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1.
Biomolecules ; 12(11)2022 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-36358968

RESUMO

Ayahuasca is a psychoactive brew traditionally used in indigenous and religious rituals and ceremonies in South America for its therapeutic, psychedelic, and entheogenic effects. It is usually prepared by lengthy boiling of the leaves of the bush Psychotria viridis and the mashed stalks of the vine Banisteriopsis caapi in water. The former contains the classical psychedelic N,N-dimethyltryptamine (DMT), which is thought to be the main psychoactive alkaloid present in the brew. The latter serves as a source for ß-carbolines, known for their monoamine oxidase-inhibiting (MAOI) properties. Recent preliminary research has provided encouraging results investigating ayahuasca's therapeutic potential, especially regarding its antidepressant effects. On a molecular level, pre-clinical and clinical evidence points to a complex pharmacological profile conveyed by the brew, including modulation of serotoninergic, glutamatergic, dopaminergic, and endocannabinoid systems. Its substances also interact with the vesicular monoamine transporter (VMAT), trace amine-associated receptor 1 (TAAR1), and sigma-1 receptors. Furthermore, ayahuasca's components also seem to modulate levels of inflammatory and neurotrophic factors beneficially. On a biological level, this translates into neuroprotective and neuroplastic effects. Here we review the current knowledge regarding these molecular interactions and how they relate to the possible antidepressant effects ayahuasca seems to produce.


Assuntos
Alcaloides , Banisteriopsis , Alucinógenos , Alucinógenos/farmacologia , N,N-Dimetiltriptamina/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Antidepressivos/farmacologia
2.
CNS Spectr ; : 1-14, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35837681

RESUMO

This article is a clinical guide which discusses the "state-of-the-art" usage of the classic monoamine oxidase inhibitor (MAOI) antidepressants (phenelzine, tranylcypromine, and isocarboxazid) in modern psychiatric practice. The guide is for all clinicians, including those who may not be experienced MAOI prescribers. It discusses indications, drug-drug interactions, side-effect management, and the safety of various augmentation strategies. There is a clear and broad consensus (more than 70 international expert endorsers), based on 6 decades of experience, for the recommendations herein exposited. They are based on empirical evidence and expert opinion-this guide is presented as a new specialist-consensus standard. The guide provides practical clinical advice, and is the basis for the rational use of these drugs, particularly because it improves and updates knowledge, and corrects the various misconceptions that have hitherto been prominent in the literature, partly due to insufficient knowledge of pharmacology. The guide suggests that MAOIs should always be considered in cases of treatment-resistant depression (including those melancholic in nature), and prior to electroconvulsive therapy-while taking into account of patient preference. In selected cases, they may be considered earlier in the treatment algorithm than has previously been customary, and should not be regarded as drugs of last resort; they may prove decisively effective when many other treatments have failed. The guide clarifies key points on the concomitant use of incorrectly proscribed drugs such as methylphenidate and some tricyclic antidepressants. It also illustrates the straightforward "bridging" methods that may be used to transition simply and safely from other antidepressants to MAOIs.

3.
Artigo em Inglês | MEDLINE | ID: mdl-35829812

RESUMO

Although results are still preliminary, ketamine and classical hallucinogens have shown promise in recent years as novel, fast-acting antidepressants, especially for the treatment of unipolar treatment-resistant depression (TRD). Depression also seems to be related to abnormal levels of peripheral inflammatory and neurotrophic biomarkers, which may one day help to diagnose of this disorder. In this context, this systematic review of clinical trials evaluated the current evidence that relates the antidepressant effects of ketamine and classical hallucinogens on TRD with changes in inflammatory and neurotrophic biomarkers. Twelve studies were found (n = 587), 2 with oral ayahuasca (1 mL/kg) and 10 with ketamine (mostly intravenous 0.5 mg/kg) administration. Results for all biomarkers assessed were contradictory and thus inconclusive. Randomized controlled trials with bigger samples and higher statistical power are warranted to clarify if peripheral biomarkers can confidently be used to indicate and measure ketamine's and classical hallucinogens' antidepressant effect. The PROSPERO ID for this study is CRD42021249089.

