scholarly journals The Faster-Onset Antidepressant Effects of Hypidone Hydrochloride (YL-0919) in Monkeys Subjected to Chronic Unpredictable Stress

2020 ◽  
Vol 11 ◽  
Author(s):  
Yong-Yu Yin ◽  
Chao-Yang Tian ◽  
Xin-Xin Fang ◽  
Chao Shang ◽  
Li-Ming Zhang ◽  
...  
Keyword(s):  
Social Status ◽  
Antidepressant Drugs ◽  
Onset Time ◽  
Antidepressant Effect ◽  
Chronic Unpredictable Stress ◽  
Once Daily ◽  
Cynomolgus Monkeys ◽  
Monkey Model ◽  
Antidepressant Effects ◽  
Significant Depression

Given the limited monkey models of depression available to date, as well as the procedural complexity and time investments that they involve, the ability to test the efficacy and time course of antidepressants in monkey models is greatly restricted. The present study attempted to build a simple and feasible monkey model of depression with chronic unpredictable stress (CUS) and evaluate the antidepressant effect and onset time of fluoxetine hydrochloride (FLX) and the new drug hypidone hydrochloride (YL-0919), a potent and selective 5-HT reuptake inhibitor, 5-HT1A receptor partial agonist and 5-HT6 receptor full agonist. Female cynomolgus monkeys with low social status in their colonies were selected and subjected to CUS for 8 weeks by means of food and water deprivation, space restriction, loud noise, strobe light, and intimidation with fake snakes. Huddling, self-clasping, locomotion and environmental exploration were monitored to evaluate behavioral changes. In addition, the window-opening test was used to evaluate the exploratory interest of the monkeys. The present results revealed that CUS-exposed monkeys displayed significant depression-like behaviors, including significant decreases in exploratory interest, locomotion, and exploration as well as significant increases in huddling and self-clasping behavior and the level of fecal cortisol after 8 weeks of CUS. Treatment with FLX (2.4 mg/kg, i. g.) or YL-0919 (1.2 mg/kg, i. g.) markedly reversed the depression-like behaviors caused by CUS, producing significant antidepressant effects. YL-0919 (once daily for 9 days) had a faster-onset antidepressant effect, compared with FLX (once daily for 17 days). In summary, the present study first established a CUS model using female cynomolgus monkeys with low social status and then successfully evaluated the onset time of 5-HTergic antidepressants. The results suggested that monkeys exposed to CUS displayed significant depression-like behaviors, and both FLX and YL-0919 produced antidepressant effects in this model. Moreover, YL-0919 appeared to act faster than FLX. The present study provides a promising prospect for the evaluation of fast-onset antidepressant drugs based on a CUS monkey model.

scholarly journals ‘It's the way that you look at it’—a cognitive neuropsychological account of SSRI action in depression

2013 ◽  
Vol 368 (1615) ◽  
pp. 20120407 ◽  
Author(s):  
Catherine J. Harmer ◽  
Philip J. Cowen
Keyword(s):  
Emotional Processing ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Antidepressant Drugs ◽  
Antidepressant Effect ◽  
Emotional Information ◽  
Emotional Environment ◽  
Antidepressant Effects ◽  
Conscious Level ◽  
Neuropsychological Theory ◽  
The Way

The fact that selective serotonin reuptake inhibitors (SSRIs) have antidepressant effects in some patients supports the notion that serotonin plays a role in the mode of action of antidepressant drugs. However, neither the way in which serotonin may alleviate depressed mood  nor the reason why several weeks needs to elapse before the full antidepressant effect of treatment is expressed  is known. Here, we propose a neuropsychological theory of SSRI antidepressant action based on the ability of SSRIs to produce positive biases in the processing of emotional information. Both behavioural and neuroimaging studies show that SSRI administration produces positive biases in attention, appraisal and memory from the earliest stages of treatment, well before the time that clinical improvement in mood becomes apparent. We suggest that the delay in the clinical effect of SSRIs can be explained by the time needed for this positive bias in implicit emotional processing to become apparent at a subjective, conscious level. This process is likely to involve the re-learning of emotional associations in a new, more positive emotional environment. This suggests intriguing links between the effect of SSRIs to promote synaptic plasticity and neurogenesis, and their ability to remediate negative emotional biases in depressed patients.

