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Figure 1.
Flow of Patients During the Study
Flow of Patients During the Study

AE indicates adverse event.

Figure 2.
Total Score Mean (SEM) Change From Baseline for the Clinician-Rated Montgomery-Åsberg Depression Rating Scale (MADRS), Patient-Rated MADRS, and 16-Item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR16) (Intent-to-Treat Sample)
Total Score Mean (SEM) Change From Baseline for the Clinician-Rated Montgomery-Åsberg Depression Rating Scale (MADRS), Patient-Rated MADRS, and 16-Item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR16) (Intent-to-Treat Sample)

MMRM indicates mixed-effects model for repeated measures. Error bars indicate SEMs.

aP < .05 (2-sided, unadjusted for multiple comparisons) for 1.5 mg vs placebo. Only showing day 42 testing.

Table 1.  
Demographics and Clinical Characteristics at Baselinea
Demographics and Clinical Characteristics at Baselinea
Table 2.  
Overview of Primary, Secondary, and Exploratory End Points at Day 42 (Intent-to-Treat Sample)
Overview of Primary, Secondary, and Exploratory End Points at Day 42 (Intent-to-Treat Sample)
Table 3.  
Adverse Events With Incidence of at Least 5% (in Any Arm)
Adverse Events With Incidence of at Least 5% (in Any Arm)
1.
Nemeroff  CB.  Prevalence and management of treatment-resistant depression.  J Clin Psychiatry. 2007;68(suppl 8):17-25.PubMedArticle
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Nelson  JC.  The STAR*D study: a four-course meal that leaves us wanting more.  Am J Psychiatry. 2006;163(11):1864-1866.PubMedArticle
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Rush  AJ, Trivedi  MH, Wisniewski  SR,  et al; STAR*D Study Team.  Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression.  N Engl J Med. 2006;354(12):1231-1242.PubMedArticle
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Paykel  ES.  Partial remission, residual symptoms, and relapse in depression.  Dialogues Clin Neurosci. 2008;10(4):431-437.PubMed
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Iovieno  N, van Nieuwenhuizen  A, Clain  A, Baer  L, Nierenberg  AA.  Residual symptoms after remission of major depressive disorder with fluoxetine and risk of relapse.  Depress Anxiety. 2011;28(2):137-144.PubMedArticle
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Duman  RS, Li  N, Liu  R-J, Duric  V, Aghajanian  G.  Signaling pathways underlying the rapid antidepressant actions of ketamine.  Neuropharmacology. 2012;62(1):35-41.PubMedArticle
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Zarate  CA  Jr, Singh  JB, Quiroz  JA,  et al.  A double-blind, placebo-controlled study of memantine in the treatment of major depression.  Am J Psychiatry. 2006;163(1):153-155.PubMedArticle
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Zarate  CA  Jr, Payne  JL, Quiroz  J,  et al.  An open-label trial of riluzole in patients with treatment-resistant major depression.  Am J Psychiatry. 2004;161(1):171-174.PubMedArticle
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Manji  HK, Quiroz  JA, Sporn  J,  et al.  Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression.  Biol Psychiatry. 2003;53(8):707-742.PubMedArticle
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Zarate  CA  Jr, Singh  JB, Carlson  PJ,  et al.  A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.  Arch Gen Psychiatry. 2006;63(8):856-864.PubMedArticle
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Berman  RM, Cappiello  A, Anand  A,  et al.  Antidepressant effects of ketamine in depressed patients.  Biol Psychiatry. 2000;47(4):351-354.PubMedArticle
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Sheng  M, Hoogenraad  CC.  The postsynaptic architecture of excitatory synapses: a more quantitative view.  Annu Rev Biochem. 2007;76:823-847.PubMedArticle
17.
Tebano  MT, Martire  A, Rebola  N,  et al.  Adenosine A2A receptors and metabotropic glutamate 5 receptors are co-localized and functionally interact in the hippocampus: a possible key mechanism in the modulation of N-methyl-D-aspartate effects.  J Neurochem. 2005;95(4):1188-1200.PubMedArticle
18.
Krystal  JH, Sanacora  G, Duman  RS.  Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond.  Biol Psychiatry. 2013;73(12):1133-1141.PubMedArticle
19.
Chaki  S, Ago  Y, Palucha-Paniewiera  A, Matrisciano  F, Pilc  A.  mGlu2/3 and mGlu5 receptors: potential targets for novel antidepressants.  Neuropharmacology. 2013;66:40-52.PubMedArticle
20.
Lindemann  L, Porter  RH, Scharf  SH,  et al.  Pharmacology of basimglurant (RO4917523, RG7090), a unique metabotropic glutamate receptor 5 negative allosteric modulator in clinical development for depression.  J Pharmacol Exp Ther. 2015;353(1):213-233.PubMedArticle
21.
Jaeschke  G, Kolczewski  S, Spooren  W,  et al.  Metabotropic glutamate receptor 5 negative allosteric modulators: discovery of 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, RO4917523), a promising novel medicine for psychiatric diseases.  J Med Chem. 2015;58(3):1358-1371.PubMedArticle
22.
clinicaltrials.gov. A Study of RO4917523 in Patients With Treatment Resistant Depression. NCT00809562. https://clinicaltrials.gov/ct2/show/NCT00809562. Accessed March 3, 2015.
23.
American Psychiatric Association.  Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text revision. Washington, DC: American Psychiatric Association; 2000.
24.
Sheehan  DV, Lecrubier  Y, Sheehan  KH,  et al.  The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10.  J Clin Psychiatry. 1998;59(suppl 20):22-33.PubMed
25.
Chandler  GM, Iosifescu  DV, Pollack  MH,  et al.  Validation of the Massachusetts General Hospital Antidepressant History Questionnaire (ATRQ).  CNS Neurosci Ther. 2009;16:322-325.PubMedArticle
26.
Montgomery  SA, Åsberg  M.  A new depression scale designed to be sensitive to change.  Br J Psychiatry. 1979;134:382-389.PubMedArticle
27.
Guy  W, ed. Clinical global impressions (028-CGI). In: ECDEU Assessment Manual for Psychopharmacology. Washington, DC: National Institute of Mental Health, US Dept of Health, Education, and Welfare; 1976:215-222. Publication 76-338.
28.
Knauz  R, DeBonis  D, Sachs  GS. Reliability and validity of clinician and computer administered MADRS assessed in randomized controlled trials. Poster presentation at: 49th Annual National Institute of Mental Health New Clinical Drug Evaluation Unit Meeting; June 30, 2009; Hollywood, FL.
29.
Sachs  GS, Arkow  M, DeBonis  D. Comparison of computer vs site-based rater administration of the MADRS in placebo controlled trials. Poster presentation at: 50th Anniversary Meeting of the American College of Neuropsychopharmacology (ACNP); December 5, 2011; Waikoloa Village, HI.
30.
Sachs  GS, DeBonis  D. Can a computer administer the MADRS? Comparison with site-based raters in three global clinical trials. Poster presentation at: American Psychiatric Association (APA) Annual Meeting; May 5-9, 2012; Philadelphia, PA.
31.
Rush  AJ, Trivedi  MH, Ibrahim  HM,  et al.  The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression.  Biol Psychiatry. 2003;54(5):573-583.PubMedArticle
32.
Endicott  J, Nee  J, Harrison  W, Blumenthal  R.  Quality of Life Enjoyment and Satisfaction Questionnaire: a new measure.  Psychopharmacol Bull. 1993;29(2):321-326.PubMed
33.
Sheehan  DV.  The Anxiety Disease. New York, NY: Scribners; 1983.
34.
Mundt  JC, Greist  JH, Gelenberg  AJ, Katzelnick  DJ, Jefferson  JW, Modell  JG.  Feasibility and validation of a computer-automated Columbia-Suicide Severity Rating Scale using interactive voice response technology.  J Psychiatr Res. 2010;44(16):1224-1228.PubMedArticle
35.
Iovieno  N, Papakostas  GI.  Correlation between different levels of placebo response rate and clinical trial outcome in major depressive disorder: a meta-analysis.  J Clin Psychiatry. 2012;73(10):1300-1306.PubMedArticle
36.
Baldessarini  RJ, Faedda  GL, Offidani  E,  et al.  Antidepressant-associated mood-switching and transition from unipolar major depression to bipolar disorder: a review.  J Affect Disord. 2013;148(1):129-135.PubMedArticle
37.
Tondo  L, Vázquez  G, Baldessarini  RJ.  Mania associated with antidepressant treatment: comprehensive meta-analytic review.  Acta Psychiatr Scand. 2010;121(6):404-414.PubMedArticle
38.
clinicaltrials.gov. A Human Proof of Concept Study for [11C]-RO5011232 as Radiotracer and Study of the Binding of RO4917523 to Human mGlu5 Brain Receptor at Steady-State in Healthy Volunteers. NCT01483469. https://clinicaltrials.gov/ct2/show/NCT01483469. Accessed March 3, 2016.
Original Investigation
July 2016

