5-HT) pathways contribute to psoriasis pathobiology. Disruptions incite increased inflammatory mediators, keratinocyte activation and deterioration, and worsening symptoms. Brilaroxazine (RP5063), which displays potent high binding affinity to D2/3/4 and 5-HT1A/2A/2B/7 receptors and a moderate affinity to serotonin transporter (SERT), may affect the underlying psoriasis pathology. METHODS: An imiquimod-induced psoriatic mouse model (BALB/c) evaluated brilaroxazine's activity in a topical liposomal-aqueous gel (Lipogel) formulation. Two of the three groups (n = 6 per) underwent induction with 5% imiquimod, and one group received topical brilaroxazine Lipogel (Days 1-11). Assessments included (1) Psoriasis Area and Severity Index (PASI) scores (Days 1-12), skin histology for Baker score based on H&E stained tissue (Day 12), and serum blood collection for serum cytokine analysis (Day 12). One-way ANOVA followed by post hoc Dunnett's t-test evaluated significance (p < 0.05). RESULTS: Imiquimod-induced animal Baker scores were higher versus Sham non-induced control's results (p < 0.001). Brilaroxazine Lipogel had significantly (p = 0.003) lower Baker scores versus the induced Psoriasis group. Brilaroxazine PASI scores were lower (p = 0.03) versus the induced Psoriasis group (Days 3-12), with the greatest effect in the last 3 days. The induced Psoriasis group showed higher Ki-67 and TGF-ß levels versus non-induced Sham controls (p = 0.001). The brilaroxazine Lipogel group displayed lower levels of these cytokines versus the induced Psoriasis group, Ki-67 (p = 0.001) and TGF-ß (p = 0.008), and no difference in TNF-α levels versus Sham non-induced controls. CONCLUSION: Brilaroxazine Lipogel displayed significant activity in imiquimod-induced psoriatic animals, offering a novel therapeutic strategy.

A Review of the Cardiovascular Safety of Prucalopride in Patients With Chronic Idiopathic Constipation.

Prokinetic agents, specifically 5-hydroxytryptamine type 4 (5-HT 4 ) receptor agonists, have been shown to provide relief in chronic idiopathic constipation (CIC). The first-generation 5-HT 4 agonists were initially withdrawn from use owing to associations with serious cardiovascular (CV) events. This review summarizes CV safety data for prucalopride, a high-affinity 5-HT 4 agonist approved in the United States in 2018 for adults with CIC. No significant effects of prucalopride on CV safety were observed in animal models or early-phase clinical studies, including a thorough QT study at therapeutic (2 mg) or supratherapeutic (10 mg) doses. Among 1,750 patients with CIC who received prucalopride (2-4 mg) in 5 phase 3 studies, no trends in CV adverse events, electrocardiogram parameters, or blood pressure were documented; ≤1.0%-2.0% of patients had prolonged QT interval corrected for heart rate (HR) using Fridericia formula after placebo or prucalopride treatment, and low HR occurred in ≤6.1% and ≤3.3% of these patients, respectively. In two 24-month observational studies among 2,468 patients, changes in electrocardiogram parameters over time were minor, except at occasional time points when significant changes from baseline were reported for HR or QT interval. In a real-world European CV safety study among 35,087 patients (prucalopride, 5,715; polyethylene glycol 3350 [PEG3350], 29,372), results were consistent for no evidence of increased risk of major adverse CV events among patients treated with prucalopride vs PEG3350 (incidence rate ratio = 0.64; 95% confidence interval 0.36-1.14). Studies to date have not raised concerns regarding the impact of prucalopride treatment on CV parameters.

Amitriptyline inhibits bronchoconstriction and directly promotes dilatation of the airways.

