Involvement of Kynurenine Metabolism in Bipolar Disorder: An Updated Review

We argue that the global burden of mental illness is underestimated and examine the reasons for under-estimation 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. Using published data, we estimate the disease burden for mental illness to show that the global burden of mental illness accounts for 32·4% of years lived with disability (YLDs) and 13·0% of disability-adjusted life-years (DALYs), instead of the earlier estimates suggesting 21·2% of YLDs and 7·1% of DALYs. Currently used approaches underestimate the burden of mental illness by more than a third. Our estimates place mental illness a distant first in global burden of disease in terms of YLDs, and level with cardiovascular and circulatory diseases in terms of DALYs. The unacceptable apathy of governments and funders of global health must be overcome to mitigate the human, social, and economic costs of mental illness. Show more

There is limited information on the prevalence and correlates of bipolar spectrum disorder in international population-based studies using common methods. 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. 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. Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) disorders, severity, and treatment. 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. 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. Show more

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. Show more