Extrapyramidal Research Articles

SLC9A6-Linked Parkinson Syndrome in Female Heterozygotes Is Associated With PET-Detectable Tau Pathology.

A previous postmortem study of men with Christianson syndrome, a disorder caused by loss-of-function mutations in the gene SLC9A6, reported a mechanistic link between pathologic tau accumulation and progressive symptoms such as cerebellar atrophy and cognitive decline. This study aimed to characterize the relationships between neuropathologic manifestations and tau accumulation in heterozygous women with SLC9A6 mutation. We conducted a multimodal neuroimaging and plasma biomarker study on 3 middle-aged heterozygous women with SLC9A6 mutations (proband 1: mid-50s; proband 2: early 50s; proband 3: mid-40s) presenting with progressive extrapyramidal symptoms. Examinations included 11C-PiB PET; 18F-florzolotau PET; structural MRI; and plasma measures of neurofilament light chain (NfL) polypeptide, glial fibrillary acidic protein, phosphorylated (p)Tau181, Aβ40, and Aβ42. Neuroimaging results of all 3 patients were compared with those of 12 healthy age-matched women (49.8 ± 4.7 years) while plasma biomarker levels of probands 1 and 2 were compared with those of 14 age-matched healthy women (54.1 ± 9.0 years). Proband 1 was diagnosed with Parkinson disease while probands 2 and 3 were diagnosed with atypical parkinsonism. 11C-PiB PET results were negative in all patients. 18F-florzolotau PET revealed focal tau accumulations in all 3 patients, predominantly in the striatum contralateral to motor symptoms. Moreover, greater extrapyramidal symptom severity was associated with higher standardized uptake value ratios (SUVRs) for 18F-florzolotau in the striatum. Multiple comparisons showed significantly higher 18F-florzolotau SUVR values in both the caudate and putamen of proband 1, who exhibited the most severe extrapyramidal signs, while no significant increases in 18F-florzolotau SUVR values were detected in any brain region of probands 2 and 3. Structural MRI revealed slightly lower regional subcortical and gray matter volumes in all patients but not significant after multiple comparisons. Finally, plasma NfL concentration was significantly higher in probands 1 and 2 compared with healthy controls. Our 18F-florzolotau PET analysis revealed greater tau accumulation in the striatum of heterozygous women with SLC9A6 mutation associated with worsening extrapyramidal symptom severity. The heterozygosity of loss-of-function SLC9A6 mutations further suggests that tauopathy may be a primary contributor to extrapyramidal signs.

A Review on Therapeutic Strategies against Parkinson's Disease: Current Trends and Future Perspectives.

Parkinson's Disease (PD) is the most common neurodegenerative disorder after Alzheimer's Disease and is clinically expressed by movement disorders, such as tremor, bradykinesia, and rigidity. It occurs mainly in the extrapyramidal system of the brain and is characterized by dopaminergic neuron degeneration. L-DOPA, dopaminergic agonists, anticholinergic drugs, and MAO-B inhibitors are currently used as therapeutic agents against PD, however, they have only symptomatic efficacy, mainly due to the complex pathophysiology of the disease. This review summarizes the main aspects of PD pathology, as well as, discusses the most important biochemical dysfunctions during PD, and presents novel multi-targeting compounds, which have been tested for their activity against various targets related to PD. This review selects various research articles from main databases concerning multi-targeting compounds against PD. Molecules targeting more than one biochemical pathway involved in PD, expected to be more effective than the current treatment options, are discussed. A great number of research groups have designed novel compounds following the multi-targeting drug approach. They include structures combining antioxidant, antiinflammatory, and metal-chelating properties. These compounds could be proven useful for effective multi-targeted PD treatment. Multi-targeting drugs could be a useful tool for the design of effective antiparkinson agents. Their efficacy towards various targets implicated in PD could be the key to the radical treatment of this neurodegenerative disorder.

