Blood metabolomics analysis identifies abnormalities in the citric acid cycle, urea cycle, and amino acid metabolism in bipolar disorder

Yoshimi, Noriko; Futamura, Takashi; Kakumoto, Keiji; Salehi, Alireza; Sellgren, Carl M.; Holmén-Larsson, Jessica; Jakobsson, Joel; Pålsson, Erik; Landén, Mikael; Hashimoto, Kenji

doi:10.1016/j.bbacli.2016.03.008

Cited by 91 publications

(69 citation statements)

References 67 publications

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“…In a metabolomics study that also used only male patients and HC, Yoshimi et al . reported elevated mean serum lactate, though not significant ( P = 0.321), for BD patients ( n = 54) in comparison to HC ( n = 40) . This study used the same subject population as another Yoshimi et al .…”

Section: Resultsmentioning

confidence: 84%

“…reported a significant lactate increase in the red blood cells of lithium‐treated BD patients and this increase is likely confounded by the fact that the blood sat at room temperature . Interestingly, the other two studies that did not report any significant differences in the peripheral lactate levels in BD compared to HC, excluded female participants. For these reasons, it is difficult to draw conclusions from the peripheral lactate data in BD.…”

Section: Discussionmentioning

confidence: 99%

“…After applying the inclusion and exclusion criteria to our search results, we identified 12 studies for the systematic review (Table 1) 4,7,8,[10][11][12][13][14][15][16][17][18] and five studies for the meta-analysis ( Fig. 1).…”

Section: Systematic Overviewmentioning

confidence: 99%

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Lactate in bipolar disorder: A systematic review and meta‐analysis

Kuang¹,

Duong²,

Jeong

et al. 2018

Psychiatry Clin Neurosci

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Bipolar disorder (BD) is a debilitating mood disorder with no specific biological marker. No novel treatment has been developed specifically for BD in the last several decades. Although the pathophysiology of BD remains unclear, there is strong evidence in the literature supporting the role of mitochondrial dysfunction in BD. In this systematic review, we identified and investigated 12 studies that measure lactate, which is a direct marker for mitochondrial dysfunction, in BD patients and healthy controls. Six studies measured lactate levels in the brain through proton echo-planar spectroscopy or magnetic resonance spectroscopy and five of these studies reported significantly elevated lactate levels in patients with BD. Two studies reporting cerebrospinal fluid lactate levels also found significantly elevated lactate in BD compared to healthy controls. Two other studies that reported peripheral lactate levels did not demonstrate significant findings. The meta-analysis, using standardized means and a random-effect model for five studies that measured brain lactate levels, corroborated the findings of the systematic review. Although the meta-analysis had a nearly significant overall effect (Z = 1.97, P = 0.05), high statistical heterogeneity (I = 86%) and possible publication bias suggest that the results should be interpreted with caution. To validate lactate abnormalities in BD, further studies should be carried out, including larger sample sizes, not excluding female patients, and using standardized methodologies. Peripheral lactate levels and other bioenergetic markers should be thoroughly studied to better understand the role of mitochondrial dysfunction in BD and to help develop more objective diagnostic tools.

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Section: Resultsmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Lactate in bipolar disorder: A systematic review and meta‐analysis

Kuang¹,

Duong²,

Jeong

et al. 2018

Psychiatry Clin Neurosci

View full text Add to dashboard Cite

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“…Bipolar disorder (BD), formerly called manic depression, causes extreme mood swings that include emotional highs (mania or hypomania) and lows (depression). Three groups published using 3 different sample types, plasma [137], CSF [130] and serum [136] to both understand the biology of BD and seek biomarkers for diagnosis. Hashimoto [130] aptly used the specificity of CE-MS to understand the role of mitochondrial dysfunction in BD, finding isocitrate as a diagnostic biomarker in CSF.…”