Efficacy and Safety of Basimglurant as Adjunctive Therapy for Major DepressionA Randomized Clinical Trial

Author Affiliations
  • 1Pharmaceutical Research and Early Development, Translational Medicine Neuroscience, Roche Innovation Center, Basel, Switzerland
  • 2Pharmaceutical Research and Early Development, Translational Medicine Neuroscience, Roche Innovation Center, New York, New York
  • 3Biostatistics, Roche Innovation Center, Basel, Switzerland
  • 4Biostatistics, Roche Product Development, Roche Innovation Center, New York, New York
  • 5Pharmaceutical Research and Early Development, Clinical Development-Operations, Roche Innovation Centre, Welwyn, United Kingdom
  • 6Clinical Development Neuroscience, Roche Innovation Center, Basel, Switzerland
  • 7Pharmaceutical Research and Early Development, Translational Medicine Neuroscience, Ophthalmology, and Rare Diseases, Roche Innovation Center, Basel, Switzerland
JAMA Psychiatry. 2016;73(7):675-684. doi:10.1001/jamapsychiatry.2016.0838
Abstract

Importance  Antagonism of the postsynaptic metabotropic glutamate subtype 5 receptor is a novel approach to modulate glutamatergic function and has proven efficacy in a number of preclinical behavioral models of depression.