4.
Expert Opin Drug Saf ; 21(6): 789-801, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35301934

RESUMO

INTRODUCTION: Ayahuasca is a psychedelic brew originally used by Amazonian indigenous groups and in religious rituals. Pre-clinical and observational studies have demonstrated its possible potential as an antidepressant, and open- and placebo-controlled clinical trials corroborated these results. For it to become an approved treatment for depression, its safety and tolerability need to be assessed and documented. AREAS COVERED: We have gathered data regarding the occurrence of adverse events (AEs) in all reported randomized, placebo-controlled trials with healthy and clinical populations involving ayahuasca administration (n = 108 ayahuasca administrations). We systematically categorized these results, recorded their prevalence, and discussed the possible mechanisms related to their emergence. EXPERT OPINION: There were no reports of serious AEs, indicating a relative safety of ayahuasca administration in controlled settings. Most common AEs included nausea, vomiting, headaches, and transient increases in cardiovascular measurements. Ayahuasca research is still in its infancy, especially concerning the absence of large and robust clinical trials to verify its antidepressant effects. Dose standardization, legal prohibition of the possession of its alkaloids and how traditional communities will be compensated if ayahuasca becomes an approved medicine are the biggest obstacles to overcome for its future use in the therapeutic context.


Assuntos
Antidepressivos , Banisteriopsis , Antidepressivos/efeitos adversos , Banisteriopsis/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
5.
Curr Neuropharmacol ; 20(10): 1988-2000, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35236264

RESUMO

BACKGROUND: The substantial female hormone fluctuations associated with pregnancy and postpartum have been linked to a greater risk of developing depressive symptoms, particularly in high-risk women (HRW), i.e. those with histories of mood sensitivity to female hormone fluctuations. We have shown that glutamate (Glu) levels in the medial prefrontal cortex (MPFC) decrease during perimenopause, a period of increased risk of developing a major depressive episode. Our team has also demonstrated that percentage gray matter (%GM), another neural correlate of maternal brain health, decreases in the MPFC during pregnancy. OBJECTIVE: To investigate MPFC Glu levels and %GM from late pregnancy up to 7 weeks postpartum in HRW and healthy pregnant women (HPW). METHODS: Single-voxel spectra were acquired from the MPFC of 41 HPW and 22 HRW using 3- Tesla in vivo proton magnetic resonance spectroscopy at five different time points. RESULTS: We observed a statistically significant interaction between time and group for the metabolite Glu, with Glu levels being lower for HRW during pregnancy and early postpartum (p<0.05). MPFC %GM was initially lower during pregnancy and then significantly increased over time in both groups (p<0.01). CONCLUSION: This investigation suggests that the vulnerability towards PPD is associated with unique fluctuations of MPFC Glu levels during pregnancy and early postpartum period. Our results also suggest that the decline in MPFC %GM associated with pregnancy seems to progressively recover over time. Further investigations are needed to determine the specific role that female hormones play on the physiological changes in %GM during pregnancy and postpartum.


Assuntos
Depressão Pós-Parto , Transtorno Depressivo Maior , Depressão Pós-Parto/metabolismo , Transtorno Depressivo Maior/metabolismo , Feminino , Ácido Glutâmico/metabolismo , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/metabolismo , Hormônios/metabolismo , Humanos , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/metabolismo , Gravidez , Estudos Prospectivos
6.
Cell Mol Neurobiol ; 42(1): 225-242, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33839994

RESUMO

Phenelzine (PLZ) is a monoamine oxidase (MAO)-inhibiting antidepressant with anxiolytic properties. This multifaceted drug has a number of pharmacological and neurochemical effects in addition to inhibition of MAO, and findings on these effects have contributed to a body of evidence indicating that PLZ also has neuroprotective/neurorescue properties. These attributes are reviewed in this paper and include catabolism to the active metabolite ß-phenylethylidenehydrazine (PEH) and effects of PLZ and PEH on the GABA-glutamate balance in brain, sequestration of reactive aldehydes, and inhibition of primary amine oxidase. Also discussed are the encouraging findings of the effects of PLZ in animal models of stroke, spinal cord injury, traumatic brain injury, and multiple sclerosis, as well other actions such as reduction of nitrative stress, reduction of the effects of a toxin on dopaminergic neurons, potential anticonvulsant actions, and effects on brain-derived neurotrophic factor, neural cell adhesion molecules, an anti-apoptotic factor, and brain levels of ornithine and N-acetylamino acids.


