Serotonin Antagonist Research Articles

Expert opinions on pharmacological symptomatic treatment of behavioral symptoms in frontotemporal dementia: A survey of the Neuropsychiatric International Consortium on Frontotemporal Dementia (NIC-FTD).

Behavioral variant frontotemporal dementia (bvFTD) is essentially characterized by progressive changes in personality and cognition. Clinically, bvFTD presents with often profound behavioral symptomatology. Despite the high burden of these symptoms for both patients and caregivers, there is no general consensus on an effective pharmacological symptomatic treatment. Interestingly, for multiple similar symptoms in primary psychiatric disorders, there is consensus on an effective pharmacological treatment. The aim of this study is to explore currently preferred clinical practices in the pharmacological treatment of specific core behavioral symptoms in bvFTD by world-leading clinical experts. A digital survey was conducted among members of the Neuropsychiatric International Consortium on Frontotemporal Dementia, comprising neurologists, psychiatrists, and neuropsychiatrists. Respondents recommended pharmacological treatments targeting symptoms including disinhibition, apathy, loss of empathy, hyperorality, perseverative/compulsive behaviors, and positive psychotic symptoms. Of 48 respondents with a median experience of 11.5 years in treating bvFTD, disinhibition was most frequently targeted (58.4%), followed by perseverative/compulsive behaviors (46.5%). Recommended drug classes included atypical antipsychotics (35.1%), selective serotonin reuptake inhibitors (31.2%), antiepileptics (10.0%), serotonin antagonist and reuptake inhibitors (8.4%), benzodiazepines (4.0%), and others (11.4%). Our survey revealed diverse pharmacological treatment practices for behavioral symptoms in bvFTD, reflecting the expected radical heterogeneity in pharmacological treatment strategies. Notwithstanding this, results from this explorative survey could further inform future research directions, and thus in turn potentially aid in establishing more consensus on effective pharmacological management of bvFTD, while the field awaits the development of highly anticipated disease-modifying treatment(s).

Human short-latency reflexes show precise short-term gain adaptation after prior motion.

The central nervous system adapts the gain of short-latency reflex loops to changing conditions. Experiments on biomimetic robots showed that reflex modulation could substantially increase energy efficiency and stability of periodic motions if, unlike known mechanisms, the reflex modulation both acted precisely on the muscles involved and lasted after the motion. This study tests the presence of such a mechanism by having participants repeatedly rotate either their right elbow or shoulder joint, before perturbing either joint. The results demonstrate a mechanism that modulates short-latency reflex gains after prior motion with joint-specific precision. Enhanced gains were observed hundreds of milliseconds after movement cessation, a time scale well-suited to quickly adapt overall periodic motion cycles. A serotonin antagonist significantly decreased these post-movement gains diffusely across joints. But blocking serotonin did not affect the joint-specificity of the gain scaling more than a placebo, suggesting that serotonin sets the overall reflex gain across joints after movement by an effect that is modulated in a joint-specific manner by an unidentified neural circuit. These results confirm the existence of a new, joint-specific, fast, persistent adaptation of short-latency reflex loops induced by motion in human arms.

Phytocannabinoids restore seizure-induced alterations in emotional behaviour in male rats.

Epilepsy often presents with severe emotional comorbidities including anxiety and abnormal fear responses which impose a significant burden on, and reduce, quality of life in people living with the disease. Our lab has recently shown that kindled seizures lead to changes in emotional processing resulting from the downregulation of anandamide signalling within the amygdala. Phytocannabinoids derived from the Cannabis sativa plant have attracted a lot of interest as a new class of drugs with potential anticonvulsant effects. Among the wide number of compounds occurring in Cannabis sativa, Δ9- tetrahydrocannabinol (THC), the one responsible for its main psychoactive effects, and the nonpsychoactive cannabidiol (CBD) have been extensively examined under pre-clinical and clinical contexts to control seizures, however, neither have been assessed in the context of the management of emotional comorbidities associated with seizure activity. We used two behavioural procedures to assess anxiety- and fear-like responding in adult male Long-Evans rats: elevated plus maze and auditory fear conditioning. In agreement with previous reports, we found seizure-induced increases in anxiety- and fear-like responding. These effects were reversed by either CBD (vaporized) or THC (oral). We also found that antagonism of serotonin 1 A receptors prior to CBD exposure prevented its protective effects. Phytocannabinoids offer a novel and reliable opportunity to treat seizure induced comorbid emotional alterations.

