Opinion
EDITORIAL
Bitopertin The Good News and Bad News Donald C. Goff, MD
In this issue, Umbricht and colleagues1 reported improvement of negative symptoms of schizophrenia associated with 2 of 3 doses of the glycine transporter type 1 inhibitor bitopertin (RG1678) in a phase 2 placebo-controlled, 8-week add-on trial. Although the therapeutic effect was only modest, this is very welcome news because the path to drug develRelated article page 637 opment in schizophrenia has been littered with disappointments. The example of clozapine, which was synthesized in 1958 and received Food and Drug Administration approval in 1989, provided impetus to develop similarly effective new compounds. Since then, a series of preclinical and clinical studies by Paul Janssen, MD, pioneered the addition of 5-hydroxytryptamine type 2A antagonism to D2 antagonism, which launched risperidone, the first of the newer-generation antipsychotics, and refinement of dopamine D2 receptor partial agonism led to aripiprazole. Both developments achieved a reduction in neurologic adverse effects, but the promise of clozapine has yet to be realized. Other approaches that followed from discoveries in neuroscience have failed or have yet to reach clinical validation. Bitopertin represents the culmination of more than 2 decades of basic and clinical research on the glutamatergic model of schizophrenia.2 The glutamatergic model of schizophrenia followed from the observation that blockade of N-methyl-D-aspartate (NMDA) receptor–gated channels by phencyclidine or ketamine produces symptoms characteristic of schizophrenia.3 Subsequently, convergent support came from animal models, ketamine provocation studies in humans, genetic studies, and postmortem studies. The drugs that were available to test the hypothesis were limited by poor brain penetrance (glycine, Dserine, and D-alanine) or by partial activity (D-cycloserine and sarcosine) and as a group produced mixed results with a tendency for positive effects in early, smaller trials and negative results in later, larger trials.4-6 This lack of consistency may reflect the inherent limitations of these early agents, inadequate dosing, or methodological problems associated with large-scale replication trials such as high placebo response rates, participant heterogeneity, or lack of precision in measures of negative symptoms. The unreliability of clinical trials has also plagued the development of the other leading glutamatergic candidate, LY2140023 monohydrate, an mGlu2/3 agonist that demonstrated significant efficacy in a first trial but was not effective in a subsequent trial in which placebo response was much greater. In addition, unlike first-generation antipsychotics, second-generation antipsychotics may enjamapsychiatry.com
hance NMDA receptor signaling—positive results with the glycine site agonists came mostly from early studies in which they were combined with first-generation antipsychotics. In short, results have been promising but inconsistent with agents acting at the glycine modulatory site of the NMDA receptor, but a more rigorous test of this approach awaited the arrival of a more suitable compound such as bitopertin. Bitopertin is a highly selective and potent glycine transporter type 1 reuptake inhibitor that increases synaptic glycine levels and thereby facilitates NMDA-channel opening. Excessive calcium influx through the NMDA-gated channel can be neuroxotic—a risk that is counterbalanced by several safe guards that may complicate this therapeutic approach. For example, activation of the glycine site results in downregulation of the NMDA receptor by endocytosis.7 In addition, an endogenous antagonist at the glycine site, kynurenic acid, competes with glycine and D-serine in the modulation of glutamatergic signaling. The team of investigators at F. Hoffmann–La Roche Ltd performed positron-emission tomography and cerebrospinal fluid studies with bitopertin in healthy participants, informed by animal behavioral studies, to determine receptor occupancy and resulting glycine concentrations in the central nervous system; this allowed them to estimate the range of therapeutic concentrations.8 Their elegant preparatory work proved to be critical because they identified an inverted U therapeutic window dose-response relationship and managed to capture this segment of the dose-response curve in the range of doses administered in this study. Their results suggest that roughly 50% occupancy and a corresponding moderate, 2-fold elevation of glycine levels may be optimal. The investigators also carefully selected participants to enrich their sample with primary negative symptoms and excluded patients taking clozapine because of evidence that it may have actions at the glycine site. The results must be considered exploratory because this was a dose-finding proof-of-concept trial that examined several bitopertin doses without statistical correction. The 2 lower bitopertin doses, 10 mg daily and 30 mg daily, produced a moderate improvement in negative symptoms, which was statistically significant in adherent patients who completed the trial but was not significant in the more conservative intent-to-treat analysis, which included dropouts. It is noteworthy that the global rating of negative symptom improvement was also significantly improved, suggesting a clinically relevant effect. On the other hand, bitopertin did not affect measures of cognition or psychosis, which is puzzling because impairments in JAMA Psychiatry June 2014 Volume 71, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a Indiana University School of Medicine User on 05/11/2015
621
Opinion Editorial
these domains are prominent with NMDA-channel blockade. As a phase 2 exploratory study, these results are quite encouraging and consistent with a priori hypotheses. And now the bad news. On January 21, 2014, Roche announced that 2 phase 3 trials of bitopertin for negative symptoms failed to achieve primary end points. Once again, we are faced with the dilemma of an initial rigorous trial providing support for a compound that is well grounded in preclinical and clinical studies, followed by a failure to replicate. We must wait until more information is available about the more ARTICLE INFORMATION Author Affiliation: New York Langone Medical Center, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York. Corresponding Author: Donald C. Goff, MD, New York Langone Medical Center, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962 ([email protected]). Published Online: April 2, 2014. doi:10.1001/jamapsychiatry.2014.257. Conflict of Interest Disclosures: Dr Goff received an honorarium from F. Hoffmann–La Roche Ltd for a consultation 3 years ago and provided comments on the manuscript prior to submission. REFERENCES 1. Umbricht D, Alberati D, Martin-Facklam M, et al. Effect of bitopertin, a glycine reuptake inhibitor, on
recent negative studies to determine whether the failure to replicate can be understood by aspects of study design or implementation or by participant heterogeneity. It is clear that advances in basic neuroscience and drug development must be matched by improved clinical trial methods including identification of biomarkers to reduce the problem of patient heterogeneity. Otherwise, promising new agents associated with moderate therapeutic effects may be abandoned despite the potential for large and consistent effects if a personalized medicine approach can be achieved.
