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2.
Neuropsychopharmacology ; 48(1): 186-190, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35768568

RESUMO

Major depressive disorder is a prevalent and heterogeneous disorder with treatment resistance in at least 50% of individuals. Most of the initial studies focused on the monoamine system; however, recently other mechanisms have come under investigation. Specific to the current issue, studies show synaptic involvement in depression. Other articles in this issue report on reductions in synaptic density, dendritic spines, boutons and glia associated with stress and depression. Importantly, it appears that some drugs (e.g., ketamine) may lead to rapid synaptic restoration or synaptogenesis. Direct evidence for this comes from preclinical work. However, neuroimaging studies, such as magnetic resonance imaging (MRI) and positron emission tomography (PET), have become useful in assessing these changes in vivo. Here, we describe the use of neuroimaging techniques in the evaluation of synaptic alterations associated with depression in humans, as well as measurement of synaptic restoration after administration of ketamine. Although more research is desired, use of these techniques widen our understanding of depression and move us further along the path to targeted and effective treatment for depression.


Assuntos
Transtorno Depressivo Maior , Ketamina , Humanos , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/tratamento farmacológico , Ketamina/farmacologia , Ketamina/uso terapêutico , Depressão/tratamento farmacológico , Neuroimagem , Tomografia por Emissão de Pósitrons
3.
Neuropsychopharmacology ; 48(1): 54-60, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35995973

RESUMO

Neuronal and synaptic plasticity are widely used terms in the field of psychiatry. However, cellular neurophysiologists have identified two broad classes of plasticity. Hebbian forms of plasticity alter synaptic strength in a synapse specific manner in the same direction of the initial conditioning stimulation. In contrast, homeostatic plasticities act globally over longer time frames in a negative feedback manner to counter network level changes in activity or synaptic strength. Recent evidence suggests that homeostatic plasticity mechanisms can be rapidly engaged, particularly by fast-acting antidepressants such as ketamine to trigger behavioral effects. There is increasing evidence that several neuropsychoactive compounds either directly elicit changes in synaptic activity or indirectly tap into downstream signaling pathways to trigger homeostatic plasticity and subsequent behavioral effects. In this review, we discuss this recent work in the context of a wider paradigm where homeostatic synaptic plasticity mechanisms may provide novel targets for neuropsychiatric treatment advance.


Assuntos
Ketamina , Sinapses , Plasticidade Neuronal/fisiologia , Homeostase/fisiologia , Neurônios , Ketamina/farmacologia
4.
Synapse ; 77(1): e22253, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36121749

RESUMO

Anorexia nervosa (AN) is a mental illness with the highest rates of mortality and relapse, and no approved pharmacological treatment. Using an animal model of AN, called activity-based anorexia (ABA), we showed earlier that a single intraperitoneal injection of ketamine at a dose of 30 mg/kg (30mgKET), but not 3 mg/kg (3mgKET), has a long-lasting effect upon adolescent females of ameliorating anorexia-like symptoms through the following changes: enhanced food consumption and body weight; reduced running and anxiety-like behavior. However, there were also individual differences in the drug's efficacy. We hypothesized that individual differences in ketamine's ameliorative effects involve drebrin A, an F-actin-binding protein known to be required for the activity-dependent trafficking of NMDA receptors (NMDARs). We tested this hypothesis by electron microscopic quantifications of drebrin A immunoreactivity at excitatory synapses of pyramidal neurons (PN) and GABAergic interneurons (GABA-IN) in deep layer 1 of prefrontal cortex (PFC) of these mice. Results reveal that (1) the areal density of excitatory synapses on GABA-IN is greater for the 30mgKET group than the 3mgKET group; (2) the proportion of drebrin A+ excitatory synapses is greater for both PN and GABA-IN of 30mgKET than 3mgKET group. Correlation analyses with behavioral measurements revealed that (3) 30mgKET's protection is associated with reduced levels of drebrin A in the cytoplasm of GABA-IN and higher levels at extrasynaptic membranous sites of PN and GABA-IN; (5) altogether pointing to 30mgKET-induced homeostatic plasticity that engages drebrin A at excitatory synapses of both PN and GABA-IN.


