Screening of alcohol use disorders in psychiatric outpatients: influence of gender, age, and psychiatric diagnosis. / Cribaje de trastornos por uso de alcohol en pacientes psiquiátricos ambulatorios: influencia de género, edad, y diagnóstico psiquiátrico.

Alcohol use disorders (AUD) are 2 times higher among psychiatric patients than in the general population. The under-recognition of this dual diagnosis can entail several negative outcomes. Early assessment with a screening tool like the CAGE questionnaire could be an opportunity to improve patients' prognoses. The objective of this study is to assess AUD risk in an outpatient psychiatric sample with a modified CAGE, considering the influence of age, gender and clinical psychiatric diagnosis. An observational, multicentric, descriptive study was carried out. The 4-item CAGE scale, camouflaged in a healthy lifestyle questionnaire, was implemented, using a cut-off point of one. 559 outpatients were assessed. 54% were female and the average age was 50.07 years. 182 patients presented a CAGE score ≥1 (45.1% of men and 21.9% of women). Gender was the strongest predictor of a positive result in CAGE, as men were 3.03 times more likely to score ≥1 on the CAGE questionnaire (p < .001, 95% CI: 0.22-0.49). Patients with bipolar and personality disorders had the highest rates of CAGE scores ≥1 (45.2 and 44.9%, respectively), with a significant association between diagnosis and a positive score (p = .002). Patients above 60 years were 2.5 times less likely to score ≥1 on the CAGE (p = .017, 95% CI: 0.19-0.85). Specific screening questionnaires, like the CAGE scale, can be an easy and useful tool in the assessment of AUD risk in psychiatric outpatients. Male patients with a bipolar or personality disorder present a higher risk of AUD.

Los trastornos por uso de alcohol (TUA) son 2 veces más frecuentes en pacientes psiquiátricos que en la población general. El infradiagnóstico de patología dual puede tener diversas consecuencias negativas; una valoración precoz con herramientas de cribaje como la escala CAGE podría mejorar el pronóstico de estos pacientes. El objetivo de este estudio es valorar el riesgo de TUA en pacientes psiquiátricos ambulatorios con una CAGE modificada, considerando la influencia de edad, género, y diagnóstico psiquiátrico. Se realizó un estudio descriptivo observacional, multicéntrico. La escala CAGE de 4 ítems, camuflada en un cuestionario de vida saludable, se aplicó utilizando el punto de corte de 1. Se valoraron 559 pacientes. El 54% eran mujeres, y la edad media fue de 50,07 años. 182 pacientes presentaron una puntuación ≥1 (45,1% de los hombres y 21,9% de las mujeres). El género fue el predictor principal de un resultado positivo en la escala CAGE, siendo 3,03 veces más probable que los hombres obtengan una puntuación ≥1 (p < ,001, 95% IC: 0,22-0,49). El trastorno bipolar y los trastornos de personalidad presentaron las tasas más altas de puntuaciones ≥1 (45,2 y 44,9%, respectivamente) con una asociación significativa entre diagnóstico y un resultado positivo (p = ,002). Los pacientes de más de 60 años mostraron 2,5 veces menos probabilidades de obtener una puntuación positiva (p = ,017, 95% IC: 0,19-0,85). Cuestionarios específicos, como CAGE, pueden ser herramientas sencillas y útiles para valorar el riesgo de TUA en pacientes psiquiátricos ambulatorios. Los pacientes hombres con trastorno bipolar o de personalidad presentan un riesgo más elevado de TUA.

