Brain Metabolic Alterations in Medication-Free Patients With BipolarDisorder

Dager, Stephen R.; Friedman, Seth D.; Parow, Aimee; Demopulos, Christina M.; Stoll, Andrew L.; Lyoo, In Kyoon; Dünner, David L.; Renshaw, Perry F.

doi:10.1001/archpsyc.61.5.450

Cited by 415 publications

(320 citation statements)

References 81 publications

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“…As mentioned above, Dager et al (2004) found above-normal Glx in left cingulate. In bipolar patients with acute mania, dorsolateral prefrontal cortical [Glx] and [Cr] (trend only) were increased in comparison to age-matched controls .…”

Section: Discussionsupporting

confidence: 62%

“…As the glutamateglutamine cycle (Shen and Rothman, 2002) and energetic metabolism (Magistretti et al, 1993) involve neurons and glia, our two findings may reflect dysregulation of neurons and/or glia in bipolar depression. In a mixed outpatient group of bipolar patients studied by Dager et al (2004), gray matter lactate and Glx (glutamate + glutamine) were increased; the authors proposed that these increases might suggest a dynamic shift in energy redox state from oxidative phosphorylation towards glycolysis. [Glx], [Glu], and [Cr] levels in our sample may be coupled in a similar manner.…”

Section: Discussionmentioning

confidence: 99%

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Increased Anterior Cingulate/Medial Prefrontal Cortical Glutamate and Creatine in Bipolar Depression

Frye

Watzl

Banakar

et al. 2007

Neuropsychopharmacol

198

126

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Proton magnetic resonance spectroscopy ( 1 HMRS) is an in vivo brain imaging method that can be used to investigate psychotropic drug mechanism of action. This study evaluated baseline 1 HMRS spectra of bipolar depressed patients and whether the level of cerebral metabolites changed after an open trial of lamotrigine, an anti-glutamatergic mood stabilizer. Twenty-three bipolar depressed and 12 control subjects underwent a MRS scan of the anterior cingulate/medial prefrontal cortex. The scan was performed on a GE whole-body 1.5 T MRI scanner using single-voxel PRESS (TE/TR ¼ 30/3000 ms, 3 Â 3 Â 3 cm 3 and post-processed offline with LCModel. Baseline CSF-corrected absolute concentrations of glutamate + glutamine ([Glx]), glutamate ([Glu]), and creatine + phosphocreatine ([Cr]) were significantly higher in bipolar depressed subjects vs healthy controls. The non-melancholic subtype had significantly higher baseline [Glx] and [Glu] levels than the melancholic subtype. Remission with lamotrigine was associated with significantly lower post-treatment glutamine ([Gln]) in comparison to non-remission. These data suggest that non-melancholic bipolar depression is characterized by increased glutamate coupled with increased energy expenditure. Lamotrigine appears to reduce glutamine levels associated with treatment remission. Further study is encouraged to determine if these MR spectroscopic markers can delineate drug mechanism of action and subsequent treatment response.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Increased Anterior Cingulate/Medial Prefrontal Cortical Glutamate and Creatine in Bipolar Depression

Frye

Watzl

Banakar

et al. 2007

Neuropsychopharmacol

198

126

View full text Add to dashboard Cite

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“…It has also been shown that acute mania is associated with higher levels of Glx in left dorsolateral prefrontal cortex in adults with bipolar disorder (Michael et al, 2003a-c). The elevation of Glx has also been demonstrated in medication-free adult patients with bipolar disorder in recent study by Dager et al (2004). Glutamate serves as an important excitatory neurotransmitter that can act in a functional role in synaptic plasticity crucial to learning and memory, as well as potential damaging agent involved in neuropathological conditions such as seizures, hypoxia, and hypoglycemia (Cooper et al, 1996).…”

Section: Discussionmentioning

confidence: 95%

Measurement of Brain Metabolites in Patients with type 2 Diabetes and Major Depression Using Proton Magnetic Resonance Spectroscopy

