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1.
Current and Future Treatments in Alzheimer's Disease.
Atri, A
Seminars in neurology. 2019;(2):227-240
Abstract
The foundation of current Alzheimer's disease (AD) treatment involves pharmacological and nonpharmacological management and care planning predicated on patient-centered psychoeducation, shared goal-setting, and decision-making forged by a strong triadic relationship between clinician and the patient-caregiver dyad. Food and Drug Administration (FDA) approved AD medications, cholinesterase-inhibitors (ChEIs), and the N-methyl-d-aspartate (NMDA) antagonist memantine, when utilized as part of a comprehensive care plan, while generally considered symptomatic medications, can provide modest "disease course-modifying" effects by enhancing cognition, and reducing loss of independence. When combined, pharmacologic and nonpharmacologic treatments can meaningfully mitigate symptoms and reduce clinical progression and care burden. AD pharmacotherapy first involves identification and elimination of potentially harmful medications and supplements. First line treatment for neuropsychiatric symptoms and problem behaviors is nonpharmacological and involves psychoeducation, trigger identification, and implementation, iterative evaluation, and adjustment of behavioral and environmental interventions. Intensive research efforts are underway to develop more accurate and practical AD diagnostic biomarkers and clinical tools and better therapeutics. Ongoing research studies for primary and secondary prevention of AD and clinical trials evaluating symptomatic and disease-modifying treatments in symptomatic AD are directed at diverse therapeutic targets including neurochemicals, amyloid and tau pathological processes, mitochondria, inflammatory pathways, neuroglia, and multimodal lifestyle interventions.
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2.
The Therapeutic Impact of New Migraine Discoveries.
Vécsei, L, Lukács, M, Tajti, J, Fülöp, F, Toldi, J, Edvinsson, L
Current medicinal chemistry. 2019;(34):6261-6281
Abstract
BACKGROUND Migraine is one of the most disabling neurological conditions and associated with high socio-economic costs. Though certain aspects of the pathomechanism of migraine are still incompletely understood, the leading hypothesis implicates the role of the activation of the trigeminovascular system. Triptans are considered to be the current gold standard therapy for migraine attacks; however, their use in clinical practice is limited. Prophylactic treatment includes non-specific approaches for migraine prevention. All these support the need for future studies in order to develop innovative anti-migraine drugs. OBJECTIVE The present study is a review of the current literature regarding new therapeutic lines in migraine research. METHODS A systematic literature search in the database of PUBMED was conducted concerning therapeutic strategies in a migraine published until July 2017. RESULTS Ongoing clinical trials with 5-HT1F receptor agonists and glutamate receptor antagonists offer promising new aspects for acute migraine treatment. Monoclonal antibodies against CGRP and the CGRP receptor are revolutionary in preventive treatment; however, further long-term studies are needed to test their tolerability. Preclinical studies show positive results with PACAP- and kynurenic acid-related treatments. Other promising therapeutic strategies (such as those targeting TRPV1, substance P, NOS, or orexin) have failed to show efficacy in clinical trials. CONCLUSION Due to their side-effects, current therapeutic approaches are not suitable for all migraine patients. Especially frequent episodic and chronic migraine represents a therapeutic challenge for researchers. Clinical and preclinical studies are needed to untangle the pathophysiology of migraine in order to develop new and migraine-specific therapies.
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3.
Novel drugs and early polypharmacotherapy in status epilepticus.
Amengual-Gual, M, Sánchez Fernández, I, Wainwright, MS
Seizure. 2019;:79-88
Abstract
PURPOSE Rescue medications for status epilepticus (SE) have a relatively high rate of failure. The purpose of this review is to summarize the evidence for the efficacy of novel drugs and early polypharmacotherapy for SE. METHOD Literature review. RESULTS New drugs and treatment strategies aim to target the pathophysiology of SE in order to improve seizure control and outcomes. Changes at the synapse level during SE include a progressive decrease in synaptic GABAA receptors and increase in synaptic NMDA receptors. These changes tend to promote self-sustaining seizures. Current SE guidelines recommend a rapid stepwise treatment using benzodiazepines in monotherapy as the first-line treatment, targeting GABAA synaptic receptors. Novel treatment approaches target GABAA synaptic and extrasynaptic receptors with allopregnanolone, and NMDA receptors with ketamine. Novel rescue treatments used for SE include topiramate, brivaracetam, and perampanel, which are already marketed in epilepsy. Some available drugs not marketed for use in epilepsy have been used in the treatment of SE, and other agents are being studied for this purpose. Early polytherapy, most frequently combining a benzodiazepine with a second-line drug or an NMDA receptor antagonist, might potentially increase seizure control with relatively minor increase in side effects. Although many preclinical studies support novel drugs and early polytherapy in SE, human studies are scarce and inconclusive. Currently, evidence is lacking to recommend specific combinations of these new agents. CONCLUSIONS Novel drugs and strategies target the underlying pathophysiology of SE with the intent to improve seizure control and outcomes.
