scholarly journals A Multiscale View of the Mechanisms Underlying Ketamine’s Antidepressant Effects: An Update on Neuronal Calcium Signaling

2021 ◽  
Vol 15 ◽  
Author(s):  
Ayako Kawatake-Kuno ◽  
Toshiya Murai ◽  
Shusaku Uchida
Keyword(s):  
Calcium Signaling ◽  
Neural Plasticity ◽  
Psychiatric Research ◽  
Antidepressant Effect ◽  
Neurotransmitter System ◽  
Excitatory Neurotransmitter ◽  
Antidepressant Effects ◽  
Glutamatergic Signaling ◽  
Antidepressant Efficacy ◽  
The Central Nervous System

Major depressive disorder (MDD) is a debilitating disease characterized by depressed mood, loss of interest or pleasure, suicidal ideation, and reduced motivation or hopelessness. Despite considerable research, mechanisms underlying MDD remain poorly understood, and current advances in treatment are far from satisfactory. The antidepressant effect of ketamine is among the most important discoveries in psychiatric research over the last half-century. Neurobiological insights into the ketamine’s effects have shed light on the mechanisms underlying antidepressant efficacy. However, mechanisms underlying the rapid and sustained antidepressant effects of ketamine remain controversial. Elucidating such mechanisms is key to identifying new therapeutic targets and developing therapeutic strategies. Accumulating evidence demonstrates the contribution of the glutamatergic pathway, the major excitatory neurotransmitter system in the central nervous system, in MDD pathophysiology and antidepressant effects. The hypothesis of a connection among the calcium signaling cascade stimulated by the glutamatergic system, neural plasticity, and epigenetic regulation of gene transcription is further supported by its associations with ketamine’s antidepressant effects. This review briefly summarizes the potential mechanisms of ketamine’s effects with a specific focus on glutamatergic signaling from a multiscale perspective, including behavioral, cellular, molecular, and epigenetic aspects, to provide a valuable overview of ketamine’s antidepressant effects.

Novel therapeutic targets for bipolar disorder

2017 ◽  
Author(s):  
Ioline D. Henter ◽  
Rodrigo Machado-Vieira
Keyword(s):  
Bipolar Disorder ◽  
Mood Disorders ◽  
Bipolar Depression ◽  
Nmda Antagonist ◽  
Excitatory Neurotransmitter ◽  
Residual Symptoms ◽  
Antidepressant Effects ◽  
The Central Nervous System ◽  
Depressive Episodes

The long-term course of bipolar disorder (BD) comprises recurrent depressive episodes and persistent residual symptoms for which standard therapeutic options are scarce and often ineffective. Glutamate is the major excitatory neurotransmitter in the central nervous system, and glutamate and its cognate receptors have consistently been implicated in the pathophysiology of mood disorders and in the development of novel therapeutics for these disorders. Since the rapid and robust antidepressant effects of the N-methyl-D-aspartate (NMDA) antagonist ketamine were first observed in 2000, other NMDA receptor antagonists have been studied in major depressive disorder (MDD) and BD. This chapter reviews the clinical evidence supporting the use of novel glutamate receptor modulators for treating BD—particularly bipolar depression. We also discuss other promising, non-glutamatergic targets for potential rapid antidepressant effects in mood disorders, including the cholinergic system, the melatonergic system, the glucocorticoid system, the arachidonic acid (AA) cascade, and oxidative stress and bioenergetics.

scholarly journals Immunoregulation and antidepressant effect of ketamine

2021 ◽  
Vol 12 (1) ◽  
pp. 218-236
Author(s):  
Nan Zhang ◽  
Lihua Yao ◽  
Peilin Wang ◽  
Zhongchun Liu
Keyword(s):  
Disease Burden ◽  
Severe Disease ◽  
Mental Health Disorder ◽  
Antagonistic Effect ◽  
Antidepressant Effect ◽  
Future Research ◽  
Recurrence Rates ◽  
Aspartate Receptor ◽  
Antidepressant Effects ◽  
Common Mental Health Disorder

