Memantine, as described by Dr Rands, would appear to be a suitable candidate as a neuroprotective agent for people with schizophrenia, based on its NMDA-receptor-blocking properties. This drug is currently in use as a treatment for people with moderate to severe Alzheimer's dementia.

As shown by Theberge et al (Reference Theberge, Bartha and Drost2002, Reference Theberge, Al-Semaan and Williamson2003), glutamate levels in first-episode schizophrenia are higher than normal in the anterior cingulate and lower than normal in this same region in the chronic stages of illness. As shown in this same work, N-acetylaspartate levels correlate negatively with duration of positive symptoms. This work, as well as the phosphorus work by our team (Jensen et al, Reference Jensen, Miller and Williamson2000, Reference Jensen, Al-Semaan and Williamson2002), suggests a gradual neurodegenerative process in the anterior cingulate in schizophrenia, possibly initiated by an early neurodevelopmental anomaly involving basal ganglia–thalamocortical neuronal circuits or the structures which regulate these circuits. As Dr Rands points out, memantine would partially block the NMDA receptors preventing excitotoxic damage in the anterior cingulate and connected structures, thus slowing the progression of symptoms. However, there are other considerations. There is evidence that excitotoxicity is linked to non-NMDA receptors (Reference Tsai and CoyleTsai & Coyle, 2002) which may not be affected by this approach. Furthermore, another NMDA-blocker, phencyclidine, can actually cause a paradoxical increase in glutamate activity which could aggravate the condition.

In summary, we agree that treatment options for schizophrenia should begin to focus more on this neuroprotective strategy. Although current medications may alleviate positive symptoms, they are relatively ineffective for negative symptoms and are often inadequate in preventing the psychosocial deterioration seen in chronic schizophrenia. Treatment with memantine could theoretically slow the progression of negative symptoms when administered to patients in the early stages of schizophrenia but the overall effects of these drugs are difficult to predict and it is our view that some caution is indicated in planning long-term trials of these medications in people with schizophrenia.