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OBJECTIVE: The goal of this study was to explore the association of timing of and frequency of meals with markers of cardiometabolic risk in patients with bipolar disorder in out-patient maintenance treatment. METHODS: We used Pittsburgh Sleep Diary and actigraphy measures for individuals with bipolar I disorder. Linear and logistic regression analyses were used to determine whether dinnertime, instability of dinnertime, and/or interval between meals were associated with metabolic syndrome and its components. RESULTS: Later dinnertime was associated with greater waist circumference (ß = 0.25, P = 0.02) after adjusting for age, sex, dinner-to-bed interval, and sleep duration. Longer breakfast-to-lunch intervals were also associated with greater waist circumferences (ß =-.35, P = .002) after adjusting for age, sex, and sleep duration. Neither instability of dinnertime nor number of meals per day was associated with the metabolic syndrome or its components. CONCLUSION: Weight gain is often perceived as inevitable side-effect of medications. While patients often need to be on medication to function, a more careful lifestyle assessment with attention to social rhythms and timing of activities may be critical not only for mood stability, but also to reduce cardiovascular risk.
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Trastorno Bipolar/metabolismo , Enfermedades Cardiovasculares/metabolismo , Comidas/fisiología , Actigrafía , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pacientes Ambulatorios , Análisis de Regresión , Factores de Riesgo , Circunferencia de la CinturaRESUMEN
Psychiatric disorders have traditionally been classified using a static, categorical approach. However, this approach falls short in facilitating understanding of the development, common comorbid diagnoses, prognosis and treatment of these disorders. We propose a 'staging' model of bipolar disorder that integrates genetic and neural information with mood and activity symptoms to describe how the disease progresses over time. From an early, asymptomatic, but 'at-risk' stage to severe, chronic illness, each stage is described with associated neuroimaging findings as well as strategies for mapping genetic risk factors. Integrating more biologic information relating to cardiovascular and endocrine systems, refining methodology for modeling dimensional approaches to disease and developing outcome measures will all be crucial in examining the validity of this model. Ultimately, this approach should aid in developing targeted interventions for each group that will reduce the significant morbidity and mortality associated with bipolar disorder.
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Trastorno Bipolar/diagnóstico , Trastorno Bipolar/terapia , Estudios Longitudinales , Trastorno Bipolar/epidemiología , Trastorno Bipolar/genética , Comorbilidad , Progresión de la Enfermedad , Predisposición Genética a la Enfermedad , Humanos , Modelos Biológicos , Neuroimagen , Factores de RiesgoRESUMEN
Diffusion tensor imaging (DTI) studies consistently reported abnormalities in fractional anisotropy (FA) and radial diffusivity (RD), measures of the integrity of white matter (WM), in bipolar disorder (BD), that may reflect underlying pathophysiologic processes. There is, however, a pressing need to identify peripheral measures that are related to these WM measures, to help identify easily obtainable peripheral biomarkers of BD. Given the high lipid content of axonal membranes and myelin sheaths, and that elevated serum levels of lipid peroxidation are reported in BD, these serum measures may be promising peripheral biomarkers of underlying WM abnormalities in BD. We used DTI and probabilistic tractography to compare FA and RD in ten prefrontal-centered WM tracts, 8 of which are consistently shown to have abnormal FA (and/or RD) in BD, and also examined serum lipid peroxidation (lipid hydroperoxides, LPH and 4-hydroxy-2-nonenal, 4-HNE), in 24 currently euthymic BD adults (BDE) and 19 age- and gender-matched healthy adults (CONT). There was a significant effect of group upon FA in these a priori WM tracts (BDE
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Trastorno Bipolar/sangre , Trastorno Bipolar/patología , Encéfalo/patología , Peroxidación de Lípido , Fibras Nerviosas Mielínicas/patología , Vías Nerviosas/patología , Adulto , Aldehídos/sangre , Anisotropía , Biomarcadores/sangre , Trastorno Bipolar/tratamiento farmacológico , Imagen de Difusión Tensora , Femenino , Humanos , Peróxidos Lipídicos/sangre , Masculino , Modelos Estadísticos , Análisis Multivariante , Corteza Prefrontal/patología , Procesamiento de Señales Asistido por ComputadorRESUMEN
Differentiating bipolar from recurrent unipolar depression is a major clinical challenge. In 18 healthy females and 36 females in a depressive episode--18 with bipolar disorder type I, 18 with recurrent unipolar depression--we applied pattern recognition analysis using subdivisions of anterior cingulate cortex (ACC) blood flow at rest, measured with arterial spin labelling. Subgenual ACC blood flow classified unipolar v. bipolar depression with 81% accuracy (83% sensitivity, 78% specificity).