Repeated ketamine administration redeems the time lag for citalopram's antidepressant-like effects

2015 ◽  
Vol 30 (4) ◽  
pp. 504-510 ◽  
Author(s):  
G.-F. Zhang ◽  
W.-X. Liu ◽  
L.-L. Qiu ◽  
J. Guo ◽  
X.-M. Wang ◽  
...  
Keyword(s):  
Remission Rate ◽  
Time Lag ◽  
Onset Time ◽  
Preference Test ◽  
Mild Stress ◽  
Once Daily ◽  
Treatment Regimens ◽  
Antidepressant Effects ◽  
Swimming Test ◽  
Sucrose Preference Test

AbstractCurrent available antidepressants exhibit low remission rate with a long response lag time. Growing evidence has demonstrated acute sub-anesthetic dose of ketamine exerts rapid, robust, and lasting antidepressant effects. However, a long term use of ketamine tends to elicit its adverse reactions. The present study aimed to investigate the antidepressant-like effects of intermittent and consecutive administrations of ketamine on chronic unpredictable mild stress (CUMS) rats, and to determine whether ketamine can redeem the time lag for treatment response of classic antidepressants. The behavioral responses were assessed by the sucrose preference test, forced swimming test, and open field test. In the first stage of experiments, all the four treatment regimens of ketamine (10 mg/kg ip, once daily for 3 or 7 consecutive days, or once every 7 or 3 days, in a total 21 days) showed robust antidepressant-like effects, with no significant influence on locomotor activity and stereotype behavior in the CUMS rats. The intermittent administration regimens produced longer antidepressant-like effects than the consecutive administration regimens and the administration every 7 days presented similar antidepressant-like effects with less administration times compared with the administration every 3 days. In the second stage of experiments, the combination of ketamine (10 mg/kg ip, once every 7 days) and citalopram (20 mg/kg po, once daily) for 21 days caused more rapid and sustained antidepressant-like effects than citalopram administered alone. In summary, repeated sub-anesthestic doses of ketamine can redeem the time lag for the antidepressant-like effects of citalopram, suggesting the combination of ketamine and classic antidepressants is a promising regimen for depression with quick onset time and stable and lasting effects.

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.

Local Delivery of Ibuprofen via Controlled-release Polymers Prevents Angiographic Vasospasm in a Monkey Model of Subarachnoid Hemorrhage

2005 ◽  
Vol 57 (suppl_1) ◽  
pp. 184-190 ◽  
Author(s):  
Gustavo Pradilla ◽  
Quoc-Anh Thai ◽  
Federico G. Legnani ◽  
Richard E. Clatterbuck ◽  
Philippe Gailloud ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Subarachnoid Hemorrhage ◽  
Controlled Release ◽  
Adhesion Molecule ◽  
Subarachnoid Space ◽  
Intercellular Adhesion Molecule ◽  
Intercellular Adhesion Molecule 1 ◽  
Cynomolgus Monkeys ◽  
Monkey Model ◽  
Angiographic Vasospasm