Ajilore¹,

Haroon²,

Kumaran³

et al. 2006

Neuropsychopharmacol

109

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Type 2 diabetes and major depression are disorders that are mutual risk factors and may share similar pathophysiological mechanisms. To further understand these shared mechanisms, the purpose of our study was to examine the biochemical basis of depression in patients with type 2 diabetes using proton MRS. Patients with type 2 diabetes and major depression (n ¼ 20) were scanned along with patients with diabetes alone (n ¼ 24) and healthy controls (n ¼ 21) on a 1.5 T MRI/MRS scanner. Voxels were placed bilaterally in dorsolateral white matter and the subcortical nuclei region, both areas important in the circuitry of late-life depression. Absolute values of myoinositol, creatine, N-acetyl aspartate, glutamate, glutamine, and choline corrected for CSF were measured using the LC-Model algorithm. Glutamine and glutamate concentrations in depressed diabetic patients were significantly lower (po0.001) in the subcortical regions as compared to healthy and diabetic control subjects. Myo-inositol concentrations were significantly increased (po0.05) in diabetic control subjects and depressed diabetic patients in frontal white matter as compared to healthy controls. These findings have broad implications and suggest that alterations in glutamate and glutamine levels in subcortical regions along with white matter changes in myo-inositol provide important neurobiological substrates of mood disorders.

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“…1 H MRS studies that have demonstrated an increase in myo-inositol in bipolar patients, 35,36 although not all 1 H MRS studies have identified this effect. [37][38][39] Glutamate and phosphocholine are unresolvable in in vivo spectra, however, and many studies normalize 1 H MRS spectra to the creatine peak precluding it from being quantified. Myo-inositol and creatine changes seen in the bipolar patient samples were mirrored by opposing changes seen in rat brain tissue after chronic treatment with either valproate or lithium.…”

Section: Post-mortem Brain Tissue Analysismentioning

confidence: 99%

“…Levels of lactate were also found to be increased in the post-mortem brain tissue of patients with bipolar disorder, consistent with the observed creatine changes discussed above suggesting an alteration in energy metabolism. Lactate increases have previously been noted using in vivo MRS. 37,39 Phosphoethanolamine and phosphocholine. Phosphoethanolamine and phosphocholine are precursors to membrane phospholipids in the cell.…”

Section: Post-mortem Brain Tissue Analysismentioning

confidence: 99%

Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder

et al. 2008

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Bipolar affective disorder is a severe and debilitating psychiatric condition characterized by the alternating mood states of mania and depression. Both the molecular pathophysiology of the disorder and the mechanism of action of the mainstays of its treatment remain largely unknown. Here, 1 H NMR spectroscopy-based metabonomic analysis was performed to identify molecular changes in post-mortem brain tissue (dorsolateral prefrontal cortex) of patients with a history of bipolar disorder. The observed changes were then compared to metabolic alterations identified in rat brain following chronic oral treatment with either lithium or valproate. This is the first study to use 1 H NMR spectroscopy to study post-mortem bipolar human brain tissue, and it is the first to compare changes in disease brain with changes induced in rat brain following mood stabilizer treatment. Several metabolites were found to be concordantly altered in both the animal and human tissues. Glutamate levels were increased in post-mortem bipolar brain, while the glutamate/glutamine ratio was decreased following valproate treatment, and c-aminobutyric acid levels were increased after lithium treatment, suggesting that the balance of excitatory/inhibitory neurotransmission is central to the disorder. Both creatine and myo-inositol were increased in the post-mortem brain but depleted with the medications. Lastly, the level of N-acetyl aspartate, a clinically important metabolic marker of neuronal viability, was found to be unchanged following chronic mood stabilizer treatment. These findings promise to provide new insight into the pathophysiology of bipolar disorder and may be used to direct research into novel therapeutic strategies.

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Brain Metabolic Alterations in Medication-Free Patients With BipolarDisorder

Cited by 415 publications

References 81 publications

Increased Anterior Cingulate/Medial Prefrontal Cortical Glutamate and Creatine in Bipolar Depression

Increased Anterior Cingulate/Medial Prefrontal Cortical Glutamate and Creatine in Bipolar Depression

Measurement of Brain Metabolites in Patients with type 2 Diabetes and Major Depression Using Proton Magnetic Resonance Spectroscopy

Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder

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