INTRODUCTION: The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß2-sympathomimetics) and, depending on the severity of disease, additional long-term treatment (including inhaled glucocorticoids, long-acting ß2-sympathomimetics, anticholinergics, anti-IL-4R antibodies). The antidepressant amitriptyline has been identified as a relevant down-regulator of immunological TH2-phenotype in asthma, acting-at least partially-through inhibition of acid sphingomyelinase (ASM), an enzyme involved in sphingolipid metabolism. Here, we investigated the non-immunological role of amitriptyline on acute bronchoconstriction, a main feature of airway hyperresponsiveness in asthmatic disease. METHODS: After stimulation of precision cut lung slices (PCLS) from mice (wildtype and ASM-knockout), rats, guinea pigs and human lungs with mediators of bronchoconstriction (endogenous and exogenous acetylcholine, methacholine, serotonin, endothelin, histamine, thromboxane-receptor agonist U46619 and leukotriene LTD4, airway area was monitored in the absence of or with rising concentrations of amitriptyline. Airway dilatation was also investigated in rat PCLS by prior contraction induced by methacholine. As bronchodilators for maximal relaxation, we used IBMX (PDE inhibitor) and salbutamol (ß2-adrenergic agonist) and compared these effects with the impact of amitriptyline treatment. Isolated perfused lungs (IPL) of wildtype mice were treated with amitriptyline, administered via the vascular system (perfusate) or intratracheally as an inhalation. To this end, amitriptyline was nebulized via pariboy in-vivo and mice were ventilated with the flexiVent setup immediately after inhalation of amitriptyline with monitoring of lung function. RESULTS: Our results show amitriptyline to be a potential inhibitor of bronchoconstriction, induced by exogenous or endogenous (EFS) acetylcholine, serotonin and histamine, in PCLS from various species. The effects of endothelin, thromboxane and leukotrienes could not be blocked. In acute bronchoconstriction, amitriptyline seems to act ASM-independent, because ASM-deficiency (Smdp1-/-) did not change the effect of acetylcholine on airway contraction. Systemic as well as inhaled amitriptyline ameliorated the resistance of IPL after acetylcholine provocation. With the flexiVent setup, we demonstrated that the acetylcholine-induced rise in central and tissue resistance was much more marked in untreated animals than in amitriptyline-treated ones. Additionally, we provide clear evidence that amitriptyline dilatates pre-contracted airways as effectively as a combination of typical bronchodilators such as IBMX and salbutamol. CONCLUSION: Amitriptyline is a drug of high potential, which inhibits acute bronchoconstriction and induces bronchodilatation in pre-contracted airways. It could be one of the first therapeutic agents in asthmatic disease to have powerful effects on the TH2-allergic phenotype and on acute airway hyperresponsiveness with bronchoconstriction, especially when inhaled.

Brain serotonin 1A receptor binding: relationship to peripheral blood DNA methylation, recent life stress and childhood adversity in unmedicated major depression.

BACKGROUND: Childhood and lifetime adversity may reduce brain serotonergic (5-HT) neurotransmission by epigenetic mechanisms. AIMS: We tested the relationships of childhood adversity and recent stress to serotonin 1A (5-HT1A) receptor genotype, DNA methylation of this gene in peripheral blood monocytes and in vivo 5-HT1A receptor binding potential (BPF) determined by positron emission tomography (PET) in 13 a priori brain regions, in participants with major depressive disorder (MDD) and healthy volunteers (controls). METHOD: Medication-free participants with MDD (n = 192: 110 female, 81 male, 1 other) and controls (n = 88: 48 female, 40 male) were interviewed about childhood adversity and recent stressors and genotyped for rs6295. DNA methylation was assayed at three upstream promoter sites (-1019, -1007, -681) of the 5-HT1A receptor gene. A subgroup (n = 119) had regional brain 5-HT1A receptor BPF quantified by PET. Multi-predictor models were used to test associations between diagnosis, recent stress, childhood adversity, genotype, methylation and BPF. RESULTS: Recent stress correlated positively with blood monocyte methylation at the -681 CpG site, adjusted for diagnosis, and had positive and region-specific correlations with 5-HT1A BPF in participants with MDD, but not in controls. In participants with MDD, but not in controls, methylation at the -1007 CpG site had positive and region-specific correlations with binding potential. Childhood adversity was not associated with methylation or BPF in participants with MDD. CONCLUSIONS: These findings support a model in which recent stress increases 5-HT1A receptor binding, via methylation of promoter sites, thus affecting MDD psychopathology.

