Cerebrospinal fluid oxidative stress metabolites in patients with bipolar disorder and healthy controls: a longitudinal case-control study

Knorr, Ulla; Simonsen, Anja Hviid; Roos, Peter; Weimann, Allan; Henriksen, Trine; Christensen, Ellen Margrethe; Vinberg, Maj; Mikkelsen, R.L.; Kirkegaard, Tove; Jensen, Rigmor; Akhøj, Morten; Forman, Julie Lyng; Poulsen, Henrik Enghusen; Hasselbalch, Steen G.; Kessing, Lars Vedel

doi:10.1038/s41398-019-0664-6

“…Several biological mechanisms have been proposed as potential underlying causes of BD. These include mitochondrial dysfunction (Jeong et al, 2020;Kato, 2017;Scaini et al, 2021;Scaini et al, 2016), oxidative stress (Knorr et al, 2019;Steullet et al, 2018), and neurotransmitter disruption (Liu, Zhao, & Guo, 2018;Martino & Magioncalda, 2021). Increasing numbers of genetic, biological, and neuroimaging studies have begun to address these hypotheses in recent years.…”

Section: Mechanisms and Pathophysiology Of Bdmentioning

confidence: 99%

Ketogenic diet as a metabolic therapy for bipolar disorder: Clinical developments

Yu

¹

,

Ozveren

²

,

Dalai

³

2021

Preprint

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Background: Bipolar disorder is a neurodevelopmental illness characterized by severe biphasic changes in mood, energy, or thought. Key underlying metabolic pathologies thought to play a role include dysfunction in energy metabolism. The purpose of this article is to review the findings to date of the effects of a low carbohydrate ketogenic diet (KD) on mood symptoms in preclinical and clinical models of bipolar illness. The review highlights the underlying metabolic pathologies of bipolar disorder (BD) and potential therapeutic effects of the KD on these pathologies. The article also explores the potential effects of a KD on metabolic health in BD, including proposed mechanisms of action.Summary: Recent findings support the idea that bipolar disorder, along with other psychiatric disease, may have roots of metabolic dysfunction: cerebral glucose hypometabolism, oxidative stress, as well as mitochondrial and neurotransmitter dysfunction which has downstream effects on synapse connections. A KD provides alternative fuel to the brain aside from glucose and is believed to contain beneficial neuroprotective effects, including stabilization of brain networks, reduction of inflammation and oxidative stress. Several beneficial metabolic effects on insulin resistance, weight, and lipids have been shown. Based on its effectiveness in treating epilepsy, the KD has garnered recent interest in its application for mood disorders as it may imitate the pharmacological effects of mood stabilizers, commonly prescribed agents in the treatment of both BD and epilepsy. Additionally, it may improve metabolic dysfunction often seen in BD and repair deficits in energy metabolism. Limited case studies on KD treatment in BD have been reported; however, studies addressing the potential therapeutic effects of KD on metabolic abnormalities in mental illness are promising. Literature of plausible mechanisms and reports of improvements in psychosis, cognition and mood symptoms have been increasing.Conclusions: Preliminary findings support further testing of a low carbohydrate KD as a potential therapeutic tool in repairing energy metabolism in bipolar illness. Further research and clinical trials are needed to evaluate the efficacy of a KD as a supplemental or co-treatment of bipolar illness and the first open-label trial testing the diet in bipolar illness is currently underway at Stanford.

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“…Several biological mechanisms have been proposed as potential underlying causes of BD. These include mitochondrial dysfunction (Jeong et al, 2020;Kato, 2017;Scaini et al, 2021;Scaini et al, 2016), oxidative stress (Knorr et al, 2019;Steullet et al, 2018), and neurotransmitter disruption (Liu, Zhao, & Guo, 2018;Martino & Magioncalda, 2021). Increasing numbers of genetic, biological, and neuroimaging studies have begun to address these hypotheses in recent years.…”

Section: Mechanisms and Pathophysiology Of B Dmentioning

confidence: 99%

The use of a low carbohydrate, ketogenic diet in bipolar disorder: systematic review

