A New Class of Antipsychotic Drugs

d-Cycloserine has a very narrow therapeutic window. Goff and colleagues²⁰ found that doses higher than 100 mg worsened the symptoms of schizophrenia, as well as the symptoms of patients who received clozapine. This raises an intriguing possibility that part of clozapine’s action may involve the NMDA-glycine site. This hypothesis is consistent with the negative findings for glycine, d-serine, and sarcosine in patients who were treated with clozapine.¹⁷

Almost all the studies of the NMDA-enhancing agents were performed with patients on stable doses of antipsychotics. NMDA-enhancing agents as a whole are effective for patients who receive antipsychotics other than clozapine, including both typical and atypical antipsychotics, but not in patients treated with clozapine. Scores on the Clinical Global Impression Improvement Scale were between 2 and 3, indicating a mild to moderate improvement that could be clinically observed. The addition of NMDA-enhancing agents to atypical antipsychotics (risperidone and olanzapine) resulted in significant improvements in total psychopathology, negative symptoms, cognitive symptoms, and depressive symptoms.^9,18,19 These findings underscore the significance of NMDA enhancement as a new therapeutic approach in an era in which atypical antipsychotics are becoming the primary drugs for most patients who have schizophrenia. We theorize that this may involve a synergistic therapeutic effect of the atypical antipsychotics and NMDA-enhancing agents, providing an intriguing augmentation strategy for patients whose disorder is resistant or only partially responsive to atypical antipsychotics.

Adverse effects and safety
Except for GI upset and nausea in some glycine trials, other adverse effects have not been significantly different between treatment with placebo and with the NMDA-enhancing agents.^17-21 Adding NMDA-enhancing agents to other antipsychotics similarly showed a good safety profile and did not worsen the adverse effects of concomitant antipsychotics, which are mediated by D2, 5-HT2, histamine, muscarinic, or other receptors. Nevertheless, long-term studies are needed to thoroughly evaluate the safety of the NMDA-enhancing agents. If confirmed by results from additional studies, these would be safe antipsychotic agents devoid of the adverse effects of extrapyramidal symptoms, tardive dyskinesia, and metabolic syndrome. These advantages will help a substantial portion of patients who experience serious adverse effects while taking the existing antipsychotics.

In fact, given that NMDA-enhancing agents were found to significantly improve extrapyramidal symptoms on both the Simpson-Angus Scale and Abnormal Involuntary Movement Scale measurements, it is possible that NMDA-enhancing agents may produce both better and safer therapeutic results. A recent study found that coadministration of an NMDA-enhancing agent can reduce the dosage of an antipsychotic required to reach the same level of symptom reduction in schizophrenia while minimizing adverse effects.²¹ Therefore, the add-on strategy may actually lead to a reduction of dose-related adverse effects associated with currently used antipsychotics. Alternatively, both D₂ blockers and NMDA enhancers may address different dimensions of the illness, with their effects being additive, or even synergistic, without negating each other.

Perspective
While the results of the trials with NMDA-enhancing agents are encouraging, most studies involve small series. The optimal dosage for each individual agent is unknown, except for d-cycloserine, which has marginal therapeutic effects in a narrow therapeutic window. Thus far, NMDA-enhancing agents have been tested mainly as add-on treatment for patients on stable antipsychotic regimens. Our belief that the NMDA-enhancing agents should be tested as monotherapy for psychosis is encouraged by initial findings, particularly in antipsychotic-naive patients.¹⁴ In addition to efficacy in treating schizophrenia, the addition of NMDA-enhancing agents has been shown to be beneficial in Alzheimer disease, posttraumatic stress disorder, autism, and phobias.^22-25 In theory, any neuro-psychiatric disorder involving attenuated NMDA function could benefit from the strategy of enhancing the NMDA function.

NMDA hypofunction may be more prominent early in the disease process and, consequently, the disease may be more amendable by early use of NMDA-enhancing agents. Clearly, the new therapeutic approach of enhancing NMDA neurotransmission is still in its early development. Nonetheless, NMDA-enhancing agents improve a wide spectrum of symptoms of schizophrenia with minimal adverse effects and a satisfactory safety profile. Among the 3 agents analyzed, the full agonists, d-serine and glycine, and the GlyT1 inhibitor, sarcosine, have a better symptom profile than the partial agonist, d-cycloserine; there are preliminary suggestions that the GlyT1 inhibitor is more effective than the glycine site agonist.

Given that hypo-NMDA neurotransmission plays a role in neurotoxicity and the developmental risks of schizophrenia, correction of NMDA hypofunction early on could not only benefit the symptoms but also improve the disease course. This notion is supported by our recent finding that antipsychotic-naive patients benefit more from sarcosine therapy than patients who have been previously treated with an antipsychotic.

In the future, it would be interesting to explore the role of NMDA-enhancement treatment, not only as symptom treatment but also as illness prevention and long-term function outcome. Moreover, larger placebo-controlled studies are warranted to compare NMDA-enhancing agents with antipsychotics to determine their respective strengths and weaknesses. The addition of NMDA-enhancing agents to the antipsychotic armamentarium should enlarge our range of choices for individually tailoring or combining agents for additive effects or synergism. Innovative application of other potential targets to enhance NMDA neurotransmission may be beneficial not only for patients with schizophrenia but for those with other neuropsychiatric conditions (Figure).