Involvement of Kynurenine Metabolism in Bipolar Disorder: An Updated Review
TL;DR: In this paper, the authors introduce the altered kynurenine (KYN) pathway and describe the immune dysregulation in patients with bipolar disorder, as well as their interactions with the immune system.
Abstract: Bipolar disorder (BD) is a severe affective disorder, mainly characterized by alternative depressive and manic or hypomanic episodes, yet the pathogenesis of BD has not been fully elucidated. Recent researches have implicated the altered kynurenine (KYN) metabolism involved in the neurobiology of BD. Excessive activation of the immune system also occurs in patients with BD, which further accelerates the KYN pathway for tryptophan metabolism. Changes of the KYN metabolites have effects on neuronal receptors and are involved in neuroendocrine transmissions. Interactions between KYN metabolism and the immune system may contribute to the neuropathogenesis of BD. Various studies have shown that alterations of the KYN metabolites were associated with mood, psychotic symptoms, and cognitive functions in patients with BD. In this review, we briefly introduce the KYN pathway and describe the immune dysregulation in BD as well as their interactions. We then focus on the research advances on the KYN metabolism in BD, which hold promise for identifying novel treatment targets in patients stricken with this disorder.
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TL;DR: It was found that PCP-induced psychotomimetic effects are associated with submicromolar serum concentrations of PCP and the findings suggest that endogenous dysfunction of NMDA receptor-mediated neurotransmission might contribute to the pathogenesis of schizophrenia.
Abstract: Objective: Phencyclidine (PCP, “angel dust”) induces a psychotomimetic state that closely resembles schizophrenia. As opposed to amphetamine-induced psychosis, PCP-induced psychosis incorporates both positive (e.g., hallucinations, paranoia) and negative (e.g., emotional withdrawal, motor retardation) schizophrenic symptoms. PCP-induced psychosis also uniquely incorporates the formal thought disorder and neuropsychological deficits associated with schizophrenia. The purpose of the present paper is to review recent advances in the study of the molecular mechanisms of PCP action and to describe their implications for the understanding ofschizophrenic pathophysiology. Methoc�: Twenty-five papers were identified that described the clinicaldose and serum and CSF levelsat which PCP induces its psychotomimetic effects. The dose range ofPCP-induced effects were compared to the dose range at which PCP interacts with specific molecular targets and affects neurotransmission. Results: It was found that PCP-induced psychotomimetic effects are associated with submicromolar serum concentrations of PCP. At these concentrations PCP interacts selectively with a specific binding site (PCP receptor) that is associated with the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. Occupation ofits receptor by PCP induces noncompetitive inhibition of NMDA receptor-mediated neurotransmission. Other NMDA antagonists such as the dissociative anesthetic ketamine induce PCP-like neurobehavioral effects in proportion to their potency in binding to the PCP receptor and inducing NMDA receptor inhibition. Conclusions: These findings suggestthat endogenous dysfunction ofNMDA receptor-mediated neurotransmission might contribute to the pathogenesis of schizophrenia. The relative implications of the PCP and amphetamine models ofschizophrenia are discussedin relationship to the diagnosis and etiology of schizophrenia. (Am J Psychiatry1991;148:1301-1308)
2,883 citations
TL;DR: The uniform increases in clinical correlates, suicidal behavior, and comorbidity across each diagnostic category provide evidence for the validity of the concept of BPS.
Abstract: Context There is limited information on the prevalence and correlates of bipolar spectrum disorder in international population-based studies using common methods. Objectives To describe the prevalence, impact, patterns of comorbidity, and patterns of service utilization for bipolar spectrum disorder (BPS) in the World Health Organization World Mental Health Survey Initiative. Design, Setting, and Participants Cross-sectional, face-to-face, household surveys of 61 392 community adults in 11 countries in the Americas, Europe, and Asia assessed with the World Mental Health version of the World Health Organization Composite International Diagnostic Interview, version 3.0, a fully structured, lay-administered psychiatric diagnostic interview. Main Outcome Measures Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) disorders, severity, and treatment. Results The aggregate lifetime prevalences were 0.6% for bipolar type I disorder (BP-I), 0.4% for BP-II, 1.4% for subthreshold BP, and 2.4% for BPS. Twelve-month prevalences were 0.4% for BP-I, 0.3% for BP-II, 0.8% for subthreshold BP, and 1.5% for BPS. Severity of both manic and depressive symptoms as well as suicidal behavior increased monotonically from subthreshold BP to BP-I. By contrast, role impairment was similar across BP subtypes. Symptom severity was greater for depressive episodes than manic episodes, with approximately 74.0% of respondents with depression and 50.9% of respondents with mania reporting severe role impairment. Three-quarters of those with BPS met criteria for at least 1 other disorder, with anxiety disorders (particularly panic attacks) being the most common comorbid condition. Less than half of those with lifetime BPS received mental health treatment, particularly in low-income countries, where only 25.2% reported contact with the mental health system. Conclusions Despite cross-site variation in the prevalence rates of BPS, the severity, impact, and patterns of comorbidity were remarkably similar internationally. The uniform increases in clinical correlates, suicidal behavior, and comorbidity across each diagnostic category provide evidence for the validity of the concept of BPS. Treatment needs for BPS are often unmet, particularly in low-income countries.
1,978 citations
TL;DR: Evidence is provided for a previously unidentified pathophysiological function of the AHR that is constitutively generated by human tumours via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology.
Abstract: Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.
1,462 citations
TL;DR: It is argued that the global burden of mental illness is underestimated and the reasons for under-estimation are examined to identify five main causes: overlap between psychiatric and neurological disorders; the grouping of suicide and self-harm as a separate category; conflation of all chronic pain syndromes with musculoskeletal disorders; exclusion of personality disorders from disease burden calculations; and inadequate consideration of the contribution of severe mental illness to mortality from associated causes.
1,444 citations