Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research


Magnetic resonance spectroscopy (MRS) affords a noninvasive window on in vivo brain chemistry and, as such, provides a unique opportunity to gain insight into the biochemical pathology of bipolar disorder. Studies utilizing proton (1H) MRS have identified changes in cerebral concentrations of N-acetyl aspartate, glutamate/glutamine, choline-containing compounds, myo-inositol, and lactate in bipolar subjects compared to normal controls, while studies using phosphorus (31P) MRS have examined additional alterations in levels of phosphocreatine, phosphomonoesters, and intracellular pH. We hypothesize that the majority of MRS findings in bipolar subjects can be fit into a more cohesive bioenergetic and neurochemical model of bipolar illness that is both novel and yet in concordance with findings from complementary methodological approaches. In this review, we propose a hypothesis of mitochondrial dysfunction in bipolar disorder that involves impaired oxidative phosphorylation, a resultant shift toward glycolytic energy production, a decrease in total energy production and/or substrate availability, and altered phospholipid metabolism.


Bipolar disorder remains a prevalent and serious psychiatric disorder.1 Although a number of pharmacological treatments for bipolar disorder exist, including mood stabilizers such as lithium and valproic acid, none have emerged as singularly effective against all aspects of the illness. Furthermore, the large range of available remedies implies a poor understanding of the underlying pathophysiology of bipolar disorder.

Magnetic resonance spectroscopy (MRS) affords a noninvasive window on in vivo brain chemistry and, as such, provides a unique opportunity to gain insight into the biochemical pathology of bipolar disorder. Studies utilizing proton (1H) MRS have identified changes in cerebral concentrations of N-acetyl aspartate (NAA), glutamate/glutamine (Glx), choline (Cho)-containing compounds, myo-inositol (mI), and lactate in bipolar subjects compared to normal controls, while studies using phosphorus (31P) MRS have examined additional alterations in levels of phosphocreatine (PCr), phosphomonoesters (PMEs), and intracellular pH (pHi). However, published reports have generally focused on only one such abnormality at a time, and there remains a lack of coherent models to unify this wide variety of biochemical findings.

It is our hypothesis that the majority of MRS findings in bipolar subjects can be fit into a more cohesive bioenergetic and neurochemical model of bipolar illness that is both novel and yet in concordance with findings from complementary methodological approaches. In this review, we propose a hypothesis of mitochondrial dysfunction in bipolar disorder that involves impaired oxidative phosphorylation, a resultant shift toward glycolytic energy production, a decrease in total energy production and/or substrate availability, and altered phospholipid metabolism (Figure 1). This new understanding of bipolar illness as a matter of possible mitochondrial dysfunction has the potential both to lead to more sophisticated diagnostic techniques and to point toward innovative and hopefully more effective treatments.

Figure 1

MRS indications of mitochondrial dysfunction in bipolar disorder. Summary of recent MRS research on metabolite alterations in bipolar subjects and how these results may be integrated into a hypothesis of mitochondrial dysfunction.

Reduced N-acetyl-aspartate in bipolar disorder: marker of mitochondrial dysfunction

Some of the earliest MRS findings in support of a mitochondrial dysfunction hypothesis of bipolar disorder are the repeated observations of decreased cerebral NAA in bipolar subjects compared to normal controls (Table 1). As the most prominent metabolite peak on the 1H spectrum, NAA levels are typically reported as a ratio using the total creatine signal (creatine plus phosphocreatine, Cr + PCr) as an internal reference peak (NAA/Cr + PCr).2, 3 In healthy individuals, NAA is present in the brain at concentrations of 8–10 mmol/l,4 and thus follows glutamate as the second most abundant amino acid in the central nervous system.5 After early research with rat brain mitochondria suggested that NAA is of mitochondrial origin,6 Truckenmiller et al7 demonstrated that NAA is synthesized in mitochondria by the membrane-bound enzyme L-aspartate N-acetyltransferase, a catalyst that is found only in the brain (Figure 2). Further studies also indicated that the synthesis of NAA is energy dependent, and stimulated by adenosine diphosphate (ADP).6

Table 1 Published MRS research on NAA/Cr + PCr and NAA levels in bipolar subjects
Figure 2

Aspects of mitochondrial function visible by MRS. A summary of mitochondrial function in the neuron. Compounds visible by MRS are identified by colored borders.

Despite its prevalence in the human brain, the exact function of NAA remains unclear. Some studies have indicated that NAA may play a role in the provision of carbon for lipid and myelin formation,8 and other research suggests that NAA may be instrumental in protecting neurons against osmotic stress.8, 9 It has also been suggested that NAA may serve as a readily available precursor of N-acetyl aspartyl glutamate (NAAG), a molecule with neurotransmitter-like properties.10 Most recently, however, Madhavarao et al11 have proposed a model in which the synthesis of NAA is an important component of the ‘mini citric acid cycle.’ In this process, the extra demand for ATP in neurons is largely met by the oxidation of glutamate via the aspartate aminotransferase pathway. By converting one of the products of this cycle, aspartate, into NAA, NAA biosynthesis is thought to help steer the reaction toward continuing energy production. Additionally, NAA is able to substitute for citrate as an acetate carrier to the cytoplasm, since citrate is not produced during the mini citric acid cycle. In this way, NAA is hypothesized to play an integral role in the energetics of neuronal mitochondria (Figure 2).11

Consequently, although reductions in NAA concentration were formerly thought to indicate neuronal death,12 recent research has suggested that decreased levels of NAA are more accurately consistent with impaired mitochondrial energy production.8, 13 For example, although traumatic brain injury (TBI) is associated with immediate reductions in NAA, several studies have reported that these levels appear to recover significantly with time, which could not occur if NAA levels were decreased by cell death alone.13, 14 In fact, research on cerebral injury by Demougeot et al15 has indicated that cellular dysfunction can actually cause greater measurable reductions in NAA than neuronal loss. Abnormally low ratios of NAA/Cr + PCr have been observed in patients with a number of mitochondrial encephalomyopathies,16 and studies using mitochondrial respiratory chain inhibitors have also shown that reductions in NAA are correlated with decreases in O2 consumption and ATP production.7, 14, 17 When taken together, these studies suggest that NAA levels are closely related to mitochondrial energy metabolism, and thus may serve as a measure of mitochondrial function.8, 17, 18

A number of 1H MRS studies have demonstrated reduced NAA levels in patients with bipolar disorder compared to normal controls2, 5, 19, 20, 21 (Table 1). Although the use of Cr as a reference peak has been criticized due to observations of alterations in this signal following treatment with lithium and/or sodium valproate,22 findings of decreased NAA/Cr + PCr ratios in bipolar subjects have been corroborated by observations of similarly significant reductions in NAA levels measured relative to voxel H2O levels.5, 19 Furthermore, a number of studies have noted negative correlations between NAA/Cr + PCr or NAA levels and illness duration,2, 5, 20 which implies that reductions in NAA levels in bipolar subjects may become more pronounced with time. If NAA concentration is interpreted as a measure of mitochondrial function, the collected findings of decreased NAA in bipolar subjects compared to normal controls serve as support for a theory of mitochondrial dysfunction in bipolar illness.

Researchers have also investigated whether observations of reduced NAA in bipolar subjects may be due to various treatments for the disorder, in particular lithium administration. However, several trials have suggested that lithium administration actually increases NAA levels in the brain23, 24, 25 (Table 2). A number of 1H MRS studies have reported increased NAA/Cr + PCr and absolute NAA levels associated with lithium administration not only in bipolar subjects,23, 24, 25 but also in healthy controls.24 Even in contrast with these results, studies led by Brambilla et al26 in healthy individuals and by Friedman et al27 in bipolar subjects have found that lithium administration does not appear to be associated with significant differences in NAA concentration. Thus, there remains a lack of MRS evidence that lithium administration is associated with the reduced NAA levels repeatedly observed in bipolar subjects. Consequently, it is more probable that these reports may reflect an underlying—and possibly mitochondrial—pathophysiology to bipolar illness.

Table 2 Published MRS research on NAA/Cr + PCr and NAA levels in bipolar subjects: effect of Li administration

It is important to note that decreased cerebral NAA levels in bipolar patients have not been observed in all MRS investigations. Unaltered NAA levels in bipolar subjects have been observed by Ohara et al28 in the lenticular nuclei, by Hamakawa et al29 in the frontal lobes, and by Castillo et al30 in bipolar children (Table 1). However, seven of the 10 bipolar subjects studied by Ohara et al28 and 13 of the 23 studied by Hamakawa et al29 were undergoing lithium treatment, while the children studied by Castillo et al30 were only given a 1 week medication washout period. Since there is evidence that lithium administration may increase NAA levels in bipolar subjects,24 it is possible that the results of these three studies were confounded by the history of lithium treatment in their subject populations. Additionally, a further seven of the subjects in the study by Hamakawa et al29 were receiving other pharmacological treatments; only three bipolar subjects were effectively medication free. Consequently, it is also possible that the unaltered NAA levels observed in these studies were due to the normalizing effects of these unidentified treatments.

In contrast with the majority of published MRS research on bipolar disorder, one study by Deicken et al31 reported increased thalamic NAA in male bipolar subjects compared to normal controls. However, all but two of the bipolar subjects in this study were taking maintenance medications such as lithium and divalproex, which may have contributed to the observed increases in NAA.24, 31 Furthermore, since positron emission tomography (PET) studies have reported increases in the concentration of thalamic monoaminergic synaptic terminals in bipolar patients,32, 33 it is possible that Deicken et al's31 observations of increased thalamic NAA were due to increased synaptic density rather than metabolic abnormality. Similarly, with regard to the findings of Ongur et al34 of regionally reduced glial cell number and density in patients with bipolar disorder, it is also possible that Deicken et al's31 findings may be due to glial cell hypoplasia in the thalamus. Further studies are required to fully evaluate these possibilities.

