Role of endogenous ouabain in the etiology of bipolar disorder

Abstract Background Bipolar disorder is a severe psychiatric illness with poor prognosis and problematic and suboptimal treatments. Understanding the pathoetiologic mechanisms may improve treatment and outcomes. Discussion Dysregulation of cationic homeostasis is the most reproducible aspect of bipolar pathophysiology. Correction of ionic balance is the universal mechanism of action of all mood stabilizing medications. Recent discoveries of the role of endogenous sodium pump modulators (which include ‘endogenous ouabain’) in regulation of sodium and potassium distribution, inflammation, and activation of key cellular second messenger systems that are important in cell survival, and the demonstration that these stress-responsive chemicals may be dysregulated in bipolar patients, suggest that these compounds may be candidates for the coupling of environmental stressors and illness onset. Specifically, individuals with bipolar disorder appear to be unable to upregulate endogenous ouabain under conditions that require it, and therefore may experience a relative deficiency of this important regulatory hormone. In the absence of elevated endogenous ouabain, neurons are unable to maintain their normal resting potential, become relatively depolarized, and are then susceptible to inappropriate activation. Furthermore, sodium pump activity appears to be necessary to prevent inflammatory signals within the central nervous system. Nearly all available data currently support this model, but additional studies are required to solidify the role of this system. Conclusion Endogenous ouabain dysregulation appears to be a reasonable candidate for understanding the pathophysiology of bipolar disorder.

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The Expanding Role of Antipsychotics

CNS Spectrums ◽

10.1017/s1092852900027140 ◽

2004 ◽

Vol 9 (S1) ◽

pp. 7-12

Author(s):

Philip G. Janicak

Keyword(s):

Bipolar Disorder ◽

Manic Episode ◽

Acute Mania ◽

Psychotic Symptoms ◽

Primary Therapy ◽

Obsessive Compulsive ◽

Stabilizing Agent ◽

Compulsive Disorder ◽

Bipolar Patients

Antipsychotics have been utilized in the treatment of bipolar disorder for many decades and were the mainstay of treatment before lithium was reintroduced in the late 1960s. Today, many bipolar patients who present with psychotic features are misdiagnosed and prescribed an antipsychotic for another disorder. Estimates of psychotic symptoms in bipolar disorder, particularly during a manic episode, are ≥50% by clinical assessment and even higher by individual reports. Thus, antipsychotics are frequently used: as first treatment for psychosis not recognized as bipolar disorder, and as an adjunct to a mood-stabilizing agent in bipolars with psychotic symptoms.Most recently, antipsychotics have been examined for their mood-stabilizing properties as well (Slide 9). One may conceptualize using a selective serotonin reuptake inhibitor (SSRI) antidepressant for disorders such as panic disorder or obsessive-compulsive disorder, and using an antiepileptic as a mood-stabilizing agent; however, it is more difficult to accept that an agent approved for treatment of psychosis can be a primary therapy for bipolar disorder. Data from the monotherapy trials suggest that second-generation antipsychotics (SGAs) are at least as effective as lithium and valproic acid for acute mania. There is a very large database indicating that SGAs can be utilized as monotherapy for acute mania. However, there is limited data on the role of these agents in prevention of relapse and recurrence and in their efficacy for depression in the context of bipolar disorder. More studies will be needed to clarify whether SGAs should be used as monotherapy or whether they would be best used as augmenting agents in severe and psychotically manic or depressed patients.

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Impaired recognition of happy facial expressions in bipolar disorder

Acta Neuropsychiatrica ◽

10.1017/neu.2014.6 ◽

2014 ◽

Vol 26 (4) ◽

pp. 253-259 ◽

Cited By ~ 8

Author(s):

Linette Lawlor-Savage ◽

Scott R. Sponheim ◽

Vina M. Goghari

Keyword(s):

Bipolar Disorder ◽

Emotion Recognition ◽

Facial Expressions ◽

Processing Speed ◽

Facial Emotion Recognition ◽

Facial Emotion ◽

Recognition Ability ◽

Recognition Condition ◽

Bipolar Patients

BackgroundThe ability to accurately judge facial expressions is important in social interactions. Individuals with bipolar disorder have been found to be impaired in emotion recognition; however, the specifics of the impairment are unclear. This study investigated whether facial emotion recognition difficulties in bipolar disorder reflect general cognitive, or emotion-specific, impairments. Impairment in the recognition of particular emotions and the role of processing speed in facial emotion recognition were also investigated.MethodsClinically stable bipolar patients (n = 17) and healthy controls (n = 50) judged five facial expressions in two presentation types, time-limited and self-paced. An age recognition condition was used as an experimental control.ResultsBipolar patients’ overall facial recognition ability was unimpaired. However, patients’ specific ability to judge happy expressions under time constraints was impaired.ConclusionsFindings suggest a deficit in happy emotion recognition impacted by processing speed. Given the limited sample size, further investigation with a larger patient sample is warranted.

