Search Results (202)

Background: Medically unexplained oral symptoms/syndromes (MUOS), such as Burning Mouth Syndrome and Persistent Idiopathic Facial Pain, present significant management challenges due to the lack of standardized treatments and high-level evidence. While pharmacotherapy is often employed, real-world data on treatment adherence—a pragmatic proxy for effectiveness and tolerability—remain sparse, especially in Japan. This study aimed to describe the real-world prescribing patterns of antidepressants and dopamine receptor partial agonists (DPAs) for MUOS and retrospectively investigate their association with treatment continuation. Methods: This retrospective observational study analyzed data from patients initiating pharmacotherapy for MUOS at a specialized clinic in Japan (April 2021–March 2023). We used Cox proportional hazards models to evaluate treatment continuation for amitriptyline monotherapy and antidepressant–aripiprazole adjunctive therapy. The primary outcome was the time to discontinuation. Dosage effects were modeled using B-splines to capture nonlinearity. Results: Among 702 MUOS patients who started pharmacotherapy, 493 received amitriptyline as the first prescription, and 108 received aripiprazole as an adjunctive therapy. For amitriptyline monotherapy, a nonlinear relationship was observed between dosage and discontinuation risk, with a relatively lower hazard around 25 mg/day across age groups. In the antidepressant–aripiprazole adjunctive group, the overall hazard ratio for discontinuation was higher (HR = 4.75, p < 0.0005) compared to non-adjunctive therapy, likely due to indication bias reflecting more treatment-resistant cases. However, within the aripiprazole adjunctive group, a U-shaped relationship was identified between maximum aripiprazole dosage and discontinuation risk, with the lowest hazard (HR ≈ 0.30) observed at approximately 1.7–1.8 mg/day. Mild side effects such as drowsiness, dry mouth, constipation, tremor, insomnia, and weight gain were noted, but no severe adverse events occurred. Conclusions: This real-world data analysis suggests specific dosage ranges (amitriptyline ≈ 25 mg/day; aripiprazole augmentation ≈ 1.7–1.8 mg/day) are associated with longer treatment continuation in MUOS patients. Treatment continuation reflects a crucial balance between symptom relief and tolerability, essential for managing these chronic conditions. It is critical to emphasize that these findings are descriptive and observational, derived from a specialized setting, and do not constitute prescriptive recommendations. They highlight the importance of individualized dosing. Definitive evidence-based strategies require validation through prospective randomized controlled trials. Full article

Pituitary pars intermedia dysfunction (PPID) is a common, slowly progressive, neurodegenerative disorder of the older horse. Oxidative damage to the hypothalamic periventricular neurons results in loss of dopaminergic inhibition of the pars intermedia region of the pituitary gland. Consequently, there is increased production of the pro-opiomelanocortin (POMC)-derived hormones normally produced by this region, as well as initial melanocyte hypertrophy and hyperplasia, followed by adenomatous change. Clinical signs that are highly suggestive of the disease are generalised and regional hypertrichosis and delayed/abnormal coat shedding. Numerous clinical signs provide a moderate clinical suspicion, including hyperhidrosis, abnormal fat distribution/regional adiposity, epaxial muscle atrophy/loss of topline, laminitis, weight loss, recurrent infections, behavioural changes/lethargy, polyuria and polydipsia, a pot-bellied appearance, bulging supraorbital fat pads, reduced wound healing, lordosis and infertility. In all animals, a diagnosis of PPID is made based on the signalment, clinical signs and results of further diagnostic tests, with age being a crucial factor to consider. Currently recommended further diagnostic tests are measurement of basal adrenocorticotrophic hormone (ACTH) concentrations (all year) and evaluation of the ACTH response to thyrotrophin-releasing hormone (TRH) using seasonally adjusted references intervals (non-autumn). Animals should also be tested for insulin dysregulation, as laminitis risk in PPID is associated with hyperinsulinaemia. PPID can be managed but not cured; it is a lifelong condition. The individual clinical signs can be managed, e.g., clipping the excessive haircoat and providing unrestricted access to water for individuals with polydipsia. Alternatively, pharmacological management can be employed, and the dopamine-2 receptor agonist pergolide is licensed/approved for the treatment of equine PPID. This should be prescribed in combination with dietary recommendations based on the body condition score and insulin sensitivity status of the individual animal. Full article

