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EClinicalMedicine Mar 2024Antipsychotics are the gold standard treatment for schizophrenia, but many patients who receive treatment experience persistent symptoms. The aim of this network...
BACKGROUND
Antipsychotics are the gold standard treatment for schizophrenia, but many patients who receive treatment experience persistent symptoms. The aim of this network meta-analysis was to determine the efficacy of augmentation drugs for the treatment of schizophrenia.
METHODS
In accordance with the PRISMA statement, the PubMed, Web of Science, Google Scholar, CENTRAL, clinical trial and EUDRACT databases were searched from inception to May 15th, 2023. To ensure the robustness of the results, only double-blind randomised controlled trials with a low risk of bias (measured by the Risk Of Bias v2 (ROB2) tool) were included. The studies were categorised according to the background regimen: participants were treated with risperidone, mixed antipsychotics or clozapine. A Bayesian network meta-analysis was conducted using a random effects model. PROSPERO register: CRD42023420964.
FINDINGS
A total of 44 trials (comprising 45 augmentation drugs and 3358 participants) were included in the analysis. One-third of the drugs (16 drugs) demonstrated significant efficacy vs. placebo for at least one outcome. The most notable effect sizes (ESs) were observed for the use of tropisetron (standard mean difference: -0.83 [95% interval confidence -1.12 to -0.55]), memantine (-0.50 [-0.66 to -0.32]) and minocycline (-0.56 [-0.72 to -0.39]) to treat negative symptoms among patients treated with risperidone (moderate-to-high ESs). Studies involving mixed antipsychotics yielded lower ESs (small-to-moderate). Sodium benzoate (-0.41 [-0.60 to -0.21]) and memantine (-0.23 [-0.36 to -0.11]) were found have significant effects on positive symptoms, while memantine demonstrated efficacy for negative symptoms (-0.32 [-0.45 to -0.19]) and general psychopathology (-0.32 [-0.44 to -0.20]). Studies focusing exclusively on patients treated with clozapine revealed that duloxetine produced the best results (negative symptoms: -1.12 [-1.35 to -0.91]). Sodium benzoate was the only augmentation drug that demonstrated efficacy in relieving persistent positive symptoms (-0.32 [-0.59 to -0.08]) among patients treated with clozapine. Treatment with clozapine in combination with antipsychotics yielded small-to-moderate ESs.
INTERPRETATION
The GRADE framework indicated that the quality of the evidence among the included studies was moderate, primarily due to the limited number of randomised controlled trials with a low risk of bias. Important drugs did not appear in these results due to insufficient low-risk-of-bias data for these medications. These results highlight new pathways for treating schizophrenia that should be incorporated into future guidelines after further validation.
FUNDING
No funding.
PubMed: 38356727
DOI: 10.1016/j.eclinm.2024.102473 -
Frontiers in Pharmacology 2024Alois Alzheimer described the first patient with Alzheimer's disease (AD) in 1907 and today AD is the most frequently diagnosed of dementias. AD is a multi-factorial... (Review)
Review
Alois Alzheimer described the first patient with Alzheimer's disease (AD) in 1907 and today AD is the most frequently diagnosed of dementias. AD is a multi-factorial neurodegenerative disorder with familial, life style and comorbidity influences impacting a global population of more than 47 million with a projected escalation by 2050 to exceed 130 million. In the USA the AD demographic encompasses approximately six million individuals, expected to increase to surpass 13 million by 2050, and the antecedent phase of AD, recognized as mild cognitive impairment (MCI), involves nearly 12 million individuals. The economic outlay for the management of AD and AD-related cognitive decline is estimated at approximately 355 billion USD. In addition, the intensifying prevalence of AD cases in countries with modest to intermediate income countries further enhances the urgency for more therapeutically and cost-effective treatments and for improving the quality of life for patients and their families. This narrative review evaluates the pathophysiological basis of AD with an initial focus on the therapeutic efficacy and limitations of the existing drugs that provide symptomatic relief: acetylcholinesterase inhibitors (AChEI) donepezil, galantamine, rivastigmine, and the N-methyl-D-aspartate receptor (NMDA) receptor allosteric modulator, memantine. The hypothesis that amyloid-β (Aβ) and tau are appropriate targets for drugs and have the potential to halt the progress of AD is critically analyzed with a particular focus on clinical trial data with anti-Aβ monoclonal antibodies (MABs), namely, aducanumab, lecanemab and donanemab. This review challenges the dogma that targeting Aβ will benefit the majority of subjects with AD that the anti-Aβ MABs are unlikely to be the "magic bullet". A comparison of the benefits and disadvantages of the different classes of drugs forms the basis for determining new directions for research and alternative drug targets that are undergoing pre-clinical and clinical assessments. In addition, we discuss and stress the importance of the treatment of the co-morbidities, including hypertension, diabetes, obesity and depression that are known to increase the risk of developing AD.