Assuntos
Anorexia Nervosa , Ketamina , Camundongos , Feminino , Animais , Ketamina/farmacologia , Anorexia Nervosa/tratamento farmacológico , Anorexia Nervosa/metabolismo , Anorexia/tratamento farmacológico , Anorexia/metabolismo , Individualidade , Sinapses/metabolismo , Modelos Animais de Doenças , Córtex Pré-Frontal/metabolismo , Citoplasma/metabolismo , Ácido gama-Aminobutírico/metabolismo
5.
J Affect Disord ; 320: 29-36, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36181911

RESUMO

BACKGROUND: The antidepressant effects of ketamine in patients with anxious depression (AD) remain unclear. Functional connectivity (FC) differences in the amygdala have been linked to depression improvement after ketamine treatment in depressed patients, but their role in AD patients is uncertain. We investigated the correlation between depression improvement after ketamine treatment and amygdala FC in AD patients. METHODS: Thirty-one AD patients and 18 non-anxious depression (NAD) patients received six intravenous ketamine infusions (0.5 mg/kg) over two weeks. AD patients were further divided into responders (defined as a ≥50% MADRS total score reduction on day 13) and non-responders. The FC of the amygdala subregions, including the laterobasal amygdala (LBA), centromedial amygdala (CMA), and superficial amygdala, were compared between the groups. Receiver operating characteristic curves were used to predict treatment response after ketamine infusions. RESULTS: The baseline FC difference in the left LBA and the left precuneus between responders and non-responders among AD patients was found to be associated with depression improvement and was a significant predictor of treatment response to ketamine. A marked reduction in baseline LBA-precuneus FC after ketamine infusion was observed in responders. Unlike in patients with NAD, a lower right CMA-right middle temporal gyrus FC was found in AD patients. LIMITATIONS: The sample size is rather small. CONCLUSIONS: Our findings may suggest that amygdala FC is a significant predictor of treatment response to ketamine infusions in patients with AD. Further studies exploring the potential antidepressant mechanisms of ketamine may aid in the treatment of AD patients.


Assuntos
Transtorno Depressivo Resistente a Tratamento , Ketamina , Humanos , Ketamina/uso terapêutico , Depressão , NAD , Antidepressivos/uso terapêutico , Tonsila do Cerebelo/diagnóstico por imagem , Infusões Intravenosas , Transtorno Depressivo Resistente a Tratamento/diagnóstico por imagem , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico
6.
Emerg Med Clin North Am ; 41(1): 117-129, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36424036

RESUMO

Polytrauma patients often require medications to treat pain, treat agitation, and facilitate painful procedures. Though analgesia will be deferred in obtunded patients in profound shock, reduced-dose opioids or ketamine should be administered to unstable patients with severe pain with good mental status. Agitation commonly complicates polytrauma presentations, and is treated according to the danger it presents to patient and staff. Severe agitation can be effectively managed with dissociative-dose ketamine, which facilitates ongoing resuscitation, including CT. Severely painful procedures can be effectively facilitated by propofol or dissociative-dose ketamine, with continuous attention to ventilation and application of a step-by-step response to hypoventilation.


Assuntos
Ketamina , Traumatismo Múltiplo , Propofol , Humanos , Ketamina/uso terapêutico , Dor/tratamento farmacológico , Dor/etiologia , Propofol/efeitos adversos , Analgésicos Opioides/uso terapêutico , Traumatismo Múltiplo/complicações , Traumatismo Múltiplo/terapia
7.
J Ethnopharmacol ; 301: 115767, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36206872

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Persistent ketamine insults to the central nervous system block NMDA receptors and disrupt putative neurotransmission, oxido-nitrosative, and inflammatory pathways, resulting in schizophrenia-like symptoms in animals. Previously, the ethnomedicinal benefits of Carpolobia lutea against insomnia, migraine headache, and insanity has been documented, but the mechanisms of action remain incomplete. AIM OF THE STUDY: Presently, we explored the neuro-therapeutic role of Carpolobia lutea ethanol extract (C. lutea) in ketamine-induced schizophrenia-like symptoms in mice. MATERIALS AND METHODS: Sixty-four male Swiss (22 ± 2 g) mice were randomly assigned into eight groups (n = 8/group) and exposed to a reversal ketamine model of schizophrenia. For 14 days, either distilled water (10 mL/kg; p.o.) or ketamine (20 mg/kg; i.p.) was administered, following possible reversal treatments with C. lutea (100, 200, 400, and 800 mg/kg; p.o.), haloperidol (1 mg/kg, p.o.), or clozapine (5 mg/kg; p.o.) beginning on days 8-14. During the experiment, a battery of behavioral characterizations defining schizophrenia-like symptoms were obtained using ANY-maze software, followed by neurochemical, oxido-inflammatory and histological assessments in the mice brains. RESULTS: A 7-day reversal treatment with C. lutea reversed predictors of positive, negative and cognitive symptoms of schizophrenia. C. lutea also mitigated ketamine-induced neurochemical derangements as evidenced by modulations of dopamine, glutamate, norepinephrine and serotonin neurotransmission. Also, the increased acetylcholinesterase activity, malondialdehyde nitrite, interleukin-6 and tumor necrosis-factor-α concentrations were reversed by C. lutea accompanied with elevated levels of catalase, superoxide dismutase and reduced glutathione. Furthermore, C. lutea reversed ketamine-induced neuronal alterations in the prefrontal cortex, hippocampus and cerebellum sections of the brain. CONCLUSION: These findings suggest that C. lutea reverses the cardinal symptoms of ketamine-induced schizophrenia in a dose-dependent fashion by modulating the oxido-inflammatory and neurotransmitter-related mechanisms.