Reversal and Preventive Pleiotropic Mechanisms Involved in the Antipsychotic-Like Effect of Taurine, an Essential ß-Amino Acid in Ketamine-Induced Experimental Schizophrenia in Mice.

Schizophrenia is a life disabling, multisystem neuropsychiatric disease mostly derived from complex epigenetic-mediated neurobiological changes causing behavioural deficits. Neurochemical disorganizations, neurotrophic and neuroimmune alterations are some of the challenging neuropathologies proving unabated during psychopharmacology of schizophrenia, further bedeviled by drug-induced metabolic derangements including alteration of amino acids. In first-episode schizophrenia patients, taurine, an essential ß-amino acid represses psychotic-symptoms. However, its anti-psychotic-like mechanisms remain incomplete. This study evaluated the ability of taurine to prevent or reverse ketamine-induced experimental psychosis and the underlying neurochemical, neurotrophic and neuroinmune mechanisms involved in taurine's clinical action. The study consisted of three different experiments with Swiss mice (n = 7). In the drug alone, mice received saline (10 mL/kg/p.o./day), taurine (50 and 100 mg/kg/p.o./day) and risperidone (0.5 mg/kg/p.o./day) for 14 days. In the preventive study of separate cohort, mice were concomitantly given ketamine (20 mg/kg/i.p./day) from days 8 to 14. In the reversal study, mice received ketamine for 14 days before taurine or risperidone treatments from days 8 to 14 respectively. Afterwards, stereotypy behaviour, social, non-spatial memory deficits, and body weights were assessed. Neurochemical (dopamine, 5-hydroxytryptamine, glutamic acid decarboxylase, (GAD)), brain derived-neurotrophic factor (BDNF) and pro-inflammatory cytokines [tumor necrosis factor-alpha, (TNF-α), interleukin-6, (IL-6)] were assayed in the striatum, prefrontal-cortex and hippocampal area. Taurine attenuates ketamine-induced schizophrenia-like behaviour without changes in body weight. Taurine reduced ketamine-induced dopamine and 5-hydroxytryptamine changes, and increased GAD and BDNF levels in the striatum, prefrontal-cortex and hippocampus, suggesting increased GABAergic and neurotrophic transmissions. Taurine decreases ketamine-induced increased in TNF-α and IL-6 concentrations in the striatum, prefrontal-cortex and hippocampus. These findings also suggest that taurine protects against schizophrenia through neurochemical modulations, neurotrophic enhancement, and inhibition of neuropathologic cytokine activities.

Isopropyl alcohol inhalation versus 5-HT3 antagonists for treatment of nausea: a meta-analysis of randomised controlled trials.

PURPOSE: Nausea is a common and unpleasant sensation for which current therapies such as serotonin (5-HT3) antagonists are often ineffective, while also conferring a risk of potential adverse events. Isopropyl alcohol (IPA) has been proposed as a treatment for nausea. We aimed to compare IPA with 5-HT3 antagonists for the treatment of nausea across all clinical settings. METHODS: MEDLINE, EMBASE, PubMed, CENTRAL and CINAHL were searched from inception to 17 July 2023 for randomised controlled trials (RCTs) comparing inhaled IPA and a 5-HT3 antagonist for treatment of nausea. Severity and duration of nausea, rescue antiemetic use, adverse events and patient satisfaction were the outcomes sought. Risk of bias (RoB) was assessed using Cochrane RoB 2. Random-effects model was used for meta-analysis. Combination of meta-analyses and narrative review was used to synthesise findings. The evidence was appraised using GRADE. RESULTS: From 1242 records, 4 RCTs were included with 382 participants. Participants receiving IPA had a significantly lower mean time to 50% reduction in nausea (MD - 20.06; 95% CI - 26.26, - 13.85). Nausea score reduction at 30 min was significantly greater in the IPA group (MD 21.47; 95% CI 15.47, 27.47). IPA led to significantly reduced requirement for rescue antiemetics (OR 0.60; 95% CI 0.37, 0.95; p = 0.03). IPA led to no significant difference in patient satisfaction when compared with a 5-HT3 antagonist. The overall GRADE assessment of evidence quality ranged from very low to low. CONCLUSION: IPA may provide rapid, effective relief of nausea when compared with 5-HT3 antagonists.

