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Molecular Psychiatry Aug 2021Calcium signalling has long been implicated in bipolar disorder, especially by reports of altered intracellular calcium ion concentrations ([Ca]). However, the evidence... (Meta-Analysis)
Meta-Analysis
Calcium signalling has long been implicated in bipolar disorder, especially by reports of altered intracellular calcium ion concentrations ([Ca]). However, the evidence has not been appraised critically. We carried out a systematic review and meta-analysis of studies of cellular calcium indices in bipolar disorder. 2281 records were identified and 117 screened, of which 32 were eligible and 21 were suitable for meta-analyses. The latter each involved up to 642 patients and 404 control subjects. We found that basal free intracellular [Ca] is increased in bipolar disorder, both in platelets and in lymphocytes. The effect size is 0.55, with an estimated elevation of 29%. It is observed in medication-free patients. It is present in mania and bipolar depression, but data are equivocal for euthymia. Cells from bipolar disorder individuals also show an enhanced [Ca] response to stimulation with 5-HT or thrombin, by an estimated 25%, with an effect size of 0.63. In studies which included other diagnoses, intracellular basal [Ca] was higher in bipolar disorder than in unipolar depression, but not significantly different from schizophrenia. Functional parameters of cellular Ca (e.g. calcium transients), and neuronal [Ca], have been much less investigated, and no firm conclusions can be drawn. In summary, there is a robust, medium effect size elevation of basal and stimulated free intracellular [Ca] in bipolar disorder. The results suggest altered calcium functioning in the disorder, and encourage further investigations into the underlying mechanisms, and the implications for pathophysiology and therapeutics.
Topics: Bipolar Disorder; Blood Platelets; Calcium; Depressive Disorder; Humans; Schizophrenia
PubMed: 31801967
DOI: 10.1038/s41380-019-0622-y -
Molecular Neuropsychiatry Apr 2020Glutamate is implicated in the neuropathology of both major depressive disorder and bipolar disorder. Excitatory amino acid transporter 2 (EAAT2) is the major glutamate... (Review)
Review
Glutamate is implicated in the neuropathology of both major depressive disorder and bipolar disorder. Excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the mammalian brain, removing glutamate from the synaptic cleft and transporting it into glia for recycling. It is thereby the principal regulator of extracellular glutamate levels and prevents neuronal excitotoxicity. EAAT2 is a promising target for elucidating the mechanisms by which the glutamate-glutamine cycle interacts with neuronal systems in mood disorders. Forty EAAT2 studies (published January 1992-January 2018) were identified via a systematic literature search. The studies demonstrated that chronic stress/steroids were most commonly associated with decreased EAAT2. In rodents, EAAT2 inhibition worsened depressive behaviors. Human EAAT2 expression usually decreased in depression, with some regional brain differences. Fewer data have been collected regarding the roles and regulation of EAAT2 in bipolar disorder. Future directions for research include correlating EAAT2 and glutamate levels in vivo, elucidating genetic variability and epigenetic regulation, clarifying intracellular protein and pharmacologic interactions, and examining EAAT2 in different bipolar mood states. As part of a macromolecular complex within glia, EAAT2 may contribute significantly to intracellular signaling, energy regulation, and cellular homeostasis. An enhanced understanding of this system is needed.
PubMed: 32399469
DOI: 10.1159/000501885 -
Molecular Psychiatry Aug 2020Various neuropathological findings have been reported in bipolar disorder (BD). However, it is unclear which findings are well established. To address this gap, we... (Meta-Analysis)
Meta-Analysis
Various neuropathological findings have been reported in bipolar disorder (BD). However, it is unclear which findings are well established. To address this gap, we carried out a systematic review of the literature. We searched over 5000 publications, identifying 103 data papers, of which 81 were eligible for inclusion. Our main findings can be summarised as follows. First, most studies have relied on a limited number of brain collections, and have used relatively small sample sizes (averaging 12 BD cases and 15 controls). Second, surprisingly few studies have attempted to replicate closely a previous one, precluding substantial meta-analyses, such that the latter were all limited to two studies each, and comprising 16-36 BD cases and 16-74 controls. As such, no neuropathological findings can be considered to have been established beyond reasonable doubt. Nevertheless, there are several replicated positive findings in BD, including decreased cortical thickness and glial density in subgenual anterior cingulate cortex, reduced neuronal density in some amygdalar nuclei, and decreased calbindin-positive neuron density in prefrontal cortex. Many other positive findings have also been reported, but with limited or contradictory evidence. As an important negative result, it can be concluded that gliosis is not a feature of BD; neither is there neuropathological evidence for an inflammatory process.
