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

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

doi:10.1016/j.pnpbp.2016.01.009

Cited by 58Treatment of Major DepressionNeuroscience and Neuropharmacology ResearchAnxiety, Depression, Psychometrics, Treatment, Cognitive Processes

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

Kent, Justine M., Daly, Ella, Kezic, Iva, Lane, Rosanne, Lim, Pilar, De Smedt, Heidi, De Boer, Peter, Van Nueten, Luc +2 more·2016·Progress in Neuro-Psychopharmacology and Biological Psychiatry

DOI 10.1016/j.pnpbp.2016.01.009

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Abstract

This phase 2a, randomized, multicenter, double-blind, proof-of-concept study was designed to evaluate, efficacy, safety and tolerability of JNJ-40411813/ADX71149, a novel metabotropic glutamate 2 receptor positive allosteric modulator as an adjunctive treatment for major depressive disorder (MDD) with significant anxiety symptoms. Eligible patients (18-64 years) had a DSM-IV diagnosis of MDD, Hamilton Depression Rating Scale-17 (HDRS17) score of ≥ 18, HDRS17 anxiety/somatization factor score of ≥ 7, and an insufficient response to current treatment with a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor. The doubly-randomized, 8-week double-blind treatment phase was comprised of two 4-week periods, from which a combined test statistic was generated, with pre-determined weights assigned to each of the 2 treatment periods. Period 1: patients (n=121) were randomly assigned (1:1) to JNJ-40411813 (n=62; 50mg to 150 mg b.i.d, flexibly dosed) or placebo (n=59); Period 2: placebo-treated patients (n=22) who continued to meet entry severity criteria were re-randomized (1:1) to JNJ-40411813 or placebo, while other patients underwent sham re-randomization and continued on their same treatment. Of 121 randomized patients, 100 patients (82.6%) were completers. No efficacy signal was detected on the primary endpoint, the 6-item Hamilton Anxiety Subscale (HAM-A6, p=0.51). Efficacy signals (based on prespecified 1-sided p<0.20) were evident on several secondary outcome measures of both depression (HDRS17 total score, 6-item subscale of HDRS17 assessing core depressive symptoms [HAM-D6], and Inventory of Depressive Symptomatology [IDS-C30]) and anxiety (HDRS17 anxiety/somatization factor, IDS-C30 anxiety subscale). Although well-tolerated, the results do not suggest efficacy for JNJ-40411813 as an adjunctive treatment for patients with MDD with significant anxious symptoms in the dose range studied.

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Two studies examining the efficacy of ziprasidone showed that it was not effective in patients neither with nor without anxious depression.
“Two studies examining the efficacy of ziprasidone showed that this was not effective in patients neither with nor without anxious depression [56,57].”
From Patients with anxious depression: overview of prevalence, pathophysiology and impact on course and treatment outcome (2018) · cites this paper as [56]