Mirtazapine: A One-Drug Intervention for the Physical and Psychological Symptoms of End-Stage Renal Disease (ESRD).

Patients with end-stage renal disease (ESRD), especially those on dialysis, experience myriad medical and psychological symptoms that impact theirquality of life. These symptoms range from nausea, emesis, and insomnia to pruritus, anxiety, depression, and loss of appetite. These symptoms often require multiple medications (e.g., anticholinergics, antihistamines, tricyclics, benzodiazepines, and Z-drugs), which can lead to polypharmacy, medication non-adherence, and potentially harmful drug-drug interactions, especially in older ESRD patients, a population with an age-related decline in drug metabolism, multimorbidity, and polypharmacy. The current perspective article will discuss evidence from extant literature supporting mirtazapine (a noradrenergic antagonist and selective serotonin antagonist, NASSA) as a potentially useful one-stop pharmacologic agent to alleviate multiple symptoms that ESRD patients face. A one-stop strategy has the potential to decrease polypharmacy, reduce adverse drug-drug and drug-disease interactions, reduce healthcare costs, and improve the quality of life in ESRD patients. Mirtazapine use in an ESRD setting merits a large randomized pragmatic double-blinded controlled trial to evaluate its efficacy as a potential pharmacotherapeutic agent for the management of multiple disabling gastrointestinal and other neuropsychological symptoms in older adults living with ESRD.

A randomized, double-blind, placebo-controlled phase II study of olanzapine-based prophylactic antiemetic therapy for delayed and persistent nausea and vomiting in patients with HER2-positive or HER2-low breast cancer treated with trastuzumab deruxtecan: ERICA study (WJOG14320B)

Nausea and vomiting are common adverse events associated with trastuzumab deruxtecan (T-DXd). We evaluated the efficacy of an olanzapine-based triplet regimen for preventing nausea and vomiting in patients receiving first cycle T-DXd. This multi-institutional, randomized, double-blind, placebo-controlled (ERICA) phase II study enrolled patients with HER2-positive/HER2-low metastatic breast cancer receiving their first cycle of T-DXd. Patients were randomized to olanzapine 5 mg or placebo once daily (1:1 ratio) from Day 1 to 6, plus a 5-hydroxytryptamine type 3-receptor antagonist (5-HT3RA) and dexamethasone 6.6 mg intravenously or 8 mg orally on Day 1. The total observation period was 504 hours (21 days) from the first T-DXd administration. The primary endpoint was complete response (CR), defined as no emetic events and no rescue medications, in the delayed phase (24-120 hours post-T-DXd), with the type I error rate of 0.2 (one-sided) for the comparison. Secondary endpoints included no nausea rate in the delayed and persistent phases (120-504 hours), adverse event by CTCAE and PRO-CTCAE. In total, 168 patients were enrolled at 43 sites in Japan (Nov 2021-Sep 2023) with 162 patients (olanzapine, n = 80; placebo, n = 82) included in the per protocol set. The primary endpoint was met as the delayed phase CR rate was significantly greater with olanzapine than placebo (70.0% versus 56.1%, P = 0.047). Efficacy was maintained in the persistent phase (63.9% versus 44.4%). No nausea rate was also greater with olanzapine (delayed phase: 57.5% versus 37.8%; persistent phase: 51.4% versus 31.9%). CR rates in the delayed phase favored olanzapine across subgroups. Appetite loss was also decreased with olanzapine. Hyperglycemia and somnolence were mostly of low-grade severity. Olanzapine 5mg for 6 days with 5-HT3RA and dexamethasone appears effective for T-DXd-treated patients to prevent delayed and persistent nausea and vomiting.