Assuntos
Etanol , Esquizofrenia , Animais , Masculino , Camundongos , Acetilcolinesterase/metabolismo , Antipsicóticos/farmacologia , Etanol/farmacologia , Ketamina/efeitos adversos , Receptores de N-Metil-D-Aspartato , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo
8.
Sci Total Environ ; 857(Pt 2): 159351, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36243065

RESUMO

Z-drugs, benzodiazepines and ketamine are classes of psychotropic drugs prescribed for treating anxiety, sleep disorders and depression with known side effects including an elevated risk of addiction and substance misuse. These drugs have a strong potential for misuse, which has escalated over the years and was hypothesized here to have been exacerbated during the COVID-19 pandemic. Wastewater-based epidemiology (WBE) constitutes a fast, easy, and relatively inexpensive approach to epidemiological surveys for understanding the incidence and frequency of uses of these drugs. In this study, we analyzed wastewater (n = 376) from 50 cities across the United States and Mexico from July to October 2020 to estimate drug use rates during a pandemic event. Both time and flow proportional composite and grab samples of untreated municipal wastewater were analyzed using solid-phase extraction followed by liquid chromatography-tandem mass spectrometry to determine loadings of alprazolam, clonazepam, diazepam, ketamine, lorazepam, nordiazepam, temazepam, zolpidem, and zaleplon in raw wastewater. Simultaneously, prescription data of the aforementioned drugs were extracted from the Medicaid database from 2019 to 2021. Results showed high detection frequencies of ketamine (90 %), lorazepam (87 %), clonazepam (76 %) and temazepam (73 %) across both Mexico and United States and comparatively lower detection frequencies for zaleplon (22 %), zolpidem (9 %), nordiazepam (<1 %), diazepam (<1 %), and alprazolam (<1 %) during the pandemic. Average mass consumption rates, estimated using WBE and reported in units of mg/day/1000 persons, ranged between 62 (temazepam) and 1100 (clonazepam) in the United States. Results obtained from the Medicaid database also showed a significant change (p < 0.05) in the prescription volume between the first quarter of 2019 (before the pandemic) and the first quarter of 2021 (pandemic event) for alprazolam, clonazepam and lorazepam. Study results include the first detections of zaleplon and zolpidem in wastewater from North America.


Assuntos
COVID-19 , Ketamina , Humanos , Estados Unidos/epidemiologia , Benzodiazepinas , Alprazolam/análise , Águas Residuárias/análise , Pandemias , Nordazepam/análise , Zolpidem/análise , Clonazepam/análise , Lorazepam/análise , Espectrometria de Massas em Tandem/métodos , COVID-19/epidemiologia , Temazepam/análise , México/epidemiologia , Diazepam
9.
J Affect Disord ; 321: 140-146, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36302492

