- Email: [email protected]
Toward Illness Phase–Specific Pharmacotherapy for Schizophrenia
Commentary
Biological Psychiatry
Toward Illness Phase–Specific Pharmacotherapy for Schizophrenia John H. Krystal and Alan Anticevic All antipsychotics approved by the U.S. Food and Drug Administration for the treatment of schizophrenia act primarily to reduce the stimulation of dopamine D2 receptors. This finding would seem to imply that all patients, or perhaps just patients who are responsive to pharmacotherapy, manifest overstimulation of D2 receptors by dopamine (1). It also reflects a failure of medication development efforts to address adequately the heterogeneous pathophysiologies associated with schizophrenia. Given recent prominence of the hypothesis that early intervention may lead to better long-term outcomes, it may be timely to draw attention to one potential source of heterogeneity within and across patients—the dynamic time-dependent neurobiological evolution of schizophrenia across its course of illness. This interest is further fueled by an article in this issue of Biological Psychiatry, which suggests that patients early in their course of illness respond favorably to monotherapy with pomaglumetad methionil, a drug that is metabolized into an agonist of metabotropic glutamate 2/3 (mGluR2/3) receptor. The article also reports the provocative finding that the same drug is not only ineffective but also may worsen clinical outcomes for patients with long-standing illness (2). Although the article presents results supporting alternative hypotheses, the focus of this commentary is on the possible implications for illness phase– specific pharmacotherapies. The notion of illness phase–specific pharmacotherapy is predicated on the hypothesis of a dynamic schizophrenia neurobiology that evolves over the course of illness. This commentary has very limited room to review this hypothesis critically; also, nearly all clinical data on patients with chronic illness are confounded by the effects of antipsychotic treatment. Nonetheless, one might build on a published schema (3) that describes schizophrenia as progressing through four phases: 1) predrome—before the onset of obvious symptoms; 2) prodrome—symptoms and cognitive impairments are present but in an attenuated form; 3) syndrome—patients fully express the disorder; and 4) chronic illness—symptoms, cognitive dysfunction, and functional impairments persist at fluctuating levels and may progress despite treatment. Although this progression in symptom profiles suggests a changing neurobiology, these phases have yet to be linked to particular neurobiological features that would indicate the need for phase-specific pharmacotherapies. Perhaps it is time to characterize explicitly the developmental neurobiology of schizophrenia so that this knowledge might inform the pharmacotherapy of this disorder. This approach would first need to be rooted in the genetics and epigenetics of schizophrenia that implicate disturbances in glutamate synaptic signaling, calcium signaling, and
immunologic mechanisms in the pathophysiology of schizophrenia (4). Disturbances in these separate functions would be hypothesized to produce a direct impact on brain function and secondarily brain development. Furthermore, some of these primary “insults” may evoke homeostatic responses within neurons and networks. For example, Kimoto et al. (5) argued that deficits in glutamate synaptic signaling might play a role in the failure of interneuron populations to develop normally. Along with the normal developmental proliferation of excitatory synapses (6), the reduction in gamma-aminobutyric acid (GABA) signaling might serve to restore the balance between excitation and inhibition within local and distributed networks. These two adaptations may contribute to delaying the onset of symptoms in most patients until adolescence. However, it is evident that this inhibition comes at a cost. Adding GABA deficits to glutamate synaptic deficits may restore excitatory/ inhibitory balance, but it does not normalize the function of these networks. The resulting GABA deficits may disinhibit excitatory drive to dopaminergic projections to the dorsal striatum (7) contributing to the emergence of psychosis. They also may make cortical network function inefficient and cause neural computations underlying cortical representations to become less precise and prone to distortion (8). This sort of adaptive compromise is sometimes referred to as allostasis to distinguish it from true homeostasis. Furthermore, there is growing evidence that deficits in inhibitory tuning of cortical network function may evoke their own compensatory response, a functional and structural synaptic downscaling, perhaps contributing to some regional reductions in functional or structural connectivity (9,10). This synaptic downscaling might accelerate the impact of developmentally programmed synaptic elimination that begins in adolescence (6) and compound the impact of the initial, “primary” glutamate synaptic pathology. Collectively, neurodevelopmental and homeostatic processes may create overlapping time-dependent sources of cortical network dysfunction that map onto clinical phases previously outlined for schizophrenia (Figure 1). We hypothesize that cellular and network adaptations to the initial glutamate synaptic dysfunction delay the onset of cardinal symptoms. These disruptions may emerge as subtle synaptic deficits and deficits in GABA tuning, but they still compromise cortical function (and perhaps contribute to cognitive deficits). At this stage, symptom severity might be reduced by attenuating cortical excitability. Also, reductions in cortical excitability might attenuate synaptic downscaling that might be triggered by network disinhibition. However, once this synaptic downscaling occurs, the same reductions in network excitability may lose their efficacy or even worsen symptoms
SEE CORRESPONDING ARTICLE ON PAGE 754
738 Published by Elsevier Inc on behalf of Society of Biological Psychiatry Biological Psychiatry December 1, 2015; 78:738–740 www.sobp.org/journal
http://dx.doi.org/10.1016/j.biopsych.2015.08.017 ISSN: 0006-3223
Biological Psychiatry
Commentary
medications to patients who might stand to benefit optimally.