Yu

¹

,

Ozveren

²

,

Dalai

³

2021

Preprint

2

0

View full text Add to dashboard Cite

Background: Bipolar disorder is a neurodevelopmental illness characterized by severe biphasic changes in mood, energy, or thought. Key underlying metabolic pathologies thought to play a role include dysfunction in energy metabolism. The purpose of this article is to review the findings to date of the effects of a low carbohydrate ketogenic diet (KD) on mood symptoms in preclinical and clinical models of bipolar illness. The review highlights the underlying metabolic pathologies of bipolar disorder (BD) and potential therapeutic effects of the KD on these pathologies. The article also explores the potential effects of a KD on metabolic health in BD, including proposed mechanisms of action.Summary: Recent findings support the idea that bipolar disorder, along with other psychiatric disease, may have roots of metabolic dysfunction: cerebral glucose hypometabolism, oxidative stress, as well as mitochondrial and neurotransmitter dysfunction which has downstream effects on synapse connections. A KD provides alternative fuel to the brain aside from glucose and is believed to contain beneficial neuroprotective effects, including stabilization of brain networks, reduction of inflammation and oxidative stress. Several beneficial metabolic effects on insulin resistance, weight, and lipids have been shown. Based on its effectiveness in treating epilepsy, the KD has garnered recent interest in its application for mood disorders as it may imitate the pharmacological effects of mood stabilizers, commonly prescribed agents in the treatment of both BD and epilepsy. Additionally, it may improve metabolic dysfunction often seen in BD and repair deficits in energy metabolism. Limited case studies on KD treatment in BD have been reported; however, studies addressing the potential therapeutic effects of KD on metabolic abnormalities in mental illness are promising. Literature of plausible mechanisms and reports of improvements in psychosis, cognition and mood symptoms have been increasing.Conclusions: Preliminary findings support further testing of a low carbohydrate KD as a potential therapeutic tool in repairing energy metabolism in bipolar illness. Further research and clinical trials are needed to evaluate the efficacy of a KD as a supplemental or co-treatment of bipolar illness and the first open-label trial testing the diet in bipolar illness is currently underway at Stanford.

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“…Furthermore, magnetic resonance spectroscopy (MRS) studies in BPAD patients revealed lower levels of the mitochondrial-deriving amino acid N-acetyl aspartate (NAA) in the hippocampus and PFC ( Yildiz-Yesilogu and Ankerst, 2006 ; Frey et al, 2007 ), increased brain lactate ( Machado-Vieira et al, 2017 ), and alterations in phosphocreatine ( Kato et al, 1994 ), creatine kinase reaction rate constant ( Du et al, 2018 ), and ATP levels after stimulation ( Yuksel et al, 2015 ). Further observations include evidence of systemic impairment in mitochondria-dependent energy production in BPAD patients [reviewed in Nierenberg et al (2013) ], including reduced intracellular pH and higher plasma lactate levels ( Kato and Kato, 2000 ; Machado-Vieira et al, 2017 ; Jeong et al, 2020 ), higher levels of cerebrospinal fluid oxidative stress markers ( Knorr et al, 2019 ), increased lipid peroxidation and DNA/RNA oxidative damage, and higher levels of nitric oxide ( Brown et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

The Neurometabolic Basis of Mood Instability: The Parvalbumin Interneuron Link—A Systematic Review and Meta-Analysis

Pinna

¹

,

Colasanti

²

2021

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The neurobiological bases of mood instability are poorly understood. Neuronal network alterations and neurometabolic abnormalities have been implicated in the pathophysiology of mood and anxiety conditions associated with mood instability and hence are candidate mechanisms underlying its neurobiology. Fast-spiking parvalbumin GABAergic interneurons modulate the activity of principal excitatory neurons through their inhibitory action determining precise neuronal excitation balance. These interneurons are directly involved in generating neuronal networks activities responsible for sustaining higher cerebral functions and are especially vulnerable to metabolic stress associated with deficiency of energy substrates or mitochondrial dysfunction. Parvalbumin interneurons are therefore candidate key players involved in mechanisms underlying the pathogenesis of brain disorders associated with both neuronal networks’ dysfunction and brain metabolism dysregulation. To provide empirical support to this hypothesis, we hereby report meta-analytical evidence of parvalbumin interneurons loss or dysfunction in the brain of patients with Bipolar Affective Disorder (BPAD), a condition primarily characterized by mood instability for which the pathophysiological role of mitochondrial dysfunction has recently emerged as critically important. We then present a comprehensive review of evidence from the literature illustrating the bidirectional relationship between deficiency in mitochondrial-dependent energy production and parvalbumin interneuron abnormalities. We propose a mechanistic explanation of how alterations in neuronal excitability, resulting from parvalbumin interneurons loss or dysfunction, might manifest clinically as mood instability, a poorly understood clinical phenotype typical of the most severe forms of affective disorders. The evidence we report provides insights on the broader therapeutic potential of pharmacologically targeting parvalbumin interneurons in psychiatric and neurological conditions characterized by both neurometabolic and neuroexcitability abnormalities.

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Cerebrospinal fluid oxidative stress metabolites in patients with bipolar disorder and healthy controls: a longitudinal case-control study

Cited by 43 publications

References 38 publications

Ketogenic diet as a metabolic therapy for bipolar disorder: Clinical developments

Ketogenic diet as a metabolic therapy for bipolar disorder: Clinical developments

The use of a low carbohydrate, ketogenic diet in bipolar disorder: systematic review

The Neurometabolic Basis of Mood Instability: The Parvalbumin Interneuron Link—A Systematic Review and Meta-Analysis

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