Oral Cannabis Extract for Secondary Prevention of Chemotherapy-Induced Nausea and Vomiting: Final Results of a Randomized, Placebo-Controlled, Phase II/III Trial.

The aim of this randomized, placebo-controlled, two-stage, phase II/III trial was to determine the efficacy of an oral cannabis extract in adults with refractory nausea and/or vomiting during moderately or highly emetogenic, intravenous chemotherapy despite guideline-consistent antiemetic prophylaxis. Here, we report results of the prespecified combined analysis including the initial phase II and subsequent phase III components. Study treatment consisted of oral capsules containing either tetrahydrocannabinol 2.5 mg plus cannabidiol 2.5 mg capsules (THC:CBD) or matching placebo, taken three times a day from days -1 to 5, in addition to guideline-consistent antiemetics. The primary measure of effect was the difference in the proportions of participants with no vomiting or retching and no use of rescue medications (a complete response) during hours 0-120 after the first cycle of chemotherapy on study (cycle A). We recruited 147 evaluable of a planned 250 participants from 2016 to 2022. Background antiemetic prophylaxis included a corticosteroid and 5-hydroxytryptamine antagonist in 97%, a neurokinin-1 antagonist in 80%, and olanzapine in 10%. THC:CBD compared with placebo improved the complete response rate from 8% to 24% (absolute difference 16%, 95% CI, 4 to 28, P = .01), with similar effects for absence of significant nausea, use of rescue medications, daily vomits, and the nausea scale on the Functional Living Index-Emesis quality-of-life questionnaire. More frequent bothersome adverse events of special interest included sedation (18% v 7%), dizziness (10% v 0%), and transient anxiety (4% v 1%). There were no serious adverse events attributed to THC:CBD. THC:CBD is an effective adjunct for chemotherapy-induced nausea and vomiting despite standard antiemetic prophylaxis, but was associated with additional adverse events. Drug availability, cultural attitudes, legal status, and preferences may affect implementation. Future analyses will evaluate the cost-effectiveness of THC:CBD.

Focal pharmacological manipulation of serotonin signaling in the amygdala does not alter social behavior.

Serotonin signaling plays critical roles in social and emotional behaviors. Likewise, decades of research demonstrate that the amygdala is a prime modulator of social behavior. Permanent excitotoxic lesions and transient amygdala inactivation consistently increase social behaviors in non-human primates. In rodents, acute systemic administration of drugs that increase serotonin signaling is associated with decreased social interactions. However, in primates, the direct involvement of serotonin signaling in the amygdala, particularly in affiliative social interaction, remains unexplored. Here, we examined the effects of serotonin manipulations within the amygdala on social behavior in eight pairs of familiar male macaques. We microinfused drugs targeting the serotonin system into either the basolateral (BLA) or central (CeA) amygdala and measured changes in social behavior. Surprisingly, the results demonstrated no significant differences in social behavior following the infusion of a selective serotonin reuptake inhibitor, 5-HT1A agonist or antagonist, 5-HT2A agonist or antagonist, or 5-HT3 agonist or antagonist into either the BLA or CeA. These findings suggest that serotonin signaling in the amygdala does not directly contribute to the regulation of social behavior between familiar conspecifics. Future research should explore alternative mechanisms and potential interactions with other brain regions to gain a comprehensive understanding of the complex neural circuitry governing social behavior.

2,5-Dimethoxy-4-iodoamphetamine and altanserin induce region-specific shifts in dopamine and serotonin metabolization pathways in the rat brain