Houpo paiqi mixture promotes intestinal motility in constipated rats by modulating gut microbiota and activating 5-HT-cAMP-PKA signal pathway.

AIMS: Constipation is a common functional gastrointestinal disorder, which needs more effective treatment approaches. Houpo Paiqi Mixture (HPPQM) is a type of Chinese patent medicine developed from a classical formula that has been widely applied to the treatment of intestinal motility disorder. Here we aim to assess the effectiveness of HPPQM in the treatment of constipation in rat models and its potential mechanism. METHODS AND RESULTS: UPLC-MS/MS was performed to investigate the chemical component of HPPQM. Rats were randomly divided into normal control, constipation model (CM), HPPQM (low, middle and high dose) and mosapride groups. Loperamide 8 mg/kg was given orally to induce CM. The small intestine motility, colonic contraction, rectum propulsion, and histological feature of the colon were significantly improved in HPPQM group, compared with CM group (P < 0.05). Results of 16S rRNA sequencing revealed that HPPQM treatment strikingly restructured intestinal microbiota in constipated rats by increasing the relative abundances of Bacteroides and Akkermansia and decreasing the relative abundances of Prevotella and Lactobacillus. The levels of GPR43, 5-HT, 5-HT4R, cAMP, PKA were decreased while SERT was increased in constipated rats (P < 0.05), which could be restored to normal levels by treatment with HPPQM (P < 0.05). Differences in amplitude between experimental CLSMs (with HPPQM added) and control CLSMs were discovered, starting at the concentration of 40 nL/mL (P < 0.05). It was found that GLPG0974 and GR113808 could significantly reduce this reactivity (P < 0.05). CONCLUSIONS: HPPQM manifested a curative effect in constipated rats by promoting intestinal motility. The underlying mechanisms might be related to modulating gut microbiota and activating 5-HT-cAMP-PKA signal pathway.

Serotonin reuptake inhibition for the prevention of vasovagal syncope: a systematic review and meta-analysis.

PURPOSE: Vasovagal syncope is a common clinical condition that lacks effective medical therapies despite being associated with significant morbidity. Current guidelines suggest that serotonin-specific reuptake inhibitors might suppress vasovagal syncope but supporting studies have been small and heterogenous. The purpose of this study was to evaluate the efficacy of serotonin-specific reuptake inhibitors to prevent syncope in patients with recurrent vasovagal syncope by conducting a systematic review and meta-analysis of published studies. METHODS: Relevant randomized controlled trials were identified from the MEDLINE and Embase databases without language restriction from inception to August 2022, and ClinicalTrials.gov. All studies were conducted in clinical syncope populations and compared the benefit of serotonin versus placebo. Weighted relative risks were estimated using random effects meta-analysis techniques. RESULTS: Three studies (n = 204) met inclusion criteria. Patients were 42 ± 13 years of age and 51% female. Serotonin-specific reuptake inhibitors were found to substantially reduce the likelihood of a patient having at least one recurrence of vasovagal syncope [relative risk (RR) 0.34 (0.20-0.60), p < 0.01] with minimal between-study heterogeneity (I2 = 0%, p = 0.67). Serotonin-specific reuptake inhibitors in two reports provided significant protection against clinical presyncope [RR 0.43 (0.24-0.77), p < 0.01], with minimal between-study heterogeneity (I2 = 0%, p = 0.80). CONCLUSIONS: Serotonin-specific reuptake inhibitors may be effective in preventing syncope induced by head-up tilt testing and in syncope in the community in randomized, double-blinded clinical trials.

Novel multi-target ligands of dopamine and serotonin receptors for the treatment of schizophrenia based on indazole and piperazine scaffolds-synthesis, biological activity, and structural evaluation.