Abstract OBJECTIVE: Adhesion and migration of leukocytes into the periadventitial space play a role in the pathophysiology of vasospasm after subarachnoid hemorrhage (SAH). Intercellular adhesion molecule-1 is a determinant cell adhesion molecule involved in this process. Ibuprofen has been shown to inhibit intercellular adhesion molecule-1 upregulation and prevent vasospasm in animal models of SAH. In this study, we report the toxicity and efficacy of locally delivered ibuprofen incorporated into controlled-release polymers to prevent vasospasm in a monkey model of SAH. METHODS: Ibuprofen was incorporated into ethylene-vinyl acetate (EVAc) polymers at 45% loading (wt:wt). For the toxicity study, cynomolgus monkeys (n = 5) underwent surgical implantation of either blank/EVAc polymers (n = 3) or 45% ibuprofen/EVAc polymers (n = 2) in the subarachnoid space, were followed up for 13 weeks, and were killed for histopathological analysis. For the efficacy study, cynomolgus monkeys (n = 14) underwent cerebral angiography 7 days before and 7 days after surgery and SAH and were randomized to receive either a 45% ibuprofen/EVAc polymer (n = 7; mean dose of ibuprofen, 6 mg/kg) or blank EVAc polymers (n = 7) in the subarachnoid space. Angiographic vasospasm was determined by digital image analysis. Student's t test was used for analysis. RESULTS: Animals implanted with ibuprofen polymers showed no signs of local or systemic toxicity. Animals treated with ibuprofen polymers had 91 ± 9% lumen patency of the middle cerebral artery, compared with 53 ± 11% of animals treated with blank/EVAc polymers (P < 0.001). CONCLUSION: Ibuprofen polymers are safe and prevent angiographic vasospasm after SAH in the monkey model. These findings support the role of cell adhesion molecules and inflammation in the pathophysiology of vasospasm.

13. FGF2 Gene is required for Antidepressant Treatment Effects

2018 ◽  
Author(s):  
Jessica MacGregor
Keyword(s):  
Open Field ◽  
Antidepressant Treatment ◽  
Forced Swim Test ◽  
Antidepressant Drugs ◽  
Preference Test ◽  
Antidepressant Effect ◽  
Plus Maze ◽  
Brain Changes ◽  
Carry Over ◽  
Sucrose Preference Test

gene in humans have been shown to predict non-responsiveness to antidepressant drugs; suggesting that FGF2 is required for antidepressants to work. In this study, we hypothesized that antidepressants will not work in rodents that lack the FGF2 gene. Hence, we tested antidepressant treatment in transgenic mice that had the FGF2 gene knocked out. Chronic unpredictable stress (CUS) has been used for several decades to produce a reliable depressive and anxious phenotype in mice. This study followed a CUS paradigm and used fluoxetine (Prozac) as antidepressant treatment. Mice received daily fluoxetine administration beginning on week three of CUS and continued until the end of week five to provide an antidepressant effect and reverse the effects of stress. To test for levels of anxiety and depression, a battery of behavioral tests was conducted which began from the least stressful (i.e. sucrose preference test, open field maze, elevated plus maze) to the most stressful test (forced swim test) to prevent testing carry-over effects. AnyMaze software was used to measure behavior in the open field and elevated plus mazes by recording the amount of time each mouse spent in certain parts of the maze. Future studies will examine brain changes associated with FGF2 gene deletion – particularly in astrocyte cells – which might be necessary for successful antidepressant action. Hopefully, this will elucidate novel therapeutic targets for antidepressant and anti-anxiety medication. 

Discovery of a Rapidly Metabolized, Long-Acting β2 Adrenergic Receptor Agonist with a Short Onset Time Incorporating a Sulfone Group Suitable for Once-Daily Dosing

2013 ◽  
Vol 57 (1) ◽  
pp. 159-170 ◽  
Author(s):  
Panayiotis A. Procopiou ◽  
Victoria J. Barrett ◽  
Keith Biggadike ◽  
Peter R. Butchers ◽  
Andrew Craven ◽  
...  
Keyword(s):  
Adrenergic Receptor ◽  
Receptor Agonist ◽  
Onset Time ◽  
Once Daily ◽  
Sulfone Group ◽  
Β2 Adrenergic Receptor ◽  
Long Acting ◽  
Adrenergic Receptor Agonist

scholarly journals Corticosterone as a Potential Confounding Factor in Delineating Mechanisms Underlying Ketamine’s Rapid Antidepressant Actions

