The Glutamate/Glutamine Theory for Schizophrenia

I have already discussed amino acids in some of my previous articles (1-5). However, I have never devoted an entire article to the glutamate/glutamine theory. I always favored the tryptophan theory. However, there is some evidence in favor of the glutamate theory. Both theories may be valid. The glutamate theory may explain some forms of mental illness, and the tryptophan theory may explain others. Another possibility is that both tryptophan and glutamate flood the brain cells at the same time.

Glutamate

"Many years of research has investigated the dopamine hypothesis and glutamate hypothesis of schizophrenia, but more recently the field is scrutinizing the combined interactions of the glutamatergic and dopaminergic systems." A. Bradford

Centre for Integrative Neuroscience CINS, School of Biological and Biomedical Sciences, Durham University, DH1 3LE, UK

This quote is from Ref. 6.

"The glutamate model of schizophrenia proposes that altered glutamatergic neurotransmission is fundamental to the development of the disorder. In addition, its potential to mediate neurotoxicity raises the possibility that glutamate dysfunction could underlie neuroanatomic changes in schizophrenia." James M. Stone (a), Fern Day (a), Helen Tsagaraki (a), Isabel Valli (a), Mary A. McLean (b), David J. Lythgoe (a), Ruth L. O'Gorman (a), Gareth J. Barker (a), Philip K. McGuire (a)

(a) Institute of Psychiatry, King's College London, University College London, United Kingdom

(b) Institute of Neurology, University College London, United Kingdom

The above quote is from Ref. 7. The Gale Health Reference Center database is very good for English language articles. However, the Pubmed database has abstracts of foreign language articles also. I use both databases extensively.

Treatment

"Oral high-dose glycine administration has been used as an adjuvant treatment for schizophrenia to enhance glutamate neurotransmission and mitigate glutamate system hypofunction thought to contribute to the disorder. Prior studies in schizophrenia subjects documented clinical improvements after 2 weeks of oral glycine administration, suggesting that brain glycine levels are sufficiently elevated to evoke a clinical response within that time frame." Marc J. Kaufman (a), Andrew P. Prescot (a), Dost Ongur (a), A. Eden Evins (b), Tanya L. Barros (a), Carissa L. Medeiros (a), Julie Covell (a), Liqun Wang (c), Maurizio Fava (b), Perry F. Renshaw (a)(d)

(a) Brain Imaging Center, McLean Hospital, Harvard Medical School, Belmont, MA 02478, United States

(b) Massachusetts General Hospital, Boston, MA 02114, United States

(c) Translational Medicine and Genetics, GlaxoSmithKline, Greenford, United Kingdom

(d) The Brain Institute, University of Utah, Salt Lake City, UT, United States

The above quote favoring glycine treatment is from Ref. 8. I am skeptical of this treatment.

GLX

"Brain white matter metabolite abnormalities are shown in elderly patients with schizophrenia; specifically, we observed overall decreased NA and MI, elevated GLX, and a trend for elevation of CHO in schizophrenic subjects compared to healthy volunteers. Decreased NA suggests decreased neuronal content or neuronal dysfunction, while decreased MI suggests decreased glial content or function, and elevated GLX may reflect a hyperglutamatergic state in the white matter regions of these patients."

Linda Chang, M.D.,¹ Joseph Friedman, M.D.,² Thomas Ernst, Ph.D.,¹ Kai Zhong, Ph.D.,³ Nicholas D. Tsopelas, M.D.,⁴ and Kenneth Davis, M.D.²

¹ Department of Medicine, John A. Burns School of Medicine, Honolulu, HI 96813² Department of Psychiatry, Mount Sinai Medical Center, New York, NY³ Department of Diagnostic Radiology, Diagnostic Physics, University of Magdeburg, Magdeburg, Germany⁴ Western Psychiatric Institute and Clinic, Pittsburgh, PAPlease address all correspondences to: Linda Chang, M.D., Dept. of Medicine, John A. Burns School of Medicine, Queen's University Tower, 1356 Lusitana Street, Honolulu, HI 96813, Tel: (808) 586-7468, FAX (808) 586-7486, E-mail:lchang@hawaii.edu

The above quote is from Ref. 9. This report showed elevated brain GLX. GLX is glutamate+glutamine. These two amino acids are often lumped together like this because they are interchangeable. They are very close chemical relatives.

