Materiały źródłowe

• #1 Molecular Mechanisms of Bipolar Disorder: Progress Made and Future Challenges

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5306135/

  Bipolar disorder (BD) is a chronic and progressive psychiatric illness characterized by mood oscillations, with episodes of mania and depression. Current knowledge of the pathophysiology and molecular mechanisms causing BD is still modest. […] A major challenge in BD is the development of effective drugs with low toxicity for the patients. In this review article, we focus on the progress made and future challenges we face in determining the pathophysiology and molecular pathways involved in BD, such as circadian and metabolic perturbations, mitochondrial and endoplasmic reticulum (ER) dysfunction, autophagy and glutamatergic neurotransmission; which may lead to the development of new drugs. […] The reduced understanding of the underlying pathophysiology and neurobiology of the disorder hampered the development of effective drugs. Neuroimaging studies have consistently revealed structural changes in the brain of BD patients.

• #2 The underlying neurobiology of bipolar disorder

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1525098/

  Clinical studies over the past decades have attempted to uncover the biological factors mediating the pathophysiology of bipolar disorder (BD) utilizing a variety of biochemical and neuroendocrine strategies. […] However, recent studies have also implicated critical signal transduction pathways as being integral to the pathophysiology and treatment of BD, in addition to a growing body of data suggesting that impairments of neuroplasticity and cellular resilience may also underlie the pathophysiology of the disorder. […] The pathophysiology is undoubtedly mediated by a network of interconnected limbic, striatal and fronto-cortical neurotransmitter neuronal circuits, and the interacting cholinergic, catecholaminergic and serotonergic neurotransmitter systems thus represent very attractive candidates.

• #3 The underlying neurobiology of bipolar disorder

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1525098/

  Clinical studies over the past decades have attempted to uncover the biological factors mediating the pathophysiology of bipolar disorder (BD) utilizing a variety of biochemical and neuroendocrine strategies. […] However, recent studies have also implicated critical signal transduction pathways as being integral to the pathophysiology and treatment of BD, in addition to a growing body of data suggesting that impairments of neuroplasticity and cellular resilience may also underlie the pathophysiology of the disorder. […] The pathophysiology is undoubtedly mediated by a network of interconnected limbic, striatal and fronto-cortical neurotransmitter neuronal circuits, and the interacting cholinergic, catecholaminergic and serotonergic neurotransmitter systems thus represent very attractive candidates.

• #4 The underlying neurobiology of bipolar disorder

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1525098/

  A true understanding of the pathophysiology of BD must address its neurobiology at different physiological levels, i.e. molecular, cellular, systems, and behavioral. […] It is at these levels that some compelling protein candidates have been identified as the targets for the actions of mood stabilizing agents; however, the precise manner in which these candidate molecular and cellular targets may or may not relate to the faulty expression of susceptibility gene products is yet to be determined. […] The subsequent challenge for the basic and clinical neuroscientist will be the integration of these molecular/cellular changes to the systems and ultimately to the behavioral level wherein the clinical expression of BD becomes fully elaborated. […] This article will focus upon recent data linking signaling abnormalities and impairments of neuroplasticity with the underlying neurobiology of BD.

• #5 Bipolar Disorder: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/286342-overview

  The pathophysiology of bipolar disorder has not been determined, and no objective biologic markers correspond definitively with the disease state. However, twin, family, and adoption studies all indicate that bipolar disorder has a significant genetic component. In fact, first-degree relatives of a person with bipolar disorder are approximately 7 times more likely to develop bipolar disorder than the rest of the population, and the heritability of bipolar I disorder (BPI) has recently been estimated at 0.73. […] The genetic component of bipolar disorder appears to be complex: The condition is likely to be caused by multiple different common disease alleles, each of which contributes a relatively low degree of risk on its own. Such disease genes can be difficult to find without very large sample sizes, on the order of thousands of subjects.

• #6 Bipolar disorder – Wikipedia

  https://en.wikipedia.org/wiki/Bipolar_disorder

  While the causes of this mood disorder are not clearly understood, both genetic and environmental factors are thought to play a role. Genetic factors may account for up to 7090% of the risk of developing bipolar disorder. Many genes, each with small effects, may contribute to the development of the disorder. Environmental risk factors include a history of childhood abuse and long-term stress. […] The precise mechanisms that cause bipolar disorder are not well understood. Bipolar disorder is thought to be associated with abnormalities in the structure and function of certain brain areas responsible for cognitive tasks and the processing of emotions. A neurologic model for bipolar disorder proposes that the emotional circuitry of the brain can be divided into two main parts. The ventral system (regulates emotional perception) includes brain structures such as the amygdala, insula, ventral striatum, ventral anterior cingulate cortex, and the prefrontal cortex. The dorsal system (responsible for emotional regulation) includes the hippocampus, dorsal anterior cingulate cortex, and other parts of the prefrontal cortex. The model hypothesizes that bipolar disorder may occur when the ventral system is overactivated and the dorsal system is underactivated.

• #7 Bipolar Disorder: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/286342-overview

  The pathophysiology of bipolar disorder has not been determined, and no objective biologic markers correspond definitively with the disease state. However, twin, family, and adoption studies all indicate that bipolar disorder has a significant genetic component. In fact, first-degree relatives of a person with bipolar disorder are approximately 7 times more likely to develop bipolar disorder than the rest of the population, and the heritability of bipolar I disorder (BPI) has recently been estimated at 0.73. […] The genetic component of bipolar disorder appears to be complex: The condition is likely to be caused by multiple different common disease alleles, each of which contributes a relatively low degree of risk on its own. Such disease genes can be difficult to find without very large sample sizes, on the order of thousands of subjects.

• #8 Bipolar Disorder: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/286342-overview

  Genome-wide association studies (GWASs) for bipolar disorder were published in 2007 and 2008, and a collaborative analysis of the last 3 studies gave combined support for 2 particular genes, ANK3 (ankyrin G) and CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel) in a sample of 4387 cases and 6209 controls. […] Both ANK3 and subunits of the calcium channel are downregulated in mouse brain in response to lithium, which indicates a possible therapeutic mechanism of action of one of the most effective treatments for bipolar disorder. […] CACNA1C, on chromosome 12, encodes the alpha subunit of the L-type voltage-gated calcium ion channel found in the brain. L-type calcium channel blockers have been used to treat bipolar disorder, and there has been speculation that at least some mood stabilizers may mediate their effects via modulating calcium channel signaling in bipolar illness.

• #9 Biology of bipolar disorder – Wikipedia

  https://en.wikipedia.org/wiki/Biology_of_bipolar_disorder

  The familial transmission of mania and depression are largely independent of each other. This raises the possibility that bipolar is actually two biologically distinct but highly comorbid conditions. […] Significant overlaps with schizophrenia have been reported at CACNA1C, ITIH, ANK3, and ZNF804A. […] This overlap is congruent with the observation that relatives of probands with schizophrenia are at higher risk for bipolar disorder and vice versa. […] The „kindling model” of mood disorders suggests that major environmental stressors trigger initial mood episodes, but as mood episodes occur, weaker and weaker triggers can precipitate an affective episode. […] This model was initially created for epilepsy, to explain why weaker and weaker electrical stimulation was necessary to elicit a seizure as the disease progressed.

• #10 Bipolar Disorder: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/286342-overview

  Genome-wide association studies (GWASs) for bipolar disorder were published in 2007 and 2008, and a collaborative analysis of the last 3 studies gave combined support for 2 particular genes, ANK3 (ankyrin G) and CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel) in a sample of 4387 cases and 6209 controls. […] Both ANK3 and subunits of the calcium channel are downregulated in mouse brain in response to lithium, which indicates a possible therapeutic mechanism of action of one of the most effective treatments for bipolar disorder. […] CACNA1C, on chromosome 12, encodes the alpha subunit of the L-type voltage-gated calcium ion channel found in the brain. L-type calcium channel blockers have been used to treat bipolar disorder, and there has been speculation that at least some mood stabilizers may mediate their effects via modulating calcium channel signaling in bipolar illness.

• #11 Bipolar Disorder: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/286342-overview

  Genome-wide association studies (GWASs) for bipolar disorder were published in 2007 and 2008, and a collaborative analysis of the last 3 studies gave combined support for 2 particular genes, ANK3 (ankyrin G) and CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel) in a sample of 4387 cases and 6209 controls. […] Both ANK3 and subunits of the calcium channel are downregulated in mouse brain in response to lithium, which indicates a possible therapeutic mechanism of action of one of the most effective treatments for bipolar disorder. […] CACNA1C, on chromosome 12, encodes the alpha subunit of the L-type voltage-gated calcium ion channel found in the brain. L-type calcium channel blockers have been used to treat bipolar disorder, and there has been speculation that at least some mood stabilizers may mediate their effects via modulating calcium channel signaling in bipolar illness.

• #12 Bipolar disorder – Wikipedia

  https://en.wikipedia.org/wiki/Bipolar_disorder

  Bipolar disorder is associated with reduced expression of specific DNA repair enzymes and increased levels of oxidative DNA damages. The AKAP11 gene was recently discovered as the first gene linked to bipolar disorder. The exomes of around 14,000 individuals with bipolar disorder were analysed and compared to those without the condition. The findings were combined with data from another study in the Schizophrenia Exome Sequencing Meta-Analysis (SCHEMA), examining the genome sequences of 24,000 people alongside the original 14,000 bipolar disorder cases. This study identified genetic variants, including the AKAP11 gene, associated with an increased risk of bipolar disorder. The AKAP11 gene’s interaction with the GSK3B protein, a molecular target of lithium, points to a possible mechanism behind the medication’s therapeutic effects.

• #13 Neuromolecular Etiology of Bipolar Disorder: Possible Therapeutic Targets of Mood Stabilizers

  https://www.cpn.or.kr/journal/view.html?doi=10.9758/cpn.2022.20.2.228

  Bipolar disorder is a mental illness that causes extreme mood swings and has a chronic course. However, the mechanism by which mood episodes with completely opposite characteristics appear repeatedly, or a mixture of symptoms appears, in patients with bipolar disorder remains unknown. Therefore, mood stabilizers are indicated only for single mood episodes, such as manic episodes and depressive episodes, and no true mood-stabilizing drugs effective for treating both manic and depressive episodes currently exist. Therefore, in this review, therapeutic targets that facilitate the development of mood stabilizers were examined by reviewing the current understanding of the neuromolecular etiology of bipolar disorder. […] In bipolar disorder, neurotransmitters are abnormally regulated in the brain. Biogenic amine neurotransmission functions in the limbic system are impaired, influencing sleep, appetite, alertness, sexual function, endocrine function, and the regulation of emotions such as fear and anger. Neurotransmitters have been the focus of numerous studies of the pathogenesis of bipolar disorder.

