Schloesser RJ, Huang J, Klein PS, Manji HK. Cellular plasticity cascades in the pathophysiology and treatment of bipolar disorder. Neuropsychopharmacology 33: 110-133

Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA.
Neuropsychopharmacology (Impact Factor: 7.05). 02/2008; 33(1):110-33. DOI: 10.1038/sj.npp.1301575
Source: PubMed


Bipolar disorder (BPD) is characterized by recurrent episodes of disturbed affect including mania and depression as well as changes in psychovegetative function, cognitive performance, and general health. A growing body of data suggests that BPD arises from abnormalities in synaptic and neuronal plasticity cascades, leading to aberrant information processing in critical synapses and circuits. Thus, these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters. In addition, commonly used mood-stabilizing drugs that are effective in treating BPD have been shown to target intracellular signaling pathways that control synaptic plasticity and cellular resilience. In this article we draw on clinical, preclinical, neuroimaging, and post-mortem data to discuss the neurobiology of BPD within a conceptual framework while highlighting the role of neuroplasticity in the pathophysiology and treatment of this disorder.

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    • "This reflects altered hierarchy because frontal brain areas relate to higher-level processing thus consisting of higher hierarchical levels. Hampered plasticity and neuronal degeneration have been repeatedly found to correlate with depression [27] [28] [29] [30]. A review by Masi and Brovedani [31] describes recent studies indicating that an impairment of synaptic plasticity (neurogenesis, axon branching , dendritogenesis and synaptogenesis) in specific areas of the CNS, particularly the hippocampus, may be a core factor in the pathophysiology of depression. "
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    ABSTRACT: Clinical brain profiling is an attempt to map a descriptive nosology in psychiatry to underlying constructs in neurobiology and brain dynamics. This paper briefly reviews the motivation behind clinical brain profiling (CBP) and presents some provisional validation using clinical assessments and meta-analyses of neuroscientific publications. The paper has four sections. In the first, we review the nature and motivation for clinical brain profiling. This involves a description of the key aspects of functional anatomy that can lead to psychopathology. These features constitute the dimensions or categories for a profile of brain disorders based upon pathophysiology. The second section describes a mapping or translation matrix that maps from symptoms and signs, of a descriptive sort, to the CBP dimensions that provide a more mechanistic explanation. We will describe how this mapping engenders archetypal diagnoses, referring readers to tables and figures. The third section addresses the construct validity of clinical brain profiling by establishing correlations between profiles based on clinical ratings of symptoms and signs under classical diagnostic categories with the corresponding profiles generated automatically using archetypal diagnoses. We then provide furthervalidation by performing a cluster analysis on the symptoms and signs and showing how they correspond to the equivalent brain profiles based upon clinical and automatic diagnosis. In the fourth section, we address the construct validity of clinical brain profiling by looking for associations between pathophysiological mechanisms (such as connectivity and plasticity) and nosological diagnoses (such as schizophrenia and depression). Based upon the mechanistic perspective offered in the first section, we test some particular hypotheses about double dissociations using a meta-analysis of PubMed searches. The final section concludes with perspectives for the future and outstanding validation issues for clinical brain profiling.
    Full-text · Article · Oct 2014 · Medical Hypotheses
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    • "Studies have shown that dysfunction of several intracellular signaling pathways may affect neuroplasticity and cellular resilience in BD, including mechanisms involving neurotransmitters, glucocorticoids, neurotrophic and anti-apoptotic factors, cell survival pathways, and calcium signaling, among others (Schloesser et al., 2008; Hunsberger et al., 2009). For instance, increased levels of calcium have been found in platelets, lymphocytes, and lymphoblastoid cells from patients with BD (Dubovsky et al., 1992; Perova et al., 2008), and an increased susceptibility to cell death in olfactory neuroepithelium has also been reported (McCurdy et al., 2006). "
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    ABSTRACT: Bipolar disorder (BD) is a severe chronic psychiatric disorder that has been associated with cellular dysfunctions related to mitochondria, neurotrophin levels, and oxidative stress. Evidence has shown that endoplasmic reticulum (ER) stress may be a common pathway of the cellular changes described in BD. In the present study we assessed unfolded protein response (UPR) and the effects of this cellular process on lymphocytes from patients with BD. We also evaluated whether the stage of chronicity of BD was associated with changes in UPR parameters. Cultured lymphocytes from 30 patients with BD and 32 age- and sex-matched controls were treated with tunicamycin, an ER stressor, for 12 or 24 h to measure levels of UPR-related proteins (GRP78, eIF2α-P, and CHOP) using flow cytometry, and for 48 h to analyse ER stress-induced cell death. In healthy controls but not in patients we found an increase in levels of GRP78, eIF2α-P, and CHOP after ER stress induction. In addition, tunicamycin-induced cell death was significantly higher in patients compared to controls. More importantly, early-stage patients did not differ from controls while the late-stage patients showed an impaired ER stress response. Thus, dysfunction in ER-related stress response may be associated with decreased cellular resilience in BD and illness progression.
    Full-text · Article · May 2014 · The International Journal of Neuropsychopharmacology
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    • "A recent genome-wide association study of bipolar disorders (BD), which is another chronic major mental illness composed of recurrent episodic mood disturbances ranging from mania to severe depression, revealed that most of the highly significant associations were implicated in signaling cascades of plasticity [46]. It has been proposed that abnormalities in neuroplasticity lead to maladaptive developments in neural circuits, affecting the information processing that mediates various facets of BD symptomatology [47, 48]. Another study using peripheral biomarkers suggested that BD patients show increased oxidative stress and decreased neuron-specific endolase, a neuronal glycolytic enzyme known to mediate neuroplastic pathways and cell survival [49]. "
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    ABSTRACT: There is growing evidence that the imbalance between oxidative stress and the antioxidant defense system may be associated with the development neuropsychiatric disorders, such as depression and anxiety. Major depression and anxiety are presently correlated with a lowered total antioxidant state and by an activated oxidative stress (OS) pathway. The classical antidepressants may produce therapeutic effects other than regulation of monoamines by increasing the antioxidant levels and normalizing the damage caused by OS processes. This chapter provides an overview of recent work on oxidative stress markers in the animal models of depression and anxiety, as well as patients with the aforementioned mood disorders. It is well documented that antioxidants can remove the reactive oxygen species (ROS) and reactive nitrogen species (RNS) through scavenging radicals and suppressing the OS pathway, which further protect against neuronal damage caused oxidative or nitrosative stress sources in the brain, hopefully resulting in remission of depression or anxiety symptoms. The functional understanding of the relationship between oxidative stress and depression and anxiety may pave the way for discovery of novel targets for treatment of neuropsychiatric disorders.
    Full-text · Article · Mar 2014 · Current Neuropharmacology
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