Novel Pharmacologic Targets for the Treatment of Negative Symptoms in Schizophrenia

Robert W. Buchanan, MD

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore

While positive symptoms of schizophrenia tend to respond well to antipsychotic therapy, negative symptoms (eg, blunted affect, poverty of speech, social withdrawal) are largely unresponsive to antipsychotic treatment, resulting in long-term morbidity and poor outcome. To try to address the treatment of negative symptoms, a number of pharmacologic approaches that target different neurotransmitter systems, including dopaminergic, serotonergic, cholinergic, and glutamatergic systems, have been examined. (For more information on these systems, see “Understanding the Physiology of Schizophrenia” by Brian Kirkpatrick, MD.)

The discovery that PCP may induce schizophrenia-like symptoms (both positive and negative) via NMDA receptor blockade has led to increased attention to the importance of the glutamate system in the pathophysiology of schizophrenia and suggests that agents that target the glutamate system, including NMDA receptors, glycine transporters, and AMPA receptors, may be of potential benefit for the treatment of negative symptoms in schizophrenia.1

NMDA Receptors

Research into NMDA glutamate receptors has found that antagonism of these receptors produces the positive, negative, and cognitive symptoms of schizophrenia.2 Therefore, the hypothesis arose that NMDA receptors are hypoactive in people with schizophrenia. Subsequently, trials have been conducted to examine whether agents that indirectly increase the activity of NMDA receptors would reverse these symptoms. The use of agents that directly enhance NMDA function have been avoided, since excessive NMDA activity may lead to excitotoxicity and cell death.

A number of approaches have been examined to increase NMDA receptor activity, including agents that enhance NMDA receptor function through the glycine modulatory site. Novel agents that act at the NMDA receptor glycine site include the naturally occurring amino acids glycine and d-serine (both agonists) and an analogue of d-serine called d-cycloserine (a partial agonist).

AV 1. Adjunctive Glycine and d-Cycloserine Vs Placebo for Negative Symptoms (00:33)

Reprinted with permission from Buchanan et al4; analysis used a mixed-model ANOVA
Abbreviations are defined before the References

Glycine. Glycine, one of the smallest amino acids commonly found in proteins, is required for NMDA receptor activation. Glycine binds to the glycine modulatory site of the NMDA receptor complex. Early, small studies of adjunctive glycine showed a beneficial effect on negative symptoms in schizophrenia. For example, Heresco-Levy and colleagues3 added 0.8 g/kg/day of glycine to antipsychotic regimens for participants with treatment-resistant schizophrenia (N = 22) over 6 weeks. Glycine was well tolerated and significantly reduced negative symptoms according to PANSS negative symptom scores (P < .001) and improved BPRS total scores (P < .001), showing promising results for glycine as a short-term add-on treatment for primary negative symptoms.

Conversely, the larger, multisite, 16-week CONSIST study4 examined adjunctive glycine and d-cycloserine versus placebo in participants with persistent moderate-to-severe negative symptoms (N = 157). The results showed no significant differences in change in SANS total scores between the glycine (60 g/d) and placebo subjects, suggesting that extended glycine administration may not be an effective strategy for treating negative symptoms (AV 1).4

d-Serine. As an amino acid that helps regulate memory formation, d-serine is essential in the process of long-term potentiation. It is 3 times more potent than glycine and more readily crosses the blood-brain barrier5; therefore, d-serine can be prescribed in smaller doses than glycine.

AV 2. Adjunctive d-Serine Vs Placebo for Negative Symptoms (00:40)

Data from Heresco-Levy et al6
Abbreviations are defined before the References

As add-on therapy, a double-blind, 6-week crossover study6 of d-serine found significant improvements on PANSS measures of negative and cognitive symptoms (P < .001) for participants with schizophrenia taking risperidone or olanzapine (N = 39; AV 2).6 The 30 mg/kg/day dose of d-serine was well tolerated, and about one-third of participants experienced more than a 20% reduction in BPRS total scores. These results suggest that drugs that easily cross the blood-brain barrier and that act as glycine-site agonists may be beneficial for treating negative symptoms.


d-Cycloserine. d-Cycloserine, an antibiotic used as a second-line treatment of tuberculosis, acts as a partial agonist of the glycine site.5 In an 8-week trial7 of participants with schizophrenia taking first-generation antipsychotics (N = 39), add-on d-cycloserine reduced the SANS total score by 23%, compared with a 7% reduction with placebo. The most improved negative symptom was blunted affect. In contrast, the longer-term CONSIST study4 did not show a significant improvement in SANS total scores for add-on d-cycloserine compared with placebo (see AV 1). In a more recent study,8 add-on d-cycloserine, 50 mg, was administered once per week. d-Cycloserine significantly improved SANS total scores in 33 outpatients with schizophrenia who were taking any antipsychotic except clozapine.