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Trastorno Bipolar/diagnóstico , Trastorno Depresivo/diagnóstico , Giro del Cíngulo/irrigación sanguínea , Diagnóstico Diferencial , Femenino , Humanos , Reconocimiento de Normas Patrones Automatizadas , Recurrencia , Sensibilidad y EspecificidadRESUMEN
There are many new advances in neuroscience and mental health which should lead to a greater understanding of the neurobiological dysfunction in neuropsychiatric disorders and new developments for early, effective treatments. To do this, a biomarker approach combining genetic, neuroimaging, cognitive and other biological measures is needed. The aim of this article is to highlight novel approaches for pharmacological and non-pharmacological treatment development. This article suggests approaches that can be taken in the future including novel mechanisms with preliminary clinical validation to provide a toolbox for mechanistic studies and also examples of translation and back-translation. The review also emphasizes the need for clinician-scientists to be trained in a novel way in order to equip them with the conceptual and experimental techniques required, and emphasizes the need for private-public partnership and pre-competitive knowledge exchange. This should lead the way for important new holistic treatment developments to improve cognition, functional outcome and well-being of people with neuropsychiatric disorders.
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Descubrimiento de Drogas/métodos , Trastornos Mentales/tratamiento farmacológico , Animales , Biomarcadores , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Intervención Médica Temprana/métodos , Humanos , Terapia Molecular Dirigida/métodos , Apoyo a la Investigación como AsuntoRESUMEN
BACKGROUND: The pathways to increased cardiovascular risk in bipolar disorder include health behaviors, psychosocial stress and long-term medication exposure. However, the evidence that the association between cardiovascular risk factors and bipolar disorder remains significant after controlling for these co-factors suggests that additional important risk factors have yet to be identified. Our hypothesis is that disturbances in the sleep-wake cycle are an important and under-recognized pathway through which affective disorders lead to increased cardiovascular risk. METHODS: In patients with bipolar disorder type 1 in clinical remission, we: 1) explored whether sleep disturbance predicted the endorsement of NCEP ATP-III criteria for dyslipidemia, independent of other lifestyle factors and 2) tested the association between low HDL (NCEP-ATP III) and sleep duration measured with actigraphy over an eight-day period. RESULTS: Median sleep duration is significantly associated with low HDL. The risk of having low HDL increases by 1.23 with every 30 minutes of reduced sleep time. LIMITATIONS: Since sleep patterns in patients with bipolar disorder are variable and irregular, it is possible that other sleep characteristics, not present during the span of our study, or the variability itself may be what drives the increased cardiovascular risk. CONCLUSIONS: Sleep characteristics of patients with bipolar disorder in clinical remission are associated with cardiovascular risk. More specifically, sleep duration was associated with low HDL. Clinicians should pay special attention to sleep hygiene in treating individuals with bipolar disorder, even when they are in clinical remission.
