Glutamate modulators for the treatment of schizophrenia have generated some interest because several lines of evidence support the idea that a weakened glutamatergic tone in the brains of schizophrenics upsets a balance between glutamatergic and dopaminergic transmission. This imbalance may then predispose schizophrenics to a risk of sensory overload and exaggerated responsiveness of the monoaminergic systems, which could lead to the onset of psychosis. Several types of glutamate modulators are in development, including AMPA receptor modulators, glycine N-methyl-d-aspartate-associated agonists, and unspecified N-methyl-d-aspartate-receptor modulators. Various unspecified N-methyl-d-aspartate-receptor modulators have entered preclinical studies, but because of the paucity of data and the difficulty in proving efficacy for negative and cognitive symptoms, they are not discussed further in this section.
Mechanism Of Action
Data supporting the role of AMPA glutamate receptors in the pathophysiology of schizophrenia are open to question. The expression of AMPA receptors in schizophrenic patients has been shown to be reduced in various regions in the brain (primarily the hippocampus), although not all studies confirm this observation. Because AMPA receptors play a primary role in neurotransmission, decreased activity could underlie some cognitive symptoms of schizophrenia. These agents, through their modulation of AMPA receptors, amplify glutamate activity. Long-term potentiation, an N-methyl-d-aspartate-dependent phenomenon that seems to be critical for cognition, is indirectly enhanced by these agents’ ability to amplify glutamate activity.
In development by Cortex Pharmaceuticals, CX-516 (Ampalex) is the lead drug of potential therapeutics called AMPAkines, a group of compounds with modulatory effects on the AMPA receptor. The agent is in Phase II trials in the United States for schizophrenia. In October 2001, Cortex was awarded a Phase II Small Business Innovative Research (SBIR) grant from the U.Spain. National Institutes of Mental Health (National Institutes of Mental Heath) to further evaluate CX-516 in schizophrenia. The funding is being used to support a Phase lib, randomized, double-blind, placebo-controlled study evaluating CX-516’s efficacy when dosed concomitantly with olanzapine.
Treatment with CX-516 adjunctively with an antipsychotic appears to improve certain domains of cognitive function, although the statistical significance of this improvement is not clear. Two small, four-week, placebo-controlled trials involving 19 schizophrenia patients examined CX-516’s efficacy and side-effect profile when dosed concomitantly with clozapine. Because of the small study size, statistical analysis was not performed. According to the results, which were presented in summary form, the combination was well tolerated although one patient developed hypertension, which was judged to possibly be related to CX-516. The authors also noted an improvement in tardive dyskinesia in CX-516-treated patients. This finding contrasts with a preclinical study showing this agent enhanced dyskinesia produced by levadopa in monkeys. Compared with placebo recipients, patients receiving CX-516 exhibited improvements in negative symptoms (Positive and Negative Syndrome Scale negative) and in several domains of cognitive functioning, including verbal learning, memory, attention, and problem-solving. According to a January 25, 2001, Cortex press release, this improvement apparently persisted for a few weeks after therapy cessation. However, the large relative improvement in negative symptoms with CX-516 compared with placebo at follow-up reflected a worsening in the placebo group rather than delayed improvement with CX-516.
Results from a case series study using CX-516 as a mono therapy are not promising. This double-blind, placebo-controlled study enrolled eight patients with schizophrenia who were moderately to severely ill and partially responsive to antipsychotics. Patients were randomized to receive either CX-516 (300-900 mg tid) monotherapy or placebo for four weeks. Only four patients (two treated with CX-516 and two treated with placebo) completed the study, rendering statistical conclusions impossible. Consequently, results were presented in descriptive form. Of the four patients who received CX-516, adverse events were transient but included serious side effects such as leukopenia (one patient) and elevation in liver enzymes (two patients). Three patients on CX-516 experienced increased dyskinesias. At the end of the study, two patients treated with CX-516 experienced mild improvements in positive symptoms, while the other two experienced worsening positive symptoms. Two patients had worsening of negative symptoms while the other two stayed the same. Cognitive scores for patients treated with CX-516 showed no overall improvement and sometimes a mild worsening, although two patients showed mild improvement on measures of verbal memory and attention. Given that this study was extremely small and included severely ill patients, the authors caution against making strong conclusions about the drug’s efficacy.
CX-516’s lack of efficacy as a monotherapy was also seen in animal models (Johnson SA, 1999). Rodent studies showed that CX-516, given alone, was ineffective in reducing methamphetarnine-induced hyperactivity. However, when the compound was administered in combination with small doses of typical or atypical antipsychotics, a significant reduction in this behavior was noted.
Taken together, the available evidence suggests that CX-516 could potentially fill a market niche as an adjunctive therapy for cognitive impairment, a frequent and disabling feature of psychosis. Ultimately, the drug’s commercial success will depend on the following factors:
• Whether CX-516 can serve as a useful adjunct to other antipsychotics.
• Whether CX-516 can improve cognitive function over and above other agents used in isolation. This issue is a particular concern with the atypical antipsychotics that also ameliorate certain forms of cognitive deficit.
Although the glutamatergic role in schizophrenia is intriguing, the future of AMPA receptor modulators such as CX-516 is uncertain. Clinical trials (albeit preliminary and small in size) with other glutamatergic transmission-diminishing drugs (i.e., topiramate, lamotrigine) have yielded inconclusive results, ranging from the reduction of negative and cognitive symptoms to a lack of therapeutic effect.
An additional hurdle to CX-516’s success appears to be its one-hour half-life, which represents a very short duration of action even with frequent dosing. Combined with the drug’s low potency, this short half-life would require patients to take CX-516 three times a day as seen in trials. Keeping in mind the compliance issues surrounding the treatment of psychotic patients, such frequent dosing represents a significant problem.
In January 1999, Cortex Pharmaceuticals and Organon signed an agreement granting Organon a worldwide license for the development and commercialization of AMPAkines, a group of compounds with modulatory effects on the AMPA receptor, for the treatment of schizophrenia. Organon is developing the AMPAkine Org-24448 for this indication. It is in Phase II trials in the United States.
Lacking preclinical or clinical data for Org-24448, data from CX-516 is cited here as a proxy. Therefore, based upon trial data from CX-516, treatment with Org-24448 is expected to result in minor improvements in certain aspects of cognition such as verbal learning, memory, attention, and problem solving. Although Org-24448 may provide some cognitive benefit, this benefit is unlikely to be highly significant (based upon limited data from CX-516) or to translate into an improved quality of life for the patient. Thus this drug will be used in patients who are so severely ill that any improvement in cognition is considered helpful and worth the cost of treatment.