PubMed: 38868666
DOI: 10.3389/fphar.2024.1399121 -
Movement Disorders Clinical Practice Jul 2023Memantine is an -methyl--aspartate (NMDA) receptor antagonist that is used to treat moderate to severe Alzheimer's Dementia (AD) and has been speculated to provide...
BACKGROUND
Memantine is an -methyl--aspartate (NMDA) receptor antagonist that is used to treat moderate to severe Alzheimer's Dementia (AD) and has been speculated to provide clinical benefits in Huntington's disease (HD).
OBJECTIVE
To assess the effectiveness of memantine on the trajectory of cognitive decline in individuals with manifest HD.
METHODS
Using participants from the Enroll-HD study, the primary analysis compared trajectories in cognition over a 5-year period using linear mixed effect models of prevalent and incident memantine users who were propensity-score-matched with non-users on measures of disease progression and demographics.
RESULTS
In the primary analysis there were no significant differences in the trajectories between memantine users and non-users on any primary outcomes of interest.
CONCLUSIONS
Memantine use was not associated with any clinical benefit for individuals with manifest HD. Further studies are warranted to assess the impact of memantine on clinical outcomes in HD.
PubMed: 37476323
DOI: 10.1002/mdc3.13763 -
Journal of Neurology, Neurosurgery, and... Jul 2023Measuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of...
BACKGROUND
Measuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD).
METHODS
We measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers () and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes). We compared inflammation between asymptomatic carriers who remained clinically normal ('asymptomatic non-converters') and those who became symptomatic ('asymptomatic converters') using area under the curve analyses. Discrimination accuracy was compared with that of plasma neurofilament light chain (NfL).
RESULTS
We studied 394 participants (non-carriers=143, =117, =62, =72). In , higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. In higher TNFα was associated with faster functional decline (B=0.09 (0.03, 0.16), p=0.006) and cognitive decline (B=-0.16 (-0.22, -0.10), p<0.001), while higher IL-6 was associated with faster functional decline (B=0.12 (0.03, 0.21), p=0.01). TNFα was higher in asymptomatic converters than non-converters (β=0.29 (0.09, 0.48), p=0.004) and improved discriminability compared with plasma NfL alone (ΔR=0.16, p=0.007; NfL: OR=1.4 (1.03, 1.9), p=0.03; TNFα: OR=7.7 (1.7, 31.7), p=0.007).
CONCLUSIONS
Systemic proinflammatory protein measurement, particularly TNFα, may improve clinical prognosis in autosomal dominant FTLD pathogenic variant carriers who are not yet exhibiting severe impairment. Integrating TNFα with markers of neuronal dysfunction like NfL could optimise detection of impending symptom conversion in asymptomatic pathogenic variant carriers and may help personalise therapeutic approaches.