• #14 The underlying neurobiology of bipolar disorder

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1525098/

  The stimulus for the study of the biogenic amines in patients with BD was provided by the discovery of effective pharmacologic treatments for depression and mania. […] The clinical picture of BD involves disruption of behavior, circadian rhythms, neurophysiology of sleep, neuroendocrine and biochemical regulation within the brain. […] These complex illness manifestations are undoubtedly mediated by a network of interconnected neurotransmitter pathways; the monoamine neurotransmitter systems are ideally placed to mediate such complex behavioral effects, and thus represent attractive candidate systems underlying the pathophysiology of BD. […] Studies have also reported decreased radioligand binding to the serotonin transporter (which takes up serotonin from the synaptic cleft) both in platelets and in the midbrain of depressed patients.

• #15 The underlying neurobiology of bipolar disorder

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1525098/

  The pharmacological bridge also supports the notion that manipulation of the dopaminergic system is capable of modulating the illness. […] Several lines of evidence point to a role of dopamine (DA) system in mood disorders. […] The strongest direct finding from clinical studies implicating DA in depression is reduced homovanillic acid (HVA, the major DA metabolite) in the CSF; indeed, this is one of the most consistent biochemical findings in depression. […] Evidence accumulating from various laboratories has clearly demonstrated that lithium, at therapeutically relevant concentrations, exerts major effects on the PKC signaling cascade. […] In view of the pivotal role of the PKC signaling pathway in the regulation of neuronal excitability, neurotransmitter release, and long-term synaptic events, it was postulated that the attenuation of PKC activity may play a role in the antimanic effects of lithium and VPA.

• #16 Lithium’s Mechanism of Action – A Synopsis and Visual Guide

  https://psychscenehub.com/psychinsights/lithium-mechanism-action-synopsis-visual-guide/

  Lithium is a unique agent that has been used for over half a century for the treatment of bipolar affective disorder. Lithium has compelling evidence in the treatment of mania, acute bipolar depression and prophylaxis in bipolar affective disorder. […] Despite its first discovery 1949 and its subsequent use, the exact mechanisms of action in lithium are unclear. […] In this article, we focus on two key aspects: Lithium’s action on neurotransmitters and second messenger systems; Intracellular mechanisms of action which converge towards neuroprotection. […] Dopamine is an excitatory neurotransmitter that plays an important role in the pathogenesis of bipolar affective disorder. Dopamine transmission is known to be elevated during mania and decreased in clinical depression. […] The subunits of the dopamine associated G protein have been reported to be higher in bipolar disorder patients and may contribute to the pathophysiology of bipolar affective disorder. Lithium administration alters the functionality of these subunits especially the equilibrium between active and inactive subunits thus likely correcting the dopamine dysregulation.

• #17 The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment | Molecular Psychiatry

  https://www.nature.com/articles/mp201716

  Bipolar affective disorder is a common neuropsychiatric disorder. […] The dopamine hypothesis has been a key theory of the pathophysiology of both manic and depressive phases of the illness for over four decades. […] Converging findings from pharmacological and imaging studies support the hypothesis that a state of hyperdopaminergia, specifically elevations in D2/3 receptor availability and a hyperactive reward processing network, underlies mania. […] Thus, it can be speculated that a failure of dopamine receptor and transporter homoeostasis might underlie the pathophysiology of this disorder. […] This model, if confirmed, has implications for developing new treatment strategies such as reducing the dopamine synthesis and/or release in mania and DAT blockade in bipolar depression. […] The dopamine hypothesis of BD dates back at least to the 1970s.

• #18 The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment | Molecular Psychiatry

  https://www.nature.com/articles/mp201716

  If hyperdopaminergia underlies the development of manic symptoms, then hypodopaminergia might underlie the depressive phase of the illness. […] Thus, opposite changes in dopaminergic function were hypothesised to underlie the opposing affective poles of the disorder. […] This theory did not explain how hyper- or hypodopaminergia would arise and subsequent versions proposed an additional component to the hypothesis, where an intrinsic dysregulation in the homoeostatic regulation of dopaminergic function leads to cyclical changes in dopaminergic neurotransmission. […] Thus, faulty homoeostatic mechanisms responding to hyperdopaminergia in the manic phase of the illness are proposed to result in an excessive reduction in dopaminergic function, rapidly leading to a hypodopaminergic state and depression.

• #19 Molecular Mechanisms of Bipolar Disorder: Progress Made and Future Challenges

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5306135/

  All of these observations converge to support the hypothesis that a metabolic shift occurs from oxidative phosphorylation to the less-efficient pathway glycolysis in the brain of BD individuals. […] Glutamate and -aminobutyric acid (GABA) are the major excitatory and inhibitory neurotransmitters in the brain, respectively. […] Adult BD patients show a consistent increase in glutamate levels in the frontal brain areas compared to healthy controls; these increases are independent of the mood phase. […] Studies using transcranial magnetic stimulation paradigms showed a significant deficit in cortical inhibition in BD patients compared to healthy controls, which is in agreement with the data showing increased glutamatergic neurotransmission in BD patients. […] The development of novel treatments for psychiatric disorders has been hindered by the slow progress in our understanding of the underlying neurobiology, which results from the difficulty of developing faithful animal and cellular models.

• #20 Molecular Mechanisms of Bipolar Disorder: Progress Made and Future Challenges

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5306135/

  All of these observations converge to support the hypothesis that a metabolic shift occurs from oxidative phosphorylation to the less-efficient pathway glycolysis in the brain of BD individuals. […] Glutamate and -aminobutyric acid (GABA) are the major excitatory and inhibitory neurotransmitters in the brain, respectively. […] Adult BD patients show a consistent increase in glutamate levels in the frontal brain areas compared to healthy controls; these increases are independent of the mood phase. […] Studies using transcranial magnetic stimulation paradigms showed a significant deficit in cortical inhibition in BD patients compared to healthy controls, which is in agreement with the data showing increased glutamatergic neurotransmission in BD patients. […] The development of novel treatments for psychiatric disorders has been hindered by the slow progress in our understanding of the underlying neurobiology, which results from the difficulty of developing faithful animal and cellular models.

• #21 Lithium’s Mechanism of Action – A Synopsis and Visual Guide

  https://psychscenehub.com/psychinsights/lithium-mechanism-action-synopsis-visual-guide/

  Patients with bipolar affective disorder have diminished GABA neurotransmission. Thus, low GABA levels can result in excitatory toxicity. […] Lithium increases the levels of GABA which in turn reduces glutamate and downregulates the NMDA receptor. […] Bipolar disorder has significant dysregulation of intracellular calcium. […] Lithium inhibits the PI cycle which reduces intracellular calcium which in turn reduces excitatory toxicity. […] In bipolar disorder, there are several hypotheses that are postulated to lead to neuroprogression. […] Lithium enhances neuroprotective effects by preventing apoptosis and promoting cellular longevity. […] Oxidative stress is known to play a significant role in bipolar affective disorder. Furthermore, mitochondrial dysfunction is present in bipolar affective disorder.

• #22 Lithium’s Mechanism of Action – A Synopsis and Visual Guide

  https://psychscenehub.com/psychinsights/lithium-mechanism-action-synopsis-visual-guide/

  Patients with bipolar affective disorder have diminished GABA neurotransmission. Thus, low GABA levels can result in excitatory toxicity. […] Lithium increases the levels of GABA which in turn reduces glutamate and downregulates the NMDA receptor. […] Bipolar disorder has significant dysregulation of intracellular calcium. […] Lithium inhibits the PI cycle which reduces intracellular calcium which in turn reduces excitatory toxicity. […] In bipolar disorder, there are several hypotheses that are postulated to lead to neuroprogression. […] Lithium enhances neuroprotective effects by preventing apoptosis and promoting cellular longevity. […] Oxidative stress is known to play a significant role in bipolar affective disorder. Furthermore, mitochondrial dysfunction is present in bipolar affective disorder.

• #23 The underlying neurobiology of bipolar disorder

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1525098/

  The stimulus for the study of the biogenic amines in patients with BD was provided by the discovery of effective pharmacologic treatments for depression and mania. […] The clinical picture of BD involves disruption of behavior, circadian rhythms, neurophysiology of sleep, neuroendocrine and biochemical regulation within the brain. […] These complex illness manifestations are undoubtedly mediated by a network of interconnected neurotransmitter pathways; the monoamine neurotransmitter systems are ideally placed to mediate such complex behavioral effects, and thus represent attractive candidate systems underlying the pathophysiology of BD. […] Studies have also reported decreased radioligand binding to the serotonin transporter (which takes up serotonin from the synaptic cleft) both in platelets and in the midbrain of depressed patients.

• #24 Understanding the Mechanism of Action of Lithium and the Pathophysiology of Bipolar Disorder with Molecular Imaging of the Serotonin System

  https://columbia.demo.elsevierpure.com/es/projects/understanding-the-mechanism-of-action-of-lithium-and-the-pathophy

  Bipolar disorder is a chronic, disabling psychiatric disorder with a lifetime mortality rate from suicide between 10-20%. […] Some of the more compelling evidence for disordered neurobiology in bipolar disorder implicates the brain’s serotonin system, and actions of lithium specifically on the serotonin 1A receptor may be central to its antidepressive and antisuicidal properties. […] Characterizing the mechanisms by which lithium works in bipolar disorder promises to provide direct molecular targets for treatments that act similarly, but without the level of intolerability and risk of toxicity. […] Based on findings from animal models, we hypothesize that lithium downregulates the presynaptic 5-HT1A receptor, upregulates the postsynaptic 5-HT1A receptor, and upregulates 5-HTT. […] Elucidating the mechanism of one of the most effective pharmacological treatments in bipolar disorder promises to directly aid in the development of therapeutic agents that are more broadly tolerable and don’t have a high potential of organ toxicities of lithium.

• #25 Neuromolecular Etiology of Bipolar Disorder: Possible Therapeutic Targets of Mood Stabilizers

  https://www.cpn.or.kr/journal/view.html?doi=10.9758/cpn.2022.20.2.228

  Increased activity of the hypothalamic-pituitary-adrenal (HPA) cortex axis is a characteristic response to stress in mammals. Abnormal HPA axis activity is observed in psychiatric illnesses, including major depressive disorder. Overactivity of the HPA axis, such as increased corticotrophin-releasing hormone activity, has been reported in bipolar disorder, which may be associated with mixed manic episodes or depressive episodes more than with typical manic episodes. […] Theories have been proposed regarding the changes in neurotransmitters and neuroendocrine systems that partly explain the pathophysiological mechanisms of mood stabilizers and antidepressants in treating bipolar disorder. However, these theories need further validation. […] In summary, the neurobiological etiology of bipolar disorder is multifactorial. However, it can be estimated from an integrated point of view that mood episodes, treatment responses, and medical diseases resulting from the sequelae of bipolar disorder might be originated from the neuromolecular pathophysiology of bipolar disorder.