The Secure Therapeutic Effects of Recently Developed Antipsychotic Drugs and Updated Neural Networks in Schizophrenia

Introduction: Schizophrenia and schizoaffective disorder are treated in most cases with antipsychotic drugs of the second generation. These drugs block dopaminergic and serotonergic receptors, i.e., D2 and 5-HT2A receptors, and cause different adverse effects, for example, movement disturbances of the extrapyramidal system and adverse effects of vital parameters and of the heart. These drugs treat positive symptoms in schizophrenia and, to a lesser extent, negative symptoms. This review presents the development of newer antipsychotic drugs. Methods/Material: References were taken from PubMed after using the following keywords: schizophrenia, schizoaffective disorder, antipsychotic drug, neurotransmitter and neuropeptide. Among these newer antipsychotic drugs are cariprazine, brexipiprazole and lumateperone, which exert a partial agonistic effect at D2 and 5-HT2A receptors, pimavanserin, a 5-HT2A receptor antagonist which treats negative symptoms in schizophrenia as an add-on therapy, olanzapine combined with samidorphan, which reduces weight gain, and M4 or M1 receptor agonists, for example, xanomeline with an antipsychotic effect combined with trospium, an anticholinergic drug. Neural networks were updated in order to deduce the antipsychotic mechanism of action of newer antipsychotic drugs, especially xanomeline. Results: The newer antipsychotic drugs cariprazine, brexipiprazole and lumateperone show antipsychotic, antimanic and anti-depressive effects, however, the efficacy on psychotic symptoms in long-term treatment has not yet been examined. Pimavanserin reduces negative symptoms in schizophrenia as an additional pharmacotherapy to treat this disorder. Olanzapine combined with samidorphan exerts good antipsychotic effects and reduces weight gain. The new antipsychotic drug xanomeline, the antipsychotic effect of which is quite different from the antidopaminergic effect, treats positive and negative symptoms in schizophrenia. Its mechanism of action was deduced from the neural networks presented. The long-term efficacy should still be examined. Conclusion: This review is focused on newer antipsychotic drugs. The long-term efficacy of cariprazine, brexipiprazole and lumateperone in the treatment of schizophrenia should be examined furthermore. Neural networks in the brain areas involved in schizophrenia should be examined and updated furthermore. Newer antipsychotic drugs, for example, xanomeline, an M4 or M1 receptor agonist, which has been combined with trospium, an anticholinergic drug, the mechanism of action of which can be derived from the neural network suggested in this review.

D1 dopamine receptor antagonists as a new therapeutic strategy to treat autistic-like behaviours in lysosomal storage disorders.

Lysosomal storage disorders characterized by defective heparan sulfate (HS) degradation, such as Mucopolysaccharidosis type IIIA-D (MPS-IIIA-D), result in neurodegeneration and dementia in children. However, dementia is preceded by severe autistic-like behaviours (ALBs), presenting as hyperactivity, stereotypies, social interaction deficits, and sleep disturbances. The absence of experimental studies on ALBs' mechanisms in MPS-III has led clinicians to adopt symptomatic treatments, such as antipsychotics, which are used for non-genetic neuropsychiatric disorders. However, they have limited efficacy in MPS-III and lead to higher extrapyramidal effects, leaving ALBs in MPS-IIIA as an unmet medical need with a significant burden on patients and their families. Using mouse and cellular models of MPS-IIIA, we have previously shown that ALBs result from increased proliferation of mesencephalic dopamine neurons during embryogenesis. In adulthood, MPS-IIIA mice exhibit an imbalance of dopaminergic receptor subtypes, resulting in striatal overstimulation of the D1 dopamine receptor (D1R)-direct pathway, contrasting with a downregulation of the D2 dopamine receptor (D2R)-indirect pathway. In this study, we aimed to provide an evidence-based pharmacological approach for managing ALBs in MPS-IIIA. We hypothesized that rebalancing dopaminergic receptor signalling with a D1R antagonist, rather than a D2 antagonist, would lead to safe and effective treatment. Neither risperidone nor methylphenidate improves ALBs in the MPS-IIIA mouse model, with the former showing increased cataleptic (extrapyramidal-like) side effects compared to littermate wild-type animals. Methylphenidate, however, showed some beneficial effects on neuroinflammation and later manifesting dementia-like behaviours. In contrast, ecopipam, a D1 antagonist already used in the clinic for other neuropsychiatric disorders, rescues ALBs, cognition, D1 hyperactivity, and does not worsen neurodegenerative signs. These results align with recent evidence highlighting the clinical relevance of D1 antagonists for neuropsychiatric disorders and pave the way for their use in managing psychotic symptoms in neurodegenerative disorders such as dementia with Lewy bodies.