negative symptoms of schizophrenia: a randomized, double-blind, proof-of-concept study [published online April 2, 2014]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2014.163. 2. Coyle JT. NMDA receptor and schizophrenia: a brief history. Schizophr Bull. 2012;38(5):920-926. 3. Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. 1991;148(10):1301-1308. 4. Singh SP, Singh V. Meta-analysis of the efficacy of adjunctive NMDA receptor modulators in chronic schizophrenia. CNS Drugs. 2011;25(10):859-885. 5. Buchanan RW, Javitt DC, Marder SR, et al. The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry. 2007;164(10):15931602.
6. Weiser M, Heresco-Levy U, Davidson M, et al. A multicenter, add-on randomized controlled trial of low-dose d-serine for negative and cognitive symptoms of schizophrenia. J Clin Psychiatry. 2012; 73(6):e728-e734. 7. Nong Y, Huang YQ, Ju W, et al. Glycine binding primes NMDA receptor internalization. Nature. 2003;422(6929):302-307. 8. Martin-Facklam M, Pizzagalli F, Zhou Y, et al. Glycine transporter type 1 occupancy by bitopertin: a positron emission tomography study in healthy volunteers. Neuropsychopharmacology. 2013;38 (3):504-512.
The Social Brain, Stress, and Psychopathology Tor D. Wager, PhD; Peter J. Gianaros, PhD
Social discrimination can have pervasive effects on human health and performance. This notion is a major thread binding together findings in social psychology, health psychology, and epidemiology. From a psychiatric perspective, it may also be critical for a more complete etiological picture Related article page 672 of psychopathology. Social influences can be subtle but powerful. For example, priming racial identity can influence physiological measures of threat and performance on benchmark tests like the Scholastic Aptitude Test.1,2 As emphasized in the article by Akdeniz et al,3 ethnic minority immigrants are at greater risk than their native counterparts for schizophrenia,4 and this risk may extend to other mental and physical health disorders.5 To fully understand, prevent, and treat schizophrenia and other brain disorders, we need to understand the relationships between social context, stress, and brain health that cut across diverse psychiatric and neurological conditions. Perennial questions in the study of virtually every major disorder are what confers risk for illness and how can those risks be minimized. Even in disorders that are highly heritable such as schizophrenia, there is a long history of re622
search on social and environmental factors,6 and the relationship between genetic risk and schizophrenia onset may be highly dependent on the social and physical environment. However, research has now shifted away from early theories about parenting styles and toward biological explanations. As demonstrated by Akdeniz and colleagues, social and biological explanations are not an either/or proposition. Akdeniz and colleagues used functional magnetic resonance imaging to probe social stress–related activity in native German individuals and immigrants by asking them to perform a math task under social-evaluative threat—observation by authority figures coupled with negative feedback about performance. Immigrants showed stronger stress responses than their German counterparts in the pregenual anterior cingulate cortex, a part of the ventromedial prefrontal cortex (vmPFC) implicated in the generation and regulation of social threat and other emotional states. The vmPFC comprises several subregions (Figure) that regulate brainstem governors of physiological responses to threat.7,8 Thus, the brain findings suggest a link between migrant status—a demographic variable typically studied in sociological contexts—and biological responsivity to social threat. Studies of demographic variables are inherently observational, and inevitably questions arise. Is it really immigrant sta-
JAMA Psychiatry June 2014 Volume 71, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a Indiana University School of Medicine User on 05/11/2015
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EDITORIAL
Bitopertin The Good News and Bad News Donald C. Goff, MD
In this issue, Umbricht and colleagues1 reported improvement of negative symptoms of schizophrenia associated with 2 of 3 doses of the glycine transporter type 1 inhibitor bitopertin (RG1678) in a phase 2 placebo-controlled, 8-week add-on trial. Although the therapeutic effect was only modest, this is very welcome news because the path to drug develRelated article page 637 opment in schizophrenia has been littered with disappointments. The example of clozapine, which was synthesized in 1958 and received Food and Drug Administration approval in 1989, provided impetus to develop similarly effective new compounds. Since then, a series of preclinical and clinical studies by Paul Janssen, MD, pioneered the addition of 5-hydroxytryptamine type 2A antagonism to D2 antagonism, which launched risperidone, the first of the newer-generation antipsychotics, and refinement of dopamine D2 receptor partial agonism led to aripiprazole. Both developments achieved a reduction in neurologic adverse effects, but the promise of clozapine has yet to be realized. Other approaches that followed from discoveries in neuroscience have failed or have yet to reach clinical validation. Bitopertin represents the culmination of more than 2 decades of basic and clinical research on the glutamatergic model of schizophrenia.2 The glutamatergic model of schizophrenia followed from the observation that blockade of N-methyl-D-aspartate (NMDA) receptor–gated channels by phencyclidine or ketamine produces symptoms characteristic of schizophrenia.3 Subsequently, convergent support came from animal models, ketamine provocation studies in