Schizophrenia (Sz) patients, especially treated with atypical antipsychotics, are at high risk of... more Schizophrenia (Sz) patients, especially treated with atypical antipsychotics, are at high risk of the development of metabolic syndrome that increases morbidity and mortality and impairs compliance with treatment. Mechanism of the high association of metabolic syndrome with the use of atypical antipsychotics is not clear. Literature and our data suggest that chronic inflammation- or stress-induced dysregulation of the peripheral down-stream kynurenine (Kyn) metabolism, shared by both Sz and metabolic syndrome, contributes to the development of metabolic syndrome in Sz patients treated with atypical antipsychotics. Correction of dysregulation of the peripheral down-stream metabolism of Kyn would prevent/treat metabolic syndrome. This is a pre-clinical trial of the effect of benserazide (BRZ), an inhibitor of the key enzymes of Kyn metabolism, on olanzapine-induced mouse model of metabolic syndrome. Olanzapine is one of the most effective atypical antipsychotics but has high potential to induce metabolic syndrome. Olanzapine (4 mg/kg, p.o) and/or BRZ (100 mg/day, p.o.) were administered to 6-week-old C57Bl/6 female mice, 5 days/week, for 10 weeks. The study was approved by the Tufts Medical Center Institutional Animal Care and Use Committee. BRZ attenuated olanzapine-induced excessive weight gain, impairment of glucose tolerance, and elevation of plasma cholesterol and triglycerides. Present results suggest that peripheral down-stream Kyn metabolism is a new target for prevention/treatment of olanzapine-induced metabolic syndrome. BRZ has a high translational potential as medication already approved for human use.
This book was written so that early- and mid-career psychiatrists and psychiatrists in training c... more This book was written so that early- and mid-career psychiatrists and psychiatrists in training can catch a glimpse of the changing health care environment and the new roles psychiatrists will play in it. While the book summarizes where we are today, the majority of its pages are devoted to forward thinking, i.e., exploring the world of psychiatry that we expect will unfold during the next quarter century. Of course, this centers on the majority of our patients that currently have very limited access to psychiatric services, since they are seen in the medical setting, where psychiatrists rarely practice either due to workforce limitations or financial barriers. Chapter authors share information about the prevalence of psychiatric illness in medical patients, the impact that poor treatment has on total health outcomes and cost, promising models of integrated care that place psychiatrists in a central role as contributors to total health improvement, fiscal and clinical steps that need to be taken to transition from standalone psychiatric services to integrated services, and training and research agendas that will, looking forward, allow psychiatrists to play a central role in integrated health care.
Present review focuses on the possible role of tryptophan (Trp) – kynurenine (Kyn) pathwayin the ... more Present review focuses on the possible role of tryptophan (Trp) – kynurenine (Kyn) pathwayin the mechanism(s) of COVID-19 associated psychiatric complications. SARS-CoV-2 infection, that causes COVID-19, triggers overproduction of interferon-gamma (IFNG), a pro-inflammatory cytokine. IFNG activates indoleamine 2,3-dioxygenase-1 (IDO), enzyme that catalyzes Trp conversion into Kyn, and enzymes of down-stream Kyn pathway that catalyze Kyn conversion into 3-hydroxykynurenine, kynurenic and anthranilic acids in brain and peripheral organs. We reviewed data on SARS-CoV-2 - IFNG – induced changes of peripheral Trp – Kyn pathway, considering their translational potential for personalized psychiatric care. Elevated blood levels of Trp – Kyn pathway metabolites were correlated with the severity of symptoms and predicted the negative outcomes in COVID-19 patients. Association of Trp – Kyn pathway up-regulation with psychiatric complication in non-COVID-19 patients suggests that activation of these pathways contribute to the mechanism(s) of COVID-19 associated psychiatric conditions as well. Increased risk of psychiatric complications in carriers of T (high producer) allele of polymorphic IFNG gene and elevation of serum levels of Kyn and its metabolites in interferon-alpha treated hepatitis C virus patients provides further support for such a suggestion. Assessment of blood levels of Kyn and its metabolites, and polymorphism of Trp – Kyn pathway genes might be developed into personalized biological markers predicting gender/aging dependent individual’s risk of psychiatric complications in COVID-19 patients. Up-regulation of IFNG and IDO is necessary for anti-viral protection. Therefore, inhibition of down-stream Kyn pathway should be considered as a new target for prevention/treatment of COVID-19 and COVID-19-associated psychiatric complications
Cognitive capability impacts individual functioning in every life domain such as social, emotiona... more Cognitive capability impacts individual functioning in every life domain such as social, emotional, academic, and occupational. Understanding the mechanism through which cognitive impairment can influence an individual’s susceptibility to homelessness is essential to providing effective services for improving health outcomes among this population. This chapter details the relationship between cognitive impairment and homelessness, with a focus on defining the clinical descriptions and diagnostic guidelines. It also discusses the bidirectional cause-and-effect association between homelessness and cognitive impairment, particularly reviewing disorders of cognition including schizophrenia, bipolar disorder, intellectual disability, autism spectrum disorder, childhood trauma, malnutrition, traumatic brain injury, and substance abuse. Lastly, this chapter uses the clinical correlations taken from available literature between homelessness and cognitive impairment to make recommendations o...