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Trastorno Bipolar/etiología , Dislipidemias/complicaciones , Trastornos del Sueño-Vigilia/complicaciones , Actigrafía , Adulto , Anciano , Trastorno Bipolar/terapia , Enfermedades Cardiovasculares/etiología , HDL-Colesterol/sangre , HDL-Colesterol/deficiencia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Factores de Riesgo , Sueño/fisiología , Factores de TiempoRESUMEN
More than 10 years prior to the anticipated 2013 publication of DSM-5, processes were set in motion to assess the research and clinical issues that would best inform future diagnostic classification of mental disorders. These efforts intended to identify the clinical and research needs within various populations, examine the current state of the science to determine the empirical evidence for improving criteria within and across disorders, and stimulate research in areas that could potentially provide evidence for change. In the second phase of the revision process, the American Psychiatric Institute for Research and Education (APIRE) recently completed the 5-year international series of 13 diagnostic conferences convened by APA/APIRE in collaboration with the World Health Organization and the National Institutes of Health (NIH), under a cooperative grant funded by the NIH. From these conferences, the DSM-5 Task Force and Work Groups have developed plans for potential revisions for DSM-5, including the incorporation of dimensional approaches within and across diagnostic groups to clarify heterogeneity, improve diagnostic validity, and enhance clinical case conceptualization. Use of dimensions for measurement-based care has been shown to be feasible in psychiatric and primary care settings and may inform monitoring of disorder threshold, severity, and treatment outcomes. The integration of dimensions with diagnostic categories represents an exciting and potentially transformative approach for DSM-5 to simultaneously address DSM-IV's clinical short-comings and create novel pathways for research in neurobiology, genetics, and psychiatric epidemiology.
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Manual Diagnóstico y Estadístico de los Trastornos Mentales , Trastornos Mentales/diagnóstico , Comités Consultivos , Humanos , InvestigaciónRESUMEN
BACKGROUND: One aim of personalized medicine is to determine which treatment is to be preferred for an individual patient, given all patient information available. Particularly in mental health, however, there is a lack of a single objective, reliable measure of outcome that is sensitive to crucial individual differences among patients. METHOD: We examined the feasibility of quantifying the total clinical value provided by a treatment (measured by both harms and benefits) in a single metric. An expert panel was asked to compare 100 pairs of patients, one from each treatment group, who had participated in a randomized clinical trial (RCT) involving interpersonal psychotherapy (IPT) and escitalopram, selecting the patient with the preferred outcome considering both benefits and harms. RESULTS: From these results, an integrated preference score (IPS) was derived, such that the differences between any two patients' IPSs would predict the clinicians' preferences. This IPS was then computed for all patients in the RCT. A second set of 100 pairs was rated by the panel. Their preferences were highly correlated with the IPS differences (r=0.84). Finally, the IPS was used as the outcome measure comparing IPT and escitalopram. The 95% confidence interval (CI) for the effect size comparing treatments indicated clinical equivalence of the treatments. CONCLUSIONS: A metric that combines benefits and harms of treatments could increase the value of RCTs by making clearer which treatments are preferable and, ultimately, for whom. Such methods result in more precise estimation of effect sizes, without increasing the required sample size.
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Modelos Estadísticos , Evaluación de Resultado en la Atención de Salud/métodos , Medicina de Precisión , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Adulto , Antidepresivos de Segunda Generación/uso terapéutico , Citalopram/uso terapéutico , Intervalos de Confianza , Interpretación Estadística de Datos , Trastorno Depresivo/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Psicoterapia , Equivalencia TerapéuticaRESUMEN
BACKGROUND: Although many studies suggest that, on average, depression-specific psychotherapy and antidepressant pharmacotherapy are efficacious, we know relatively little about which patients are more likely to respond to one versus the other. We sought to determine whether measures of spectrum psychopathology are useful in deciding which patients with unipolar depression should receive pharmacotherapy versus depression-specific psychotherapy. METHOD: A total of 318 adult out-patients with major depression were randomly assigned to escitalopram pharmacotherapy or interpersonal psychotherapy (IPT) at academic medical centers at Pittsburgh, Pennsylvania and Pisa, Italy. Our main focus was on predictors and moderators of time to remission on monotherapy at 12 weeks. RESULTS: Participants with higher scores on the need for medical reassurance factor of the Panic-Agoraphobic Spectrum Self-Report (PAS-SR) had more rapid remission with IPT and those with lower scores on the psychomotor activation factor of the Mood Spectrum Self-Report (MOODS-SR) experienced more rapid remission with selective serotonin reuptake inhibitor (SSRI) pharmacotherapy. Non-specific predictors of longer time to remission with monotherapy included several panic spectrum and mood spectrum factors and the Social Phobia Spectrum (SHY) total score. Higher baseline scores on the 17- and 25-item Hamilton Depression Rating Scales (HAMD-17 and HAMD-25) and the Work and Social Adjustment Scale (WSAS) also predicted a longer time to remission, whereas being married predicted a shorter time to remission. CONCLUSIONS: This exploratory study identified several non-specific predictors but few moderators of psychotherapy versus pharmacotherapy outcome. It offers useful indicators of the characteristics of patients that are generally difficult to treat, but only limited guidance as to who benefits from IPT versus SSRI pharmacotherapy.