PurposeFor understanding the neurochemical mechanism of neuropsychiatric conditions associated with cognitive deficits it is of major relevance to elucidate the influence of serotonin (5-HT) agonists and antagonists on memory function as well dopamine (DA) and 5-HT release and metabolism. In the present study, we assessed the effects of the 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) and the 5-HT2A receptor altanserin (ALT) on object and place recognition memory and cerebral neurotransmitters and metabolites in the rat. MethodsRats underwent a 5-min exploration trial in an open field with two identical objects. After systemic injection of a single dose of either DOI (0.1 mg/kg), ALT (1 mg/kg) or the respectice vehicle (0.9 % NaCl, 50 % DMSO), rats underwent a 5-min test trial with one of the objects replaced by a novel one and the other object transferred to a novel place. Upon the assessment of object exploration and motor/exploratory behaviors, rats were sacrificed. DA, 5-HT and metabolite levels were analyzed in cingulate (CING), caudateputamen (CP), nucleus accumbens (NAC), thalamus (THAL), dorsal (dHIPP) and ventral hippocampus (vHIPP), brainstem and cerebellum with high performance liquid chromatography. ResultsDOI decreased rearing but increased head-shoulder motility relative to vehicle. Memory for object and place after both DOI and ALT was not different from vehicle. Network analyses indicated that DOI inhibited DA metabolization in CING, CP, NAC, and THAL, but facilitated it in dHIPP. Likewise, DOI inhibited 5-HT metabolization in CING, NAC, and THAL. ALT facilitated DA metabolization in the CING, NAC, dHIPP, vHIPP, and CER, but inhibited it in the THAL. Additionally, ALT facilitated 5-HT metabolization in NAC and dHIPP. ConclusionsDOI and ALT differentially altered the quantitative relations between the neurotransmitter/metabolite levels in the individual brain regions, by inducing region-specific shifts in the metabolization pathways. Findings are relevant for understanding the neurochemistry underlying DAergic and/or 5-HTergic dysfunction in neurological and psychiatric conditions.

Pharmacokinetics of Trazodone in Hispaniolan Parrots (Amazona ventralis).

The objective of this study was to establish the pharmacokinetics of a single oral dose of trazodone in the Hispaniolan Amazon parrot (Amazona ventralis). Trazodone is a selective serotonin antagonist and reuptake inhibitor used commonly in both human and veterinary medicine as an antidepressant behavioral modification medicine. A single oral dose of compounded trazodone hydrochloride solution (20 mg/mL) at 50 mg/kg was administered to a total of 7 healthy adult Hispaniolan Amazon parrots. The 7 healthy adult parrots ranged in age from 10 to 15 years and weighed 228 to 323g. Blood was collected at baseline (2 weeks before study) and at 1, 2, 4, 6, 10, and 14 hours post-drug administration. Plasma concentrations of both trazodone and its active metabolite m-chlorophenylpiperazine (mCPP) were measured via liquid chromatography tandem mass spectrometry. Noncompartmental pharmacokinetic analysis was completed. The half-life (t1/2) ± SD of trazodone for the Hispaniolan parrots was 1.89 ± 0.49 hours, and the t1/2 ± SD of mCPP metabolite was 1.9 ± 0.55 hours. Maximum serum drug concentrations, or Cmax (ng/mL), were 738.3 ± 285.3 for trazodone. Times to achieve Cmax (hours) for trazadone and the mCPP metabolite were 1 hour and 2 hours postdosing, respectively. While this study did not establish the behavioral effects of trazodone, no adverse side effects were observed throughout the 48-hour period following drug administration and blood collection. Our results indicate that the oral administration of a 50-mg/kg single dose of trazodone to Hispaniolan parrots may be considered a safe dose. Plasma concentrations are comparable to previously published values in humans, dogs, horses, and pigeons (Columba livia domestica) for up to 14 hours following dosing. This study indicates that further studies are needed to establish the pharmacodynamics and the efficacy of trazodone in the medical management of behavioral problems in psittacine species.

Management of serotonin syndrome (toxicity)