Substance use disorders (SUDs) remain a major public health challenge, with existing pharmacotherapies offering limited long-term efficacy. Traditional treatments focus on dopaminergic systems but often overlook the complex interplay between metabolic signals, neuroplasticity, and conditioned behaviors that perpetuate addiction. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), originally developed for type 2 diabetes and obesity, have recently emerged as promising modulators of reward-related brain circuits. This review synthesizes current evidence on the role of glucagon-like peptide-1 (GLP-1) and its receptor in modulating craving and substance-seeking behaviors. We highlight how GLP-1 receptors are expressed in addiction-relevant brain regions, including the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC), where their activation influences dopaminergic, glutamatergic, and GABAergic neurotransmission. In addition, we explore how GLP-1 signaling affects reward processing through gut–brain vagal pathways, hormonal crosstalk, and neuroinflammatory mechanisms. Preclinical studies demonstrate that GLP-1RAs attenuate intake and relapse-like behavior across a range of substances, including alcohol, nicotine, and cocaine. Early-phase clinical trials support their safety and suggest potential efficacy in reducing craving. By integrating findings from molecular signaling, neurocircuitry, and behavioral models, this review provides a translational perspective on GLP-1RAs as an emerging treatment strategy in addiction medicine. We propose that targeting gut–brain metabolic signaling could provide a novel framework for understanding and treating SUDs. Full article

Background and aim of this review: The ongoing opioid epidemic underscores the urgent need for innovative pharmacological and behavioral interventions to mitigate the impact of opioid use disorder (OUD). This review aims to explore theoretical overlaps between the neurobiological mechanisms underlying OUD development and the pharmacodynamic profile of methylphenidate (MPH). Particular attention is given to the potential shared molecular targets, safety considerations, and therapeutic implications of MPH use in this clinical context. Main finding: In the development of opioid dependence, the negative reinforcement of the dopaminergic transmission of the mesocorticolimbic pathway induced by the supraspinal action of opioid receptor agonists plays a major role. The induced state of hypodopaminergic and hyperadrenergic modulates the underlying disease process by affecting cognitive control, affective regulation, and motivational drive. MPH, acting as a dopamine reuptake inhibitor and modulator of vesicular monoamine transporter 2 (VMAT-2), increases extracellular dopamine availability and enhances dopaminergic signaling, suggesting potential utility in restoring dopaminergic tone in OUD. Additionally, MPH has shown efficacy in hypoactive delirium in patients with terminal cancer, improving both cognitive function and psychomotor drive. Conclusions and future perspectives: There appear to be converging neurobiological mechanisms between the action of MPH and the pathophysiology of OUD, particularly within the dopaminergic system. However, well-designed clinical trials are essential to identify the patient subgroups that may benefit from adjunctive MPH treatment, to evaluate its efficacy in this setting, and to assess the long-term safety and risk profile of stimulant use in individuals with OUD. Full article

When non-functioning pituitary adenomas (NFPAs) behave aggressively or recur after first-line surgical treatment, it can be challenging to decide whether and how to escalate therapy. Up to 47% of patients with residual tumor after transsphenoidal surgery will show disease recurrence or progression and may require an intervention. Repeat surgical resection can be attempted in select cases if the tumor is accessible; for the remainder of patients, non-surgical treatment options may need to be considered. Radiotherapy can control tumor growth in 75% of NFPAs, but confers increased risk of hypopituitarism and other disorders. Currently, there are no medical therapies approved for patients with recurrent or aggressive NFPA. However, several have been investigated, including temozolomide, somatostatin receptor ligands, dopamine agonists, immune checkpoint inhibitors, vascular endothelial growth factor inhibitors, and peptide receptor radionuclide therapy. We present a review of the available evidence to provide guidance for pituitary endocrinologists and neuro-oncologists when treating patients with recurrent or aggressive NFPA. Full article