Acknowledgments and Disclosures
Figure 1. Developmental schema for neurobiological progression of schizophrenia that might be consistent with the distinct pattern of clinical response to pomaglumetad methionil as reported by Kinon et al. (2). This schema is a very superficial representation of the actual neural mechanisms, which are inordinately more complex. It begins by suggesting that the premorbid state (predrome) is associated with glutamate synaptic abnormalities arising from genetic and epigenetic causes. This deficit in excitatory connectivity is compensated for, in part, by synaptic proliferation and downregulation of gamma-aminobutyric acid (GABA) signaling. The GABA signaling deficits would create their own imbalance between excitatory and inhibitory signaling (E/I imbalance) and other network disturbances that have been described in “at-risk,” “attenuated symptom,” and early course schizophrenia populations. The resulting disinhibition and hyperconnectivity may contribute to synaptic downscaling over time, exacerbating the impact of programmed synaptic elimination.
as a consequence of exacerbating the impact of synaptic functional and structural downscaling. The conceptual model outlined here provides a context for interpreting the provocative findings presented by Kinon et al. (2). If the course of early schizophrenia is characterized by a relative state of network disinhibition in circuits associated with psychosis, mGluR2/3 might alleviate symptoms by attenuating cortico-limbic excitability. Kinon et al. found that mGluR2/3 agonism reduced symptoms in this population. If this network-based hypothesis is confirmed, the markers of network disinhibition might serve as biomarkers predictive of clinical response or surrogate biomarkers for clinical response. The model would also predict that as illness progressed, synaptic downscaling would progress as well. Eventually, deficits in synaptic connectivity would independently contribute to symptoms. This progression might explain why the dose of the mGluR2/3 agonist that reduced symptoms in the patients in the early course of schizophrenia produced no apparent benefit for the patients with chronic disease. The model would also predict the worsening of psychosis in patients with long-standing illness by the higher dose of pomaglumetad methionil. In conclusion, focusing on the neurobiology of schizophrenia outside of its developmental context has supported a static view of its pathophysiology. However, this approach has not effectively guided the development of glutamatergic pharmacotherapies. As treatments are developed that target signaling mechanisms intrinsic to cortical microcircuits, it may be essential to account for the development of these circuits to enable effective targeting of
This work was supported by the National Center for Advancing Translational Science Grant No. 1UH2TR000960-01 (JHK), Department of Veterans Affairs National Center for Posttraumatic Stress Disorder (PTSD) (JHK), National Institute on Alcohol Abuse and Alcoholism Grant Nos. P50AA12870 and M01RR00125 (JHK), Yale Center for Clinical Investigation Grant No. UL1 RR024139 (JHK), National Institutes of Health Grant Nos. DP50D012109-03 and R03MH105765-01 (AA), and National Alliance for Research on Schizophrenia and Depression Independent Investigator Award (AA). JHK is a consultant for AbbVie, AMGEN, Astellas Pharma Global Development, AstraZeneca Pharmaceuticals, Biomedisyn Corporation, Bristol-Myers Squibb, Eli Lilly and Company, Euthymics Bioscience and Neurovance (a subsidiary of Euthymics Bioscience), Forum Pharmaceuticals, Janssen Research and Development, Lundbeck Research USA, Novartis Pharma AG, Otsuka America Pharmaceutical, Sunovion Pharmaceuticals, and Takeda Industries; is on the scientific advisory board for Lohocla Research Corporation, Mnemosyne Pharmaceuticals, Naurex, and Pfizer Pharmaceuticals; holds stock in Biohaven Medical Sciences and stock options in Mnemosyne Pharmaceuticals; and holds three patents/ inventions: 1) U.S. Patent 5 447 948 (Sep 5, 1995), 2) U.S. Patent 8 778 979 B2 (Jul 15, 2014), and 3) U.S. Patent application 14/197 767 filed on Mar 5, 2014, U.S. Patent application or Patent Cooperation Treaty international application 14/306 382 filed on Jun 17, 2014. AA reports no biomedical financial interests or potential conflicts of interest.