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Citalopram/uso terapéutico , Trastorno Depresivo Mayor/terapia , Psicoterapia , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Adulto , Afecto , Ansiedad/psicología , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/psicología , Femenino , Humanos , Masculino , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Escalas de Valoración Psiquiátrica , Pruebas Psicológicas , Inducción de Remisión , Factores de TiempoRESUMEN
BACKGROUND: Cognitive impairment in bipolar disorder has been associated with poor functional outcomes. We examined the relation of self-reported cognitive problems to employment trajectory in patients diagnosed with bipolar I disorder. METHODS: 154 bipolar I disorder patients were followed for 15-43months at the Bipolar Disorders Center for Pennsylvanians. Using a multinomial logistic regression we examined predictors of employment group including self-reported cognitive problems, mood symptoms, education and age. Cognitive functioning was measured via 4 self-report items assessing memory/concentration at baseline and termination. Employment status was recorded at baseline and termination. Employment was categorized as working (full-time, part-time, homemaker, volunteer) or not working (leave of absence, disability, unemployed, no longer volunteering) at each time point. Patients were categorized as good stable, improving, worsening and poor stable. RESULTS: Baseline self-reported concentration problems and years of education significantly predicted employment trajectory. LIMITATIONS: Post-hoc analyses of existing clinical data. CONCLUSIONS: Self-reported concentration problems assessed in the context of specific areas of functioning may serve as a sensitive predictor of functional outcome in patients diagnosed with bipolar I disorder.
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Trastorno Bipolar/diagnóstico , Trastorno Bipolar/rehabilitación , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/rehabilitación , Rehabilitación Vocacional , Autorrevelación , Adolescente , Adulto , Atención , Trastorno Bipolar/psicología , Escalas de Valoración Psiquiátrica Breve/estadística & datos numéricos , Trastornos del Conocimiento/psicología , Evaluación de la Discapacidad , Femenino , Humanos , Masculino , Trastornos de la Memoria/diagnóstico , Trastornos de la Memoria/psicología , Trastornos de la Memoria/rehabilitación , Psicometría , Estadística como Asunto , Encuestas y Cuestionarios , Temperamento , Adulto JovenRESUMEN
Ticks infest a wide range of hosts while bypassing their immune, inflammatory and haemostatic responses during their extended feeding, which may last for more than two weeks. Here, we present a transcriptome analysis of 3868 expressed sequence tags (ESTs) from three cDNA libraries generated from the salivary glands of adult female Ambyomma americanum ticks at different stages of feeding. We applied a normalization step for one library, significantly decreasing the abundance of mitochondrial sequences amongst the 2292 sequences from the normalized library. Our ESTs include homologues that may modulate haemostatic, immune and inflammatory responses of the hosts. Other ESTs probably represent important components of the highly efficient secretory pathways for salivary proteins and concomitantly transmitted pathogens.