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Immunology of Bipolar Disorder

Immunopsychiatry ◽

10.1093/med/9780190884468.003.0012 ◽

2018 ◽

pp. 211-226

Author(s):

Izabela G. Barbosa ◽

Moises E. Bauer ◽

Jair C. Soares ◽

Antônio L. Teixeira

Keyword(s):

Bipolar Disorder ◽

Mononuclear Cells ◽

Immune Cell ◽

Course Of Illness ◽

Wide Range ◽

High Prevalence ◽

The Central Nervous System ◽

Immune Changes ◽

Inflammatory Changes

Bipolar disorder (BD) is a severe, chronic, and recurrent psychiatric illness. It has been associated with a high prevalence of medical and psychiatric comorbidities, cognitive impairment, and a progressive course of illness. Its neurobiology is not completely understood, but recent evidence has shown a wide range of immune changes. Here we review several data supporting the presence of immunological dysfunction in BD: (1) increased frequency of autoimmune diseases; (2) distinct immune cell profile; (3) altered release of cytokines by stimulated mononuclear cells; (4) elevated levels of circulating immune markers; (5) inflammatory changes in the central nervous system; (6) relationship with clinical comorbidities; and (7) the effect of current treatments on the immune system and the role of immunomodulatory agents.

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Gender Differences in Complete Blood Count and Inflammatory Ratios among Patients with Bipolar Disorder

Brain Sciences ◽

10.3390/brainsci11030363 ◽

2021 ◽

Vol 11 (3) ◽

pp. 363

Author(s):

Laura Fusar-Poli ◽

Andrea Amerio ◽

Patriciu Cimpoesu ◽

Pietro Grimaldi Filioli ◽

Antimo Natale ◽

...

Keyword(s):

Gender Differences ◽

Bipolar Disorder ◽

Blood Count ◽

Complete Blood Count ◽

Low Cost ◽

Female Group ◽

State Dependent ◽

And Gender ◽

Bipolar Patients

Background: Evidence suggested that inflammation may be involved in the etiopathogenesis of bipolar disorder (BD), a chronic psychiatric condition affecting around 2-3% of the general population. However, little is known regarding potential gender differences in peripheral biomarkers of BD, such as neutrophil-to-lymphocyte (NLR), platelet-to-lymphocyte (PLR), and monocyte-to-lymphocyte (MLR) ratios. Methods: In total, 197 females and 174 males with BD in different phases (i.e., (hypo)mania, depression, euthymia) were recruited. A blood sample was drawn to perform a complete blood count (CBC). NLR, PLR, and MLR were subsequently calculated, and differences were computed according to the illness phase and gender. Results: PLR was consistently higher in (hypo)manic than depressed patients, in both males and females. No significant gender differences in PLR value were found when considering only (hypo)mania. Conversely, NLR was increased in (hypo)mania only among males, and gender differences were retrieved in the (hypo)manic subgroup. The findings related to MLR were only marginally significant. Higher platelets values were associated with (hypo)mania only in the female group. Basophils and eosinophils appeared gender- but not state-dependent. Conclusions: Our findings provide further evidence that increased PLR levels may be associated with (hypo)mania in bipolar patients, regardless of gender. Moreover, the usefulness of NLR as a peripheral biomarker of BD appeared limited to males while the role of platelets to females. As CBC represents a low-cost and easily accessible test, researchers should investigate in-depth its potential usefulness as a biomarker of BD and other psychiatric disorders.