Background/Objectives: Pituitary apoplexy (PA) is a rare medical emergency characterized by the sudden onset of symptoms resulting from hemorrhage and/or infarction within the pituitary gland. Precipitating factors include the use of dopamine agonists (DAs), whose main indication is the treatment of prolactin (PRL)-secreting pituitary neuroendocrine tumors (PitNETs), but which can also be considered in non-functioning PitNETs. Here we report a case of PA in a patient taking cabergoline for a non-functioning PitNET, followed by a review of the literature focusing on the cases of PA associated with the use of DAs. Methods: A review of the literature was performed, searching Pubmed for other clinical cases of PA associated with the use of DAs, from inception to March 2025. Results: We found 43 cases of PA associated with the use of DAs. All the patients had secreting tumors: 86% were classified as PRL-secreting PitNETs, 7% were classified as GH-secreting PitNETs, and 4.6% included a mixed PRL/GH-secreting PitNET and a TSH-secreting PitNET. By contrast, here we present a case of PA in a non-functioning PitNET during cabergoline therapy. Our patient was managed conservatively and endocrine function recovered spontaneously. In our case, cabergoline might have promoted PA, which is consistent with the reported efficacy of cabergoline in inducing tumor shrinkage of non-functioning PitNETs that express dopamine 2 receptors, including silent PIT1 and SF1 or NULL tumors. Conclusions: Our case confirms cabergoline efficacy in non-functioning PitNETs and sheds light on a possible complication of its use. Patients, particularly those with large tumors, should be closely monitored for this occurrence. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are long-acting drugs that have gathered a lot of attention worldwide for their utility in the treatment landscape of type 2 diabetes mellitus and obesity. Their widespread global use has been accompanied by an additional observation related to a potential reduction in alcohol consumption. Preclinical studies in animal models, along with preliminary clinical findings, suggest that GLP-1 RAs may exert beneficial effects on alcohol use disorder (AUD). The latter represents a significant public health challenge, contributing to a broad spectrum of health, social, and economic burdens. Concurrently, the use of GLP-1 RAs in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) has been associated with a clinically meaningful reduction in all-cause mortality, major cardiovascular events, and progression to metabolic dysfunction-associated steatohepatitis (MASH). In this current opinion article, we firstly summarize the current literature dealing with the effect of GLP-1 RAs on AUD based on findings from experimental and human clinical studies. Additionally, beyond their role in MASLD, we explore in detail the potential impact of GLP-1 RAs on patients with alcoholic liver disease (ALD) and metabolic and alcohol-related/associated liver disease (MetALD). Finally, we highlight current challenges and unresolved issues, including concerns related to safety, accessibility, cost, and limitations in the clinical application of GLP-1 RAs. Full article

Clinically nonfunctioning pituitary tumors (CNFPTs) typically do not cause hormonal excess, progress insidiously, and are often large and invasive at presentation. Complete resection is frequently not attainable; radiotherapy (RT) may effectively limit growth but carries a significant risk of hypopituitarism. Medical therapy with dopamine D2 receptor agonists and/or somatostatin analogs has been explored in CNFPTs but have yielded inconsistent results, and there is an unmet need for novel efficacious and safe medical therapies. The authors used the PubMed database to identify and review articles published from January 1982 to July 2024, that discussed the medical treatment of CNFPTs. The most commonly studied medical therapies were somatostatin receptor ligands (SRLs) and dopamine D2 receptor agonists. Of 111 patients with CNFPTs treated with SRLs, 31 (28%) exhibited tumor shrinkage. Following dopamine agonist treatment in 355 patients, tumor shrinkage occurred in 113 (32%), tumor stabilization in 182 (51%), and tumor growth in 60 (17%). The efficacy of other less commonly employed therapies such as GnRH analogs, PRRT, and temozolomide was also reviewed. Efficacious and safe medical therapies evaluated in robust randomized placebo-controlled clinical trials are needed to improve the management of CNFPTs. Full article

Background/Objectives: G protein-coupled trace amine-associated receptors (TAARs) belong to a family of biogenic amine-sensing receptors. TAAR1 is the best-investigated receptor of this family, and TAAR1 agonists are already being tested in clinical studies for the treatment of schizophrenia, anxiety, and depression. Meanwhile, other TAARs (TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9 in humans) are mostly known for their olfactory function, sensing innate odors. At the same time, there is growing evidence that these receptors may also be involved in brain function. TAAR8 is the least studied TAAR family member, and currently, there is no data on its function in the mammalian central nervous system. Methods: We generated triple knockout (tTAAR8-KO) mice lacking all murine Taar8 isoforms (Taar8a, Taar8b, and Taar8c) using CRISPR-Cas9 technology. In this study, we performed the first phenotyping of tTAAR8-KO mice for behavioral, electrophysiological, and neurochemical characteristics. Results: During the study, we found a number of alterations specific to tTAAR8-KO mice compared to controls. tTAAR8-KO mice demonstrated better short-term memory, more depressive-like behavior, and higher body temperature. Also, we observed changes in the dopaminergic system, brain electrophysiological activity, and adult neurogenic functions in mice lacking Taar8 isoforms. Conclusions: Based on the data obtained, it can be assumed that the physiological TAAR8 role is not limited only to the innate olfactory function, as previously proposed. TAAR8 could be involved in brain function, in particular in dopamine function regulation. Full article