Clinical Diagnosis and Differential Diagnosis Between CSF1R- and AARS2-Related Leukoencephalopathy.

CSF1R-related leukoencephalopathy (CSF1R-L) and AARS2-related leukoencephalopathy (AARS2-L) were two disease entities sharing similar phenotype and even pathological changes. Although clinically, radiologically, and pathologically similar, they were caused by mutation of two different genes. As the rarity of the two diseases, the differential diagnosis of them was difficult. 23 CSF1R-L and 6 AARS2-L patients were enrolled from the Leukoencephalopathy Clinic, Peking Union Medical College Hospital in China. Detailed clinical information, neuroimaging manifestations, and genetic data were collected and analyzed. Demographically, female patients were more in AARS2-L than CSF1R-L. Clinically, cognitive impairment and emotion/personality change were common in both groups. Bulbar palsy, extrapyramidal symptoms, and hemiplegia/pyramidal impairment were more common in CSF1R-L, while ataxia was significantly more common in AARS2-L. Abnormal menstruation including infertility was significantly more in AARS2-L. Radiologically, similar features were found, including lateral ventricle-centered white matter lesions, involving corpus callosum, avoiding U fibers. The lesions showed persistent hyperintensity on DWI image and were not contrasted after gadolinium enhancement. In CSF1R-L, the lesions could be widespread confluent or patchy and spotted, extending to centrum semiovale and subcortical white matter occasionally, which was significantly different from AARS2-L. Besides, brain stem lesion caused by pyramidal degeneration, spotted or linear calcification and obviously brain atrophy were common in CSF1R-L. In AARS2-L, periventricular white matter rarefaction was significantly common. No genotype and phenotype association was found in these two diseases. Although similar, there were several clinical and radiological features helping differentiating the two distinct diseases.

Extrapyramidal effects in a young child with acute organophosphorus insecticide poisoning

Extrapyramidal effects in a young child with acute organophosphorus insecticide poisoning

Pharmacotherapy for Agitation Management in a Pediatric Emergency Department.

In the treatment of agitation in a pediatric emergency department (PED), it is common to use once or as needed (PRN) medications when nonpharmacological management options have failed. Currently, there is limited available evidence on the treatment of pediatric agitation. The objective of this analysis was to characterize the prescribing practices of once or PRN medications for the treatment of agitation in a PED at an academic medical center. This was a retrospective chart review of all encounters in which a patient was administered once or PRN medications for agitation treatment in the PED from July 1, 2021, to June 30, 2022. Once or PRN medications were defined as any medication in the antipsychotic, benzodiazepine, and barbiturate classes along with diphenhydramine, clonidine, ketamine, and guanfacine. The primary outcome was to describe the prescribing patterns of the most utilized agents for the treatment of agitation in the PED. Secondary outcomes were to assess effectiveness and safety of the agents utilized. We reviewed 109 patient encounters in which a once or PRN medication was used for agitation treatment. The most common initial regimens were benzodiazepine monotherapy (n = 47; 43%), antipsychotic monotherapy (n = 23; 21%), and concurrent use of an antipsychotic, benzodiazepine, and diphenhydramine (n = 16; 15%). Patients required another administration of a once or PRN medication within 5 to 120 minutes of initial administration 11% (n = 12) of the time. No patients required rapid sequence intubation and one patient (0.9%) needed treatment for extrapyramidal symptoms. Results indicate that there is not a standard regimen choice in the treatment of agitation in the PED; however, benzodiazepine monotherapy was used most frequently. Few adverse events occurred. Further research is needed to identify the optimal regimen choice for patients presenting with agitation in a PED.

