Skip to main content
SpringerLink
Log in

Mavoglurant Augmentation in OCD Patients Resistant to Selective Serotonin Reuptake Inhibitors: A Proof-of-Concept, Randomized, Placebo-Controlled, Phase 2 Study

  • Original Research
  • Published:
Advances in Therapy Aims and scope Submit manuscript

Abstract

Introduction

To determine if mavoglurant (modified release) as an augmentation therapy to selective serotonin reuptake inhibitors (SSRIs) could have beneficial effects reducing Yale–Brown Obsessive Compulsive Scale (Y-BOCS) total score in patients with obsessive–compulsive disorder (OCD) resistant to SSRI treatment.

Methods

This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2 study. Patients remained on their SSRI treatment and mavoglurant or placebo was added on. Non-smoking men and women aged 18–65 years primarily diagnosed with OCD according to Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR) criteria were randomized (1:1) to mavoglurant or placebo groups. After 50 patients were randomized, an interim analysis was conducted to determine whether the study should be continued. The primary outcome measure was absolute change in Y-BOCS from baseline at week 17. Safety was assessed by recording adverse events (AEs) and serious adverse events (SAEs).

Results

Interim analysis led to a decision to terminate the study. In total 38 (76.0%) participants completed 17 weeks of treatment and 37 (74.0%) completed the study. There was no significant difference in least squares (LS) mean change from baseline at week 17 in Y-BOCS total score for mavoglurant compared with placebo groups [−6.9 (1.75) vs. −8.0 (1.78), respectively; LS mean difference 1.1; 95% CI −3.9, 6.2; p = 0.671]. The incidence of AEs was higher in the mavoglurant compared with the placebo group (80.8% vs. 70.8%, respectively).

Conclusion

This study of mavoglurant in OCD was terminated because of the lack of efficacy at interim analysis. The study did not support the use of an antagonist of mGluR5 receptors for OCD treatment.

Trial Registration

The study was registered with ClinicalTrials.gov: NCT01813019.

Funding

This study was sponsored by Novartis Pharma AG, Basel, Switzerland.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Bokor G, Anderson PD. Obsessive–compulsive disorder. J Pharm Pract. 2014;27(2):116–30.

    Article  PubMed  Google Scholar 

  2. Pauls DL, Abramovitch A, Rauch SL, Geller DA. Obsessive–compulsive disorder: an integrative genetic and neurobiological perspective. Nat Rev Neurosci. 2014;15(6):410–24.

    Article  CAS  PubMed  Google Scholar 

  3. Fontenelle LF, Mendlowicz MV, Versiani M. The descriptive epidemiology of obsessive–compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(3):327–37.

    Article  PubMed  Google Scholar 

  4. Ruscio AM, Stein DJ, Chiu WT, Kessler RC. The epidemiology of obsessive–compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry. 2010;15(1):53–63.

    Article  CAS  PubMed  Google Scholar 

  5. van Grootheest DS, Cath DC, Beekman AT, Boomsma DI. Twin studies on obsessive–compulsive disorder: a review. Twin Res Hum Genet. 2005;8(5):450–8.

    Article  PubMed  Google Scholar 

  6. Stewart SE, Yu D, Scharf JM, et al. Genome-wide association study of obsessive–compulsive disorder. Mol Psychiatry. 2013;18(7):788–98.

    Article  CAS  PubMed  Google Scholar 

  7. Bronstein YL, Cummings JL. Neurochemistry of frontal subcortical circuits. In: Lichter DG, Cummings JL, editors. Frontal-subcortical circuits in psychiatric and neurological disorders. New York: Guilford; 2001. p. 63–6.

    Google Scholar 

  8. Sundaram RS, Gowtham L, Nayak BS. The role of excitatory neurotransmitter glutamate in brain physiology and pathology. Asian J Pharm Clin Res. 2012;5(2):1–7.