Cribaje de trastornos por uso de alcohol en pacientes psiquiátricos ambulatorios: influencia de género, edad, y diagnóstico psiquiátrico / Screening of alcohol use disorders in psychiatric outpatients: influence of gender, age, and psychiatric diagnosis

Los trastornos por uso de alcohol (TUA) son 2 veces más frecuentes en pacientes psiquiátricos que en la población general. El infradiagnóstico de patología dual puede tener diversas consecuencias negativas; una valoración precoz con herramientas de cribaje como la escala CAGE podría mejorar el pronóstico de estos pacientes. El objetivo de este estudio es valorar el riesgo de TUA en pacientes psiquiátricos ambulatorios con una CAGE modificada, considerando la influencia de edad, género, y diagnóstico psiquiátrico. Se realizó un estudio descriptivo observacional, multicéntrico. La escala CAGE de 4 ítems, camuflada en un cuestionario de vida saludable, se aplicó utilizando el punto de corte de 1. Se valoraron 559 pacientes. El 54% eran mujeres, y la edad media fue de 50,07 años. 182 pacientes presentaron una puntuación ≥1 (45,1% de los hombres y 21,9% de las mujeres). El género fue el predictor principal de un resultado positivo en la escala CAGE, siendo 3,03 veces más probable que los hombres obtengan una puntuación ≥1 (p < ,001, 95% IC: 0,22-0,49). El trastorno bipolar y los trastornos de personalidad presentaron las tasas más altas de puntuaciones ≥1 (45,2 y 44,9%, respectivamente) con una asociación significativa entre diagnóstico y un resultado positivo (p = ,002). Los pacientes de más de 60 años mostraron 2,5 veces menos probabilidades de obtener una puntuación positiva (p = ,017, 95% IC: 0,19-0,85). Cuestionarios específicos, como CAGE, pueden ser herramientas sencillas y útiles para valorar el riesgo de TUA en pacientes psiquiátricos ambulatorios. Los pacientes hombres con trastorno bipolar o de personalidad presentan un riesgo más elevado de TUA

Alcohol use disorders (AUD) are 2 times higher among psychiatric patients than in the general population. The under-recognition of this dual diagnosis can entail several negative outcomes. Early assessment with a screening tool like the CAGE questionnaire could be an opportunity to improve patients’ prognoses. The objective of this study is to assess AUD risk in an outpatient psychiatric sample with a modified CAGE, considering the influence of age, gender and clinical psychiatric diagnosis. An observational, multicentric, descriptive study was carried out. The 4-item CAGE scale, camouflaged in a healthy lifestyle questionnaire, was implemented, using a cut-off point of one. 559 outpatients were assessed. 54% were female and the average age was 50.07 years. 182 patients presented a CAGE score ≥1 (45.1% of men and 21.9% of women). Gender was the strongest predictor of a positive result in CAGE, as men were 3.03 times more likely to score ≥1 on the CAGE questionnaire (p < .001, 95% CI: 0.22-0.49). Patients with bipolar and personality disorders had the highest rates of CAGE scores ≥1 (45.2 and 44.9%, respectively), with a significant association between diagnosis and a positive score (p = .002). Patients above 60 years were 2.5 times less likely to score ≥1 on the CAGE (p = .017, 95% CI: 0.19-0.85). Specific screening questionnaires, like the CAGE scale, can be an easy and useful tool in the assessment of AUD risk in psychiatric outpatients. Male patients with a bipolar or personality disorder present a higher risk of AUD

Lessons from Cuba for Global Precision Medicine: CYP2D6 Genotype Is Not a Robust Predictor of CYP2D6 Ultrarapid Metabolism.

A long-standing question and dilemma in precision medicine is whether and to what extent genotyping or phenotyping drug metabolizing enzymes such as CYP2D6 can be used in real-life global clinical and societal settings. Although in an ideal world using both genotype and phenotype biomarkers are desirable, this is not always feasible for economic and practical reasons. Moreover, an additional barrier for clinical implementation of precision medicine is the lack of correlation between genotype and phenotype, considering that most of the current methods include only genotyping. Thus, the present study evaluated, using dextromethorphan as a phenotyping probe, the relationship between CYP2D6 phenotype and CYP2D6 genotype, especially for the ultrarapid metabolizer (UM) phenotype. We report in this study, to the best of our knowledge, the first comparative clinical pharmacogenomics study in a Cuban population sample (N = 174 healthy volunteers) and show that the CYP2D6 genotype is not a robust predictor of the CYP2D6 ultrarapid metabolizer (mUM) status in Cubans. Importantly, the ultrarapid CYP2D6 phenotype can result in a host of health outcomes, such as drug resistance associated with subtherapeutic drug concentrations, overexposure to active drug metabolites, and altered sensitivity to certain human diseases by virtue of altered metabolism of endogenous substrates of CYP2D6. Hence, phenotyping tests for CYP2D6 UMs appear to be a particular necessity for precision medicine in the Cuban population. Finally, in consideration of ethical and inclusive representation in global science, we recommend further precision medicine biomarker research and funding in support of neglected or understudied populations worldwide.