Assuntos
Antidepressivos , Inibidores da Monoaminoxidase , Fármacos Neuroprotetores , Fenelzina , Animais , Antidepressivos/farmacologia , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Fármacos Neuroprotetores/farmacologia , Fenelzina/farmacologia , Ratos , Ratos Sprague-Dawley
7.
Front Neurol ; 12: 721126, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34650506

RESUMO

Major depressive disorder (MDD) is a prominent cause of disability worldwide. Current antidepressant drugs produce full remission in only about one-third of MDD patients and there are no biomarkers to guide physicians in selecting the best treatment for individuals. There is an urgency to learn more about the etiology of MDD and to identify new targets that will lead to improved therapy and hopefully aid in predicting and preventing MDD. There has been extensive interest in the roles of the immune system and the gut microbiome in MDD and in how these systems interact. Gut microbes can contribute to the nature of immune responses, and a chronic inflammatory state may lead to increased responsiveness to stress and to development of MDD. The gut microbiome-immune system-brain axis is bidirectional, is sensitive to stress and is important in development of stress-related disorders such as MDD. Communication between the gut and brain involves the enteric nervous system (ENS), the autonomic nervous system (ANS), neuroendocrine signaling systems and the immune system, and all of these can interact with the gut microbiota. Preclinical studies and preliminary clinical investigations have reported improved mood with administration of probiotics and prebiotics, but large, carefully controlled clinical trials are now necessary to evaluate their effectiveness in treating MDD. The roles that several gut microbe-derived molecules such as neurotransmitters, short chain fatty acids and tryptophan play in MDD are reviewed briefly. Challenges and potential future directions associated with studying this important axis as it relates to MDD are discussed.

8.
Front Psychiatry ; 12: 754032, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34707525

RESUMO

Dementia, of which Alzheimer's disease (AD) is the most common form, is characterized by progressive cognitive deterioration, including profound memory loss, which affects functioning in many aspects of life. Although cognitive deterioration is relatively common in aging and aging is a risk factor for AD, the condition is not necessarily a part of the aging process. The N-methyl-D-aspartate glutamate receptor (NMDAR) and its co-agonist D-serine are currently of great interest as potential important contributors to cognitive function in normal aging and dementia. D-Serine is necessary for activation of the NMDAR and in maintenance of long-term potentiation (LTP) and is involved in brain development, neuronal connectivity, synaptic plasticity and regulation of learning and memory. In this paper, we review evidence, from both preclinical and human studies, on the involvement of D-serine (and the enzymes involved in its metabolism) in regulation of cognition. Potential mechanisms of action of D-serine are discussed in the context of normal aging and in dementia, as is the potential for using D-serine as a potential biomarker and/or therapeutic agent in dementia. Although there is some controversy in the literature, it has been proposed that in normal aging there is decreased expression of serine racemase and decreased levels of D-serine and down-regulation of NMDARs, resulting in impaired synaptic plasticity and deficits in learning and memory. In contrast, in AD there appears to be activation of serine racemase, increased levels of D-serine and overstimulation of NMDARs, resulting in cytotoxicity, synaptic deficits, and dementia.

9.
Biomolecules ; 11(7)2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34356654

RESUMO

Clozapine is superior to other antipsychotics as a therapy for treatment-resistant schizophrenia and schizoaffective disorder with increased risk of suicidal behavior. This drug has also been used in the off-label treatment of bipolar disorder, major depressive disorder (MDD), and Parkinson's disease (PD). Although usually reserved for severe and treatment-refractory cases, it is interesting that electroconvulsive therapy (ECT) has also been used in the treatment of these psychiatric disorders, suggesting some common or related mechanisms. A literature review on the applications of clozapine and electroconvulsive therapy (ECT) to the disorders mentioned above was undertaken, and this narrative review was prepared. Although both treatments have multiple actions, evidence to date suggests that the ability to elicit epileptiform activity and alter EEG activity, to increase neuroplasticity and elevate brain levels of neurotrophic factors, to affect imbalances in the relationship between glutamate and γ-aminobutyric acid (GABA), and to reduce inflammation through effects on neuron-glia interactions are common underlying mechanisms of these two treatments. This evidence may explain why clozapine is effective in a range of neuropsychiatric disorders. Future increased investigations into epigenetic and connectomic changes produced by clozapine and ECT should provide valuable information about these two treatments and the disorders they are used to treat.


