Clinical Psychopharmacology and Neuroscience最新文献

Schizophrenia is a chronic and severe mental illness associated with substantial morbidity and mortality. Antipsychotics primarily rely on direct dopamine blockade, leading to potential life-interfering adverse events. The purpose of this review is to describe the safety and efficacy of xanomeline-trospium (Cobenfy^TM), a Food and Drug Administration approved treatment for schizophrenia in adults. Xanomeline has a novel mechanism of action for the treatment of schizophrenia acting as a dual muscarinic-1 and muscarinic-4 preferring receptor agonist. Two phase 3 trials with a xanomeline- trospium up to 125 mg/30 mg 2 times daily for patients with schizophrenia saw significant reductions in PANSS positive and negative subscales, PANSS Marder negative factors, and CGI-S scale scores compared to placebo. The Cohen's d effect for the primary endpoint was around 0.60 in both trials. The medication was well-tolerated in all clinical trials with the most common adverse events being rated as mild-to-moderate. Two long-term, open-label studies with xanomeline-trospium showed that after 52 weeks of treatment more than 75% of participants achieved a > 30% improvement on PANSS total score with a mean decrease in score by 33.3 points. Other improvements were reductions in PANSS positive and negative subscales, PANSS Marder negative factor score, and CGI-S score. In both long-term studies, patients previously in the placebo groups during either phase 2 or phase 3 trials achieved a statistically significant improvement on all efficacy measures starting at week 2. These data suggest that xanomeline-trospium is an effective and well tolerated treatment for schizophrenia with a novel mechanism of action.

Objective: Psychosocial and genetic factors are considered to play roles in the etiological mechanisms of major depressive disorder (MDD). The involvement of miRNAs in the etiopathogenesis of depression and childhood traumas is still unclear. This study aims to reveal potential differences in miRNA levels between patients with depression and healthy individuals and assess their connection to childhood traumas.

Methods: This study included fifty patients with MDD and 33 healthy controls. The targeting of the 3'UTR regions of the BDNF, SLC6A4/SERT/5-HTT, HTR1a, and HTR2a genes by 8 miRNAs was analyzed to explore their potential involvement in depression and childhood traumas. The Hamilton Depression Rating Scale, the Hamilton Anxiety Rating Scale, and the Childhood Trauma Questionnaire-28 were administered to the participants.

Results: Patients with MDD exhibited significantly lower expression levels of miR-335 and miR-4775, as well as significantly higher expression levels of miR-15, miR-16, miR-17, miR-92, miR-182, and miR-206, when compared to healthy controls using the 2^-(ΔΔCt) method. Only miR-17 and miR-92 were associated with childhood traumas in the patients with depression.

Conclusion: Our research reveals a possible involvement of miRNAs in the pathophysiology of depression and highlights a potential relationship between childhood traumas and specific miRNAs in depressed patients.

Objective: Epothilone D (EpoD), microtubule (MT) stabilizing agent, demonstrated promising results in the animal models of Alzheimer's disease, Parkinson's disease and schizophrenia. The present study sought to investigate preventive effects of EpoD on altered changes of MT related proteins and endoplasmic reticulum (ER) stress proteins induced by social defeat stress (SDS).

Methods: We measured protein expression levels of α-tubulin and its post-translational modifications, MT-associated protein 2, stathmin1 and 2 with their phosphorylated forms, and ER stress markers, 78-kDa glucose-regulated protein (GRP-78) and CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP) in the prefrontal cortex (PFC) and hippocampus (HIP) of C57BL/6J strain mice treated with EpoD (2 mg/kg) or its vehicle, dimethylsulfoxide (DMSO), and exposed to SDS.

Results: We observed lower levels of acetylated α-tubulin, MAP2, p-STMN (Ser16), and GRP-78 in the PFC of the EpoD-Con group when compared to the DMSO-Con group. On the other hand, in the HIP, there were significantly higher levels of tyrosinated α-tubulin and GRP-78 in the EpoD-Defeat group compared to the DMSO-Defeat group. Furthermore, the level of MAP2 in the HIP was found to be lower in the EpoD-Con group compared to the DMSO-Con group.