humans, genetic studies, and postmortem studies. The drugs that were available to test the hypothesis were limited by poor brain penetrance (glycine, Dserine, and D-alanine) or by partial activity (D-cycloserine and sarcosine) and as a group produced mixed results with a tendency for positive effects in early, smaller trials and negative results in later, larger trials.4-6 This lack of consistency may reflect the inherent limitations of these early agents, inadequate dosing, or methodological problems associated with large-scale replication trials such as high placebo response rates, participant heterogeneity, or lack of precision in measures of negative symptoms. The unreliability of clinical trials has also plagued the development of the other leading glutamatergic candidate, LY2140023 monohydrate, an mGlu2/3 agonist that demonstrated significant efficacy in a first trial but was not effective in a subsequent trial in which placebo response was much greater. In addition, unlike first-generation antipsychotics, second-generation antipsychotics may enjamapsychiatry.com
hance NMDA receptor signaling—positive results with the glycine site agonists came mostly from early studies in which they were combined with first-generation antipsychotics. In short, results have been promising but inconsistent with agents acting at the glycine modulatory site of the NMDA receptor, but a more rigorous test of this approach awaited the arrival of a more suitable compound such as bitopertin. Bitopertin is a highly selective and potent glycine transporter type 1 reuptake inhibitor that increases synaptic glycine levels and thereby facilitates NMDA-channel opening. Excessive calcium influx through the NMDA-gated channel can be neuroxotic—a risk that is counterbalanced by several safe guards that may complicate this therapeutic approach. For example, activation of the glycine site results in downregulation of the NMDA receptor by endocytosis.7 In addition, an endogenous antagonist at the glycine site, kynurenic acid, competes with glycine and D-serine in the modulation of glutamatergic signaling. The team of investigators at F. Hoffmann–La Roche Ltd performed positron-emission tomography and cerebrospinal fluid studies with bitopertin in healthy participants, informed by animal behavioral studies, to determine receptor occupancy and resulting glycine concentrations in the central nervous system; this allowed them to estimate the range of therapeutic concentrations.8 Their elegant preparatory work proved to be critical because they identified an inverted U therapeutic window dose-response relationship and managed to capture this segment of the dose-response curve in the range of doses administered in this study. Their results suggest that roughly 50% occupancy and a corresponding moderate, 2-fold elevation of glycine levels may be optimal. The investigators also carefully selected participants to enrich their sample with primary negative symptoms and excluded patients taking clozapine because of evidence that it may have actions at the glycine site. The results must be considered exploratory because this was a dose-finding proof-of-concept trial that examined several bitopertin doses without statistical correction. The 2 lower bitopertin doses, 10 mg daily and 30 mg daily, produced a moderate improvement in negative symptoms, which was statistically significant in adherent patients who completed the trial but was not significant in the more conservative intent-to-treat analysis, which included dropouts. It is noteworthy that the global rating of negative symptom improvement was also significantly improved, suggesting a clinically relevant effect. On the other hand, bitopertin did not affect measures of cognition or psychosis, which is puzzling because impairments in JAMA Psychiatry June 2014 Volume 71, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a Indiana University School of Medicine User on 05/11/2015
621
Opinion Editorial
these domains are prominent with NMDA-channel blockade. As a phase 2 exploratory study, these results are quite encouraging and consistent with a priori hypotheses. And now the bad news. On January 21, 2014, Roche announced that 2 phase 3 trials of bitopertin for negative symptoms failed to achieve primary end points. Once again, we are faced with the dilemma of an initial rigorous trial providing support for a compound that is well grounded in preclinical and clinical studies, followed by a failure to replicate. We must wait until more information is available about the more ARTICLE INFORMATION Author Affiliation: New York Langone Medical Center, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York. Corresponding Author: Donald C. Goff, MD, New York Langone Medical Center, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962 ([email protected]). Published Online: April 2, 2014. doi:10.1001/jamapsychiatry.2014.257. Conflict of Interest Disclosures: Dr Goff received an honorarium from F. Hoffmann–La Roche Ltd for a consultation 3 years ago and provided comments on the manuscript prior to submission. REFERENCES 1. Umbricht D, Alberati D, Martin-Facklam M, et al. Effect of bitopertin, a glycine reuptake inhibitor, on
recent negative studies to determine whether the failure to replicate can be understood by aspects of study design or implementation or by participant heterogeneity. It is clear that advances in basic neuroscience and drug development must be matched by improved clinical trial methods including identification of biomarkers to reduce the problem of patient heterogeneity. Otherwise, promising new agents associated with moderate therapeutic effects may be abandoned despite the potential for large and consistent effects if a personalized medicine approach can be achieved.