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4.
NMDA antagonists for treating the non-motor symptoms in Parkinson's disease.
Vanle, B, Olcott, W, Jimenez, J, Bashmi, L, Danovitch, I, IsHak, WW
Translational psychiatry. 2018;(1):117
Abstract
Among patients with Parkinson's disease (PD), depression is prevalent and disabling, impacting both health outcomes and quality of life. There is a critical need for alternative pharmacological methods to treat PD depression, as mainstream antidepressant drugs are largely ineffective in this population. Currently, there are no recommendations for the optimal treatment of PD neuropsychiatric symptoms. Given the dual antidepressant and anti-dyskinetic effects of ketamine and other N-methyl-D-aspartate (NMDA) antagonists for PD, this review aims to examine the current evidence of NMDA antagonists for treating neuropsychiatric symptoms, including memantine, amantadine, ketamine, dizoclopine, and d-cycloserine. A comprehensive literature search was conducted using the PubMed database. We also searched the following databases up to March 1, 2018: Ovid MEDLINE, PsycINFO, CINAHL, Google Scholar, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. The following keywords were used: NMDA antagonist and Parkinson's disease. Two authors independently reviewed the articles identified from the search using specific selection criteria, focusing on studies of mood, psychiatric condition, depression, cognition, and quality of life, and the consensus was reached on the 20 studies included. There is a preliminary evidence that NMDA antagonists may modulate psychiatric symptoms in PD. However, current evidence of psychiatric symptom-modifying effects is inconclusive and requires that further trials be conducted in PD. The repurposing of old NMDA antagonists, such as ketamine for depression and newer therapies, such as rapastinel, suggests that there is an emerging place for modulating the glutamatergic system for treating non-motor symptoms in PD.
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5.
Predictors of Response to Ketamine in Treatment Resistant Major Depressive Disorder and Bipolar Disorder.
Rong, C, Park, C, Rosenblat, JD, Subramaniapillai, M, Zuckerman, H, Fus, D, Lee, YL, Pan, Z, Brietzke, E, Mansur, RB, et al
International journal of environmental research and public health. 2018;(4)
Abstract
OBJECTIVES Extant evidence indicates that ketamine exerts rapid antidepressant effects in treatment-resistant depressive (TRD) symptoms as a part of major depressive disorder (MDD) and bipolar disorder (BD). The identification of depressed sub-populations that are more likely to benefit from ketamine treatment remains a priority. In keeping with this view, the present narrative review aims to identify the pretreatment predictors of response to ketamine in TRD as part of MDD and BD. METHOD Electronic search engines PubMed/MEDLINE, ClinicalTrials.gov, and Scopus were searched for relevant articles from inception to January 2018. The search term ketamine was cross-referenced with the terms depression, major depressive disorder, bipolar disorder, predictors, and response and/or remission. RESULTS Multiple baseline pretreatment predictors of response were identified, including clinical (i.e., Body Mass Index (BMI), history of suicide, family history of alcohol use disorder), peripheral biochemistry (i.e., adiponectin levels, vitamin B12 levels), polysomnography (abnormalities in delta sleep ratio), neurochemistry (i.e., glutamine/glutamate ratio), neuroimaging (i.e., anterior cingulate cortex activity), genetic variation (i.e., Val66Met BDNF allele), and cognitive functioning (i.e., processing speed). High BMI and a positive family history of alcohol use disorder were the most replicated predictors. CONCLUSIONS A pheno-biotype of depression more, or less likely, to benefit with ketamine treatment is far from complete. Notwithstanding, metabolic-inflammatory alterations are emerging as possible pretreatment response predictors of depressive symptom improvement, most notably being cognitive impairment. Sophisticated data-driven computational methods that are iterative and agnostic are more likely to provide actionable baseline pretreatment predictive information.
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6.
What is in the Myopathy Literature?
Lacomis, D
Journal of clinical neuromuscular disease. 2018;(4):217-223
Abstract
This update covers the results of a randomized, placebo-controlled study that provides evidence that lamotrigine is effective in treating nondystrophic myotonias. Next, an overview of adverse effects of immune checkpoint inhibitors is provided, and the association of autoimmune myopathy and these monoclonal antibody therapies is discussed in light of recent reports. Last, the utility of electrodiagnostic testing in patients with intensive care unit weakness is addressed with emphasis on the high sensitivity and specificity of prolonged compound muscle action potential amplitudes in diagnosing critical illness myopathy.