Antidopaminergic medications in Huntington's disease

Huntington's disease (HD) is a progressive neurodegenerative disorder marked by motor, cognitive, and behavioral impairments. Antidopaminergic medications (ADMs), such as VMAT2 inhibitors and antipsychotics, are commonly used to manage HD motor disturbances and behavioral disorders. For patients and caregivers, ADMs are an important tool for managing symptoms that negatively affect daily life. However, the impact of ADM use in HD is not firmly understood due to a lack of robust, systematic studies that assessed their overall effect on HD disease. A mounting body of evidence suggests these medications may be associated with worse clinical measures of cognitive function and functional impairment. While regulatory guidelines highlight adverse effects like sedation, cognitive dysfunction, and extrapyramidal symptoms, it is unclear whether ADMs directly impact disease progression or if the side effects mimic or exacerbate measures of HD symptoms in clinical trials. Given ADM effects on the central nervous system and biological uncertainty within HD outcomes, clinical trial designs should recognize the impact of ADMs on key outcomes, as measured by acceptable scales including Total Functional Capacity, Stoop Word Reading, Symbol Digit Modality Test, and the composite Unified Huntington's Disease Rating Scale. The development of novel HD interventions requires consideration of concomitant ADM use that may influence measures of disease presentation. In this review, we highlight the role of ADMs in HD management, their symptomatic benefits and potential risks, especially with high dose associated side effects, interactions with CYP2D6 inhibitors, and the individualized need for careful dose monitoring for clinical care and trial design.

DRopEridol for Abdominal pain in the emergency department for Morphine Equivalent Reduction. The DREAMER study.

Droperidol is a dopamine-2 receptor antagonist in the class of butyrophenone antipsychotics with antiemetic, sedative, analgesic, and anxiolytic properties. In the postoperative setting, droperidol provides an opioid sparing effect and decreases nausea/vomiting. Another butyrophenone antipsychotic, haloperidol, has been shown to reduce morphine milliequivalents (MME) administered when used for abdominal pain in the emergency department (ED). The purpose of this study is to evaluate if the use of droperidol for undifferentiated abdominal pain reduces the amount of MME administered in the ED. This retrospective, single-center study included patients ≥18years old who presented to the ED for undifferentiated abdominal pain. Patients must have had two separate encounters for abdominal pain, one encounter where they received droperidol and one encounter where they did not receive droperidol but did receive an opioid. The primary outcome was the difference in MME administered between the two separate patient encounters. Secondary outcomes included utilization rates of rescue antiemetics, rescue analgesics, admission to the hospital, hospital length of stay, and adverse effects (including arrhythmias and extrapyramidal symptoms). Fifty patients with self-matched encounters were evaluated. A majority of the patients were female (33/50, 66%) with a median age of 38years old. All doses of droperidol were intravenous and the majority of patients received a dose of 2.5mg (34/50, 68%; range 1.25-5mg). Non-droperidol encounters received significantly more MME compared to droperidol encounters (19.4 MME [IQR 12-30] vs 10 MME [IQR 0-20], p-value 0.0002). There were no statistically significant differences between the secondary outcomes. Among patients presenting to the ED for abdominal pain, droperidol administration resulted in a significant reduction in MME administration. Future research should include prospective studies, comparison of droperidol to haloperidol, and investigate droperidol use beyond the ED for these encounters.

A Case of Wilson's Disease Preceded by Schizophrenia-like Symptoms with Frontal-dominant Leukoencephalopathy.

We herein report a 26-year-old man diagnosed with Wilson's disease (WD), initially treated for schizophrenia for 11 years. At 26 years old, he was admitted because of status epilepticus. Brain magnetic resonance imaging revealed frontal-dominant leukoencephalopathy with cystic changes and basal ganglia atrophy. The diagnosis of WD was confirmed based on neuropsychiatric symptoms, Kayser-Fleischer rings, abnormal copper metabolism, and a genetic analysis of ATP7B. Psychotic symptoms in WD can precede neurological manifestations, and extrapyramidal signs may be mistaken for drug-induced Parkinsonism. WD should be considered in patients presenting with progressive Parkinsonism preceded by schizophrenia-like psychiatric symptoms.