Article Information From the Departments of Psychiatry (JHK, AA), Neurobiology (JHK), and Psychology (AA), Psychiatry Service, Yale University School of Medicine; Yale-New Haven Hospital (JHK); and Abraham Ribicoff Research Facilities (AA), Connecticut Mental Health, New Haven, Connecticut. Address correspondence to John H. Krystal, M.D., Department of Psychiatry, Yale University School of Medicine, 300 George Street #901, New Haven, CT 06511; E-mail: [email protected]. Received Aug 5, 2015; accepted Aug 19, 2015; revised Aug 17, 2015.
References 1.
2.
3. 4.
5.
6. 7.
8.
Frankle WG, Gil R, Hackett E, Mawlawi O, Zea-Ponce Y, Zhu Z, et al. (2004): Occupancy of dopamine D2 receptors by the atypical antipsychotic drugs risperidone and olanzapine: Theoretical implications. Psychopharmacology (Berl) 175:473–480. Kinon BJ, Millen BA, Zhang L, McKinzie DL (2015): Exploratory analysis for a targeted patient population responsive to the metabotropic glutamate 2/3 receptor agonist pomaglumetad methionil in schizophrenia. Biol Psychiatry 78:754–762. Insel TR (2010): Rethinking schizophrenia. Nature 468:187–193. Schizophrenia Working Group of the Psychiatric Genomics Consortium. (2014): Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421–427. Kimoto S, Zaki MM, Bazmi HH, Lewis DA (2015): Altered markers of cortical gamma-aminobutyric acid neuronal activity in schizophrenia: Role of the NARP gene. JAMA Psychiatry 72:747–756. Huttenlocher PR (1979): Synaptic density in human frontal cortex— developmental changes and effects of aging. Brain Res 163:195–205. de la Fuente-Sandoval C, Leon-Ortiz P, Favila R, Stephano S, Mamo D, Ramirez-Bermudez J, et al. (2011): Higher levels of glutamate in the associative-striatum of subjects with prodromal symptoms of schizophrenia and patients with first-episode psychosis. Neuropsychopharmacology 36:1781–1791. Murray JD, Anticevic A, Gancsos M, Ichinose M, Corlett PR, Krystal JH, et al. (2014): Linking microcircuit dysfunction to cognitive impairment: Effects of disinhibition associated with schizophrenia in a cortical working memory model. Cereb Cortex 24:859–872.
Biological Psychiatry December 1, 2015; 78:738–740 www.sobp.org/journal
739
Biological Psychiatry
Commentary
9.
740
Schobel SA, Chaudhury NH, Khan UA, Paniagua B, Styner MA, Asllani I, et al. (2013): Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver. Neuron 78:81–93.
10.
Anticevic A, Corlett PR, Cole MW, Savic A, Gancsos M, Tang Y, et al. (2015): N-methyl-D-aspartate receptor antagonist effects on prefrontal cortical connectivity better model early than chronic schizophrenia. Biol Psychiatry 77:569–580.
