Глутаматергические лекарственные средства для лечения шизофрении

Glutamatergic drugs in development

Target	Proposed mechanism	Proposed agents	Phase of development
Glycine/D-serine receptor	Allosteric modulator of the NMDA receptor	Glycine, D-serine, D-alanine, D-cycloserine	Phase II
Glycine-type I transport inhibitor	Blocks the reuptake of glycine, akin to SSRIs’ action on serotonin	Sarcosine, RG1678	Phase II/III
Metabotropic glutamate type 2/3 (mGluR2/3)	Blocks presynaptic glutamate release	LY-2140023	Phase II
Redox sensitive site	Allosteric modulator of the NMDA receptor	N-acetylcysteine	Phase II
D-amino acid oxidase (DAAO) inhibitors	Inhibits the enzyme that metabolizes D-serine	Remains in preclinical stage
Tetrahydrobiopterin (BH4)	Indirectly modulates glutamatergic system	Remains in preclinical stage
NMDA: N-methyl-D-aspartate; SSRIs: selective serotonin reuptake inhibitors

Glycine/D-serine site agonists. To date, most studies have used glutamatergic drugs adjunctive to antipsychotics and targeted the glycine/D-serine modulatory site, in part because glycine and D-serine are natural compounds and therefore FDA approval for their use could be obtained without the extensive preclinical development usually required for new chemical entities.¹⁶ Unfortunately, these agents are less potent than traditional pharmaceuticals, and delivering optimal doses may be impossible. Nevertheless, positive studies with these compounds have provided proof-of-concept for development of agents with higher affinity and specificity.

Studies have used glycine administered at doses up to 60 g/d, D-serine up to 8 g/d, or D-alanine approximately 6 g/d. For glycine, 60 g/d is the highest dose that can be given because of concerns about tolerability and replacement of other essential amino acids. D-serine originally was tested at approximately 2 g/d with promising results, but a recent open-label trial suggested that higher doses may be more efficacious.¹⁷ D-serine doses are limited by potential renal toxicity, as demonstrated in rodents studies.

Although not all studies of glycine/D-serine site agonists have been positive, a recent meta-analysis suggests significant improvement in negative symptoms across studies.¹⁸ Variability in statistical results across studies is related primarily to degree of placebo effect within individual trials, with a mean improvement in negative symptoms of approximately 15%. Glycine/D-serine site agonists seem to be less effective when combined with clozapine, possibly because clozapine may already enhance the glutamatergic system and increase synaptic glycine levels.⁶

One study that evaluated effects of open-label glycine in individuals with schizophrenia symptoms observed a large effect-size improvement, including early remission in 3 of 10 patients.¹⁹ These data—if confirmed by double-blind trials—would indicate that glycine/d-serine site agonists might have utility in treating the schizophrenia prodrome.

Glycine transport inhibitors. A potential indirect approach to raising glycine levels in the brain is using GlyT1-type glycine transport inhibitors (GTIs). GlyT1 transporters are co-localized in brain with NMDARs and modulate local glycine levels. Rather than binding directly to the NMDAR glycine binding site, GTIs increase glycine levels in the synapse by preventing its removal by GlyT1 transporters. Their function is analogous to using selective serotonin reuptake inhibitors to increase serotonin levels in patients with depression.⁶

Sarcosine (N-methylglycine) is a naturally occurring GlyT1 inhibitor that has been used in early clinical trials in Taiwan. Initial studies with sarcosine showed efficacy similar to—and in some cases better than—that of direct glycine/D-serine site agonists when added to first-generation or non-clozapine second-generation antipsychotics.¹⁸ Sarcosine also has been found to be effective for acute treatment of schizophrenia.²⁰ At present, however, sarcosine is not available for experimental use in the United States because of toxicity considerations.

Using high-affinity GTIs for schizophrenia was first proposed in the mid-1990s,⁶ but such compounds are only now entering clinical efficacy studies. Most recently, phase II results were presented for RG1678, a compound developed by Hoffman LaRoche.²¹ The study targeted persistent negative symptoms in patients receiving chronic antipsychotic treatment. Adding RG1678, 10 mg and 30 mg, to antipsychotics led to significant improvement in persistent negative symptoms vs placebo. These promising results are being followed up in phase III studies.

Other glutamatergic options. Few compounds are available to modulate NMDARs at sites other than the glycine/D-serine site. One study administered N-acetylcysteine, a glutathione precursor, as a potential treatment for persistent negative symptoms.²² Encouraging clinical results were observed in this double-blind study, along with improvement in electrophysiologic measures, negative symptoms, and overall functioning, but the study was limited by relatively high rates of noncompletion. Preclinical studies have combined D-serine with an inhibitor of D-amino acid oxidase to prevent D-serine breakdown.²³ In rodents, this approach produces a 30-fold increase in D-serine potency.

Tetrahydrobiopterin (BH₄) is a cofactor for enzymes responsible for the synthesis of dopamine and other monoamines, and presynaptic release of dopamine and glutamate. Reductions in BH₄ levels have been reported in schizophrenia, which suggests that this compound may be etiologically important.²⁴ Researchers have initiated a study of this compound in schizophrenia.

Other schizophrenia models propose that the crucial issue is not NMDA blockade but subsequent dysregulation of presynaptic glutamate release. Type 2/3 metabotropic glutamate receptors (mGluR2/3) are located on presynaptic glutamate terminals and inhibit presynaptic glutamate release. mGluR2/3 agonists have been shown to reverse ketamine’s effects in humans and in animal models,^25,26 which suggests a potential role in schizophrenia treatment.

The first mGluR2/3 agonist entered into monotherapy clinical efficacy trials for schizophrenia was LY-2140023. In an initial trial, this compound showed significant efficacy in improving positive and negative symptoms, comparable to that of olanzapine.²⁷ However, a follow-up study failed because of a large placebo effect,²⁸ which leaves the efficacy question unresolved.In contrast to mGluR2/3, type 5 metabotropic receptors (mGluR5) are co-localized with NMDA receptors and potentiate activation. Thus, mGluR5 agonists also may be effective for treating schizophrenia. These compounds remain in preclinical development. Other approaches, such as stimulating specific types of GABA receptors to overcome glutamatergic deficits, remain promising but have not been tested in definitive clinical trials.
Glutamate: New hope for schizophrenia treatment