Topics: Humans; C9orf72 Protein; Disease Progression; Frontotemporal Dementia; Frontotemporal Lobar Degeneration; Inflammation; Interleukin-6; Mutation; tau Proteins; Tumor Necrosis Factor-alpha
PubMed: 36977552
DOI: 10.1136/jnnp-2022-330866 -
Chinese Clinical Oncology Aug 2023The use of prophylactic cranial irradiation (PCI) remains an important component in the management of small cell lung cancer (SCLC). This is due to the high rates of... (Review)
Review
The use of prophylactic cranial irradiation (PCI) remains an important component in the management of small cell lung cancer (SCLC). This is due to the high rates of subclinical brain metastases at the time of diagnosis. Following a response to initial treatment, PCI historically has been associated with improvements in overall survival and decreased development of brain metastases in patients with limited stage (LS-SCLC) and extensive stage (ES-SCLC) SCLC. However, PCI is commonly withheld in these settings in favor of observation, largely due to its association with cognitive sequelae following treatment. While randomized data has demonstrated that in patients with ES-SCLC, PCI may be withheld in favor of close MRI surveillance without a detriment in overall survival or cognitive functioning, these patients did not undergo formal neuropsychological assessments. In recent years, cognitive sparing techniques incorporated into whole brain radiation therapy and PCI, such as the addition of memantine and hippocampal avoidance, have demonstrated significant improvements in cognitive outcomes. As the overall survival in patients with SCLC continues to improve due to the incorporation of novel systemic therapies (e.g., immune checkpoint inhibitors), the role of PCI and maximizing quality of life remains a highly relevant topic. This article reviews the role of PCI and cognitive-sparing techniques in the management of SCLC.
Topics: Humans; Small Cell Lung Carcinoma; Lung Neoplasms; Quality of Life; Brain Neoplasms; Cognition; Cranial Irradiation
PubMed: 37574573
DOI: 10.21037/cco-23-12 -
Annals of Medicine and Surgery (2012) Feb 2024Lewy body dementia (LBD) is situated at the convergence of neurodegenerative disorders, posing an intricate and diverse clinical dilemma. The accumulation of abnormal... (Review)
Review
Lewy body dementia (LBD) is situated at the convergence of neurodegenerative disorders, posing an intricate and diverse clinical dilemma. The accumulation of abnormal protein in the brain, namely, the Lewy body causes disturbances in typical neural functioning, leading to a range of cognitive, motor, and mental symptoms that have a substantial influence on the overall well-being and quality of life of affected individuals. There is no definitive cure for the disease; however, several nonpharmacological and pharmacological modalities have been tried with questionable efficacies. The aim of this study is to figure out the role of different interventional strategies in the disease. Donepezil, rivastigmine, memantine, and galantamine were the commonly used drugs for LBD. Together with that, levodopa, antipsychotics, armodafinil, piracetam, and traditional medications like yokukansan were also used, when indicated. Talking about nonpharmacological measures, exercise, physical therapy, multicomponent therapy, occupational therapy, psychobehavioral modification, transcranial stimulation, and deep brain stimulation have been used with variable efficacies. Talking about recent advances in the treatment of LBD, various disease-modifying therapies like ambroxol, neflamapimod, irsenontrine, nilotinib, bosutinib, vodobatinib, clenbuterol, terazosin, elayta, fosgonimeton, and anle138b are emerging out. However, there drugs are still in the different phases of clinical trials and are not commonly used in clinical practice. With the different pharmacological and nonpharmacological modalities we have for treatment of LBD, all of them offer symptomatic relief only. Being a degenerative disease, definite cure of the disease can only be possible with regenerative measures.
PubMed: 38333295
DOI: 10.1097/MS9.0000000000001664 -
Annals of Palliative Medicine Nov 2023Improvements in radiation delivery and systemic therapies have resulted in few remaining indications for palliative whole brain radiation therapy (WBRT). Most centers...