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Insanity defence in bipolar patients at the time of committing murder according to Iranian law: Case studies

Medico-Legal Journal ◽

10.1177/0025817219876548 ◽

2019 ◽

Vol 88 (1) ◽

pp. 24-29

Author(s):

Azadeh Memarian ◽

Seyed Hossein Moosavinezhad Baboli ◽

Hanieh Saboori Shekofteh

Keyword(s):

Bipolar Disorder ◽

Social Media ◽

Public Education ◽

Forensic Psychiatry ◽

Legal Responsibility ◽

Criminal Behaviour ◽

Iranian Law ◽

The Family ◽

Bipolar Patients

Bipolar disorder is a chronic, relapsing illness characterised by recurrent episodes of manic or depressive symptoms, with intervening periods that are relatively (but not fully) symptom-free. Studies have found higher rates of psychiatric disorders in homicide offenders than in the general population. The insanity defence is a legal construct that, under some circumstances, excuses defendants with mental illness from legal responsibility for criminal behaviour. Here we report two cases of family murder by the mother of the family caused by bipolar disease. The role of the forensic psychiatrist in diagnosing insanity during the commission of a crime is very important as these patients should be diagnosed, treated as soon as possible, and monitored. Public education through social media should be considered to reduce crimes in societies. Diagnosing insanity during the commission of a crime is very important and requires high precision forensic psychiatry. Public education through social media should be considered to reduce crimes in societies.

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Investigation of the impact of an ADCY2 polymorphism as a predictive biomarker in bipolar disorder, suicide tendency and response to lithium carbonate therapy: the first report from Iran

Pharmacogenomics ◽

10.2217/pgs-2020-0058 ◽

2020 ◽

Vol 21 (14) ◽

pp. 1011-1020

Author(s):

Sara Sadat Aghabozorg Afjeh ◽

Jamal Shams ◽

Safar Hamednia ◽

Behzad Boshehri ◽

Amir Olfat ◽

...

Keyword(s):

Bipolar Disorder ◽

Suicide Ideation ◽

Lithium Carbonate ◽

Predictive Biomarker ◽

Amplification Refractory Mutation System ◽

Cerebral Endothelium ◽

Mutation System ◽

Bipolar Patients ◽

The Impact

High rates of mortality due to both suicide and medical comorbidities in bipolar patients can be decreased through the administration of lithium, which affects the cerebral endothelium as well as neurons. To investigate the role of ADCY2 in risk of bipolar disorder, we genotyped the ADCY2 rs2290910 in bipolar patients and healthy controls using amplification refractory mutation system PCR. This polymorphism was associated with risk of bipolar disorder (odds ratio [OR]: 0.430; 95% CI: 0.296–0.624; p = 0.001). The C allele was more frequent in suicide ideation group compared other groups (OR: 2.7; 95% CI: 1.386–5.302; p = 0.004). The T allele was more frequent in suicide attempt group compared with suicide ideation group (OR: 0.238; 95% CI: 0.111–0.509; p = 0.001).

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Disruption in the Blood-Brain Barrier: The Missing Link between Brain and Body Inflammation in Bipolar Disorder?

Neural Plasticity ◽

10.1155/2015/708306 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 78

Author(s):

Jay P. Patel ◽

Benicio N. Frey

Keyword(s):

Bipolar Disorder ◽

Blood Brain Barrier ◽

Peripheral Blood ◽

Critical Role ◽

Brain Barrier ◽

Inflammatory Conditions ◽

Blood Brain ◽

The Central Nervous System ◽

The Brain

The blood-brain barrier (BBB) regulates the transport of micro- and macromolecules between the peripheral blood and the central nervous system (CNS) in order to maintain optimal levels of essential nutrients and neurotransmitters in the brain. In addition, the BBB plays a critical role protecting the CNS against neurotoxins. There has been growing evidence that BBB disruption is associated with brain inflammatory conditions such as Alzheimer’s disease and multiple sclerosis. Considering the increasing role of inflammation and oxidative stress in the pathophysiology of bipolar disorder (BD), here we propose a novel model wherein transient or persistent disruption of BBB integrity is associated with decreased CNS protection and increased permeability of proinflammatory (e.g., cytokines, reactive oxygen species) substances from the peripheral blood into the brain. These events would trigger the activation of microglial cells and promote localized damage to oligodendrocytes and the myelin sheath, ultimately compromising myelination and the integrity of neural circuits. The potential implications for research in this area and directions for future studies are discussed.

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Altered plasma glutathione levels in bipolar disorder indicates higher oxidative stress; a possible risk factor for illness onset despite normal brain-derived neurotrophic factor (BDNF) levels

Psychological Medicine ◽

10.1017/s0033291714000014 ◽

2014 ◽

Vol 44 (11) ◽

pp. 2409-2418 ◽

Cited By ~ 48

Author(s):

A. R. Rosa ◽

N. Singh ◽

E. Whitaker ◽

M. de Brito ◽

A. M. Lewis ◽

...