These study results indicate that intermittent exposure to glutamatergic agents may be more beneficial in stimulating NMDA receptor activity than continuous exposure. However, further study is needed to determine whether these agents are effective for treating negative symptoms.

Glycine Transporters

Another approach to regulating NMDA glutamate receptor functioning is using glycine reuptake inhibitors, which block the activity of glycine transporters. For example, glycine transporter-1 (or GlyT1) transports glycine from the glutamatergic synapse into neighboring astrocytes, which control glycine concentrations at postsynaptic NMDA receptors, making it a novel target for pharmacotherapy in disorders with NMDA receptor hypofunction.9 GlyT1 inhibitors have a similar mechanism of action to drugs that inhibit reuptake of other neurotransmitters, such as SSRIs, which act at the serotonin transporter.10 Two GlyT1 reuptake inhibitors currently being tested are sarcosine (N-methylglycine) and RG1678.

Sarcosine. Sarcosine, an amino acid resulting from glycine synthesis, is a potent inhibitor of astrocytic GlyT1. In a 6-week trial, Tsai et al11 studied sarcosine versus placebo as add-on therapy to stable antipsychotic regimens in 38 participants with schizophrenia. Participants who received 2 g/day of sarcosine showed significant improvement in negative symptoms according to SANS total scores compared with placebo (P < .0001) and tolerated the medication well. These results indicate that GlyT1 is a viable therapeutic target to enhance NMDA receptor hypofunction in people with schizophrenia.

RG1678. The drug RG1678 was designed to inhibit GlyT1, thereby raising synaptic glycine levels and normalizing glutamate levels. An 8-week, phase II multicenter trial12 assessed RG1678 for 323 participants with schizophrenia with predominantly negative symptoms who were taking second-generation antipsychotics. Participants taking add-on RG1678, 10 mg/day or 30 mg/day, had significantly improved negative symptoms versus placebo according to PANSS negative symptom scores. All doses of RG1678 were well tolerated; however, the 60 mg/day dose was not significantly superior to placebo on any of the outcome measures. Phase III trials are underway in the United States and other countries, which may demonstrate that GlyT1 inhibition can specifically improve patients’ negative symptoms.

AMPA Receptors

In addition to the NMDA receptor, the AMPA receptor is the other main type of glutamate receptor and often resides at the same synapse as NMDA receptors. To get full excitation of NMDA receptors, AMPA receptors must also be stimulated. Therefore, drugs that activate AMPA receptors can indirectly modify the activity of NMDA receptors. Drugs called ampakines, which are positive allosteric modulators and bind to AMPA receptors, may enhance memory and learning, and are currently being tested in people with schizophrenia to improve cognitive function.


Multiple neurotransmitter systems have been implicated in the pathophysiology of negative symptoms. The glutamatergic system has become a viable treatment target, and drugs that are being studied for adjunctive use include NMDA receptor glycine site agonists or partial agonists, glycine reuptake inhibitors, and positive allosteric modulators of AMPA receptors. The focus on new glutamatergic agents shows promise for improving negative and cognitive symptoms in patients with schizophrenia.

Clinical Points


  • Understand that the glutamatergic system may represent a new therapeutic target for people with schizophrenia who present with predominant negative symptoms
  • Recognize the role of adjunctive NMDA receptor glycine site agonists and glycine reuptake inhibitors in treating negative symptoms of schizophrenia
  • Recognize the role of NMDA receptor glycine site agonists and ampakines in possibly treating cognitive symptoms of schizophrenia
  • Understand that glutamatergic agents may be most beneficial when used at a smaller dose, when prescribed over a shorter period of time, or when the blood-brain barrier is easily crossed

Drug List

clozapine (Clozaril, FazaClo, and others), cycloserine (Seromycin), olanzapine (Zyprexa), risperidone (Risperdal and others)


AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, ANOVA = analysis of variance, BPRS = Brief Psychiatric Rating Scale, CONSIST = Cognitive and Negative Symptoms in Schizophrenia Trial, GlyT1  = glycine transporter-1, NMDA = N-methyl-d-aspartate, PANSS = Positive and Negative Syndrome Scale, PCP = phencyclidine, SANS = Scale for the Assessment of Negative Symptoms, SSRI = selective serotonin reuptake inhibitors

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