OBJECTIVES: To describe patterns of cognitive deficits and activities of daily living (ADLs) in o... more OBJECTIVES: To describe patterns of cognitive deficits and activities of daily living (ADLs) in older people with diabetes mellitus. DESIGN: Cross-sectional, population-based study. SETTING: Three homecare agency areas in Boston, Mas-sachusetts. PARTICIPANTS: Two hundred ninety-one homebound people aged 60 and older; 40 % with diabetes mellitus. MEASUREMENTS: Demographic data; evidence of dia-betes mellitus and other diseases; Mini-Mental State Ex-amination and tests of memory and executive function; ADLs. RESULTS: Executive and visuospatial functions were more impaired in individuals with diabetes mellitus than in those without, as assessed using Block Design (mean
Depression is a common side-effect of interferon (IFN)-alpha treatment of hepatitis C virus (HCV)... more Depression is a common side-effect of interferon (IFN)-alpha treatment of hepatitis C virus (HCV) infection and melanoma. Disturbances of tryptophan (TRP) metabolism might contribute to development of IFN-alpha–associated depression due to IFN-alpha-induced activation of indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme of TRP–kynurenine (KYN) metabolism. The increased frequency of high producer (T) allele of IFN-gamma (IFNG) (+874) gene, that encodes IFNG production, in depressed patients suggested that increased IDO activity might be a risk factor for depression. The present study assessed KYN/TRP ratio (KTR) as a marker of IDO activity in American Caucasian HCV patients awaiting IFN-alpha treatment. KTR did not differ between 43 patients who did and 37 patients who did not develop depression. TRP concentrations were higher in patients who experienced depression. Odds of development of depression increased with elevation of serum TRP levels from 33% (TRP levels 16000 pmol/...
Dr. Koran has received research grants from Forest Pharmaceuticals, Pfizer, Eli Lilly, Ortho-McNe... more Dr. Koran has received research grants from Forest Pharmaceuticals, Pfizer, Eli Lilly, Ortho-McNeil, Somaxon, and Jazz Pharmaceuticals. He has received honoraria from the Forest Pharmaceuticals Speakers Bureau and the Pfizer Speakers Bureau. He has received consultant fees from Cypress Bioscience. Dr. Hanna reports no competing interests. Dr. Hollander has received research grants from the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Drug Abuse, the Office of Orphan Products Development of the U.S. Food and Drug Administration, Pfizer, GlaxoSmithKline, Wyeth, Eli Lilly, Janssen, and Abbott. He has served on advisory boards for Forest Pharmaceuticals, Abbott, and Somaxon. Dr. Nestadt reports no competing interests. Dr. Simpson reports no competing interests. The Executive Committee on Practice Guidelines has reviewed this guideline and found no evidence of influence from these relationships.
Objectives: Major depressive disorder (MDD) is associated with dysregulations of leptin and trypt... more Objectives: Major depressive disorder (MDD) is associated with dysregulations of leptin and tryptophan–kynurenine (Trp–Kyn) (TKP) pathways. Leptin, a pro-inflammatory cytokine, activates Trp conversion into Kyn. However, leptin association with down-stream Kyn metabolites in MDD is unknown. Methods: Fasting plasma samples from 29 acutely ill drug-naïve (n = 16) or currently non-medicated (⩾6 weeks; n = 13) MDD patients were analyzed for leptin, Trp, Kyn, its down-stream metabolites (anthranilic [AA], kynurenic [KYNA], xanthurenic [XA] acids and 3-hydroxykynurenine [3HK]), C-reactive protein (CRP), neopterin, body mass index (BMI), and insulin resistance (HOMA-IR). Depression severity was assessed by HAM-D-21. Results: In female (n = 14) (but not in male) patients HAM-D-21 scores correlated with plasma levels of AA (but not other Kyn metabolites) (rho = −0.644, P = .009) and leptin (Spearman’s rho = −0.775, P = .001). Inclusion of AA into regression analysis improved leptin predictio...