Biological Psychiatry December 1, 2015; 78:738–740 www.sobp.org/journal
Biological Psychiatry
Toward Illness Phase–Specific Pharmacotherapy for Schizophrenia John H. Krystal and Alan Anticevic All antipsychotics approved by the U.S. Food and Drug Administration for the treatment of schizophrenia act primarily to reduce the stimulation of dopamine D2 receptors. This finding would seem to imply that all patients, or perhaps just patients who are responsive to pharmacotherapy, manifest overstimulation of D2 receptors by dopamine (1). It also reflects a failure of medication development efforts to address adequately the heterogeneous pathophysiologies associated with schizophrenia. Given recent prominence of the hypothesis that early intervention may lead to better long-term outcomes, it may be timely to draw attention to one potential source of heterogeneity within and across patients—the dynamic time-dependent neurobiological evolution of schizophrenia across its course of illness. This interest is further fueled by an article in this issue of Biological Psychiatry, which suggests that patients early in their course of illness respond favorably to monotherapy with pomaglumetad methionil, a drug that is metabolized into an agonist of metabotropic glutamate 2/3 (mGluR2/3) receptor. The article also reports the provocative finding that the same drug is not only ineffective but also may worsen clinical outcomes for patients with long-standing illness (2). Although the article presents results supporting alternative hypotheses, the focus of this commentary is on the possible implications for illness phase– specific pharmacotherapies. The notion of illness phase–specific pharmacotherapy is predicated on the hypothesis of a dynamic schizophrenia neurobiology that evolves over the course of illness. This commentary has very limited room to review this hypothesis critically; also, nearly all clinical data on patients with chronic illness are confounded by the effects of antipsychotic treatment. Nonetheless, one might build on a published schema (3) that describes schizophrenia as progressing through four phases: 1) predrome—before the onset of obvious symptoms; 2) prodrome—symptoms and cognitive impairments are present but in an attenuated form; 3) syndrome—patients fully express the disorder; and 4) chronic illness—symptoms, cognitive dysfunction, and functional impairments persist at fluctuating levels and may progress despite treatment. Although this progression in symptom profiles suggests a changing neurobiology, these phases have yet to be linked to particular neurobiological features that would indicate the need for phase-specific pharmacotherapies. Perhaps it is time to characterize explicitly the developmental neurobiology of schizophrenia so that this knowledge might inform the pharmacotherapy of this disorder. This approach would first need to be rooted in the genetics and epigenetics of schizophrenia that implicate disturbances in glutamate synaptic signaling, calcium signaling, and
immunologic mechanisms in the pathophysiology of schizophrenia (4). Disturbances in these separate functions would be hypothesized to produce a direct impact on brain function and secondarily brain development. Furthermore, some of these primary “insults” may evoke homeostatic responses within neurons and networks. For example, Kimoto et al. (5) argued that deficits in glutamate synaptic signaling might play a role in the failure of interneuron populations to develop normally. Along with the normal developmental proliferation of excitatory synapses (6), the reduction in gamma-aminobutyric acid (GABA) signaling might serve to restore the balance between excitation and inhibition within local and distributed networks. These two adaptations may contribute to delaying the onset of symptoms in most patients until adolescence. However, it is evident that this inhibition comes at a cost. Adding GABA deficits to glutamate synaptic deficits may restore excitatory/ inhibitory balance, but it does not normalize the function of these networks. The resulting GABA deficits may disinhibit excitatory drive to dopaminergic projections to the dorsal striatum (7) contributing to the emergence of psychosis. They also may make cortical network function inefficient and cause neural computations underlying cortical representations to become less precise and prone to distortion (8). This sort of adaptive compromise is sometimes referred to as allostasis to distinguish it from true homeostasis. Furthermore, there is growing evidence that deficits in inhibitory tuning of cortical network function may evoke their own compensatory response, a functional and structural synaptic downscaling, perhaps contributing to some regional reductions in functional or structural connectivity (9,10). This synaptic downscaling might accelerate the impact of developmentally programmed synaptic elimination that begins in adolescence (6) and compound the impact of the initial, “primary” glutamate synaptic pathology. Collectively, neurodevelopmental and homeostatic processes may create overlapping time-dependent sources of cortical network dysfunction that map onto clinical phases previously outlined for schizophrenia (Figure 1). We hypothesize that cellular and network adaptations to the initial glutamate synaptic dysfunction delay the onset of cardinal symptoms. These disruptions may emerge as subtle synaptic deficits and deficits in GABA tuning, but they still compromise cortical function (and perhaps contribute to cognitive deficits). At this stage, symptom severity might be reduced by attenuating cortical excitability. Also, reductions in cortical excitability might attenuate synaptic downscaling that might be triggered by network disinhibition. However, once this synaptic downscaling occurs, the same reductions in network excitability may lose their efficacy or even worsen symptoms
SEE CORRESPONDING ARTICLE ON PAGE 754
738 Published by Elsevier Inc on behalf of Society of Biological Psychiatry Biological Psychiatry December 1, 2015; 78:738–740 www.sobp.org/journal
http://dx.doi.org/10.1016/j.biopsych.2015.08.017 ISSN: 0006-3223
Biological Psychiatry
Commentary
medications to patients who might stand to benefit optimally.