Section: Medical Applicationsmentioning

confidence: 99%

Capillary electrophoresis mass spectrometry based metabolomics

Buko¹

2017

J Appl Bioanal

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IntroductionSince its first formal definition more than a decade ago, metabolomics, or, the comprehensive analysis of all metabolites present within a biological system, has attracted growing interest in clinical research by academia, industry and government labs. This is most prevalent in biomarker and drug development applications where a considerable change has been witnessed in how new diagnoses, prognoses, and therapeutic options are being discovered and developed using omic technologies. Moreover, many chronic diseases suggest a strong metabolic involvement or even a clear metabolic cause, including cancer. Together with the other omic disciplines, including genomics and proteomics, metabolomics plays a key role in the implementation of personalized medicine; evidence-based medicine designed for individually designed healthcare strategies. In turn, biomarker discovery and the understanding of biochemical pathways typically rely on a multimodal approach. Among these modalities, there continues to be a growing interest in CE-MS based development and implementation in clinical development. Formulating the problemDepending on how you classify the metabolome, there is a complex chemical space separated by hydrophilicity, polarity and size, excluding a broad range of metabolites classified as lipids, separately referred to as lipidomics. This class of metabolites also covers a large range of physical properties for which specifically designed platforms work the best. For example, for years liquid chromatography-mass spectrometry (LC-MS) has been used to capture a host of hydrophilic and hydrophobic metabolites, while gas chromatography-mass spectrometry (GC-MS) has been used to capture small molecular weight metabolites. For this review, the metabolome refers to endogenous molecules with a molecular weight typically less than 1000 Kd. To measure, catalogue, and compare the entirety of the metabolic space, the implementation of comprehensive mass spectral databases was needed (e.g., Human Metab- Because of this diversity in physical properties and size of the metabolome in biological systems, there has been a need for the development of several analytical protocols based on different chromatographic methods to select specific subgroups of metabolites based on these different chemical properties beyond the technical capabilities of LC-MS and GC-MS. These new methods have their own advantages for selecting specific types of molecules: lipids, nucleotides, aminoacids or steroids. Nonmass spectrometric methods such as nuclear magnetic resonance (NMR) and non-chromatographic methods such as matrix-assisted laser desorption-time of flight (MALDI-TOF) imaging are successfully being used for selected metabolomic analyses. The focus of this review is recent publications that use CE-MS to extend the polar metabolome beyond what is observed by LC-MS and GC-MS. Metabolomics -current methods

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“…Yoshimi and colleagues obtained additional evidences corroborating the theory of mitochondrial dysfunction in BD. Through metabolomic assays of cerebrospinal fluid (CSF) obtained from BD patients, they observed that deregulation of isocitrate metabolism in the mitochondrial citric acid cycle is relevant in the pathogenesis of BD [87]. Moreover, mitochondrial dysfunction has been identified as the cause of the neuroprogression and cognitive impairment observed in BD.…”

mentioning

confidence: 99%

The ups and downs of cellular stress: the “MAM hypothesis” for Bipolar disorder pathophysiology

Pereira¹,

Resende²,

Morais³

et al. 2017

IJCNMH

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Mental health problems constitute the largest single source of world economic burden, with an estimated global cost greater than cardiovascular disease, cancer or diabetes individually. In the European Union mental disorders affect millions of people and these numbers are expected to rise as result of Europe's ageing population. Given the biological causes of many of these disorders, most studies focus on their molecular basis. Bipolar disorder (BD) is characterized by mood swings between depression and mania resulting in cognitive and functional impairments that require lifetime treatment. Recurrent mood episodes, residual symptoms, functional impairment, psychosocial disability with high rates of divorce, unemployment, drug abuse and suicide attempting, and significant medical comorbidities such as metabolic and cardiovascular diseases cannot be efficiently controlled even with proper use of current treatments. Moreover, delayed diagnosis/misdiagnosis is frequent because reliable biomarkers are absent. Therefore, a better understanding of BD pathophysiology is a prerequisite for the design of new drugs and their implementation in clinical practice as well as to develop biomarkers for a more accurate and earlier diagnosis and/or evaluation of therapeutic response. This review summarises the association between decreased cellular resilience towards stress and BD. Since the key stress-response mediator Mitochondria-Associated Membranes (MAMs) modulate several BD relevant processes such as mitochondrial dysfunction and oxidative stress, Ca 2+ deregulation and cytoskeleton abnormalities, endoplasmic reticulum stress responses, loss of proteostasis and inflammasome activation, we propose the "MAM hypothesis" for BD pathophysiology. Targeting MAM-associated signaling pathways can be a promising investigation avenue to identify novel therapeutic strategies.Keywords: Bipolar disorder, Endoplasmic reticulum, Mitochondria, Mitochondria-associated membranes, Cellular resilience, Cellular stress, Plasticity. Bipolar DisorderBD is a chronic psychiatric illness with a remitting course, affecting 2.4% of the general population [1], characterized by mood swings between manic and depressive states that result in cognitive and functional impairments, high health care costs and premature mortality [2,3]. BD is the sixth leading cause of disability worldwide responsible for loss of more disability-adjusted life-years than all forms of cancer and major neurological conditions [4]. BD is associated with greatly impaired quality of life and increased physical health burden [5]. Moreover, BD patients tend to have high rates of divorce, unemployment, drug abuse and crime as consequence of impaired social cognition, and its impact on patients can be devastating, with approximately 23% of patients with BD reported having suicide attempts [6]. Moreover, individuals with BD diagnosis have a high risk of medical comorbidities such as metabolic (diabetes, obesity and metabolic syndrome) and cardiovascular disorders [7].Current knowl...

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Blood metabolomics analysis identifies abnormalities in the citric acid cycle, urea cycle, and amino acid metabolism in bipolar disorder

Cited by 91 publications

References 67 publications

Lactate in bipolar disorder: A systematic review and meta‐analysis

Lactate in bipolar disorder: A systematic review and meta‐analysis

Capillary electrophoresis mass spectrometry based metabolomics

The ups and downs of cellular stress: the “MAM hypothesis” for Bipolar disorder pathophysiology

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