• #26 SciELO Brazil – Neurobiology of bipolar disorders: a review of genetic components, signaling pathways, biochemical changes, and neuroimaging findings Neurobiology of bipolar disorders: a review of genetic components, signaling pathways, biochemical chang

  https://www.scielo.br/j/rbp/a/4pR74J7vkqQcQ746366fN9c/

  The hypothalamic-pituitary-adrenal (HPA) axis is the primary mediator of the biological response to stress. […] Abnormalities in this system have been associated with the clinical course of BD and may contribute to increased risk of clinical relapse following an intense psychosocially stressful event. […] A meta-analysis has demonstrated that BD is related to a more prominent activity level of the HPA axis, as evidenced by increased basal cortisol, postdexamethasone (PDEX) cortisol, and adrenocorticotropic hormone (ACTH) levels, along with a higher response to the dexamethasone (DEX)/corticotropin releasing hormone (CRH) test. […] Sleep disturbances commonly occur in BD and are part of the diagnostic criteria for BD. […] Dampened and shifted circadian rhythms may explain some of the sleep disturbances frequently reported by patients with BD. […] The first studies using computed tomography (CT) have shown structural abnormalities as significantly larger ventricular-to-brain ratios in groups of individuals with BD compared with controls.

• #27 Longitudinal hair cortisol in bipolar disorder and a mechanism based on HPA dynamics | bioRxiv

  https://www.biorxiv.org/content/10.1101/2023.07.03.546860v1

  Bipolar disorder (BD) is a dynamic disease in which mania, depression and mixed states vary on a timescale of months to years. BD patients characteristically exhibit elevated levels of the hormone cortisol. […] Although BD is a dynamic disease that is related to cortisol, longitudinal cortisol dynamics in BD have rarely been studied. […] Cortisol was measured in 12 cm hair samples from people with BD (n=26) and controls (n=59), corresponding to one year of cortisol data. […] In line with the notion that cortisol correlates with mood, we find that the mean frequency spectrum of depression (n=266) and mania (n=273) scores from a large longitudinal study of BD is similar to the hair cortisol spectrum from the present cohort. […] High ER causes fluctuations in which cortisol is elevated for months, as shown by a mathematical model of the hypothalamic-pituitary-adrenal (HPA) axis that regulates cortisol. […] Thus, this study combines longitudinal cortisol measurements and mathematical modeling to provide a potential mechanistic link between the timescales of cortisol and moods in BD.

• #28 The underlying neurobiology of bipolar disorder

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1525098/

  Clinical studies over the past decades have attempted to uncover the biological factors mediating the pathophysiology of bipolar disorder (BD) utilizing a variety of biochemical and neuroendocrine strategies. […] However, recent studies have also implicated critical signal transduction pathways as being integral to the pathophysiology and treatment of BD, in addition to a growing body of data suggesting that impairments of neuroplasticity and cellular resilience may also underlie the pathophysiology of the disorder. […] The pathophysiology is undoubtedly mediated by a network of interconnected limbic, striatal and fronto-cortical neurotransmitter neuronal circuits, and the interacting cholinergic, catecholaminergic and serotonergic neurotransmitter systems thus represent very attractive candidates.

• #29 The underlying neurobiology of bipolar disorder

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1525098/

  The pharmacological bridge also supports the notion that manipulation of the dopaminergic system is capable of modulating the illness. […] Several lines of evidence point to a role of dopamine (DA) system in mood disorders. […] The strongest direct finding from clinical studies implicating DA in depression is reduced homovanillic acid (HVA, the major DA metabolite) in the CSF; indeed, this is one of the most consistent biochemical findings in depression. […] Evidence accumulating from various laboratories has clearly demonstrated that lithium, at therapeutically relevant concentrations, exerts major effects on the PKC signaling cascade. […] In view of the pivotal role of the PKC signaling pathway in the regulation of neuronal excitability, neurotransmitter release, and long-term synaptic events, it was postulated that the attenuation of PKC activity may play a role in the antimanic effects of lithium and VPA.

• #30 Frontiers | Non-canonical pathways in the pathophysiology and therapeutics of bipolar disorder

  https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1228455/full

  Another non-canonical pathway of interest in psychiatry is the GSK3/Wnt signaling pathway, which has been shown to play a role in developing and maintaining neuronal circuits in the brain and regulating adult neurogenesis. […] PKC signaling plays a crucial role in several pathological mechanisms, including neuronal excitability, neurotransmitter release, energy homeostasis, synaptic neurotransmission, glutamate signaling, neuroinflammation, neuroplasticity, mitochondrial dysfunction, oxidative stress, and apoptosis. […] Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptic plasticity and memory. […] Although mood disorders have not traditionally been regarded as developmental disorders, there has been a growing appreciation for the role of gene–environment interactions and early life events in their etiology.

• #31 Frontiers | Non-canonical pathways in the pathophysiology and therapeutics of bipolar disorder

  https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1228455/full

  Another non-canonical pathway of interest in psychiatry is the GSK3/Wnt signaling pathway, which has been shown to play a role in developing and maintaining neuronal circuits in the brain and regulating adult neurogenesis. […] PKC signaling plays a crucial role in several pathological mechanisms, including neuronal excitability, neurotransmitter release, energy homeostasis, synaptic neurotransmission, glutamate signaling, neuroinflammation, neuroplasticity, mitochondrial dysfunction, oxidative stress, and apoptosis. […] Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptic plasticity and memory. […] Although mood disorders have not traditionally been regarded as developmental disorders, there has been a growing appreciation for the role of gene–environment interactions and early life events in their etiology.

• #32 The underlying neurobiology of bipolar disorder

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1525098/

  This evidence suggests that lithium’s and VPA’s effect on GSK-3 may play important roles in regulating processes such as synaptic plasticity and cell survival in the mature CNS. […] The increased gray matter finding has recently been replicated in a cross-sectional MRI study: Sassi et al found that lithium treated bipolar patients had a statistically higher cortical gray matter volume when compared either to non-treated bipolar patients or control subjects.

• #33 Bipolar Disorder: Neurochemistry and Drug Mechanisms – R H Belmaker – Discovery Medicine

  https://www.discoverymedicine.com/R-H-Belmaker/2009/07/25/bipolar-disorder-neurochemistry-and-drug-mechanisms/

  With the discovery of the importance of the PI cycle as a second messenger system, the lithium-induced reduction of inositol immediately assumed potential importance as a key mechanism of lithium action. […] Lithium inhibits the last step in this process, by inhibiting IMPase, reducing inositol levels. […] Lithium was found to decrease the mRNA and protein levels of proapoptotic factors and increase those of a cytoprotective factor Bcl-2. […] GSK-3 is directly inhibited by lithium, but only at concentrations that are at the upper end of effective treatment. […] Valproate was found to increase the induction of genes related to endoplasmic reticulum stress and to ameliorate the impaired response of such a gene. […] The neurochemical and neuro-imaging findings in bipolar disorder are difficult to replicate and are not yet of diagnostic value for individual patients.

• #34 Inflammatory signaling mechanisms in bipolar disorder | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-021-00742-6

  This positive feedback loop is suggested to contribute to the chronic neurodegeneration observed in BD, in part by modulating GSK-3 activitya key regulator of mitochondrial metabolism, DNA repair, inflammation, and apoptosis, which has been extensively implicated in BD. […] Indeed, TNF- has been shown to modulate many dysfunctional processes in BD including synaptic plasticity, neurotransmission, neurogenesis, neuronal survival, apoptosis, and even cognitive/behavioral functioning. […] Given the pervasive influence of immune/inflammatory dysfunction on BD and its numerous comorbidities, significant potential exists in targeting this system. […] Overall, it appears that inflammatory signaling mediates a strong connection between cellular stress, neuronal viability, and overt symptomatology. The hypothesis that BD incurs a low grade, proinflammatory state, exacerbated during acute mood episodes is potentially reinforced by the notion that anti-inflammatory therapies appear to be far more efficacious in mania and depression than in the maintenance phase. […] In summary, the NLRP3 inflammasome serves a central mediator of inflammatory signaling in BD, linking other cellular stress systems to immune cell activation. It also provides a common thread between mood symptoms and metabolic comorbidities.

• #35 Frontiers | Non-canonical pathways in the pathophysiology and therapeutics of bipolar disorder

  https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1228455/full

  Inflammation is a non-canonical pathway that has received much attention in recent years. Studies have shown that chronic inflammation can be triggered by a variety of factors, including stress, infection, and poor diet, all of which can contribute to the development of mood disorders, including BD. […] The putative link between BD and mitochondrial dysfunction rests on the notion that mitochondrial dysfunction is a critical pathological factor that can be intimately linked to a wide range of processes associated with treatment outcomes and disease progression or severity. […] BD is characterized by altered intracellular calcium homeostasis. Indeed, altered intracellular calcium is considered the most reproducible cellular abnormality and biomarker in BD research. […] Oxidative stress is characterized by increased free radicals, which attack proteins, DNA, and lipids.

• #36 Lithium’s Mechanism of Action – A Synopsis and Visual Guide

  https://psychscenehub.com/psychinsights/lithium-mechanism-action-synopsis-visual-guide/

  Patients with bipolar affective disorder have diminished GABA neurotransmission. Thus, low GABA levels can result in excitatory toxicity. […] Lithium increases the levels of GABA which in turn reduces glutamate and downregulates the NMDA receptor. […] Bipolar disorder has significant dysregulation of intracellular calcium. […] Lithium inhibits the PI cycle which reduces intracellular calcium which in turn reduces excitatory toxicity. […] In bipolar disorder, there are several hypotheses that are postulated to lead to neuroprogression. […] Lithium enhances neuroprotective effects by preventing apoptosis and promoting cellular longevity. […] Oxidative stress is known to play a significant role in bipolar affective disorder. Furthermore, mitochondrial dysfunction is present in bipolar affective disorder.

• #37 Bipolar Disorder: Neurochemistry and Drug Mechanisms – R H Belmaker – Discovery Medicine

  https://www.discoverymedicine.com/R-H-Belmaker/2009/07/25/bipolar-disorder-neurochemistry-and-drug-mechanisms/

  The disease mechanism of bipolar disorder remains to be resolved. Abnormalities of interactions between neurotransmitters and cell signaling events are likely to play a role. […] Overall this story has been heroic and exciting but it has left us in 2005 still without any biological diagnostic test or clear pathophysiological abnormality in manic-depressive illness. […] The pharmacological bridge involves choosing a hypothesis of a neurochemical abnormality, say decreased inositol levels in bipolar disorders, and testing the hypothesis with a clinical intervention based on that hypothesis, say giving inositol to bipolar patients. […] Thus, abnormalities of inositol metabolism and of its cell signaling system (phosphatidylinositol cycle) are a central area of research today. […] A widespread hypothesis explaining lithium’s therapeutic and prophylactic effect in affective disorders is that inhibition of IMPase impairs the operation of the phosphatidylinositol (PI) cycle.

