NMDAR antagonists also reproduce the widespread neuropsychological abnormalities of schizophrenia (Figure).6 Ketamine infusion results in the severity and type of disorganized thinking seen in schizophrenia. Given the importance of neurocognitive dysfunction to the conceptualization of schizophrenia, these findings further support a glutamatergic model.
Sensory processing deficits
A key difference between dopaminergic and glutamatergic models is prediction of sensory processing deficits. Traditionally, dopaminergic models have viewed cognitive deficits of schizophrenia as being driven “top down” from higher order brain regions such as the prefrontal cortex, or from local dysfunction within regions such as the striatum.11 In contrast, glutamatergic models predict that deficits also should be observed within sensory brain regions, such as the primary auditory and visual cortex.
Because of the focus on higher-level brain dysfunction, little research on sensory processing deficits was performed until recently. It has become increasingly clear that:
- patients with schizophrenia show severe deficits in early auditory and visual processing
- these deficits significantly contribute to patterns of cognitive dysfunction and psychosocial impairment.12,13
In the auditory system, patients show deficits in pitch perception and, specifically, the ability to match tones after a brief delay. Schizophrenia patients show dysfunction in a specific part of the visual system called the magnocellular visual system. Deficits in these regions lead to impaired ability to detect emotion based on vocal intonation or facial expression, among other deficits.
In addition, reading ability—which was once thought to be normal in patients with schizophrenia—has been found to be severely disturbed.14 As in developmental dyslexia, impairments relate to dysfunction of underlying auditory and visual brain regions. Administering NMDAR antagonists to humans or animals causes deficits in the auditory and visual system similar to those seen in schizophrenia, which confirms the importance of NMDA dysfunction.
Glutamate-based treatments
Because NMDAR antagonists can induce schizophrenia symptoms, the most straightforward approach for treatment is to develop compounds that stimulate glutamate or NMDAR function (Table). The NMDAR contains modulatory sites that may be appropriate targets for drug development, including one that binds the amino acids glycine and D-serine and a redox site that is sensitive to brain glutathione levels. Reductions in brain D-serine and glutathione levels have been reported in schizophrenia, which suggests that impaired NMDAR regulation may contribute directly to brain dysfunction.15 Other treatment approaches being developed include targeting glycine transporters, which indirectly regulate brain levels of glycine, or metabotropic glutamate receptors, which modulate both pre-synaptic glutamate release and post-synaptic NMDAR function.
Table
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.