Objective  To evaluate the safety and efficacy of basimglurant modified-release (MR) vs placebo as adjunctive therapy to ongoing antidepressant medication therapy in patients with MDD who had inadequate response within the current episode.

Design, Setting, and Participants  In this phase 2b, double blind, randomized clinical trial of 333 adult patients with a DSM-IV-TR diagnosis of MDD across 59 research clinics globally, patients were assigned to 1 of 2 doses of basimglurant MR (0.5 or 1.5 mg) or placebo once daily, adjunctive to ongoing antidepressant medication therapy (selective serotonin reuptake inhibitor or serotonin and norepinephrine reuptake inhibitor). Patients were enrolled from October 5, 2011, through July 26, 2013.

Interventions  Six-week treatment with 0.5 mg of basimglurant MR, 1.5-mg basimglurant MR, or placebo once daily, adjunctive to ongoing antidepressant medication therapy.

Main Outcomes and Measures  The primary end point was the mean change from baseline score on the Montgomery-Åsberg Depression Rating Scale (MADRS), as rated by the clinician at week 6. Other measures included patient-rated MADRS, Quick Inventory of Depressive Symptomatology–Self-Report, Clinical Global Impression–Improvement, Patient Global Impression–Improvement, and Clinical Global Impression–Severity Scales and adverse events.

Results  A total of 596 patients were screened, and 333 were randomized into the study (mean [SD] age, 47 [11.2] years; 216 female [65.1%]). The primary end point (mean change in clinician-rated MADRS score from baseline to end of treatment) was not met (effect size [ES] = 0.16, P = .42; intent-to-treat [ITT] mixed-effects model for repeated measures [MMRM] analysis for comparing 1.5-mg basimglurant MR and placebo). Across secondary and exploratory end points, 1.5-mg basimglurant MR revealed larger improvements vs placebo on the patient-rated MADRS (−16.2 vs −13.3, ES = 0.28, nominal P = .04), Quick Inventory of Depressive Symptomatology–Self-Report (−7.5 vs −5.8; ES = 0.37, nominal P = .009), Clinical Global Impression–Improvement mean score, and Patient Global Impression–Improvement mean score. Improvements were also seen in the patient-rated MADRS remission rate (36.0% vs 22.0%; nominal P = .03) and response rate (50.5% vs 40.4%; nominal P = .13), A 0.5-mg dose of basimglurant MR had no benefit over placebo in any of these measures. The most common adverse event was dizziness, which was mostly transient and of mild intensity.

Conclusions and Relevance  No difference was observed on the study’s primary outcome measure, the clinician-rated MADRS change from baseline to end of treatment, between adjunctive basimglurant MR vs placebo. Adjunctive 1.5-mg basimglurant MR daily revealed, however, an antidepressant effect across secondary end points, particularly in patient-rated measures. These findings combined with good tolerability warrant further investigation with this compound in depressive disorders.

Trial Registration  clinicaltrials.gov Identifier: NCT01437657

Introduction

Major depressive disorder (MDD) remains an area of considerable medical need despite many agents having been approved for treatment of this illness. Response rates (reduction in symptoms of at least 50% from baseline) for initial treatment are estimated to be approximately 50%, whereas remission (the virtual absence of symptoms), considered to be the goal of treatment, only ranges from 15% up to 40%.1 The results of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial have provided sobering conclusions regarding the efficacy of approved antidepressant treatments, with only one-third of patients achieving remission with initial therapy, and remission decreasing even further with each successive treatment attempt (36.8% after the first attempt, 30.6% after the second attempt, 13.7% after the third attempt, and 13.0% after the fourth attempt).2 Moreover, various switching strategies used as second-line treatment did not yield very different results.3

Failure to obtain remission in MDD using largely monoaminergic-based pharmacotherapy, therefore, remains a common clinical problem. Persistent depressive symptoms are a significant predictor of relapse and poor functional outcome.46 Patients who are resistant to treatment use a disproportionately larger share of health care resources, have significantly more claims for comorbid conditions, and have an associated higher loss of productivity compared with patients with major depression who respond to treatment. New treatments that address inadequate response to antidepressant therapy in MDD would fulfill an important medical need.

