Glutamate Receptors Are Focus of Schizophrenia Research

LAS VEGAS – In the opinion of Dr. Leslie Citrome, the clinical evidence for using adjunctive lithium and anticonvulsants in patients with schizophrenia is generally weak. Yet, clinicians continue to prescribe them.

"It’s kind of puzzling," Dr. Citrome said at the psychopharmacology conference sponsored by the Nevada Psychiatric Association. "When you count out the number of randomized, controlled trials, they do exist. They just don’t show a signal for efficacy, with the possible exception of lamotrigine plus clozapine. But we’re still doing it. Why? I think it’s because studies of these adjunctive agents may have not looked at chronically ill, refractory patients.

"Maybe the right trials weren’t done. Or maybe it’s so hard to gather together the right patients for that trial," said Dr. Citrome of the department of psychiatry and behavioral sciences at New York Medical College, Valhalla. "I think that is the biggest obstacle. Schizophrenia is many different diseases. It’s foolhardy to think that it’s all one pathophysiological process solved by one drug. Once we have a better idea of the different kinds of schizophrenia, then I think we’ll have greater chance and finding answers."

Until then, finding medical treatments that work "is very difficult," he said. "These are very challenging patients. By the time we end up treating them in some settings they’ve been ill for 10, 20, or 30 years."

In an effort to improve therapeutic options for patients with schizophrenia, several agents that affect glutamate receptors are being actively studied in randomized, controlled trials. If the successes that were observed in early clinical trials hold out to be true in the long term, "we are going to have drugs that affect the glutamate system directly and possibly [can be] used every day in the management of patients with schizophrenia," Dr. Citrome said. "Not today, but maybe within 5 or 10 years. This is a very active field of study."

Glutamate is distributed widely and is the primary excitatory neurotransmitter in the human central nervous system. It connects to dopamine neurons, "sometimes directly, sometimes through a [gamma-aminobutyric] interneuron, so there is a framework of how glutamate can impact on dopamine and affect the mesolimbic pathway and thus address psychotic symptoms, as well as [affect] the mesocortical pathway and impact cognition and mood," he said.

Early studies have demonstrated that antagonists to glutamate receptors exacerbate psychotic symptoms and cognitive impairment in patients with schizophrenia, and can induce positive and cognitive symptoms in healthy volunteers. Susceptibility genes for schizophrenia can influence the function of glutamate receptors.

The two main categories of glutamate receptors are ionotropic, which involve ion channels, and metabotropic, which involve G (guanine nucleotide–binding) proteins and chemical second messengers. The three different types of ionotropic glutamate receptors are AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), kainate, and NMDA (N-methyl-D-aspartate). "NMDA receptors won’t work without AMPA or kainate, so they’re all interrelated in some way," Dr. Citrome said. "AMPA and kainate are the ones that work quickly, while NMDA can lead to changes in plasticity over time. NMDA is really where it’s at in terms of where the research is going on, but all three types work in tandem; they don’t work in isolation."

Dr. Citrome went on to explain that for an NMDA receptor to be activated, both glutamate and glycine are required. "D-serine also has high affinity for the glycine site on NMDA receptors," he said. "An analogue of D-serine, D-cycloserine is also active at the glycine co-agonist site of NMDA receptors." In clinical trials of NMDA agonists combined with antipsychotic agents that involved a total of 300 patients, negative symptoms improved in range from 10% to nearly 40% (Clin. Schizophr. Relat. Psychoses 2010;4:189-200).

The glycine transmitter type 1 (GlyT1) reuptake pump is the major route of inactivation of synaptic glycine, Dr. Citrome said. GlyT1 inhibitors such as sarcosine "are analogous to drugs that inhibit reuptake of other neurotransmitters, such as SSRIs and their actions at the serotonin transporter," he said. "When GlyT1 pumps are blocked by a GlyT1 inhibitor, this increases the synaptic availability of glycine-enhancing NMDA neurotransmission."

Proposed agents that target the GlyT1 transport inhibitor include sarcosine and Roche’s RG1678. The latter agent is currently in phase II and phase III trials with an eye toward commercialization.

"What’s exciting about glutamatergic drugs is that it’s not about dopamine anymore," Dr. Citrome said. "These agents don’t block dopamine."

Phase II and III testing is also under way with Eli Lilly’s LY-2140023, an agent that targets metabotropic glutamate type 2/3 (mGluR2/3) receptors.

Dr. Citrome disclosed that in the past 24 months he has engaged in collaborative research with, or has received consulting or speaking fees from Alexza, Alkermes, AstraZeneca, Avanir, Bristol-Myers Squibb, Eli Lilly, Janssen, Lundbeck, Merck, Novartis, Noven, Otsuka, Pfizer, Shire, Sunovion, and Valeant.