• #38 Bipolar Disorder: Neurochemistry and Drug Mechanisms – R H Belmaker – Discovery Medicine

  https://www.discoverymedicine.com/R-H-Belmaker/2009/07/25/bipolar-disorder-neurochemistry-and-drug-mechanisms/

  With the discovery of the importance of the PI cycle as a second messenger system, the lithium-induced reduction of inositol immediately assumed potential importance as a key mechanism of lithium action. […] Lithium inhibits the last step in this process, by inhibiting IMPase, reducing inositol levels. […] Lithium was found to decrease the mRNA and protein levels of proapoptotic factors and increase those of a cytoprotective factor Bcl-2. […] GSK-3 is directly inhibited by lithium, but only at concentrations that are at the upper end of effective treatment. […] Valproate was found to increase the induction of genes related to endoplasmic reticulum stress and to ameliorate the impaired response of such a gene. […] The neurochemical and neuro-imaging findings in bipolar disorder are difficult to replicate and are not yet of diagnostic value for individual patients.

• #39 Molecular Mechanisms of Bipolar Disorder: Progress Made and Future Challenges

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5306135/

  The mechanisms underlying weight gain and metabolic imbalance in BD patients are poorly understood. […] The principal functions of the ER are protein synthesis, folding and post-translational modifications, but it also interacts functionally with mitochondria to control calcium signaling and apoptosis. […] Several studies using BD patient-derived lymphoblastoid cell lines or blood cells showed an impaired response to ER stress. […] Overall, these data suggest that the adaptive response of BD cells to ER stress is compromised, which may decrease the resilience of cells to stress conditions. […] Mitochondrial dysfunction is a central feature in BD, characterized by impaired oxidative phosphorylation and changes in mitochondrial morphology and number and in calcium signaling. […] The tricarboxylic acid cycle (TCA) is a fundamental component of aerobic respiration and is also disturbed in BD.

• #40 Molecular Mechanisms of Bipolar Disorder: Progress Made and Future Challenges

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5306135/

  The mechanisms underlying weight gain and metabolic imbalance in BD patients are poorly understood. […] The principal functions of the ER are protein synthesis, folding and post-translational modifications, but it also interacts functionally with mitochondria to control calcium signaling and apoptosis. […] Several studies using BD patient-derived lymphoblastoid cell lines or blood cells showed an impaired response to ER stress. […] Overall, these data suggest that the adaptive response of BD cells to ER stress is compromised, which may decrease the resilience of cells to stress conditions. […] Mitochondrial dysfunction is a central feature in BD, characterized by impaired oxidative phosphorylation and changes in mitochondrial morphology and number and in calcium signaling. […] The tricarboxylic acid cycle (TCA) is a fundamental component of aerobic respiration and is also disturbed in BD.

• #41 Molecular Mechanisms of Bipolar Disorder: Progress Made and Future Challenges

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5306135/

  All of these observations converge to support the hypothesis that a metabolic shift occurs from oxidative phosphorylation to the less-efficient pathway glycolysis in the brain of BD individuals. […] Glutamate and -aminobutyric acid (GABA) are the major excitatory and inhibitory neurotransmitters in the brain, respectively. […] Adult BD patients show a consistent increase in glutamate levels in the frontal brain areas compared to healthy controls; these increases are independent of the mood phase. […] Studies using transcranial magnetic stimulation paradigms showed a significant deficit in cortical inhibition in BD patients compared to healthy controls, which is in agreement with the data showing increased glutamatergic neurotransmission in BD patients. […] The development of novel treatments for psychiatric disorders has been hindered by the slow progress in our understanding of the underlying neurobiology, which results from the difficulty of developing faithful animal and cellular models.

• #42 Frontiers | Non-canonical pathways in the pathophysiology and therapeutics of bipolar disorder

  https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1228455/full

  Inflammation is a non-canonical pathway that has received much attention in recent years. Studies have shown that chronic inflammation can be triggered by a variety of factors, including stress, infection, and poor diet, all of which can contribute to the development of mood disorders, including BD. […] The putative link between BD and mitochondrial dysfunction rests on the notion that mitochondrial dysfunction is a critical pathological factor that can be intimately linked to a wide range of processes associated with treatment outcomes and disease progression or severity. […] BD is characterized by altered intracellular calcium homeostasis. Indeed, altered intracellular calcium is considered the most reproducible cellular abnormality and biomarker in BD research. […] Oxidative stress is characterized by increased free radicals, which attack proteins, DNA, and lipids.

• #43 Lithium’s Mechanism of Action – A Synopsis and Visual Guide

  https://psychscenehub.com/psychinsights/lithium-mechanism-action-synopsis-visual-guide/

  Lithium stimulates the mitochondrial respiratory chain complexes and in doing so protects against oxidative stress. […] BDNF is an important neuroprotective protein which is known to be decreased in both manic and depressed phases of bipolar affective disorder. […] Lithium increases BDNF and Bcl-2. […] Lithium has been shown to increase synaptic plasticity and decrease GSK expression. […] Lithium both reduces and induces autophagy.

• #44 Frontiers | Non-canonical pathways in the pathophysiology and therapeutics of bipolar disorder

  https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1228455/full

  Another non-canonical pathway of interest in psychiatry is the GSK3/Wnt signaling pathway, which has been shown to play a role in developing and maintaining neuronal circuits in the brain and regulating adult neurogenesis. […] PKC signaling plays a crucial role in several pathological mechanisms, including neuronal excitability, neurotransmitter release, energy homeostasis, synaptic neurotransmission, glutamate signaling, neuroinflammation, neuroplasticity, mitochondrial dysfunction, oxidative stress, and apoptosis. […] Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptic plasticity and memory. […] Although mood disorders have not traditionally been regarded as developmental disorders, there has been a growing appreciation for the role of gene–environment interactions and early life events in their etiology.

• #45 Lithium’s Mechanism of Action – A Synopsis and Visual Guide

  https://psychscenehub.com/psychinsights/lithium-mechanism-action-synopsis-visual-guide/

  Lithium stimulates the mitochondrial respiratory chain complexes and in doing so protects against oxidative stress. […] BDNF is an important neuroprotective protein which is known to be decreased in both manic and depressed phases of bipolar affective disorder. […] Lithium increases BDNF and Bcl-2. […] Lithium has been shown to increase synaptic plasticity and decrease GSK expression. […] Lithium both reduces and induces autophagy.

• #46 SciELO Brazil – Neurobiology of bipolar disorders: a review of genetic components, signaling pathways, biochemical changes, and neuroimaging findings Neurobiology of bipolar disorders: a review of genetic components, signaling pathways, biochemical chang

  https://www.scielo.br/j/rbp/a/4pR74J7vkqQcQ746366fN9c/

  Currently, a range of studies show decreased levels of BDNF and its receptor TrkB in both blood and brain of patients with BD. […] Mitochondria are organelles that are responsible, both directly and indirectly, for cellular functions such as energy production; they also function as sources of cellular growth substrates and play crucial roles in oxidative/nitrosative stress, cell resilience and cell death. […] For more than 50 years, multiple studies have highlighted mitochondrial dysfunction as a common pathway in BD pathophysiology, triggered by mechanisms such as impaired oxidative phosphorylation, shift to glycolytic production of energy, general decrease in energy, and abnormalities in the morphology and intracellular distribution of mitochondria. […] A considerable number of studies in the literature has shown an increase in lactate levels and a reduction in intracellular pH (ipH) in the brain of patients with BD, possibly indicating altered mitochondrial function and a glycolytic shift consistent with impaired mitochondrial metabolism in BD.

• #47 Lithium’s Mechanism of Action – A Synopsis and Visual Guide

  https://psychscenehub.com/psychinsights/lithium-mechanism-action-synopsis-visual-guide/

  Lithium stimulates the mitochondrial respiratory chain complexes and in doing so protects against oxidative stress. […] BDNF is an important neuroprotective protein which is known to be decreased in both manic and depressed phases of bipolar affective disorder. […] Lithium increases BDNF and Bcl-2. […] Lithium has been shown to increase synaptic plasticity and decrease GSK expression. […] Lithium both reduces and induces autophagy.

• #48 Advances in the understanding of the pathophysiology of schizophrenia and bipolar disorder through induced pluripotent stem cell models | JPN

  https://www.jpn.ca/content/49/2/E109

  One of the molecular pathways that has gained attention in studies using stem cells to explore the neurodevelopmental hypothesis is the Wnt signalling pathway. […] Different alterations of the Wnt pathway in iPSC from patients with schizophrenia have been reported. […] Overall, the current results of iPSC models of schizophrenia have shown how alterations traced in levels of Wnt, molecular signalling cascades, and the concentration of microRNAs might lead to defects in different neurodevelopmental processes such as neuronal proliferation, maturation, and migration. […] Similar evidence of altered Wnt pathways has been found in iPSC-derived neurons of patients with bipolar disorder. […] Studies on bipolar disorder have also shown that altered expression of brain-derived neurotrophic factor (BDNF) may play a role in the pathogenesis of this condition.

• #49 Frontiers | Non-canonical pathways in the pathophysiology and therapeutics of bipolar disorder

  https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1228455/full

  Inflammation is a non-canonical pathway that has received much attention in recent years. Studies have shown that chronic inflammation can be triggered by a variety of factors, including stress, infection, and poor diet, all of which can contribute to the development of mood disorders, including BD. […] The putative link between BD and mitochondrial dysfunction rests on the notion that mitochondrial dysfunction is a critical pathological factor that can be intimately linked to a wide range of processes associated with treatment outcomes and disease progression or severity. […] BD is characterized by altered intracellular calcium homeostasis. Indeed, altered intracellular calcium is considered the most reproducible cellular abnormality and biomarker in BD research. […] Oxidative stress is characterized by increased free radicals, which attack proteins, DNA, and lipids.

• #50 Bipolar Disorder and Immune Dysfunction: Epidemiological Findings, Proposed Pathophysiology and Clinical Implications

  https://www.mdpi.com/2076-3425/7/11/144

  Bipolar disorder (BD) is strongly associated with immune dysfunction. Replicated epidemiological studies have demonstrated that BD has high rates of inflammatory medical comorbidities, including autoimmune disorders, chronic infections, cardiovascular disease and metabolic disorders. […] Several mechanisms have been identified to explain the bidirectional relationship between BD and immune dysfunction. Key mechanisms include cytokine-induced monoamine changes, increased oxidative stress, pathological microglial over-activation, hypothalamic-pituitary-adrenal (HPA) axis over-activation, alterations of the microbiome-gut-brain axis and sleep-related immune changes. […] The inflammatory-mood pathway presents several potential novel targets in the treatment of BD. […] The hypothesis that immune dysfunction may be a mediator of disease progression in BD was first proposed by Horrobin & Lieb (1981) who hypothesized that immune modulation may be a key mechanism of action in lithium’s mood stabilizing effects.