As described, findings of decreased NAA in bipolar disorder have been replicated across numerous subject groups by a variety of different research teams (Tables 1 and 2). Together, these studies provide intriguing support for the possibility of mitochondrial involvement in the pathophysiology of bipolar disorder.

Mitochondrial dysfunction in bipolar disorder: evidence for a glycolytic shift

MRS research has also provided insight into the possible nature of mitochondrial impairment in bipolar disorder. Specifically, findings of both decreased pHi and increased levels of lactate in bipolar subjects suggest a shift away from oxidative phosphorylation toward glycolysis, thus reducing efficiency and reducing total energy output (Figure 2).

Decreased intracellular pH in bipolar disorder

As reported by Kato and co-workers, at the present time, reduced pHi has only been observed in pathological states that are known to arise from ischemic insult to the brain, including white matter hyperintensities,35 acute stroke,36 and subarachnoid hemorrhage.37 Additionally, recent research has confirmed that mitochondrial dysfunction plays a central role in ischemic injury, especially in cases of reperfusion following cerebral ischemia.38, 39, 40, 41, 42, 43, 44 Consequently, findings of decreased pHi in bipolar subjects compared to normal controls suggest that impaired mitochondrial function may be an integral component of bipolar illness.

31P MRS research has not only consistently reported reduced pHi in bipolar subjects, but has also suggested that this alteration may be state dependent (Table 3). Several studies have found significantly reduced pHi in both the basal ganglia45 and whole brain45, 46, 47, 48, 49 of bipolar subjects in the euthymic state. However, some of these same studies also indicated that bipolar subjects in the depressed47 or manic states46 had significantly higher pHi than euthymic patients. Furthermore, since pHi has been shown to be significantly correlated with duration of lithium treatment,50 and lower pHi to be associated with a better response to lithium,51 it is unlikely that reduced pHi in euthymic bipolar subjects is due to lithium administration. Instead, Kato and Kato52 have hypothesized that the decreased pHi observed in euthymic bipolar subjects is a trait of the illness itself. Specifically, these researchers have suggested that manic and depressive states may be at least partially caused by the brain's attempts to correct this pH imbalance by causing an overactivation of monoaminergic systems, which has been known to increase pHi at least in hippocampal neurons.53 Such a theory would also thus explain the more normalized pHi of bipolar patients in the manic and depressive states.52

Table 3 Published MRS findings of reduced pHi in bipolar subjects

Elevated lactate in bipolar disorder

Reductions in cerebral pHi such as those observed in bipolar subjects have also frequently been linked to increased levels of lactate, a condition that is known to result from mitochondrial dysfunction. When mitochondrial function is inhibited, rendering the respiratory chain of cellular metabolism unavailable, the only mode of energy production available to the cell is anaerobic glycolysis. During this process, pyruvate is used as a hydrogen acceptor to recover NAD from NADH, thus converting pyruvate into lactate (Figure 2). An increase in lactate concentration therefore suggests an increase in the rate of glycolysis, and consequently also implies an inhibition of the mitochondrial oxidative phosphorylation process; lactate is known to accumulate only when oxidative phosphorylation is unable to meet energy requirements and the cell is forced to rely on the glycolytic process.54 As a result, elevated lactate levels are commonly used to diagnose and confirm mitochondrial disorders, particularly those that affect the central nervous system.16, 55, 56, 57 Additionally, animal studies have confirmed that significant increases in brain lactate, as well as decreases in pHi, occur as a result of induced, isolated mitochondrial failure.58 In one study, in which Clausen et al58 used cyanide to induce mitochondrial failure in the feline brain, an analysis of corresponding extracellular lactate concentrations and brain tissue pH suggests a logarithmic relationship between the two measurements (pH=7.949–0.138(ln[Lac]), p(b0)=0.0258, p(b1)=0.1921). Thus, it is possible that seemingly distinct findings of increased lactate and decreased pHi are linked by a common cause of mitochondrial dysfunction.

There have been few MRS studies of lactate in bipolar subjects to date, most likely due to the relatively low concentration of lactate in the human brain (<0.7 mM) as well as difficulties in distinguishing the lactate signal from that of overlapping lipids and macromolecules.59 However, a recent 1H MRS study by Dager et al60 found elevated lactate levels in the gray matter of medication-free bipolar subjects when compared to normal controls. Furthermore, according to the logarithmic relationship suggested by Clausen et al's58 data of induced mitochondrial failure in felines, the 0.22 mM difference in lactate concentration reported by Dager between bipolar subjects and controls would correspond to a pH difference of approximately 0.016, which is the exact pH difference observed between these two populations in the most recent study of cerebral pHi in bipolar disorder, published by Hamakawa et al.45 These findings thus suggest that the reduced pHi observed in bipolar subjects may be the result of increased levels of lactate, which is in direct concordance with the hypothesis of a glycolytic shift in bipolar disorder.

Alterations in the glutamate/glutamine cycle: possible applications to bipolar disorder

Further insight into the possibility of a glycolytic shift in bipolar disorder has been provided by 1H MRS studies of the glutamate/glutamine cycle in bipolar subjects. After glutamate is released from nerve terminals, it is taken up by surrounding glial cells and converted to glutamine. This glutamine is then released by the glia, taken up again by the neurons, and converted back into glutamate for further release into the synaptic cleft. A number of investigations have reported increased levels of Glx, the combined signal arising primarily from glutamate and glutamine, in the frontal lobes, basal ganglia, left dorsolateral prefrontal cortex (DLPFC), and global gray matter of drug-free bipolar subjects30, 60, 61 (Table 4). Although the Glx peak is difficult to separate into glutamate and glutamine at the relatively low magnetic field strengths used in human studies,62 an increased Glx signal is likely to imply alterations in the overall glutamate/glutamine cycle.

Table 4 Published MRS research on glutamate/glutamine (Glx) levels in bipolar subjects

Findings of increased Glx in bipolar subjects suggest that the hypothesized glycolytic shift underlying the pathology of bipolar disorder may be linked to some degree of glutamate-induced neuronal hyperactivation. As suggested by Dager et al60, increased levels of the excitatory neurotransmitter glutamate in the brain would place abnormally large demands on neuronal energy metabolism, similar to but less severe than the excitotoxic mechanism of cell death that occurs during stroke. If cells are unable to meet such increased energy requirements through mitochondria-based oxidative phosphorylation, rates of glycolysis would increase, thus causing the increased levels of lactate and decreased pHi observed in studies of bipolar disorder60 (Table 3). However, further research is needed to confirm this particular aspect of the mitochondrial dysfunction hypothesis of bipolar disorder.

Relatively few MRS studies have examined the effect of treatment on Glx levels in bipolar patients. However, work by Friedman et al27 has indicated that lithium administration may have a strong normalizing effect upon Glx levels in bipolar patients, thus precluding any findings of significant differences between bipolar subjects taking lithium and healthy controls. Since the majority of research subjects with bipolar disorder are required to continue maintenance medications for ethical reasons, it is likely that more universal observations of increased Glx in bipolar patients are confounded by the prevalence of lithium and other pharmacological treatments for the illness.

Interestingly, parallel findings of increased glutamate, glutamine, and lactate have lent support to theories of mitochondrial dysfunction in Huntington's disease (HD).63 Recent research on HD, an autosomal dominant, progressively neurodegenerative disorder, has led to both excitotoxic and energy metabolism theories of pathophysiology.64 Preclinical studies have suggested that HD can be mimicked in animals with the intrastriatal injection of certain excitotoxins that activate the N-methyl-D-aspartate (NMDA) glutamate receptor, as well as by injection of toxins that block mitochondrial oxidative phosphorylation.65, 66 Similar to studies of bipolar disorder, 1H MRS investigations of HD have observed both elevated Glx/Cr + PCr and lactate in the basal ganglia of HD patients when compared to normal controls64, 67 In fact, a recent study by Jenkins et al63 observed significantly increased levels of glutamine in a transgenic mouse model of HD, and described these results as ‘evidence of a profound metabolic defect.’ It is thus possible that similar MRS findings in bipolar subjects may indicate a similar pathology of excitotoxicity and mitochondrial dysfunction.

Decreased high-energy compounds in bipolar disorder: evidence for impaired energy production

In continuing support of the hypothesis of a glycolytic shift in bipolar disorder, measurements of PCr, the most prominent peak on the 31P MRS spectrum,68 have also been found to be altered in bipolar subjects (Table 5). Acting as a reservoir for the generation of ATP, the high-energy compound PCr is synthesized from Cr and ATP by the catalyzing agent creatine kinase (CPK) (Figure 2).69 During periods of acute neuronal activity, as molecules of ATP are utilized by Na+/K+ ATPase, PCr is rapidly broken down in order to maintain the overall concentration of ATP.69, 70 Although short-term decreases in PCr concentration thus indicate immediate cell activity, as can be observed in episodes of photic stimulation,71 long-term abnormalities in PCr concentration generally reflect much larger alterations in cellular metabolism, and in particular an insufficient supply of the ATP needed for normal cellular function.72 In this way, continually decreased levels of PCr are suggestive of hypometabolism, possibly due to mitochondrial dysfunction, and may directly indicate a shift in energy production toward the less-efficient glycolysis.72, 73 Persistently low brain PCr values have been found in patients with a number of mitochondrial disorders, including mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), Leigh's disease, progressive external opthalmoplegia (PEO), and Leber's hereditary optic atropy.74, 75 Reduced PCr concentrations have also been reported in migraine, which has been postulated to be associated with abnormal mitochondrial function.76, 77

Table 5 Published MRS findings of decreased PCr concentration in bipolar subjects

Several 31P MRS studies have suggested a connection between decreased levels of PCr and bipolar disorder (Table 5). A study by Kato et al78 of bipolar patients across the full range of mood states (depressed, manic, and euthymic) observed significantly reduced PCr in the left frontal lobe of depressed patients and in the right frontal lobe of manic and euthymic patients, compared to healthy controls. Additionally, PCr levels were found to be significantly and negatively correlated with Hamilton Depression Rating Scale (HDRS) scores.78 A similar study by Kato et al,49only 1 year earlier, also reported significantly decreased whole brain PCr in bipolar II patients, but, interestingly, not bipolar I patients, relative to normal controls.