During the last decade, evidence has accumulated indicating the pathophysiologic role of deregulated cortical glutamatergic pathways in major depression, including the demonstration of abnormal levels of glutamate and altered expression of glutamate receptors in patients with depression.713 Supportive evidence of the antidepressant effects of antiglutamatergic drugs stems from pilot clinical trials with ketamine, an N-methyl-d-aspartate (NMDA) channel-blocking agent, which have a fast-acting antidepressant effect in treatment-resistant patients.14,15 The postsynaptic colocalization of NMDA receptors and metabotropic glutamate subtype 5 (mGlu5) receptors in cortical and limbic regions16 and the downstream effects of mGlu5 receptor blockade down-regulating NMDA function17 provide a strong rationale for the potential antidepressant effect of mGlu5 receptor antagonism. Given the concerns regarding the clinical use of ketamine, including psychotigenic effects and potential for addiction,18 mGlu5-negative allosteric modulators become an even more attractive target for the development of novel antidepressants.19

Basimglurant is a potent, selective, and safe mGlu5-negative allosteric modulator with good oral bioavailability and long half-life supportive of once-daily administration in humans. It also possesses robust antidepressant and anxiolytic-like properties in preclinical models.20,21 Unpublished data (clinicaltrials.gov, NCT00809562) from a placebo-controlled study22 in inpatients with treatment-resistant depression treated for 10 days revealed that 0.1 mg to 1.5-mg basimglurant was well tolerated, with trends of clinical effects warranting further evaluation in a larger, well-powered clinical trial. A modified-release (MR) formulation was developed to improve safety and tolerability vs the immediate-release (IR) formulation used in earlier clinical studies. This MR formulation improved the pharmacokinetics by decreasing the maximum concentration by approximately 50% and prolonging the time to reach the maximum concentration to approximately 5 hours relative to the IR formulation. These differences between the MR and IR formulations did not affect the overall exposure (area under the curve). The aim of this study was to evaluate the safety and efficacy of once-daily basimglurant MR or placebo added to continuing antidepressant medication therapy in patients with MDD who had inadequate response to at least 1 but no more than 3 treatment failures within the current episode of depression.

Box Section Ref ID

Key Points

  • Question Does basimglurant modified-release (MR), a metabotropic glutamate subtype 5 receptor–negative allosteric modulator, improve outcomes in major depressive disorder when added to a current antidepressant medication treatment?

  • Findings In this randomized clinical trial of 333 adults with major depressive disorder, no difference was observed in the primary outcome measure, the clinician-rated Montgomery-Åsberg Depression Rating Scale change from baseline to end of treatment, between basimglurant MR (0.5 or 1.5 mg) vs placebo. However, 1.5-mg basimglurant MR had a consistent antidepressant effect across secondary end points, particularly in patient-rated measures.

  • Meaning These findings, combined with adequate tolerability, warrant further investigation with this compound in depressive disorders.

Methods
Study Design

This randomized, double-blind, placebo-controlled, multicenter phase 2 study (Modulating Receptors of Glutamate for Alleviating Depression [MARIGOLD]) was composed of a screening period of 2 weeks or less, a 6-week double-blind treatment, and a 3-week posttreatment follow-up period. Patients were enrolled from 59 sites across the United States, Latin America (Chile and Mexico), Europe (Germany, Poland, Russia, and Romania), and Asia (Japan) from October 5, 2011, through July 26, 2013. Data analysis was performed from November 12, 2013, to September 27, 2014. The study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization, Good Clinical Practice guidelines, and local regulatory requirements. The institutional review board or ethics committee approved the protocol at each site. All patients gave written informed consent to participate in the study. An independent data safety monitoring board composed of nonsponsor members reviewed unmasked safety data at predefined intervals and made recommendations to the sponsor’s chief medical officer regarding the continued conduct of the study. After randomization, study visits occurred at days 3, 7, 14, 21, 28, 35, 42, and 63. The trial protocol can be found in the Supplement.

Patients

Male and female outpatients (age range, 18-70 years) who met the DSM-IV-TR criteria for an MDD episode without psychotic features were enrolled.23 Diagnoses were made by the Mini-International Neuropsychiatric Interview (MINI)24 and confirmed by a computer-administered diagnostic interview, which was completed by patients and reviewed via a central vendor (Bracket Global) specialized in MDD diagnosis. The computer-administered diagnostic interview is a complement to the MINI, focusing on the key dimensions of MDD to supplement the categorical diagnostic tool (the MINI). Bracket Global clinicians reviewed the data for diagnostic flags that could indicate uncertainty in the diagnosis required for participation, such as symptoms suggestive of previous hypomanic episodes, lack of treatment response, or a substance abuse component. In these cases, Bracket Global clinicians contacted sites to discuss questionable individuals in a process designed as a consultation. Patients had to have inadequate response to ongoing antidepressant therapy with a selective serotonin reuptake inhibitor or serotonin and norepinephrine reuptake inhibitor. Patients had to have 1 but no more than 3 treatment failures of adequate dose and duration (>6 weeks) according to the Massachusetts General Hospital Antidepressant Treatment History Questionnaire25 in the current episode. Inadequate response was defined as having a clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS)26 total score greater than 25 and a Clinical Global Impression–Severity (CGI-S)27 score greater than 4 at screening. In addition, patients had to have a score greater than 23 on a computer-assisted, self-administered version of the MADRS (the patient-rated MADRS)2830 and a discrepancy of 7 points or fewer with the clinician-rated MADRS score.

