A New Class of Antipsychotic Drugs

NMDA-enhancing treatments
In contrast to early studies, which suggested that the therapeutic effects of NMDA-enhancing agents added to antipsychotics were mainly on negative symptoms, more recent findings suggest that the effects extend to positive, cognitive, and depressive symptoms when compared with placebo alone.^4-7,9 Overall, the effect sizes are in the small to medium range and are similar to those seen with atypical antipsychotics.¹³

The wide spectrum of the therapeutic effects of the NMDA-enhancing agents would imply that their efficacy may not be limited to treatment of schizophrenia but that they can potentially be useful for other mental disorders involving psychotic, cognitive, or mood manifestations. In fact, efficacy results for these agents have led to recent studies to evaluate them as sole pharmacotherapeutic agents, as exemplified by a recent trial of sarcosine in antipsychotic-free patients.¹⁴

Effects on negative and cognitive symptom domains
Negative symptoms are often refractory to antipsychotic treatment with the exception of clozapine (and, to a lesser degree, the other atypical antipsychotics). The NMDA-enhancing agents have a therapeutic effect on the negative symptoms in patients with chronic schizophrenia who have been receiving stable doses of antipsychotics before the initiation of the NMDA-enhancing agents.^4-9,14 The improvement in negative symptoms by NMDA-enhancing agents can have critical implications in the long-term functional outcome of patients with schizophrenia since negative symptoms are one of the main causes of disability and poor outcome.¹³

Neurocognitive impairment is similarly associated with the limited outcome and poor functioning in patients with schizophrenia.¹⁵ It has been suggested that cognitive impairment may have a stronger relationship with poor outcome than other symptom domains.¹³ While there is a significant effect of NMDA-enhancing agents on scores on the Positive and Negative Syndrome Scale (PANSS) cognitive-subscale, most studies have been short-term trials that looked at symptom reduction and thus lack an assess­ment of cognitive domains by neurocognitive testing.^5,6,9 Taken together, it is premature to draw any conclusions regarding the cognition-improving effect of the NMDA-enhancing agents. It is also critically important to conduct long-term trials and neu­­ro­cog­ni­tive studies to determine wheth­er the symptom reduction, particularly the reductions in negative and cognitive symptoms, can improve and sustain the cognition and long-term functional outcome of patients who have schizophrenia.

Effect of different NMDA-enhancing agents
Given that the NMDA-enhancing agents are not a homogeneous group, their varied efficacy is not surprising. d-Serine and glycine treatment has a more comprehensive symptom-improvement profile than does d-cycloserine. Specifically, the effects of d-serine and glycine are greater than those of d-cycloserine on negative symptoms.^4-7,9,14 This is probably because d-serine and glycine are full agonists whereas d-cycloserine is a partial agonist that cannot fully activate the NMDA receptor. When combined with a substantial NMDA agonist, d-cycloserine behaves like an antagonist, thereby worsening the psychosis. In fact, the results of d-cycloserine trials are mixed. Consistent with its role as a full agonist and its low CNS bio-availability by peripheral administration, higher doses of glycine are more effective for negative symptoms than the lower doses used in earlier studies.⁴

d-Serine significantly improves negative, positive, cognitive, depressive, and total psychopathology. While the effects of d-serine are similar to those of glycine in negative, cognitive, depressive, and total psychopathology, d-serine, but not glycine, also improves positive symptoms. This can be explained by the better central bioavailability of serine. Future studies on optimal glycine and d-serine dosing can clarify whether the difference is caused by central bio-availability. d-Alanine, another full agonist of the NMDA-glycine site, has thus far been tested only by our group and has shown a comprehensive efficacy profile similar to that of d-serine.⁶

Although there are several GlyT1 inhibitors in preclinical development, only sarcosine has been clinically tested in 5 studies: 3 studies in stable patients with chronic schizophrenia, 1 in patients with acute exacerbation, and 1 in which sarcosine was used as the sole antipsychotic agent.^9,14,16-19 In trials with stable chronically ill patients who received antipsychotics other than clozapine, the efficacy of sarcosine was similar to that of d-serine and d-alanine.^9,19 In addition, 2 recent studies suggest that sarcosine, more than d-serine, can be of benefit to both acutely ill and chronically stable patients with schizophrenia.^18,19 Compared with those in the placebo group, patients in the sarcosine group rather than patients in the d-serine group were more likely to respond. Both sarcosine and d-serine are superior to placebo in score-changing rates of the PANSS-total and Quality-of-Life scales. In addition, sarcosine distinctly elicited better response rates than control when administered as the sole antipsychotic agent, particularly in antipsychotic-naive patients.¹⁴ Taken together, these findings indicate the interesting possibility that the GlyT1 inhibitor may be more effective than NMDA-glycine site agonists at the doses being tested for the treatment of schizophrenia. One possibility is that the anatomical distribution of GlyT1 is more relevant than the NMDA receptor per se to the circuitries involved in schizophrenia. Nevertheless, further confirmation and parallel comparison are required to determine effective dosing ranges and to compare the effectiveness of the full agonist of the NMDA-glycine site with the GlyT1 for treating schizophrenia. Caution is needed in interpreting these exploratory studies; all but 1 of which were performed by our group with similar design and inclusion/exclusion criteria.