However, MRS research in rat brains has indicated that chronic administration of either lithium or sodium valproate can cause a significant decrease in the 1H Cr + PCr signal.22 Consequently, it is possible that the decreased PCr levels observed in these studies were due to the pharmacological effects of these treatments. Of the 40 bipolar patients observed in Kato et al's78 1995 study, 24 were reported to be taking lithium, and an additional six to be using other therapies. Similarly, the bipolar II patients in Kato et al's49 1994 study were permitted the use of a range of medications. Nonetheless, these alterations of PCr in bipolar disorder are consistent with some degree of mitochondrial involvement in both the illness and its treatment.

Impaired phospholipid metabolism in bipolar disorder

Further support for a theory of mitochondrial dysfunction in bipolar disorder has arisen from MRS studies of phospholipid metabolism in bipolar subjects. In a normal brain cell, the synthesis and maintenance of the cell membrane require between 10 and 15% of net brain ATP production (Figure 3).79 If less energy is produced in the cell overall, it is likely that aspects of phospholipid metabolism, including de novo phospholipid biosynthesis, would also be impaired. Several MRS studies have indicated that phospholipid metabolism is indeed abnormal in bipolar patients, as evidenced by alterations in levels of Cho, mI, inositol monophosphates, and PMEs (Tables 6, 7, 8, 9 and 10). Accordingly, we hypothesize that these alterations are the direct result of energy shortages caused by mitochondrial dysfunction.

Figure 3

Aspects of phospholipid metabolism visible by MRS. A partial representation of phospholipid metabolism in the neuron. Compounds visible by MRS are identified by patterned borders. Processes requiring ATP are marked with solid arrows.

Table 6 Published MRS research on Cho/Cr + PCr and Cho levels in bipolar subjects
Table 7 Published MRS research on Cho/Cr + PCr and Cho levels in bipolar subjects: effect of Li administration
Table 8 Published MRS research on mI levels in bipolar subjects
Table 9 Published MRS findings on PME levels in bipolar subjects: bipolar euthymic vs normal controls
Table 10 Published MRS findings on PME levels in bipolar subjects: bipolar depressed/manic vs bipolar euthymic

Elevated total choline in bipolar disorder: evidence for impaired membrane metabolism

One of the most frequently replicated MRS findings in bipolar disorder is that of an increased Cho signal (Table 6). This signal, often referred to as ‘total Cho,’ ‘Cho-containing compounds,’ or ‘cytosolic Cho,’ consists primarily of phosphocholine (PC) and glycerophosphocholine (GPC), with less than 5% of the signal arising from free Cho itself (Figure 3).59, 80 The total observable Cho concentration in the human brain has been measured at 1–2 mM, with approximately 0.6 mM of PC and 1.0 mM of GPC.81, 82, 83, 84

Cho is required for the synthesis of both the neurotransmitter acetylcholine and the phospholipid phosphatidylcholine (Figure 3). Although acetylcholine is produced only by cholinergic neurons, phosphatidylcholine is produced in all cells as a major membrane constituent.80, 85 Consequently, although small changes in the Cho signal may arise from shuttling between the intracellular and extracellular pools, larger alterations in the Cho signal are generally associated with alterations in membrane synthesis and composition.59, 80 Significant increases in the Cho resonance are commonly observed in neurodegenerative disorders such as Alzheimer's disease and multiple sclerosis (MS), as well as cases of ischemia and head trauma, presumably due to the liberation of Cho-containing compounds during membrane breakdown.54, 59, 86 Increased Cho signals can also be associated with cancer, most likely due to the increased cellular density found in tumors.54, 87

A number of studies have suggested that increased Cho levels may be linked to mitochondrial dysfunction. Perhaps most notably, a 2000 study by Farber et al88 sought to test the hypothesis that the increased Cho signal observed in Alzheimer's disease is due to accelerated phospholipid turnover ultimately caused by mitochondrial dysfunction. Normal brain cells were treated with the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP) in the presence of glucose, leaving glycolysis as the only mode of energy production. Enhanced phospholipid turnover was confirmed by the observation of an apparent acceleration of the first two enzymatic steps of phosphatidylcholine synthesis, which resulted in an accumulation of CDP-choline and subsequent lack of diacylglycerol, as well as an increased accumulation of the membrane breakdown product GPC.88 Although further research is required to elucidate the exact mechanisms that underlie these findings, Farber et al88 did conclude that ‘inhibitors of mitochondrial oxidative phosphorylation cause a remarkable acceleration of phosphatidylcholine turnover.’

Several 1H MRS studies have reported elevated Cho/Cr + PCr ratios and Cho concentrations in bipolar patients compared to healthy controls, particularly in the basal ganglia (Table 6). However, additional MRS investigations of both the hippocampus,5, 21 and DLPFC2 have reported finding no significant differences in Cho/Cr + PCr or absolute Cho levels between bipolar subjects and controls. Studies of children with bipolar disorder have similarly noted no significant differences in Cho concentrations between bipolar and control subjects.20, 30 Nonetheless, it remains possible that findings of increased Cho concentration in bipolar subjects may be indicative of impaired phospholipid metabolism and thus also of mitochondrial dysfunction.

Although studies of human erythrocytes have indicated that lithium exerts a strong and specific inhibitory effect on human Cho transport and, thus, substantially elevates erythrocyte Cho concentrations,89 several MRS studies have reported little to no association between elevated brain Cho concentration and lithium treatment (Table 7). A study by Sharma et al23 reported finding higher Cho/Cr + PCr in the basal ganglia region of bipolar subjects taking lithium compared to normal controls, but a more recent study by Wu et al90 contradicted these results by reporting that lithium-treated bipolar patients had significantly lower Cho/Cr + PCr in the temporal lobe than healthy control subjects. Consequently, if lithium administration does exert a significant effect on brain Cho metabolism, this effect remains to be clarified.

Increased myo-inositol in bipolar disorder: further evidence for impaired membrane metabolism

1H MRS research has also reported alterations of the mI signal in bipolar subjects (Table 8). This signal, one of the three most intense resonances in 1H MRS, consists primarily of the cyclic sugar alcohol mI, with minor contributions (less than 5%) from various inositol sugar phosphates and glycine (Figure 3).59 In a healthy adult brain, mI concentrations range from 4 to 8 mmol/kgww,80 but these levels are known to fluctuate more than any other major compounds in the 1H spectrum; mI concentrations may reach three times the normal adult values in newborn infants and hypernatremic states and have been observed to drop to almost zero in cases of hepatic encephalopathy.91

The function of cerebral mI is not entirely understood. mI has been identified as an essential requirement for cell growth, an osmolite, a storage form for glucose, and a possible glial marker.92, 93 However, mI is widely recognized for its role as precursor to the phospholipid membrane component phosphatidylinositol and as a substrate for the phosphoinositide second-messenger system.59, 91, 94 Consequently, alterations in mI levels have the potential to reflect abnormalities in both membrane metabolism and intracellular signaling mechanisms.59 Decreased levels of mI have been observed in cases of chronic hepatic encephalopathy, hypoxic encephalopathy, stroke, tumor, and hyponatremia,91, 95 while increased concentrations have been observed in conditions such as Alzheimer's disease, diabetes mellitus, recovered hypoxia, hyperosmolar states, and the neonatal brain.91 Concerning membrane metabolism in particular, abnormally high levels of mI have also been associated with cases of MS plaque, HIV infection, and metachromatic leukodystrophy, and these findings have led some researchers to label mI as a breakdown product of myelin.91

In the study of affective disorders, mI has most often been examined with regard to its apparent involvement in the mechanism of action of lithium. A number of studies have demonstrated that at therapeutically relevant concentrations, lithium is a potent, noncompetitive inhibitor of inositol-1-phosphatase, an enzyme that normally serves to recycle inositol sugar phosphates back into the free inositol pool. This inhibition leads to an accumulation of inositol-1-phosphate (a component of the PME signal in 31P MRS) and a simultaneous decrease in levels of mI.96, 97, 98 Since sufficient supplies of mI are necessary both for the re-synthesis of certain membrane components and to maintain the phosphoinositide intracellular signaling system, it has been suggested that lithium achieves its effects through this depletion of the free inositol pool.99, 100

Several MRS studies have supported this theory with findings of decreased mI levels in subjects undergoing acute lithium administration (Table 8). As lithium continues to be one of the most common and effective pharmacological treatment for bipolar disorder, MRS measurements of mI levels in bipolar subjects must be considered with lithium administration as a confounding factor; observations of both increased or decreased mI concentrations (as well as those of altered PMEs, due to the possible accumulation of inositol-1-phosphate; see the following section) in bipolar individuals may be due to the effects of lithium treatment rather than the disease itself.

Importantly, however, it is also possible that the effect of lithium on inositol and PME levels may not remain constant with continuous administration. Although several studies have demonstrated that acute lithium administration does initially cause a large increase in PME levels (attributed to increased inositol-1-phosphate) and a decrease in mI,101 a 31P study by Renshaw et al102 in cats observed that such increased PME levels subsequently decline after 3 weeks of lithium administration. Consequently, since lithium is frequently used as a long-term treatment regimen for bipolar disorder, it is possible that PME levels in individuals with a history of lithium treatment may have normalized after an initial increase. For example, a 2002 study by Silverstone et al103 found no differences in mI or PME concentrations between bipolar patients under chronic lithium treatment and normal controls, and thus suggested that long-term lithium treatment may normalize the phosphoinositide cycle of individuals with bipolar disorder. Similarly, a study by Brambilla et al26 of healthy controls before and after lithium administration found no significant differences in mI concentration after 4 weeks of lithium treatment.