RESUMO

BACKGROUND: The goal of this study was to replicate previous findings of three distinct treatment response pathways associated with repeated intravenous (IV) ketamine infusions among patients with major depressive disorder (MDD). METHODS: We conducted growth mixture modeling to estimate latent classes of change in depression (Quick Inventory of Depressive Symptomatology-Self Report, QIDS-SR) across six treatment visits in 298 patients with MDD treated with IV ketamine in an outpatient community clinic. Mean age was 40.36 and patients were primarily male (58.4 %). The sample had relatively severe depression (QIDS-SR = 16.61) at pre-treatment and the majority had not responded to at least two prior medications. RESULTS: Best-fit indices indicated three trajectory groups to optimally demonstrate non-linear, quadratic changes in depressive symptoms during ketamine treatment. Two groups had severe depression at baseline but diverged into a group of modest improvement over the treatment course (n = 78) and a group of patients with rapid improvement (n = 103). A third group had moderate depression at baseline with moderate improvement during the treatment course (n = 117). Additional planned trajectory comparisons showed that suicidality at entry was higher in the high depression groups and that change in suicidality severity followed that of depression. LIMITATIONS: This was a retrospective analysis of a naturalistic sample. Patients were unblinded and more heterogenous than those included in most controlled clinical trial samples. CONCLUSIONS: This replication study in an independent community-based ketamine clinic sample revealed similar response trajectories, with only about a third of depressed patients benefitting substantially from an acute induction course of ketamine infusions.


Assuntos
Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Ketamina , Humanos , Masculino , Adulto , Ketamina/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Estudos Retrospectivos , Resultado do Tratamento , Antidepressivos/uso terapêutico , Infusões Intravenosas , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico
10.
Neuropharmacology ; 222: 109308, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36341809

RESUMO

Ketamine exerts rapid and long-lasting antidepressant effects in patients with treatment-resistant depression. However, its clinical use is limited by its undesirable psychotomimetic side effects. Accumulating evidence from preclinical studies has shown that the antidepressant effects of ketamine are dependent on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) activation, which triggers activation of the mechanistic target of rapamycin pathway and brain-derived neurotrophic factor release. Thus, AMPA-R has emerged as a promising new target for novel antidepressants with a rapid onset of action. However, almost all known AMPA-R potentiators carry the risk of a narrow bell-shaped dose-response curve and a poor safety margin against seizures. Our data suggest that agonistic activity is not only related to the risks of bell-shaped dose-response curves and seizures but also to the reduced synaptic transmission and procognitive effects of AMPA-R potentiators. In this review, we describe our original screening approach that led to the discovery of an investigational AMPA-R potentiator with low agonistic activity, TAK-653. We further review the in vitro and in vivo profiles of TAK-653, including its procognitive and antidepressant-like effects, as well as its safety profile, in comparison with known AMPA-R potentiators with agonistic activity and AMPA, an AMPA-R agonist. The low agnostic activity of TAK-653 may overcome limitations of known AMPA-R potentiators. This article is part of the Special Issue on 'Ketamine and its Metabolites'.


Assuntos
Ketamina , Humanos , Ketamina/farmacologia , Ketamina/uso terapêutico , Receptores de AMPA , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico , Antidepressivos/farmacologia , Convulsões/tratamento farmacológico
11.
Neuropharmacology ; 222: 109305, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36354092

RESUMO

Depression is a well-known serious mental illness, and the onset of treatment using traditional antidepressants is frequently delayed by several weeks. Moreover, numerous patients with depression fail to respond to therapy. One major breakthrough in antidepressant therapy is that subanesthetic ketamine doses can rapidly alleviate depressive symptoms within hours of administering a single dose, even in treatment-resistant patients. However, specific mechanisms through which ketamine exerts its antidepressant effects remain elusive, leading to concerns regarding its rapid and long-lasting antidepressant effects. N-methyl-d-aspartate receptor (NMDAR) antagonists like ketamine are reportedly associated with serious side effects, such as dissociative symptoms, cognitive impairment, and abuse potential, limiting the large-scale clinical use of ketamine as an antidepressant. Herein, we reviewed the pharmacological properties of ketamine and the mechanisms of action underlying the rapid antidepressant efficacy, including the disinhibition hypothesis and synaptogenesis, along with common downstream effector pathways such as enhanced brain-derived neurotrophic factor and tropomyosin-related kinase B signaling, activation of the mechanistic target of rapamycin complex 1 and transforming growth factor ß1. We focused on evidence supporting the relevance of these potential mechanisms of ketamine and its metabolites in mediating the clinical efficacy of the drug. Given its reported antidepressant efficacy in preclinical studies and limited undesirable adverse effects, (R)-ketamine may be a safer, more controllable, rapid antidepressant. Overall, understanding the potential mechanisms of action of ketamine and its metabolites in combination with pharmacology may help develop a new generation of rapid antidepressants that maximize antidepressant effects while avoiding unfavorable adverse effects. This article is part of the Special Issue on 'Ketamine and its Metabolites'.


