Drugs targeting glutamate 'active field of study': better therapeutic options for managing patients with schizophrenia daily may be in the offing.
"It's kind of puzzling," Dr. Citrome said at the conference. "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 a greater chance of 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 (al-pha-amino-3-hydroxy-5-methyl-4-isoxa-zolepropionic 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, adding that "d-serine also has high affinity for the glycine site on NMDA receptors."
And 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%. 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, Janssen, Eli Lilly, Lundbeck, Merck, Novartis, Noven, Otsuka, Pfizer, Shire, Sunovion, and Valeant.
EXPERT ANALYSIS FROM A PSYCHOPHARMACOLOGY CONFERENCE SPONSORED BY THE NEVADA PSYCHIATRIC ASSOCIATION
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|Title Annotation:||ADULT PSYCHIATRY|
|Publication:||Clinical Psychiatry News|
|Date:||Mar 1, 2012|
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