Efficacy and safety of an adjunctive mGlu2 receptor positive allosteric modulator to a SSRI/SNRI in anxious depression

Kent, Justine; Daly, Ella; Kezic, I.; Lane, Rosanne; Lim, Pilar; Smedt, Heidi De; Boer, P. de; Nueten, Luc Van; Drevets, Wayne C.; Ceusters, Marc

doi:10.1016/j.pnpbp.2016.01.009

Cited by 44 publications

(31 citation statements)

References 33 publications

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“…The top‐line data of a recent clinical study in patients with anxious depression did not support further development of JNJ‐40411813 for this indication (Kent et al. ). However, data from an exploratory schizophrenia trial indicate that add‐on treatment with JNJ‐40411813 may provide benefit to patients with prominent negative symptoms of schizophrenia (De Boer et al.…”

Section: Discussionmentioning

confidence: 97%

Preclinical evaluation of the antipsychotic potential of the mGlu2‐positive allosteric modulator JNJ‐40411813

Lavreysen

Langlois

Donck

et al. 2015

Pharmacology Res & Perspec

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JNJ-40411813/ADX71149 (1-butyl-3-chloro-4-(4-phenylpiperidin-1-yl) pyridin-2(1H)-one) is a positive allosteric modulator (PAM) of the mGlu2 receptor, which also displays 5-Hydroxytryptamine (5HT2A) antagonism after administration in rodents due to a rodent-specific metabolite. JNJ-40411813 was compared with the orthosteric mGlu2/3 agonist LY404039 (4-amino-2-thiabicyclo [3.1.0] hexane-4,6-dicarboxylic acid 2,2-dioxide), the selective mGlu2 PAM JNJ-42153605 (3-(cyclopropylmethyl)-7-(4-phenylpiperidin-1-yl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine) and the 5HT2A antagonist ritanserin in rodent models for antipsychotic activity and potential side effects, attempting to differentiate between the various compounds and mechanisms of action. In mice, JNJ-40411813, JNJ-42153605, and LY404039 inhibited spontaneous locomotion and phencyclidine- and scopolamine-induced but not d-amphetamine-induced hyperlocomotion; the 5HT2A antagonist ritanserin inhibited only spontaneous locomotion and phencyclidine-induced hyperlocomotion. As measured by 2-deoxyglucose uptake, all compounds reversed memantine-induced brain activation in mice. The two mGlu2 PAMs and LY404039, but not ritanserin, inhibited conditioned avoidance behavior in rats. Like ritanserin, the mGlu2 ligands antagonized 2,5-dimethoxy-4-methylamphetamine-induced head twitches in rats. LY404039 but not the mGlu2 PAMs impaired rotarod performance in rats and increased the acoustic startle response in mice. Our results show that although 5HT2A antagonism has effect in some models, mGlu2 receptor activation is sufficient for activity in several animal models of antipsychotic activity. The mGlu2 PAMs mimicked the in vivo pharmacodynamic effects observed with LY404039 except for effects on the rotarod and acoustic startle, suggesting that they produce a primary activity profile similar to that of the mGlu2/3 receptor agonist while they can be differentiated based on their secondary activity profile. The results are discussed in light of clinical data available for some of these molecules, in particular JNJ-40411813.

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Section: Discussionmentioning

confidence: 97%

Preclinical evaluation of the antipsychotic potential of the mGlu2‐positive allosteric modulator JNJ‐40411813

Lavreysen

Langlois

Donck

et al. 2015

Pharmacology Res & Perspec

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“…While the results of testing LY354740 on the rat DRL 72-s schedule appears to be congruent with the known clinical actions of this drug as an anxiolytic drug lacking apparent antidepressant activity, the reason for the dissociation on DRL 72-s behavior between LY354740 on one hand and the preclinical antidepressant-like effects of mGlu2 receptor PAMs (Table 2) is not known. Only a mGlu2 receptor PAM has been tested in the clinic and the results of that trial did not support moving that mGlu2 receptor PAM forward for further clinical testing (Kent et al, 2016). However, ruling out potential antidepressant action of mGlu2 receptor PAMs is difficult given translational challenges in extrapolating to an optimal single dose of a PAM or agonist to test in a clinical trial.…”

Section: Discussionmentioning

confidence: 99%

Extending the Specificity of DRL 72-s Behavior for Screening Antidepressant-Like Effects of Glutamatergic Clinically Validated Anxiolytic or Antidepressant Drugs in Rats