Schizophrenia is a chronic mental disorder that is not satisfactorily treated with available antipsychotics. The presented study focuses on the search for new antipsychotics by optimising the compound D2AAK3, a multi-target ligand of G-protein-coupled receptors (GPCRs), in particular D2, 5-HT1A, and 5-HT2A receptors. Such receptor profile may be beneficial for the treatment of schizophrenia. Compounds 1-16 were designed, synthesised, and subjected to further evaluation. Their affinities for the above-mentioned receptors were assessed in radioligand binding assays and efficacy towards them in functional assays. Compounds 1 and 10, selected based on their receptor profile, were subjected to in vivo tests to evaluate their antipsychotic activity, and effect on memory and anxiety processes. Molecular modelling was performed to investigate the interactions of the studied compounds with D2, 5-HT1A, and 5-HT2A receptors on the molecular level. Finally, X-ray study was conducted for compound 1, which revealed its stable conformation in the solid state.

Survey-Based Analysis of the Clinical Treatment Status of Irritable Bowel Syndrome in Korea.

BACKGROUND: The quality-of-life of patients with irritable bowel syndrome is low; incorrect diagnosis/treatment causes economic burden and inappropriate consumption of medical resources. This survey-based study aimed to analyze the current status of irritable bowel syndrome treatment to examine differences in doctors' perceptions of the disease, and treatment patterns. METHODS: From October 2019 to February 2020, the irritable bowel syndrome and Intestinal Function Research Study Group of the Korean Society of Neurogastroenterology and Motility conducted a survey on doctors working in primary, secondary, and tertiary healthcare institutions. The questionnaire included 37 items and was completed anonymously using the NAVER platform (a web-based platform), e-mails, and written forms. RESULTS: A total of 272 doctors responded; respondents reported using the Rome IV diagnostic criteria (amended in 2016) for diagnosing and treating irritable bowel syndrome. Several differences were noted between the primary, secondary, and tertiary physicians' groups. The rate of colonoscopy was high in tertiary healthcare institutions. During a colonoscopy, the necessity of random biopsy was higher among physicians who worked at tertiary institutions. 'The patient did not adhere to the diet' as a reason for ineffectiveness using low-fermentable oligo-, di-, and mono-saccharides, and polyols diet treatment was higher among physicians in primary/secondary institutions, and 'There are individual differences in terms of effectiveness' was higher among physicians in tertiary institutions. In irritable bowel syndrome constipation predominant subtype, the use of serotonin type 3 receptor antagonist (ramosetron) and probiotics was higher in primary/secondary institutions, while serotonin type 4 receptor agonist was used more in tertiary institutions. In irritable bowel syndrome diarrhea predominant subtype, the use of antispasmodics was higher in primary/secondary institutions, while the use of serotonin type 3 receptor antagonist (ramosetron) was higher in tertiary institutions. CONCLUSION: Notable differences were observed between physicians in primary/secondary and tertiary institiutions regarding the rate of colonoscopy, necessity of random biopsy, the reason for the ineffectiveness of low-fermentable oligo-, di-, and mono-saccharides, and polyols diet, and use of drug therapy in irritable bowel syndrome. In South Korea, irritable bowel syndrome is diagnosed and treated according to the Rome IV diagnostic criteria, revised in 2016.

In Vivo Evaluation of Almotriptan malate Formulation through Intranasal Route for the Treatment of Migraine: Systematic Development and Pharmacokinetic Assessment.

Migraine headaches are usually intolerable, and a quick-relief treatment remains an unmet medical need. Almotriptan malate is a serotonin (5-HT1B/1D) receptor agonist approved for the treatment of acute migraine in adults. It is currently available in an oral tablet dosage form and has a Tmax of 1-3 h, and therefore, there is a medical need to develop a non-invasive rapidly acting formulation. We have developed an intranasal formulation of almotriptan malate using the quality-by-design (QbD) approach. A 2-factor 3-level full factorial design was selected to build up the experimental setting. The developed formulation was characterized for pH, viscosity, in vitro permeation, ex vivo permeation, and histopathological tolerance. To assess the potential of the developed formulation to produce a rapid onset of action following intranasal delivery, a pharmacokinetic study was performed in the Sprague-Dawley rat model and compared to the currently available marketed oral tablet formulation. For this, the LC-MS/MS bioanalytical method was developed and used for the determination of plasma almotriptan malate concentrations. Results of a pharmacokinetic study revealed that intranasal administration of optimized almotriptan malate formulation enabled an almost five-fold reduction in Tmax and about seven-fold increase in bioavailability in comparison to the currently available oral tablet formulation, suggesting the potential of developed almotriptan malate intranasal formulation in producing a rapid onset of action as well as enhanced bioavailability.

