Brain Energy Metabolism In Bipolar Depression

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Bipolar disorder as manifested by its opposite poles of depression and mania is characterized by decreased or increased motoric and mental energy expenditure. Does such a unique presentation suggest altered states of brain energy metabolism in this disorder?

Although the brain makes up about 2% of our total body weight, it consumes about 20% and 25% of total body dioxide and glucose, respectively. Neural activity is dependent upon energy metabolism mainly for the active transport of ions and other molecules through cellular membranes needed for neural excitation. Energy consumption is particularly high for Na+/K+-ATPase and Ca2+-ATPase in plasma and endoplasmic membranes. Brain energy metabolism is reflected in ade-nosine-triphosphate (ATP) turnover. ATP, an energy-rich molecule with two high-energy phosphoanhydride bonds, is the energy donor in most energy-consuming processes, and its production in the brain is highly regulated. Another energy-rich molecule with high-energy phosphate is creatine phosphate, which enables the production of ATP from ade-nosine diphosphate via the creatine kinase/creatine phosphate system. This system may also function in regulating mitochondrial activity.

The key cellular organelle in cellular energy production is the mitochondrion. The electron flow in the mitochondria produces large amounts of energy converted into the chemical energy of ATP during oxidative phosphorylation in the mitochondria. The mechanisms of neuronal energy metabolism are not fully understood. Ames (2000) proposed the following percentages for energetic demands of neuronal key cellular processes: vegetative metabolism, 5%-15%; gated sodium influx through plasma membranes, 40%-50%; calcium influx from organelles, 3%-7%; processing of neurotransmitters, 10%-20%; intracellular signaling systems, 20%-30%; and axonal and dendritic transport 5%-15%. Agents decreasing the activity of gated sodium influx through plasma membranes or affecting second messenger intracellular systems may affect energy metabolism.

Positron emission tomography (PET) studies report reduced blood flow in depressed mood states, including bipolar depression (Baxter et al. 1985; Drevets et al. 1997; Ketter et al. 2001). PET studies reported lower fluorodeoxyglucose (FDG) uptake in the prefrontal and temporal cortexes and higher uptake in the occipital cortex of depressed patients compared with healthy controls, although in manic states the reverse direction of results was less clear. Single-photon emission computed tomography studies suggested lower cerebral blood flow in the frontal and temporal cortexes of bipolar disorder patients, particularly in the left hemisphere (Strakowski et al. 2000).

Magnetic resonance spectroscopy (MRS) provides a noninvasive window into brain neurochemistry. Decreased beta and total nucleotide triphosphate (primarily ATP) was reported in major depression in the frontal lobe (Volz et al. 1998) and basal ganglia (Moore et al. 1997). Kato et al. (1992) reported that creatine phosphate (CP)—but not ATP—is low in the frontal lobe of major depression patients; additionally, it was lower in severely depressed patients than in mildly depressed patients. These data suggest that depressive states may be associated with lower levels of high phosphorous energy metabolites.

Kato et al. (1994) reported reduction of brain phosphocreatine in bipolar disorder type II—but not in bipolar disorder type I—by the use of 31P-MRS, which was found in the frontal lobes of patients during depressive, manic, and euthymic states. Kato et al. (1995) further noted a lateralized abnormality of high-energy phosphate metabolism in the frontal lobes of patients with bipolar disorder detected by phase-encoded 31P-MRS reporting low CP levels in the left frontal lobe during depressive states. Yildiz et al. (2001) conducted a meta-analysis of 31P-MRS studies in bipolar disorder supporting phospholipid and high-energy phosphate alterations in bipolar disorder that were prima-

rily reflected by increased phosphomonoesters and decreased phospho-creatine in the depressed state, supporting abborent energy metabolism in bipolar illness.

Brain cellular pH was found to be decreased in bipolar disorder and it was suggested as being a state marker of altered brain energy metabolism, probably reflecting mitochondrial dysfunction. Increased lactate levels are generally associated with relatively low pH, and lactate is now also suggested as being involved in brain bioenergetics. Kato et al. (1998) reported decreased intracellular pH in euthymic patients, who are also drug free, whereas pH was normal in manic or depressive states. Hamakawa et al. (2004) reported reduced intracellular pH in the basal ganglia and whole brain measured by 31P-MRS in bipolar disorder.

Dager et al. (2004) studied 32 medication-free patients with bipolar depression or with mixed mood state who showed elevated gray matter lactate and glutamine, glutamate, and y-aminobutyric acid. An inverse correlation between the 17-item Ham-D and white matter creatine (cre-atine and phosphocreatine) was observed in bipolar patients. This implies a shift in energy metabolism from oxidative metabolism to glycolysis, possibly due to mitochondrial alterations.

Implications for Future Treatments

Future treatments of bipolar depression could be based on enhancing brain energy metabolism. Since oral creatine enters the brain and has been shown to raise brain creatine, we are conducting a study of creat-ine in bipolar depression.

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