• #51 Bipolar Disorder and Immune Dysfunction: Epidemiological Findings, Proposed Pathophysiology and Clinical Implications

  https://www.mdpi.com/2076-3425/7/11/144

  Bipolar disorder (BD) is strongly associated with immune dysfunction. Replicated epidemiological studies have demonstrated that BD has high rates of inflammatory medical comorbidities, including autoimmune disorders, chronic infections, cardiovascular disease and metabolic disorders. […] Several mechanisms have been identified to explain the bidirectional relationship between BD and immune dysfunction. Key mechanisms include cytokine-induced monoamine changes, increased oxidative stress, pathological microglial over-activation, hypothalamic-pituitary-adrenal (HPA) axis over-activation, alterations of the microbiome-gut-brain axis and sleep-related immune changes. […] The inflammatory-mood pathway presents several potential novel targets in the treatment of BD. […] The hypothesis that immune dysfunction may be a mediator of disease progression in BD was first proposed by Horrobin & Lieb (1981) who hypothesized that immune modulation may be a key mechanism of action in lithium’s mood stabilizing effects.

• #52 Bipolar Disorder and Immune Dysfunction: Epidemiological Findings, Proposed Pathophysiology and Clinical Implications

  https://www.mdpi.com/2076-3425/7/11/144

  Numerous mechanisms have been identified which may mediate the bidirectional interaction between BD and immune dysfunction. […] Central to the inflammatory-mood pathway is the ability of peripherally circulating cytokines to traverse the blood-brain-barrier (BBB). […] Pro-inflammatory cytokines may directly and indirectly alter monoamine levels in the CNS through numerous pathways. […] Inflammation may also directly alter levels of dopamine and norepinephrine. […] Taken together, pro-inflammatory signaling may decrease the levels of dopamine, norepinephrine and serotonin, which has long been associated with worsening mood and cognitive symptoms. […] The interaction between lithium and the immune system is complex as lithium has been shown to have both anti-inflammatory and pro-inflammatory effects.

• #53 Bipolar Disorder and Immune Dysfunction: Epidemiological Findings, Proposed Pathophysiology and Clinical Implications

  https://www.mdpi.com/2076-3425/7/11/144

  Numerous mechanisms have been identified which may mediate the bidirectional interaction between BD and immune dysfunction. […] Central to the inflammatory-mood pathway is the ability of peripherally circulating cytokines to traverse the blood-brain-barrier (BBB). […] Pro-inflammatory cytokines may directly and indirectly alter monoamine levels in the CNS through numerous pathways. […] Inflammation may also directly alter levels of dopamine and norepinephrine. […] Taken together, pro-inflammatory signaling may decrease the levels of dopamine, norepinephrine and serotonin, which has long been associated with worsening mood and cognitive symptoms. […] The interaction between lithium and the immune system is complex as lithium has been shown to have both anti-inflammatory and pro-inflammatory effects.

• #54 Bipolar Disorder and Immune Dysfunction: Epidemiological Findings, Proposed Pathophysiology and Clinical Implications

  https://www.mdpi.com/2076-3425/7/11/144

  Numerous mechanisms have been identified which may mediate the bidirectional interaction between BD and immune dysfunction. […] Central to the inflammatory-mood pathway is the ability of peripherally circulating cytokines to traverse the blood-brain-barrier (BBB). […] Pro-inflammatory cytokines may directly and indirectly alter monoamine levels in the CNS through numerous pathways. […] Inflammation may also directly alter levels of dopamine and norepinephrine. […] Taken together, pro-inflammatory signaling may decrease the levels of dopamine, norepinephrine and serotonin, which has long been associated with worsening mood and cognitive symptoms. […] The interaction between lithium and the immune system is complex as lithium has been shown to have both anti-inflammatory and pro-inflammatory effects.

• #55 Bipolar Disorder and Immune Dysfunction: Epidemiological Findings, Proposed Pathophysiology and Clinical Implications

  https://www.mdpi.com/2076-3425/7/11/144

  Numerous mechanisms have been identified which may mediate the bidirectional interaction between BD and immune dysfunction. […] Central to the inflammatory-mood pathway is the ability of peripherally circulating cytokines to traverse the blood-brain-barrier (BBB). […] Pro-inflammatory cytokines may directly and indirectly alter monoamine levels in the CNS through numerous pathways. […] Inflammation may also directly alter levels of dopamine and norepinephrine. […] Taken together, pro-inflammatory signaling may decrease the levels of dopamine, norepinephrine and serotonin, which has long been associated with worsening mood and cognitive symptoms. […] The interaction between lithium and the immune system is complex as lithium has been shown to have both anti-inflammatory and pro-inflammatory effects.

• #56 SciELO Brazil – Neurobiology of bipolar disorders: a review of genetic components, signaling pathways, biochemical changes, and neuroimaging findings Neurobiology of bipolar disorders: a review of genetic components, signaling pathways, biochemical chang

  https://www.scielo.br/j/rbp/a/4pR74J7vkqQcQ746366fN9c/

  Several clinical and animal studies have reported alterations in various energetic metabolism components, including downregulation of nuclear mRNA molecules and proteins involved in the Krebs cycle, electron transport chain (ETC) I-IV complexes, and creatine kinase, as well as a marked decrease in the activity of ETC complexes and Krebs cycle enzymes. […] The accumulating evidence reviewed above delineates multifaceted mitochondrial dysfunction as a pathological factor in BD. […] Immune dysfunction in BD is supported by pre-clinical and clinical evidence showing elevated levels of pro-inflammatory cytokines, including interleukin-4 (IL-4), interleukin-1beta (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, soluble interleukin-2 receptor (sIL-2R), and soluble receptor of TNF-type 1 (STNFR1), among others, in patients compared to controls.

• #57 Inflammatory signaling mechanisms in bipolar disorder | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-021-00742-6

  Given the frequency of immune-inflammatory comorbidities in BD, we suggest that a detailed understanding of this dynamic may yield significant benefit in treating not only mood symptoms, but many other disorders associated with BD. In presenting several convergent mechanisms, we suggest that future therapeutic efforts in these systems connected to inflammatory signaling may hold particular relevance in screening and drug development. […] Overall, evidence suggests that many BD patients experience a chronic, low-grade inflammatory state that may be differentially enhanced during acute mood episodes, which may exacerbate other pathological mechanisms mentioned throughout this review and contribute to overall cognitive decline and neuroprogression. […] Notably, TNF- seems to have special significance, appearing consistently elevated across all stages of mania and depression.

• #58 Inflammatory signaling mechanisms in bipolar disorder | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-021-00742-6

  This positive feedback loop is suggested to contribute to the chronic neurodegeneration observed in BD, in part by modulating GSK-3 activitya key regulator of mitochondrial metabolism, DNA repair, inflammation, and apoptosis, which has been extensively implicated in BD. […] Indeed, TNF- has been shown to modulate many dysfunctional processes in BD including synaptic plasticity, neurotransmission, neurogenesis, neuronal survival, apoptosis, and even cognitive/behavioral functioning. […] Given the pervasive influence of immune/inflammatory dysfunction on BD and its numerous comorbidities, significant potential exists in targeting this system. […] Overall, it appears that inflammatory signaling mediates a strong connection between cellular stress, neuronal viability, and overt symptomatology. The hypothesis that BD incurs a low grade, proinflammatory state, exacerbated during acute mood episodes is potentially reinforced by the notion that anti-inflammatory therapies appear to be far more efficacious in mania and depression than in the maintenance phase. […] In summary, the NLRP3 inflammasome serves a central mediator of inflammatory signaling in BD, linking other cellular stress systems to immune cell activation. It also provides a common thread between mood symptoms and metabolic comorbidities.

• #59 Inflammatory signaling mechanisms in bipolar disorder | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-021-00742-6

  This positive feedback loop is suggested to contribute to the chronic neurodegeneration observed in BD, in part by modulating GSK-3 activitya key regulator of mitochondrial metabolism, DNA repair, inflammation, and apoptosis, which has been extensively implicated in BD. […] Indeed, TNF- has been shown to modulate many dysfunctional processes in BD including synaptic plasticity, neurotransmission, neurogenesis, neuronal survival, apoptosis, and even cognitive/behavioral functioning. […] Given the pervasive influence of immune/inflammatory dysfunction on BD and its numerous comorbidities, significant potential exists in targeting this system. […] Overall, it appears that inflammatory signaling mediates a strong connection between cellular stress, neuronal viability, and overt symptomatology. The hypothesis that BD incurs a low grade, proinflammatory state, exacerbated during acute mood episodes is potentially reinforced by the notion that anti-inflammatory therapies appear to be far more efficacious in mania and depression than in the maintenance phase. […] In summary, the NLRP3 inflammasome serves a central mediator of inflammatory signaling in BD, linking other cellular stress systems to immune cell activation. It also provides a common thread between mood symptoms and metabolic comorbidities.

• #60 Inflammatory signaling mechanisms in bipolar disorder | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-021-00742-6

  This positive feedback loop is suggested to contribute to the chronic neurodegeneration observed in BD, in part by modulating GSK-3 activitya key regulator of mitochondrial metabolism, DNA repair, inflammation, and apoptosis, which has been extensively implicated in BD. […] Indeed, TNF- has been shown to modulate many dysfunctional processes in BD including synaptic plasticity, neurotransmission, neurogenesis, neuronal survival, apoptosis, and even cognitive/behavioral functioning. […] Given the pervasive influence of immune/inflammatory dysfunction on BD and its numerous comorbidities, significant potential exists in targeting this system. […] Overall, it appears that inflammatory signaling mediates a strong connection between cellular stress, neuronal viability, and overt symptomatology. The hypothesis that BD incurs a low grade, proinflammatory state, exacerbated during acute mood episodes is potentially reinforced by the notion that anti-inflammatory therapies appear to be far more efficacious in mania and depression than in the maintenance phase. […] In summary, the NLRP3 inflammasome serves a central mediator of inflammatory signaling in BD, linking other cellular stress systems to immune cell activation. It also provides a common thread between mood symptoms and metabolic comorbidities.

• #61 Bipolar Disorder: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/286342-overview

  Another approach to delineating the pathophysiology of bipolar disorder involves studying changes in gene expression induced in rodent brains after administration of pharmacologic agents used to treat bipolar disorder. […] Neuroimaging studies of individuals with bipolar disorder or other mood disorders also suggest evidence of cell loss or atrophy in these same brain regions. Thus, another suggested cause of bipolar disorder is damage to cells in the critical brain circuitry that regulates emotion. […] According to this hypothesis, mood stabilizers and antidepressants are thought to alter mood by stimulating cell survival pathways and increasing levels of neurotrophic factors to improve cellular resiliency.