Acknowledgments and Disclosures
Figure 1. Developmental schema for neurobiological progression of schizophrenia that might be consistent with the distinct pattern of clinical response to pomaglumetad methionil as reported by Kinon et al. (2). This schema is a very superficial representation of the actual neural mechanisms, which are inordinately more complex. It begins by suggesting that the premorbid state (predrome) is associated with glutamate synaptic abnormalities arising from genetic and epigenetic causes. This deficit in excitatory connectivity is compensated for, in part, by synaptic proliferation and downregulation of gamma-aminobutyric acid (GABA) signaling. The GABA signaling deficits would create their own imbalance between excitatory and inhibitory signaling (E/I imbalance) and other network disturbances that have been described in “at-risk,” “attenuated symptom,” and early course schizophrenia populations. The resulting disinhibition and hyperconnectivity may contribute to synaptic downscaling over time, exacerbating the impact of programmed synaptic elimination.
as a consequence of exacerbating the impact of synaptic functional and structural downscaling. The conceptual model outlined here provides a context for interpreting the provocative findings presented by Kinon et al. (2). If the course of early schizophrenia is characterized by a relative state of network disinhibition in circuits associated with psychosis, mGluR2/3 might alleviate symptoms by attenuating cortico-limbic excitability. Kinon et al. found that mGluR2/3 agonism reduced symptoms in this population. If this network-based hypothesis is confirmed, the markers of network disinhibition might serve as biomarkers predictive of clinical response or surrogate biomarkers for clinical response. The model would also predict that as illness progressed, synaptic downscaling would progress as well. Eventually, deficits in synaptic connectivity would independently contribute to symptoms. This progression might explain why the dose of the mGluR2/3 agonist that reduced symptoms in the patients in the early course of schizophrenia produced no apparent benefit for the patients with chronic disease. The model would also predict the worsening of psychosis in patients with long-standing illness by the higher dose of pomaglumetad methionil. In conclusion, focusing on the neurobiology of schizophrenia outside of its developmental context has supported a static view of its pathophysiology. However, this approach has not effectively guided the development of glutamatergic pharmacotherapies. As treatments are developed that target signaling mechanisms intrinsic to cortical microcircuits, it may be essential to account for the development of these circuits to enable effective targeting of
This work was supported by the National Center for Advancing Translational Science Grant No. 1UH2TR000960-01 (JHK), Department of Veterans Affairs National Center for Posttraumatic Stress Disorder (PTSD) (JHK), National Institute on Alcohol Abuse and Alcoholism Grant Nos. P50AA12870 and M01RR00125 (JHK), Yale Center for Clinical Investigation Grant No. UL1 RR024139 (JHK), National Institutes of Health Grant Nos. DP50D012109-03 and R03MH105765-01 (AA), and National Alliance for Research on Schizophrenia and Depression Independent Investigator Award (AA). JHK is a consultant for AbbVie, AMGEN, Astellas Pharma Global Development, AstraZeneca Pharmaceuticals, Biomedisyn Corporation, Bristol-Myers Squibb, Eli Lilly and Company, Euthymics Bioscience and Neurovance (a subsidiary of Euthymics Bioscience), Forum Pharmaceuticals, Janssen Research and Development, Lundbeck Research USA, Novartis Pharma AG, Otsuka America Pharmaceutical, Sunovion Pharmaceuticals, and Takeda Industries; is on the scientific advisory board for Lohocla Research Corporation, Mnemosyne Pharmaceuticals, Naurex, and Pfizer Pharmaceuticals; holds stock in Biohaven Medical Sciences and stock options in Mnemosyne Pharmaceuticals; and holds three patents/ inventions: 1) U.S. Patent 5 447 948 (Sep 5, 1995), 2) U.S. Patent 8 778 979 B2 (Jul 15, 2014), and 3) U.S. Patent application 14/197 767 filed on Mar 5, 2014, U.S. Patent application or Patent Cooperation Treaty international application 14/306 382 filed on Jun 17, 2014. AA reports no biomedical financial interests or potential conflicts of interest.