Keyword(s):

Oxidative Stress ◽

Bipolar Disorder ◽

Neurotrophic Factor ◽

Redox State ◽

Brain Derived Neurotrophic Factor ◽

Normal Brain ◽

Total Glutathione ◽

Illness Onset ◽

Plasma Glutathione ◽

Bipolar Patients

BackgroundOxidative stress and neurotrophic factors have been implicated in the pathophysiology of bipolar disorder. Our objective was to determine whether plasma glutathione or brain-derived neurotrophic factor (BDNF) levels were abnormal in bipolar disorder and therefore useful as possible biomarkers.MethodBlood samples were collected from subsyndromal, medicated bipolar I patients (n = 50), recruited from OXTEXT, University of Oxford, and from 50 matched healthy controls. Total and oxidized glutathione levels were measured using an enzymatic recycling method and used to calculate reduced, percentage oxidized, ratio of reduced:oxidized and redox state. BDNF was measured using an enzyme-linked immunoassay. Self-monitored mood scores for the bipolar group were available (Quick Inventory of Depressive Symptomatology and the Altman Self-Rating Mania Scale) over an 8-week period.ResultsCompared with controls, bipolar patients had significantly lower levels of total glutathione and it was more oxidized. BDNF levels were not different. Age of illness onset but not current mood state correlated with total glutathione levels and its oxidation status, so that lower levels of total and reduced glutathione were associated with later onset of disease, not length of illness.ConclusionsPlasma glutathione levels and redox state detect oxidative stress even in subsyndromal patients with normal BDNF. It may relate to the onset and development of bipolar disorder. Plasma glutathione appears to be a suitable biomarker for detecting underlying oxidative stress and for evaluating the efficacy of antioxidant intervention studies.

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A Comprehensive Review on the Role of Non-Coding RNAs in the Pathophysiology of Bipolar Disorder

International Journal of Molecular Sciences ◽

10.3390/ijms22105156 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5156

Author(s):

Soudeh Ghafouri-Fard ◽

Elham Badrlou ◽

Mohammad Taheri ◽

Kenneth Dürsteler ◽

Annette Beatrix Brühl ◽

...

Keyword(s):

Bipolar Disorder ◽

Targeted Therapies ◽

Glutamatergic Synapses ◽

Redox Modulation ◽

Altered Expression ◽

Comprehensive Review ◽

Morphine Addiction ◽

Non Coding Rnas ◽

Bipolar Patients

Aim: Bipolar disorder is a multifactorial disorder being linked with dysregulation of several genes. Among the recently acknowledged factors in the pathophysiology of bipolar disorder are non-coding RNAs (ncRNAs). Methods: We searched PubMed and Google Scholar databases to find studies that assessed the expression profile of miRNAs, lncRNAs and circRNAs in bipolar disorder. Results: Dysregulated ncRNAs in bipolar patients have been enriched in several neuron-related pathways such as GABAergic and glutamatergic synapses, morphine addiction pathway and redox modulation. Conclusion: Altered expression of these transcripts in bipolar disorder provides clues for identification of the pathogenesis of this disorder and design of targeted therapies for the treatment of patients.

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Oxidative Stress and Bipolar Mood Disorder: An Important Yet Ambiguous Relationship

Journal of Pharmaceutical Care ◽

10.18502/jpc.v9i4.8225 ◽

2022 ◽

Author(s):

Sara Rahsepar ◽

Amirhooshang Mohammadpour

Keyword(s):

Oxidative Stress ◽

Bipolar Disorder ◽

Thiobarbituric Acid ◽

Bipolar Mood Disorder ◽

Oxidative Markers ◽

Stress Oxidative ◽

Bipolar Patients ◽

The Relationship ◽

And Oxidative Stress

Bipolar disorder is a chronic psychological condition that disturbs many patients' lives around the world. The exact pathophysiology of bipolar disorder is yet unknown, but there are several hypotheses to explain this condition. One of the most challenging theories is the role of oxidative stress in the progression of bipolar disorder. Here, we conducted a narrative review to gather the studies that investigated the relationship between bipolar disorder and oxidative stress. We searched PubMed, Scopus, Web of science, and google scholar databases using the following keywords: “bipolar disorder,” “oxidative stress,” “oxidative markers,” and “bipolar patients.” A majority of studies showed that oxidative markers such as Thiobarbituric acid reactive substances are significantly higher in bipolar patients compared to healthy subjects. Based on the included articles, bipolar disorder is associated with oxidative stress. Nevertheless, further well-established Cohorts are required to support these results.

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