• #62 Biology of bipolar disorder – Wikipedia

  https://en.wikipedia.org/wiki/Biology_of_bipolar_disorder

  While parallels have been drawn between bipolar disorder and epilepsy, supporting the kindling hypothesis, this model is generally not supported by studies directly assessing it in bipolar subjects. […] The main loci of neuroimaging and neuropathological findings in bipolar have been proposed to constitute dysfunction in a „visceromotor” network, composed of the medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), hippocampus, amygdala, hypothalamus, striatum and thalamus. […] A model of functional neuroanatomy produced by a workgroup led by Stephen M. Strakowski concluded that bipolar was characterized by reduced connectivity, due to abnormal pruning or development, in the prefrontal-striatal-pallidal-thalamic-limbic network leading to dysregulated emotional responses.

• #63 Biology of bipolar disorder – Wikipedia

  https://en.wikipedia.org/wiki/Biology_of_bipolar_disorder

  While parallels have been drawn between bipolar disorder and epilepsy, supporting the kindling hypothesis, this model is generally not supported by studies directly assessing it in bipolar subjects. […] The main loci of neuroimaging and neuropathological findings in bipolar have been proposed to constitute dysfunction in a „visceromotor” network, composed of the medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), hippocampus, amygdala, hypothalamus, striatum and thalamus. […] A model of functional neuroanatomy produced by a workgroup led by Stephen M. Strakowski concluded that bipolar was characterized by reduced connectivity, due to abnormal pruning or development, in the prefrontal-striatal-pallidal-thalamic-limbic network leading to dysregulated emotional responses.

• #64 Biology of bipolar disorder – Wikipedia

  https://en.wikipedia.org/wiki/Biology_of_bipolar_disorder

  Dysregulation of limbic structures is evinced by the fact that hyperactivity in the amygdala in response to facial stimuli has been consistently reported in mania. […] These findings support dysfunctional emotional circuits in bipolar. […] A general reduction in ventrolateral prefrontal cortex activity is observed in bipolar, and is lateralized with regard to mood (i.e., left-depression, right-mania), and may underlie amygdala abnormalities. […] Combined, these abnormalities support the prefrontal-striatal-pallidial-thalamic limbic network underlying dysfunction in emotional regulation in bipolar disorder.

• #65 Biology of bipolar disorder – Wikipedia

  https://en.wikipedia.org/wiki/Biology_of_bipolar_disorder

  Dysregulation of limbic structures is evinced by the fact that hyperactivity in the amygdala in response to facial stimuli has been consistently reported in mania. […] These findings support dysfunctional emotional circuits in bipolar. […] A general reduction in ventrolateral prefrontal cortex activity is observed in bipolar, and is lateralized with regard to mood (i.e., left-depression, right-mania), and may underlie amygdala abnormalities. […] Combined, these abnormalities support the prefrontal-striatal-pallidial-thalamic limbic network underlying dysfunction in emotional regulation in bipolar disorder.

• #66 Biology of bipolar disorder – Wikipedia

  https://en.wikipedia.org/wiki/Biology_of_bipolar_disorder

  Dysregulation of limbic structures is evinced by the fact that hyperactivity in the amygdala in response to facial stimuli has been consistently reported in mania. […] These findings support dysfunctional emotional circuits in bipolar. […] A general reduction in ventrolateral prefrontal cortex activity is observed in bipolar, and is lateralized with regard to mood (i.e., left-depression, right-mania), and may underlie amygdala abnormalities. […] Combined, these abnormalities support the prefrontal-striatal-pallidial-thalamic limbic network underlying dysfunction in emotional regulation in bipolar disorder.

• #67 Biology of bipolar disorder – Wikipedia

  https://en.wikipedia.org/wiki/Biology_of_bipolar_disorder

  Dysregulation of limbic structures is evinced by the fact that hyperactivity in the amygdala in response to facial stimuli has been consistently reported in mania. […] These findings support dysfunctional emotional circuits in bipolar. […] A general reduction in ventrolateral prefrontal cortex activity is observed in bipolar, and is lateralized with regard to mood (i.e., left-depression, right-mania), and may underlie amygdala abnormalities. […] Combined, these abnormalities support the prefrontal-striatal-pallidial-thalamic limbic network underlying dysfunction in emotional regulation in bipolar disorder.

• #68 Bipolar disorder – Wikipedia

  https://en.wikipedia.org/wiki/Bipolar_disorder

  While the causes of this mood disorder are not clearly understood, both genetic and environmental factors are thought to play a role. Genetic factors may account for up to 7090% of the risk of developing bipolar disorder. Many genes, each with small effects, may contribute to the development of the disorder. Environmental risk factors include a history of childhood abuse and long-term stress. […] The precise mechanisms that cause bipolar disorder are not well understood. Bipolar disorder is thought to be associated with abnormalities in the structure and function of certain brain areas responsible for cognitive tasks and the processing of emotions. A neurologic model for bipolar disorder proposes that the emotional circuitry of the brain can be divided into two main parts. The ventral system (regulates emotional perception) includes brain structures such as the amygdala, insula, ventral striatum, ventral anterior cingulate cortex, and the prefrontal cortex. The dorsal system (responsible for emotional regulation) includes the hippocampus, dorsal anterior cingulate cortex, and other parts of the prefrontal cortex. The model hypothesizes that bipolar disorder may occur when the ventral system is overactivated and the dorsal system is underactivated.

• #69 Bipolar disorder – Wikipedia

  https://en.wikipedia.org/wiki/Bipolar_disorder

  While the causes of this mood disorder are not clearly understood, both genetic and environmental factors are thought to play a role. Genetic factors may account for up to 7090% of the risk of developing bipolar disorder. Many genes, each with small effects, may contribute to the development of the disorder. Environmental risk factors include a history of childhood abuse and long-term stress. […] The precise mechanisms that cause bipolar disorder are not well understood. Bipolar disorder is thought to be associated with abnormalities in the structure and function of certain brain areas responsible for cognitive tasks and the processing of emotions. A neurologic model for bipolar disorder proposes that the emotional circuitry of the brain can be divided into two main parts. The ventral system (regulates emotional perception) includes brain structures such as the amygdala, insula, ventral striatum, ventral anterior cingulate cortex, and the prefrontal cortex. The dorsal system (responsible for emotional regulation) includes the hippocampus, dorsal anterior cingulate cortex, and other parts of the prefrontal cortex. The model hypothesizes that bipolar disorder may occur when the ventral system is overactivated and the dorsal system is underactivated.

• #70 Circadian Misalignment and Bipolar Disorder

  https://www.chronobiologyinmedicine.org/journal/view.php?number=27

  Evidence for circadian rhythm misalignment in bipolar disorder suggests that circadian rhythm phase shift is a key pathophysiologic mechanism. […] Mood disorder has been reported to be associated with circadian rhythm disturbance, especially in bipolar disorder. […] The irregularity of the sleep-wake cycle worsens the manic/depressive symptoms, which can be easily understood empirically. […] Studies have determined that circadian rhythm misalignment is a biomarker in mood episodes. […] This study suggests that acute mood episodes are related to circadian rhythm misalignment between the individuals endogenous circadian rhythms and his or her physical environment. […] Based on these results, Figure 2 shows the circadian rhythm phase shift according to episodes of mood disorders. […] The circadian phase shift hypothesis of mood episodes is based on the fact that mood episodes last for a relatively long time.

• #71 Circadian Misalignment and Bipolar Disorder

  https://www.chronobiologyinmedicine.org/journal/view.php?number=27

  Evidence for circadian rhythm misalignment in bipolar disorder suggests that circadian rhythm phase shift is a key pathophysiologic mechanism. […] Mood disorder has been reported to be associated with circadian rhythm disturbance, especially in bipolar disorder. […] The irregularity of the sleep-wake cycle worsens the manic/depressive symptoms, which can be easily understood empirically. […] Studies have determined that circadian rhythm misalignment is a biomarker in mood episodes. […] This study suggests that acute mood episodes are related to circadian rhythm misalignment between the individuals endogenous circadian rhythms and his or her physical environment. […] Based on these results, Figure 2 shows the circadian rhythm phase shift according to episodes of mood disorders. […] The circadian phase shift hypothesis of mood episodes is based on the fact that mood episodes last for a relatively long time.

• #72 Circadian Misalignment and Bipolar Disorder

  https://www.chronobiologyinmedicine.org/journal/view.php?number=27

  Evidence for circadian rhythm misalignment in bipolar disorder suggests that circadian rhythm phase shift is a key pathophysiologic mechanism. […] Mood disorder has been reported to be associated with circadian rhythm disturbance, especially in bipolar disorder. […] The irregularity of the sleep-wake cycle worsens the manic/depressive symptoms, which can be easily understood empirically. […] Studies have determined that circadian rhythm misalignment is a biomarker in mood episodes. […] This study suggests that acute mood episodes are related to circadian rhythm misalignment between the individuals endogenous circadian rhythms and his or her physical environment. […] Based on these results, Figure 2 shows the circadian rhythm phase shift according to episodes of mood disorders. […] The circadian phase shift hypothesis of mood episodes is based on the fact that mood episodes last for a relatively long time.

• #73 Circadian Misalignment and Bipolar Disorder

  https://www.chronobiologyinmedicine.org/journal/view.php?number=27

  Evidence for circadian rhythm misalignment in bipolar disorder suggests that circadian rhythm phase shift is a key pathophysiologic mechanism. […] Mood disorder has been reported to be associated with circadian rhythm disturbance, especially in bipolar disorder. […] The irregularity of the sleep-wake cycle worsens the manic/depressive symptoms, which can be easily understood empirically. […] Studies have determined that circadian rhythm misalignment is a biomarker in mood episodes. […] This study suggests that acute mood episodes are related to circadian rhythm misalignment between the individuals endogenous circadian rhythms and his or her physical environment. […] Based on these results, Figure 2 shows the circadian rhythm phase shift according to episodes of mood disorders. […] The circadian phase shift hypothesis of mood episodes is based on the fact that mood episodes last for a relatively long time.

• #74 Circadian Misalignment and Bipolar Disorder

  https://www.chronobiologyinmedicine.org/journal/view.php?number=27

  Evidence for circadian rhythm misalignment in bipolar disorder suggests that circadian rhythm phase shift is a key pathophysiologic mechanism. […] Mood disorder has been reported to be associated with circadian rhythm disturbance, especially in bipolar disorder. […] The irregularity of the sleep-wake cycle worsens the manic/depressive symptoms, which can be easily understood empirically. […] Studies have determined that circadian rhythm misalignment is a biomarker in mood episodes. […] This study suggests that acute mood episodes are related to circadian rhythm misalignment between the individuals endogenous circadian rhythms and his or her physical environment. […] Based on these results, Figure 2 shows the circadian rhythm phase shift according to episodes of mood disorders. […] The circadian phase shift hypothesis of mood episodes is based on the fact that mood episodes last for a relatively long time.