    Google Scholar 

  9. Meldrum BS. Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr. 2000;130(4S Suppl):1007s–15s.

    CAS  PubMed  Google Scholar 

  10. Wu K, Hanna GL, Rosenberg DR, Arnold PD. The role of glutamate signaling in the pathogenesis and treatment of obsessive–compulsive disorder. Pharmacol Biochem Behav. 2012;100(4):726–35.

    Article  CAS  PubMed  Google Scholar 

  11. Ting JT, Feng G. Neurobiology of obsessive–compulsive disorder: insights into neural circuitry dysfunction through mouse genetics. Curr Opin Neurobiol. 2011;21(6):842–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kariuki-Nyuthe C, Gomez-Mancilla B, Stein DJ. Obsessive compulsive disorder and the glutamatergic system. Curr Opin Psychiatry. 2014;27(1):32–7.

    Article  PubMed  Google Scholar 

  13. Ting JT, Feng G. Glutamatergic synaptic dysfunction and obsessive–compulsive disorder. Curr Chem Genomics. 2008;2:62–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Akkus F, Terbeck S, Ametamey SM, et al. Metabotropic glutamate receptor 5 binding in patients with obsessive–compulsive disorder. Int J Neuropsychopharmacol. 2014;17(12):1915–22.

    Article  CAS  PubMed  Google Scholar 

  15. Fontenelle LF, Nascimento AL, Mendlowicz MV, Shavitt RG, Versiani M. An update on the pharmacological treatment of obsessive–compulsive disorder. Expert Opin Pharmacother. 2007;8(5):563–83.

    Article  CAS  PubMed  Google Scholar 

  16. Fenske JN, Schwenk TL. Obsessive compulsive disorder: diagnosis and management. Am Fam Physician. 2009;80(3):239–45.

    PubMed  Google Scholar 

  17. Fenske JN, Petersen K. Obsessive–compulsive disorder: diagnosis and management. Am Fam Physician. 2015;92(10):896–903.

    PubMed  Google Scholar 

  18. Soomro GM, Altman D, Rajagopal S, Oakley-Browne M. Selective serotonin re-uptake inhibitors (SSRIs) versus placebo for obsessive compulsive disorder (OCD). Cochrane Database Syst Rev. 2008;1:CD001765.

    Google Scholar 

  19. Arumugham SS, Reddy JYC. Augmentation strategies in obsessive–compulsive disorder. Expert Rev Neurother. 2013;13(2):187–202.

    Article  CAS  PubMed  Google Scholar 

  20. Albert U, Carmassi C, Cosci F, et al. Role and clinical implications of atypical antipsychotics in anxiety disorders, obsessive–compulsive disorder, trauma-related, and somatic symptom disorders: a systematized review. Int Clin Psychopharmacol. 2016;31(5):249–58.

    Article  PubMed  Google Scholar 

  21. Haghighi M, Jahangard L, Mohammad-Beigi H, et al. In a double-blind, randomized and placebo-controlled trial, adjuvant memantine improved symptoms in inpatients suffering from refractory obsessive–compulsive disorders (OCD). Psychopharmacology. 2013;228(4):633–40.

    Article  CAS  PubMed  Google Scholar 

  22. Bruno A, Micò U, Pandolfo G, et al. Lamotrigine augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive–compulsive disorder: a double-blind, placebo-controlled study. J Psychopharmacol. 2012;26(11):1456–62.

    Article  PubMed  Google Scholar 

  23. Paydary K, Akamaloo A, Ahmadipour A, Pishgar F, Emamzadehfard S, Akhondzadeh S. N-Acetylcysteine augmentation therapy for moderate-to-severe obsessive–compulsive disorder: randomized, double-blind, placebo-controlled trial. J Clin Pharm Ther. 2016;41(2):214–9.

    Article  CAS  PubMed  Google Scholar 

  24. Vranesic I, Ofner S, Flor PJ, et al. AFQ056/mavoglurant, a novel clinically effective mGluR5 antagonist: identification, SAR and pharmacological characterization. Bioorg Med Chem. 2014;22(21):5790–803.