Marek

Salek

2020

J Pharmacol Exp Ther

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Both an agonist and its associated prodrug for metabotropic glutamate2/3 (mGlu2/3) receptors demonstrated anxiolytic efficacy in large, randomized, multicenter, doubleblind, placebo-controlled trials studying patients with generalized anxiety disorder (GAD). These mGlu2/3 receptor agonists produced robust preclinical anxiolytic-like effects in rodent models. Several different mGlu2 receptor positive allosteric modulators have been found to produce antidepressant-like effects on several preclinical screening paradigms including differential-reinforcement-of-low rate 72-s (DRL 72-s) behavior (increased reinforcers, decreased response rate and cohesive rightward shifts in interresponse time (IRT) distributions). While mGlu2/3 receptor agonists have not been tested formally for therapeutic effects in treating patients with major depressive disorder (MDD), these compounds generally fail to exert antidepressant-like effects in preclinical screening paradigms and did not improve depressive symptoms in GAD trials. Thus, the present studies were designed to test the potential antidepressant-like effects of the mGlu2/3 receptor agonist 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicarboxylate monohydrate (LY354740) on the DRL 72-s schedule. LY354740 did not test similar to clinically validated antidepressant drugs when administered alone or when coadministered with the selective serotonin reuptake inhibitor (SSRI) fluoxetine in rats. Another glutamate-based antidepressant drug, the uncompetitive NMDA channel blocker racemic ketamine, exerted antidepressant-like effects when administered at subanesthetic doses in rats. The findings further support the specificity of rat DRL 72-s behavior when screening for anxiolytic vs antidepressant drugs; and extend testing of compounds with glutamatergic mechanisms of action.

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“…To address this, we used subscales of the HAM-A and HAM-D to investigate the relationship between oxidative stress and “core” symptoms of anxiety and depression. To measure core anxiety, we used the Hamilton Core Anxiety Scale (HAM-A 6 ; Bech, 2006, Bech et al, 2005 and Kent et al, 2016). The HAM-A 6 includes the items anxious mood, tension, fears, intellectual, somatic (muscular), and anxious behavior at interview.…”

Section: Methodsmentioning

confidence: 99%

Severity of anxiety– but not depression– is associated with oxidative stress in Major Depressive Disorder

Steenkamp

Hough

Reus

et al. 2017

Journal of Affective Disorders

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Background Oxidative stress is implicated in both depression and anxiety, but it is currently unclear whether this relates to syndromal diagnoses or trans-diagnostic dimensional symptoms. We examined the relationship between oxidative stress and severity of depression and anxiety symptoms in individuals with Major Depressive Disorder (MDD). Methods Plasma oxidative stress markers F2-isoprostanes and oxidized glutathione (GSSG), and the antioxidant reduced glutathione (GSH), were assessed in 69 physically healthy, medication-free MDD subjects. Symptoms of anxiety and depression were assessed using the Hamilton Anxiety (HAM-A) and Hamilton Depression (HAM-D) Rating Scales. Total HAM-A and HAM-D scores, along with “core” anxiety and depression subscales, and individual HAM-D items “psychic anxiety” and “depressed mood,” were related to oxidative stress markers. Analyses controlled for age, sex, BMI, and smoking. Results Total HAM-A ratings were positively associated with F2-isoprostanes (β=.26, p=0.042) and GSSG (β=.25, p=0.049), but not GSH (β=.05, p=0.711). Core anxiety severity was positively associated with F2-isoprostanes (β=.34, p=0.012) and GSSG, although this did not reach significance (β=.24, p=0.074). None of the biological markers were significantly associated with total HAM-D or core depression ratings (all p>0.13). Subjects scoring high on “psychic anxiety” had elevated F2-isoprostanes (p=0.030) and GSSG (p=0.020). This was not seen with “depressed mood” scores (all p>0.12). Limitations We assessed peripheral oxidative markers, but their relationship to the brain is unclear. Conclusions Oxidative stress is more closely related to anxiety than depression symptoms in MDD. This highlights the importance of relating oxidative stress to specific symptoms and could provide new insights into the biological correlates of affective disorders.

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Efficacy and safety of an adjunctive mGlu2 receptor positive allosteric modulator to a SSRI/SNRI in anxious depression

Cited by 44 publications

References 33 publications

Preclinical evaluation of the antipsychotic potential of the mGlu2‐positive allosteric modulator JNJ‐40411813

Preclinical evaluation of the antipsychotic potential of the mGlu2‐positive allosteric modulator JNJ‐40411813

Extending the Specificity of DRL 72-s Behavior for Screening Antidepressant-Like Effects of Glutamatergic Clinically Validated Anxiolytic or Antidepressant Drugs in Rats

Severity of anxiety– but not depression– is associated with oxidative stress in Major Depressive Disorder

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