Association Between Dynapenia/Sarcopenia, Extrapyramidal Symptoms, Negative Symptoms, Body Composition, and Nutritional Status in Patients with Chronic Schizophrenia.

Background/Objectives: This study aimed to determine the association between chronic schizophrenia, extrapyramidal symptoms (EPSs), body composition, nutritional status, and dynapenia/sarcopenia. Methods: Data from 68 chronic patients with schizophrenia were analyzed using Spearman's rho correlation coefficients, Kruskal-Wallis test, Mann-Whitney U test, and Cramér's V statistics. Results: Among the participants, 32.4% had no loss of muscle mass or function, 39.7% had dynapenia, and 27.9% had sarcopenia. This study identified five key findings: (1) Bilateral grip strength, skeletal muscle index, and walking speed are interrelated, with higher negative symptom scores linked to slower movement and rigidity, particularly in the sarcopenia group, indicating that negative symptoms may contribute to muscle weakness and progression to sarcopenia. (2) Increasing age is associated with a decrease in chlorpromazine equivalent dose and an increase in the severity of EPSs. (3) Blood urea nitrogen (BUN)/creatinine ratio and all sarcopenia risk indicators were significantly negatively correlated. (4) Dynapenia and sarcopenia groups exhibited significant differences in muscle mass and nutritional status compared to the non-penia group, including reduced muscle mass, lower basal metabolic rate, and lower visceral fat levels. (5) There was an association between the Barthel Index (BI) score for activities of daily living (ADL) and dynapenia/sarcopenia. Particularly with regard to ADL, it seems necessary to pay attention to muscle weakness in partially independent patients who score 60 points or more. Conclusions: BUN/creatinine ratio, BI, EPSs, body mass index, grip strength, total protein, and albumin were useful indicators for detecting the risk of dynapenia/sarcopenia in routine psychiatric care.

Effectiveness and safety of aripiprazole oral solution in the acute treatment of schizophrenia in Chinese patients

BackgroundThis study investigates the effectiveness and safety of aripiprazole oral solution in Chinese patients with schizophrenia.MethodsThis was a multicenter, single-arm phase IV study involving 134 patients in China in the acute stage of schizophrenia from May 2021 to July 2022. The patients received aripiprazole oral solution 10 − 30 mg/d for 12 weeks. The effectiveness endpoints included the Positive and Negative Symptom Scale (PANSS) and the Clinical Global Impression (CGI) scale score. The safety endpoints included adverse events, laboratory inspection indicators (including the serum prolactin level [PRL]), and waist circumferences (WC).ResultsUltimately, 86 patients (64.18%) completed the trial, and 21 patients (15.67%) dropped out due to poor effectiveness. From baseline to week eight, 43.28% of patients had a PANSS reduction of ≥ 50%, 82.84% of patients improved in the CGI-Improvement (CGI-I scale score of 1 − 3), and the percentage of patients with abnormal PRL and waist circumferences decreased significantly. In total, 45 patients (33.58%) experienced mild adverse drug reactions predominately manifested as extrapyramidal symptoms (EPSs; 9.70%), constipation (8.96%), and palpitations (7.46%). Upon further subgroup analysis, aripiprazole oral solution demonstrated significantly improved effectiveness in first-episode schizophrenia patients and those with symptoms of agitation.ConclusionsAripiprazole oral solution displayed positive clinical effectiveness and favorable tolerability in Chinese patients in the acute stage of schizophrenia.Clinical trial registrationClinical trial registration number: ChiCTR2100044653. Name of trial registration: A real-world study of Aripiprazole Oral Solution in the treatment of schizophrenia (Registration date: 25/03/2021). The full trial protocol can be accessed at the Chinese Clinical Trial Registry ( http://www.chictr.org.cn/).