Serotonin syndrome (toxicity), resulting from an excessive accumulation of serotonin in the central nervous system, it can occur due to various factors such as the initiation of medication, overdose or drug interactions. Diagnosing serotonin toxicity presents challenges as there are no definitive criteria. This review delves into the pathophysiology, incidence, clinical assessment and management of serotonin toxicity, stressing the significance of promptly recognizing and managing severe cases. Diagnosis relies primarily relies on clinical assessment due to the absence of specific laboratory tests. The Hunter Serotonin Toxicity criteria are commonly utilized but have only been validated in the overdose setting. Assessing the severity of toxicity is crucial for guiding management decisions. Supportive care, discontinuation of causative agents and symptomatic treatment are prioritized in management. Mild toxicity often requires withdrawal or reduction of the serotonergic agent, while more severe toxicity requires more aggressive resuscitative and supportive care. Severe serotonin toxicity characterized by hyperthermia and rigidity requires aggressive supportive measures, including benzodiazepines, intubation, paralysis and active cooling. Animal studies suggest potential benefits of 5-HT2A receptor antagonists in preventing hyperthermia and fatalities, but only at high doses. Their clinical effectiveness remains uncertain, and evidence is predominately from case series and case reports. Although commonly used, serotonin antagonists like cyproheptadine lack conclusive evidence of efficacy. Other serotonin antagonists such as chlorpromazine and olanzapine have been explored but evidence is limited to case reports. Hence, the cornerstone of treating severe cases does not lie in 'antidote' administration or even diagnosis but in effective early resuscitative and supportive care.

Agomelatine promotes differentiation of oligodendrocyte precursor cells and preserves white matter integrity after cerebral ischemic stroke

White matter injury contributes to neurological disorders after acute ischemic stroke (AIS). The repair of white matter injury is dependent on the re-myelination by oligodendrocytes. Both melatonin and serotonin antagonist have been proved to protect against post-stroke white matter injury. Agomelatine (AGM) is a multi-functional treatment which is both a melatonin receptor agonist and selective serotonin receptor antagonist. Whether AGM protects against white matter injury after stroke and the underlying mechanisms remain elusive. Here, using the transient middle cerebral artery occlusion (tMCAO) model, we evaluated the therapeutic effects of AGM in stroke mice. Sensorimotor and cognitive functions, white matter integrity, oligodendroglial regeneration and re-myelination in stroke hemisphere after AGM treatment were analyzed. We found that AGM efficiently preserved white matter integrity, reduced brain tissue loss, attenuated long-term sensorimotor and cognitive deficits in tMCAO models. AGM treatment promoted OPC differentiation and enhanced re-myelination both in vitro, ex vivo and in vivo, although OPC proliferation was unaffected. Mechanistically, AGM activated low density lipoprotein receptor related protein 1 (LRP1), peroxisome proliferator-activated receptor γ (PPARγ) signaling thus promoted OPC differentiation and re-myelination after stroke. Inhibition of PPARγ or knock-down of LRP1 in OPCs reversed the beneficial effects of AGM. Altogether, our data indicate that AGM represents a novel therapy against white matter injury after cerebral ischemia.

The Involvement of the Serotonergic System in Ketamine and Fluoxetine Combination-induced Cognitive Impairments in Mice.

Glutamatergic N-methyl-D-aspartate (NMDA) receptors play vital roles in memory formation. Changes in the activity of these receptors influence memory processes. Ketamine is a noncompetitive NMDA receptor antagonist drug with promising mood-altering and pain-reducing effects in low doses. These effects are believed to be related to altered serotonergic transmission. The present study investigated the involvement of the serotonergic system in low-dose ketamine administrations' effects on memory acquisition, consolidation, and retrieval processes. Sixty-four male BALB/c mice were used in this experiment and separated into 8t groups. Mice were treated subchronically with a selective serotonin reuptake inhibitor, fluoxetine, and a serotonin depletion agent, p-chlorophenylalanine (pCPA). A serotonin antagonist, methiothepin, and ketamine were acutely administered 60 minutes before or after the behavioral tests. A passive avoidance (PA) test measured emotional memory acquisition, consolidation, and retrieval processes. Hippocampi malondialdehyde (MDA) levels were analyzed, and histopathological examinations were performed. Ketamine alone did not significantly affect memory encoding processes in the PA test, while the ketamine-fluoxetine combination disrupted memory consolidation. Fluoxetine negatively affected the memory acquisition process, which was normalized during the consolidation and retrieval trials. Drug applications did not significantly alter hippocampal MDA levels. In all ketamine-applied groups, histopathologic alterations were evident. Low-dose ketamine administration induces neurodegeneration, and it also impairs memory functions when combined with fluoxetine, indicating increased serotonergic transmission may be involved in the memory-impairing and neurotoxic effects of ketamine.