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Che, T., Teng, X., Huang, Q., Mu, Y., Tang, X., Mu, X., & Wei, Y. (2018) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s167608 · Cited by 26 · see citing works
“50% reduction from the baseline HDRS-17 score, and the remission was defined as an absolute HDRS-17 score #7 at the end of the trial.(21) The HbA1c, BMI, and FPG were also viewed as the secondary outcomes, which were used to assess the efficacy of agomelatine and fluoxetine on glycemic control.”
Method
Pharmacotherapy of Anxiety Disorders: Current and Emerging Treatment Options
Garakani, A., Murrough, J. W., Freire, R. C. R., Thom, R. P., Larkin, K., Buono, F. D., & Iosifescu, D. V. (2021) · FOCUS The Journal of Lifelong Learning in Psychiatry · doi:10.1176/appi.focus.19203 · Cited by 27 · see citing works
Strategies for Treatment of Disease-Associated Dementia Beyond Alzheimer's Disease: An Update
Khan, S. S., Khatik, G. L., & Datusalia, A. K. (2022) · Current Neuropharmacology · doi:10.2174/1570159x20666220411083922 · Cited by 25 · see citing works
“ADX-71149/ JNJ40411813 NCT01582815 PAM of mGlu2 Major Depressive Disorder Phase II No significant effect [234]”
Constitutive activity of the metabotropic glutamate receptor 2 explored with a whole-cell label-free biosensor
Doornbos, M. L. J., der Linden, I. V., Vereyken, L., Tresadern, G., IJzerman, A. P., Lavreysen, H., & Heitman, L. H. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.03.026 · Cited by 20 · see citing works
Effect of mGluR2 positive allosteric modulation on frontostriatal working memory activation in schizophrenia
Wolf, D. H., Zheng, D., Kohler, C. G., Turetsky, B. I., Ruparel, K., Satterthwaite, T. D., Elliott, M. A., March, M. E., Cross, A. J., Smith, M. A., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01320-w · Cited by 19 · see citing works
Emerging Medications for Treatment-Resistant Depression: A Review with Perspective on Mechanisms and Challenges
Lucido, M. J., & Dunlop, B. W. (2025) · Brain Sciences · doi:10.3390/brainsci15020161 · Cited by 19 · see citing works
“…pre-synaptically, and their activation inhibits glutamate release. mGlu2/3 antagonists and negative allosteric modulators, such as decoglurant, have thus far failed to demonstrate efficacy in patients with MDD with an inadequate response to pharmacotherapy (EudraCT number 2011-002160-24) [107,108].”
Allosteric modulation of metabotropic glutamate receptors in alcohol use disorder: Insights from preclinical investigations
Johnson, K. A., & Lovinger, D. M. (2020) · Advances in pharmacology · doi:10.1016/bs.apha.2020.02.002 · Cited by 18 · see citing works
Panic results in unique molecular and network changes in the amygdala that facilitate fear responses
Molosh, A. I., Dustrude, E. T., Lukkes, J. L., Fitz, S. D., Caliman, I. F., de Abreu, A. R. R., Dietrich, A. D., Truitt, W. A., Donck, L. V., Ceusters, M., et al. (2018) · Molecular Psychiatry · doi:10.1038/s41380-018-0119-0 · Cited by 18 · see citing works
Cortical influences of serotonin and glutamate on layer V pyramidal neurons
Marek, G. J., & Schoepp, D. D. (2021) · Progress in brain research · doi:10.1016/bs.pbr.2020.11.002 · Cited by 15 · see citing works
Effectiveness of positive allosteric modulators of metabotropic glutamate receptor 2/3 (mGluR2/3) in animal models of schizophrenia
Olivares-Berjaga, D., Martínez-Pinteño, A., Rodríguez, N., Mas, S., Morén, C., Parellada, E., & Gassó, P. (2025) · Translational Psychiatry · doi:10.1038/s41398-024-03194-2 · Cited by 14 · see citing works
Fragment Based Optimization of Metabotropic Glutamate Receptor 2 (mGluR2) Positive Allosteric Modulators in the Absence of Structural Information
Szabó, G., Turos, G., Kolok, S., Vastag, M., Sánta, Z., Dékány, M., Lévay, G. I., Greiner, I., Minami, N., Tatsuya, W., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00161 · Cited by 14 · see citing works
Impact of allosteric modulation: Exploring the binding kinetics of glutamate and other orthosteric ligands of the metabotropic glutamate receptor 2
Doornbos, M. L. J., Vermond, S. C., Lavreysen, H., Tresadern, G., IJzerman, A. P., & Heitman, L. H. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.07.014 · Cited by 13 · see citing works
“Two positive allosteric modulators (PAMs) have advanced into clinical trials: AZD8529 [13,14] and JNJ-40411813/ADX71149 [15,16].”
Background
Combined mGlu2 orthosteric stimulation and positive allosteric modulation alleviates l-DOPA-induced psychosis-like behaviours and dyskinesia in the parkinsonian marmoset
Nuara, S. G., Hamadjida, A., Kwan, C., Bédard, D., Frouni, I., Gourdon, J. C., & Huot, P. (2020) · Journal of Neural Transmission · doi:10.1007/s00702-020-02185-z · Cited by 12 · see citing works
Advances in translating mGlu2 and mGlu3 receptor selective allosteric modulators as breakthrough treatments for affective disorders and alcohol use disorder
Tyler, R. E., Besheer, J., & Joffe, M. E. (2022) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2022.173450 · Cited by 9 · see citing works
Development of Clickable Photoaffinity Ligands for Metabotropic Glutamate Receptor 2 Based on Two Positive Allosteric Modulator Chemotypes
Hellyer, S. D., Aggarwal, S., Chen, A. N. Y., Leach, K., Lapinsky, D. J., & Gregory, K. J. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00009 · Cited by 8 · see citing works
Efficacy, safety, and tolerability of JNJ-61393215 (tebideutorexant), a selective orexin-1 receptor antagonist, as adjunctive treatment for major depressive disorder with anxious distress: A double-blind, placebo-controlled, randomized phase 2a study
Schmidt, M. E., Moyer, J. A., Kezic, I., Zhou, X., Samtani, M. N., Bleys, C., Dallas, S., Salvadore, G., & Drevets, W. C. (2025) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2025.03.007 · Cited by 7 · see citing works
Neurotoxic/Neuroprotective Effects of Clozapine and the Positive Allosteric Modulator of mGluR2 JNJ-46356479 in Human Neuroblastoma Cell Cultures
Gassó, P., Martínez-Pinteño, A., Rodríguez, N., Madero, S., Gómez, M., Segura, À. G., García‐Rizo, C., Morén, C., Mas, S., & Parellada, E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032054 · Cited by 6 · see citing works
“It should be noted that although there are no clinical data for JNJ, the doses of JNJ-40411813 used in the exploratory phase 2a clinical trial were up to 150 mg/day [32], so they correspond to low clinical doses of CLZ.”
Result
Metabotropic glutamate receptor homo- and heterodimers exhibit distinct responses to orthosteric and allosteric ligands
McCullock, T. W., Couch, T. A., & Kammermeier, P. J. (2024) · Molecular Pharmacology · doi:10.1016/j.molpha.2025.100063 · Cited by 5 · see citing works
Fragment-Based Optimization of Dihydropyrazino-Benzimidazolones as Metabotropic Glutamate Receptor-2 Positive Allosteric Modulators against Migraine
Szabó, G., Erdélyi, P., Kolok, S., Vastag, M., Halász, A. S., Kis-Varga, I., Lévay, G. I., Béni, Z., Kóti, J., Greiner, I., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00563 · Cited by 4 · see citing works
Recent advances in the medicinal chemistry of group II and group III mGlu receptors
Jin, C., & Ma, S. (2017) · MedChemComm · doi:10.1039/c6md00612d · Cited by 4 · see citing works
A randomized, double‐blind, placebo‐controlled, time‐to‐event study of the efficacy and safety of JNJ ‐40411813 in combination with levetiracetam or brivaracetam in patients with focal onset seizures
French, J. A., Bosak, M., Kerr, W. T., Smekens, P., Mistry, D., der Geyten, S. V., & Ford, L. (2025) · Epilepsia · doi:10.1111/epi.18707 · Cited by 2 · see citing works
“11,12 In preclinical data, JNJ-40411813 was observed to show synergistic activity with levetiracetam or brivaracetam, which are ASMs thought to bind to and regulate SV2a, a vesicular protein in the presynaptic terminal involved in glutamate release.”
mGlu Receptor Modulation in Murine Models of Stress and Affective Disorders
Maksymetz, J., & Joffe, M. E. (2021) · Neuromethods · doi:10.1007/978-1-0716-1107-4_13 · Cited by 2 · see citing works
Metabotropic Glutamate Receptors in Anxiety Disorder
Xu, J., & Zhu, Y. (2023) · IntechOpen eBooks · doi:10.5772/intechopen.1002630 · Cited by 1 · see citing works
Current practice in pharmacological treatment of generalized anxiety disorder
Useinova, A. N., Ayrapetova, A. A., Savshak, M. V., Li, Y. R., Tarusov, N. I., Kondakov, D. M., Boyko, M. V., Solomko, D. V., Seitmemetova, U. M., & Davydova, D. S. (2024) · Vestnik nevrologii psihiatrii i nejrohirurgii (Bulletin of Neurology Psychiatry and Neurosurgery) · doi:10.33920/med-01-2407-10 · Cited by 1 · see citing works
Metabolic stress and antipsychotic treatment induced gene expression alterations in human cell
Kálmán, S. (2016) · doi:10.14232/phd.2988
Unique pharmacology of mGlu homo- and heterodimersPreprint
McCullock, T. W., Couch, T. A., & Kammermeier, P. J. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.11.18.623856
Dusting off old blueprints: Is it time to reconsider metabotropic glutamate receptor 2 for therapeutic drug development?
Bespalov, A., Lütjens, R., & Doller, D. (2024) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2024.173908
BindingDB Entry 50047870: Discovery of 8-Trifluoromethyl-3-cyclopropylmethyl-7-[(4-(2,4-difluorophenyl)-1-piperazinyl)methyl]-1,2,4-triazolo[4,3-a]pyridine (JNJ-46356479), a Selective and Orally Bioavailable mGlu2 Receptor Positive Allosteric Modulator (PAM).
BindingDB (2018) · UC San Diego · doi:10.7270/q27m09wc
BindingDB Entry 50006765: Covalent Allosteric Probe for the Metabotropic Glutamate Receptor 2: Design, Synthesis, and Pharmacological Characterization.
BindingDB (2021) · UC San Diego · doi:10.7270/q2cf9tcs
BindingDB Entry 50006767: Fragment Based Optimization of Metabotropic Glutamate Receptor 2 (mGluR2) Positive Allosteric Modulators in the Absence of Structural Information.
BindingDB (2021) · UC San Diego · doi:10.7270/q27s7s1b
BindingDB Entry 50000671: Discovery and Kinetic Profiling of 7-Aryl-1,2,4-triazolo[4,3-a]pyridines: Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2.
BindingDB (2019) · UC San Diego · doi:10.7270/q24b33rj
BindingDB Entry 50014912: Fragment-Based Optimization of Dihydropyrazino-Benzimidazolones as Metabotropic Glutamate Receptor-2 Positive Allosteric Modulators against Migraine.
BindingDB (2023) · UC San Diego · doi:10.7270/q2fj2mpb