Pentoxifylline adjunct to risperidone for negative symptoms of stable schizophrenia: A randomized, double-blind, placebo-controlled trial

Abstract Background Negative symptoms of schizophrenia represent an unmet therapeutic need for many patients on whom pentoxifylline may be effective in terms of its dopaminergic, anti-inflammatory, and cerebral blood flow-increasing properties. This study aimed to evaluate pentoxifylline as a therapeutic agent for improving negative symptoms of schizophrenia. Methods Chronic schizophrenia outpatients experiencing significant negative symptoms were randomly allocated to receive pentoxifylline 400 mg or matched placebo q12hr for eight weeks. All patients were clinically stable as they had received risperidone for at least two months, which was continued. The participants were assessed using the Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale (HDRS), Extrapyramidal Symptom Rating Scale (ESRS), and side effect checklist. Results The patients’ baseline characteristics were comparable between the groups. There was a significant time-treatment interaction effect on PANSS negative subscale scores (ηP2=0.075), with the pentoxifylline group showing significantly greater reductions until weeks 4 (Cohen’s d=0.512) and 8 (Cohen’s d=0.622). Also, this group showed a significantly better response by week 8. Other PANSS scores, HDRS scores, ESRS scores, and side effect frequencies were comparable between the groups. Pentoxifylline showed a non-significant higher remission of 37.1% compared to 14.7% in the placebo group. Conclusions Pentoxifylline was beneficial for the primary negative symptoms of chronic schizophrenia safely and tolerably.

Evaluating Adverse Drug Reactions, Their Reporting Rates and Their Impact on Attitudes Toward Pharmacotherapy Among Female Patients with Schizophrenia: Insights and Implications from a Cross-Sectional Study

Background/Objectives: Schizophrenia is a chronic psychiatric disorder usually managed with antipsychotics, which can cause adverse drug reactions (ADRs) that may impact patients’ attitudes toward their treatment, as well as treatment adherence. This study aimed to assess the influence of ADRs and other factors on treatment attitudes among female patients with schizophrenia. Methods: A cross-sectional study was conducted at the Vrapče Psychiatry Clinic with 109 female schizophrenia patients. The DAI-10 (Drug Attitude Inventory) questionnaire was used to assess attitudes toward treatment. Data on their demographic details, pharmacotherapy, ADR occurrence and ADR reporting rates were collected. Multiple regression analyses were used to identify predictors of DAI-10 scores. Results: Patients using more medications and those experiencing ADRs had lower DAI-10 scores, indicating less favorable attitudes (F (2, 106) = 7.364, p = 0.001, R2 = 0.105). ADRs, primarily extrapyramidal symptoms and weight gain, were reported by 43.1% of patients; however, only one patient formally reported them. First-generation antipsychotics were associated with a higher prevalence of ADRs (χ2 = 4.969, df = 1, p = 0.022). Conclusion: Negative experiences with ADRs significantly impact patients’ attitudes and adherence. Low ADR reporting rates highlight the need for better pharmacovigilance education. Enhancing patient awareness may foster more positive attitudes and adherence, potentially improving patient outcomes.

The impact of emotional burnout in psychiatrists on the outcomes of the care they provide

The quality of medical care largely depends on the mental well-being of medical staff. One of the most common manifestations of work-related distress is emotional burnout syndrome (EBS). The emotional burnout in psychiatrists is favored by many specific work factors.Objective: to investigate the relationship between EBS in psychiatrists and the outcomes of the care they provide.Material and methods. Eighty-two psychiatrists working in psychiatric clinics in Moscow took part in the study. They completed the Maslach Burnout Inventory on their own. Two hundred medical records of hospitalized patients suffering from paranoid schizophrenia were selected. A total of 100 patient records of psychiatrists with emotional burnout and 100 patient records of psychiatrists without emotional burnout were analyzed.Results. Emotional burnout was found in 25.6% of psychiatrists. In cases of emotional burnout, psychiatrists were more likely to prescribe anticholinergic corrective medication for extrapyramidal symptoms (61% versus 44%; p=0.023). The presence of emotional burnout in psychiatrists correlated with a longer duration of hospitalization of patients they cared for (31.2 versus 29 days; p=0.004) and with more frequent polypharmacy (67% versus 51%; p=0.031).Conclusion. Emotional burnout in psychiatrists has a negative impact on the quality of care they provide.