CYP2D6 -1584C>G promoter polymorphism and debrisoquine ultrarapid hydroxylation in healthy volunteers.

BACKGROUND & AIM: The CYP2D6 -1584C>G polymorphism (rs1080985) has been identified as a major factor for CYP2D6 expression and function, with the mutant -1584G promoter type being consistently associated with significantly greater expression than -1584C. It may therefore be associated with ultrarapid metabolism. The objective of the present study was to explore the relationship between the CYP2D6 -1584C>G polymorphism and the debrisoquine metabolic ratio in healthy volunteers in order to evaluate its potential impact on the ultrarapid CYP2D6 hydroxylation capacity. MATERIALS & METHODS: The CYP2D6 -1584C>G polymorphism was analyzed in 320 unrelated healthy individuals who were previously phenotyped for debrisoquine hydroxylation. RESULTS: The metabolic ratio (log10 mean ± standard deviation) of individuals with the -1584G allele was lower than that of individuals with the -1584C allele for carriers of one active CYP2D6 gene (-0.13 ± 0.33 and 0.17 ± 0.52, respectively; p < 0.05) or two active CYP2D6 genes (-0.32 ± 0.39 and -0.20 ± 0.44, respectively; p < 0.05). CONCLUSION: The presence of the -1584G allele in the promoter region of the CYP2D6 gene was related to a high CYP2D6 hydroxylation capacity.

High-performance liquid chromatography method using ultraviolet detection for the quantification of aripiprazole and dehydroaripiprazole in psychiatric patients.

BACKGROUND: Aripiprazole (ARI) is an antipsychotic drug that is metabolized to dehydroaripiprazole (DARI) by CYP2D6. Because of the large interindividual variability in ARI and DARI plasma concentrations, therapeutic drug monitoring may be of use in psychiatric patients during treatment with ARI. The aim of the present study was to develop a simple and reliable method for the quantitative determination of ARI and DARI in plasma using liquid-liquid extraction and reverse-phase high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. The method was tested in psychiatric patients during regular treatment with ARI. METHODS: Separation was by the liquid-liquid method, and UV detection at 254 nm. Linear responses for ARI and DARI were obtained between 2 and 1000 ng/mL, and precision assays were lower than 10.4 for both analytes. RESULTS: Lower limit of quantification and detection were 1 and 0.38 ng/mL for ARI and 0.78 and 0.44 ng/mL for DARI, respectively. The method was successfully applied to plasma samples drawn from 22 patients with concentrations ranging between 2 and 189 ng/mL for ARI and between 11 and 359 ng/mL for DARI. CONCLUSIONS: The chromatographic method developed has been demonstrated to be sensitive and reliable for the measurement of ARI and DARI simultaneously in human plasma, and the present method represents an alternative procedure to evaluate plasma concentration in patients during treatment with ARI.

Relation between CYP2D6 genotype, personality, neurocognition and overall psychopathology in healthy volunteers.