Assuntos
Antipsicóticos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Clozapina/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Antipsicóticos/uso terapêutico , Transtorno Bipolar/terapia , Clozapina/uso terapêutico , Transtorno Depressivo Maior/terapia , Eletroconvulsoterapia/métodos , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/terapia , Esquizofrenia/terapia
10.
Handb Clin Neurol ; 183: 221-234, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34389119

RESUMO

Autoimmune encephalitis often produces signs and symptoms that appear to be at the interface between neurology and psychiatry. Since psychiatric symptoms are often prominent, patients are often first seen in a psychiatric setting. Therefore it is important that psychiatrists, as well as neurologists, be able to recognize autoimmune encephalitis, a task that is often difficult. Early diagnosis of autoimmune encephalitis is crucial as this will usually result in a better outcome for the patient. This chapter provides an introduction to various autoimmune encephalitides and describes their pathophysiology and the possible associated neuropsychiatric, neuropsychological (cognitive), and neurological (sensory-motor) signs and symptoms. This chapter also reviews the possible treatments of these associated signs and symptoms.


Assuntos
Encefalite , Doença de Hashimoto , Autoanticorpos , Emoções , Encefalite/diagnóstico , Doença de Hashimoto/diagnóstico , Humanos
11.
Med Biol Eng Comput ; 59(5): 1099-1110, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33881705

RESUMO

There is now a relatively large body of evidence suggesting a relationship between dysfunction of myelin and oligodendrocytes and the etiology of several neuropsychiatric disorders, including depression and schizophrenia, and also suggesting that ultrasound methods may alleviate some of the symptoms of depression. We have applied low-intensity pulsed ultrasound (LIPUS) to the brains of mice treated with the demyelinating drug cuprizone, a drug that has been used as the basis for a rodent model relevant to a number of psychiatric and neurologic disorders including depression, schizophrenia, and multiple sclerosis. Prior to conducting the studies in mice, preliminary studies were carried out on the effects of LIPUS in vitro in neuron-like SH-SY5Y cells and primary glial cells. In subsequent studies in mice, female C57BL/6 mice were restrained in plastic tubes for 20 min daily with the ultrasound transducer near the end of the tube directly above the mouse's head. LIPUS was used at an intensity of 25 mW/cm2 once daily for 22 days in control mice and in mice undergoing daily repetitive restraint stress (RRS). Behavioral or neurochemical studies were done on the mice or the brain tissue obtained from them. The studies in vitro indicated that LIPUS stimulation at an intensity of 15 mW/cm2 delivered for 5 min daily for 3 days in an enclosed sterile cell culture plate in an incubator increased the viability of SH-SY5Y and primary glial cells. In the studies in mice, LIPUS elevated levels of doublecortin, a marker for neurogenesis, in the cortex compared to levels in the RRS mice and caused a trend in elevation of brain levels of brain-derived neurotrophic factor in the hippocampus relative to control levels. LIPUS also increased sucrose preference (a measure of the attenuation of anhedonia, a common symptom of several psychiatric disorders) in the RRS model in mice. The ability of LIPUS administered daily to rescue damaged myelin and oligodendrocytes was studied in mice treated chronically with cuprizone for 35 days. LIPUS increased cortex and corpus callosum levels of myelin basic protein, a protein marker for mature oligodendrocytes, and neural/glial antigen 2, a protein marker for oligodendrocyte precursor cells, relative to levels in the cuprizone + sham animals. These results of this exploratory study suggest that future comprehensive time-related studies with LIPUS on brain chemistry and behavior related to neuropsychiatric disorders are warranted. Exploratory Study on Neurochemical Effects of Low Intensity Pulsed Ultrasound in Brains of Mice. Upper part of figure: LIPUS device and in-vitro cell experimental set-up. The center image is the LIPUS generating box; the image in the upper left shows the cell experiment set-up; the image in the upper right shows a zoomed-in sketch for the cell experiment; the image in the lower left shows the set-up of repetitive restraint stress (RRS) with a mouse; the image in the lower middle shows the set-up of LIPUS treatment of a mouse; the image in the lower right shows a zoomed-in sketch for the LIPUS treatment of a mouse.