Suicide continues to be a major health concern globally despite many initiatives to identify risk... more Suicide continues to be a major health concern globally despite many initiatives to identify risk factors and methods for suicide prevention. We have carried out a detailed narrative review of the literature from 2016 to 2019 using the headings of Personal resilience (P1), People (P2), Places (P3), Prevention (P4), Promoting collaboration (P5), and Promoting research (P6) in order to support an integrated approach to suicide prevention and the promotion of personal and population resilience. We have made 10 key recommendations on how this can be moved forward.
Background Depression often precedes the onset of Alzheimer's disease (AD) before the appear... more Background Depression often precedes the onset of Alzheimer's disease (AD) before the appearance of cognitive symptoms. Plasma Amyloid-β peptide 42 (Aβ42) declines before and soon after the onset of AD, yet the relationship between plasma Aβ42 and depression ...
Background Depression often precedes the onset of Alzheimer's disease (AD) before the appear... more Background Depression often precedes the onset of Alzheimer's disease (AD) before the appearance of cognitive symptoms. Plasma Amyloid-β peptide 42 (Aβ42) declines before and soon after the onset of AD, yet the relationship between plasma Aβ42 and depression ...
Endocrinology, diabetes and metabolism journal, 2017
Insulin resistance (IR), obesity and other components of metabolic syndrome [MetS] are highly ass... more Insulin resistance (IR), obesity and other components of metabolic syndrome [MetS] are highly associated with Alzheimer's (AD) and Parkinson's (PD) diseases. Dysregulation of kynurenine (Kyn) pathway (KP) of tryptophan (Trp) metabolism was suggested as major contributor to pathogenesis of AD and PD and MetS. KP, the major source of NAD in humans, occurs in brain and peripheral organs. Considering that some, but not all, peripherally originated derivatives of Kyn penetrate blood brain barrier, dysregulation of central and peripheral KP might have different functional impact. Up-regulated Kyn formation from Trp was discovered in central nervous system of AD and PD while assessments of peripheral KP in these diseases yield controversial results. We were interested to compare peripheral kynurenines in AD and PD with emphasis on MetS-associated kynurenines, i.e., kynurenic (KYNA) and anthranilic (ANA) acids and 3-hydroxykynurenine (3-HK). Serum concentrations of KP metabolites we...
Schizophrenia (Sz) patients, especially treated with atypical antipsychotics, are at high risk of... more Schizophrenia (Sz) patients, especially treated with atypical antipsychotics, are at high risk of the development of metabolic syndrome that increases morbidity and mortality and impairs compliance with treatment. Mechanism of the high association of metabolic syndrome with the use of atypical antipsychotics is not clear. Literature and our data suggest that chronic inflammation- or stress-induced dysregulation of the peripheral down-stream kynurenine (Kyn) metabolism, shared by both Sz and metabolic syndrome, contributes to the development of metabolic syndrome in Sz patients treated with atypical antipsychotics. Correction of dysregulation of the peripheral down-stream metabolism of Kyn would prevent/treat metabolic syndrome. This is a pre-clinical trial of the effect of benserazide (BRZ), an inhibitor of the key enzymes of Kyn metabolism, on olanzapine-induced mouse model of metabolic syndrome. Olanzapine is one of the most effective atypical antipsychotics but has high potential to induce metabolic syndrome. Olanzapine (4 mg/kg, p.o) and/or BRZ (100 mg/day, p.o.) were administered to 6-week-old C57Bl/6 female mice, 5 days/week, for 10 weeks. The study was approved by the Tufts Medical Center Institutional Animal Care and Use Committee. BRZ attenuated olanzapine-induced excessive weight gain, impairment of glucose tolerance, and elevation of plasma cholesterol and triglycerides. Present results suggest that peripheral down-stream Kyn metabolism is a new target for prevention/treatment of olanzapine-induced metabolic syndrome. BRZ has a high translational potential as medication already approved for human use.
This book was written so that early- and mid-career psychiatrists and psychiatrists in training c... more This book was written so that early- and mid-career psychiatrists and psychiatrists in training can catch a glimpse of the changing health care environment and the new roles psychiatrists will play in it. While the book summarizes where we are today, the majority of its pages are devoted to forward thinking, i.e., exploring the world of psychiatry that we expect will unfold during the next quarter century. Of course, this centers on the majority of our patients that currently have very limited access to psychiatric services, since they are seen in the medical setting, where psychiatrists rarely practice either due to workforce limitations or financial barriers. Chapter authors share information about the prevalence of psychiatric illness in medical patients, the impact that poor treatment has on total health outcomes and cost, promising models of integrated care that place psychiatrists in a central role as contributors to total health improvement, fiscal and clinical steps that need to be taken to transition from standalone psychiatric services to integrated services, and training and research agendas that will, looking forward, allow psychiatrists to play a central role in integrated health care.