• #75 Circadian Misalignment and Bipolar Disorder

  https://www.chronobiologyinmedicine.org/journal/view.php?number=27

  Previous evidence suggests that the mechanism underlying the antidepressant effect is a process in which the delayed circadian rhythm is restored to normal by treatment. […] It is still unclear whether the circadian rhythm misalignment observed in mood bipolar disorder is the cause or result of mood disorder. However, based on inference from previous findings, it is not a simple indicator of the condition that is expressed as a result of mood disturbance, but is likely to be a pathological mechanism that contributes to the development of mood disorder.

• #76 What drives mood swings in bipolar disorder? Study points to a second brain clock | Newsroom – McGill University

  https://www.mcgill.ca/newsroom/channels/news/what-drives-mood-swings-bipolar-disorder-study-points-second-brain-clock-362917

  A brain rhythm working in tandem with the body’s natural sleep-wake cycle may explain why bipolar patients alternate between mania and depression, according to new research. […] The findings suggest that regularly occurring mood switches in bipolar disorder patients are controlled by two clocks: the biological 24-hour clock, and a second clock that is driven by dopamine-producing neurons that typically influence alertness. A manic or depressed state may arise depending on how these two clocks, which run at different speeds, align at a given time. […] When they disrupted dopamine-producing neurons in the brain’s reward centre, these rhythms ceased, highlighting dopamine as a key factor in the mood swings of bipolar disorder. […] Our discovery of a dopamine-based arousal rhythm generator provides a novel and distinct target for treatment, which should aim at correcting or silencing this clock to reduce the frequency and intensity of mood episodes, said Storch. […] What remains unknown is the exact molecular workings of the dopamine clock, as well as the genetic and environmental factors that may activate it in humans.

• #77 What drives mood swings in bipolar disorder? Study points to a second brain clock | Newsroom – McGill University

  https://www.mcgill.ca/newsroom/channels/news/what-drives-mood-swings-bipolar-disorder-study-points-second-brain-clock-362917

  A brain rhythm working in tandem with the body’s natural sleep-wake cycle may explain why bipolar patients alternate between mania and depression, according to new research. […] The findings suggest that regularly occurring mood switches in bipolar disorder patients are controlled by two clocks: the biological 24-hour clock, and a second clock that is driven by dopamine-producing neurons that typically influence alertness. A manic or depressed state may arise depending on how these two clocks, which run at different speeds, align at a given time. […] When they disrupted dopamine-producing neurons in the brain’s reward centre, these rhythms ceased, highlighting dopamine as a key factor in the mood swings of bipolar disorder. […] Our discovery of a dopamine-based arousal rhythm generator provides a novel and distinct target for treatment, which should aim at correcting or silencing this clock to reduce the frequency and intensity of mood episodes, said Storch. […] What remains unknown is the exact molecular workings of the dopamine clock, as well as the genetic and environmental factors that may activate it in humans.

• #78 What drives mood swings in bipolar disorder? Study points to a second brain clock | Newsroom – McGill University

  https://www.mcgill.ca/newsroom/channels/news/what-drives-mood-swings-bipolar-disorder-study-points-second-brain-clock-362917

  A brain rhythm working in tandem with the body’s natural sleep-wake cycle may explain why bipolar patients alternate between mania and depression, according to new research. […] The findings suggest that regularly occurring mood switches in bipolar disorder patients are controlled by two clocks: the biological 24-hour clock, and a second clock that is driven by dopamine-producing neurons that typically influence alertness. A manic or depressed state may arise depending on how these two clocks, which run at different speeds, align at a given time. […] When they disrupted dopamine-producing neurons in the brain’s reward centre, these rhythms ceased, highlighting dopamine as a key factor in the mood swings of bipolar disorder. […] Our discovery of a dopamine-based arousal rhythm generator provides a novel and distinct target for treatment, which should aim at correcting or silencing this clock to reduce the frequency and intensity of mood episodes, said Storch. […] What remains unknown is the exact molecular workings of the dopamine clock, as well as the genetic and environmental factors that may activate it in humans.

• #79 What drives mood swings in bipolar disorder? Study points to a second brain clock | Newsroom – McGill University

  https://www.mcgill.ca/newsroom/channels/news/what-drives-mood-swings-bipolar-disorder-study-points-second-brain-clock-362917

  A brain rhythm working in tandem with the body’s natural sleep-wake cycle may explain why bipolar patients alternate between mania and depression, according to new research. […] The findings suggest that regularly occurring mood switches in bipolar disorder patients are controlled by two clocks: the biological 24-hour clock, and a second clock that is driven by dopamine-producing neurons that typically influence alertness. A manic or depressed state may arise depending on how these two clocks, which run at different speeds, align at a given time. […] When they disrupted dopamine-producing neurons in the brain’s reward centre, these rhythms ceased, highlighting dopamine as a key factor in the mood swings of bipolar disorder. […] Our discovery of a dopamine-based arousal rhythm generator provides a novel and distinct target for treatment, which should aim at correcting or silencing this clock to reduce the frequency and intensity of mood episodes, said Storch. […] What remains unknown is the exact molecular workings of the dopamine clock, as well as the genetic and environmental factors that may activate it in humans.

• #80 What drives mood swings in bipolar disorder? Study points to a second brain clock | Newsroom – McGill University

  https://www.mcgill.ca/newsroom/channels/news/what-drives-mood-swings-bipolar-disorder-study-points-second-brain-clock-362917

  A brain rhythm working in tandem with the body’s natural sleep-wake cycle may explain why bipolar patients alternate between mania and depression, according to new research. […] The findings suggest that regularly occurring mood switches in bipolar disorder patients are controlled by two clocks: the biological 24-hour clock, and a second clock that is driven by dopamine-producing neurons that typically influence alertness. A manic or depressed state may arise depending on how these two clocks, which run at different speeds, align at a given time. […] When they disrupted dopamine-producing neurons in the brain’s reward centre, these rhythms ceased, highlighting dopamine as a key factor in the mood swings of bipolar disorder. […] Our discovery of a dopamine-based arousal rhythm generator provides a novel and distinct target for treatment, which should aim at correcting or silencing this clock to reduce the frequency and intensity of mood episodes, said Storch. […] What remains unknown is the exact molecular workings of the dopamine clock, as well as the genetic and environmental factors that may activate it in humans.

• #81 Bipolar Disorder: the Implications of Metabolism and Inflammation to Pathogenesis and Treatment | European Psychiatry | Cambridge Core

  https://www.cambridge.org/core/journals/european-psychiatry/article/bipolar-disorder-the-implications-of-metabolism-and-inflammation-to-pathogenesis-and-treatment/EFAEE7E616B246A169E6AC796FE03CE2

  Replicated evidence indicates that bipolar disorder is associated with alterations in molecular, cellular, and neuro systems that involve disparate metabolic and inflammatory pathways. […] Consensus exists that available treatments for bipolar disorder are neither disease modifying nor targeting critical effector systems implicated in this disorder. […] This presentation will provide a rationale for exploring drug development opportunities for critical metabolic systems including glucagon-like-peptide and insulin systems as well as critical inflammatory pathways.

• #82 Lithium’s Mechanism of Action – A Synopsis and Visual Guide

  https://psychscenehub.com/psychinsights/lithium-mechanism-action-synopsis-visual-guide/

  Lithium is a unique agent that has been used for over half a century for the treatment of bipolar affective disorder. Lithium has compelling evidence in the treatment of mania, acute bipolar depression and prophylaxis in bipolar affective disorder. […] Despite its first discovery 1949 and its subsequent use, the exact mechanisms of action in lithium are unclear. […] In this article, we focus on two key aspects: Lithium’s action on neurotransmitters and second messenger systems; Intracellular mechanisms of action which converge towards neuroprotection. […] Dopamine is an excitatory neurotransmitter that plays an important role in the pathogenesis of bipolar affective disorder. Dopamine transmission is known to be elevated during mania and decreased in clinical depression. […] The subunits of the dopamine associated G protein have been reported to be higher in bipolar disorder patients and may contribute to the pathophysiology of bipolar affective disorder. Lithium administration alters the functionality of these subunits especially the equilibrium between active and inactive subunits thus likely correcting the dopamine dysregulation.

• #83 Lithium’s Mechanism of Action – A Synopsis and Visual Guide

  https://psychscenehub.com/psychinsights/lithium-mechanism-action-synopsis-visual-guide/

  Lithium is a unique agent that has been used for over half a century for the treatment of bipolar affective disorder. Lithium has compelling evidence in the treatment of mania, acute bipolar depression and prophylaxis in bipolar affective disorder. […] Despite its first discovery 1949 and its subsequent use, the exact mechanisms of action in lithium are unclear. […] In this article, we focus on two key aspects: Lithium’s action on neurotransmitters and second messenger systems; Intracellular mechanisms of action which converge towards neuroprotection. […] Dopamine is an excitatory neurotransmitter that plays an important role in the pathogenesis of bipolar affective disorder. Dopamine transmission is known to be elevated during mania and decreased in clinical depression. […] The subunits of the dopamine associated G protein have been reported to be higher in bipolar disorder patients and may contribute to the pathophysiology of bipolar affective disorder. Lithium administration alters the functionality of these subunits especially the equilibrium between active and inactive subunits thus likely correcting the dopamine dysregulation.

• #84 Underlying molecular mechanism of bipolar disorder | ScienceDaily

  https://www.sciencedaily.com/releases/2017/05/170508162227.htm

  Scientists have identified the molecular mechanism behind lithium’s effectiveness in treating bipolar disorder patients. […] The study utilized human induced pluripotent stem cells (hiPS cells) to map lithium’s response pathway, enabling the larger pathogenesis of bipolar disorder to be identified. […] These results are the first to explain the molecular basis of the disease, and may support the development of a diagnostic test for the disorder as well as predict the likelihood of patient response to lithium treatment. […] Importantly, our findings open a clear path to finding safe and effective new drugs. […] We realized that studying the lithium response could be used as a 'molecular can-opener’ to unravel the molecular pathway of this complex disorder, that turns out not to be caused by a defect in a gene, but rather by the posttranslational regulation (phosphorylation) of the product of a gene — in this case, CRMP2, an intracellular protein that regulates neural networks.