Patients were excluded if having any other major Axis I diagnoses (generalized anxiety disorder secondary to depression was allowed), a lifetime history of psychotic symptoms or bipolar disorder, a significant personality disorder, a mood disorder owing to a medical condition or substance use, recent alcohol or substance abuse, or a significant risk of suicidal behavior. Other reasons for exclusion included treatment with a combination of antidepressants, having undergone electroconvulsive therapy or repetitive transcranial magnetic stimulation during the current episode or having a history of failure to these therapies, having ever used vagus nerve stimulation or deep brain stimulation, or planning to begin psychotherapy during the study (unless it had been ongoing for ≥90 days before screening). Fluvoxamine maleate was prohibited because of the theoretical potential to interact with basimglurant (via inhibition of hepatic cytochrome P450 1A2 enzymes).

Treatment

After eligibility was confirmed, patients were randomized (1:1:1 ratio) to receive 6-week double-blind treatment, adjunctive to their ongoing antidepressant medication therapy, with 0.5 mg of basimglurant MR, 1.5-mg basimglurant MR, or placebo orally and once daily (Figure 1). The randomization was stratified by geographic region. Treatment adherence was assessed at each visit based on the returned capsule count.

Ongoing antidepressant therapy was maintained at the same dose for the 6-week double-blind period but could have been adjusted as deemed necessary in the follow-up period. Use of other psychotropic medications was prohibited 2 weeks before randomization with the exception of preexisting stable regimens of benzodiazepines. For acute anxiety and/or insomnia, rescue medication with a benzodiazepine (≤2 mg of lorazepam equivalent) or nonbenzodiazepine (eg, ≤10 mg of zolpidem tartrate or zaleplon) was allowed on a restricted basis.

Efficacy Evaluations

The primary end point was the mean change in the clinician-rated MADRS total score from baseline to end of treatment. Secondary end points included change in CGI-S and Clinical Global Impression–Improvement (CGI-I) scores from baseline to end of treatment, MADRS remission rates (MADRS total score ≤10) at end of treatment, MADRS response rates (≥50% reduction in MADRS total score from baseline), the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR16)31 change from baseline to end of treatment, and the Patient Global Impression of Improvement (PGI-I) score at end of treatment. Exploratory end points included change in Quality of Life Enjoyment and Satisfaction Questionnaire–Short Form (Q-LES-Q-SF)32 and Sheehan Disability Scale (SDS)33 scores from baseline to end of treatment. The patient-rated MADRS total score change from baseline to day 42 was a post hoc analysis and not a prespecified end point.

Investigators and site raters received standardized training on all scales to ensure consistency across the study. All raters performing the clinician-rated MADRS, CGI-I, and CGI-S had to meet minimum qualification criteria and become certified to rate patients. Efforts were made to ensure the same rater conducted all assessments of a particular scale for a given patient to minimize scoring variability. In addition, a rater monitoring program was implemented for quality control purposes. Scores on the clinician- and patient-rated MADRS were continually reviewed for consistency by the ratings vendor, whose clinicians held calls with site raters to discuss sources of discordance and offer retraining when warranted. For the primary efficacy measure (clinician-rated MADRS), 226 raters were approved and certified to perform ratings.

Safety and Tolerability

Safety and tolerability assessments included the monitoring of spontaneously reported adverse events (AEs), physical examination, vital signs and body weight, and 12-lead electrocardiography performed in triplicate. Laboratory tests included measurement of hematologic, chemical, and thyroid parameters; urinalysis; urine drugs of abuse screening; and pregnancy testing. The incidence of suicidal ideation and behavior was monitored using the Columbia-Suicide Severity Rating Scale, interactive voice response version,34 at each visit.

Statistical Analysis

Two patient samples were defined: an intent-to-treat (ITT) sample (all randomized patients who received at least 1 dose of the randomized study drug) and the safety sample (all patients who received at least 1 dose of the study medication, whether withdrawn prematurely or not). The ITT sample was the primary analysis sample for all analyses of primary and secondary clinical efficacy data.

For all efficacy variables, the baseline value was defined as the last nonmissing value taken before the start of the double-blind period. The primary end point and continuous secondary end points were analyzed using a mixed-effects model for repeated measures to use all the data collected over time. This method allowed a general unstructured covariance matrix and enabled inclusion of data from patients who had missing data at some scheduled time points. The model included the baseline value as covariate; the categorical variables treatment, geographic region (Europe, Latin America, Japan, and United States), and visit time point; and an interaction term of visit with treatment. Ordered categorical data (CGI-S, CGI-I, and PGI-I scores) were analyzed using the Wilcoxon rank sum test. Binary data, such as responders or remissions, were analyzed using the Fisher exact test. Unadjusted, unpaired, 2-sided P values were estimated. All exploratory variables and safety and tolerability were summarized descriptively.

