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Objectives-Bipolar disorder (BPD) affects more than 2 million adults in the USA and ranks among the top 10 causes of worldwide disabilities. Despite its prevalence, very little is known about the etiology of BPD. Recent evidence suggests that cellular energy metabolism is disturbed in BPD. Mitochondrial function is altered, and levels of high-energy phosphates, such as phosphocreatine (PCr), are reduced in the brain. This evidence has led to the hypothesis that deficiencies in energy metabolism could account for some of the pathophysiology observed in BPD. To further explore this hypothesis, we examined levels of creatine kinase (CK) mRNA, the enzyme involved in synthesis and metabolism of PCr, in the hippocampus (HIP) and dorsolateral prefrontal cortex (DLPFC) of control, BPD and schizophrenia subjects. Results-Both CK isoforms were downregulated in BPD. Furthermore, mRNA transcripts for oligodendrocyte-specific proteins were downregulated in the DLPFC, whereas the mRNA for the neuron-specific protein microtubule-associated protein 2 was downregulated in the HIP. Methods-TissueConclusion-Although some of the downregulation of CK might be explained by cell loss, a more general mechanism seems to be responsible. The downregulation of CK transcripts, if translated into protein levels, could explain the reduction of high-energy phosphates previously observed in BPD. © Blackwell Munksgaard, 2006 Bipolar disorder (BPD) is a common and severe mood disorder that affects more than 2 million adults in the USA (1, 2). BPD is associated with increased risk of suicide and a high socioeconomic burden. Although the clinical features of BPD have long been recognized (3), the disease mechanism(s) remain(s) unknown (4), and treatment resistance is high (1, 5).Recent studies suggest altered energy metabolism and mitochondrial pathology in BPD (6, 7). Spectroscopic studies have shown a decrease in both pH and high-energy phosphates, such as phosphocreatine (PCr) and ATP, in the frontal and temporal lobes of bipolar subjects (8-11); postmortem studies in the human hippocampus (HIP) of BPD subjects showed a decrease in the expression of nuclear genes coding for mRNAs of the mitochondrial respiratory chain (12); and studies in lymphoblastoid cell lines showed a downregulation of the mitochondrial complex I subunit gene, NDUFV2 (24-kDa subunit of the mitochondrial NADH:ubiquinone oxidoreductase), and different haplotype frequencies of four polymorphisms in the upstream region of NDUFV2 (13,14).Creatine kinase (CK) is the enzyme responsible for the reversible transfer of the Nphosphoryl group from PCr to ADP to yield ATP and creatine (Cr) (15)(16)(17). In tissues with high energy demands, such as the brain, CK serves two purposes: the first is to shuttle phosphate groups from the site of energy production, the mitochondria, to sites of energy consumption, such as ATP-dependent ion pumps and neurotransmitter transporters in neurons and glia (18). The second function is to retrieve ATP from PCr during periods of intense energ...

Lithium (Li) is frequently used in the treatment of bipolar disorder (BPD), a debilitating condition that is increasingly diagnosed in children and adolescents. Because the symptoms of BPD in children are different from the typical symptoms in adulthood and have significant overlap with other childhood psychiatric disorders, this disorder is notoriously difficult to diagnose. This raises the possibility that some children not affected by BPD are treated with Li during key periods of brain development. The objective of this investigation was to examine the long-term effects of Li on the developing brain via a series of behavioral and molecular studies in rats. Rat pups were reared on Li chow for 3 weeks. Parallel groups were tested while on Li chow or 2 and 6 weeks after discontinuation of treatment. We found increased measures of anxiety-like behavior at all times tested. Gene microarray studies of the amygdala revealed that Li affected the expression of gene transcripts of the synapse and the cytoskeleton, suggesting that the treatment induced synaptic adjustments. Our study indicates that Li can alter the trajectory of brain development. Although the effects of Li on the normal brain seems unfavorable, effects on the abnormal brain cannot be determined from these studies alone and may well be therapeutic. Our results indicate that Li administration to the normal brain has the potential for lasting adverse effects.