AIMS: A lower serotonin/higher dopamine tone in CYP2D6 poor metabolizers (PMs) versus extensive metabolizers (EMs) has been postulated, which is consistent with our prior research showing behavioral traits related to anxiety and impulsivity in PMs. This tone could also be related to PMs vulnerability to cognitive functioning and/or psychopathology. Therefore, the present study aimed to analyze the relationship between CYP2D6 genotype and personality, cognition and psychopathological vulnerability. The influence of affective state in these relationships was also analyzed. MATERIALS & METHODS: A total of 144 healthy volunteers from the University of Extremadura (Spain) were evaluated by CYP2D6 genotypes, overall psychopathology (Symptom Checklist-90-revised [SCL-90-R]), personality (Karolinska Scales of Personality [KSP] and Temperament and Character Inventory [TCI-R]) and on cognitive functions with computerized CANTAB tests. RESULTS: PMs (n = 11) versus EMs (n = 133) (Mann-Whitney U-tests) presented higher 'impulsivity' in both KSP and TCI-R, and better performance of sustained attention (on the Rapid Visual Information Processing test) and lower overall psychopathology with all PMs scoring below 0.7 on SCL-90-R ('positive affect' group). There were differences between all participants scoring below (n = 107) and above (n = 37) 0.7 on SCL-90-R in most personality measures. Comparisons between PMs (n = 11) and EMs (n = 96) with SCL-90-R less than 0.7 maintained those results for KSP and CANTAB but also yielded greater scores on the TCI-R-'perfectionism' subscale in PMs. In multivariate analyses controlled for age, sex and psychopathology, KSP-impulsiveness, CANTAB-sustained attention, spatial working memory and paired associate learning were significantly different in PMs versus EMs. CONCLUSION: In the studied population of healthy volunteers, PMs versus EMs showed lower vulnerability to psychopathology and greater impulsivity. Moreover, differences in neurocognition were found. The cross-study reproducibility of the relationship between CYP2D6 and personality may be difficult due to the influence of psychopathology among other factors. The personality and cognitive factors found in PMs appear compatible with a low serotonin/high dopamine balance.

Relation between CYP2D6 phenotype and genotype and personality in healthy volunteers.

OBJECTIVES: Our group has previously show that interindividual variability in CYP2D6 hydroxylation capacity was related to personality differences in cognitive social anxiety. Thus, we aimed to analyze whether this relationship between personality and CYP2D6 phenotype and genotype was found in a similar population of healthy volunteers from a different latitude and culture by using the same methodology. METHODS: A total of 253 university students and staff from Havana Psychiatric Hospital and Calixto García Medical School in Cuba completed the Karolinska Scales of Personality (KSP), and were evaluated on debrisoquine hydroxylation capacity and CYP2D6 genotypes. KSP scores were compared between four groups, divided according to their CYP2D6 metabolic capacity: one of poor and three of extensive metabolizers. Furthermore, KSP scores were compared between another four different groups divided according to their number of CYP2D6 active genes: zero, one, two, and more than two. RESULTS: In Cubans, the differences in cognitive social anxiety-related personality traits across the four CYP2D6 hydroxylation capacity groups were strikingly similar to those found in Spaniards. These differences also came out to be significant for psychic anxiety (p = 0.02) and socialization (p = 0.02). The same pattern of results obtained for the subscales of psychic anxiety, socialization, psychasthenia and inhibition of aggression with regard to phenotype in both the Cuban and Spanish studies were seen with regard to CYP2D6 genotypes. CONCLUSIONS: Corroborating these results further strengthens evidence of the relationship between CYP2D6 metabolic capacity and personality. In this population of healthy Cuban volunteers, the CYP2D6 hydroxylation capacity was related to the degree of anxiety and socialization. These results support the postulated reduction of serotonin in CYP2D6 poor metabolizers, which may be associated with a cluster of behavioral traits (e.g., anxiety, impulsivity). Thus, research is warranted to determine CYP2D6 functional implications for interindividual differences in vulnerability to neuropsychiatric diseases and drug response.

[Study of debrisoquine hydroxylation polymorphism (CYP2D6) in the Cuban population compared to Spaniards]. / Estudio farmacogenético del polimorfismo metabólico de la debrisoquina (CYP2D6) en la población cubana en relación con la española.