• #85 Underlying molecular mechanism of bipolar disorder | ScienceDaily

  https://www.sciencedaily.com/releases/2017/05/170508162227.htm

  Scientists have identified the molecular mechanism behind lithium’s effectiveness in treating bipolar disorder patients. […] The study utilized human induced pluripotent stem cells (hiPS cells) to map lithium’s response pathway, enabling the larger pathogenesis of bipolar disorder to be identified. […] These results are the first to explain the molecular basis of the disease, and may support the development of a diagnostic test for the disorder as well as predict the likelihood of patient response to lithium treatment. […] Importantly, our findings open a clear path to finding safe and effective new drugs. […] We realized that studying the lithium response could be used as a 'molecular can-opener’ to unravel the molecular pathway of this complex disorder, that turns out not to be caused by a defect in a gene, but rather by the posttranslational regulation (phosphorylation) of the product of a gene — in this case, CRMP2, an intracellular protein that regulates neural networks.

• #86 Underlying molecular mechanism of bipolar disorder | ScienceDaily

  https://www.sciencedaily.com/releases/2017/05/170508162227.htm

  Scientists have identified the molecular mechanism behind lithium’s effectiveness in treating bipolar disorder patients. […] The study utilized human induced pluripotent stem cells (hiPS cells) to map lithium’s response pathway, enabling the larger pathogenesis of bipolar disorder to be identified. […] These results are the first to explain the molecular basis of the disease, and may support the development of a diagnostic test for the disorder as well as predict the likelihood of patient response to lithium treatment. […] Importantly, our findings open a clear path to finding safe and effective new drugs. […] We realized that studying the lithium response could be used as a 'molecular can-opener’ to unravel the molecular pathway of this complex disorder, that turns out not to be caused by a defect in a gene, but rather by the posttranslational regulation (phosphorylation) of the product of a gene — in this case, CRMP2, an intracellular protein that regulates neural networks.

• #87 Underlying molecular mechanism of bipolar disorder | ScienceDaily

  https://www.sciencedaily.com/releases/2017/05/170508162227.htm

  Scientists have identified the molecular mechanism behind lithium’s effectiveness in treating bipolar disorder patients. […] The study utilized human induced pluripotent stem cells (hiPS cells) to map lithium’s response pathway, enabling the larger pathogenesis of bipolar disorder to be identified. […] These results are the first to explain the molecular basis of the disease, and may support the development of a diagnostic test for the disorder as well as predict the likelihood of patient response to lithium treatment. […] Importantly, our findings open a clear path to finding safe and effective new drugs. […] We realized that studying the lithium response could be used as a 'molecular can-opener’ to unravel the molecular pathway of this complex disorder, that turns out not to be caused by a defect in a gene, but rather by the posttranslational regulation (phosphorylation) of the product of a gene — in this case, CRMP2, an intracellular protein that regulates neural networks.

• #88 Underlying molecular mechanism of bipolar disorder | ScienceDaily

  https://www.sciencedaily.com/releases/2017/05/170508162227.htm

  Thus, the study demonstrated that bipolar disorder can be rooted in physiological — not necessarily genetic — mechanisms. […] This 'molecular can-opener’ approach — using a drug known to have a useful action without exactly knowing why — allowed us to examine and understand an underlying pathogenesis of bipolar disorder.

• #89 Underlying molecular mechanism of bipolar disorder | ScienceDaily

  https://www.sciencedaily.com/releases/2017/05/170508162227.htm

  Thus, the study demonstrated that bipolar disorder can be rooted in physiological — not necessarily genetic — mechanisms. […] This 'molecular can-opener’ approach — using a drug known to have a useful action without exactly knowing why — allowed us to examine and understand an underlying pathogenesis of bipolar disorder.

• #90 Bipolar Disorder and Immune Dysfunction: Epidemiological Findings, Proposed Pathophysiology and Clinical Implications

  https://www.mdpi.com/2076-3425/7/11/144

  Bipolar disorder (BD) is strongly associated with immune dysfunction. Replicated epidemiological studies have demonstrated that BD has high rates of inflammatory medical comorbidities, including autoimmune disorders, chronic infections, cardiovascular disease and metabolic disorders. […] Several mechanisms have been identified to explain the bidirectional relationship between BD and immune dysfunction. Key mechanisms include cytokine-induced monoamine changes, increased oxidative stress, pathological microglial over-activation, hypothalamic-pituitary-adrenal (HPA) axis over-activation, alterations of the microbiome-gut-brain axis and sleep-related immune changes. […] The inflammatory-mood pathway presents several potential novel targets in the treatment of BD. […] The hypothesis that immune dysfunction may be a mediator of disease progression in BD was first proposed by Horrobin & Lieb (1981) who hypothesized that immune modulation may be a key mechanism of action in lithium’s mood stabilizing effects.

• #91 Inflammatory signaling mechanisms in bipolar disorder | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-021-00742-6

  This positive feedback loop is suggested to contribute to the chronic neurodegeneration observed in BD, in part by modulating GSK-3 activitya key regulator of mitochondrial metabolism, DNA repair, inflammation, and apoptosis, which has been extensively implicated in BD. […] Indeed, TNF- has been shown to modulate many dysfunctional processes in BD including synaptic plasticity, neurotransmission, neurogenesis, neuronal survival, apoptosis, and even cognitive/behavioral functioning. […] Given the pervasive influence of immune/inflammatory dysfunction on BD and its numerous comorbidities, significant potential exists in targeting this system. […] Overall, it appears that inflammatory signaling mediates a strong connection between cellular stress, neuronal viability, and overt symptomatology. The hypothesis that BD incurs a low grade, proinflammatory state, exacerbated during acute mood episodes is potentially reinforced by the notion that anti-inflammatory therapies appear to be far more efficacious in mania and depression than in the maintenance phase. […] In summary, the NLRP3 inflammasome serves a central mediator of inflammatory signaling in BD, linking other cellular stress systems to immune cell activation. It also provides a common thread between mood symptoms and metabolic comorbidities.

• #92 Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine | Molecular Psychiatry

  https://www.nature.com/articles/s41380-023-02134-8

  Our discovery is critical there currently are no psychiatric medications that directly target mitochondrial dysfunction. […] Trimetazidine is being assessed for its efficacy in treating bipolar depression in an international multi-site clinical trial. […] The main mechanism of trimetazidine is modulating mitochondrial energy production. […] Trimetazidine, though introduced as an anti-anginal agent to increase metabolic efficiency when metabolic processes are compromised, is postulated to have a cytoprotective action as above. […] Such literature strongly suggests the potential of trimetazidine to address key elements of bipolar depressions pathophysiology. […] Trimetazidine has also been shown to increase antioxidant activity measured by increased glutathione, glutathione peroxidase, superoxide dismutase (SOD), and catalase.

• #93 Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine | Molecular Psychiatry

  https://www.nature.com/articles/s41380-023-02134-8

  Our discovery is critical there currently are no psychiatric medications that directly target mitochondrial dysfunction. […] Trimetazidine is being assessed for its efficacy in treating bipolar depression in an international multi-site clinical trial. […] The main mechanism of trimetazidine is modulating mitochondrial energy production. […] Trimetazidine, though introduced as an anti-anginal agent to increase metabolic efficiency when metabolic processes are compromised, is postulated to have a cytoprotective action as above. […] Such literature strongly suggests the potential of trimetazidine to address key elements of bipolar depressions pathophysiology. […] Trimetazidine has also been shown to increase antioxidant activity measured by increased glutathione, glutathione peroxidase, superoxide dismutase (SOD), and catalase.

• #94 Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine | Molecular Psychiatry

  https://www.nature.com/articles/s41380-023-02134-8

  Our discovery is critical there currently are no psychiatric medications that directly target mitochondrial dysfunction. […] Trimetazidine is being assessed for its efficacy in treating bipolar depression in an international multi-site clinical trial. […] The main mechanism of trimetazidine is modulating mitochondrial energy production. […] Trimetazidine, though introduced as an anti-anginal agent to increase metabolic efficiency when metabolic processes are compromised, is postulated to have a cytoprotective action as above. […] Such literature strongly suggests the potential of trimetazidine to address key elements of bipolar depressions pathophysiology. […] Trimetazidine has also been shown to increase antioxidant activity measured by increased glutathione, glutathione peroxidase, superoxide dismutase (SOD), and catalase.

• #95 Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine | Molecular Psychiatry

  https://www.nature.com/articles/s41380-023-02134-8

  Our discovery is critical there currently are no psychiatric medications that directly target mitochondrial dysfunction. […] Trimetazidine is being assessed for its efficacy in treating bipolar depression in an international multi-site clinical trial. […] The main mechanism of trimetazidine is modulating mitochondrial energy production. […] Trimetazidine, though introduced as an anti-anginal agent to increase metabolic efficiency when metabolic processes are compromised, is postulated to have a cytoprotective action as above. […] Such literature strongly suggests the potential of trimetazidine to address key elements of bipolar depressions pathophysiology. […] Trimetazidine has also been shown to increase antioxidant activity measured by increased glutathione, glutathione peroxidase, superoxide dismutase (SOD), and catalase.

• #96 Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine | Molecular Psychiatry

  https://www.nature.com/articles/s41380-023-02134-8

  Our discovery is critical there currently are no psychiatric medications that directly target mitochondrial dysfunction. […] Trimetazidine is being assessed for its efficacy in treating bipolar depression in an international multi-site clinical trial. […] The main mechanism of trimetazidine is modulating mitochondrial energy production. […] Trimetazidine, though introduced as an anti-anginal agent to increase metabolic efficiency when metabolic processes are compromised, is postulated to have a cytoprotective action as above. […] Such literature strongly suggests the potential of trimetazidine to address key elements of bipolar depressions pathophysiology. […] Trimetazidine has also been shown to increase antioxidant activity measured by increased glutathione, glutathione peroxidase, superoxide dismutase (SOD), and catalase.

• #97 Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine | Molecular Psychiatry

  https://www.nature.com/articles/s41380-023-02134-8

  Overall, evidence for mitochondrial dysfunction, inflammation and oxidative stress in bipolar depression is consistent with many replicated findings across tissue types, molecular assays, and ethnicities. […] A particularly compelling hypothesis is that bipolar depression is a state of decreased mitochondrial energy generation, which may be overcompensated by increased mitochondrial energy generation in mania. […] Trimetazidines main activity in boosting mitochondrial energy generation only when mitochondrial function is reduced, while also targeting inflammation and oxidative stress that occurs in both depression and mania in bipolar disorder makes it a promising novel pharmacotherapy candidate to be tested in clinical trials.

• #98 Mount Sinai Researchers Identify Brain Mechanism for Resilience in People with High Risk of Bipolar Disorder | Mount Sinai – New York

  https://www.mountsinai.org/about/newsroom/2017/mount-sinai-researchers-identify-brain-mechanism-for-resilience-in-people-with-high-risk-of-bipolar-disorder

  Based on these results, the researchers are conducting a series of follow-up experiments to test whether it is possible to rewire at-risk patients’ brains by simple computerized tasks that enhance brain connectivity. Initial results suggest that simple interventions may restore the functional architecture of the brain and reduce the severity of symptoms in patients.

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