Glucagon-like peptide-1 receptor agonists, originally developed for the treatment of metabolic disorders, have recently emerged as promising candidates for the management of substance use disorders. This review synthesizes preclinical, clinical, and translational evidence on the effects of glucagon-like peptide-1 receptor agonists across addiction models involving alcohol, nicotine, psychostimulants, and opioids. In animal studies, glucagon-like peptide-1 receptor agonists consistently reduce drug intake, attenuate dopamine release in reward circuits, and decrease relapse-like behavior. Clinical and observational studies provide preliminary support for these findings, particularly among individuals with comorbid obesity or insulin resistance. However, several translational barriers remain, including limited blood–brain barrier penetration, species differences in pharmacokinetics, and variability in treatment response due to genetic and metabolic factors. Ethical considerations and methodological heterogeneity further complicate clinical translation. Future directions include the development of central nervous system penetrant analogues, personalized medicine approaches incorporating pharmacogenomics, and rigorously designed trials in diverse populations. Glucagon-like peptide-1 receptor agonists may offer a novel therapeutic strategy that addresses both metabolic and neuropsychiatric dimensions of addiction, warranting further investigation to define their role in the evolving landscape of substance use disorder treatment. Full article

Alzheimer’s disease (AD) is characterized by the progressive loss of cognitive function and is frequently accompanied by neuropsychiatric symptoms (NPS). Pathologically, AD is defined by two hallmark features: the extracellular accumulation of β-amyloid and the intracellular hyperphosphorylation of the tau protein. In addition to these primary changes, several other abnormalities are associated with the disease, including neuroinflammation, synaptic loss, oxidative stress, neurotransmitter imbalance, and genetic and epigenetic alterations. NPS in AD encompass a range of symptoms, such as anxiety, apathy, agitation, depression, and psychosis. These symptoms are thought to arise partly from the damage caused by the pathological hallmarks of AD, which impair various neurotransmitter systems. Altered levels of several neurotransmitters, including gamma-aminobutyric acid (GABA), serotonin (5-HT), dopamine (DA), and the cholinergic and noradrenergic systems, have been implicated in the development of agitation. Additionally, reduced endocannabinoid system (ECS) functionality, particularly cannabinoid receptor 1 (CB1R), has been linked to neurobehavioral alterations. Preclinical studies suggest that a decrease in CB1R levels is associated with aggressive behavior, and CB1R agonists have demonstrated beneficial effects in alleviating agitation and related symptoms. Given these findings, the current review focuses on the therapeutic potential of targeting neurotransmitter systems and CB1R dysfunction to manage agitation in AD. Full article

Schizophrenia is a complex neuropsychiatric disorder composed of primary cluster-positive symptoms, negative symptoms, disorganization, neurocognitive deficits, and social cognitive impairments. While traditional antipsychotics primarily target dopamine pathways, they provide limited efficacy against cognitive deficits and negative symptoms. Growing evidence implicates glutamatergic dysregulation, particularly N-methyl-D-aspartate receptor (NMDA-R) hypofunction, in the pathophysiology of schizophrenia, making glutamate modulation a promising therapeutic approach. This review explores emerging glutamate-based treatment strategies, including NMDA receptor modulators, metabotropic glutamate receptor (mGluR) agents, glutamate transporter regulators, and kynurenine pathway inhibitors. We summarize preclinical and clinical findings on NMDA co-agonists (D-serine and glycine), glycine transporter inhibitors, D-amino acid oxidase inhibitors, and mGluR-targeted therapies, highlighting their mechanisms, efficacy, and limitations. In addition, we discuss novel interventions aimed at restoring glutamate homeostasis, including neuroinflammatory modulation and synaptic plasticity enhancers. Despite promising results, many glutamate-targeting therapies have yielded inconsistent clinical outcomes, underscoring the need for biomarker-driven patient selection and optimized treatment protocols. We propose that integrating glutamate modulators with existing antipsychotic regimens may enhance therapeutic response while minimizing side effects. Future research should focus on refining glutamate-based interventions, identifying predictive biomarkers, and addressing the heterogeneity in schizophrenia pathology. With continued advancements, glutamate modulation has the potential to transform schizophrenia treatment, particularly for cognitive and negative symptoms that remain largely unaddressed by current therapies. Full article