Assuntos
Disfunção Cognitiva , Ketamina , Humanos , Ketamina/farmacologia , Ketamina/uso terapêutico , Depressão , Psicoterapia , Transtornos Dissociativos
12.
Artigo em Inglês | MEDLINE | ID: mdl-36209771

RESUMO

The NMDA antagonist ketamine demonstrated a fast antidepressant activity in treatment-resistant depression. Pre-clinical studies suggest that de novo synthesis of the brain-derived neurotrophic factor (BDNF) in the PFC might be involved in the rapid antidepressant action of ketamine. Applying a genetic model of impaired glutamate release, this study aims to further identify the molecular mechanisms that could modulate antidepressant action and resistance to treatment. To that end, mice knocked-down for the vesicular glutamate transporter 1 (VGLUT1+/-) were used. We analyzed anhedonia and helpless behavior as well as the expression of the proteins linked to glutamate transmission in the PFC of mice treated with ketamine or the reference antidepressant reboxetine. Moreover, we analyzed the acute effects of ketamine in VGLUT1+/- mice pretreated with chronic reboxetine or those that received a PFC rescue expression of VGLUT1. Chronic reboxetine rescued the depressive-like phenotype of the VGLUT1+/- mice. In addition, it enhanced the expression of the proteins linked to the AMPA signaling pathway as well as the immature form of BDNF (pro-BDNF). Unlike WT mice, ketamine had no effect on anhedonia or pro-BDNF expression in VGLUT1+/- mice; it also failed to decrease phosphorylated eukaryote elongation factor 2 (p-eEF2). Nevertheless, we found that reboxetine administered as pretreatment or PFC overexpression of VGLUT1 did rescue the antidepressant-like activity of acute ketamine in the mice. Our results strongly suggest that not only do PFC VGLUT1 levels modulate the rapid-antidepressant action of ketamine, but also highlight a possible mechanism for antidepressant resistance in some patients.


Assuntos
Ketamina , Proteína Vesicular 1 de Transporte de Glutamato , Animais , Camundongos , Anedonia , Antidepressivos/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/metabolismo , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Ketamina/farmacologia , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Reboxetina/farmacologia , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo
13.
PLoS One ; 17(12): e0278216, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36454774

RESUMO

Phosphodiesterase 1B (PDE1B) and PDE10A are dual-specificity PDEs that hydrolyse both cyclic adenosine monophosphate and cyclic guanosine monophosphate, and are highly expressed in the striatum. Several reports have suggested that PDE10A inhibitors may present a promising approach for the treatment of positive symptoms of schizophrenia, whereas PDE1B inhibitors may present a novel mechanism to modulate cognitive deficits. Previously, we have reported a novel dual inhibitor of PDE1B and PDE10A, compound 2 [(3-fluorophenyl)(2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone] which has shown inhibitory activity for human recombinant PDE1B and PDE10A in vitro. In the present study, the safety profile of compound 2 has been evaluated in rats in the acute oral toxicity study, as well as; the antipsychotic-like effects in the rat model of schizophrenia. Compound 2 was tolerated up to 1 g/kg when administered at a single oral dose. Additionally, compound 2 has strongly suppressed ketamine-induced hyperlocomotion, which presented a model for the positive symptoms of schizophrenia. It has also shown an ability to attenuate social isolation induced by chronic administration of ketamine and enhanced recognition memory of rats ​in the novel object recognition test. Altogether, our results suggest that compound 2 represents a promising therapy for the treatment of the three symptomatic domains of schizophrenia.


Assuntos
Antipsicóticos , Transtornos Cognitivos , Ketamina , Esquizofrenia , Humanos , Animais , Ratos , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Esquizofrenia/tratamento farmacológico , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Diester Fosfórico Hidrolases
14.
Transl Psychiatry ; 12(1): 500, 2022 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-36463316