Because of the widespread use of lithium, there are few MRS data from bipolar subjects that can be analyzed without regard to its effects (Table 8). However, one study by Davanzo et al104 did report increased mI/Cr + PCr levels in the anterior cingulate of children and adolescents with bipolar disorder who had never been treated with lithium, when compared to normal controls. Sharma et al23 also reported findings of increased inositol in the basal ganglia of bipolar patients vs comparison subjects, although patients in this study were not lithium free. Additionally, a study by Winsberg et al2, in which bipolar patients were reportedly drug free for at least 2 weeks before examination, found a nearly significant trend (P=0.06) toward higher levels of mI/Cr + PCr in the right DLPFC of bipolar subjects vs controls. Although the confounding effects of lithium cause difficulty in the interpretation of mI levels in bipolar patients, it may yet be argued that elevated mI levels suggest an increase in membrane breakdown and inhibition of membrane metabolism in bipolar disorder that may be caused by mitochondrial dysfunction.

Altered phosphomonoesters: evidence for state-dependent abnormalities of membrane metabolism in bipolar disorder

Interestingly, 31P MRS studies of PME levels in bipolar subjects have indicated that some abnormalities in bipolar membrane metabolism may be state dependent, specifically differing during periods of euthymia, mania, and depression (Tables 9 and 10). Similar to the multicomponent Cho signal, the PME signal observed by 31P MRS is the combined product of multiple compounds. In vitro and in vivo assays have determined that the most abundant components of the PME signal are the membrane precursors phosphoethanolamine (PE) and PC, but the signal also includes various sugar and inositol phosphates (Figure 3).105, 106

Because of the multiple membrane metabolites represented in this signal, alterations in PME levels are thought to reflect concurrent alterations in phospholipid membrane metabolism. Specifically, an increase of the PME peak has been suggested to indicate an increased rate of membrane phospholipid turnover.94 Increased PME levels have been observed in the neonate brain, tumors,36, 107 and the regenerating liver.108 In contrast, decreased PME levels, possibly reflecting a stagnation or halt of membrane synthesis, have been associated with chronic cerebral infarction,35 severe demyelinating disorders,12 anorexia nervosa,109 and schizophrenia (particularly the negative symptoms thereof).110, 111

In consideration of the previously noted 1H MRS findings of increased Cho and mI in bipolar subjects, it is important to recognize the partial inclusion of these metabolites within the PME peak. Specifically, alterations in the Cho or inositol pathways may also be reflected in alterations of the PME signal, since this peak includes both PC (30%) and inositol monophosphates (less than 5%).112 However, since these various metabolites are only components of the larger PME resonance, PME measurements may provide independently significant insights into phospholipid metabolism.

Unlike many MRS findings in bipolar patients, research on PME levels in bipolar disorder has indicated the possibility of state-dependent changes in concentration. Specifically, while several studies have observed increased PME signals in bipolar patients in the manic or depressed states compared to those in euthymia, a number of investigations have reported decreased PME levels in euthymic bipolar subjects compared to normal controls (Table 9). Many of these findings were also evaluated in a meta-analysis of 31P MRS research on bipolar disorder by Yildiz et al113, which confirmed reports of significantly lower PME levels in euthymic bipolar subjects vs normal controls. One 1998 study by Kato et al48 did not find a difference in PME levels between euthymic bipolar subjects and controls, but had an extremely small sample group of only seven subjects. It thus remains possible that observations of decreased PME levels in euthymic bipolar patients reflect a general inhibition of membrane synthesis that may be related to mitochondrial impairment.

However, when euthymic bipolar subjects are compared to others in the depressed or manic states, MRS research has illustrated a considerably different picture (Table 10). Individual studies by Kato et al have reported significantly elevated PME levels in both depressed47 and manic46 bipolar subjects compared to those in euthymia, and the later meta-analysis by Yildiz et al113 also found significantly increased PME levels in depressed vs euthymic bipolar subjects. Like measurements of altered pHi in bipolar subjects (Table 3), these state-dependent abnormalities in PME concentration may be the result of the brain's attempts to normalize membrane metabolic processes that are impaired due to mitochondrial dysfunction.

As discussed in the previous section, numerous studies have indicated that acute lithium administration is associated with a large increase in PME levels,101 although it has also been reported that these levels later normalize with continued lithium treatment.102 Importantly, however, a dual lithium and 31P MRS study by Kato et al46 found that PME levels in bipolar patients in both the euthymic and manic states did not correlate with brain lithium concentrations. Additionally, in 1991, Kato et al114 found PME levels in manic bipolar patients on lithium to be significantly greater than those of euthymic bipolar patients who were also on lithium. Consequently, Kato's team was led to conclude that ‘PME levels in the manic state cannot be attributed solely to elevation of brain lithium concentrations.’46 Instead, observations of both increased and decreased PME levels in bipolar subjects may yet signify abnormal membrane metabolism and thus further support the hypothesis of mitochondrial dysfunction as an underlying pathology of bipolar illness.

Connection to other findings in bipolar research

Although this review has focused on MRS findings in particular, the hypothesis of mitochondrial dysfunction in bipolar disorder is also supported by research using other methodologies. For example, the possibility of mitochondrial dysfunction can be easily linked to the previously developed and more traditional hypotheses of intracellular signaling alterations as key aspects of bipolar pathophysiology.1 A number of studies of bipolar subjects have reported various abnormalities of second-messenger systems, including alterations in cyclic AMP (cAMP) signaling,115 protein kinase C (PKC) signaling,116 and the overall phosphatidylinositol pathway (reviewed by Soares and Mallinger117). In addition, studies have consistently reported that agonist-stimulated calcium response, an important factor in intracellular second-messenger systems, is enhanced in platelets in patients with bipolar disorder (reviewed by Yamawaki et al118). Given that recent research has demonstrated the important role of mitochondria in sequestering increased intracellular calcium caused by agonist stimulation (reviewed by Simpson and Russell119), it is possible that the mitochondrial dysfunction suggested by MRS research in bipolar disorder is directly related to these previously observed alterations of calcium response and intracellular signaling systems in bipolar patients.

The mitochondrial dysfunction hypothesis of bipolar disorder may also account for the repeated indications of altered cerebral metabolism observed in functional studies of bipolar patients. A number of PET studies have demonstrated that cerebral glucose metabolic rates are significantly decreased in bipolar subjects in depressed or mixed mood states.120, 121, 122, 123, 124, 125 Additional studies have reported that these low metabolic rates also tend to increase with symptom remission126 or a shift to a more euthymic or hypomanic state.125 PET studies of bipolar individuals in the manic state have reported decreased regional cerebral blood flow (rCBF) in the right ventral temporal lobe,127 orbitofrontal cortex,128 and frontal regions compared to normal controls,129 although a 2000 study by Blumberg et al130 found manic patients to have significant higher rCBF in the left dorsal anterior cingulate cortex (ACC) and left head of the caudate when compared to a separate sample of euthymic bipolar patients. Although PET research cannot identify the etiology of these metabolic differences in bipolar patients, it is possible that they are related to the mitochondrial dysfunction suggested by MRS studies.

Furthermore, investigations of mitochondrial genetics have also found significant evidence of abnormal mitochondrial function in bipolar disorder. Using a quantitative polymerase chain reaction (PCR) method, a 1997 study by Kato et al131 found a significantly higher ratio of deleted to wild-type mitochondrial DNA (mtDNA) in the cerebral cortex of patients with bipolar disorder compared to age-matched controls. After 3 years, Kato et al also reported a significantly higher rate of the 5178C mtDNA genotype, known to be associated with an increased risk and earlier onset of both Alzheimer's and Parkinson's disease,132 in bipolar patients compared to controls.133 In addition, bipolar patients with the 5178C genotype exhibited significantly lower brain pHi than patients with the 5178A genotype,133 which suggests a possible connection between abnormal mtDNA and the reduced pH levels consistently reported in bipolar patients (Table 3). Finally, in a 2004 study of mRNA expression in the hippocampus of patients with bipolar disorder and schizophrenia compared to healthy controls, Konradi et al134 found bipolar subjects to have significantly decreased expression of nuclear messenger RNA coding for mitochondrial proteins. Specifically, patients with bipolar disorder were characterized by ‘a pronounced and extensive decrease in the expression of genes regulating oxidative phosphorylation and the ATP-dependent process of proteasome degradation.’134 Especially when viewed in light of the MRS evidence presented in this review, these findings considerably strengthen the hypothesis of mitochondrial dysfunction in bipolar disorder.


Although MRS research on bipolar disorder, to date, has largely focused on individual brain metabolite abnormalities, it is our hypothesis that the compilation of these single-compound findings illustrates an intriguing pattern of mitochondrial dysfunction in bipolar illness (Figure 1). The integration of such a large and seemingly disparate collection of MRS findings in bipolar subjects into a single theory of mitochondrial dysfunction has enormous potential for advancing the study of bipolar illness, particularly in terms of treatment. Investigations of mitochondria-based neurological disorders, including HD, Parkinson's disease, amyotrophic later sclerosis (ALS), and mitochondrial cytopathies, have led to the development of a number of therapies that target cellular energy dysfunction.135 If mitochondrial dysfunction is involved in its underlying pathology, such therapies may also prove beneficial in the treatment of bipolar disorder. Studies of HD, an illness with an MRS profile similar to that of bipolar disorder (increased concentrations of lactate, glutamate, and Cho, as well as decreased NAA levels136), have found that Cr supplementation in particular can significantly increase brain concentrations of Cr and ATP to normal levels, thus exerting a neuroprotective effect and slowing the process of brain atrophy.137, 138 Additional studies of Parkinson's disease and TBI have also investigated the potential use of compounds that may improve cellular energy function, such as coenzyme Q10, Gingko biloba, nicotinamide, and lipoic acid, but evidence as to the therapeutic efficacy of these treatments remains extremely limited.135, 139, 140 Yet if bipolar disorder can be viewed in terms of its possible basis in mitochondrial dysfunction, such therapies have the potential to ameliorate aspects of the disease that are only minimally addressed by current treatment methods.