Refs. 10-14 add more support to the glutamate theory. It seems that a lot of studies have shown increased glutamate in the brain in mental disease.

Conclusions

Glutamine is in the following foods:

Beans, brewer's yeast, brown rice bran, caseinate, dairy products, eggs, fish, lactalbumin, legumes, meat, nuts, seafood, seeds, soy, whey, whole grains. Hydrolysis of gluten, beet root or other proteins.

Glutamic acid is in the following foods:

Meat, poultry, fish, eggs, dairy products, and protein-rich plant foods.

For the normal person, these amino acids are useful. Glutamic acid is an excitatory neurotransmitter in the central nervous system. Glutamine serves as a source of fuel for cells lining the intestines. However, unfortunately it is possible to be allergic to glutamine as in celiac disease.

These are nonessential amino acids, meaning that the body can make them from other amino acids. Therefore a strict diet would be low in protein. A good start would be the vegan diet, which is relatively low in protein. However, wheat has gluten, and it should be avoided. If these amino acids are the problem in schizophrenia, then a diet low in them should help.

However, there is always the possibility that the elevated GLX in the brain in schizophrenia could be a side effect of the disease, not the cause of it. For example, a flooding of the brain cells with tryptophan could cause an increase in these amino acids. Tryptophan could be the worst offending amino acid. For this reason more research needs to be done. Tryptophan is tricky because carbohydrates have the effect of pumping tryptophan into the brain by a complex process involving insulin. Thus a low protein diet might not work if tryptophan was the culprit. The diet would also have to restrict carbohydrates.

References

1. http://www.associatedcontent.com/article/754745/histopathology_as_an_approach_to_schizophrenia.html

2. www.associatedcontent.com/article/754463/mental_health_science.html

3. www.associatedcontent.com/article/754821/the_pathological_anatomy_of_schizophrenia.html

4. www.associatedcontent.com/article/748865/schizophrenia_as_an_encephalopathy.html

5. http://www.associatedcontent.com/article/630989/the_riddle_of_mental_illness.html

6. Bradford, A. "The dopamine and glutamate theories of schizophrenia: A short review." Current Anaesthesia & Critical Care 20.5-6 (Oct-Dec 2009): 240(2). Health Reference Center Academic. Gale. Newton Free Library. 24 Sept. 2009.

7. "Glutamate Dysfunction in People with Prodromal Symptoms of Psychosis: Relationship to Gray Matter Volume.(Report)." Biological Psychiatry 66.6 (Sept 15, 2009): 533(7). Health Reference Center Academic. Gale. Newton Free Library. 24 Sept. 2009.

8. "Oral glycine administration increases brain glycine/creatine ratios in men: A proton magnetic resonance spectroscopy study.(Report)." Psychiatry Research: Neuroimaging 173.2 (August 30, 2009): 143(7). Health Reference Center Academic. Gale. Newton Free Library. 24 Sept. 2009.

9. Brain metabolite abnormalities in the white matter of elderly schizophrenic subjects: implication for glial dysfunction. Linda Chang, Joseph Friedman, Thomas Ernst, Kai Zhong, Nicholas D. Tsopelas, and Kenneth DavisBiol Psychiatry. Author manuscript; available in PMC 2008 December 15.

10. Javitt DC. Glutamate and Schizophrenia: Phencyclidine, N-Methyl-d-Aspartate Receptors, and Dopamine-Glutamate Interactions. International Review Neurobiology. 2007;78:69-108.

11. Stone JM, Morrison P, Pilowsky LS. Glutamate and dopamine dysregulation in schizophrenia - a synthesis and selective review. Journal of Psychopharmacology. 2007.

12. Coyle JT. Glutamate and schizophrenia: beyond the dopamine hypothesis. Cellular Molecular Neurobiology. 2006;26:365-384.

13. Theberge J, Bartha R, Drost D, Menon R, Malla A, Takhar J, et al. Glutamate and glutamine measured with 4.0 T proton MRS in never-treated patients with schizophrenia and healthy volunteers. American Journal of Psychiatry. 2002;159:1944-1946.

14. Tebartz van Elst L, Valerius G, Buchert M, Thiel T, Rusch N, Bubl E, et al. Increased prefrontal and hippocampal glutamate concentration in schizophrenia: evidence from a magnetic resonance spectroscopy study. Biological Psychiatry. 2005;58:724-730.