Implications of Pimavanserin in Patients with Dementia-related Psychosis: A Systematic Review

Psychosis in patients with dementia-related disorders has long been a challenging issue to be tackled by the medical fraternity. Although atypical antipsychotics (AP) are in use for the same reason, there has always been a question regarding their safety and tolerability in this group of patients. Pimavanserin, a serotonin receptor inverse agonist or antagonist, is the only drug that is Food and Drug Administration-licensed to be used for the treatment of Parkinson’s disease psychosis. This systematic review, which was conducted in line with Preferred Reporting Items for Systematic Reviews and Meta-analyses 2020, had the objective of examining the effects of pimavanserin in patients with dementia-related psychosis (DRP). Among the publications (January 1, 2013–July 12, 2023) we gathered and examined were case–control and cohort studies, systematic reviews, meta-analyses, clinical trials, literature reviews, and randomized and nonrandomized control trials. The databases used to construct this list of publications were PubMed, Cochrane Library, and Google Scholar. These three databases yielded 157 reports in total once the relevant filters were applied. They were then further screened and put through quality evaluation processes, which led to the final nine papers that were included in this systematic review. We concluded from our review that pimavanserin proves to be a promising alternative for the treatment of DRP, showing significant improvements and fewer side effects compared to other atypical AP.

Cyproheptadine in serotonin syndrome: A retrospective study.

Serotonin syndrome (SS) is an iatrogenic life-threatening condition caused by serotonergic agents. The treatment for SS involves the administration of a serotonin antagonist (cyproheptadine). However, the dosing schedule for cyproheptadine is not uniform in the literature. We retrospectively evaluated 23 adult patients (>18 years) admitted to the Neurology Department and met the Hunter criteria for SS. The mean age was 35.2 years, and 52% were female. Ten patients were managed in the intensive care unit (ICU), whereas thirteen patients were admitted to the ward. Hyperreflexia was the most common clinical feature (100%), followed by clonus (91%), tachycardia (83%), and tremor (83%). Other common clinical features were rigidity (65%), increased bowel sound (61%), diaphoresis (48%), fever (43%), hypertension (39%), and myoclonus (30%). All but one patient received two or more serotonergic drugs. Tramadol was the most common serotonergic agent (39%), followed by sodium valproate (21%), and amitriptyline (21%). Cyproheptadine was administered to all patients. All patients admitted in the ICU received a loading dose of 12 mg followed by 2 mg every 2 h for at least 24 h. All patients admitted to the ward were given 4 mg of cyproheptadine three times each day. Every patient showed at least some response to cyproheptadine within 24 h. The total doses of cyproheptadine and the length of treatment differed between patients. Any response to cyproheptadine at a therapeutic dose within 24 h, even a partial one, could be a diagnostic indicator of the existence of SS.

Recent Advancements and Developments in the Biological Importance of 1,3,5‐Triazines

AbstractNitrogen‐bearing heterocycles are ubiquitous in landscapes and have a great impact on living nature. Structural motifs are present in diverse natural products like vitamins, antibiotics, and alkaloids, as well as pharmaceuticals. The 1,3,5‐Triazines are the primitive class of heterocyclic motifs and are used in various synthetic and medicinal applications. This review covers an exhaustive exploration of literature reports and describes various synthetic strategies and pharmacological activities of 1,3,5‐triazine moiety. Synthetic strategies include multicomponent reaction, metal catalyst reaction, microwave‐assisted strategy, etc. to construct 1,3,5‐triazine moiety. Pharmacological activities include anticancer, antimalarial, antibacterial, antifungal, antiviral, anti‐tubercular, anti‐leishmanial, anti‐inflammatory, histamine antagonist, serotonin antagonist, etc. For anticancer activity, 1,3,5‐triazine moiety‐containing compounds were tested on different cell lines, and inhibitory activity was also mentioned. The involvement of this scaffold in the treatment of various diseases and disorders makes this scaffold important from a research perspective. Therefore, there is a need to present the combined data of research and reviews to the researchers to develop new molecules. For that reason, the review included information from articles published from 1978 onwards.