Tegaserod: What's Old Is New Again.

Irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) are common gastrointestinal disorders imposing considerable impact on the quality of life and well-being of affected individuals. A paucity of evidence-based treatment options exist for CIC and IBS-C sufferers. Tegaserod, a 5-HT4 agonist, has a substantial body of preclinical and clinical study evidence to support its beneficial role in modulating sensorimotor function of the luminal gastrointestinal tract. Tegaserod was first approved for use by the U.S. Food and Drug Administration for the management of IBS-C and CIC in 2002 and 2004, respectively. Tegaserod enjoyed a successful uptake in the management of these disorders during its first several years of availability in the United States, but was later withdrawn from the market in 2007 over concerns related to adverse cardiovascular events. Since then, additional safety data has been generated, and following a resubmission and review by the Food and Drug Administration, in April 2019, tegaserod was once again approved for use in IBS-C under a more restricted labeling, confining use to women under 65 years of age without heart disease or additional cardiovascular risk factors. This review summarizes the regulatory journey of tegaserod and details the existing pharmacokinetic, physiologic, clinical, and safety data of tegaserod generated over the last 2 decades. The discussion also examines the future of tegaserod in the treatment of these constipation disorders, as well as its potential role in other related disorders of brain-gut interaction.

ERICH3: vesicular association and antidepressant treatment response.

Selective serotonin reuptake inhibitors (SSRIs) are standard of care for major depressive disorder (MDD) pharmacotherapy, but only approximately half of these patients remit on SSRI therapy. Our previous genome-wide association study identified a single-nucleotide polymorphism (SNP) signal across the glutamate-rich 3 (ERICH3) gene that was nearly genome-wide significantly associated with plasma serotonin (5-HT) concentrations, which were themselves associated with SSRI response for MDD patients enrolled in the Mayo Clinic PGRN-AMPS SSRI trial. In this study, we performed a meta-analysis which demonstrated that those SNPs were significantly associated with SSRI treatment outcomes in four independent MDD trials. However, the function of ERICH3 and molecular mechanism(s) by which it might be associated with plasma 5-HT concentrations and SSRI clinical response remained unclear. Therefore, we characterized the human ERICH3 gene functionally and identified ERICH3 mRNA transcripts and protein isoforms that are highly expressed in central nervous system cells. Coimmunoprecipitation identified a series of ERICH3 interacting proteins including clathrin heavy chain which are known to play a role in vesicular function. Immunofluorescence showed ERICH3 colocalization with 5-HT in vesicle-like structures, and ERICH3 knock-out dramatically decreased 5-HT staining in SK-N-SH cells as well as 5-HT concentrations in the culture media and cell lysates without changing the expression of 5-HT synthesizing or metabolizing enzymes. Finally, immunofluorescence also showed ERICH3 colocalization with dopamine in human iPSC-derived neurons. These results suggest that ERICH3 may play a significant role in vesicular function in serotonergic and other neuronal cell types, which might help explain its association with antidepressant treatment response.

Dose-Response Relationship in Selective Serotonin and Norepinephrine Reuptake Inhibitors in the Treatment of Major Depressive Disorder: A Meta-Analysis and Network Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Selective serotonin and norepinephrine reuptake inhibitors (SNRI) are among the most prescribed antidepressants, and dose escalation is a frequently applied strategy after non-response to an initially prescribed dose. OBJECTIVE: This meta-analysis aimed to find evidence of a dose-response relationship or to the contrary in direct comparisons of different SNRI doses in patients with major depressive disorder. METHODS: A systematic literature search for RCTs comparing at least two doses of SNRIs was carried out in CENTRAL, PubMed, PsycINFO, and EMBASE. Doses were classified as high, medium, and low according to manufacturers' product monographs and analyses at the level of SNRIs as a group and for single substances, accompanied by sensitivity network meta-analyses (Prospero CRD42018081031). RESULTS: From 2,070 studies screened, we included 26 studies with a total of 10,242 patients. Comparisons of medium versus low and high versus medium doses resulted in clinically and statistically non-significant standardized mean differences of -0.06 (-0.16 to 0.04) and -0.06 (-0.16 to 0.03) in favor of higher doses. In the analyses of single substances, no statistically significant results emerged, and many contrasts yielded very small effect sizes. Dropouts due to side effects tended to be more frequent with higher doses. Heterogeneity was low. Network meta-analyses of direct comparisons supported the findings, as did a risk of bias analysis. CONCLUSION: Based on the lack of positive evidence for a dose-response relationship in SNRIs as a group and in single SNRIs, we recommend prescribing medium doses. In case of insufficient response, we do not recommend increasing the dose of SNRIs.