P.2.f.005 Efficacy and safety of a novel mGlu2 receptor positive allosteric modulator as an adjunctive treatment in anxious depression
Daly, E., Kent, J. S., Drevets, W. C., Kezic, I., Lane, R. M., Lim, P., SMEDT, H. D., Mazzucco, C., Boer, P. D., Nueten, L. V., et al. (2014) · European Neuropsychopharmacology · doi:10.1016/s0924-977x(14)70726-6 · Cited by 1 · see citing works
Efficacy, safety, and tolerability of JNJ-61393215 (tebideutorexant), a selective orexin-1 receptor antagonist, as adjunctive treatment for major depressive disorder with anxious distress: A double-blind, placebo-controlled, randomized phase 2a study
Schmidt, M. E., Moyer, J. A., Kezic, I., Zhou, X., Samtani, M. N., Bleys, C., Dallas, S., Salvadore, G., & Drevets, W. C. (2025) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2025.03.007 · Cited by 7 · see citing works
Characterization of the Novel Positive Allosteric Modulator of the Metabotropic Glutamate Receptor 4 ADX88178 in Rodent Models of Neuropsychiatric Disorders
Kalinichev, M., Poul, E. L., Boléa, C., Girard, F., Campo, B., Fonsi, M., Royer-Urios, I., Browne, S. E., Uslaner, J. M., Davis, M. J., et al. (2014) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.114.214437 · Cited by 70 · see citing works
Adjunctive brexpiprazole in patients with major depressive disorder and anxiety symptoms: an exploratory study
Davis, L. L., Ota, A., Perry, P. P., Tsuneyoshi, K., Weiller, E., & Baker, R. A. (2016) · Brain and Behavior · doi:10.1002/brb3.520 · Cited by 23 · see citing works
Pharmacological and pharmacokinetic properties of JNJ‐40411813, a positive allosteric modulator of the mGlu2 receptor
Lavreysen, H., Ahnaou, A., Drinkenburg, W. H. I. M., Langlois, X., Mackie, C. E., Pype, S., Lütjens, R., Poul, E. L., Trabanco, A. A., & Cid, J. M. (2014) · Pharmacology Research & Perspectives · doi:10.1002/prp2.96 · Cited by 47 · see citing works