Furthermore, an understanding of bipolar illness in terms of mitochondrial dysfunction may greatly affect the usage of those treatments currently available. A number of MRS studies have indicated that lithium, the most commonly used pharmacotherapy for bipolar disorder,1 may increase NAA levels in bipolar subjects (Table 1b) and thus ostensibly improve mitochondrial function, but a study by Silverstone et al25 reported that this effect is not associated with the administration of sodium valproate. In fact, research on the mechanism of action of valproate has suggested that the drug has a high degree of interference with cellular energy metabolism, and may impair brain fuel utilization (reviewed by Bolaños and Medina141). Consequently, if bipolar disorder does stem from some degree of mitochondrial dysfunction, it may be important to investigate whether the augmentation of valproate administration with agents that counteract the drug's effects on cellular energetics would improve the clinical efficacy of the treatment regimen as a whole. In addition, research on neuroleptics has indicated that typical and atypical antipsychotics have substantially different effects on respiratory enzyme activity levels.142 Although typical agents inhibit Complex I of the electron transport chain143, 144 and thus may cause significant reductions in synaptic ATP synthesis and mitochondrial respiration,145 atypical agents have comparatively no effect on electron transfer activities.142 Consideration of the possible mitochondrial factors underlying bipolar disorder may thus prove valuable in the choice and prescription of such antipsychotic treatments.

A recent feature review published in Molecular Psychiatry proposes that novel treatments developed specifically for bipolar disorder will arise from either ‘(1) understanding the mechanism of action of current medications and thereafter designing novel drugs that mimic these mechanism(s)’ or ‘(2) basing medication development upon the hypothetical or proven underlying pathophysiology of bipolar disorder.’146 We feel that the hypothesis of mitochondrial dysfunction in bipolar disorder, as supported by evidence from MRS, has the potential to fulfill both these objectives. It remains our hope that, in the future, a better understanding of both current therapies and the underlying pathophysiology of bipolar illness may lead to the development of more sophisticated treatments, and consequently improve the quality of life of thousands of affected individuals.


  1. 1

    Belmaker RH . Bipolar disorder. N Engl J Med 2004; 351: 476–486.

    Article  CAS  Google Scholar 

  2. 2

    Winsberg ME, Sachs N, Tate DL, Adalsteinsson E, Spielman D, Ketter TA . Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder. Biol Psychiatry 2000; 47: 475–481.

    Article  CAS  Google Scholar 

  3. 3

    Birken DL, Oldendorf WH . N-acetyl-L-aspartic acid: a literature review of a compound prominent in 1H-NMR spectroscopic studies of brain. Neurosci Biobehav Rev 1989; 13: 23–31.

    Article  CAS  Google Scholar 

  4. 4

    Urenjak J, Williams SR, Gadian DG, Noble M . Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types. J Neurosci 1993; 13: 981–989.

    Article  CAS  Google Scholar 

  5. 5

    Deicken RF, Pegues MP, Anzalone S, Feiwell R, Soher B . Lower concentration of hippocampal N-acetylaspartate in familial bipolar I disorder. Am J Psychiatry 2003; 160: 873–882.

    Article  Google Scholar 

  6. 6

    Patel TB, Clark JB . Synthesis of N-acetyl-L-aspartate by rat brain mitochondria and its involvement in mitochondrial/cytosolic carbon transport. Biochem J 1979; 184: 539–546.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Truckenmiller ME, Namboodiri MA, Brownstein MJ, Neale JH . N-acetylation of L-aspartate in the nervous system: differential distribution of a specific enzyme. J Neurochem 1985; 45: 1658–1662.

    Article  CAS  Google Scholar 

  8. 8

    Clark JB . N-acetyl aspartate: a marker for neuronal loss or mitochondrial dysfunction. Dev Neurosci 1998; 20: 271–276.

    Article  CAS  Google Scholar 

  9. 9

    Baslow MH . N-acetylaspartate in the vertebrate brain: metabolism and function. Neurochem Res 2003; 28: 941–953.

    Article  CAS  Google Scholar 

  10. 10

    Blakely RD, Coyle JT . The neurobiology of N-acetylaspartylglutamate. Int Rev Neurobiol 1988; 30: 39–100.

    Article  CAS  Google Scholar 

  11. 11

    Madhavarao CN, Chinopoulos C, Chandrasekaran K, Namboodiri MA . Characterization of the N-acetylaspartate biosynthetic enzyme from rat brain. J Neurochem 2003; 86: 824–835.

    Article  CAS  Google Scholar 

  12. 12

    van der Knaap MS, van der Grond J, Luyten PR, den Hollander JA, Nauta JJ, Valk J . 1H and 31P magnetic resonance spectroscopy of the brain in degenerative cerebral disorders. Ann Neurol 1992; 31: 202–211.

    Article  CAS  Google Scholar 

  13. 13

    De Stefano N, Matthews PM, Arnold DL . Reversible decreases in N-acetylaspartate after acute brain injury. Magn Reson Med 1995; 34: 721–727.

    Article  CAS  Google Scholar 

  14. 14

    Signoretti S, Marmarou A, Tavazzi B, Lazzarino G, Beaumont A, Vagnozzi R . N-acetylaspartate reduction as a measure of injury severity and mitochondrial dysfunction following diffuse traumatic brain injury. J Neurotrauma 2001; 18: 977–991.

    Article  CAS  Google Scholar 

  15. 15

    Demougeot C, Garnier P, Mossiat C, Bertrand N, Giroud M, Beley A et al. N-acetylaspartate, a marker of both cellular dysfunction and neuronal loss: its relevance to studies of acute brain injury. J Neurochem 2001; 77: 408–415.

    Article  CAS  Google Scholar 

  16. 16

    Mathews PM, Andermann F, Silver K, Karpati G, Arnold DL . Proton MR spectroscopic characterization of differences in regional brain metabolic abnormalities in mitochondrial encephalomyopathies. Neurology 1993; 43: 2484–2490.

    Article  CAS  Google Scholar 

  17. 17

    Bates TE, Strangward M, Keelan J, Davey GP, Munro PM, Clark JB . Inhibition of N-acetylaspartate production: implications for 1H MRS studies in vivo. Neuroreport 1996; 7: 1397–1400.

    Article  CAS  Google Scholar 

  18. 18

    Brenner R, Bates TE, Davies SEC, Munro PMG, Williams SCR, Clark JB et al. Abnormal neuronal mitochondria: a cause of reduction in N-acetyl containing compounds (NA) in demyelinating disease. J Neurol 1994; 241: S29.

  19. 19

    Cecil KM, DelBello MP, Morey R, Strakowski SM . Frontal lobe differences in bipolar disorder as determined by proton MR spectroscopy. Bipolar Disord 2002; 4: 357–365.

    Article  CAS  Google Scholar 

  20. 20

    Chang K, Adleman N, Dienes K, Barnea-Goraly N, Reiss A, Ketter T . Decreased N-acetylaspartate in children with familial bipolar disorder. Biol Psychiatry 2003; 53: 1059–1065.

    Article  CAS  Google Scholar 

  21. 21

    Bertolino A, Frye M, Callicott JH, Mattay VS, Rakow R, Shelton-Repella J et al. Neuronal pathology in the hippocampal area of patients with bipolar disorder: a study with proton magnetic resonance spectroscopic imaging. Biol Psychiatry 2003; 53: 906–913.

    Article  Google Scholar 

  22. 22

    O'Donnell T, Rotzinger S, Nakashima TT, Hanstock CC, Ulrich M, Silverstone PH . Chronic lithium and sodium valproate both decrease the concentration of myo-inositol and increase the concentration of inositol monophosphates in rat brain. Brain Res 2000; 880: 84–91.

    Article  CAS  Google Scholar 

  23. 23

    Sharma R, Venkatasubramanian PN, Barany M, Davis JM . Proton magnetic resonance spectroscopy of the brain in schizophrenic and affective patients. Schizophr Res 1992; 8: 43–49.

    Article  CAS  Google Scholar 

  24. 24

    Moore GJ, Bebchuk JM, Hasanat K, Chen G, Seraji-Bozorgzad N, Wilds IB et al. Lithium increases N-acetyl-aspartate in the human brain: in vivo evidence in support of bcl-2's neurotrophic effects? Biol Psychiatry 2000; 48: 1–8.

    Article  CAS  Google Scholar 

  25. 25

    Silverstone PH, Wu RH, O'Donnell T, Ulrich M, Asghar SJ, Hanstock CC . Chronic treatment with lithium, but not sodium valproate, increases cortical N-acetyl-aspartate concentrations in euthymic bipolar patients. Int Clin Psychopharmacol 2003; 18: 73–79.

    Article  Google Scholar 

  26. 26

    Brambilla P, Stanley JA, Sassi RB, Nicoletti MA, Mallinger AG, Keshavan MS et al. H MRS study of dorsolateral prefrontal cortex in healthy individuals before and after lithium administration. Neuropsychopharmacology 2004; 29: 1918–1924.

    Article  CAS  Google Scholar 

  27. 27

    Friedman SD, Dager SR, Parow A, Hirashima F, Demopulos C, Stoll AL et al. Lithium and valproic acid treatment effects on brain chemistry in bipolar disorder. Biol Psychiatry 2004; 56: 340–348.

    Article  CAS  Google Scholar 

  28. 28

    Ohara K, Isoda H, Suzuki Y, Takehara Y, Ochiai M, Takeda H et al. Proton magnetic resonance spectroscopy of the lenticular nuclei in bipolar I affective disorder. Psychiatry Res 1998; 84: 55–60.

