The Na,K-ATPase hypothesis for bipolar illness

doi:10.1016/0006-3223(94)00201-D

Biological Psychiatry

Volume 37, Issue 4, 15 February 1995, Pages 235-244

https://doi.org/10.1016/0006-3223(94)00201-D Get rights and content

A cellular model for bipolar illness is presented. It is propounded that alterations in the activity of the membrane sodium- and potassium-activated adenosine triphosphatase pump (Na,K-ATPase) may be responsible for alterations in neuronal excitability and activity. Specifically, a reduction in Na,K-ATPase activity can lead to both mania and depression by increasing membrane excitability and decreasing neurotransmitter release, respectively. Supporting evidence is reviewed, and clinical and research implications are discussed.

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Biological rhythms are correlated with Na<sup>+</sup>, K<sup>+</sup>-ATPase and oxidative stress biomarkers: A translational study on bipolar disorder
2023, Journal of Affective Disorders
Bipolar disorder (BD) is a chronic, severe, and multifactorial psychiatric disorder. Although biological rhythms alterations, sodium potassium pump (Na⁺, K⁺-ATPase) changes, and oxidative stress appear to play a critical role in the etiology and pathophysiology of BD, the inter-connection between them has not been described. Therefore this study evaluated the association between biological rhythms, Na⁺, K⁺-ATPase, and oxidative stress parameters in BD patients and the preclinical paradoxical sleep deprivation model (PSD).
A translational study was conducted, including a case-control protocol with 36 BD and 46 healthy controls (HC). Subjects completed the Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN). In addition, Erythrocyte Na⁺, K⁺-ATPase activity, and oxidative and nitrosative stress markers were assessed (4-hydroxynonenal [4-HNE], 8-isoprostane [8-ISO], thiobarbituric acid reactive substances [TBARS], carbonyl, 3-nitrotyrosine [3-nitro]). In the preclinical protocol, the same biomarkers were evaluated in the frontal cortex, hippocampus, and striatum from mice submitted to the PSD.
BD patients had a significantly higher total score of BRIAN versus HCs. Additionally, individuals with BD showed decreased Na⁺, K⁺-ATPase activity and increased oxidative stress parameters compared to HC without psychiatric disorders. This difference was driven by actively depressed BD subjects. The mice submitted to the PSD also demonstrated decreased Na⁺, K⁺-ATPase activity and increased oxidative stress parameters.
BRIAN biological underpinning is less well characterized; We did not control for medication status; Sample size is limited; PSD it is not a true model of BD.
The present study found a significant correlation between Na⁺, K⁺-ATPase and oxidative stress with changes in biological rhythms, reinforcing the importance of these parameters to BD.
Folic acid does not have an anti-manic effect but protect the brain against oxidative stress in an animal model of mania induced by ouabain
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Bipolar disorder (BD) is a complex and severe mental disorder that affects 1–3 % of the world population. Studies have suggested the involvement of oxidative stress in the physiopathology of this psychiatry disorder. Folic acid (FA), a vitamin from the B complex, is a nutraceutical that has recently been researched as a possible treatment for BD since folate is reduced in patients with the disorder. The present study aimed to evaluate the effects of lithium (Li) and FA on behavioral changes and oxidative stress parameters in an animal model of mania induced by ouabain (OUA).
Wistar rats received a single intracerebroventricular (ICV) injection of OUA or artificial cerebrospinal fluid (aCSF). From the day following ICV injection, the rats were treated for seven days with gavage injections of Li (47.5 mg/kg/mL), FA (50 mg/kg/mL), or water (1 mL/kg). On the 7th day after OUA injection, locomotor activity was measured using the open-field test. In addition, the oxidative stress parameters were evaluated in rats' frontal cortex, striatum, and hippocampus.
OUA induced mania-like behavior and oxidative stress in rats' brains, but Li could reverse these alterations. FA did not affect behavior parameters; however, it presents an antioxidant effect on the brain structures evaluated.
The study was only evaluated male rats and ICV injection is an invasive procedure.
These results indicate that even though FA has an effect against the oxidative stress induced by OUA, this effect was not strong enough to interfere with behavior parameters.
Catatonia Secondary to Depolarization Block
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Catatonia is a severe psychomotor disorder that is associated with a 60-fold increased risk of premature death. Its occurrence has been associated with multiple psychiatric diagnoses, the most common being type I bipolar disorder. Catatonia can be understood as a disorder of ion dysregulation with reduced clearance of intracellular sodium ions. As the intraneuronal sodium concentration increases, the transmembrane potential is increased, and the resting potential may ultimately depolarize above the cellular threshold potential creating a condition known as depolarization block. Neurons in depolarization block do not respond to stimulation but are constantly releasing neurotransmitter; they mirror the clinical state of catatonia – active but non-responsive. Hyperpolarizing neurons, e.g., with benzodiazepines, is the most effective treatment.