Results
Patient Disposition and Characteristics

Figure 1 illustrates the disposition of patients during the study. A total of 596 patients were screened. The main reasons for screen failures, which totaled 263, were failure to meet inclusion criteria with regard to disease severity or MADRS score criteria not met (n = 96 patients screened) and a positive serologic test result for human immunodeficiency virus or hepatitis B or C virus (n = 49 patients screened). Of the 333 patients randomized into the study (mean [SD] age, 47 [11.2] years; 240 white patients [72.3%]; 216 female patients [65.1%]), all but 1 were included in the ITT sample (332 patients [99.7%]; same as the safety sample). This 1 patient was randomized to the placebo group but withdrew consent on study day 1 before receiving the study treatment. The treatment blind was not broken prematurely by the sponsor or investigator during the study. The proportion of patients who withdrew because of refusal of treatment (including withdrawal of consent and failure to cooperate) was similar between the placebo and 1.5-mg basimglurant MR arms (4 and 5 patients, respectively) and somewhat lower in the 0.5-mg basimglurant MR arm (2 patients). The number of patients withdrawn for protocol violations was slightly higher in the 0.5-mg basimglurant MR arm (4 patients) compared with the placebo (1 patient) and 1.5-mg basimglurant MR arms (2 patients).

The patients’ demographic characteristics were generally well matched across all 3 treatment arms (Table 1). All patients had a primary diagnosis of MDD, with a mean MADRS total score of approximately 31 and a mean QIDS-SR16 total score of approximately 14, corresponding to moderate to severe depression. Most patients had recurrent depression (89.0%-91.1%), with the mean number of episodes ranging from 4 to 5 across the 3 treatment arms. Within the current episode, most of the patients reported a single treatment failure (80.4%-83.5%).

The most common class of baseline antidepressant therapy was selective serotonin reuptake inhibitors (received by 74.7%-83.5% of patients). The distribution of antidepressant treatments was similar across study arms, although fewer patients received sertraline hydrochloride in the 1.5-mg basimglurant MR arm (21.6% vs 31.2%-33.0%).

Efficacy

Mean change in clinician-rated MADRS total score from baseline to day 42 (primary end point) was reduced in each treatment arm (−14.6 in the placebo arm, −14.1 in the 0.5-mg basimglurant MR arm, and −16.1 in the 1.5-mg basimglurant MR arm) (Figure 2). Neither active treatment arm was found to be significantly different from placebo (for the 0.5-mg arm, adjusted P = .74 and effect size [ES] = −0.05; for the 1.5-mg arm, adjusted P = .42 and ES = 0.16). The post hoc analysis of the patient-rated MADRS revealed larger differences between 1.5-mg basimglurant MR and placebo compared with the clinician-rated MADRS (−16.2 vs −13.3; 2-sided P = .04, ES = 0.28) (Figure 2).

The proportion of patients taking basimglurant who experienced remission (total score ≤10) or response (≥50% reduction in total score) based on the clinician-rated MADRS at day 42 was not different from placebo. However, remission and response rates based on the post hoc patient-rated MADRS in the ITT sample (last observation carried forward) were greater in the 1.5-mg basimglurant MR arm than in placebo (36.0% vs 22.0%; 2-sided P = .03 and 50.5% vs 40.4%; 2-sided P = .13, for remission and response, respectively).

For the QIDS-SR16, a decrease from baseline to day 42 (ie, improvement) was observed in the 1.5-mg basimglurant MR arm compared with placebo (−7.5 vs −5.8; 2-sided P = .009) (Figure 2). The decrease of 7.5 points observed for 1.5-mg basimglurant MR represented an approximately 50% reduction in score from baseline compared with the decrease of 5.8 points for placebo (approximately 40% reduction). The associated ES of 0.37 is clinically relevant.

The results for other secondary and exploratory efficacy measures are given in Table 2. For 1.5-mg basimglurant MR, improvements at day 42 vs placebo were seen in the CGI-I, PGI-I, Q-LES-Q-SF, and SDS (sum of items 2-3). The SDS total scores could not be calculated for all patients because a significant proportion of them (25.2%-34.9%) were not working for reasons other than depression (and did not score item 1).

Safety and Tolerability

Basimglurant MR at daily doses of 0.5 and 1.5 mg for 6 weeks was generally safe and well tolerated. The overall proportion of patients withdrawn because of AEs was similar across study arms (4.6%, 5.4%, and 7.2% in the placebo arm, 0.5-mg basimglurant MR arm, and 1.5-mg basimglurant MR arm, respectively). The AEs occurring at an incidence of 5% or higher in any treatment arm are given in Table 3.

The most frequent AEs, occurring in the nervous system disorders class, were dizziness (37 [11.1%] of patients), somnolence (30 [9.0%]), and headache (28 [8.4%]). The incidence of dizziness was dose related (26 [23.4%] patients in the 1.5-mg basimglurant MR arm compared with 5 [4.5%] in the 0.5-mg basimglurant MR arm and 6 [5.5%] in the placebo arm). Mild dizziness AEs were reported by 26 patients (70.3%), moderate by 10 (27.0%), and severe by 1 (2.7%). With the exception of 2 patients (1 in each active arm), all dizziness AEs resolved without sequelae. Dizziness AEs were generally transient and resolved without intervention after several days, and most reported no accompanying events, such as vertigo, nausea, vomiting, ataxia, headache, or syncope. One patient in the 1.5-mg basimglurant MR arm reported severe dizziness and vertigo concurrently and was withdrawn.