Crocus sativus (saffron) adjunct to risperidone for negative symptoms of schizophrenia: a randomized, double-blind, placebo-controlled trial.

Current treatments for schizophrenia encounter resistance, limited efficacy, and limiting complications, necessitating novel approaches. The effects of saffron on negative symptoms were investigated as it has shown neuroprotective and antipsychotic properties. Fifty-six clinically stable chronic schizophrenic outpatients were equally assigned to saffron 15 mg q12hr or placebo groups while continuing risperidone. The Positive and Negative Syndrome Scale (PANSS) was used to assess schizophrenia-related symptoms in weeks 4 and 8. Also, the patients were assessed for the Hamilton depression rating scale (HDRS) and adverse effects. The baseline characteristics of the groups were comparable (Ps > 0.05). There were significant time-treatment interaction effects on negative ( = 0.137), general psychopathology ( = 0.193), and total ( = 0.113) PANSS scores. Affirmatively, their reductions were significantly greater in the saffron group until weeks 4 (Cohen's ds = 0.922, 0.898, and 0.759, respectively) and 8 (Cohen's ds = 0.850, 1.047, and 0.705, respectively). Regarding the negative symptoms, a better 25% response rate was obtained in the saffron group until the endpoint (P = 0.003). The HDRS scores, extrapyramidal symptom rating scale scores, and side effect frequencies were comparable between the groups (Ps > 0.05). Saffron was beneficial for primary negative symptoms of chronic schizophrenia in a safe and tolerable manner. It also outperformed placebo in improving general psychopathology and total symptoms.

Exploring the Pharmacological and Clinical Features of Lumateperone: A Promising Novel Antipsychotic.

Lumateperone is a novel antipsychotic recently approved for the treatment of schizophrenia. Its unique pharmacological profile includes modulation of serotonergic, dopaminergic, and glutamatergic neurotransmission, differentiating it from other second-generation antipsychotics. This paper explores the pharmacological features and clinical potential of lumateperone across neuropsychiatric conditions. A review of current literature, including pharmacokinetic and pharmacodynamic studies, was conducted. It focused on lumateperone's mechanism of action and receptor-binding profile, and clinical trials assessing its efficacy and safety in schizophrenia and other psychiatric disorders. Lumateperone demonstrates high affinity for 5-HT2A receptors, moderate affinity for D2 receptors, and low affinity for H1 and 5-HT2C receptors. It acts as a presynaptic D2 agonist and a postsynaptic antagonist, contributing to a favorable side-effect profile with reduced extrapyramidal symptoms. Clinical trials suggest that lumateperone is effective in reducing both positive and negative symptoms of schizophrenia, with minimal metabolic and cardiovascular risks. It is also being explored as an adjunctive therapy for major depressive disorder and bipolar depression. Lumateperone presents a promising therapeutic option for schizophrenia with a novel mechanism of action and a favorable safety profile. Its potential application in other psychiatric conditions warrants further investigation, particularly in treatment-resistant populations.

NOTCH3 variants of unknown significance underpin vascular dysfunction in neurodegenerative disease: a case series of three nfvPPA-FTD patients.

The NOTCH3 gene encodes for an evolutionarily conserved protein, whose functions encompass both embryonic cell proliferation and adult tissue-specific differentiation. Among others, a pivotal role in maintaining functional integrity of neurovascular unit (NVU) is supported by the association of several NOTCH3 gene mutations with neuroimaging markers of cerebral small vessel disease (SVD). Indeed, a pathogenic role of NOTCH3 is recognised in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). However, an increasing number of NOTCH3 variants with unclear pathogenic role have been identified in patients suspected of having CADASIL. The following case series describes three patients under the age of 65 with clinical diagnosis of nonfluent-variant of primary progressive aphasia (nfvPPA), whose genetic analysis revealed the presence of three distinct novel variants of unknown significance (VUS) in NOTCH3 gene. The diagnostic work-up revealed common features among the patients: clinical presentation -nfvPPA at neuropsychological evaluation with consistent extrapyramidal symptoms; neuroimaging -low brain MR burden of SVD and FDG-PET impairment of cortical areas involved in speech production network; and biomarkers -Cerebrospinal fluid (CSF) analysis negative for Alzheimer's Disease (AD), corroborating suspicion of underlying Frontotemporal Lobe Degeneration (FTLD). The retrieved VUS in NOTCH3 suggest that the involvement of Notch signalling in pathophysiology of neurodegenerative disease is more complex and needs to be fully explored. Rare variants in SVD-associated genes may influence progression of neurodegeneration via the dysfunction of several vascular pathways.