RESUMO

The NMDA-R hypofunction model of schizophrenia started with the clinical observation of the precipitation of psychotic symptoms in patients with schizophrenia exposed to PCP or ketamine. Healthy volunteers exposed to acute low doses of ketamine experienced mild psychosis but also negative and cognitive type symptoms reminiscent of the full clinical picture of schizophrenia. In rodents, acute systemic ketamine resulted in a paradoxical increase in extracellular frontal glutamate as well as of dopamine. Similar increase in prefrontal glutamate was documented with acute ketamine in healthy volunteers with 1H-MRS. Furthermore, sub-chronic low dose PCP lead to reductions in frontal dendritic tree density in rodents. In post-mortem ultrastructural studies in schizophrenia, a broad reduction in dendritic complexity and somal volume of pyramidal cells has been repeatedly described. This most likely accounts for the broad, subtle progressive cortical thinning described with MRI in- vivo. Additionally, prefrontal reductions in the obligatory GluN1 subunit of the NMDA-R has been repeatedly found in post-mortem tissue. The vast 1H-MRS literature in schizophrenia has documented trait-like small increases in glutamate concentrations in striatum very early in the illness, before antipsychotic treatment (the same structure where increased pre-synaptic release of dopamine has been reported with PET). The more recent genetic literature has reliably detected very small risk effects for common variants involving several glutamate-related genes. The pharmacological literature has followed two main tracks, directly informed by the NMDA-R hypo model: agonism at the glycine site (as mostly add-on studies targeting negative and cognitive symptoms); and pre-synaptic modulation of glutamatergic release (as single agents for acute psychosis). Unfortunately, both approaches have failed so far. There is little doubt that brain glutamatergic abnormalities are present in schizophrenia and that some of these are related to the etiology of the illness. The genetic literature directly supports a non- specific etiological role for glutamatergic dysfunction. Whether NMDA-R hypofunction as a specific mechanism accounts for any important component of the illness is still not evident. However, a glutamatergic model still has heuristic value to guide future research in schizophrenia. New tools to jointly examine brain glutamatergic, GABA-ergic and dopaminergic systems in-vivo, early in the illness, may lay the ground for a next generation of clinical trials that go beyond dopamine D2 blockade.


Assuntos
Ketamina , Esquizofrenia , Humanos , Dopamina , Ketamina/farmacologia , N-Metilaspartato , Ácido Glutâmico
15.
BMC Anesthesiol ; 22(1): 368, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36457068

RESUMO

BACKGROUND: Propofol is an intravenous (IV) anesthetic medication widely used for procedural sedation, operative anesthesia, and in intensive care unit (ICU), but the incidence of pain during IV infusion can reach 28-90%. Ketamine can attenuate pain associated with IV propofol injection through local and central analgesic effects. Ketamine is gradually being transitioned to its S-enantiomer, esketamine, which has a similar mechanism of action. The purpose of our study is to determine the half effective dose (ED50), 95% effective dose (ED95), and 99% effective dose (ED99) of esketamine for attenuating propofol injection pain using Dixon's up-and-down method to provide a reference for optimal dose selection for surgeries and procedures. METHODS: Thirty gynecological patients undergoing hysteroscopic surgery were enrolled in a sequential method to determine the effective dose of esticketamine for analgesic propofol injection in order of operation. This study was based on the sequential allocation up-and-down rule designed by Dixon, and each patient was induced by esticketamine combined with propofol. During induction, the target dose of esketamine was first given via venous access in the left hand of the patient, and 30 s later, a fixed dose of 2 mg/kg (1 ml/s) of propofol was given. Patient perception of pain was scored with the verbal rating scale (VRS) every 5 s after the start of the propofol infusion, and the evaluation was stopped once the patient became unresponsive. The dosage of esketamine was increased or decreased up or down according to the patient's pain response. The initial dose of esketamine was 0.2 mg/kg, and the gradient of adjacent dose was 0.02 mg/kg. If the pain response assessment of the upper patient was positive (+), the dose of esselketamine in the next patient was increased by 0.02 mg/kg; if the pain response assessment of the upper patient was negative (-), the dose of esselketamine in the next patient was decreased by 0.02 mg/kg. The tests were carried out sequentially, with the pain response changing from positive to negative or from negative to positive, and the tests were stopped after at least 6 crossover points, and the effective dose of esticketamine was calculated using probit probability regression analysis. RESULTS: The ineffective group comprised patients with a positive pain response and the effective group comprised patients with a negative pain response. The 95% CI was set as the confidence interval of effective dose ED value,and we found esketamine's ED50 = 0.143 mg/kg (0.120, 0.162 mg/kg), ED95 = 0.176 mg/kg (0.159, 0.320 mg/kg), and ED99 = 0.189 mg/kg (0.167, 0.394 mg/kg). The esketamine dose and VRS score during propofol injection were significantly different between the two groups (P < 0.05), whereas surgical duration, emergence time, visual analogue scale (VAS) score of postoperative uterine contraction pain, and Riker sedation/anxiety scale (SAS) score were not significantly different. Bradycardia occurred in only one patient during anesthesia induction, while hemodynamics was stable in the rest of the patients without obvious adverse reactions. CONCLUSION: Small doses of esketamine combined with propofol can be safely and effectively used for hysteroscopic surgery. We recommended a dose of 0.2 mg/kg IV esketamine before induction of anesthesia to reduce the pain of propofol injection. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100048951. Date of registration: July 19, 2021.


