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1.
Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation.
McIntyre, RS, Rosenblat, JD, Nemeroff, CB, Sanacora, G, Murrough, JW, Berk, M, Brietzke, E, Dodd, S, Gorwood, P, Ho, R, et al
The American journal of psychiatry. 2021;(5):383-399
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Abstract
Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of the literature with respect to the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. The authors also provide guidance for the implementation of these agents in clinical practice, with particular attention to practice parameters at point of care. Areas of consensus and future research vistas are discussed.
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2.
Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants.
Kadriu, B, Greenwald, M, Henter, ID, Gilbert, JR, Kraus, C, Park, LT, Zarate, CA
The international journal of neuropsychopharmacology. 2021;(1):8-21
Abstract
BACKGROUND The glutamatergic modulator ketamine has created a blueprint for studying novel pharmaceuticals in the field. Recent studies suggest that "classic" serotonergic psychedelics (SPs) may also have antidepressant efficacy. Both ketamine and SPs appear to produce rapid, sustained antidepressant effects after a transient psychoactive period. METHODS This review summarizes areas of overlap between SP and ketamine research and considers the possibility of a common, downstream mechanism of action. The therapeutic relevance of the psychoactive state, overlapping cellular and molecular effects, and overlapping electrophysiological and neuroimaging observations are all reviewed. RESULTS Taken together, the evidence suggests a potentially shared mechanism wherein both ketamine and SPs may engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. It is postulated that, though distinct, both ketamine and SPs appear to produce acute alterations in cortical network activity that may initially produce psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. However, despite some commonalities between the psychoactive component of these pharmacologically distinct therapies-such as engagement of the downstream glutamatergic pathway-the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research. CONCLUSIONS Rapid-acting antidepressants currently under investigation may share some downstream pharmacological effects, suggesting that their antidepressant effects may come about via related mechanisms. Given the prototypic nature of ketamine research and recent progress in this area, this platform could be used to investigate entirely new classes of antidepressants with rapid and robust actions.
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3.
Ketamine in seizure management and future pharmacogenomic considerations.
Borsato, GS, Siegel, JL, Rose, MQ, Ojard, M, Feyissa, AM, Quinones-Hinojosa, A, Jackson, DA, Rogers, ER, Freeman, WD
The pharmacogenomics journal. 2020;(3):351-354
Abstract
Ketamine is a noncompetitive N-methyl-D-aspartate antagonist with emerging evidence for use in medically refractory epilepsy. We describe the novel use of low-dose intravenous (IV) ketamine transitioning to enteral formulation in a patient with drug-resistant localization-related refractory epilepsy. We performed a National Library of Medicine (NLM) literature review using search terms "ketamine", "low dose", and "seizure" for similar cases, followed by an illustrative clinical case. Our NLM search engine methodology yielded 24 hits, none of which described use of low-dose ketamine for seizures. Anesthetic doses are used for status epilepticus, but we show that in a patient with postoperative worsening of his chronic seizure burden, low-dose IV ketamine can be used to avoid oversedation and intubation. We demonstrate that IV ketamine can be transitioned to oral regimen to shorten length of stay in the intensive care unit and hospital and has future CYP2B6 pharmacogenomic considerations for further dose individualization.
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4.
Galantamine-Memantine combination in the treatment of Alzheimer's disease and beyond.
Koola, MM
Psychiatry research. 2020;:113409
Abstract
Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population worldwide. Despite the major unmet clinical need, no new medications for the treatment of AD have been approved since 2003. Galantamine is an acetylcholinesterase inhibitor that is also a positive allosteric modulator at the α4β2 and α7nACh receptors. Memantine is an N-methyl-d-aspartate receptor modulator/agonist. Both galantamine and memantine are FDA-approved medications for the treatment of AD. The objective of this review is to highlight the potential of the galantamine-memantine combination to conduct randomized controlled trials (RCTs) in AD. Several studies have shown the combination to be effective. Neurodegenerative diseases involve multiple pathologies; therefore, combination treatment appears to be a rational approach. Although underutilized, the galantamine-memantine combination is the standard of care in the treatment of AD. Positive RCTs with the combination with concurrent improvement in symptoms and biomarkers may lead to FDA approval, which may lead to greater utilization of this combination in clinical practice.
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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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6.
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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7.
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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8.
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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9.
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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10.
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.