Topics: Bipolar Disorder; Brain; Gyrus Cinguli; Humans; Neuroglia; Prefrontal Cortex
PubMed: 30127470
DOI: 10.1038/s41380-018-0213-3 -
Revista Brasileira de Psiquiatria (Sao... Mar 2013The use of clinical staging models is emerging as a novel and useful paradigm for diagnosing severe mental disorders. The term "neuroprogression" has been used to define... (Review)
Review
INTRODUCTION
The use of clinical staging models is emerging as a novel and useful paradigm for diagnosing severe mental disorders. The term "neuroprogression" has been used to define the pathological reorganization of the central nervous system along the course of severe mental disorders. In bipolar disorder (BD), neural substrate reactivity is changed by repeated mood episodes, promoting a brain rewiring that leads to an increased vulnerability to life stress.
METHOD
A search in the PubMed database was performed with the following terms: "staging", "neuroprogression", "serum", "plasma", "blood", "neuroimaging", "PET scan", "fMRI", "neurotrophins", "inflammatory markers" and "oxidative stress markers", which were individually crossed with "cognition", "functionality", "response to treatments" and "bipolar disorder". The inclusion criteria comprised original papers in the English language. Abstracts from scientific meetings were not included.
RESULTS
We divided the results according to the available evidence of serum biomarkers as potential mediators of neuroprogression, with brain imaging, cognition, functioning and response to treatments considered as consequences.
CONCLUSION
The challenge in BD treatment is translating the knowledge of neuronal plasticity and neurobiology into clinical practice. Neuroprogression and staging can have important clinical implications, given that early and late stages of the disorder appear to present different biological features and therefore may require different treatment strategies.
Topics: Biomarkers; Bipolar Disorder; Disease Progression; Humans; Treatment Outcome
PubMed: 23567604
DOI: 10.1016/j.rbp.2012.09.001 -
Clinical Neurophysiology : Official... Sep 2022Bipolar disorder is characterized by aberrant neurophysiological responses as measured with electroencephalography (EEG) and magnetoencephalography (MEG), including the... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Bipolar disorder is characterized by aberrant neurophysiological responses as measured with electroencephalography (EEG) and magnetoencephalography (MEG), including the 40-Hz auditory steady-state response (ASSR). 40-Hz ASSR deficits are also found in patients with schizophrenia and may represent a transdiagnostic biomarker of neuronal circuit dysfunction. In this systematic review and meta-analysis, we summarize and evaluate the evidence for 40-Hz ASSR deficits in patients with bipolar disorder.
METHODS
We identified studies from PubMed, EMBASE, and SCOPUS. We assessed the risk of bias, calculated Hedges' g meta-level effect sizes, and investigated small-study effects using funnel plots and Egger regression.
RESULTS
Seven studies, comprising 396 patients with bipolar disorder and 404 healthy controls, were included in the meta-analysis. Studies displayed methodological heterogeneity and an overall high risk of bias. Patients with bipolar disorder showed consistent reductions in 40-Hz ASSR evoked power (Hedges' g = -0.49; 95% confidence intervals [-0.67, -0.31]) and inter-trial phase coherence (ITPC) (Hedges' g = -0.43; 95 %CI [-0.58, -0.29]) compared with healthy controls.
CONCLUSIONS
Our meta-analysis provides evidence that 40-Hz ASSRs are reduced in patients with bipolar disorder compared with healthy controls.
SIGNIFICANCE
Future large-scale studies are warranted to link 40-Hz ASSR deficits to clinical features and developmental trajectories.
Topics: Acoustic Stimulation; Bipolar Disorder; Electroencephalography; Evoked Potentials, Auditory; Humans; Magnetoencephalography; Schizophrenia
PubMed: 35853310
DOI: 10.1016/j.clinph.2022.06.014 -
NPJ Schizophrenia 2017Since Emil Kraepelin's conceptualization of endogenous psychoses as dementia praecox and manic depression, the separation between primary psychotic disorders and primary...