The Effects of Pain and Analgesic Medications on Blood Pressure.

PURPOSE OF REVIEW: To review the blood pressure (BP) effects of pain and analgesic medications and to help interpret BP changes in people suffering from acute or chronic pain. RECENT FINDINGS: Acute pain evokes a stress response which prompts a transient BP increase. Chronic pain is associated with impaired regulation of cardiovascular and analgesia systems, which may predispose to persistent BP elevation. Also analgesics may have BP effects, which vary according to the drug class considered. Data on paracetamol are controversial, while multiple studies indicate that non-steroidal anti-inflammatory drugs may increase BP, with celecoxib showing a lesser impact. Hypotension has been reported with opioid drugs. Among adjuvants, tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors could be pro-hypertensive due to potentiation of adrenergic transmission. Pain and analgesics may induce a clinically significant BP destabilization. The implications on hypertension incidence and BP control remain unclear and should be explored in future studies.

Advances in sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is the major cause of premature death in epilepsy patients, particularly those with refractory epilepsy. Sudden unexpected death in epilepsy is thought to be related to peri-ictal cardiac dysfunction, respiratory depression, and autonomic dysfunction, albeit the exact etiology is unknown. Sudden unexpected death in epilepsy prevention remains a huge challenge. The sole presence and frequency of generalized tonic-clonic seizures (GTCS) are the most important risk factors for SUDEP, and nocturnal monitoring may lower the risk with the use of remote listening devices. In addition, studies in animal models of SUDEP have discovered that multiple neurotransmitters, including serotonin (5-HT) and adenosine, may be involved in the pathophysiological mechanisms of SUDEP and that these neurotransmitters could be the targets of future pharmacological intervention for SUDEP. The latest research findings on the epidemiology, clinical risk factors, and probable causes of SUDEP are presented in this review.

Effect of ondansetron for preventing of ovarian hyperstimulation syndrome: in an experimental rat model.

Objective: Ovarian hyperstimulation syndrome is an iatrogenic condition that occurs in the treatment of infertility. There is no specific treatment available for OHSS. Cabergoline is a dopamine receptor 2 agonist and VEGF-VEGF2 receptor antagonist . Recently, cabergoline has been widely used to prevent the development of OHSS and reduce its severity Serotonin is known as a neurotransmitter and thought to have a role in the mechanism of angiogenesis and in signaling in endothelial cells. Serotonin is said to have similar effects to VEGF . Ondansetron is Selective Serotonin (5-HT3) Receptor Antagonist . It works by blocking the action of serotonin, a natural substance that may cause nausea and vomiting. In the clinical practice today, there is no choice other than cabergoline, to prevent occurrence and reduce severity of OHSS, and sometimes its effects are limited. Methods: In our study, we compared the effect of cabergoline and ondansetron. 32 immature rats were used and the OHSS model was created. Parameters such as hematocrit value , ovarian size, the number of follicles in the ovary, endometrial capillary congestion and thickness values were evaluated and compared. Results: As a result, in our study, it was seen that ondansetron was effective on OHSS in many parameters. It is thought to be as effective as cabergoline. When we look at the literature, this is the first study in which ondansetron was evaluated for this purpose. It would be good to show this effect of ondansetron with other studies.

The role of serotonin in pathogenesis of unclassified irritable bowel syndrome.