Current Understanding of Compulsive Sexual Behavior Disorder and Co-occurring Conditions: What Clinicians Should Know about Pharmacological Options.

Compulsive sexual behavior disorder (CSBD) has recently been recognized as a psychiatric disorder. Pharmacological treatments for CSBD have received little study and thus have limited empirical support. The main objective of the present work is to review existing literature on the efficacy of different drugs on the symptomatology of CSBD, including the subtype of problematic pornography use (PPU). The main pharmacological approaches to treating CSBD have included opioid antagonists (naltrexone and nalmefene), selective serotonin reuptake inhibitors (paroxetine, citalopram, fluoxetine, and sertraline), mood stabilizers (topiramate), tricyclic antidepressants (clomipramine), serotonin antagonist and reuptake inhibitors (nefazodone), and N-acetylcysteine. Since people with CSBD may experience different co-occurring disorders, these should be considered when choosing the best pharmacological treatment. Pharmacological therapy for CSBD/PPU has been suggested as an adjunct to psychological therapies, which, for the moment, have the most empirical evidence. However, to evaluate the efficacy of most of the drugs presented in this narrative review, data to date have only been available from case studies. Thus, empirical support is scant and generalizability of results is limited, highlighting the need for more research in this area.

(369) Physician Insights into the Safety of Flibanserin for the Treatment of Sexual Dysfunction in Men

Abstract Introduction Hypoactive sexual desire disorder (HSDD) is a subtype of persistent low sexual desire (LSD) associated with marked distress with no known cause. LSD/HSDD in men frequently occurs with other sexual dysfunctions. Flibanserin is a centrally-acting multifunctional serotonin agonist and antagonist approved in the United States (US) to treat acquired, generalized HSDD in certain premenopausal women. Based on its proposed mechanism of action, flibanserin is prescribed off-label to treat sexual dysfunction in men. Objective Given the lack of safety data in men, this study was conducted to capture insights from physicians on the safety of flibanserin in their male patients. Methods Dispensing data from two specialty pharmacies were used to identify physicians with experience treating male patients with flibanserin (physicians). Physicians were invited via email to participate in a brief 10-minute interview. All interviews were conducted using a standardized questionnaire containing 6 questions. The questionnaire captured general safety information and types of sexual dysfunction treated with flibanserin. Physicians were instructed not to share any patient-specific information. Interviews were conducted with each physician individually via video conference. Responses to questions were documented verbatim and summarized descriptively. Results Six physicians from different sexual health clinics in the US were invited to participate in the study, 5 of which accepted the invitation and completed the interview. All physicians prescribed flibanserin to treat LSD/HSDD. Other sexual dysfunctions treated with flibanserin included delayed orgasm (n=4), post-orgasmic illness syndrome (n=2), antidepressant (SSRI)-induced sexual dysfunction (n=2), and post-finasteride-associated sexual dysfunction (n=1). Physicians reported their male patients experienced similar but less frequent or severe side effects than reported in premenopausal women during the HSDD clinical trials, including somnolence/sleepiness (n=3), insomnia (n=2), fatigue (n=1) and dry mouth (n=1). The most frequent physician-cited side effects leading to flibanserin discontinuation were insomnia (n=2), somnolence (n=1), fatigue (n=1), and dizziness (n=1). Lack of effect was another common reason (n=3) for treatment discontinuation. No physicians reported any unanticipated flibanserin-related side effects in their male patients. Although interviews included no efficacy-related questions, physicians provided insight into flibanserin response rates they observed in their male patients when responding to safety questions, including positive response rates in LSD/HSDD and other sexual dysfunctions such as delayed orgasm. Conclusions Feedback from the participating sexual medicine physicians suggests that flibanserin may have a similar safety profile in men as observed in premenopausal women. It is reassuring that physicians reported no unanticipated or severe safety concerns in their male patients. In addition to LSD/HSDD, physicians reported positive response rates with flibanserin in their male patients treated for other sexual dysfunctions. The generalizability of these findings to other practice settings is limited. However, these safety findings and reports of positive response rates in male patients with LSD/HSDD and other sexual dysfunctions suggest that more research on the use of flibanserin in men with sexual dysfunctions is warranted. Disclosure Yes, this is sponsored by industry/sponsor: Sprout Pharmaceuticals, Inc. Clarification: Industry initiated, executed and funded study. Any of the authors act as a consultant, employee or shareholder of an industry for: Sprout Pharmaceuticals, Inc.

