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Correspondence |
Camden and Islington Mental Health and Social Care Trust, and Department of Mental Health Sciences, Royal Free and UCL Medical School, Archway Campus, Highgate Hill, London N19 5NF, UK. E-mail: Gianetta.rands{at}candi.nhs.uk
Phospholipid metabolism occurs in cell (including neuron) membranes and although regional differences are described by Jensen et al (2004), these are not neurotransmitter-specific. This research suggests increased phospholipid metabolism in the anterior cingulate area of people with schizophrenia.
Jensen et al suggest that this is supportive evidence for a neurodegenerative mechanism in schizophrenia. They also review the effects of neuroleptic and anxiolytic (including benzodiazepine) medications on brain phosphorus metabolism.
Memantine is a drug currently licensed for use in people with moderate to severe Alzheimer’s dementia. It is a non-competitive, low-affinity N-methyl-D-aspartate (NMDA) antagonist. (The NMDA receptor is a class of glutamate receptor.) Glutamate-mediated excitotoxicity and/or receptor dysfunction is involved in the pathogenesis of several neuropsychiatric and neurological disorders. Memantine partially blocks these NMDA receptors, preventing a neurotoxic influx of calcium. Theoretically, it is neuroprotective for glutamate-receiving neurons.
Given its mode of action, it should theoretically be more effective in the early stages of neurodegenerative disorders such as Alzheimer’s dementia. On these theoretical grounds it may also be neuroprotective for people with schizophrenia.
REFERENCES
Jensen, J. E., Miller, J., Williamson, P. C., et al
(2004) 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.
Room 208, Brain Imaging Center, McLean Hospital, 115 Mill Street, Belmont, MA 02478-9106, USA. E-mail: ejensen{at}mclean.harvard.edu
University of Western Ontario, Canada
McGill University, Montreal, Canada
University of Western Ontario, Canada
St Joseph’s Health Care, London, Ontario, Canada
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 (2002, 2003), 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, 2000, 2002), 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 (Tsai & 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.
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.
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.
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.
Tsai, G. & Coyle, J. T. (2002) Glutamatergic mechanisms in schizophrenia. Annual Review of Pharmacology and Toxicology, 42, 165 -179.[CrossRef][Medline]
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