    Article  CAS  Google Scholar 

  29. 29

    Hamakawa H, Kato T, Shioiri T, Inubushi T, Kato N . Quantitative proton magnetic resonance spectroscopy of the bilateral frontal lobes in patients with bipolar disorder. Psychol Med 1999; 29: 639–644.

    Article  CAS  Google Scholar 

  30. 30

    Castillo M, Kwock L, Courvoisie H, Hooper SR . Proton MR spectroscopy in children with bipolar affective disorder: preliminary observations. AJNR Am J Neuroradiol 2000; 21: 832–838.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Deicken RF, Eliaz Y, Feiwell R, Schuff N . Increased thalamic N-acetylaspartate in male patients with familial bipolar I disorder. Psychiatry Res 2001; 106: 35–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Zubieta JK, Huguelet P, Ohl F, Kilbourn MR, Koeppe RA, Frey KA . PET measures of monoaminergic synaptic density in bipolar I disorder: relationship with age of onset. Biol Psychiatry 1998; 43: S71.

    Article  Google Scholar 

  33. 33

    Zubieta JK, Huguelet P, Ohl LE, Koeppe RA, Kilbourn MR, Carr JM et al. High vesicular monoamine transporter binding in asymptomatic bipolar I disorder: sex differences and cognitive correlates. Am J Psychiatry 2000; 157: 1619–1628.

    Article  CAS  Google Scholar 

  34. 34

    Ongur D, Drevets WC, Price JL . Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA 1998; 95: 13290–13295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Sappey-Marinier D, Deicken RF, Fein G, Calabrese G, Hubesch B, Van Dyke C et al. Alterations in brain phosphorus metabolite concentrations associated with areas of high signal intensity in white matter at MR imaging. Radiology 1992; 183: 247–256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Vion-Dury J, Meyerhoff DJ, Cozzone PJ, Weiner MW . What might be the impact on neurology of the analysis of brain metabolism by in vivo magnetic resonance spectroscopy? J Neurol 1994; 241: 354–371.

    Article  CAS  Google Scholar 

  37. 37

    Brooke NS, Ouwerkerk R, Adams CB, Radda GK, Ledingham JG, Rajagopalan B . Phosphorus-31 magnetic resonance spectra reveal prolonged intracellular acidosis in the brain following subarachnoid hemorrhage. Proc Natl Acad Sci USA 1994; 91: 1903–1907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Abe K, Aoki M, Kawagoe J, Yoshida T, Hattori A, Kogure K et al. Ischemic delayed neuronal death. A mitochondrial hypothesis. Stroke 1995; 26: 1478–1489.

    Article  CAS  Google Scholar 

  39. 39

    Ankarcrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA et al. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 1995; 15: 961–973.

    Article  CAS  Google Scholar 

  40. 40

    Fiskum G, Murphy AN, Beal MF . Mitochondria in neurodegeneration: acute ischemia and chronic neurodegenerative diseases. J Cereb Blood Flow Metab 1999; 19: 351–369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Friberg H, Wieloch T . Mitochondrial permeability transition in acute neurodegeneration. Biochimie 2002; 84: 241–250.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Schinder AF, Olson EC, Spitzer NC, Montal M . Mitochondrial dysfunction is a primary event in glutamate neurotoxicity. J Neurosci 1996; 16: 6125–6133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    White RJ, Reynolds IJ . Mitochondrial depolarization in glutamate-stimulated neurons: an early signal specific to excitotoxin exposure. J Neurosci 1996; 16: 5688–5697.

    Article  CAS  Google Scholar 

  44. 44

    White RJ, Reynolds IJ . Mitochondria accumulate Ca2 + following intense glutamate stimulation of cultured rat forebrain neurones. J Physiol 1997; 498(Part 1): 31–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Hamakawa H, Murashita J, Yamada N, Inubushi T, Kato N, Kato T . Reduced intracellular pH in the basal ganglia and whole brain measured by 31P-MRS in bipolar disorder. Psychiatry Clin Neurosci 2004; 58: 82–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Kato T, Takahashi S, Shioiri T, Inubushi T . Alterations in brain phosphorous metabolism in bipolar disorder detected by in vivo31P and 7Li magnetic resonance spectroscopy. J Affect Disord 1993; 27: 53–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Kato T, Takahashi S, Shioiri T, Inubushi T . Brain phosphorous metabolism in depressive disorders detected by phosphorus-31 magnetic resonance spectroscopy. J Affect Disord 1992; 26: 223–230.

    Article  CAS  Google Scholar 

  48. 48

    Kato T, Murashita J, Kamiya A, Shioiri T, Kato N, Inubushi T . Decreased brain intracellular pH measured by 31P-MRS in bipolar disorder: a confirmation in drug-free patients and correlation with white matter hyperintensity. Eur Arch Psychiatry Clin Neurosci 1998; 248: 301–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Kato T, Takahashi S, Shioiri T, Murashita J, Hamakawa H, Inubushi T . Reduction of brain phosphocreatine in bipolar II disorder detected by phosphorus-31 magnetic resonance spectroscopy. J Affect Disord 1994b; 31: 125–133.

    Article  CAS  Google Scholar 

  50. 50

    Kato T, Shioiri T, Murashita J, Hamakawa H, Inubushi T, Takahashi S . Phosphorus-31 magnetic resonance spectroscopy and ventricular enlargement in bipolar disorder. Psychiatry Res 1994a; 55: 41–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Kato T, Inubushi T, Kato N . Prediction of lithium response by 31P-MRS in bipolar disorder. Int J Neuropsychopharmacol 2000; 3: 83–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Kato T, Kato N . Mitochondrial dysfunction in bipolar disorder. Bipolar Disord 2000; 2(3 Part 1): 180–190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Smith GA, Brett CL, Church J . Effects of noradrenaline on intracellular pH in acutely dissociated adult rat hippocampal CA1 neurones. J Physiol 1998; 512(Part 2): 487–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Rudkin TM, Arnold DL . Proton magnetic resonance spectroscopy for the diagnosis and management of cerebral disorders. Arch Neurol 1999; 56: 919–926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Lin DD, Crawford TO, Barker PB . Proton MR spectroscopy in the diagnostic evaluation of suspected mitochondrial disease. AJNR Am J Neuroradiol 2003; 24: 33–41.

    PubMed  PubMed Central  Google Scholar 

  56. 56

    Argov Z . Functional evaluation techniques in mitochondrial disorders. Eur Neurol 1998; 39: 65–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Barkovich AJ, Good WV, Koch TK, Berg BO . Mitochondrial disorders: analysis of their clinical and imaging characteristics. AJNR Am J Neuroradiol 1993; 14: 1119–1137.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Clausen T, Zauner A, Levasseur JE, Rice AC, Bullock R . Induced mitochondrial failure in the feline brain: implications for understanding acute post-traumatic metabolic events. Brain Res 2001; 908: 35–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Moore GJ, Galloway MP . Magnetic resonance spectroscopy: neurochemistry and treatment effects in affective disorders. Psychopharmacol Bull 2002; 36: 5–23.

    PubMed  PubMed Central  Google Scholar 

  60. 60

    Dager SR, Friedman SD, Parow A, Demopulos C, Stoll AL, Lyoo IK et al. Brain metabolic alterations in medication-free patients with bipolar disorder. Arch Gen Psychiatry 2004; 61: 450–458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Michael N, Erfurth A, Ohrmann P, Gossling M, Arolt V, Heindel W et al. Acute mania is accompanied by elevated glutamate/glutamine levels within the left dorsolateral prefrontal cortex. Psychopharmacology (Berl) 2003; 168: 344–346.

    Article  CAS  Google Scholar 

  62. 62

    Gruetter R, Novotny EJ, Boulware SD, Mason GF, Rothman DL, Shulman GI et al. Localized 13C NMR spectroscopy in the human brain of amino acid labeling from D-[1-13C]glucose. J Neurochem 1994; 63: 1377–1385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Jenkins BG, Klivenyi P, Kustermann E, Andreassen OA, Ferrante RJ, Rosen BR et al. Nonlinear decrease over time in N-acetyl aspartate levels in the absence of neuronal loss and increases in glutamine and glucose in transgenic Huntington's disease mice. J Neurochem 2000; 74: 2108–2119.

    Article  CAS  Google Scholar 

  64. 64

    Cudkowicz ME, Martin JB, Koroshetz WJ . The neurology of Huntington's disease. In: Joseph AB, Young RR (eds). Movement Disorders in Neurology and Neuropsychiatry. Blackwell Science Inc.: Malden, MA, 1999, pp 147–154.

    Google Scholar 

  65. 65

    Ferrante RJ, Kowall NW, Beal MF, Martin JB, Bird ED, Richardson Jr EP . Morphologic and histochemical characteristics of a spared subset of striatal neurons in Huntington's disease. J Neuropathol Exp Neurol 1987; 46: 12–27.

    Article  CAS  Google Scholar 

  66. 66

    Beal MF, Kowall NW, Ellison DW, Mazurek MF, Swartz KJ, Martin JB . Replication of the neurochemical characteristics of Huntington's disease by quinolinic acid. Nature 1986; 321: 168–171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Taylor-Robinson SD, Weeks RA, Bryant DJ, Sargentoni J, Marcus CD, Harding AE et al. Proton magnetic resonance spectroscopy in Huntington's disease: evidence in favour of the glutamate excitotoxic theory. Mov Disord 1996; 11: 167–173.

    Article  CAS  Google Scholar 

  68. 68

    de Graaf RA . Phosphorus-31 MRS. In: In vivo NMR Spectroscopy: Principles and Techniques. John Wiley & Sons Ltd: Chichester, England, 1998, pp 61–67.

    Google Scholar 

  69. 69

    Erecinska M, Silver IA . ATP and brain function. J Cereb Blood Flow Metab 1989; 9: 2–19.