Haloperidol-Induced Catalepsy and Its Correlations with Acetylcholinesterase Activity in Different Brain Structures of Mice.

Antipsychotic medicines are used to treat several psychological disorders and some symptoms caused by dementia and schizophrenia. Haloperidol (Hal) is a typical antipsychotic usually used to treat psychosis; however, its use causes motor or extrapyramidal symptoms (EPS) such as catalepsy. Hal blocks the function of presynaptic D2 receptors on cholinergic interneurons, leading to the release of acetylcholine (ACh), which is hydrolyzed by the enzyme acetylcholinesterase (AChE). This study was designed to investigate the Hal-inhibitory effects on AChE activity in regions representative of the cholinergic system of mice and potential associations between cataleptic effects generated by Hal using therapeutic doses and their inhibitory effects on AChE. The distribution of the AChE activity in the different regions of the brain followed the order striatum > hippocampus > (prefrontal cortex/hypothalamus/ cerebellum) > brainstem > septo-hippocampal system. In ex vivo assays, Hal inhibited AChE activity obtained from homogenate tissue of the striatum, hippocampus, and septo-hippocampal system in a concentration-dependent manner. The inhibitory concentration of 50% of enzyme activity (IC50) indicated that the septo-hippocampal system required a higher concentration of Hal (IC50 = 202.5 µmol·L-1) to inhibit AChE activity compared to the striatum (IC50 = 162.5 µmol·L-1) and hippocampus (IC50 = 145 µmol·L-1). In in vivo assays, male Swiss mice treated with concentrations of Hal higher than 0.1 mg·kg-1 induced cataleptic effects. Positive correlations with Spearman's correlation were observed only between the lack of cataleptic effect and the decreased AChE activity of the hippocampus in the mice treated with 0.01 mg·kg-1 of Hal but not in the striatum and septo-hippocampal system. Our results suggest that Hal could increase cholinergic effects via AChE inhibition, in addition to its dopamine antagonist effect, as an alternative approach to the treatment of behavioral disturbances associated with dementia.

Steroid-Induced Psychosis in a Child With Nephrotic Syndrome Secondary to Focal Segmental Glomerulosclerosis: A Case Report.

Corticosteroid-induced psychosis is rare and less reported in children compared to adults. However, psychosis is considered a severe adverse effect of corticosteroids in pediatric nephrotic syndrome. Steroid-induced psychosis is dose-dependent and should be treated by tapering the dose of steroids and usually initiating an atypical antipsychotic. A 13-year-old male child presented to the pediatrics outpatient department with complaints of anxiety, fearfulness, and seeing images of an old man crawling into his room and threatening to strangle him with a red rope, which led to decreased sleep. He was initiated on oral prednisolone 3 weeks ago after being diagnosed with nephrotic syndrome. A diagnosis of steroid-induced psychosis was made, and he was tapered on steroids over 6 weeks. He was then initiated on tacrolimus, quetiapine, and lorazepam and was discharged after a week. At follow-up in 4 weeks, his psychosis had resolved, and nephrotic syndrome was found to improve. Children on steroids should be closely monitored for psychotic symptoms over a prolonged duration. Although tapering the dose of steroids is the gold standard treatment of steroid-induced psychosis, cases like nephrotic syndrome demand the continuous use of an immunosuppressant. In such cases, tacrolimus has been found to be an effective alternative, although continuous monitoring for nephrotoxicity is necessary. Similarly, atypical antipsychotics (like quetiapine) are preferred for psychosis because of their lesser risk for extrapyramidal side effects compared to typicals. Parental counseling and informed consent are utmost for children on steroids or tacrolimus.