Assuntos
Ketamina , Propofol , Feminino , Gravidez , Humanos , Estudos Prospectivos , Anestésicos Intravenosos , Anestesia Geral , Dor Pós-Operatória
16.
J Avian Med Surg ; 36(3): 242-249, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36468801

RESUMO

The purpose of this study was to measure the effects of detomidine and medetomidine alone or in combination with ketamine on Schirmer tear test I (STT I) results and intraocular pressures (IOPs) in the common buzzard (Buteo buteo). Fourteen ophthalmologically healthy common buzzards were randomly assigned to 1 of 2 α-2 adrenoreceptor agonist groups: a detomidine group (group 1) and a medetomidine group (group 2). The detomidine group had 2 subgroups, detomidine alone or in combination with ketamine. Similarly, the medetomidine group had 2 subgroups, medetomidine alone or in combination with ketamine. Five minutes after α-2 adrenoreceptor agonist administration, the first measurements of STT I and IOP were collected. Ketamine was injected intramuscularly immediately after the first measurements were recorded. Schirmer tear test I and IOP measurements were repeated 5 minutes after ketamine administration. Measurements were obtained for 3 subgroups per agonist grouping: baseline 1, detomidine alone and detomidine with ketamine for group 1, and baseline 2, medetomidine alone and medetomidine with ketamine for group 2. Both IOP and STT I decreased significantly after sedation, anesthesia, or both. Intraocular pressure was significantly lower in the detomidine-ketamine group compared with the detomidine alone group. The IOP and STT I significantly decreased in both the medetomidine alone and medetomidine-ketamine groups when compared with those for all 14 unanesthetized animals before administering the α-2 adrenoreceptor agonist and ketamine. When α-2 adrenoreceptor agonists were considered as a single group (groups 1 and 2 combined), IOP also showed a significant decrease in the α-2 adrenoreceptor agonist-ketamine groups compared with the α-2 adrenoreceptor agonists alone, but STT I did not. According to the results obtained from these common buzzards, no statistical differences were found between the detomidine and medetomidine (alone) groups or detomidine-ketamine and medetomidine-ketamine groups in terms of STT I and IOP.


Assuntos
Falconiformes , Ketamina , Animais , Pressão Intraocular , Medetomidina/farmacologia , Ketamina/farmacologia , Tonometria Ocular/veterinária
18.
BMC Anesthesiol ; 22(1): 361, 2022 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-36424561

RESUMO

BACKGROUND: Post-spinal shivering is a common complication after spinal anesthesia with a high incidence among orthopedic patients. Untreated shivering may predispose to exacerbation of wound pain, increased metabolic demand, oxygen consumption, and hemostatic dysfunction. Various studies have been done on the effectiveness of preventing post-spinal shivering using ketamine and other drugs. However, little information on better prophylactic agents in terms of effectiveness and availability. Therefore, this study was intended to compare 0.25 mg/kg of Ketamine (K) versus 0.5 mg/kg of Tramadol (T) for the prevention of post-spinal shivering. METHOD: A prospective cohort study design was employed on 516 patients undergoing orthopedic surgery under spinal anesthesia, and they were selected by a consecutive sampling technique. Patients were divided into two groups based on the anesthetist in charge. Patients who received an intravenous prophylactic dose of Ketamine before spinal anesthesia are called Ketamine groups and patients who received Tramadol are called Tramadol groups (control). The severity and incidence of shivering, blood pressure, heart rate, and axillary body temperature were measured and recorded for one hour at 10-min intervals during the intraoperative period. Descriptive statistics, chi-square, independent t-test, and multivariable logistic regression were used. Significance was declared at a p-value lower than 0.05. RESULTS: The overall incidence of post-spinal shivering was 187 (36.2%), of which it was 74 (28.7%) on ketamine and 113 (43.8%) on tramadol with a p-value of 0.001. The incidence of nausea and vomiting was 157 (60.9%) on tramadol and 8 (3.1%) on ketamine, with a p-value of 0.001. Patients aged 18-35 years (AOR 0.08 (0.02, 0.27), 36-55 years (AOR 0.24, 0.07, 0.81), and those patients with a prolonged duration of surgery (AOR 1.47 (1.37-1.58)) were more likely to experience post-spinal shivering. And Low-dose ketamine has a protective effect against developing post-spinal shivering with an AOR of 0.427 (0.28-0.63). CONCLUSION: Low-dose ketamine is more effective in reducing the incidence and severity of shivering after spinal anesthesia. Therefore, we recommend using low-dose ketamine to be effective as a prophylactic for post-spinal shivering in those patients undergoing orthopedic surgery under spinal anesthesia.