    Article  CAS  Google Scholar 

  70. 70

    Sauter A, Rudin M . Determination of creatine kinase kinetic parameters in rat brain by NMR magnetization transfer. Correlation with brain function. J Biol Chem 1993; 268: 13166–13171.

    CAS  PubMed  Google Scholar 

  71. 71

    Kato T, Murashita J, Shioiri T, Hamakawa H, Inubushi T . Effect of photic stimulation on energy metabolism in the human brain measured by 31P-MR spectroscopy. J Neuropsychiatry Clin Neurosci 1996; 8: 417–422.

    Article  CAS  Google Scholar 

  72. 72

    Rothman DL . 1H NMR studies of human brain metabolism and physiology. In: Gillies RJ (ed). NMR in Physiology and Biomedicine. Academic Press: San Diego, CA, 1994, pp 353–372.

    Chapter  Google Scholar 

  73. 73

    Modica-Napolitano JS, Renshaw PF . Ethanolamine and phosphoethanolamine inhibit mitochondrial function in vitro: implications for mitochondrial dysfunction hypothesis in depression and bipolar disorder. Biol Psychiatry 2004; 55: 273–277.

    Article  CAS  Google Scholar 

  74. 74

    Eleff SM, Barker PB, Blackband SJ, Chatham JC, Lutz NW, Johns DR et al. Phosphorus magnetic resonance spectroscopy of patients with mitochondrial cytopathies demonstrates decreased levels of brain phosphocreatine. Ann Neurol 1990; 27: 626–630.

    Article  CAS  Google Scholar 

  75. 75

    Barbiroli B, Montagna P, Martinelli P, Lodi R, Iotti S, Cortelli P et al. Defective brain energy metabolism shown by in vivo31P MR spectroscopy in 28 patients with mitochondrial cytopathies. J Cereb Blood Flow Metab 1993; 13: 469–474.

    Article  CAS  Google Scholar 

  76. 76

    Barbiroli B, Montagna P, Cortelli P, Funicello R, Iotti S, Monari L et al. Abnormal brain and muscle energy metabolism shown by 31P magnetic resonance spectroscopy in patients affected by migraine with aura. Neurology 1992; 42: 1209–1214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Welch KM, Barkley GL, Tepley N, Ramadan NM . Central neurogenic mechanisms of migraine. Neurology 1993; 43(6 Suppl 3): S21–S25.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Kato T, Shioiri T, Murashita J, Hamakawa H, Takahashi Y, Inubushi T et al. Lateralized abnormality of high energy phosphate metabolism in the frontal lobes of patients with bipolar disorder detected by phase-encoded 31P-MRS. Psychol Med 1995; 25: 557–566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Purdon AD, Rapoport SI . Energy requirements for two aspects of phospholipid metabolism in mammalian brain. Biochem J 1998; 335(Part 2): 313–318.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Govindaraju V, Young K, Maudsley AA . Proton NMR chemical shifts and coupling constants for brain metabolites. NMR Biomed 2000; 13: 129–153.

    Article  CAS  Google Scholar 

  81. 81

    Bluml S, Seymour KJ, Ross BD . Developmental changes in choline- and ethanolamine-containing compounds measured with proton-decoupled (31)P MRS in in vivo human brain. Magn Reson Med 1999; 42: 643–654.

    Article  CAS  Google Scholar 

  82. 82

    Pouwels PJ, Frahm J . Regional metabolite concentrations in human brain as determined by quantitative localized proton MRS. Magn Reson Med 1998; 39: 53–60.

    Article  CAS  Google Scholar 

  83. 83

    Tan J, Bluml S, Hoang T, Dubowitz D, Mevenkamp G, Ross B . Lack of effect of oral choline supplement on the concentrations of choline metabolites in human brain. Magn Reson Med 1998; 39: 1005–1010.

    Article  CAS  Google Scholar 

  84. 84

    Wang Y, Li SJ . Differentiation of metabolic concentrations between gray matter and white matter of human brain by in vivo1H magnetic resonance spectroscopy. Magn Reson Med 1998; 39: 28–33.

    Article  CAS  Google Scholar 

  85. 85

    Freeman JJ, Jenden DJ . The source of choline for acetylcholine synthesis in brain. Life Sci 1976; 19: 949–961.

    Article  CAS  Google Scholar 

  86. 86

    Miller BL . A review of chemical issues in 1H NMR spectroscopy: N-acetyl-L-aspartate, creatine and choline. NMR Biomed 1991; 4: 47–52.

    Article  CAS  Google Scholar 

  87. 87

    Ackerstaff E, Glunde K, Bhujwalla ZM . Choline phospholipid metabolism: a target in cancer cells? J Cell Biochem 2003; 90: 525–533.

    Article  CAS  Google Scholar 

  88. 88

    Farber SA, Slack BE, Blusztajn JK . Acceleration of phosphatidylcholine synthesis and breakdown by inhibitors of mitochondrial function in neuronal cells: a model of the membrane defect of Alzheimer's disease. FASEB J 2000; 14: 2198–2206.

    Article  CAS  Google Scholar 

  89. 89

    Stoll A, Cohen B, Hanin I . Erythrocyte choline concentration in psychiatric disorders. Biol Psychiatry 1991; 29: 309–321.

    Article  CAS  Google Scholar 

  90. 90

    Wu RH, O'Donnell T, Ulrich M, Asghar SJ, Hanstock CC, Silverstone PH . Brain choline concentrations may not be altered in euthymic bipolar disorder patients chronically treated with either lithium or sodium valproate. Ann Gen Hosp Psychiatry 2004; 3: 13.

    Article  PubMed  PubMed Central  Google Scholar 

  91. 91

    Ross B, Bluml S . Magnetic resonance spectroscopy of the human brain. Anat Rec 2001; 265: 54–84.

    Article  CAS  Google Scholar 

  92. 92

    Ross BD . Biochemical considerations in 1H spectroscopy. Glutamate and glutamine; myo-inositol and related metabolites. NMR Biomed 1991; 4: 59–63.

    Article  CAS  Google Scholar 

  93. 93

    Brand A, Richter-Landsberg C, Leibfritz D . Multinuclear NMR studies on the energy metabolism of glial and neuronal cells. Dev Neurosci 1993; 15: 289–298.

    Article  CAS  Google Scholar 

  94. 94

    Kato T, Inubushi T, Kato N . Magnetic resonance spectroscopy in affective disorders. J Neuropsychiatry Clin Neurosci 1998; 10: 133–147.

    Article  CAS  Google Scholar 

  95. 95

    Videen JS, Michaelis T, Pinto P, Ross BD . Human cerebral osmolytes during chronic hyponatremia. A proton magnetic resonance spectroscopy study. J Clin Invest 1995; 95: 788–793.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    Allison JH, Stewart MA . Reduced brain inositol in lithium-treated rats. Nat New Biol 1971; 233: 267–268.

    Article  CAS  Google Scholar 

  97. 97

    Hallcher LM, Sherman WR . The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain. J Biol Chem 1980; 255: 10896–10901.

    CAS  PubMed  Google Scholar 

  98. 98

    Manji HK, Bersudsky Y, Chen G, Belmaker RH, Potter WZ . Modulation of protein kinase C isozymes and substrates by lithium: the role of myo-inositol. Neuropsychopharmacology 1996; 15: 370–381.

    Article  CAS  Google Scholar 

  99. 99

    Berridge MJ, Downes CP, Hanley MR . Neural and developmental actions of lithium: a unifying hypothesis. Cell 1989; 59: 411–419.

    Article  CAS  Google Scholar 

  100. 100

    Berridge MJ, Downes CP, Hanley MR . Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands. Biochem J 1982; 206: 587–595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Preece N, Gadian D, Houseman J, Williams S . Lithium-induced modulation of cerebral inositol phosphate metabolism in the rat: a multinuclear magnetic resonance study in vivo. Lithium 1992; 3: 287–297.

    CAS  Google Scholar 

  102. 102

    Renshaw PF, Summers JJ, Renshaw CE, Hines KG, Leigh Jr JS . Changes in the 31P-NMR spectra of cats receiving lithium chloride systemically. Biol Psychiatry 1986; 21: 694–698.

    Article  CAS  Google Scholar 

  103. 103

    Silverstone PH, Wu RH, O'Donnell T, Ulrich M, Asghar SJ, Hanstock CC . Chronic treatment with both lithium and sodium valproate may normalize phosphoinositol cycle activity in bipolar patients. Hum Psychopharmacol 2002; 17: 321–327.

    Article  CAS  Google Scholar 

  104. 104

    Davanzo P, Yue K, Thomas MA, Belin T, Mintz J, Venkatraman TN et al. Proton magnetic resonance spectroscopy of bipolar disorder versus intermittent explosive disorder in children and adolescents. Am J Psychiatry 2003; 160: 1442–1452.

    Article  Google Scholar 

  105. 105

    Gyulai L, Bolinger L, Leigh Jr JS, Barlow C, Chance B . Phosphorylethanolamine—the major constituent of the phosphomonoester peak observed by 31P-NMR on developing dog brain. FEBS Lett 1984; 178: 137–142.

    Article  CAS  Google Scholar 

  106. 106

    Pettegrew JW, Kopp SJ, Minshew NJ, Glonek T, Feliksik JM, Tow JP et al. 31P nuclear magnetic resonance studies of phosphoglyceride metabolism in developing and degenerating brain: preliminary observations. J Neuropathol Exp Neurol 1987; 46: 419–430.

    Article  CAS  Google Scholar 

  107. 107

    Ross B, Michaelis T . Clinical applications of magnetic resonance spectroscopy. Magn Reson Q 1994; 10: 191–247.