Abstract Major depressive disorder (MDD) is a common mental health disorder that brings severe disease burden worldwide. Traditional antidepressants are mainly targeted at monoamine neurotransmitters, with low remission rates and high recurrence rates. Ketamine is a noncompetitive glutamate N-methyl-d-aspartate receptor (NMDAR) antagonist, and its rapid and powerful antidepressant effects have come to light. Its antidepressant mechanism is still unclarified. Research found that ketamine had not only antagonistic effect on NMDAR but also strong immunomodulatory effect, both of which were closely related to the pathophysiology of MDD. Although there are many related studies, they are relatively heterogeneous. Therefore, this review mainly describes the immune mechanisms involved in MDD and how ketamine plays an antidepressant role by regulating peripheral and central immune system, including peripheral inflammatory cytokines, central microglia, and astrocytes. This review summarizes the related research, finds out the deficiencies of current research, and provides ideas for future research and the development of novel antidepressants.

scholarly journals Ketamine Alters Functional Plasticity of Astroglia: An Implication for Antidepressant Effect

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 573
Author(s):  
Matjaž Stenovec
Keyword(s):  
Molecular Mechanisms ◽  
Neuronal Firing ◽  
Fusion Pore ◽  
Antidepressant Effect ◽  
Intracellular Camp ◽  
Lateral Habenula ◽  
Vesicle Recycling ◽  
The Central Nervous System ◽  
Inward Rectifying Potassium Channel ◽  
Antidepressant Action

Ketamine, a non-competitive N–methyl–d–aspartate receptor (NMDAR) antagonist, exerts a rapid, potent and long-lasting antidepressant effect, although the cellular and molecular mechanisms of this action are yet to be clarified. In addition to targeting neuronal NMDARs fundamental for synaptic transmission, ketamine also affects the function of astrocytes, the key homeostatic cells of the central nervous system that contribute to pathophysiology of major depressive disorder. Here, I review studies revealing that (sub)anesthetic doses of ketamine elevate intracellular cAMP concentration ([cAMP]i) in astrocytes, attenuate stimulus-evoked astrocyte calcium signaling, which regulates exocytotic secretion of gliosignaling molecules, and stabilize the vesicle fusion pore in a narrow configuration, possibly hindering cargo discharge or vesicle recycling. Next, I discuss how ketamine affects astrocyte capacity to control extracellular K+ by reducing vesicular delivery of the inward rectifying potassium channel (Kir4.1) to the plasmalemma that reduces the surface density of Kir4.1. Modified astroglial K+ buffering impacts upon neuronal firing pattern as demonstrated in lateral habenula in a rat model of depression. Finally, I highlight the discovery that ketamine rapidly redistributes cholesterol in the astrocyte plasmalemma, which may alter the flux of cholesterol to neurons. This structural modification may further modulate a host of processes that synergistically contribute to ketamine’s rapid antidepressant action.

scholarly journals Virtual Reality Augmented Feedback Rehabilitation Associated to Action Observation Therapy in Buccofacial Apraxia: Case Report

2021 ◽  
Vol 14 ◽  
pp. 117954762199457
Author(s):  
Daniele Emedoli ◽  
Maddalena Arosio ◽  
Andrea Tettamanti ◽  
Sandro Iannaccone
Keyword(s):  
Virtual Reality ◽  
Neural Plasticity ◽  
Action Observation ◽  
Voluntary Movements ◽  
Augmented Feedback ◽  
Lower Face ◽  
Facial Movements ◽  
Upper Face ◽  
The Central Nervous System ◽  
Buccofacial Apraxia

Background: Buccofacial Apraxia is defined as the inability to perform voluntary movements of the larynx, pharynx, mandible, tongue, lips and cheeks, while automatic or reflexive control of these structures is preserved. Buccofacial Apraxia frequently co-occurs with aphasia and apraxia of speech and it has been reported as almost exclusively resulting from a lesion of the left hemisphere. Recent studies have demonstrated the benefit of treating apraxia using motor training principles such as Augmented Feedback or Action Observation Therapy. In light of this, the study describes the treatment based on immersive Action Observation Therapy and Virtual Reality Augmented Feedback in a case of Buccofacial Apraxia. Participant and Methods: The participant is a right-handed 58-years-old male. He underwent a neurosurgery intervention of craniotomy and exeresis of infra axial expansive lesion in the frontoparietal convexity compatible with an atypical meningioma. Buccofacial Apraxia was diagnosed by a neurologist and evaluated by the Upper and Lower Face Apraxia Test. Buccofacial Apraxia was quantified also by a specific camera, with an appropriately developed software, able to detect the range of motion of automatic face movements and the range of the same movements on voluntary requests. In order to improve voluntary movements, the participant completed fifteen 1-hour rehabilitation sessions, composed of a 20-minutes immersive Action Observation Therapy followed by a 40-minutes Virtual Reality Augmented Feedback sessions, 5 days a week, for 3 consecutive weeks. Results: After treatment, participant achieved great improvements in quality and range of facial movements, performing most of the facial expressions (eg, kiss, smile, lateral angle of mouth displacement) without unsolicited movement. Furthermore, the Upper and Lower Face Apraxia Test showed an improvement of 118% for the Upper Face movements and of 200% for the Lower Face movements. Conclusion: Performing voluntary movement in a Virtual Reality environment with Augmented Feedbacks, in addition to Action Observation Therapy, improved performances of facial gestures and consolidate the activations by the central nervous system based on principles of experience-dependent neural plasticity.