LAS VEGAS – In the opinion of Dr. Leslie Citrome, the clinical evidence for using adjunctive lithium and anticonvulsants in patients with schizophrenia is generally weak. Yet, clinicians continue to prescribe them.

"It’s kind of puzzling," Dr. Citrome said at the psychopharmacology conference sponsored by the Nevada Psychiatric Association. "When you count out the number of randomized, controlled trials, they do exist. They just don’t show a signal for efficacy, with the possible exception of lamotrigine plus clozapine. But we’re still doing it. Why? I think it’s because studies of these adjunctive agents may have not looked at chronically ill, refractory patients.

"Maybe the right trials weren’t done. Or maybe it’s so hard to gather together the right patients for that trial," said Dr. Citrome of the department of psychiatry and behavioral sciences at New York Medical College, Valhalla. "I think that is the biggest obstacle. Schizophrenia is many different diseases. It’s foolhardy to think that it’s all one pathophysiological process solved by one drug. Once we have a better idea of the different kinds of schizophrenia, then I think we’ll have greater chance and finding answers."

Until then, finding medical treatments that work "is very difficult," he said. "These are very challenging patients. By the time we end up treating them in some settings they’ve been ill for 10, 20, or 30 years."

In an effort to improve therapeutic options for patients with schizophrenia, several agents that affect glutamate receptors are being actively studied in randomized, controlled trials. If the successes that were observed in early clinical trials hold out to be true in the long term, "we are going to have drugs that affect the glutamate system directly and possibly [can be] used every day in the management of patients with schizophrenia," Dr. Citrome said. "Not today, but maybe within 5 or 10 years. This is a very active field of study."

Glutamate is distributed widely and is the primary excitatory neurotransmitter in the human central nervous system. It connects to dopamine neurons, "sometimes directly, sometimes through a [gamma-aminobutyric] interneuron, so there is a framework of how glutamate can impact on dopamine and affect the mesolimbic pathway and thus address psychotic symptoms, as well as [affect] the mesocortical pathway and impact cognition and mood," he said.

Early studies have demonstrated that antagonists to glutamate receptors exacerbate psychotic symptoms and cognitive impairment in patients with schizophrenia, and can induce positive and cognitive symptoms in healthy volunteers. Susceptibility genes for schizophrenia can influence the function of glutamate receptors.

The two main categories of glutamate receptors are ionotropic, which involve ion channels, and metabotropic, which involve G (guanine nucleotide–binding) proteins and chemical second messengers. The three different types of ionotropic glutamate receptors are AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), kainate, and NMDA (N-methyl-D-aspartate). "NMDA receptors won’t work without AMPA or kainate, so they’re all interrelated in some way," Dr. Citrome said. "AMPA and kainate are the ones that work quickly, while NMDA can lead to changes in plasticity over time. NMDA is really where it’s at in terms of where the research is going on, but all three types work in tandem; they don’t work in isolation."

Dr. Citrome went on to explain that for an NMDA receptor to be activated, both glutamate and glycine are required. "D-serine also has high affinity for the glycine site on NMDA receptors," he said. "An analogue of D-serine, D-cycloserine is also active at the glycine co-agonist site of NMDA receptors." In clinical trials of NMDA agonists combined with antipsychotic agents that involved a total of 300 patients, negative symptoms improved in range from 10% to nearly 40% (Clin. Schizophr. Relat. Psychoses 2010;4:189-200).

The glycine transmitter type 1 (GlyT1) reuptake pump is the major route of inactivation of synaptic glycine, Dr. Citrome said. GlyT1 inhibitors such as sarcosine "are analogous to drugs that inhibit reuptake of other neurotransmitters, such as SSRIs and their actions at the serotonin transporter," he said. "When GlyT1 pumps are blocked by a GlyT1 inhibitor, this increases the synaptic availability of glycine-enhancing NMDA neurotransmission."

Proposed agents that target the GlyT1 transport inhibitor include sarcosine and Roche’s RG1678. The latter agent is currently in phase II and phase III trials with an eye toward commercialization.

"What’s exciting about glutamatergic drugs is that it’s not about dopamine anymore," Dr. Citrome said. "These agents don’t block dopamine."

Phase II and III testing is also under way with Eli Lilly’s LY-2140023, an agent that targets metabotropic glutamate type 2/3 (mGluR2/3) receptors.

Dr. Citrome disclosed that in the past 24 months he has engaged in collaborative research with, or has received consulting or speaking fees from Alexza, Alkermes, AstraZeneca, Avanir, Bristol-Myers Squibb, Eli Lilly, Janssen, Lundbeck, Merck, Novartis, Noven, Otsuka, Pfizer, Shire, Sunovion, and Valeant.

