New Treatment Targets to Improve Symptoms in Schizophrenia

Leslie Citrome, MD, MPH

Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla

Schizophrenia causes symptoms in domains that respond separately to treatment and impair different areas of functioning. Positive symptoms are often the targets of treatment, but negative and cognitive symptoms may persist even when positive symptoms are successfully managed. New therapeutic targets are needed to address negative and cognitive symptoms.

Current Medication Strategies

Current FDA-approved agents for schizophrenia focus on antagonism or partial agonism at the dopamine D2 receptor and antagonism at the serotonin 5-HT2A receptor.1 While these medications typically alleviate positive symptoms, strategies such as combining antipsychotics or using adjunctive agents have been attempted to resolve persistent negative symptoms or cognitive impairment.

AV 1. Antipsychotic Combinations in Chronic Schizophrenia (00:24)

Based on Citrome3
*Not available in the US
Center circles indicate original treatment; outer circles represent adjunctive antipsychotics

Antipsychotic combinations. In general, antipsychotic combinations are given to patients with treatment-resistant schizophrenia or persistent negative or cognitive symptoms.2 A review3 found that only 5 of about 20 randomized controlled trials of antipsychotic combination therapy supported this approach (AV 1). Although a few studies showed modest or incremental improvement in both positive and negative symptoms,3 the potential benefits must be weighed against the risks of increased side effects, medication costs, drug interactions, and adherence problems.2

Adjunctive agents. Randomized controlled trials have examined a large number of agents added to antipsychotic treatment,3 but current evidence is insufficient to support any single augmentation strategy as a standard recommendation for treating negative or cognitive symptoms.4 Encouragingly, a meta-analysis5 of 23 trials comparing adjunctive antidepressants versus placebo for negative symptoms found a moderate effect size (–0.48) for antidepressants, but none have received regulatory approval for this indication. Also, results have been generally negative for more than 50 randomized controlled trials that focused on augmenting antipsychotics to treat cognitive dysfunction, including drugs traditionally used for Alzheimer’s disease, ADHD, and wakefulness.3 However, one promising intervention that may adequately address negative and cognitive symptoms is to use adjunctive agents that act on glutamate receptors.6

Glutamate Receptors

Glutamate, the most widely distributed excitatory neurotransmitter in the central nervous system, is involved in fast synaptic transmission, neuroplasticity, and higher cognitive functions such as memory.7 Excitation of glutamate can produce either an increase (acceleration) or a decrease (brake) in the release of dopamine in the brain, affecting areas related to the symptoms of schizophrenia (AV 2).7,8

AV 2. The Connection Between Glutamatergic Dysfunction and Deficits in Schizophrenia (00:29)

Based on Kantrowitz and Javitt8

The 2 principal types of glutamate receptors, metabotropic and ionotropic, are located in different areas of the synapse and have different functions and subgroups. Metabotropic glutamate receptors (mGluR), which involve G-proteins, activate phospholipase C or inhibit adenylate cyclase. They have 3 types, each with subgroups: type I (mGluR1 and 5), type II (mGluR2 and 3), and type III (mGluR4, 6, 7, and 8).7 Ionotropic glutamate receptors, which involve ion channels, include 3 subtypes: AMPA, kainate, and NMDA. All 3 ionotropic receptor subtypes control sodium influx and potassium efflux across the cell membrane, but NMDA receptors also allow calcium to enter the neuron.7 For the NMDA receptor to function, it must be activated by both the simultaneous binding of glutamate and glycine at different sites on the receptor and the partial depolarization of the membrane.7

The NMDA receptor hypofunction hypothesis of schizophrenia can explain the positive, negative, and cognitive symptoms of schizophrenia. This is because of the ways glutamatergic neurons can connect with neurons that release dopamine. Under normal circumstances in the mesolimbic dopamine pathway, glutamate neurons excite GABA (inhibitory) interneurons, thus acting as an indirect brake on dopamine release. With NMDA receptor hypofunctioning at the GABA interneuron, the GABA interneuron is unable to release sufficient amounts of GABA (the brake is “removed”), which results in excess dopamine being released in the mesolimbic pathway and thus producing the positive symptoms of schizophrenia.9 NMDA receptor hypofunction can also explain negative and cognitive symptoms: in the mesocortical dopamine pathways, cortical glutamate neurons act to provide tonic excitation at the dopamine neuron (direct acceleration) and more dopamine is provided to circuits going back to the cortex, particularly the dorsolateral and ventral medial prefrontal cortices. When a lack of tonic excitation occurs, such as with NMDA receptor hypofunctioning (no acceleration), insufficient dopamine reaches the cortex, resulting in the cognitive and negative symptoms of schizophrenia.9 In summary, glutamate neurons are upstream of dopamine neurons and will excite dopamine neurons if connected directly to them, but glutamate neurons can also inhibit dopamine release by connecting through inhibitory GABA interneurons, potentially explaining the positive, negative, and cognitive symptoms of schizophrenia.8