Conclusion: Our results suggest that EpoD exhibits a dual impact, manifesting both beneficial and detrimental effects on the aberrant changes of MT-related proteins and ER stress proteins induced by SDS, depending on the brain regions. These findings underscore the complexity of EpoD's effects, necessitating further exploration to understand its intricate mechanisms in cellular pathways linked to SDS.

Objective: Language disorder, a prevalent developmental disorder, impedes children's communication skills, with genetic and environmental factors playing pivotal roles in its pathomechanism. This study aims to investigate the involvement of sequence variations in SETBP1 and CNTNAP2 genes, along with environmental variables, in language disorder's etiology.

Methods: Between September 2022 and March 2023, thirty children aged 2-7 diagnosed with language disorders according to DSM-5 criteria, and evaluated using the Ankara Developmental Screening Inventory, were studied to identify genetic and environmental factors contributing to etiology.Thirty healthy children with similar age were included as a control group. DNA samples isolated from peripheral blood of both groups were analyzed for SETBP1 and CNTNAP2 genes using next-generation sequencing (custom design panel). The frequencies and clinical significance of the identified variants was evaluated, and variant verification and segregation analyses were performed by Sanger sequencing. The obtained data were compared using appropriate statistical methods.

Results: Language disorder showed a male-dominant distribution. The SETBP1 rs11082414-CC genotype frequency was significantly higher in patients (p = 0.024), and two rare variants (CNTNAP2: c.973C>G:p.P325A; CNTNAP2: c.2236 G>A:p.D746N) were exclusive to cases. In silico analyses yielded conflicting results for rare variants, inherited paternally from unaffected parents. Among non-genetic factors, patients had higher birth weights (p = 0.043) and shorter lactation durations (p = 0.044).

Conclusion: Homozygosity for SETBP1 rs11082414 polymorphic variant increases language disorder susceptibility. This study underscores the genetic dimension of language disorder, urging physicians' awareness and early intervention strategies to mitigate its impact.

Rabbit syndrome (RS), characterized by fine, rapid, rhythmic movements along the mouth's vertical axis, is typically linked to prolonged antipsychotic medication use. Emerging evidence suggests newer antipsychotics' involvement in RS, prompting investigation into its association with long-acting injectable antipsychotics (LAIs) for schizophrenia or bipolar disorder. We report a case of RS observed in a patient diagnosed with bipolar I disorder and treated with Abilify Maintena, highlighting the importance of vigilance in monitoring adverse effects. The patient, a 53-year-old male, experienced persistent manic episodes despite prior treatments. Upon initiation of Abilify Maintena 400 mg, RS symptoms manifested seven months later, remaining resistant to medication adjustments. This case emphasizes the significance of RS in LAIs-treated patients and emphasizes the need for further research into its mechanisms and optimal management strategies. Additionally, an updated review of RS associated with newer generation antipsychotics is provided to enhance understanding and clinical management.

Intracellular cyclic nucleotides (cyclic adenosine monophosphate and cyclic guanosine monophosphate) and downstream cellular signal transduction are regulated by phosphodiesterases (PDEs). The neuroplasticity, neurotransmitter pathways, and neuroinflammation-controlling functions of PDEs were demonstrated in numerous in vitro and animal model studies. We comprehensively reviewed the literature regarding the expression of PDEs in various brain regions. Subsequently, articles regarding schizophrenia and PDEs were examined. The pathophysiological mechanisms of schizophrenia and PDEs in preclinical and clinical investigations are briefly reviewed. Particularly for those who do not respond to conventional antipsychotics, specific PDE inhibitors may offer innovative therapeutic alternatives. Although the connection between schizophrenia and PDEs is intriguing, additional research is required. Comprehending the brain's PDE isoforms, their therapeutic potential, and any adverse effects of inhibiting them is essential for progress in this field.

Objective: Many studies have explored sense of self in individuals with autism spectrum disorder (ASD); however, few have reported on their experience of "disembodiment." This study aimed to investigate the differences in brain activity between patients with ASD and neurotypicals (NTs) under conditions causing disembodiment and to examine the correlation between their interoceptive abilities and disembodiment-related brain activity.