Authors: Kent, J. M., Daly, E., Kezic, I., Lane, R., Lim, P., De Smedt, H., De Boer, P., Van Nueten, L., Drevets, W. C., & Ceusters, M.
Affiliations: Janssen Research & Development (United States) (US)
Janssen (Belgium) (BE)
Corresponding author: Kent, Justine M.
ORCID: Daly, Ella
Lane, Rosanne
Drevets, Wayne C.
Ceusters, Marc
Venue: Progress in Neuro-Psychopharmacology and Biological Psychiatry
Publisher: Elsevier BV
Published: 2016-06
Volume: 67
Pages: 66-73
ISSN: 0278-5846 (ISSN-L)
DOI: 10.1016/j.pnpbp.2016.01.009
OpenAlex: W2286122167
Cited by: 53
References: 41
Citations by year: 2025: 5 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 8 · 2020: 6 · 2019: 2 · 2018: 9 · 2017: 7 · 2016: 4 · 2015: 1 · 2014: 1
FWCI: 6.47
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Progress in Neuro-Psychopharmacology and Biological Psychiatry (publishedVersion)
PubMed (publishedVersion)
Funders: Janssen Research and Development
Topics: Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Social Sciences › Psychology › Experimental and Cognitive Psychology › Anxiety, Depression, Psychometrics, Treatment, Cognitive Processes
Keywords: anxious depression, major depressive disorder, positive allosteric modulators, adjunctive therapy, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, treatment-resistant depression, anxiety symptoms, antidepressant efficacy, drug safety and tolerability
MeSH terms: Adolescent, Adult, Antidepressive Agents, Depression, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Middle Aged, Piperidines, Psychiatric Status Rating Scales, Pyridones, Treatment Outcome, Selective Serotonin Reuptake Inhibitors, Young Adult

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

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