For AEs of suicidality and hepatic disorders, no clear association to basimglurant MR treatment was noted. The suicidal ideation AE occurred in 1 patient (0.9%) in the 0.5-mg basimglurant MR arm, 1 patient (0.9%) in the 1.5-mg basimglurant MR arm, and no patients in the placebo arm. Hepatic disorders (nonserious elevations of aspartate aminotransferase, alanine aminotransferase, and bilirubin) occurred with higher frequency in the placebo arm compared with the basimglurant MR arms. Mania was reported by 2 patients in the 1.5-mg basimglurant MR arm, leading to withdrawal of both patients from the study. In each case, the AE resolved spontaneously. No clinically relevant changes in laboratory parameters, vital signs, electrocardiographic parameters, or weight indicative of any treatment-emergent AE were observed during the study. There were 6 serious AEs: 2 in the placebo arm, 3 in the 0.5-mg basimglurant MR arm, and 1 in the 1.5-mg basimglurant MR arm. One serious AE in the 0.5-mg basimglurant MR arm was considered by the investigator to be related (remotely) to treatment (acute renal failure). The serious AE resolved without sequelae.

Discussion

This was the first large-scale, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of basimglurant MR as adjunctive treatment in a sample of patients with MDD having inadequate response to 1 to 3 adequate courses of antidepressant treatment during the current episode. No difference was observed on the study’s powered primary outcome measure, the clinician-rated MADRS score change from baseline to end of treatment, between adjunctive basimglurant MR vs placebo. Nonetheless, adjunctive treatment with 1.5-mg basimglurant MR revealed an antidepressant effect across secondary and exploratory end points. Greater improvements were seen in patient-rated end points, such as the patient-rated MADRS and the QIDS-SR16, at several time points, including the day 42 end point, whereas the clinician-rated MADRS primarily revealed improvements at earlier time points only. Of note, however, the correlation coefficient between the patient-level, clinician-reported MADRS and post hoc patient-reported MADRS scores at day 42 was 0.85, suggesting a reasonably strong association. A 0.5-mg dose of basimglurant MR was not effective compared with placebo.

The presence of a high placebo response during the trial may have undermined the ability of this trial to detect a significant statistical difference between the placebo and active treatment arms for the primary end point of clinician-rated MADRS. In a meta-analysis35 of the magnitude of the placebo response rates across different studies of adjunctive therapy in depressive patients, separation of the active drug vs placebo became obscured when placebo response rates were higher than 40%, leading the authors to conclude that excessive placebo response is the most challenging obstacle for the development of new treatments in this patient population. In the current study, the response rate on the clinician-rated MADRS in the placebo group was 47%, which likely reduced the possibility of detecting an antidepressant effect of the active compound. Nevertheless, in this trial, the response rates for 1.5-mg basimglurant MR were still superior to placebo.

Overall, basimglurant MR was safe and well tolerated in combination with a selective serotonin reuptake inhibitor or serotonin or norepinephrine reuptake inhibitor, with mild transient dizziness as the most common emergent AE. Despite a higher incidence of AEs overall and AEs leading to withdrawal in patients receiving 1.5-mg basimglurant MR, completion rates were high and comparable in all groups. The incidence of mania in this study (approximately 2%) is consistent with previous studies36,37 of antidepressant use in patients with MDD, including selective serotonin reuptake inhibitors, which can be interpreted as an indication of the antidepressant effect of basimglurant MR.

In an independent study38 conducted in healthy volunteers (clinicaltrials.gov, NCT01483469) using a radiotracer technique with positron emission tomography, it was established that basimglurant is able to competitively bind to mGlu5 receptors. A correlation was established between plasma concentration and receptor occupancy. Assuming a similar pharmacokinetic-receptor occupancy association in patients vs healthy volunteers, plasma sampling in the current study population of patients with MDD confirmed that the mean steady-state concentrations would be expected to result in receptor occupancy of approximately 25% at 0.5 mg and 53% at 1.5 mg (Mallalieu et al, unpublished data, 2016).

Considering the primary end point was not met, it is possible that the study design was not able to detect a treatment effect for the compound, the study execution and/or conduct were flawed, or the scientific rationale that the compound is an effective antidepressant in humans is wrong. Because many of the sites recruited a relatively small number of patients (the study involved 59 investigational sites to recruit the 333 randomized patients), it is not possible to comprehensively evaluate the effect of investigational site or its interaction with other model terms on the statistical analysis of the efficacy results. Despite these concerns, signs of efficacy were noted in some secondary outcomes for 1.5-mg basimglurant MR, which were clearer for patient-rated measures of depressive symptoms. There is an apparent discrepancy in how patients in the study reported improvements in their depressive symptoms compared with clinicians, as evidenced by data from the QIDS-SR16 and patient-rated MADRS vs the clinician-rated MADRS. In this context, MADRS was originally designed to detect the treatment effect of monoaminergic antidepressants,26 resulting in the exclusion of items that may be relevant to treatment effects emerging from therapeutics with a different mechanism of action. In contrast, the clinician-rated and patient-rated QIDS-SR16 measures were developed to assess all the symptom domains relevant to the diagnosis of an MDD episode. In fact, in this study, improvements were observed on the QIDS-SR16 items of hypersomnia and general interest (P = .03 and .04, respectively) and feeling slowed down and energy levels (P = .08 and .09, respectively), suggesting that this scale covers relevant symptoms of depression not adequately addressed in the MADRS.