Background/Objectives: Yawning, a common physiological behavior, has emerged as a potential biomarker for drug responsiveness and side effects. This scoping review synthesizes current evidence on drug-induced yawning (DIY), focusing on its neurobiological mechanisms and clinical implications. Methods: A scoping review (INPLASY registration number: INPLASY202540048) was conducted using PubMed, Scopus, and Web of Science, including studies published in the past decade. The review adhered to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and Cochrane Handbook guidelines, ensuring systematic selection. Selected articles led to the analysis of 10 relevant studies encompassing 473 participants. Studies were evaluated for relevance to DIY, neurobiology, and clinical applications, with thematic analysis used to synthesize findings. Results: Four key themes emerged. (1) Yawning patterns: DIY involves frequent episodes (up to 80 yawns/day), varying by drug type and dosage. (2) Neurobiological mechanisms: Yawning is mediated by serotonin, dopamine, and oxytocin pathways, particularly via 5-HT2C and μ-opioid receptors. (3) Drug responsiveness: DIY is linked to SSRIs, opioids, and dopamine agonists. SSRIs induce yawning, while opioids suppress it, reflecting distinct neurochemical effects. (4) Clinical implications: Yawning may serve as a non-invasive biomarker for drug efficacy and side effects, particularly in opioid withdrawal and SSRI monitoring. Conclusions: DIY holds promise as a biomarker for drug safety and effectiveness, but research is limited by small sample sizes, methodological variability, and the absence of standardized yawning metrics. Future studies should establish consistent measures, account for interindividual variability, and evaluate DIY’s long-term clinical utility across diverse populations. Full article

Huntington disease’s (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine region (PolyQ) within the huntingtin protein (HTT). Mutated huntingtin (mHTT) is cytotoxic, particularly for striatal medium spiny neurons (MSNs), whose degeneration is the hallmark of HD. Autophagy inducers currently available promote the clearance of toxic proteins. However, due to their low selectivity and the possibility that prolonged autophagy hampers essential processes in unaffected cells, researchers have questioned their benefits in neurodegenerative diseases. Since MSNs express dopamine receptors D2 (DRD2) and D3 (DRD3) and DRD2/DRD3 agonists may activate autophagy, here, we explored how healthy and mHTT-challenged cells respond to prolonged DRD2/DRD3 agonist treatment. Autophagy activation and its effects on mHTT/polyQ clearance were studied in R6/1 mice (a genetic model of HD), their wild-type littermates, and DRD2- and DRD3-HEK cells expressing a pathogenic (Q74) and a non-pathogenic (Q23) polyQ fragment of mHTT treated with the DRD2/DRD3 agonist pramipexole. Two forms of DRD3-mediated autophagy were found: a transient mTORC1-dependent in WT mice and Q23-DRD3-HEK cells and a persistent AMPK-ULK1-activated in R6/1 mice and Q74-DRD3-HEK cells. This also promoted a robust clearance of soluble mHTT/polyQ and neuroprotection in striatal neurons and DRD3-HEK cells. The findings indicate that DRD3-induced autophagy may be a safe, disease-modifying intervention in HD patients. Full article

The α7 nicotinic acetylcholine receptor (α7-nAChR) is a pivotal regulator of neurotransmission, neuroprotection, and immune modulation in the central nervous system. This review explores its structural and functional attributes, highlighting its therapeutic potential in neurodegenerative disorders, particularly Parkinson’s disease (PD). α7-nAChRs mediate synaptic plasticity, modulate inflammatory responses, and influence dopamine release, positioning them as a promising pharmacological target. Positive allosteric modulators (PAMs) enhance α7-nAChR activity mainly by reducing desensitization, offering a superior therapeutic approach compared with direct agonists. Emerging preclinical studies suggest that α7-nAChR activation mitigates dopaminergic neurodegeneration, improves L-dopa-induced dyskinesia, and reduces neuroinflammation. Despite promising findings, clinical trials have yielded mixed results, necessitating further research into optimizing α7-targeted therapies. This review underscores the significance of α7-nAChRs in PD pathophysiology and highlights future directions for their translational potential in neuroprotection and symptomatic relief. Full article