scholarly journals Biomarkers of ketamine’s antidepressant effect: a clinical review of genetics, functional connectivity, and neurophysiology

2021 ◽  
Vol 5 ◽  
pp. 247054702110142
Author(s):  
Alexandra A. Alario ◽  
Mark J. Niciu
Keyword(s):  
Treatment Response ◽  
Antidepressant Treatment ◽  
A Priori ◽  
Antidepressant Effect ◽  
Aspartate Receptor ◽  
Neurophysiological Studies ◽  
All Cause Mortality ◽  
Antidepressant Efficacy ◽  
Glutamate Modulators ◽  
Response Biomarkers

Major depressive disorder (MDD) is one of the leading causes of morbidity and all-cause mortality (including suicide) worldwide, and, unfortunately, first-line monoaminergic antidepressants and evidence-based psychotherapies are not effective for all patients. Subanesthetic doses of the N-methyl-D-aspartate receptor antagonists and glutamate modulators ketamine and S-ketamine have rapid and robust antidepressant efficacy in such treatment-resistant depressed patients (TRD). Yet, as with all antidepressant treatments including electroconvulsive therapy (ECT), not all TRD patients adequately respond, and we are presently unable to a priori predict who will respond or not respond to ketamine. Therefore, antidepressant treatment response biomarkers to ketamine have been a major focus of research for over a decade. In this article, we review the evidence in support of treatment response biomarkers, with a particular focus on genetics, functional magnetic resonance imaging, and neurophysiological studies, i.e. electroencephalography and magnetoencephalography. The studies outlined here lay the groundwork for replication and dissemination.

Some Aspects of the Psychopharmacological Activity of Maprotiline (Ludiomil®): Effects of Single and Repeated Treatments

1978 ◽  
Vol 6 (6) ◽  
pp. 421-429 ◽  
Author(s):  
A Delini-Stula ◽  
E Radeke ◽  
A Vassout
Keyword(s):  
Nervous System ◽  
Chronic Treatment ◽  
Conditioned Fear ◽  
Conditioned Avoidance ◽  
Repeated Treatment ◽  
Antidepressant Effects ◽  
The Central Nervous System ◽  
Pre Treatment ◽  
High Doses ◽  
Psychopharmacological Activity

Three different aspects of the psychopharmacological activity of the antidepressant maprotiline were investigated: its influence on serotoninergic functions the effects produced by chronic treatment its central nervous depressant and anxiolytic properties. Study of the effects of maprotiline on 5-HTP-induced head-twitch in mice pre-treated with pargyline or on hyperpyrexia in rats provided no evidence that the drug interferes with serotonin-mediated functions in the central nervous system even after quite high doses. These findings corroborate the results of extensive neurobiochemical investigations, which failed to demonstrate any influence of maprotiline on the metabolism of serotonin. Chronic studies showed that classical effects of maprotiline such as antagonism against reserpine-induced ptosis or tetrabenazine-induced catalepsy do not change in their intensity after daily administration of the drugs in a dose of 30 mg/kg p.o.for 11 days. A new component of the action of the compound, not detectable after one single dose, seems to appear, however, after repeated treatment (8 days). This effect is manifested in the restoration of conditioned avoidance behaviour after its suppression by pre-treatment with reserpine. The same effect is produced by imipramine. It is suggested that this restorative effect may be due to an additional activation of the dopaminergic nervous system and may have a bearing on the appearance of clinical antidepressant effects. Maprotiline was found to potentiate central nervous depressant effects of drugs like chlorpromazine, phenobarbitone and propranolol. This affords further confirmation that, in addition to its antidepressant qualities, it possesses sedative actions. An anxiolytic component was also demonstrated in rats in which maprotiline suppressed the conditioned, fear-induced rise in body-temperature.