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7.
Auditory System Target Engagement During Plasticity-Based Interventions in Schizophrenia: A Focus on Modulation of N-Methyl-D-Aspartate-Type Glutamate Receptor Function.
Kantrowitz, JT, Swerdlow, NR, Dunn, W, Vinogradov, S
Biological psychiatry. Cognitive neuroscience and neuroimaging. 2018;(7):581-590
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Abstract
Cognitive deficits are predictive of long-term social and occupational functional deficits in schizophrenia but are currently without gold-standard treatments. In particular, augmentation of auditory cortical neuroplasticity may represent a rate-limiting first step before addressing higher-order cognitive deficits. We review the rationale for N-methyl-d-aspartate-type glutamate receptor (NMDAR) modulators as treatments for auditory plasticity deficits in schizophrenia, along with potential serum and electroencephalographic target engagement biomarkers for NMDAR function. Several recently published NMDAR-modulating treatment studies are covered, involving D-serine, memantine, and transcranial direct current stimulation. While all three interventions appear to modulate auditory plasticity, direct agonists (D-serine) appear to have the largest and most consistent effects on plasticity, at least acutely. We hypothesize that there may be synergistic effects of combining procognitive NMDAR-modulating approaches with auditory cortical neuroplasticity cognitive training interventions. Future studies should assess biomarkers for target engagement and patient stratification, along with head-to-head studies comparing putative interventions and potential long-term versus acute effects.
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8.
The risks associated with the use of lamotrigine during pregnancy.
Kong, L, Zhou, T, Wang, B, Gao, Z, Wang, C
International journal of psychiatry in clinical practice. 2018;(1):2-5
Abstract
OBJECTIVE This paper reviewed the relevant literature on the effects of lamotrigine on pregnancy outcomes to provide useful information regarding lamotrigine use in pregnant women with bipolar disorder. METHODS A systematic search of electronic databases and other original sources was conducted that examined the effects of lamotrigine on pregnancy outcomes. RESULTS It is not clear that foetuses of lamotrigine-exposed pregnant women are at higher risk of malformation or neurodevelopmental delay. When treating pregnant women with bipolar disorder, the risks associated with lamotrigine use have to be balanced with the risks of uncontrolled maternal symptoms. The information obtained from our review of psychotropic medications will assist clinicians in managing pregnant women with bipolar disorder. CONCLUSIONS Although lamotrigine has emerged as the safest mood stabiliser for use during pregnancy based on the clinical evidence thus far, further studies are needed to inform the best clinical practice when treating bipolar disorder in pregnant women.
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9.
Alzheimer disease: Non-pharmacological and pharmacological management of cognition and neuropsychiatric symptoms.
Loi, SM, Eratne, D, Kelso, W, Velakoulis, D, Looi, JC
Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists. 2018;(4):358-365
Abstract
OBJECTIVES This clinical update review focuses on the management of cognition and the neuropsychiatric features of Alzheimer's disease (AD) and highlights current issues regarding pharmacological and non-pharmacological treatment, putative therapeutics and recent relevant research findings in this area. CONCLUSIONS AD is a neurodegenerative progressive condition characterised by cognitive impairment and functional decline. Most people with AD will demonstrate neuropsychiatric features, better known as behavioural and psychological symptoms of dementia (BPSD). Early recognition and treatment of BPSD are essential, as these cause considerable distress and carer burden. While there are many disease-modifying therapies for the cognitive symptoms still in the research stage, only symptomatic treatments are currently available for these and the BPSD.
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10.
Clinical management of restless legs syndrome in end-stage renal disease patients.
Sahli, ZT, Jo, J, Mousa, SA, Tarazi, FI
CNS spectrums. 2017;(1):14-21
Abstract
Restless legs syndrome (RLS) is a common neurological movement disorder, characterized by restless and unpleasant sensations in the deep inside of legs. The symptoms of RLS are less noticeable during daytime, but more prevalent at night. Therefore, the disorder can induce low quality of life, insomnia, and impairment of daytime activity. RLS in end-stage renal disease (ESRD) patients is especially problematic due to premature discontinuation of dialysis and increased mortality. The prevalence of RLS among dialysis patients is much higher compared to the prevalence of the same disorder in patients with normal renal functions. Even though there are recommended treatment guidelines for the general population established by Medical Advisory Board of the RLS foundation, which include the use of dopamine agonists, levodopa, gabapentin, benzodiazepines, and opioids, limited information is available on the effects of these therapies in ESRD patients. Since the existing clinical data were extrapolated from small sample sizes in short-term clinical trials, further clinical studies are still needed to better assess the efficacy, safety, and tolerability of these medications in patients with ESRD.