Present review focuses on the possible role of tryptophan (Trp) – kynurenine (Kyn) pathwayin the ... more Present review focuses on the possible role of tryptophan (Trp) – kynurenine (Kyn) pathwayin the mechanism(s) of COVID-19 associated psychiatric complications. SARS-CoV-2 infection, that causes COVID-19, triggers overproduction of interferon-gamma (IFNG), a pro-inflammatory cytokine. IFNG activates indoleamine 2,3-dioxygenase-1 (IDO), enzyme that catalyzes Trp conversion into Kyn, and enzymes of down-stream Kyn pathway that catalyze Kyn conversion into 3-hydroxykynurenine, kynurenic and anthranilic acids in brain and peripheral organs. We reviewed data on SARS-CoV-2 - IFNG – induced changes of peripheral Trp – Kyn pathway, considering their translational potential for personalized psychiatric care. Elevated blood levels of Trp – Kyn pathway metabolites were correlated with the severity of symptoms and predicted the negative outcomes in COVID-19 patients. Association of Trp – Kyn pathway up-regulation with psychiatric complication in non-COVID-19 patients suggests that activation of these pathways contribute to the mechanism(s) of COVID-19 associated psychiatric conditions as well. Increased risk of psychiatric complications in carriers of T (high producer) allele of polymorphic IFNG gene and elevation of serum levels of Kyn and its metabolites in interferon-alpha treated hepatitis C virus patients provides further support for such a suggestion. Assessment of blood levels of Kyn and its metabolites, and polymorphism of Trp – Kyn pathway genes might be developed into personalized biological markers predicting gender/aging dependent individual’s risk of psychiatric complications in COVID-19 patients. Up-regulation of IFNG and IDO is necessary for anti-viral protection. Therefore, inhibition of down-stream Kyn pathway should be considered as a new target for prevention/treatment of COVID-19 and COVID-19-associated psychiatric complications
Cognitive capability impacts individual functioning in every life domain such as social, emotiona... more Cognitive capability impacts individual functioning in every life domain such as social, emotional, academic, and occupational. Understanding the mechanism through which cognitive impairment can influence an individual’s susceptibility to homelessness is essential to providing effective services for improving health outcomes among this population. This chapter details the relationship between cognitive impairment and homelessness, with a focus on defining the clinical descriptions and diagnostic guidelines. It also discusses the bidirectional cause-and-effect association between homelessness and cognitive impairment, particularly reviewing disorders of cognition including schizophrenia, bipolar disorder, intellectual disability, autism spectrum disorder, childhood trauma, malnutrition, traumatic brain injury, and substance abuse. Lastly, this chapter uses the clinical correlations taken from available literature between homelessness and cognitive impairment to make recommendations o...
OBJECTIVES: To describe patterns of cognitive deficits and activities of daily living (ADLs) in o... more OBJECTIVES: To describe patterns of cognitive deficits and activities of daily living (ADLs) in older people with diabetes mellitus. DESIGN: Cross-sectional, population-based study. SETTING: Three homecare agency areas in Boston, Mas-sachusetts. PARTICIPANTS: Two hundred ninety-one homebound people aged 60 and older; 40 % with diabetes mellitus. MEASUREMENTS: Demographic data; evidence of dia-betes mellitus and other diseases; Mini-Mental State Ex-amination and tests of memory and executive function; ADLs. RESULTS: Executive and visuospatial functions were more impaired in individuals with diabetes mellitus than in those without, as assessed using Block Design (mean
Depression is a common side-effect of interferon (IFN)-alpha treatment of hepatitis C virus (HCV)... more Depression is a common side-effect of interferon (IFN)-alpha treatment of hepatitis C virus (HCV) infection and melanoma. Disturbances of tryptophan (TRP) metabolism might contribute to development of IFN-alpha–associated depression due to IFN-alpha-induced activation of indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme of TRP–kynurenine (KYN) metabolism. The increased frequency of high producer (T) allele of IFN-gamma (IFNG) (+874) gene, that encodes IFNG production, in depressed patients suggested that increased IDO activity might be a risk factor for depression. The present study assessed KYN/TRP ratio (KTR) as a marker of IDO activity in American Caucasian HCV patients awaiting IFN-alpha treatment. KTR did not differ between 43 patients who did and 37 patients who did not develop depression. TRP concentrations were higher in patients who experienced depression. Odds of development of depression increased with elevation of serum TRP levels from 33% (TRP levels 16000 pmol/...