scholarly journals Mouse, rat, and dog bioavailability and mouse oral antidepressant efficacy of (2R,6R)-hydroxynorketamine

2018 ◽  
Vol 33 (1) ◽  
pp. 12-24 ◽  
Author(s):  
Jaclyn N Highland ◽  
Patrick J Morris ◽  
Panos Zanos ◽  
Jacqueline Lovett ◽  
Soumita Ghosh ◽  
...  
Keyword(s):  
Oral Administration ◽  
Learned Helplessness ◽  
Oral Bioavailability ◽  
Forced Swim Test ◽  
Abuse Potential ◽  
Absolute Bioavailability ◽  
Forced Swim ◽  
Antidepressant Effects ◽  
Immobility Time ◽  
Antidepressant Efficacy

Background: ( R,S)-ketamine has gained attention for its rapid-acting antidepressant actions in patients with treatment-resistant depression. However, widespread use of ketamine is limited by its side effects, abuse potential, and poor oral bioavailability. The ketamine metabolite, ( 2R,6R)-hydroxynorketamine, exerts rapid antidepressant effects, without ketamine’s adverse effects and abuse potential, in rodents. Methods: We evaluated the oral bioavailability of ( 2R,6R)-hydroxynorketamine in three species (mice, rats, and dogs) and also evaluated five candidate prodrug modifications for their capacity to enhance the oral bioavailability of ( 2R,6R)-hydroxynorketamine in mice. Oral administration of ( 2R,6R)-hydroxynorketamine was assessed for adverse behavioral effects and for antidepressant efficacy in the mouse forced-swim and learned helplessness tests. Results: ( 2R,6R)-hydroxynorketamine had absolute bioavailability between 46–52% in mice, 42% in rats, and 58% in dogs. Compared to intraperitoneal injection in mice, the relative oral bioavailability of ( 2R,6R)-hydroxynorketamine was 62%, which was not improved by any of the candidate prodrugs tested. Following oral administration, ( 2R,6R)-hydroxynorketamine readily penetrated the brain, with brain to plasma ratios between 0.67–1.2 in mice and rats. Oral administration of ( 2R,6R)-hydroxynorketamine to mice did not alter locomotor activity or precipitate behaviors associated with discomfort, sickness, or stereotypy up to a dose of 450 mg/kg. Oral ( 2R,6R)-hydroxynorketamine reduced forced-swim test immobility time (15–150 mg/kg) and reversed learned helplessness (50–150 mg/kg) in mice. Conclusions: These results demonstrate that ( 2R,6R)-hydroxynorketamine has favorable oral bioavailability in three species and exhibits antidepressant efficacy following oral administration in mice.

scholarly journals ANTI-DEPRESSANT EFFECT OF CEFTRIAXONE IN FORCED SWIMMING TEST AND IN TAIL SUSPENSION TEST IN MICE

2016 ◽  
Vol 8 (11) ◽  
pp. 191 ◽  
Author(s):  
Ajoy Borah ◽  
Binita Singha ◽  
Swopna Phukan
Keyword(s):  
Forced Swimming Test ◽  
Antidepressant Activity ◽  
Tail Suspension Test ◽  
Forced Swimming ◽  
Antidepressant Effect ◽  
Tail Suspension ◽  
Neuroprotective Effects ◽  
The Central Nervous System ◽  
Swimming Test ◽  
Suspension Test

Objective: Depression is a major psychiatric disorder affecting nearly 350 million people worldwide and imposes a substantial health burden on the society. Ceftriaxone has demonstrated neuroprotective effects in animals. It has also undergone trials as a treatment option for amyotrophic lateral sclerosis. This study was therefore undertaken to evaluate the antidepressant-like effect of ceftriaxone in mice.Methods: Ceftriaxone was administered at three different doses (0.130, 0.195 and 0.260g/kg) to Swiss albino mice of either sex by intra peritoneal (i. p.) route. The period of immobility in control and drug-treated mice were recorded in forced swimming test (FST) and tail suspension test (TST). The antidepressant effect of ceftriaxone indicated by the decrease in duration of immobility was compared to that of fluoxetine (0.020 g/kg, i. p.).Results: Ceftriaxone decreased the duration of immobility in mice. It showed a significant dose-dependent antidepressant effect. The antidepressant effect of 0.260g/kg of ceftriaxone was comparable to that of fluoxetine in the TST but not in the FST.Conclusion: The results of the present study indicate antidepressant activity of Ceftriaxone. The study shows that ceftriaxone has additional action on the central nervous system other than neuroprotection. Ceftriaxone therapy in cases of encephalomeningitis and in various cases of hemorrhages in the brain can, therefore, prevent the development of depression in future