Conclusions

We could not find any effect of adjunctive basimglurant MR on the a priori primary outcome of clinician-reported MADRS. However, adjunctive basimglurant 1.5 mg MR daily showed an antidepressant effect across secondary end points, particularly in patient-rated measures. We believe these findings, combined with good tolerability, warrant further investigation with this compound in depressive disorders.

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Article Information

Submitted for Publication: October 26, 2015; final revision received March 10, 2016; accepted March 13, 2016.

Corresponding Author: Jorge A. Quiroz, MD, Pharmaceutical Research and Early Development, Translational Medicine Neuroscience, Roche Innovation Center, Solid GT, 161 First St, Third Floor, Cambridge, MA 02142.

Published Online: June 15, 2016. doi:10.1001/jamapsychiatry.2016.0838.

Author Contributions: Dr Quiroz had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Quiroz, Tamburri, Deptula, Banken, Parkar, Fontoura, Santarelli.

Acquisition, analysis, or interpretation of data: Quiroz, Tamburri, Deptula, Banken, Beyer, Rabbia, Santarelli.

Drafting of the manuscript: Quiroz, Tamburri, Deptula, Banken, Beyer.

Critical revision of the manuscript for important intellectual content: Quiroz, Tamburri, Deptula, Beyer, Rabbia, Parkar, Fontoura, Santarelli.

Statistical analysis: Quiroz, Banken, Beyer, Rabbia.

Obtained funding: Santarelli.

Administrative, technical, or material support: Quiroz, Deptula, Parkar, Santarelli.

Study supervision: Quiroz, Tamburri, Deptula, Fontoura, Santarelli.

Conflict of Interest Disclosures: Drs Tamburri, Deptula, Beyer, and Fontoura, Mr Rabbia, and Ms Parkar reported being employees of and may own equity in F. Hoffmann-La Roche Ltd. Drs Quiroz, Banken, and Santarelli reported that they were employees of F. Hoffmann-La Roche Ltd during the conduct of the study, and may own equity in F. Hoffmann-La Roche Ltd. No other disclosures were reported.

Funding/Support: This study was sponsored by F. Hoffmann-La Roche Ltd.

Role of the Funder/Sponsor: All authors were employees of the sponsor at the time this study was planned and conducted. These authors were responsible for the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication.

Additional Contributions: Ronald Brenner, MD, Neurobehavioral Research Inc, Cedarhurst, New York, reviewed the clinical study report in his service as the principal investigator. Harold Murck, MD, and Kevin Craig, MD, Covance Inc, Princeton, New Jersey, received compensation as medical monitors for this study. The following investigators recruited and assessed patients for the study: Scott Aaronson, MD, Mohammed Alam, MD, Valerie Arnold, MD, George Badescu, MD, Ivan Baroya, MD, Brian Bortnick, MD, Francisco Brandi Rigal, MD, Joel Breving, MD, ScM, Wlodzimierz Chrzanowski, MD, Daniel Chueh, MD, Eda Maliche Ciorabai, MD, Bethany Davis, MD, Antoni Florkowski, MD, PhD, David Franklin, PsyD, MHA, Edward Friedman, MD, Sergio Gloger Kojchen, MD, Michael Greenbaum, MD, Daniel Gruener, MD, Jun Ishigooka, MD, PhD, Ireneusz Kaczorowski, MD, Hiroki Kikuyama, MD, PhD, Dariusz Kosior, MD, David Krefetz, DO, Evgeny Krupitsky, MD, PhD, Jelena Kunovac, MD, Olga Kushnir, MD, Jan Latala, MD, Tomasz Markowski, MD, PhD, Eliot Moon, MD, Kazuyuki Nakagome, MD, PhD, Claus Normann, MD, Jorge Ochoa Munoz, MD, Kenichi Osada, MD, PhD, Takashi Oshimo, MD, Tempei Otsubo, MD, PhD, Marvin Peyton, MD, Santiago Ramirez Diaz, MD, Kazuo Sakai, MD, PhD, Maria-Carmena Sandulescu, MD, Gregory Seal, MD, Dorina Sima, MD, PhD, Sherry Soefje, MD, Jaroslaw Strzelec, MD, PhD, Rajagopal Sunder, MD, Agata Szulc, MD, PhD, Michihiro Takahashi, MD, PhD, Osamu Takashio, MD, PhD, Kiyoshi Tanaka, MD, Kazuaki Tanaka, MD, Keiichi Tanaka, MD, Michael Thase, MD, Walter Torres Caceres, MD, Tram Tran-Johnson, PharmD, PsyD, Maria-Melania Vasile, MD, Juan Vazquez Hernandez, MD, Volker von Behren, MD, David Walling, PhD, Yoshinori Watanabe, MD, and Eiji Yoshida, MD. All investigators were compensated for their work according to the contracts made for their participation in the study.

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