Since Emil Kraepelin's conceptualization of endogenous psychoses as dementia praecox and manic depression, the separation between primary psychotic disorders and primary affective disorders has been much debated. We conducted a systematic review of case-control studies contrasting magnetic resonance imaging studies in schizophrenia and bipolar disorder. A literature search in PubMed of studies published between January 2005 and December 2016 was conducted, and 50 structural, 29 functional, 7 magnetic resonance spectroscopy, and 8 combined imaging and genetic studies were deemed eligible for systematic review. Structural neuroimaging studies suggest white matter integrity deficits that are consistent across the illnesses, while gray matter reductions appear more widespread in schizophrenia compared to bipolar disorder. Spectroscopy studies in cortical gray matter report evidence of decreased neuronal integrity in both disorders. Functional neuroimaging studies typically report similar functional architecture of brain networks in healthy controls and patients across the psychosis spectrum, but find differential extent of alterations in task related activation and resting state connectivity between illnesses. The very limited imaging-genetic literature suggests a relationship between psychosis risk genes and brain structure, and possible gene by diagnosis interaction effects on functional imaging markers. While the existing literature suggests some shared and some distinct neural markers in schizophrenia and bipolar disorder, it will be imperative to conduct large, well designed, multi-modal neuroimaging studies in medication-naïve first episode patients that will be followed longitudinally over the course of their illness in an effort to advance our understanding of disease mechanisms.
PubMed: 28560261
DOI: 10.1038/s41537-017-0013-9 -
Brain Sciences Sep 2023Five major psychiatric disorders: schizophrenia, major depressive disorder, bipolar disorder, autistic spectrum disorder, and attention-deficit/hyperactivity disorder,... (Review)
Review
Five major psychiatric disorders: schizophrenia, major depressive disorder, bipolar disorder, autistic spectrum disorder, and attention-deficit/hyperactivity disorder, show a shared genetic background and probably share common pathobiological mechanisms. S100B is a calcium-binding protein widely studied in psychiatric disorders as a potential biomarker. Our systematic review aimed to compare studies on peripheral S100B levels in five major psychiatric disorders with shared genetic backgrounds to reveal whether S100B alterations are disease-specific. EMBASE, Web of Science, and PubMed databases were searched for relevant studies published until the end of July 2023. This study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocols (PRISMA) guidelines. Overall, 1215 publications were identified, of which 111 full-text articles were included in the systematic review. Study designs are very heterogeneous, performed mostly on small groups of participants at different stages of the disease (first-episode or chronic, drug-free or medicated, in the exacerbation of symptoms or in remission), and various clinical variables are analyzed. Published results are inconsistent; most reported elevated S100B levels across disorders included in the review. Alterations in S100B peripheral levels do not seem to be disease-specific.
PubMed: 37759935
DOI: 10.3390/brainsci13091334 -
Schizophrenia Research Jan 2015Neuroinflammation and white matter pathology have each been independently associated with schizophrenia, and experimental studies have revealed mechanisms by which the... (Review)
Review
BACKGROUND
Neuroinflammation and white matter pathology have each been independently associated with schizophrenia, and experimental studies have revealed mechanisms by which the two can interact in vitro, but whether these abnormalities simultaneously co-occur in people with schizophrenia remains unclear.
METHOD
We searched MEDLINE, EMBASE, PsycINFO and Web of Science from inception through 12 January 2014 for studies reporting human data on the relationship between microglial or astroglial activation, or cytokines and white matter pathology in schizophrenia.
RESULTS
Fifteen studies totaling 792 subjects (350 with schizophrenia, 346 controls, 49 with bipolar disorder, 37 with major depressive disorder and 10 with Alzheimer's disease) met all eligibility criteria. Five neuropathological and two neuroimaging studies collectively yielded consistent evidence of an association between schizophrenia and microglial activation, particularly in white rather than gray matter regions. Ultrastructural analysis revealed activated microglia near dystrophic and apoptotic oligodendroglia, demyelinating and dysmyelinating axons and swollen and vacuolated astroglia in subjects with schizophrenia but not controls. Two neuroimaging studies found an association between carrier status for a functional single nucleotide polymorphism in the interleukin-1β gene and abnormal white as well as gray matter volumes in schizophrenia but not controls. A neuropathological study found that orbitofrontal white matter neuronal density was increased in schizophrenia cases exhibiting high transcription levels of pro-inflammatory cytokines relative to those exhibiting low transcription levels and to controls. Schizophrenia was associated with decreased astroglial density specifically in subgenual cingulate white matter and anterior corpus callosum, but not other gray or white matter areas. Astrogliosis was consistently absent. Data on astroglial gene expression, mRNA expression and protein concentration were inconsistent.