    CAS  PubMed  Google Scholar 

  108. 108

    Morikawa S, Inubushi T, Kitoh K, Kido C, Nozaki M . Chemical assessment of phospholipid and phosphoenergetic metabolites in regenerating rat liver measured by in vivo and in vitro31P-NMR. Biochim Biophys Acta 1992; 1117: 251–257.

    Article  CAS  Google Scholar 

  109. 109

    Kato T, Shioiri T, Murashita J, Inubushi T . Phosphorus-31 magnetic resonance spectroscopic observations in 4 cases with anorexia nervosa. Prog Neuropsychopharmacol Biol Psychiatry 1997; 21: 719–724.

    Article  CAS  Google Scholar 

  110. 110

    Pettegrew JW, Keshavan MS, Panchalingam K, Strychor S, Kaplan DB, Tretta MG et al. Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics. A pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy. Arch Gen Psychiatry 1991; 48: 563–568.

    Article  CAS  Google Scholar 

  111. 111

    Williamson P, Drost D, Stanley J, Carr T, Morrison S, Merskey H . Localized phosphorus 31 magnetic resonance spectroscopy in chronic schizophrenic patients and normal controls. Arch Gen Psychiatry 1991; 48: 578.

    Article  CAS  Google Scholar 

  112. 112

    Jensen JE, Drost DJ, Menon RS, Williamson PC . In vivo brain (31)P-MRS: measuring the phospholipid resonances at 4 Tesla from small voxels. NMR Biomed 2002; 15: 338–347.

    Article  CAS  Google Scholar 

  113. 113

    Yildiz A, Sachs GS, Dorer DJ, Renshaw PF . 31P nuclear magnetic resonance spectroscopy findings in bipolar illness: a meta-analysis. Psychiatry Res 2001; 106: 181–191.

    Article  CAS  Google Scholar 

  114. 114

    Kato T, Shioiri T, Takahashi S, Inubushi T . Measurement of brain phosphoinositide metabolism in bipolar patients using in vivo31P-MRS. J Affect Disord 1991; 22: 185–190.

    Article  CAS  Google Scholar 

  115. 115

    Perez J, Tardito D, Mori S, Racagni G, Smeraldi E, Zanardi R . Abnormalities of cAMP signaling in affective disorders: implication for pathophysiology and treatment. Bipolar Disord 2000; 2: 27–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Hahn CG, Friedman E . Abnormalities in protein kinase C signaling and the pathophysiology of bipolar disorder. Bipolar Disord 1999; 1: 81–86.

    Article  CAS  Google Scholar 

  117. 117

    Soares JC, Mallinger AG . Intracellular phosphatidylinositol pathway abnormalities in bipolar disorder patients. Psychopharmacol Bull 1997; 33: 685–691.

    CAS  Google Scholar 

  118. 118

    Yamawaki S, Kagaya A, Tawara Y, Inagaki M . Intracellular calcium signaling systems in the pathophysiology of affective disorders. Life Sci 1998; 62: 1665–1670.

    Article  CAS  Google Scholar 

  119. 119

    Simpson PB, Russell JT . Role of mitochondrial Ca2 + regulation in neuronal and glial cell signalling. Brain Res Brain Res Rev 1998; 26: 72–81.

    Article  CAS  Google Scholar 

  120. 120

    Buchsbaum MS, Wu J, DeLisi LE, Holcomb H, Kessler R, Johnson J et al. Frontal cortex and basal ganglia metabolic rates assessed by positron emission tomography with [18F]2-deoxyglucose in affective illness. J Affect Disord 1986; 10: 137–152.

    Article  CAS  Google Scholar 

  121. 121

    Cohen RM, Semple WE, Gross M, Nordahl TE, King AC, Pickar D et al. Evidence for common alterations in cerebral glucose metabolism in major affective disorders and schizophrenia. Neuropsychopharmacology 1989; 2: 241–254.

    Article  CAS  Google Scholar 

  122. 122

    Delvenne V, Delecluse F, Hubain PP, Schoutens A, De Maertelaer V, Mendlewicz J . Regional cerebral blood flow in patients with affective disorders. Br J Psychiatry 1990; 157: 359–365.

    Article  CAS  Google Scholar 

  123. 123

    Drevets WC, Price JL, Simpson Jr JR, Todd RD, Reich T, Vannier M et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 1997; 386: 824–827.

    Article  CAS  Google Scholar 

  124. 124

    Baxter Jr LR, Schwartz JM, Phelps ME, Mazziotta JC, Guze BH, Selin CE et al. Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry 1989; 46: 243–250.

    Article  CAS  Google Scholar 

  125. 125

    Baxter Jr LR, Phelps ME, Mazziotta JC, Schwartz JM, Gerner RH, Selin CE et al. Cerebral metabolic rates for glucose in mood disorders. Studies with positron emission tomography and fluorodeoxyglucose F 18. Arch Gen Psychiatry 1985; 42: 441–447.

    Article  Google Scholar 

  126. 126

    Ketter TA, Kimbrell TA, George MS, Dunn RT, Speer AM, Benson BE et al. Effects of mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar disorder. Biol Psychiatry 2001; 49: 97–109.

    Article  CAS  Google Scholar 

  127. 127

    Migliorelli R, Starkstein SE, Teson A, de Quiros G, Vazquez S, Leiguarda R et al. SPECT findings in patients with primary mania. J Neuropsychiatry Clin Neurosci 1993; 5: 379–383.

    Article  CAS  Google Scholar 

  128. 128

    Blumberg HP, Stern E, Ricketts S, Martinez D, de Asis J, White T et al. Rostral and orbital prefrontal cortex dysfunction in the manic state of bipolar disorder. Am J Psychiatry 1999; 156: 1986–1988.

    CAS  PubMed  Google Scholar 

  129. 129

    Rubin E, Sackeim HA, Prohovnik I, Moeller JR, Schnur DB, Mukherjee S . Regional cerebral blood flow in mood disorders: IV. Comparison of mania and depression. Psychiatry Res 1995; 61: 1–10.

    Article  CAS  Google Scholar 

  130. 130

    Blumberg HP, Stern E, Martinez D, Ricketts S, de Asis J, White T et al. Increased anterior cingulate and caudate activity in bipolar mania. Biol Psychiatry 2000; 48: 1045–1052.

    Article  CAS  Google Scholar 

  131. 131

    Kato T, Stine OC, McMahon FJ, Crowe RR . Increased levels of a mitochondrial DNA deletion in the brain of patients with bipolar disorder. Biol Psychiatry 1997; 42: 871–875.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Tanaka M, Gong JS, Zhang J, Yoneda M, Yagi K . Mitochondrial genotype associated with longevity. Lancet 1998; 351: 185–186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. 133

    Kato T, Kunugi H, Nanko S, Kato N . Association of bipolar disorder with the 5178 polymorphism in mitochondrial DNA. Am J Med Genet 2000; 96: 182–186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Konradi C, Eaton M, MacDonald ML, Walsh J, Benes FM, Heckers S . Molecular evidence for mitochondrial dysfunction in bipolar disorder. Arch Gen Psychiatry 2004; 61: 300–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Tarnopolsky MA, Beal MF . Potential for creatine and other therapies targeting cellular energy dysfunction in neurological disorders. Ann Neurol 2001; 49: 561–574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. 136

    Rosas HD, Feigin AS, Hersch SM . Using advances in neuroimaging to detect, understand, and monitor disease progression in Huntington's disease. NeuroRx 2004; 1: 263–272.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Ferrante RJ, Andreassen OA, Jenkins BG, Dedeoglu A, Kuemmerle S, Kubilus JK et al. Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease. J Neurosci 2000; 20: 4389–4397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. 138

    Dedeoglu A, Kubilus JK, Yang L, Ferrante KL, Hersch SM, Beal MF et al. Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington's disease transgenic mice. J Neurochem 2003; 85: 1359–1367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Beal MF . Bioenergetic approaches for neuroprotection in Parkinson's disease. Ann Neurol 2003; 53(Suppl 3): S39–S47; discussion S47–S48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. 140

    Zhu S, Li M, Figueroa BE, Liu A, Stavrovskaya IG, Pasinelli P et al. Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice. J Neurosci 2004; 24: 5909–5912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Bolaños JP, Medina JM . Effect of valproate on the metabolism of the central nervous system. Life Sci 1997; 60: 1933–1942.

    Article  PubMed  PubMed Central  Google Scholar 

  142. 142

    Modica-Napolitano JS, Lagace CJ, Brennan WA, Aprille JR . Differential effects of typical and atypical neuroleptics on mitochondrial function in vitro. Arch Pharm Res 2003; 26: 951–959.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. 143

    Balijepalli S, Boyd MR, Ravindranath V . Inhibition of mitochondrial complex I by haloperidol: the role of thiol oxidation. Neuropharmacology 1999; 38: 567–577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Balijepalli S, Kenchappa RS, Boyd MR, Ravindranath V . Protein thiol oxidation by haloperidol results in inhibition of mitochondrial complex I in brain regions: comparison with atypical antipsychotics. Neurochem Int 2001; 38: 425–435.

    Article  CAS  Google Scholar 

  145. 145

    Davey GP, Peuchen S, Clark JB . Energy thresholds in brain mitochondria. Potential involvement in neurodegeneration. J Biol Chem 1998; 273: 12753–12757.

    Article  CAS  Google Scholar 

  146. 146

    Gould TD, Quiroz JA, Singh J, Zarate CA, Manji HK . Emerging experimental therapeutics for bipolar disorder: insights from the molecular and cellular actions of current mood stabilizers. Mol Psychiatry 2004; 9: 734–755.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to C Stork.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Stork, C., Renshaw, P. Mitochondrial dysfunction in bipolar disorder: evidence from magnetic resonance spectroscopy research. Mol Psychiatry 10, 900–919 (2005).

Download citation


  • bipolar disorder
  • magnetic resonance spectroscopy
  • mitochondria
  • bioenergetics

Further reading


Quick links