    Article  CAS  PubMed  Google Scholar 

  25. Berg D, Godau J, Trenkwalder C, et al. AFQ056 treatment of levodopa-induced dyskinesias: results of 2 randomized controlled trials. Mov Disord. 2011;26(7):1243–50.

    Article  PubMed  Google Scholar 

  26. Targum SD, Pollack MH, Fava M. Redefining affective disorders: relevance for drug development. CNS Neurosci Ther. 2008;14(1):2–9.

    Article  PubMed  Google Scholar 

  27. Desseilles M, Witte J, Chang TE, et al. Massachusetts General Hospital SAFER criteria for clinical trials and research. Harv Rev Psychiatry. 2013;21(5):269–74.

    Article  PubMed  Google Scholar 

  28. Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale: Erlbaum; 1988.

    Google Scholar 

  29. CHMP. European Medicines Agency. Committee for Medicinal Products for Human Use. Guideline on clinical investigation of medicinal products for the treatment of obsessive compulsive disorder. CHMP/EWP/4279/02. London, UK; 2005.

  30. Ghaleiha A, Entezari N, Modabbernia A, et al. Memantine add-on in moderate to severe obsessive–compulsive disorder: randomized double-blind placebo-controlled study. J Psychiatr Res. 2013;47(2):175–80.

    Article  PubMed  Google Scholar 

  31. Heidari M, Zarei M, Hosseini SM, et al. Ondansetron or placebo in the augmentation of fluvoxamine response over 8 weeks in obsessive–compulsive disorder. Int Clin Psychopharmacol. 2014;29(6):344–50.

    Article  PubMed  Google Scholar 

  32. Ackerman DL, Greenland S. Multivariate meta-analysis of controlled drug studies for obsessive–compulsive disorder. J Clin Psychopharmacol. 2002;22(3):309–17.

    Article  CAS  PubMed  Google Scholar 

  33. Veale D, Miles S, Smallcombe N, Ghezai H, Goldacre B, Hodsoll J. Atypical antipsychotic augmentation in SSRI treatment refractory obsessive–compulsive disorder: a systematic review and meta-analysis. BMC Psychiatry. 2014;14:317.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Pallanti S, Quercioli L. Treatment-refractory obsessive–compulsive disorder: methodological issues, operational definitions and therapeutic lines. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(3):400–12.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was sponsored by Novartis Pharma AG, Basel, Switzerland. The article processing charges for this publication were funded by Novartis Pharma AG. The authors thank Ritu Hans and K Ananda Krishna from Novartis Healthcare Pvt Ltd, Hyderabad, India, for medical writing assistance and incorporating subsequent revisions. All named authors meet the International Committee of Medical Journal Editors (ICJME) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.