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Perfilación de la Expresión Génica , Ixodidae/genética , Glándulas Salivales/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , ADN Mitocondrial/genética , Femenino , Biblioteca de Genes , Proteínas de Insectos/química , Proteínas de Insectos/genética , Masculino , Datos de Secuencia Molecular , Inhibidores de Proteasas/química , Alineación de Secuencia , Análisis de Secuencia de ADNRESUMEN
BACKGROUND: The observation that bipolar disorders frequently go unrecognized has prompted the development of screening instruments designed to improve the identification of bipolarity in clinical and non-clinical samples. Starting from a lifetime approach, researchers of the Spectrum Project developed the Mood Spectrum Self-Report (MOODS-SR) that assesses threshold-level manifestations of unipolar and bipolar mood psychopathology, but also atypical symptoms, behavioral traits and temperamental features. The aim of the present study is to examine the structure of mania/hypomania using 68 items of the MOODS-SR that explore cognitive, mood and energy/activity features associated with mania/hypomania. METHODS: A data pool of 617 patients with bipolar disorders, recruited at Pittsburgh and Pisa, Italy was used for this purpose. Classical exploratory factor analysis, based on a tetrachoric matrix, was carried out on the 68 items, followed by an Item Response Theory (IRT)-based factor analytic approach. RESULTS: Nine factors were initially identified, that include Psychomotor Activation, Creativity, Mixed Instability, Sociability/Extraversion, Spirituality/Mysticism/Psychoticism, Mixed Irritability, Inflated Self-esteem, Euphoria, Wastefulness/Recklessness, and account overall for 56.4% of the variance of items. In a subsequent IRT-based bi-factor analysis, only five of them (Psychomotor Activation, Mixed Instability, Spirituality/Mysticism/Psychoticism, Mixed Irritability, Euphoria) were retained. CONCLUSIONS: Our data confirm the central role of Psychomotor Activation in mania/hypomania and support the definitions of pure manic (Psychomotor Activation and Euphoria) and mixed manic (Mixed Instability and Mixed Irritability) components, bearing the opportunity to identify patients with specific profiles for a better clinical and neurobiological definition.
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Trastorno Bipolar/diagnóstico , Inventario de Personalidad/estadística & datos numéricos , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Trastorno Bipolar/clasificación , Trastorno Bipolar/psicología , Comparación Transcultural , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Análisis Factorial , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Pennsylvania , Determinación de la Personalidad/estadística & datos numéricos , Escalas de Valoración Psiquiátrica/estadística & datos numéricos , Psicometría , Encuestas y CuestionariosRESUMEN
We hypothesize that circadian dysfunction could underlie, at least partially, the liability for bipolar 1 disorder (BD1). Our hypothesis motivated tests for the association between the polymorphisms of genes that mediate circadian function and liability for BD1. The US Caucasian patients with BD1 (DSM-IV criteria) and available parents were recruited from Pittsburgh and surrounding areas (n = 138 cases, 196 parents) and also selected from the NIMH Genetics Collaborative Initiative (n = 96 cases, 192 parents). We assayed 44 informative single-nucleotide polymorphisms (SNPs) from eight circadian genes in the BD1 samples. A population-based sample, specifically cord blood samples from local live births, served as community-based controls (n = 180). It was used as a contrast for genotype and haplotype distributions with those of patients. US patients with schizophrenia/schizoaffective disorder (SZ/SZA, n = 331) and available parents from Pittsburgh (n = 344) were assayed for a smaller set of SNPs based on the results from the BD1 samples. Modest associations with SNPs at ARNTL (BmaL1) and TIMELESS genes were observed in the BD1 samples. The associations were detected using family-based and case-control analyses, albeit with different SNPs. Associations with TIMELESS and PERIOD3 were also detected in the Pittsburgh SZ/SZA group. Thus far, evidence for association between specific SNPs at the circadian gene loci and BD1 is tentative. Additional studies using larger samples are required to evaluate the associations reported here.