Article Information From the Departments of Psychiatry (JHK, AA), Neurobiology (JHK), and Psychology (AA), Psychiatry Service, Yale University School of Medicine; Yale-New Haven Hospital (JHK); and Abraham Ribicoff Research Facilities (AA), Connecticut Mental Health, New Haven, Connecticut. Address correspondence to John H. Krystal, M.D., Department of Psychiatry, Yale University School of Medicine, 300 George Street #901, New Haven, CT 06511; E-mail: [email protected]. Received Aug 5, 2015; accepted Aug 19, 2015; revised Aug 17, 2015.
References 1.
2.
3. 4.
5.
6. 7.
8.
Frankle WG, Gil R, Hackett E, Mawlawi O, Zea-Ponce Y, Zhu Z, et al. (2004): Occupancy of dopamine D2 receptors by the atypical antipsychotic drugs risperidone and olanzapine: Theoretical implications. Psychopharmacology (Berl) 175:473–480. Kinon BJ, Millen BA, Zhang L, McKinzie DL (2015): Exploratory analysis for a targeted patient population responsive to the metabotropic glutamate 2/3 receptor agonist pomaglumetad methionil in schizophrenia. Biol Psychiatry 78:754–762. Insel TR (2010): Rethinking schizophrenia. Nature 468:187–193. Schizophrenia Working Group of the Psychiatric Genomics Consortium. (2014): Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421–427. Kimoto S, Zaki MM, Bazmi HH, Lewis DA (2015): Altered markers of cortical gamma-aminobutyric acid neuronal activity in schizophrenia: Role of the NARP gene. JAMA Psychiatry 72:747–756. Huttenlocher PR (1979): Synaptic density in human frontal cortex— developmental changes and effects of aging. Brain Res 163:195–205. de la Fuente-Sandoval C, Leon-Ortiz P, Favila R, Stephano S, Mamo D, Ramirez-Bermudez J, et al. (2011): Higher levels of glutamate in the associative-striatum of subjects with prodromal symptoms of schizophrenia and patients with first-episode psychosis. Neuropsychopharmacology 36:1781–1791. Murray JD, Anticevic A, Gancsos M, Ichinose M, Corlett PR, Krystal JH, et al. (2014): Linking microcircuit dysfunction to cognitive impairment: Effects of disinhibition associated with schizophrenia in a cortical working memory model. Cereb Cortex 24:859–872.
Biological Psychiatry December 1, 2015; 78:738–740 www.sobp.org/journal
739
Biological Psychiatry
Commentary
9.
740
Schobel SA, Chaudhury NH, Khan UA, Paniagua B, Styner MA, Asllani I, et al. (2013): Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver. Neuron 78:81–93.
10.
Anticevic A, Corlett PR, Cole MW, Savic A, Gancsos M, Tang Y, et al. (2015): N-methyl-D-aspartate receptor antagonist effects on prefrontal cortical connectivity better model early than chronic schizophrenia. Biol Psychiatry 77:569–580.
Biological Psychiatry December 1, 2015; 78:738–740 www.sobp.org/journal