Dr. Koran has received research grants from Forest Pharmaceuticals, Pfizer, Eli Lilly, Ortho-McNe... more Dr. Koran has received research grants from Forest Pharmaceuticals, Pfizer, Eli Lilly, Ortho-McNeil, Somaxon, and Jazz Pharmaceuticals. He has received honoraria from the Forest Pharmaceuticals Speakers Bureau and the Pfizer Speakers Bureau. He has received consultant fees from Cypress Bioscience. Dr. Hanna reports no competing interests. Dr. Hollander has received research grants from the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Drug Abuse, the Office of Orphan Products Development of the U.S. Food and Drug Administration, Pfizer, GlaxoSmithKline, Wyeth, Eli Lilly, Janssen, and Abbott. He has served on advisory boards for Forest Pharmaceuticals, Abbott, and Somaxon. Dr. Nestadt reports no competing interests. Dr. Simpson reports no competing interests. The Executive Committee on Practice Guidelines has reviewed this guideline and found no evidence of influence from these relationships.
Objectives: Major depressive disorder (MDD) is associated with dysregulations of leptin and trypt... more Objectives: Major depressive disorder (MDD) is associated with dysregulations of leptin and tryptophan–kynurenine (Trp–Kyn) (TKP) pathways. Leptin, a pro-inflammatory cytokine, activates Trp conversion into Kyn. However, leptin association with down-stream Kyn metabolites in MDD is unknown. Methods: Fasting plasma samples from 29 acutely ill drug-naïve (n = 16) or currently non-medicated (⩾6 weeks; n = 13) MDD patients were analyzed for leptin, Trp, Kyn, its down-stream metabolites (anthranilic [AA], kynurenic [KYNA], xanthurenic [XA] acids and 3-hydroxykynurenine [3HK]), C-reactive protein (CRP), neopterin, body mass index (BMI), and insulin resistance (HOMA-IR). Depression severity was assessed by HAM-D-21. Results: In female (n = 14) (but not in male) patients HAM-D-21 scores correlated with plasma levels of AA (but not other Kyn metabolites) (rho = −0.644, P = .009) and leptin (Spearman’s rho = −0.775, P = .001). Inclusion of AA into regression analysis improved leptin predictio...
Suicide continues to be a major health concern globally despite many initiatives to identify risk... more Suicide continues to be a major health concern globally despite many initiatives to identify risk factors and methods for suicide prevention. We have carried out a detailed narrative review of the literature from 2016 to 2019 using the headings of Personal resilience (P1), People (P2), Places (P3), Prevention (P4), Promoting collaboration (P5), and Promoting research (P6) in order to support an integrated approach to suicide prevention and the promotion of personal and population resilience. We have made 10 key recommendations on how this can be moved forward.
Background Depression often precedes the onset of Alzheimer's disease (AD) before the appear... more Background Depression often precedes the onset of Alzheimer's disease (AD) before the appearance of cognitive symptoms. Plasma Amyloid-β peptide 42 (Aβ42) declines before and soon after the onset of AD, yet the relationship between plasma Aβ42 and depression ...
Background Depression often precedes the onset of Alzheimer's disease (AD) before the appear... more Background Depression often precedes the onset of Alzheimer's disease (AD) before the appearance of cognitive symptoms. Plasma Amyloid-β peptide 42 (Aβ42) declines before and soon after the onset of AD, yet the relationship between plasma Aβ42 and depression ...
Endocrinology, diabetes and metabolism journal, 2017
Insulin resistance (IR), obesity and other components of metabolic syndrome [MetS] are highly ass... more Insulin resistance (IR), obesity and other components of metabolic syndrome [MetS] are highly associated with Alzheimer's (AD) and Parkinson's (PD) diseases. Dysregulation of kynurenine (Kyn) pathway (KP) of tryptophan (Trp) metabolism was suggested as major contributor to pathogenesis of AD and PD and MetS. KP, the major source of NAD in humans, occurs in brain and peripheral organs. Considering that some, but not all, peripherally originated derivatives of Kyn penetrate blood brain barrier, dysregulation of central and peripheral KP might have different functional impact. Up-regulated Kyn formation from Trp was discovered in central nervous system of AD and PD while assessments of peripheral KP in these diseases yield controversial results. We were interested to compare peripheral kynurenines in AD and PD with emphasis on MetS-associated kynurenines, i.e., kynurenic (KYNA) and anthranilic (ANA) acids and 3-hydroxykynurenine (3-HK). Serum concentrations of KP metabolites we...
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