BACKGROUND
Improvements in radiation delivery and systemic therapies have resulted in few remaining indications for palliative whole brain radiation therapy (WBRT). Most centers preferentially use stereotactic radiotherapy (SRT) and reserve WBRT for those with >15 lesions, leptomeningeal presentation, rapidly progressive disease, or limited estimated survival. Despite regional differences among preferred dose, fractionation, and treatment technique, we predict survival post-WBRT will remain poor-indicating appropriate application of WBRT in this era of SRT and improved systemic therapies.
METHODS
A multi-center, international retrospective analysis of patients receiving WBRT in 2022 was performed. Primary end point was survival after WBRT. De-identified data were analyzed centrally. Patients receiving WBRT as part of a curative regimen, prophylactically, or as bridging therapy were excluded. The collected data consisted of patient parameters including prescription dose and fractionation, use of neurocognitive sparing techniques and survival after WBRT. Survival was calculated via the Kaplan-Meier method.
RESULTS
Of 29,943 international RT prescriptions written at ten participating centers in 2022, 462 (1.5%) were for palliative WBRT. Participating centers were in the United States (n=138), the United Kingdom (n=111), Hong Kong (n=72), Italy (n=49), Belgium (n=45), Germany (n=27), Ghana (n=15), and Cyprus (n=5). Twenty-six different dose regimens were used. The most common prescriptions were for 3,000 cGy over 10 fractions (45.0%) and 2,000 cGy over 5 fractions (43.5%) with significant regional preferences (P<0.001). Prior SRT was delivered in 32 patients (6.7%), hippocampal avoidance (HA) was used in 44 patients (9.5%), and memantine was prescribed in 93 patients (20.1%). Survival ranged from 0 days to still surviving at 402 days post-treatment. The global median overall survival (OS) was 84 days after WBRT [95% confidence interval (CI): 68.0-104.0]. Actuarial survival at 7 days, 1 month, 3 months, and 6 months were 95%, 78%, 48%, and 32%, respectively. Twenty-seven patients (5.8%) were unable to complete their prescribed WBRT.
CONCLUSIONS
This moment-in-time analysis confirms that patients with poor expected survival are being appropriately selected for WBRT-illustrating the dwindling indications for WBRT-and demonstrates the variance in global practice. Since poor survival precludes patients from deriving benefit, memantine and HA are best suited in carefully selected cases.
Topics: Humans; Brain Neoplasms; Retrospective Studies; Memantine; Cranial Irradiation; Radiosurgery; Brain
PubMed: 37731303
DOI: 10.21037/apm-23-448 -
International Journal of Molecular... Aug 2023Alzheimer's disease (AD) is the most common form of dementia worldwide, and it contributes up to 70% of cases. AD pathology involves abnormal amyloid beta (Aβ)...
Alzheimer's disease (AD) is the most common form of dementia worldwide, and it contributes up to 70% of cases. AD pathology involves abnormal amyloid beta (Aβ) accumulation, and the link between the Aβ structure and toxicity is of major interest. NMDA receptors (NMDAR) are thought to be essential in Aβ-affected neurons, but the role of this receptor in glial impairment is still unclear. In addition, there is insufficient knowledge about the role of Aβ species regarding mitochondrial redox states in neurons and glial cells, which may be critical in developing Aβ-caused neurotoxicity. In this study, we investigated whether different Aβ species-small oligomers, large oligomers, insoluble fibrils, and monomers-were capable of producing neurotoxic effects via microglial NMDAR activation and changes in mitochondrial redox states in primary rat brain cell cultures. Small Aβ oligomers induced a concentration- and time-dependent increase in intracellular Ca and necrotic microglial death. These changes were partially prevented by the NMDAR inhibitors MK801, memantine, and D-2-amino-5-phosphopentanoic acid (DAP5). Neither microglial intracellular Ca nor viability was significantly affected by larger Aβ species or monomers. In addition, the small Aβ oligomers caused mitochondrial reactive oxygen species (mtROS)-mediated mitochondrial depolarization, glutamate release, and neuronal cell death. In microglia, the Aβ-induced mtROS overproduction was mediated by intracellular calcium ions and Aβ-binding alcohol dehydrogenase (ABAD). The data suggest that the pharmacological targeting of microglial NMDAR and mtROS may be a promising strategy for AD therapy.