Glutamate-Based Treatments

Based on the connection between glutamate and dopamine in the brain, researchers are investigating glutamate-based treatments for schizophrenia that may comprehensively address all symptom presentations. Although both metabotropic and ionotropic glutamate receptors have been researched, the majority of drug development is now being focused on NMDA receptors. Targeting NMDA receptors has yielded promising results, as evidenced by randomized controlled trials.8

AV 3. Results from a Meta-Analysis of NMDA-Enhancing Agents (00:29)

Data from Tsai and Lin12

Because NMDA receptors require both glutamate and glycine to be present, a possible method to increase NMDA receptor activity may be to increase the availability of glycine. Therapeutic options thus include administering glycine or related compounds such as d-serine or d-cycloserine.10,11 A meta-analysis12 showed that patients taking glycine or d-serine with antipsychotics (except clozapine) demonstrated improvements in multiple symptom domains, however, patients receiving adjunctive d-cycloserine did not (AV 3). Adjunctive d-serine with either risperidone or olanzapine was statistically superior (P = .02) to placebo for treating negative symptoms.12

An alternative therapeutic option to providing exogenous glycine or an analog of glycine is to increase the availability of endogenous glycine through glycine reuptake pump inhibition.11 The glycine transporter type 1 (GLYT1) reuptake pump is the major route of inactivation of synaptic glycine. Glycine is not known to be synthesized by glutamate neurons, meaning that glutamate neurons must obtain glycine from glycine neurons or glial cells.10 When the reuptake pump on the glial cell is blocked, more glycine is available at the synapse and the potential activity of the NMDA receptor is increased. One GLYT1 pump inhibitor is the natural agent N-methyl-glycine, or sarcosine. Sarcosine has been tested as monotherapy and appeared to reduce symptoms with minimal side effects, particularly for antipsychotic-naive patients with schizophrenia.13 In a meta-analysis,12 sarcosine augmentation of antipsychotics improved multiple symptom domains compared with adjunctive placebo (see AV 3), with the exception of those who were receiving clozapine.


Clozapine, an atypical antipsychotic, has been hypothesized to act, in part, by glycine transport inhibition. Its improved efficacy compared with other antipsychotics may be connected to its regulation of synaptic glycine levels.14

Bitopertin (RG1678) is a potent, noncompetitive inhibitor of GLYT1 currently in phase 3 of clinical development.15,16 Although a phase 2 randomized controlled trial15 yielded higher percentages of negative symptom responders in the 10-mg/d bitopertin group than in the placebo group (65% vs 43%; P = .013), initial results of phase 3 trials16 have not replicated these results. Phase 3 studies investigating bitopertin for suboptimally controlled symptoms of schizophrenia are in progress.16

Other Agents in Development

Unlike the treatment targets focusing on the glutamate system, the agent encenicline (EVP-6124) is hypothesized to work through a different mechanism of action. Encenicline is a selective α7 nicotinic acetylcholine (N-A7A) receptor agonist.17 N-A7A receptors are located in brain areas involved in cognitive functions such as attention and long-term and working memory. An 84-day, phase 2 trial17 of stable patients with schizophrenia tested the procognitive effects of 0.3 mg/d and 1 mg/d doses of encenicline. Both doses of encenicline had a positive effect on cognition, clinical function, and negative symptoms.17


Effective treatments for negative and cognitive symptoms remain an unmet need in schizophrenia management. Strategies such as combining antipsychotics and adding adjunctive agents to antipsychotics have yielded mostly disappointing results for both of these symptom domains. The NMDA receptor hypofunction hypothesis, with its focus on the glutamate system’s effect on dopamine, may potentially explain the positive, negative, and cognitive symptoms of schizophrenia. Therapeutic targets different from those of current antipsychotic agents are actively being investigated. Research includes adjunctive agents that bind to sites on NMDA receptors (glycine, d-serine, d-cycloserine), adjunctive glycine reuptake inhibitors (sarcosine, bitopertin), as well as agents that work through different pathways (encenicline).

Clinical Points

  • Understand that antipsychotic combinations and adjunctive strategies have minimal effect for alleviating negative and cognitive symptoms in schizophrenia
  • Watch for new agents in development that target glutamate receptors, especially NMDA receptors
  • Realize that other therapeutic agents in development act on different pathways, such as α7 nicotinic acetylcholine receptor agonists

Drug Names

aripiprazole (Abilify), clozapine (Clozaril, FazaClo, and others), cycloserine (Seromycin), olanzapine (Zyprexa and others), quetiapine (Seroquel and others), risperidone (Risperdal and others)


5-HT = serotonin, α7 = alpha-7 adrenergic receptor, ADHD = attention deficit/hyperactivity disorder, AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, BPRS = Brief Psychiatric Rating Scale, CGI = Clinical Global Impressions scale, D2 = dopamine D2 receptor, FDA = US Food and Drug Administration, GABA = γ-aminobutyric acid, GLYT1 = glycine transporter type 1, N-A7A = α7 nicotinic acetylcholine, mGluR = metabotropic glutamate receptor, NMDA = N-methyl-d-aspartate, PANSS = Positive and Negative Syndrome Scale, SANS = Scale for the Assessment of Negative Symptoms, SAPS = Scale for the Assessment of Positive Symptoms


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