Assuntos
Ketamina , Procedimentos Ortopédicos , Tramadol , Humanos , Tremor por Sensação de Frio , Tramadol/uso terapêutico , Estudos Prospectivos , Procedimentos Ortopédicos/efeitos adversos
19.
BMC Psychiatry ; 22(1): 744, 2022 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-36451150

RESUMO

BACKGROUND: Major depressive disorder (MDD) is a high risk factor for suicide, with up to 20% of MDD patients attempting suicide during their lifetime. Current treatments for MDD are slow onset of action, low efficiency, and the inability to control suicidal behaviors quickly and effectively. Intravenous ketamine has been shown to have a rapid but transient antidepressant effect, but there is still lack evidence on the efficacy and safety of intravenous esketamine in reducing suicidal ideation and depressive symptoms in MDD patients with suicidal ideation. We designed a study to investigate the effect of short-term repeated intravenous infusion of esketamine three times in MDD patients with suicidal ideation. METHODS: This study features a randomized, double-blind, placebo-controlled trial (RCT) comparing short-term repeated intravenous infusions of esketamine with placebo as a supplement to conventional antidepressants with an intervention period of 6 days and one infusion every other day, followed by 4 weeks of follow-up. These methods support the examination of the efficacy, safety, tolerability, and mechanism of action of short-term repeated intravenous infusions of esketamine in MDD patients with suicidal ideation. DISCUSSION: This is the first RCT to explore the efficacy and safety of short-term repeated infusion of esketamine on suicidal ideation and depressive symptoms in MDD patients with suicidal ideation. If proven effective and tolerated, it will provide evidence for rapid and effective treatment of suicidal ideation and depressive symptoms in MDD individuals with suicidal ideation. TRIAL REGISTRATION: Chinese Clinical Trial Register, ChiCTR2000041232 . Registered 22 December 2020.


Assuntos
Transtorno Depressivo Maior , Ketamina , Suicídio , Humanos , Ideação Suicida , Ketamina/efeitos adversos , Transtorno Depressivo Maior/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
Epilepsy Behav ; 137(Pt A): 108954, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36375305

RESUMO

INTRODUCTION: Status epilepticus (SE) continues to be a challenging neurological emergency with high morbidity and mortality. During treatment, different regimens are practiced encompassing all known seizure termination mechanisms. To our knowledge, this is the first case series report describing EEG patterns and clinical outcomes in patients treated with ketamine and perampanel (PER) concomitantly. OBJECTIVE: To assess clinical and electrographic outcomes in patients receiving dual antiglutamatergic therapy in SE. RESULTS: Twenty-one out of twenty five patients were treated with ketamine, and four patients with ketamine were associated with PER. In the ketamine plus PER group, three out of four patients had convulsive SE, and one had non-convulsive status epilepticus (NCSE), whereas eight patients in the ketamine group had NCSE. The incidence of beta pattern appearance on EEG after starting patients on ketamine and PER was achieved in all four patients (100%) compared to (61.9%) in the other group. A burst suppression pattern was recorded in 75% of patients treated with ketamine and PER, in comparison to 28.5% of patients in patients treated with a different regimen. The time to resolution of SE was significantly shorter in the ketamine group (median 24 (24-64) h vs. 6 (05-144) h p > 0.05). Moreover, the average number of days on IV anesthetic was slightly lower in a patient treated with PER concomitantly. In terms of morbidity, the average increase in mRS was also lower in the ketamine and PER group, although it was not statistically significant. CONCLUSIONS: Dual anti-glutamatergic therapy could provide a favorable approach to treating SE, which yet needs to be further investigated through larger randomized control studies.


Assuntos
Ketamina , Estado Epiléptico , Humanos , Ketamina/uso terapêutico , Eletroencefalografia , Estado Epiléptico/tratamento farmacológico , Piridonas/uso terapêutico
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