Disclosures

Daniel Rutrick has no disclosures or conflicts of interests to report. Maurizio Fava has received research support from Abbot Laboratories; Alkermes, Inc.; American Cyanamid; Aspect Medical Systems; AstraZeneca; Avanir Pharmaceuticals; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Cerecor; Clintara, LLC; Covance; Covidien; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; FORUM Pharmaceuticals; Ganeden Biotech, Inc.; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; i3 Innovus/Ingenix; Janssen R&D, LLC; Jed Foundation; Johnson & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante; Methylation Sciences Inc; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM); National Coordinating Center for Integrated Medicine (NiiCM); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; Novartis AG; Organon Pharmaceuticals; PamLab, LLC; Pfizer Inc.; Pharmacia-Upjohn; Pharmaceutical Research Associates., Inc.; Pharmavite® LLC; PharmoRx Therapeutics; Photothera; Reckitt Benckiser; Roche Pharmaceuticals; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Stanley Medical Research Institute (SMRI); Synthelabo; Takeda Pharmaceuticals; Tal Medical; Wyeth-Ayerst Laboratories. Dr. Fava has served as an advisor or consultant to Abbott Laboratories; Acadia; Affectis Pharmaceuticals AG; Alkermes, Inc.; Amarin Pharma Inc.; Aspect Medical Systems; AstraZeneca; Auspex Pharmaceuticals; Avanir Pharmaceuticals; AXSOME Therapeutics; Bayer AG; Best Practice Project Management, Inc.; Biogen; BioMarin Pharmaceuticals, Inc.; Biovail Corporation; BrainCells Inc; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon, Inc.; Cerecor; CNS Response, Inc.; Compellis Pharmaceuticals; Cypress Pharmaceutical, Inc.; DiagnoSearch Life Sciences (P) Ltd.; Dinippon Sumitomo Pharma Co. Inc.; Dov Pharmaceuticals, Inc.; Edgemont Pharmaceuticals, Inc.; Eisai Inc.; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; ePharmaSolutions; EPIX Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; Forum Pharmaceuticals; GenOmind, LLC; GlaxoSmithKline; Grunenthal GmbH; i3 Innovus/Ingenis; Intracellular; Janssen Pharmaceutica; Jazz Pharmaceuticals, Inc.; Johnson & Johnson Pharmaceutical Research & Development, LLC; Knoll Pharmaceuticals Corp.; Labopharm Inc.; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante, Inc.; Merck & Co., Inc.; MSI Methylation Sciences, Inc.; Naurex, Inc.; Nestle Health Sciences; Neuralstem, Inc.; Neuronetics, Inc.; NextWave Pharmaceuticals; Novartis AG; Nutrition 21; Orexigen Therapeutics, Inc.; Organon Pharmaceuticals; Osmotica; Otsuka Pharmaceuticals; Pamlab, LLC; Pfizer Inc.; PharmaStar; Pharmavite® LLC; PharmoRx Therapeutics; Precision Human Biolaboratory; Prexa Pharmaceuticals, Inc.; PPD; Puretech Ventures; PsychoGenics; Psylin Neurosciences, Inc.; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Rexahn Pharmaceuticals, Inc.; Ridge Diagnostics, Inc.; Roche; Sanofi-Aventis US LLC; Sepracor Inc.; Servier Laboratories; Schering-Plough Corporation; Solvay Pharmaceuticals, Inc.; Somaxon Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; Sunovion Pharmaceuticals; Supernus Pharmaceuticals, Inc.; Synthelabo; Taisho Pharmaceutical; Takeda Pharmaceutical Company Limited; Tal Medical, Inc.; Tetragenex Pharmaceuticals, Inc.; TransForm Pharmaceuticals, Inc.; Transcept Pharmaceuticals, Inc.; Vanda Pharmaceuticals, Inc.; VistaGen. Dr. Fava has had speaking or publishing roles for Adamed, Co; Advanced Meeting Partners; American Psychiatric Association; American Society of Clinical Psychopharmacology; AstraZeneca; Belvoir Media Group; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Cephalon, Inc.; CME Institute/Physicians Postgraduate Press, Inc.; Eli Lilly and Company; Forest Pharmaceuticals, Inc.; GlaxoSmithKline; Imedex, LLC; MGH Psychiatry Academy/Primedia; MGH Psychiatry Academy/Reed Elsevier; Novartis AG; Organon Pharmaceuticals; Pfizer Inc.; PharmaStar; United BioSource, Corp.; Wyeth-Ayerst Laboratories. Dr. Fava had equity holdings in Compellis; PsyBrain, Inc. He is named on patents for Sequential Parallel Comparison Design (SPCD), licensed by MGH to Pharmaceutical Product Development, LLC (PPD); and a patent application for a combination of ketamine plus scopolamine in major depressive disorder (MDD), licensed by MGH to Biohaven. Dr. Fava is a copyright holder for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte. Ltd. Gregor Hasler has received speaker, travel, and consultancy honoraria from Lundbeck, Eli Lilly, Takeda, Servier, AstraZeneca, and Sandoz. He received research grants from National Science Foundation Switzerland, OPO Foundation, Zurich, NARSAD, Novartis, Bangerter Foundation, Basel, Stanley Thomas Johnson Foundation, Bern, Helene Bieber Foundation, Zurich, Vontobel Foundation, Zurich, Hermann Foundation, Zurich, Foundation for Scientific Research, Zurich University, Zurich, Switzerland. Dan J. Stein, in the past 3 years, has received research grants and/or consultancy honoraria from AMBRF, Biocodex, Cipla, Lundbeck, National Responsible Gambling Foundation, Novartis, Servier, and Sun. Toni Donchev has no competing interests to declare. Donald Johns was an employee and shareholder of Novartis at the time of this study. He is currently an employee and shareholder of Biogen. Ganesan Subramanian is an employee and/or shareholder of Novartis. Brian Smith is an employee and/or shareholder of Novartis. Jang-Ho Cha is an employee and/or shareholder of Novartis. Fabrizio Gasparini is an employee and/or shareholder of Novartis. Magdalena Ocwieja is an employee and/or shareholder of Novartis. Baltazar Gomez-Mancilla is an employee and/or shareholder of Novartis.