The pathogenesis of irritable bowel syndrome (IBS) has not been clearly understood. Numerous factors, including neurotransmitters, can interfere with the functions of the digestive tract. AIM: The aim of present study was to determine the secretion and metabolism of serotonin in patients with unclassified irritable bowel syndrome (IBS-U). MATERIALS AND METHODS: The study included 50 healthy subjects (Controls) and 50 patients with IBS-U, diagnosed according to Rome IV Criteria of functional gastrointestinal disorders. The severity of gastrointestinal symptoms was assessed using the Gastrointestinal Symptom Rating Scale (GSRS- IBS). The quality of sleep was estimated by Insomnia Severity Index (ISI). The serum serotonin and melatonin levels and 5-hydroxyindoleacetic acid (5-HIAA) and 6-sulfatoxymelatonin (aMT6s) concentration in urine were determined with ELISA method. RESULTS: Compared to control group, patients with IBS-U had a higher serum levels (201.3 ± 37.8 vs 145.4 ± 36.9 ng/ml, p < 0.001) and lower levels of melatonin (5.86 ± 1,16 vs9.11 ±2.43 pg/ml, p < 0.001). Likewise, in IBS-U patients urinary excretion of 5-HIAA was greater, while aMT6s excretion was lower. Due to the above changes cyproheptadine (6 mg daily) or melatonin (7 mg daily) was recommended to be taken. After 12 weeks of taking cyproheptadine, the IBS symptoms disappeared in 86.6% patients, and in 20.0% of those taking melatonin. Both drugs improved sleep in equal measure. CONCLUSIONS: Increased serotonin secretion may be the cause of abdominal complaints in unclassified irritable bowel syndrome, what should be considered in its treatment.

Opposite effects of dopamine and serotonin on resting-state networks: review and implications for psychiatric disorders.

Alterations in brain intrinsic activity-as organized in resting-state networks (RSNs) such as sensorimotor network (SMN), salience network (SN), and default-mode network (DMN)-and in neurotransmitters signaling-such as dopamine (DA) and serotonin (5-HT)-have been independently detected in psychiatric disorders like bipolar disorder and schizophrenia. Thus, the aim of this work was to investigate the relationship between such neurotransmitters and RSNs in healthy, by reviewing the relevant work on this topic and performing complementary analyses, in order to better understand their physiological link, as well as their alterations in psychiatric disorders. According to the reviewed data, neurotransmitters nuclei diffusively project to subcortical and cortical regions of RSNs. In particular, the dopaminergic substantia nigra (SNc)-related nigrostriatal pathway is structurally and functionally connected with core regions of the SMN, whereas the ventral tegmental area (VTA)-related mesocorticolimbic pathway with core regions of the SN. The serotonergic raphe nuclei (RNi) connections involve regions of the SMN and DMN. Coherently, changes in neurotransmitters activity impact the functional configuration and level of activity of RSNs, as measured by functional connectivity (FC) and amplitude of low-frequency fluctuations/temporal variability of BOLD signal. Specifically, DA signaling is associated with increase in FC and activity in the SMN (hypothetically via the SNc-related nigrostriatal pathway) and SN (hypothetically via the VTA-related mesocorticolimbic pathway), as well as concurrent decrease in FC and activity in the DMN. By contrast, 5-HT signaling (via the RNi-related pathways) is associated with decrease in SMN activity along with increase in DMN activity. Complementally, our empirical data showed a positive correlation between SNc-related FC and SMN activity, whereas a negative correlation between RNi-related FC and SMN activity (along with tilting of networks balance toward the DMN). According to these data, we hypothesize that the activity of neurotransmitter-related neurons synchronize the low-frequency oscillations within different RSNs regions, thus affecting the baseline level of RSNs activity and their balancing. In our model, DA signaling favors the predominance of SMN-SN activity, whereas 5-HT signaling favors the predominance of DMN activity, manifesting in distinct behavioral patterns. In turn, alterations in neurotransmitters signaling (or its disconnection) may favor a correspondent functional reorganization of RSNs, manifesting in distinct psychopathological states. The here suggested model carries important implications for psychiatric disorders, providing novel and well testable hypotheses especially on bipolar disorder and schizophrenia.