Methods: 18 Participants with ASD and 21 NTs completed psychological evaluations, interoceptive abilities measurement, and functional magnetic resonance imaging (fMRI). The fMRI images were taken while the participants performed tasks involving ball-throwing animations. The task focused on either self-agency related to ball-throwing (Agency Task) or the spatial location of a ball (Location Task). The animations were presented from constantly changing perspective (Changing View) or fixed perspective (Fixed View). The disembodiment-related condition was the interaction between the Agency Task and Changing View.

Results: Participants with ASD exhibited higher activation than NTs in regions near the left parieto-temporo-occipital junction, left precuneus, left hippocampus, and other brain areas. Furthermore, interoceptive accuracy was negatively correlated with the activity of the left superior parietal and posterior midcingulate areas, whereas interoceptive trait prediction error was positively correlated with the activity of the left hippocampus, mid-temporal area, and left posterior cingulate area in participants with ASD.

Conclusion: These results suggest that disembodiment-related brain activation might be easily manifested by the interaction between perspective-shifting and the experience of agency, and that interoceptive abilities might be related to disembodiment-related brain activation in individuals with ASD.

This case report explores the therapeutic potential of theta burst stimulation (TBS) for cognitive enhancement in individuals with brain injuries. The study presents a 38-year-old male suffering from an organic mental disorder attributed to a traumatic brain injury (TBI), who demonstrated notable cognitive improvements following an intensive TBS protocol targeting the left dorsal lateral prefrontal cortex. The treatment led to significant enhancements in impulse control, irritability, and verbal comprehension without adverse effects. Neuropsychological assessments and brain imaging post-intervention revealed improvements in short-term memory, abstract reasoning, list-generating fluency, and increased cerebral blood flow in the prefrontal cortex. These findings suggest that TBS, by promoting neural plasticity and reconfiguring neural networks, offers a promising avenue for cognitive rehabilitation in TBI patients. Further research is warranted to optimize TBS protocols and understand the mechanisms underlying its cognitive benefits.

Objective: Cerebral ischemia is a medical condition that occurs due to poor supply of blood in the brain. Reperfusion being savage further exaggerates the tissue injury causing cerebral ischemia/reperfusion injury (CI/R). CI/R is marked by an impairment in release of neurotransmitter, excitotoxicity, oxidative stress, inflammation, and neuronal apoptosis. The current study has utilized brivaracetam (BRV), a synaptic vesicle protein 2A modulator in experimental model of CI/R injury.

Methods: CI/R injury was induced in Swiss Albino mice by occlusion of common carotid arteries followed by reperfusion. Animals were assessed for learning and memory, motor coordination (Rota rod, lateral push, and inclined beam walking test), cerebral infarction, and histopathological alterations. Biochemical assessments were made for oxidative stress (thiobarbituric acid reactive species, reduced glutathione, catalase, superoxide dismutase), inflammation (tumor necrosis factor-α and interleukin-10), and acetylcholinesterase activity (AChE) in brain supernatants.

Results: CI/R animals showed impairment in learning, memory, and motor coordination, along with increase in cerebral infarction, and histopathological alterations. Furthermore, increase in brain oxidative stress, inflammation, and AChE activity were recorded in CI/R animals. Administration of BRV (10 mg/kg and 20 mg/kg; p.o.) was observed to recuperate CI/R induced impairments in behavioral, biochemical, and histopathological analysis.

Conclusion: It may be concluded that BRV mediates neuroprotection during CI/R via decreasing brain oxidative stress, inflammation, and AChE activity.

Auditory/visual hallucinations and perceptual anomalies are one of the core symptoms experienced by patients with schizophrenia. Studies have implicated lateral occipital cortex (LOC) as one of the areas to be aberrantly functioning in schizophrenia, possibly associated with the auditory/visual symptoms of schizophrenia. Here we report of a case of a 29-year-old female diagnosed with treatment resistant schizophrenia on clozapine with persistent auditory verbal hallucinations (AVH) and visual anomalies. Upon targeting the LOC (-40, -66, -8) in this patient, there was a > 25% reduction in AVH, with reduction in the frequency of most visual anomalies and an overall significant response in terms of reduction of symptoms and improvement in functioning. We further discuss the potential of LOC as a novel target for neuromodulation in patients exhibiting perceptual abnormalities especially in auditory and visual senses.