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Longitudinal grey-matter and glutamatergic losses in first-episode schizophrenia

  • Jean Théberge (a1), Kate E. Williamson (a2), Naoko Aoyama (a3), Dick J. Drost (a1), Rahul Manchanda (a4), Ashok K. Malla (a5), Sandra Northcott (a4), Ravi S. Menon (a6), Richard W. J. Neufeld (a7), Nagalingam Rajakumar (a8), William Pavlosky (a9), Maria Densmore (a10), Betsy Schaefer (a11) and Peter C. Williamson (a12)...
Abstract
Background

Progressive volumetric changes in the brains of people with schizophrenia have been attributed to a number of factors.

Aims

To determine whether glutamatergic changes in patients with schizophrenia correlated with grey-matter losses during the first years of illness.

Method

Left anterior cingulate and thalamic glutamatergic metabolite levels and grey-matter volumes were examined in 16 patients with first-episode schizophrenia before and after 10 months and 30 months of antipsychotic treatment and in 16 healthy participants on two occasions 30 months apart.

Results

Higher than normal glutamine levels were found in the anterior cingulate and thalamus of never-treated patients. Thalamic levels of glutamine were significantly reduced after 30 months. Limited grey-matter reductions were seen in patients at 10 months followed by widespread grey-matter loss at 30 months. Parietal and temporal lobe grey-matter loss was correlated with thalamic glutamine loss.

Conclusions

Elevated glutamine levels in never-treated patients followed by decreased thalamic glutamine and grey-matter loss in connected regions could indicate either neurodegeneration or a plastic response to reduced subcortical activity.

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Copyright
Corresponding author
Dr Jean Théberge, St Joseph's Health Care, Nuclear Medicine and MR, Room B5-233, 268 Grosvenor Street, London, Ontario N6A 4V2, Canada. Tel: +1519 646 6100 (x65635); fax: +1519 646 6399; e-mail: jtheberge@lawsonimaging.ca
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Declaration of interest

None.

Funding detailed in Acknowledgements.

Footnotes
References
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Longitudinal grey-matter and glutamatergic losses in first-episode schizophrenia

  • Jean Théberge (a1), Kate E. Williamson (a2), Naoko Aoyama (a3), Dick J. Drost (a1), Rahul Manchanda (a4), Ashok K. Malla (a5), Sandra Northcott (a4), Ravi S. Menon (a6), Richard W. J. Neufeld (a7), Nagalingam Rajakumar (a8), William Pavlosky (a9), Maria Densmore (a10), Betsy Schaefer (a11) and Peter C. Williamson (a12)...
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eLetters

This could be explained by DHEA levels during schizophrenia.

James M. Howard, Biologist
12 October 2007

It is my hypothesis that schizophrenia results from reduced fetal brain growth and development due to low maternal DHEA. This underdevelopment is exposed later in life by hormones that interfere with DHEA availability, that is, cortisol and testosterone, along with the natural decline of DHEA that begins around age twenty. Therefore, schizophrenia often occurs following a stressful event (cortisol) in the late teens or early twenties (testosterone and loss of DHEA) or later in life as DHEA reaches very low levels. This loss of DHEA and antagonism bycortisol and testosterone reduce both function and tissue maintenance. Schizophrenics are characterized by low DHEA.

Even though DHEA is low in schizophrenia, prior to the onset of schizophrenia sufficient DHEA exists for total brain function. However, as DHEA availability is reduced, triggering prodromal symptoms, reduced social / behavioral function is reduced. As this occurs, use of DHEA by frontal areas is reduced. I suggest this, initially, increases availability of DHEA for midbrain structures which increases their function. I suggest this increase in function of midbrain structures is the basis of positive symptoms. As brain function declines, the brain reduces stimulation of DHEA so DHEA ultimately declines. I suggest loss of DHEA increases negative symptoms. As stated earlier, I suggest testosterone reduces DHEA; negative symptoms are increased by testosteronein male schizophrenics (Psychoneuroendocrinology. 2007 May;32(4):385-91).

It is known that DHEA promotes presynaptic glutamate release (Neuropharmacology. 2007 Mar;52(3):966-74). I suggest the foregoing explanation of schizophrenia may explain the findings of Theberge, et al. That is, DHEA availability is initially increased for midbrain structures as frontal use of DHEA decreases followed by gradual decline of overall DHEA which would initially increase glutamate levels followed by a subsequent decline in glutamate levels.
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