Compliance with Ethics Guidelines

The study was conducted according to the ethical principles of the Declaration of Helsinki of 1964, as revised in 2008. The study protocol and all amendments were reviewed by the independent ethics committee and institutional review board for each center, and informed consent was obtained from all patients prior to being included in the study.

Data Availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Author information

Authors and Affiliations

  1. Adams Clinical Trials, Watertown, MA, 02472, USA

    Daniel Rutrick

  2. MRC Unit on Anxiety and Stress Disorders, Department of Psychiatry, Groote Schuur Hospital, University of Cape Town, Cape Town, 7925, South Africa

    Dan J. Stein

  3. Novartis Healthcare Pvt. Ltd., Hyderabad, 500 081, India

    Ganesan Subramanian

  4. Novartis Pharmaceutical Corporation, Cambridge, MA, 02139, USA

    Brian Smith & Jang-Ho Cha

  5. Department of Psychiatry, Massachusetts General Hospital, Boston, MA, 02115, USA

    Maurizio Fava

  6. Division of Molecular Psychiatry, Psychiatric University Hospital, University of Bern, Bern 60, 3000, Bern, Switzerland

    Gregor Hasler

  7. Novartis Institutes for Biomedical Research, Novartis Pharma AG, 4056, Basel, Switzerland

    Fabrizio Gasparini, Magdalena Ocwieja, Donald Johns & Baltazar Gomez-Mancilla

  8. Biogen, 300 Binney Street, Cambridge, MA, 02142, USA

    Donald Johns

  9. Clinic of Psychiatry, 1606, Sofia, Bulgaria

    Toni Donchev

  10. Department Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

    Baltazar Gomez-Mancilla

Authors
  1. Daniel Rutrick
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dan J. Stein
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ganesan Subramanian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Brian Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maurizio Fava
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gregor Hasler
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jang-Ho Cha
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fabrizio Gasparini
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Toni Donchev
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Magdalena Ocwieja
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Donald Johns
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Baltazar Gomez-Mancilla
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Baltazar Gomez-Mancilla.

Additional information

Enhanced content

To view enhanced content for this article go to http://www.medengine.com/Redeem/0C47F0605521431D.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rutrick, D., Stein, D.J., Subramanian, G. et al. Mavoglurant Augmentation in OCD Patients Resistant to Selective Serotonin Reuptake Inhibitors: A Proof-of-Concept, Randomized, Placebo-Controlled, Phase 2 Study. Adv Ther 34, 524–541 (2017). https://doi.org/10.1007/s12325-016-0468-5

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12325-016-0468-5

Keywords

Search

Navigation