Polyunsaturated fatty acids changes during electroconvulsive therapy in major depressive disorder
2023, Journal of Psychiatric Research
Polyunsaturated fatty acids (PUFAs) have important electrochemical properties and have been implicated in the pathophysiology of major depressive disorder (MDD) and its treatment. However, the relation of PUFAs with electroconvulsive therapy (ECT) has never been investigated. Therefore, we aimed to explore the associations between PUFA concentrations and response to ECT in patients with MDD. We included 45 patients with unipolar MDD in a multicentre study. To determine PUFA concentrations, we collected blood samples at the first (T0) and twelfth (T12) ECT-session. We assessed depression severity using the Hamilton Rating Scale for Depression (HAM-D) at T0, T12 and at the end of the ECT-course. ECT-response was defined as ‘early response’ (at T12), ‘late response’ (after ECT-course) and ‘no’ response (after the ECT-course). The PUFA chain length index (CLI), unsaturation index (UI) and peroxidation index (PI) and three individual PUFAs (eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA] and nervonic acid [NA]) were associated with response to ECT using linear mixed models. Results showed a significant higher CLI in ‘late responders’ compared to ‘non responders’. For NA, ‘late responders’ showed significantly higher concentrations compared to ‘early’- and ‘non responders’. In conclusion, this study provides the first indication that PUFAs are associated with the efficacy of ECT. This indicates that PUFAs' influence on neuronal electrochemical properties and neurogenesis may affect ECT outcomes. Thereby, PUFAs form a potentially modifiable factor predicting ECT outcomes, that warrants further investigation in other ECT-cohorts.
Ketogenic diet as a metabolic therapy for bipolar disorder: Clinical developments
2023, Journal of Affective Disorders Reports
Key underlying metabolic pathologies are thought to play a role in bipolar disorder (BD), including dysfunctions in energy metabolism. This review highlights underlying metabolic mechanisms of BD and potential therapeutic effects of a low carbohydrate ketogenic diet (KD) on mood symptoms. Based on its robust 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, amongst other effects on stabilizing neural networks in the brain.
A literature review was conducted on current metabolic mechanisms of BD and clinical developments in KD.
Recent findings support the idea that BD may have roots of metabolic dysfunction: cerebral glucose hypometabolism, oxidative stress, as well as mitochondrial and neurotransmitter dysfunction. A KD provides alternative fuel to the brain and is believed to contain beneficial neuroprotective effects, including neural network stabilization and inflammation reduction. Several beneficial metabolic effects on insulin resistance, weight, and lipid composition have been shown.
Limited case studies on KD treatment in BD have been reported to date.
Preliminary data support further testing of a low carbohydrate KD as a potential therapeutic tool in repairing energy metabolism in bipolar illness. Additionally, it may repair deficits in energy metabolism often seen in BD. Further research and clinical trials are needed to evaluate the efficacy of a KD as a supplemental or co-treatment of bipolar illness and an open-label pilot trial testing the diet in bipolar illness is currently underway at Stanford.
Depressive-like behavior accompanies neuroinflammation in an animal model of bipolar disorder symptoms induced by ouabain
2022, Pharmacology Biochemistry and Behavior
A previous study from our Laboratory showed no alteration in inflammatory parameters seven days after ouabain (OUA) administration, a Na⁺K⁺ATPase inhibitor, which was previously considered only a mania model. However, the administration of OUA in rats was recently validated as a model of bipolar disorder (BD) symptoms, demonstrating that 14 days after single intracerebroventricular (ICV) administration, OUA also induces depressive-like behavior. Therefore, it is important to investigate the long-term effect of OUA on inflammatory parameters since this mechanism seems to play a key role in BD physiopathology.
Adult male Wistar rats received a single ICV administration of OUA or artificial cerebrospinal fluid (aCSF). From the fourth day after the ICV infusion, the rats received saline or Lithium (Li) for 14 days. The open-field test was performed on the 7th day after OUA. On the 14th day, locomotion was re-evaluated, and the forced swimming test (FST) was used to evaluate depressive-like behavior. Inflammatory parameters were assessed in the frontal cortex and hippocampus.
OUA increased the locomotion of rats after seven days, considered a mania-like behavior. In the FST, OUA increased the time of immobility on the 14th day, considered a depressive-like behavior. Li reversed the mania-like behavior and partially reversed the depressive-like behavior. Furthermore, OUA increased the levels of interleukin (IL)-1β, IL-6, IL-10, TNF-α, and CINC-1 in the frontal cortex and hippocampus. Li treatment reverses all these inflammatory alterations.
This study suggests that the long-term Na⁺K⁺ATPase inhibition effects induce depressive-like behavior, which was accompanied by inflammation in the BD symptoms model.