Assuntos
Esclerose Múltipla , Ondas Ultrassônicas , Animais , Encéfalo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina
12.
J Psychopharmacol ; 35(4): 453-458, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33740877

RESUMO

Major depressive disorder (MDD) is among the most prevalent mental health disorders worldwide, and it is associated with a reduced quality of life and enormous costs to health care systems. Available drug treatments show low-to-moderate response in most patients, with almost a third of patients being non-responders (treatment-resistant). Furthermore, most currently available medications need several weeks to achieve therapeutic effects, and the long-term use of these drugs is often associated with significant unwanted side effects and resultant reductions in treatment compliance. Therefore, more effective, safer, and faster-acting antidepressants with enduring effects are needed. Together with ketamine, psychedelics (or classic or serotoninergic hallucinogens) such as lysergic acid diethylamide (LSD), psilocybin, and ayahuasca are among the few compounds with recent human evidence of fast-acting antidepressant effects. Several studies in the 1950s to 1970s reported antidepressive and anxiolytic effects of these drugs, which are being confirmed by modern trials (LSD, one trial; psilocybin, five trials; ayahuasca, two trials). The effects of these drugs appear to be produced primarily by their agonism at serotonin (5-hydroxytryptamine, 5-HT) receptors, especially the 5-HT2A receptor. Considering the overall burden of MDD and the necessity of new therapeutic options, the promising (but currently limited) evidence of safety and efficacy of psychedelics has encouraged the scientific community to explore more fully their beneficial effects in MDD.


Assuntos
Transtorno Depressivo/tratamento farmacológico , Dietilamida do Ácido Lisérgico/farmacologia , Psilocibina/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina , Antidepressivos/farmacologia , Ensaios Clínicos como Assunto , Transtorno Depressivo/metabolismo , Transtorno Depressivo/psicologia , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/estatística & dados numéricos , Alucinógenos/farmacologia , Humanos , Ketamina/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia
14.
Artigo em Inglês | MEDLINE | ID: mdl-33316333

RESUMO

In recent years, there has been a great deal of interest in the effects of calorie reduction (calorie restriction) and fasting on depression. In the current paper, we have reviewed the literature in this area, with discussion of the possible neurobiological mechanisms involved in calorie restriction and intermittent fasting. Factors which may play a role in the effects of these dietary manipulations on health include changes involving free fatty acids, ketone bodies, neurotransmitters, cyclic adenosine monophosphate response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), cytokines, orexin, ghrelin, leptin, reactive oxygen species and autophagy. Several of these factors are potential contributors to improving symptoms of depression. Challenges encountered in research on calorie restriction and intermittent fasting are also discussed. Although much is now known about the acute effects of calorie restriction and intermittent fasting, further long term clinical studies are warranted.


Assuntos
Restrição Calórica , Depressão/dietoterapia , Jejum/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/sangue , Citocinas/sangue , Humanos , Corpos Cetônicos , Orexinas
15.
Sci Rep ; 10(1): 16429, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009442

RESUMO

Dopamine is well known to regulate movement through the differential control of direct and indirect pathways in the striatum that express D1 and D2 receptors respectively. The spinal cord also expresses all dopamine receptors; however, how the specific receptors regulate spinal network output in mammals is poorly understood. We explore the receptor-specific mechanisms that underlie dopaminergic control of spinal network output of neonatal mice during changes in spinal network excitability. During spontaneous activity, which is a characteristic of developing spinal networks operating in a low excitability state, we found that dopamine is primarily inhibitory. We uncover an excitatory D1-mediated effect of dopamine on motoneurons and network output that also involves co-activation with D2 receptors. Critically, these excitatory actions require higher concentrations of dopamine; however, analysis of dopamine concentrations of neonates indicates that endogenous levels of spinal dopamine are low. Because endogenous levels of spinal dopamine are low, this excitatory dopaminergic pathway is likely physiologically-silent at this stage in development. In contrast, the inhibitory effect of dopamine, at low physiological concentrations is mediated by parallel activation of D2, D3, D4 and α2 receptors which is reproduced when endogenous dopamine levels are increased by blocking dopamine reuptake and metabolism. We provide evidence in support of dedicated spinal network components that are controlled by excitatory D1 and inhibitory D2 receptors that is reminiscent of the classic dopaminergic indirect and direct pathway within the striatum. These results indicate that network state is an important factor that dictates receptor-specific and therefore dose-dependent control of neuromodulators on spinal network output and advances our understanding of how neuromodulators regulate neural networks under dynamically changing excitability.


