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Authors' Reply

Published online by Cambridge University Press:  02 January 2018

J. E. Jensen ,
J. Miller ,
P. C. Williamson ,
R. W. J. Neufeld ,
R. S. Menon ,
A. Malla ,
R. Manchanda ,
B. Schaefer ,
M. Densmore  and
D. J. Drost
J. E. Jensen
Affiliation:
Room 208, Brain Imaging Center, McLean Hospital, 115 Mill Street, Belmont, MA 02478–9106, USA. E-mail: ejensen@mclean.harvard.edu
J. Miller
Affiliation:
University of Western Ontario, Canada
P. C. Williamson
Affiliation:
University of Western Ontario, Canada
R. W. J. Neufeld
Affiliation:
University of Western Ontario, Canada
R. S. Menon
Affiliation:
University of Western Ontario, Canada
A. Malla
Affiliation:
McGill University Montreal, Canada
R. Manchanda
Affiliation:
University of Western Ontario, Canada
B. Schaefer
Affiliation:
University of Western Ontario, Canada
M. Densmore
Affiliation:
St Joseph's Health Care, London, Ontario, Canada
D. J. Drost
Affiliation:
St Joseph's Health Care, London, Ontario, Canada
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Abstract

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The British Journal of Psychiatry , Volume 186 , Issue 1 , January 2005 , pp. 77 - 78
Copyright
Copyright © 2005 The Royal College of Psychiatrists 

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.

References

Jensen, J. E., Miller, J., Williamson, P. C., et al (2000) Focal changes in brain energy and phospholipid metabolism in first-episode schizophrenia: 31P-MRS chemical shift imaging study at 4 Tesla. British Journal of Psychiatry, 184, 409–415.Google Scholar
Jensen, J. E., Al-Semaan, Y. M., Williamson, P. C., et al (2002) Region-specific changes in phospholipids metabolism in chronic, medicated schizophrenia: 31P-MRS study at 4.0 Tesla. British Journal of Psychiatry, 180, 39–44.Google Scholar
Theberge, J., Bartha, R., Drost, D. J., et al (2002) Glutamate and glutamine measured with 4.0 T proton MRS in never-treated patients with schizophrenia and healthy volunteers. American Journal of Psychiatry, 159, 1944–1946.CrossRefGoogle ScholarPubMed
Theberge, J., Al-Semaan, Y., Williamson, P. C., et al (2003) Glutamate and glutamine in the anterior cingulate and thalamus of medicated patients with chronic schizophrenia and healthy comparison subjects measured with 4.0-T proton MRS. American Journal of Psychiatry, 160, 2231–2233.CrossRefGoogle Scholar
Tsai, G. & Coyle, J. T. (2002) Glutamatergic mechanisms in schizophrenia. Annual Review of Pharmacology and Toxicology, 42, 165–179.Google Scholar
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