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Trastorno Bipolar/genética , Trastornos Cronobiológicos/complicaciones , Trastornos Cronobiológicos/genética , Ritmo Circadiano/genética , Predisposición Genética a la Enfermedad/genética , Esquizofrenia/genética , Factores de Transcripción ARNTL , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Relojes Biológicos/genética , Trastorno Bipolar/fisiopatología , Química Encefálica/genética , Estudios de Casos y Controles , Proteínas de Ciclo Celular , Trastornos Cronobiológicos/fisiopatología , Análisis Mutacional de ADN , Femenino , Regulación de la Expresión Génica/genética , Pruebas Genéticas , Genoma Humano/genética , Humanos , Recién Nacido , Péptidos y Proteínas de Señalización Intracelular , Masculino , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Proteínas Circadianas Period , Polimorfismo de Nucleótido Simple/genética , Trastornos Psicóticos/genética , Trastornos Psicóticos/fisiopatología , Esquizofrenia/fisiopatología , Factores de Transcripción/genéticaRESUMEN
This study evaluates the validity and the reliability of a new instrument developed to assess the psychotic spectrum: the Structured Clinical Interview for the Psychotic Spectrum (SCI-PSY). The instrument is based on a spectrum model that emphasizes soft signs, low-grade symptoms, subthreshold syndromes, as well as temperamental and personality traits comprising the clinical and subsyndromal psychotic manifestations. The items of the interview include, in addition to a subset of the DSM-IV criteria for psychotic syndromes, a number of features derived from clinical experience and from a review of the phenomenological descriptions of psychoses. Study participants were enrolled at 11 Italian Departments of Psychiatry located at 9 sites and included 77 consecutive patients with schizophrenia or schizoaffective disorder, 66 with borderline personality disorder, 59 with psychotic mood disorders, 98 with non-psychotic mood disorders and 57 with panic disorder. A comparison group of 102 unselected controls was enrolled at the same sites. The SCI-PSY significantly discriminated subjects with any psychiatric diagnosis from controls and subjects with from those without psychotic disorders. The hypothesized structure of the instrument was confirmed empirically.
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Entrevista Psicológica , Trastornos Psicóticos/diagnóstico , Adolescente , Adulto , Trastorno de Personalidad Limítrofe/diagnóstico , Trastorno de Personalidad Limítrofe/psicología , Escalas de Valoración Psiquiátrica Breve , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Humanos , Persona de Mediana Edad , Trastornos Psicóticos/psicología , Reproducibilidad de los Resultados , Esquizofrenia/diagnóstico , Psicología del Esquizofrénico , Encuestas y CuestionariosRESUMEN
BACKGROUND: Empirical data on the impact of personality pathology on acute treatment outcome for depression are mixed, in part because of challenges posed by assessing trait-like personality patterns while patients are in an active mood episode. To our knowledge, no previous study has examined the effect of personality pathology on maintenance treatment outcome. By maintenance treatment we refer to long-term treatment provided to prevent depression recurrence among remitted patients. METHOD: Structured Clinical Interviews for the DSM-III-R Personality Disorders (SCID-II) were obtained on a sample of 125 recurrently depressed women following sustained remission of the acute mood episode and prior to entering maintenance treatment. SCID-II interviews were then repeated following 1 and 2 years of maintenance interpersonal psychotherapy. RESULTS: At the pre-maintenance assessment, 21.6% of the sample met SCID-II personality disorder criteria. Co-morbid personality pathology was related to an earlier age of onset, more previous depressive episodes, and a greater need for adjunctive pharmacotherapy to achieve remission of the acute mood episode. Co-morbid personality pathology predicted both higher rates of depression recurrence and a shorter time to recurrence over the 2-year course of maintenance treatment. Notably, among those patients who remained depression-free, continuous levels of personality pathology steadily declined over the 2-year course of maintenance therapy. CONCLUSIONS: Results highlight the need for early and effective intervention of both episodic mood disorder and inter-episode interpersonal dysfunction inherent to the personality disorders. Future maintenance treatment trials are needed to clarify the relationship between episodic mood disorder and personality function over time.