LAS VEGAS – In the opinion of Dr. Leslie Citrome, the clinical evidence for using adjunctive lithium and anticonvulsants in patients with schizophrenia is generally weak. Yet, clinicians continue to prescribe them.

"It’s kind of puzzling," Dr. Citrome said at the psychopharmacology conference sponsored by the Nevada Psychiatric Association. "When you count out the number of randomized, controlled trials, they do exist. They just don’t show a signal for efficacy, with the possible exception of lamotrigine plus clozapine. But we’re still doing it. Why? I think it’s because studies of these adjunctive agents may have not looked at chronically ill, refractory patients.

"Maybe the right trials weren’t done. Or maybe it’s so hard to gather together the right patients for that trial," said Dr. Citrome of the department of psychiatry and behavioral sciences at New York Medical College, Valhalla. "I think that is the biggest obstacle. Schizophrenia is many different diseases. It’s foolhardy to think that it’s all one pathophysiological process solved by one drug. Once we have a better idea of the different kinds of schizophrenia, then I think we’ll have greater chance and finding answers."

Until then, finding medical treatments that work "is very difficult," he said. "These are very challenging patients. By the time we end up treating them in some settings they’ve been ill for 10, 20, or 30 years."

In an effort to improve therapeutic options for patients with schizophrenia, several agents that affect glutamate receptors are being actively studied in randomized, controlled trials. If the successes that were observed in early clinical trials hold out to be true in the long term, "we are going to have drugs that affect the glutamate system directly and possibly [can be] used every day in the management of patients with schizophrenia," Dr. Citrome said. "Not today, but maybe within 5 or 10 years. This is a very active field of study."

Glutamate is distributed widely and is the primary excitatory neurotransmitter in the human central nervous system. It connects to dopamine neurons, "sometimes directly, sometimes through a [gamma-aminobutyric] interneuron, so there is a framework of how glutamate can impact on dopamine and affect the mesolimbic pathway and thus address psychotic symptoms, as well as [affect] the mesocortical pathway and impact cognition and mood," he said.

Early studies have demonstrated that antagonists to glutamate receptors exacerbate psychotic symptoms and cognitive impairment in patients with schizophrenia, and can induce positive and cognitive symptoms in healthy volunteers. Susceptibility genes for schizophrenia can influence the function of glutamate receptors.

The two main categories of glutamate receptors are ionotropic, which involve ion channels, and metabotropic, which involve G (guanine nucleotide–binding) proteins and chemical second messengers. The three different types of ionotropic glutamate receptors are AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), kainate, and NMDA (N-methyl-D-aspartate). "NMDA receptors won’t work without AMPA or kainate, so they’re all interrelated in some way," Dr. Citrome said. "AMPA and kainate are the ones that work quickly, while NMDA can lead to changes in plasticity over time. NMDA is really where it’s at in terms of where the research is going on, but all three types work in tandem; they don’t work in isolation."

Dr. Citrome went on to explain that for an NMDA receptor to be activated, both glutamate and glycine are required. "D-serine also has high affinity for the glycine site on NMDA receptors," he said. "An analogue of D-serine, D-cycloserine is also active at the glycine co-agonist site of NMDA receptors." In clinical trials of NMDA agonists combined with antipsychotic agents that involved a total of 300 patients, negative symptoms improved in range from 10% to nearly 40% (Clin. Schizophr. Relat. Psychoses 2010;4:189-200).

The glycine transmitter type 1 (GlyT1) reuptake pump is the major route of inactivation of synaptic glycine, Dr. Citrome said. GlyT1 inhibitors such as sarcosine "are analogous to drugs that inhibit reuptake of other neurotransmitters, such as SSRIs and their actions at the serotonin transporter," he said. "When GlyT1 pumps are blocked by a GlyT1 inhibitor, this increases the synaptic availability of glycine-enhancing NMDA neurotransmission."

Proposed agents that target the GlyT1 transport inhibitor include sarcosine and Roche’s RG1678. The latter agent is currently in phase II and phase III trials with an eye toward commercialization.

"What’s exciting about glutamatergic drugs is that it’s not about dopamine anymore," Dr. Citrome said. "These agents don’t block dopamine."

Phase II and III testing is also under way with Eli Lilly’s LY-2140023, an agent that targets metabotropic glutamate type 2/3 (mGluR2/3) receptors.

Dr. Citrome disclosed that in the past 24 months he has engaged in collaborative research with, or has received consulting or speaking fees from Alexza, Alkermes, AstraZeneca, Avanir, Bristol-Myers Squibb, Eli Lilly, Janssen, Lundbeck, Merck, Novartis, Noven, Otsuka, Pfizer, Shire, Sunovion, and Valeant.