Cognitive impairment represents a core feature of schizophrenia in the majority of patients with the disorder.1,2
Cognitive deficits appear during the initial episode of the illness3
and may appear even in those who are not taking antipsychotic medications,4,5
suggesting that these deficits do not reflect the deteriorative effects of treatment. Cognitive impairment is associated with poor functional outcome and long-term prognosis.6
Because cognitive impairment is among the strongest predictors of functional outcome in patients with schizophrenia,6,7
the improvement of cognitive functioning has been identified as an important goal of treatment.8,9
Despite the known beneficial effects of conventional antipsychotics on positive symptoms, some studies have shown that these drugs might have negative effects on cognitive functioning,10,11
although other, more systematic analyses have suggested that such drugs provide a modest benefit.12
However, evidence also exists that atypical antipsychotic drugs might benefit cognitive functioning. Atypical antipsychotic drugs have been associated with greater improvement in cognitive functioning than conventional antipsychotic medications,13-15
although these benefits were relatively slight and have not been consistently shown. Thus, although atypical antipsychotic drugs may offer some benefits to cognitive functioning in schizophrenia,17
significant deficits still persist in this domain and alternative therapies for enhancing cognitive functioning are required.
Several novel strategies to treat cognitive impairment in schizophrenia have been explored. Extensive psychopharmacological research has focused on dopamine receptors in the prefrontal cortex, nicotinic and muscarinic acetylcholine receptors, the glutamatergic excitatory synapse, various serotonin receptors, and the γ-aminobutyric acid (GABA) system.18
Previously, Lee and colleagues19
conducted a placebo-controlled trial of galantamine, a combined acetylcholinesterase inhibitor and allosteric potentiator of the nicotinic receptor, to examine the effects of the drug on the cognitive functioning of individuals with chronic schizophrenia. This trial showed no significant effects on cognitive functioning.
Glutamate is the primary excitatory neurotransmitter for approximately 60% of neurons20
and also plays a principal role in modulating long-term potentiation. Moreover, glutamate is considered to be a key cellular mechanism in learning and memory.21
Glutamate dysregulation may be involved in the neuropathology of schizophrenia,22
as evidenced by studies using N-methyl-D-aspartate (NMDA) receptor antagonists, phencyclidine (PCP) and ketamine. PCP and ketamine produce the wide range of schizophrenic symptoms, including psychotic symptoms, negative symptoms, and cognitive impairment.23,24
NMDA hypofunctioning results in decreased stimulation of central GABAergic neurons.25
This ultimately may lead to the excessive release of glutamate into the synapse and consequently causes significant neuronal cell death.26
Thus, NMDA-mediated neuronal cell death is believed to play a role in the pathology of schizophrenia. Therefore, drugs that block excessive NMDA receptor-induced glutamate activity may attenuate this excitotoxic process.27
Memantine is currently approved for the treatment of moderate to severe Alzheimer's disease. It is a moderate affinity, noncompetitive, voltage-dependent NMDA receptor antagonist with rapid kinetics.26
These pharmacological features might allow memantine to modulate the pathological NMDA receptor activity thought to occur in Alzheimer's disease, while permitting normal physiological activation of the receptor required for learning and memory.29,30
Memantine is clinically well tolerated and lacks the psychotomimetic effects seen with other NMDA receptor antagonists such as ketamine and PCP.28,31
Because memantine treatment successfully slows neurodegeneration in dementia,32
it may also have a positive impact on the symptoms of schizophrenia.33
Krivoy and colleagues34
reported that menantine, in combination with conventional antipsychotic treatment, improved the negative symptoms of schizophrenia. Moreover, de Luceana and colleague35
reported that memantine in combination with clozapine therapy was associated with improvement in negative and positive symptoms. Lieberman and colleagues,36
however, reported that memantine was not efficacious as an adjunctive therapy.
In this randomized, double blind, placebo-controlled study, the potential effects of adjunctive memantine treatment on cognitive functioning in chronic schizophrenia was investigated. In addition, patient psychopathology was evaluated, and the adverse effects of memantine were assessed.