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Trastorno Depresivo/terapia , Trastornos de la Personalidad/prevención & control , Adulto , Edad de Inicio , Trastorno Depresivo/psicología , Femenino , Humanos , Relaciones Interpersonales , Modelos Logísticos , Trastornos de la Personalidad/diagnóstico , Trastornos de la Personalidad/psicología , Pronóstico , Psicoterapia , Recurrencia , Inducción de Remisión , Factores de TiempoRESUMEN
1. The endocrine disruptor pesticide methoxychlor undergoes O-demethylation by mammalian liver microsomes forming chiral mono-phenolic (1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(4-methoxyphenyl)ethane, i.e. mono-OH-M) and achiral bis-phenolic oestrogenic metabolites. Human liver microsomes (HLM) generated primarily the S-mono-OH-M. 2. Inhibitory monoclonal antibodies (MAb) identified those P450s catalysing the enantioselective O-demethylation of methoxychlor. In HLM, O-demethylation was inhibited by MAb anti-2C9 (30-40%), diminishing the per cent of S-mono-OH-M from about 80 to 55-60%. MAb anti-CYP1A2, 2A6, 2B6, 2C8, 2C19, 2D6 and 3A4 did not affect the demethylation rate in HLM. Nevertheless, MAb anti-CYP1A2 decreased the formation of R-mono-OH-M from 21-23 to 10-17%, indicating that CYP1A2 exhibits a role in generating the R-enantiomer. 3. Among cDNA-expressed human P450s (supersomes), CYP2C19 was the most active in demethylation, but in HLM, CYP2C19 appeared inactive (no inhibition by MAb anti-CYP2C19). There was a substantial difference in the per cent inhibition of demethylation by MAb anti-CYP2C9 and anti-rat CYP2C (MAb inhibiting all human CYP2C forms) and in altering the enantioselectivity, suggesting that demethylation by combined CYP2C8, 2C18 and 2C19 was significant (20-30%). 4. Polymorphism of methoxychlor demethylation was examined with supersomes and HLM-expressing CYP2C9 allelic variants. CYP2C9*1 and 2C9*2 were highly active; however, CYP2C9*3 appeared inactive.
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Anticuerpos Bloqueadores/farmacología , Anticuerpos Monoclonales/farmacología , Hidrocarburo de Aril Hidroxilasas/antagonistas & inhibidores , Hidrocarburo de Aril Hidroxilasas/metabolismo , Insecticidas/metabolismo , Metoxicloro/metabolismo , Microsomas Hepáticos/enzimología , Alelos , Hidrocarburo de Aril Hidroxilasas/genética , Biotransformación , Catálisis , Citocromo P-450 CYP1A2/metabolismo , Inhibidores del Citocromo P-450 CYP1A2 , Citocromo P-450 CYP2C9 , ADN Complementario/biosíntesis , ADN Complementario/genética , Remoción de Radical Alquila , Glándulas Endocrinas/efectos de los fármacos , Humanos , Técnicas In Vitro , Insecticidas/toxicidad , Metoxicloro/toxicidad , Microsomas Hepáticos/efectos de los fármacos , EstereoisomerismoRESUMEN
OBJECTIVE: To define the extent of comorbidity in depression. METHOD: The level of medical comorbidity in depression was assessed on the basis of the empirical literature and results from the National Institute of Mental Health (NIMH) conference on Depression's Toll on Other Illnesses. RESULTS: The global incidence of depression underscores the need to develop integrative treatment strategies for these disorders. An NIMH conference entitled 'The Unwanted Cotraveler: Depression's Toll on Other Illnesses' has highlighted the impact of increased depression prevalence in the presence of medical disorders. Economic data from a large health insurance claims database concludes that the presence of a psychiatric condition, particularly depression, considerably increases the medical costs, as well as the cost of caring for the psychiatric condition. CONCLUSION: Federally sponsored research intervention centres need to address these issues and provide opportunities for diverse medical specialties to collaborate on testing novel treatment approaches.