2020 ◽  
Vol 11 ◽  
Author(s):  
Lauren Wegman-Points ◽  
Brock Pope ◽  
Allison Zobel-Mask ◽  
Lori Winter ◽  
Eric Wauson ◽  
...  
Keyword(s):  
Side Effects ◽  
Molecular Mechanisms ◽  
Low Dose ◽  
Confounding Factor ◽  
Fold Increase ◽  
Antidepressant Effect ◽  
Isoflurane Anesthesia ◽  
Downstream Effector ◽  
Antidepressant Effects ◽  
Cognitive Side Effects

Recent research into the rapid antidepressant effect of subanesthetic doses of ketamine have identified a series of relevant protein cascades activated within hours of administration. Prior to, or concurrent with, these activation cascades, ketamine treatment generates dissociative and psychotomimetic side effects along with an increase in circulating glucocorticoids. In rats, we observed an over 3-fold increase in corticosterone levels in both serum and brain tissue, within an hour of administration of low dose ketamine (10 mg/kg), but not with (2R, 6R)-hydroxynorketamine (HNK) (10 mg/kg), a ketamine metabolite shown to produce antidepressant-like action in rodents without inducing immediate side-effects. Hippocampal tissue from ketamine, but not HNK, injected animals displayed a significant increase in the expression of sgk1, a downstream effector of glucocorticoid receptor signaling. To examine the role conscious sensation of ketamine’s side effects plays in the release of corticosterone, we assessed serum corticosterone levels after ketamine administration while under isoflurane anesthesia. Under anesthesia, ketamine failed to increase circulating corticosterone levels relative to saline controls. Concurrent with its antidepressant effects, ketamine generates a release of glucocorticoids potentially linked to disturbing cognitive side effects and the activation of distinct molecular pathways which should be considered when attempting to delineate the molecular mechanisms of its antidepressant function.

scholarly journals Novel Antidepressant-Like Activity of Caffeic Acid Phenethyl Ester Is Mediated by Enhanced Glucocorticoid Receptor Function in the Hippocampus

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Mi-Sook Lee ◽  
Young Han Kim ◽  
Bo-ram Lee ◽  
Seung-Hae Kwon ◽  
Won-Jin Moon ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Caffeic Acid ◽  
Behavioral Assessment ◽  
Caffeic Acid Phenethyl Ester ◽  
Mitogen Activated Protein Kinase ◽  
Antidepressant Effect ◽  
Chronic Unpredictable Stress ◽  
Western Blots ◽  
Corticosterone Secretion ◽  
Mitogen Activated Protein

Caffeic acid phenethyl ester (CAPE) is an active component of propolis that has a variety of potential pharmacological effects. Although we previously demonstrated that propolis has antidepressant-like activity, the effect of CAPE on this activity remains unknown. The present study assessed whether treatment with CAPE (5, 10, and 20 µmol/kg for 21 days) has an antidepressant-like effect in mice subjected to chronic unpredictable stress via tail suspension (TST) and forced swim (FST) tests. CAPE administration induced behaviors consistent with an antidepressant effect, evidenced by decreased immobility in the TST and FST independent of any effect on serum corticosterone secretion. Western blots, conducted subsequent to behavioral assessment, revealed that CAPE significantly decreased glucocorticoid receptor phosphorylation at S234 (pGR(S234)), resulting in an increased pGR(S220/S234) ratio. We also observed negative correlations between pGR(S220)/(S234) and p38 mitogen-activated protein kinase (p38MAPK) phosphorylation, which was decreased by CAPE treatment. These findings suggest that CAPE treatment exerts an antidepressant-like effect via downregulation of p38MAPK phosphorylation, thereby contributing to enhanced GR function.

scholarly journals Social status, environment, and atherosclerosis in cynomolgus monkeys.

1982 ◽  
Vol 2 (5) ◽  
pp. 359-368 ◽  
Author(s):  
J R Kaplan ◽  
S B Manuck ◽  
T B Clarkson ◽  
F M Lusso ◽  
D M Taub
Keyword(s):  
Social Status ◽  
Cynomolgus Monkeys
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