Assuntos
Mamíferos/metabolismo , Receptores Dopaminérgicos/metabolismo , Medula Espinal/metabolismo , Animais , Corpo Estriado/metabolismo , Dopamina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurotransmissores/metabolismo
16.
eNeuro ; 7(4)2020.
Artigo em Inglês | MEDLINE | ID: mdl-32680835

RESUMO

Spinal cord injury and peripheral nerve injuries are traumatic events that greatly impact quality of life. One factor that is being explored throughout patient care is the idea of diet and the role it has on patient outcomes. But the effects of diet following neurotrauma need to be carefully explored in animal models to ensure that they have beneficial effects. The ketogenic diet provides sufficient daily caloric requirements while being potentially neuroprotective and analgesic. In this study, animals were fed a high-fat, low-carbohydrate diet that led to a high concentration of blood ketone that was sustained for as long as the animals were on the diet. Mice fed a ketogenic diet had significantly lower levels of tyrosine and tryptophan, but the levels of other monoamines within the spinal cord remained similar to those of control mice. Mice were fed a standard or ketogenic diet for 7 d before and 28 d following the injury. Our results show that mice hemisected over the T10-T11 vertebrae showed no beneficial effects of being on a ketogenic diet over a 28 d recovery period. Similarly, ligation of the common peroneal and tibial nerve showed no differences between mice fed normal or ketogenic diets. Tests included von Frey, open field, and ladder-rung crossing. We add to existing literature showing protective effects of the ketogenic diet in forelimb injuries by focusing on neurotrauma in the hindlimbs. The results suggest that ketogenic diets need to be assessed based on the type and location of neurotrauma.


Assuntos
Dieta Cetogênica , Traumatismos da Medula Espinal , Animais , Modelos Animais de Doenças , Camundongos , Qualidade de Vida
17.
Ther Adv Psychopharmacol ; 10: 2045125320916657, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32440333

RESUMO

Ketamine, a drug introduced in the 1960s as an anesthetic agent and still used for that purpose, has garnered marked interest over the past two decades as an emerging treatment for major depressive disorder. With increasing evidence of its efficacy in treatment-resistant depression and its potential anti-suicidal action, a great deal of investigation has been conducted on elucidating ketamine's effects on the brain. Of particular interest and therapeutic potential is the ability of ketamine to exert rapid antidepressant properties as early as several hours after administration. This is in stark contrast to the delayed effects observed with traditional antidepressants, often requiring several weeks of therapy for a clinical response. Furthermore, ketamine appears to have a unique mechanism of action involving glutamate modulation via actions at the N-methyl-D-aspartate (NMDA) and α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, as well as downstream activation of brain-derived neurotrophic factor (BDNF) and mechanistic target of rapamycin (mTOR) signaling pathways to potentiate synaptic plasticity. This paper provides a brief overview of ketamine with regard to pharmacology/pharmacokinetics, toxicology, the current state of clinical trials on depression, postulated antidepressant mechanisms and potential biomarkers (biochemical, inflammatory, metabolic, neuroimaging sleep-related and cognitive) for predicting response to and/or monitoring of therapeutic outcome with ketamine.