negative symptoms of schizophrenia: a randomized, double-blind, proof-of-concept study [published online April 2, 2014]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2014.163. 2. Coyle JT. NMDA receptor and schizophrenia: a brief history. Schizophr Bull. 2012;38(5):920-926. 3. Javitt DC, Zukin SR. Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. 1991;148(10):1301-1308. 4. Singh SP, Singh V. Meta-analysis of the efficacy of adjunctive NMDA receptor modulators in chronic schizophrenia. CNS Drugs. 2011;25(10):859-885. 5. Buchanan RW, Javitt DC, Marder SR, et al. The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry. 2007;164(10):15931602.
6. Weiser M, Heresco-Levy U, Davidson M, et al. A multicenter, add-on randomized controlled trial of low-dose d-serine for negative and cognitive symptoms of schizophrenia. J Clin Psychiatry. 2012; 73(6):e728-e734. 7. Nong Y, Huang YQ, Ju W, et al. Glycine binding primes NMDA receptor internalization. Nature. 2003;422(6929):302-307. 8. Martin-Facklam M, Pizzagalli F, Zhou Y, et al. Glycine transporter type 1 occupancy by bitopertin: a positron emission tomography study in healthy volunteers. Neuropsychopharmacology. 2013;38 (3):504-512.
The Social Brain, Stress, and Psychopathology Tor D. Wager, PhD; Peter J. Gianaros, PhD
Social discrimination can have pervasive effects on human health and performance. This notion is a major thread binding together findings in social psychology, health psychology, and epidemiology. From a psychiatric perspective, it may also be critical for a more complete etiological picture Related article page 672 of psychopathology. Social influences can be subtle but powerful. For example, priming racial identity can influence physiological measures of threat and performance on benchmark tests like the Scholastic Aptitude Test.1,2 As emphasized in the article by Akdeniz et al,3 ethnic minority immigrants are at greater risk than their native counterparts for schizophrenia,4 and this risk may extend to other mental and physical health disorders.5 To fully understand, prevent, and treat schizophrenia and other brain disorders, we need to understand the relationships between social context, stress, and brain health that cut across diverse psychiatric and neurological conditions. Perennial questions in the study of virtually every major disorder are what confers risk for illness and how can those risks be minimized. Even in disorders that are highly heritable such as schizophrenia, there is a long history of re622
search on social and environmental factors,6 and the relationship between genetic risk and schizophrenia onset may be highly dependent on the social and physical environment. However, research has now shifted away from early theories about parenting styles and toward biological explanations. As demonstrated by Akdeniz and colleagues, social and biological explanations are not an either/or proposition. Akdeniz and colleagues used functional magnetic resonance imaging to probe social stress–related activity in native German individuals and immigrants by asking them to perform a math task under social-evaluative threat—observation by authority figures coupled with negative feedback about performance. Immigrants showed stronger stress responses than their German counterparts in the pregenual anterior cingulate cortex, a part of the ventromedial prefrontal cortex (vmPFC) implicated in the generation and regulation of social threat and other emotional states. The vmPFC comprises several subregions (Figure) that regulate brainstem governors of physiological responses to threat.7,8 Thus, the brain findings suggest a link between migrant status—a demographic variable typically studied in sociological contexts—and biological responsivity to social threat. Studies of demographic variables are inherently observational, and inevitably questions arise. Is it really immigrant sta-
JAMA Psychiatry June 2014 Volume 71, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a Indiana University School of Medicine User on 05/11/2015
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