Topics: Rats; Animals; Amyloid beta-Peptides; Microglia; Reactive Oxygen Species; Alzheimer Disease; Peptide Fragments; Receptors, N-Methyl-D-Aspartate
PubMed: 37569690
DOI: 10.3390/ijms241512315 -
Communications Medicine May 2024Alzheimer's disease (AD) is the most common neurodegenerative disease. Studying the effects of drug treatments on multiple health outcomes related to AD could be...
BACKGROUND
Alzheimer's disease (AD) is the most common neurodegenerative disease. Studying the effects of drug treatments on multiple health outcomes related to AD could be beneficial in demonstrating which drugs reduce the disease burden and increase survival.
METHODS
We conducted a comprehensive causal inference study implementing doubly robust estimators and using one of the largest high-quality medical databases, the Oracle Electronic Health Records (EHR) Real-World Data. Our work was focused on the estimation of the effects of the two common Alzheimer's disease drugs, Donepezil and Memantine, and their combined use on the five-year survival since initial diagnosis of AD patients. Also, we formally tested for the presence of interaction between these drugs.
RESULTS
Here, we show that the combined use of Donepezil and Memantine significantly elevates the probability of five-year survival. In particular, their combined use increases the probability of five-year survival by 0.050 (0.021, 0.078) (6.4%), 0.049 (0.012, 0.085), (6.3%), 0.065 (0.035, 0.095) (8.3%) compared to no drug treatment, the Memantine monotherapy, and the Donepezil monotherapy respectively. We also identify a significant beneficial additive drug-drug interaction effect between Donepezil and Memantine of 0.064 (0.030, 0.098).
CONCLUSIONS
Based on our findings, adopting combined treatment of Memantine and Donepezil could extend the lives of approximately 303,000 people with AD living in the USA to be beyond five-years from diagnosis. If these patients instead have no drug treatment, Memantine monotherapy or Donepezil monotherapy they would be expected to die within five years.
PubMed: 38783011
DOI: 10.1038/s43856-024-00527-6 -
Diabetes & Vascular Disease Research 2023Diabetes patients frequently experience diabetic neuropathy (DN), a microvascular complication that significantly reduces patients' quality of life. Memantine has... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Diabetes patients frequently experience diabetic neuropathy (DN), a microvascular complication that significantly reduces patients' quality of life. Memantine has demonstrated potential benefits for neuropathic pains in preclinical studies. This study aimed to assess the efficacy of memantine in the management of peripheral neuropathy in patients with type 2 diabetes mellitus (T2DM).
METHOD
This randomized clinical trial includes 143 diabetic patients (aged between 18 and 75 years) with a confirmed diagnosis of diabetic neuropathy. Patients were randomly assigned to receive memantine 5 mg twice daily for 1 week, followed by 10 mg twice daily plus gabapentin 300 mg daily ( = 72) or just gabapentin 300 mg daily ( = 71) for 8 weeks. The DN4 questionnaire, monofilament, tuning fork, and Tip-therm tests were used to measure neuropathy at baseline and after the 8-week intervention.
RESULTS
The mean score of the DN4 questionnaire in the memantine group was significantly lower than the control group (. value: .001). The number of patients with diabetic neuropathy remarkably decreased in the memantine group at the end of the study based on the performed tests (. value: .001).
CONCLUSION
Memantine functions as a beneficial agent in the management of diabetic neuropathy, which would significantly improve the quality of life in diabetic patients.
Topics: Humans; Adolescent; Young Adult; Adult; Middle Aged; Aged; Diabetic Neuropathies; Gabapentin; Memantine; Diabetes Mellitus, Type 2; Quality of Life
PubMed: 37495223
DOI: 10.1177/14791641231191093