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Depresión/complicaciones , Depresión/economía , Costos de la Atención en Salud/estadística & datos numéricos , Comorbilidad , Bases de Datos Factuales , Depresión/psicología , Política de Salud , Humanos , Seguro de Salud/estadística & datos numéricosAsunto(s)
Alelos , Amiloide/genética , Polimorfismo Genético , Precursores de Proteínas/genética , Scrapie/genética , Ovinos/genética , Animales , Secuencia de Bases , Codón/genética , Cartilla de ADN , Electroforesis en Gel de Agar , Lisina/genética , Datos de Secuencia Molecular , Oklahoma , Priones , Análisis de Secuencia de ADNRESUMEN
1. 4-Tritiated-tamoxifen (4-[(3)H]-tamoxifen) and 4-deuterated-tamoxifen (4-[(2)H]-tamoxifen) were synthesized to examine tamoxifen metabolism by human P450 (CYP) forms and also for the possibility of determining tamoxifen-4-hydroxylation in humans in vivo. 2. Liver microsomes from several species and cDNA-expressed human P450s were incubated with 4-[(3)H]-tamoxifen and the reaction monitored by assaying 4-hydroxytamoxifen (4-OH-tam) and (3)H(2)O formed. However, tamoxifen-4-hydroxylation did not generate stoichiometric amounts of (3)H(2)O and the expected unlabelled 4-OH-tam but instead yielded radiolabelled 4-OH-tam, apparently from [(3)H]-migration to the ortho-position, referred to as the NIH shift. 3. CYP2D6 was the prime catalyst of tam-4-hydroxylation, whereas CYP2B6, 2C9 and 2C19 yielded only low levels of 4-OH-tam; nevertheless, in all cases the 4-OH-tam was radioactive, apparently resulting from reactions involving an NIH shift. 4. Chicken liver microsomal preparation, being catalytically the most active in tamoxifen-4-hydroxylation, was incubated with deuterated tamoxifen (4-[(2)H]-tamoxifen) in order to determine whether an NIH shift occurs. Ion-trap mass-spectrometry of the HPLC-purified 4-OH-tam, from that incubation, indicated about 60% of [(2)H]-retention in 4-OH-tam, signifying an NIH shift. These findings indicate that the aromatic hydroxylation of tamoxifen does not entail hydroxyl insertion with an Sn2-displacement of hydrogen or a hydrogen isotope ((2)H or (3)H), but apparently involves epoxidation followed by migration of the (3)H, (2)H or (1)H to the ortho-position, and dissociation of the (1)H in preference to (3)H or (2)H, i.e. retention of the hydrogen isotope appears to be related to the bond strengths: C-(3)H>C-(2)H>C-(1)H.
Asunto(s)
Pollos/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Microsomas Hepáticos/enzimología , Tamoxifeno/metabolismo , Animales , Catálisis , Citocromo P-450 CYP2D6/genética , ADN Complementario/biosíntesis , ADN Complementario/genética , Humanos , Hidroxilación , Técnicas In Vitro , Marcaje Isotópico , Espectrometría de Masas , Ratas , UltracentrifugaciónRESUMEN
The lack of control over covariates in practice motivates the need for their adjustment when measuring the degree of association between two sets of variables, for which canonical correlation is traditionally used. In most studies however, there is also a lack of control over the attributes of responses for the sets of variables of interest. In particular, a portion of the response variable may be continuous and the other discrete. For such settings, the traditional partial canonical correlation approach is restrictive, since a covariate-adjustment for a set of continuous variables is assumed. By ignoring the assumption of continuous variates and proceeding with a partial canonical correlation analysis in the presence of continuous and discrete variates, results in canonical correlation estimates that are not consistent. In this paper we generalize the traditional partial canonical correlation approach to covariate-adjustment by allowing the response variables to contain continuous, as well as discrete, variates. The methodology is illustrated with a psychiatric application for examining which sleep variables relate to which depressive symptoms, as measured by commonly used constructs that presents with both continuous and discrete outcomes.