18.
Acta Neuropsychiatr ; 32(4): 177-185, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31791436

RESUMO

The past decade has seen a surge of reports and investigations into cases of autoimmune-mediated encephalitis. The increasing recognition of these disorders is especially of relevance to the fields of neurology and psychiatry. Autoimmune encephalitis involves antibodies against synaptic receptors, neuronal cell surface proteins and intracellular targets. These disorders feature prominent symptoms of cognitive impairment and behavioural changes, often associated with the presence of seizures. Early in the clinical course, autoimmune encephalitis may manifest as psychiatric symptoms of psychosis and involve psychiatry as an initial point of contact. Although commonly associated with malignancy, these disorders can present in the absence of an inciting neoplasm. The identification of autoimmune encephalitis is of clinical importance as a large proportion of individuals experience a response to immunotherapy. This review focuses on the current state of knowledge on n-methyl-d-aspartate (NMDA) receptor-associated encephalitis and limbic encephalitis, the latter predominantly involving antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, the γ-aminobutyric acid (GABA)B receptor and leucine-rich glioma-inactivated 1 (LGI1) protein. In addition, we briefly describe anti-dopamine D2 receptor encephalitis. A summary of the literature will focus on common clinical presentations and course, diagnostic approaches and response to treatment. Since a substantial proportion of patients with autoimmune encephalitis exhibit symptoms of psychosis, the relevance of this disorder to theories of psychosis and schizophrenia will also be discussed.


Assuntos
Sintomas Afetivos/imunologia , Doenças Autoimunes do Sistema Nervoso/imunologia , Encefalite/imunologia , Transtornos Mentais/imunologia , Neuroimunomodulação/imunologia , Autoanticorpos/sangue , Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/terapia , Encéfalo/imunologia , Encefalite/diagnóstico , Encefalite/terapia , Humanos , Prognóstico , Transtornos Psicóticos/diagnóstico , Transtornos Psicóticos/imunologia , Transtornos Psicóticos/terapia , Receptores de Neurotransmissores/imunologia , Esquizofrenia/diagnóstico , Esquizofrenia/imunologia , Esquizofrenia/terapia
19.
J Korean Med Sci ; 34(46): e297, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31779058

RESUMO

Accumulated evidence suggests that sporadic cases of Alzheimer's disease (AD) make up more than 95% of total AD patients, and diabetes has been implicated as a strong risk factor for the development of AD. Diabetes shares pathological features of AD, such as impaired insulin signaling, increased oxidative stress, increased amyloid-beta (Aß) production, tauopathy and cerebrovascular complication. Due to shared pathologies between the two diseases, anti-diabetic drugs may be a suitable therapeutic option for AD treatment. In this article, we will discuss the well-known pathologies of AD, including Aß plaques and tau tangles, as well as other mechanisms shared in AD and diabetes including reactive glia and the breakdown of blood brain barrier in order to evaluate the presence of any potential, indirect or direct links of pre-diabetic conditions to AD pathology. In addition, clinical evidence of high incidence of diabetic patients to the development of AD are described together with application of anti-diabetic medications to AD patients.


Assuntos
Doença de Alzheimer/patologia , Diabetes Mellitus Tipo 2/patologia , Doença de Alzheimer/complicações , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Astrócitos/citologia , Astrócitos/metabolismo , Encéfalo/metabolismo , Transtornos Cerebrovasculares/complicações , Transtornos Cerebrovasculares/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hipoglicemiantes/uso terapêutico , Cloreto de Lítio/uso terapêutico , Pioglitazona/uso terapêutico
20.
Expert Rev Neurother ; 19(10): 899-911, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31282772

RESUMO

Introduction: Treatment Resistant Depression (TRD) is a common and burdensome condition with poor outcomes and few treatment options. Esketamine is the S-enantiomer of ketamine and has recently been FDA approved in the United States for treating depression that has failed to respond to trials of two or more antidepressants. Areas covered: This review will briefly discuss current treatment options for TRD, then review esketamine. Relevant literature was identified through online database searches, and clinical trial data were provided by Janssen Pharmaceuticals. Pharmacology, including kinetics and dynamics, is discussed, then clinical data regarding efficacy and safety for esketamine from Phase 2-3 trials are reviewed. Expert opinion: In the expert opinion, the authors discuss multiple factors including patient, physician, and social factors that will influence the use of esketamine. While the efficacy of esketamine compared to off-label use of racemic ketamine remains unclear, both esketamine's approval for use in TRD and longer-term safety data may position it preferentially above racemic ketamine, although factors such as cost and monitoring requirements may limit its use. While questions remain regarding duration and frequency of treatment, as well as addictive potential, esketamine is a novel treatment option offering new hope for TRD.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Ketamina/uso terapêutico , Humanos
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