Patients meeting criteria for the risk syndrome for psychosis have treatment needs including positive and negative symptoms and cognitive impairment. These features could potentially respond to NMDA glycine-site agonists. The present objective was to determine which symptoms or domains of cognition promise to show the greatest response to glycine in risk syndrome patients. We conducted two short-term pilot studies of glycine used without adjunctive antipsychotic medication. In the first trial, 10 risk syndrome subjects received open-label glycine at doses titrated to 0.8 g/kg/d for 8 weeks, followed by discontinuation and 16 weeks of evaluation for durability of effects. In the second, 8 subjects were randomized to double-blind glycine vs. placebo for 12 weeks, followed by open-label glycine for another 12 weeks. Patients were evaluated every 1–2 weeks with the Scale Of Psychosis-risk Symptoms (SOPS) and before and after treatment with a neurocognitive battery. Within-group and between-group effect sizes were calculated. Effect sizes were large for positive (open-label within-group −1.10, double-blind between-group −1.11) and total (−1.39 and −1.15) symptoms and medium-to-large (−0.74 and −0.79) for negative symptoms. Medium or large effect sizes were also observed for several neurocognitive measures in the open-label study, although data were sparse. No safety concerns were identified. We conclude that glycine was associated with reduced symptoms with promising effect sizes in two pilot studies and a possibility of improvement in cognitive function. Further studies of agents that facilitate NMDA receptor function in risk syndrome patients are supported by these preliminary findings.
The N-methyl-d-aspartate receptor (NMDAR) hypoactivity model is a leading hypothesis about the neurobiology of schizophrenia ( Javitt and Zukin, 1991, Kantrowitz and Javitt, 2010, Kim et al., 1980, Krystal et al., 2002 and Olney et al., 1999). This hypothesis is based in part on exacerbation of positive and negative symptoms and cognitive impairment in schizophrenia patients by NMDAR antagonists such as ketamine and the production of similar effects in healthy humans. Evidence suggests NMDAR hypoactivity may connect to other prominent models of psychosis ( Feinberg, 1982, Howes and Kapur, 2009 and McGlashan and Hoffman, 2000) by contributing to the development of dopamine hyperactivity in striatum ( Carlsson et al., 1999 and Laruelle et al., 2003) and cortical synaptic plasticity deficits ( Collingridge and Singer, 1990, Newcomer and Krystal, 2001, Olney et al., 1999 and Shi et al., 1999).
Over the past 15 years, researchers have attempted to identify patients in the prodromal phase of psychotic disorders prospectively, based primarily on subsyndromal psychotic-like or “attenuated” positive symptoms (Miller et al., 2002 and Yung et al., 1996). Since the term “prodrome” traditionally carries a retrospective connotation, the alternative terms “risk syndrome for psychosis” (Woods et al., 2009), “at-risk mental state,” “ultra high risk,” “clinical high risk,” and most recently “attenuated psychosis syndrome” or “APS” (Carpenter and van Os, 2011) have been proposed. A recent meta-analysis of 27 studies suggested that the average rate of transition to full psychosis among such patients is 22% by one year and 36% by three years (Fusar-Poli et al., 2012). Structural thinning of cerebral cortex (Pantelis et al., 2003) and increased striatal uptake of dopamine precursor (Howes et al., 2011), neurobiological findings typical of established schizophrenia, have been reported at baseline in risk syndrome patients who later progress to psychosis, findings which increase in magnitude after progression to psychosis has occurred.
In addition to carrying substantial risk for transition to frank psychosis, risk syndrome patients meet general mental health standards for current illness (Ruhrmann et al., 2010) in that at presentation they display distressing current symptoms and functional and cognitive impairment (Woods et al., 2001 and Woods et al., 2010). Intervention studies have begun to address these patients' prevention needs (Amminger et al., 2010, McGlashan et al., 2006, McGorry et al., 2002, Morrison et al., 2004 and Yung et al., 2011), and some have started to investigate current clinical state as a treatment target (Amminger et al., 2010, McGorry et al., 2002, Ruhrmann et al., 2007, Woods et al., 2003, Woods et al., 2007 and Yung et al., 2011). Medication treatment studies have primarily focused on use of antipsychotics, but there is a compelling need for investigation of other treatments with fewer adverse effects such as the current effort and the recent omega-3 fatty acid study (Amminger et al., 2010).
Glycine is an amino acid neurotransmitter in brain that acts at the glycine/D-serine modulatory site on the NMDAR as a full coagonist with glutamate (Javitt, 2006). Based on the hypothesis that the risk syndrome may reflect an NMDAR hypofunction state, we tested the therapeutic effects of glycine in risk syndrome patients in two small, short-term pilot studies initiated in preparation for future more definitive trials.