Appraising and highlighting gaps among prophylactic intervention studies for reducing the incidence of postoperative nausea and vomiting in children: a systematic review

ObjectivesPostoperative nausea and vomiting (PONV) is a leading perioperative morbidity outcome following general anaesthesia. This systematic review aims to identify, appraise and summarise the evidence synthesis studies of prophylactic interventions...

Serotonin syndrome: An often-neglected medical emergency.

Optimum serotonin level in the serotonergic synapses of the central nervous system (CNS) is related to mood, behavior, and sleep. Serotonin syndrome (SS) is a rare yet very dangerous adverse effect resulting from increased serotonin in CNS. The diagnosis of SS is based on the presence of clinical symptoms, which can include agitation, confusion, rapid heart rate, high blood pressure, dilated pupils, muscle rigidity, tremors, sweating, and diarrhea. SS is invariably caused by inadvertent use of serotonergic medicines. There is an ever-growing list of medicines that are associated with the risk of SS. Some of the common classes of drugs that can contribute to the development of SS include selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, stimulants (e.g., amphetamines and cocaine), lithium, opioids, drugs used for recreational purposes like ecstasy Methylenedioxymethamphetamine (MDMA), and some herbal supplements (e.g., St. John's Wort). SS can occur when these medications are taken alone or in combination, especially when a new medication is added, or the dose of an existing medication is changed. The management of SS typically involves discontinuing the use of the substance that caused the excess serotonin levels and providing supportive care, such as intravenous fluids and electrolytes. In severe cases, benzodiazepines may be used to control agitation and muscle rigidity, while serotonin antagonists, such as cyproheptadine, may be used to reduce serotonin levels. The literature review points to a general unawareness among physicians about the condition or drugs associated with it. Consequently, this potentially fatal condition is overlooked. There is a need for regular information updates and reminders to all those who prescribe medications to the patients.

Functional neuroimaging biomarkers of anhedonia response to escitalopram plus adjunct aripiprazole treatment for major depressive disorder.

Identifying neuroimaging biomarkers of antidepressant response may help guide treatment decisions and advance precision medicine. To examine the relationship between anhedonia and functional neurocircuitry in key reward processing brain regions in people with major depressive disorder receiving aripiprazole adjunct therapy with escitalopram. Data were collected as part of the CAN-BIND-1 study. Participants experiencing a current major depressive episode received escitalopram for 8 weeks; escitalopram non-responders received adjunct aripiprazole for an additional 8 weeks. Functional magnetic resonance imaging (on weeks 0 and 8) and clinical assessment of anhedonia (on weeks 0, 8 and 16) were completed. Seed-based correlational analysis was employed to examine the relationship between baseline resting-state functional connectivity (rsFC), using the nucleus accumbens (NAc) and anterior cingulate cortex (ACC) as key regions of interest, and change in anhedonia severity after adjunct aripiprazole. Anhedonia severity significantly improved after treatment with adjunct aripiprazole.There was a positive correlation between anhedonia improvement and rsFC between the ACC and posterior cingulate cortex, ACC and posterior praecuneus, and NAc and posterior praecuneus. There was a negative correlation between anhedonia improvement and rsFC between the ACC and anterior praecuneus and NAc and anterior praecuneus. Eight weeks of aripiprazole, adjunct to escitalopram, was associated with improved anhedonia symptoms. Changes in functional connectivity between key reward regions were associated with anhedonia improvement, suggesting aripiprazole may be an effective treatment for individuals experiencing reward-related deficits. Future studies are required to replicate our findings and explore their generalisability, using other agents with partial dopamine (D2) agonism and/or serotonin (5-HT2A) antagonism.