scholarly journals Rapid-Acting Antidepressant Therapies

2018 ◽  
Author(s):  
Bashkim Kadriu ◽  
Subha Subramanian ◽  
Zhi-De Deng ◽  
Ioline D. Henter ◽  
Lawrence T. Park ◽  
...  
Keyword(s):  
Rapid Onset ◽  
Emergency Setting ◽  
Glutamatergic System ◽  
Major Depressive ◽  
Signaling Systems ◽  
Antidepressant Effects ◽  
Remission Rates ◽  
Electrophysiological Studies ◽  
Antidepressant Efficacy ◽  
Neural Signaling

Major depressive disorder (MDD) is a highly prevalent and debilitating illness and closely linked to suicide risk. Currently available antidepressants take weeks to work and have low remission rates; indeed, about a third of individuals with MDD fail to fully remit in response to these agents. Novel therapies that target the glutamatergic system—such as ketamine—offer rapid antidepressant effects as well as high remission rates, making them attractive therapeutic options. This chapter reviews the evidence for the antidepressant efficacy of several novel therapeutics, including ketamine, esketamine, nitrous oxide, scopolamine, GLYX-13, and buprenorphine, as well as interventional techniques such as sleep deprivation. Notably, ketamine and esketamine also rapidly reduce suicidal thoughts, making them attractive solutions in an emergency setting. Because studying the rapid onset of antidepressant effects associated with these agents has also improved our understanding of the neurocircuitry and neural signaling systems underlying MDD, some pivotal drug trials using rodents, neuroimaging, and electrophysiological studies are also reviewed.

scholarly journals The Combination of Aquilaria sinensis (Lour.) Gilg and Aucklandia costus Falc. Volatile Oils Exerts Antidepressant Effects in a CUMS-Induced Rat Model by Regulating the HPA Axis and Levels of Neurotransmitters

2021 ◽  
Vol 11 ◽  
Author(s):  
Huiting Li ◽  
Yuanhui Li ◽  
Xiaofei Zhang ◽  
Guilin Ren ◽  
Liangfeng Wang ◽  
...  
Keyword(s):  
Hpa Axis ◽  
Central Area ◽  
Preference Test ◽  
Volatile Oil ◽  
Antidepressant Effect ◽  
Mild Stress ◽  
Aquilaria Sinensis ◽  
Immobility Time ◽  
The Central Nervous System ◽  
Sucrose Preference Test

The Aquilaria sinensis (Lour.) Gilg (CX)–Aucklandia costus Falc. (MX) herbal pair is frequently used in traditional Chinese medicine prescriptions for treating depression. The volatile oil from CX and MX has been shown to have good pharmacological activities on the central nervous system, but its curative effect and mechanism in the treatment of depression are unclear. Therefore, the antidepressant effect of the volatile oil from CX–MX (CMVO) was studied in chronic unpredictable mild stress (CUMS) rats. The suppressive effects of CMVO (25, 50, 100 μL/kg) against CUMS-induced depression-like behavior were evaluated using the forced swimming test (FST), open field test (OFT) and sucrose preference test (SPT). The results showed that CMVO exhibited an antidepressant effect, reversed the decreased sugar preference in the SPT and prolongation of immobility time in the FST induced by CUMS, increased the average speed, time to enter the central area, total moving distance, and enhanced the willingness of rats to explore the environment in the OFT. Inhalational administration of CMVO decreased levels of adrenocorticotropic hormone and corticosterone in serum and the expression of corticotropin-releasing hormone mRNA in the hypothalamus, which indicated regulation of over-activation of the hypothalamic–pituitary–adrenal (HPA) axis. In addition, CMVO restored levels of 5-hydroxytryptamine (5-HT), dopamine, norepinephrine and acetylcholine in the hippocampus. The RT-PCR and immunohistochemistry results showed that CMVO up-regulated the expression of 5-HT1A mRNA. This study demonstrated the antidepressant effect of CMVO in CUMS rats, which was possibly mediated via modulation of monoamine and cholinergic neurotransmitters and regulation of the HPA axis.

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