CONCLUSION
Neuroinflammation is associated with white matter pathology in people with schizophrenia, and may contribute to structural and functional disconnectivity, even at the first episode of psychosis.
Topics: Cytokines; Databases, Bibliographic; Humans; Inflammation; Neuroglia; Schizophrenia; White Matter
PubMed: 24948485
DOI: 10.1016/j.schres.2014.04.041 -
Frontiers in Pharmacology 2021The neurobiological bases of mood instability are poorly understood. Neuronal network alterations and neurometabolic abnormalities have been implicated in the... (Review)
Review
The neurobiological bases of mood instability are poorly understood. Neuronal network alterations and neurometabolic abnormalities have been implicated in the pathophysiology of mood and anxiety conditions associated with mood instability and hence are candidate mechanisms underlying its neurobiology. Fast-spiking parvalbumin GABAergic interneurons modulate the activity of principal excitatory neurons through their inhibitory action determining precise neuronal excitation balance. These interneurons are directly involved in generating neuronal networks activities responsible for sustaining higher cerebral functions and are especially vulnerable to metabolic stress associated with deficiency of energy substrates or mitochondrial dysfunction. Parvalbumin interneurons are therefore candidate key players involved in mechanisms underlying the pathogenesis of brain disorders associated with both neuronal networks' dysfunction and brain metabolism dysregulation. To provide empirical support to this hypothesis, we hereby report meta-analytical evidence of parvalbumin interneurons loss or dysfunction in the brain of patients with Bipolar Affective Disorder (BPAD), a condition primarily characterized by mood instability for which the pathophysiological role of mitochondrial dysfunction has recently emerged as critically important. We then present a comprehensive review of evidence from the literature illustrating the bidirectional relationship between deficiency in mitochondrial-dependent energy production and parvalbumin interneuron abnormalities. We propose a mechanistic explanation of how alterations in neuronal excitability, resulting from parvalbumin interneurons loss or dysfunction, might manifest clinically as mood instability, a poorly understood clinical phenotype typical of the most severe forms of affective disorders. The evidence we report provides insights on the broader therapeutic potential of pharmacologically targeting parvalbumin interneurons in psychiatric and neurological conditions characterized by both neurometabolic and neuroexcitability abnormalities.
PubMed: 34616292
DOI: 10.3389/fphar.2021.689473 -
Frontiers in Psychiatry 2018The clinical and etiological heterogeneity of mood disorders impede identification of effective treatments for the individual patient. This highlights a need for early...
The clinical and etiological heterogeneity of mood disorders impede identification of effective treatments for the individual patient. This highlights a need for early neuronal and behavioral biomarkers for treatment efficacy, which can provide a basis for more personalized treatments. The present systematic review aimed to identify the most consistent neuronal and behavioral predictors of treatment efficacy on mood symptoms and cognitive impairment in mood disorders. We identified and included 60 original peer-reviewed studies investigating neuroimaging and behavioral predictors of treatment efficacy within the domains of emotional and non-emotional cognition, structural neuroimaging, and resting state functional connectivity in patients with unipolar or bipolar disorder. Lower baseline responsivity in limbic regions coupled with heightened medial and dorsal prefrontal responses to emotional stimuli were the most consistent predictors of response to pharmacotherapy for depression. In contrast, heightened limbic and ventral prefrontal reactivity to emotional stimuli seemed to predict efficacy of psychological interventions. Early modulation of fronto-limbic activity and reduction in negative bias were also associated with treatment response. Better performance on non-emotional tests at baseline was relatively consistently associated with efficacy on mood symptoms, whereas the association between neural activity during non-emotional tests and treatment response was less clear. Other baseline factors associated with treatment response were greater white matter integrity, resting state functional connectivity, more prefrontal gray matter volume as well as an early increase following short administered treatment. Finally, emerging evidence indicates that baseline cognitive deficits are associated with greater chances of achieving treatment efficacy on cognition. Patients' profile of emotional and non-emotional cognition and neural activity-and the early treatment-associated changes in neural and cognitive function-may be useful for guiding treatments for depression. While cognitive deficits at baseline seem to improve chances of treatment efficacy on cognition, more studies of this association are urgently needed.
PubMed: 30093870
DOI: 10.3389/fpsyt.2018.00337