Schizophrenia is a severely disabling illness, with patients experiencing deficits in a variety of functional domains.1 While currently available antipsychotics are effective in treating positive symptoms (eg, delusions and hallucinations), they are less effective in treating negative symptoms and cognitive impairment, which contribute to functional disabilities.2 A recent article by Brown and Roffman2 reviews emerging targets and adjunctive agents under investigation, which may target these domains.
For over 50 years, antipsychotic drugs have primarily targeted the dopamine system.3 However between 60% and 80% of total brain metabolic activity is utilized by glutamatergic neurons.3 Evidence for glutamate abnormalities in schizophrenia supports the development of novel antipsychotic agents targeting this system.3 Hypofunction of the inotropic glutamate receptor subtype N-methyl-D-aspartate (NMDA) appears to play a role in positive, negative, and cognitive symptoms of schizophrenia. For this reason, NMDAR modulators have become “attractive as therapeutic targets for all three schizophrenia symptoms clusters.”2
Glycine modulatory site agents
The glycine modulatory site (GMS), located on the GluN1 subunit of the NMDAR, binds to glycine or D-serine, leading to receptor activation. GMS agonists are designed to augment activation of the NMDARs.
- The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST) Trial, which compared glycine, D-cycloserine, and placebo in 157 patients with schizophrenia or schizoaffective disorder, found neither glycine nor D-cycloserine to be an effective therapeutic option for treating negative symptoms or cognitive impairments.4
- One approach to increasing GMS agonist activity is to block agonist reuptake—for example, by blocking glycine transporter type 1 (GlyT1).2 However, trials of GlyT1 inhibitors have thus far failed to demonstrate significant differences in outcome measures (eg, improvement in the Positive and Negative Symptoms Scales [PANSS]), or led to intolerable side effects.2
- Sodium benzoate, a D-amino acid oxidase inhibitor, increases the levels of D-amino acids, and enhances NMDAR signaling.2 A six-week trial of patients with schizophrenia who were receiving stable antipsychotic therapy (n=52) compared treatment with sodium benzoate to placebo. Patients receiving sodium benzoate showed improvement in all subscales of the PANSS, as well as the Global Assessment of Functioning (GAF), Clinical Global Impression (CGI), and the Hamilton Depression Rating Scale (HAM-D).5
- Sodium nitroprusside (SNP), a vasodilator that produces nitric oxide, increases cGMP production, thereby modulating NMDAR hypofunction.2 A trial of SNP infusion in symptomatic patients with schizophrenia who had been stabilized on antipsychotics (n=20) found significant improvements in the Brief Psychiatric Rating Scale (BPRS) and PANSS-negative subscale scores, in comparison with placebo-treated patients.6 Further studies are underway to replicate these initial results.
- Memantine, a low-affinity, non-selective NMDAR antagonist, is indicated for treating Alzheimer’s disease and used off-label to treat psychiatric illnesses.2 It seems paradoxical to consider this agent for treatment of schizophrenia, since its activity as an NMDA antagonist would appear to worsen psychotic symptoms. However, it appears to block NMDAR activity stimulated by low levels of glutamate, thereby perhaps protecting against neurotoxicity.2 Two small studies found it to be more effective than placebo in improving scores of positive, negative, and cognitive symptoms.7,8 However, a larger trial found no difference at endpoint in PANSS total scores, and an increase in adverse effects in the memantine group.9