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Original articleThe Na,K-ATPase hypothesis for bipolar illness

Biol Psychiatry

Biol Psychiatry

Prog Biophys Mol Biol

J Affect Disord

J Biol Chem

Lancet

Med Hypotheses

Biochem Med

Psychiatry Res

Biol Psychiatry

Biol Psychiatry

Med Hypotheses

Med Hypotheses

Life Sci

Life Sci

Life Sci

Brain Res

Lancet

Brain Res

Biol Psychiatry

Lancet

Lancet

J Psychosom Res

Psychiatry Res

Activity of erythrocyte Na,K-ATPase in manic patients

J Neurochem

Lithium retention in mania

Arch Gen Psychiatry

On the permeability of mammalian nonmyelinated fibers to sodium and to lithium ions

J Physiology (London)

Oxygen and glucose consumption related to Na+-K+ transport in canine brain

Stroke

Lithium inhibits adrenergic and cholinergic increases in GTP binding in rat cortex

Nature

Sodium balance and distribution in lithium carbonate therapy

Arch Gen Psychiatry

The influence of calcium on sodium efflux in squid axons

J Physiology

Second messenger systems and psychoactive drug action: Focus on the phosphoinositide system and lithium

Am J Psychiatry

Cerebral metabolic rates for glucose in mood disorders: Studies with positron emission tomography and fluorodeoxyglucose F 18

Arch Gen Psychiatry

Reduction of prefrontal cortex glucose metabolism common to three types of depression

Arch Gen Psychiatry

Lithium amplifies agonist-dependent phosphatidyl inositol responses in brain and salivary glands

Biochem J

Inhibition by dopamine of (Na+ + K+) ATPase activity in neostriatal neurons through D1 and D2 dopamine receptor synergism

Nature

The interrelationship between sodium and calcium fluxed across cell membranes

Rev Physiol Biochem Pharmacol

Calcium transport and buffering in neurons

Trend Neurosci

Control of intracellular calcium in presynaptic nerve terminals

Fed Proc

Calcium efflux from internally dialyzed squid axons: The influence of external and internal cations

J Supramolec Structure

Effect of sodium ions on calcium movements in isolated synaptic terminals

The plasma membrane in the control of the signaling function of calcium

Calcium: Bivalent cation in the bivalent psychoses

Biol Psychiatry

Influences of lithium ions on the transmembrane potential and cation content of cardiac cells

J Gen Physiol

Sodium and potassium transfer to CSF in severe depression

Depression, ECT, and erythrocyte adenosine triphosphatase activity

Biol Psychiatry

Mineral metabolism in melancholia

Br Med J

Mineral metabolism in mania

Br Med J

Abnormality of the blood-cerebrospinal fluid barrier of patients suffering from a depressive illness

J Neurol Neurosurg Psychiatry

Lithium, sodium and potassium transport in erythrocytes of manic-depressive patients

Acta Psychiatr Scand

Original article
The Na,K-ATPase hypothesis for bipolar illness

Oxygen and glucose consumption related to Na⁺-K⁺ transport in canine brain

Inhibition by dopamine of (Na⁺ + K⁺) ATPase activity in neostriatal neurons through D₁ and D₂ dopamine receptor synergism