BACKGROUND AND OBJECTIVE: CYP2D6 metabolic capacity shows genetic polymorphism. Two metabolic phenotypes, poor and extensive, can be determined by the ratio of debrisoquine to its metabolite in urine (MR). A subgroup of ultrarapids has been also described. We analyzed the inter-ethnic differences on the polymorphic hydroxylation of debrisoquine in a Cuban population in comparison to Spaniards. PATIENTS AND METHOD: MR in a Cuban population of 260 white and mestizo healthy volunteers was studied and compared to 925 Spanish healthy volunteers. RESULTS: The frequency of poor metabolizer in Cubans (4.6%) was almost identical to that found in Spaniards (4.9%). However, ultrarapids were lower in Cubans (3.8%) than in Spaniards (5.2%). MR in Cuban-mestizo extensive metabolizers was higher than in white (p<0.05). CONCLUSIONS: Interethnic differences on debrisoquine hydroxylation have been demonstrated in a Cuban population. Furthermore, differences on the frequency of ultrarapids between Cubans and Spaniards have been shown. These results could explain inter-individual and interethnic differences on drug response such as side effects or therapeutic failures among Cuban patients receiving treatment with CYP2D6 substrates.

Estudio farmacogenético del polimorfismo metabólico de la debrisoquina (CYP2D6) en la población cubana en relación con la española / Study of debrisoquine hydroxylation polymorphism (CYP2D6) in the Cuban population compared to Spaniards

Fundamento y objetivo: La capacidad metabólica del CYP2D6 presenta polimorfismo genético. A partir del cálculo del índice metabólico (IM) urinario de un fármaco test como la debrisoquina se ha demostrado la existencia de 2 fenotipos metabólicos: metabolizadores lentos y rápidos, entre los que hay un subgrupo de ultrarrápidos. El objetivo de este trabajo ha sido evaluar las diferencias interétnicas del polimorfismo metabólico de hidroxilación de debrisoquina en la población cubana, y compararla con la española. Pacientes y método: El IM se evaluó en 260 voluntarios sanos cubanos (divididos en blancos y mestizos) que se compararon con 925 voluntarios sanos españoles. Resultados: La frecuencia de metabolizadores lentos fue similar entre cubanos y españoles (un 4,6 y un 4,9%, respectivamente). Sin embargo, la prevalencia de metabolizadores ultrarrápidos fue menor en cubanos (3,8%) que en españoles (5,2%). El IM en metabolizadores rápidos fue mayor (p < 0,05) en los mestizos que en blancos cubanos. Conclusiones: Se observan diferencias interétnicas en el polimorfismo genético del CYP2D6 en la población cubana y en la frecuencia de metabolizadores ultrarrápidos respecto a los españoles. Estas diferencias podrían condicionar en la población cubana una variabilidad interindividual e interétnica en la respuesta a los fármacos sustratos del CYP2D6

Background and objective: CYP2D6 metabolic capacity shows genetic polymorphism. Two metabolic phenotypes, poor and extensive, can be determined by the ratio of debrisoquine to its metabolite in urine (MR). A subgroup of ultrarapids has been also described. We analyzed the inter-ethnic differences on the polymorphic hydroxylation of debrisoquine in a Cuban population in comparison to Spaniards. Patients and method: MR in a Cuban population of 260 white and mestizo healthy volunteers was studied and compared to 925 Spanish healthy volunteers. Results: The frequency of poor metabolizer in Cubans (4.6%) was almost identical to that found in Spaniards (4.9%). However, ultrarapids were lower in Cubans (3.8%) than in Spaniards (5.2%). MR in Cuban-mestizo extensive metabolizers was higher than in white (p < 0.05). Conclusions: Interethnic differences on debrisoquine hydroxylation have been demonstrated in a Cuban population. Furthermore, differences on the frequency of ultrarapids between Cubans and Spaniards have been shown. These results could explain inter-individual and interethnic differences on drug response such as side effects or therapeutic failures among Cuban patients receiving treatment with CYP2D6 substrates

Determination of debrisoquine and 4-hydroxydebrisoquine by high-performance liquid chromatography: application to the evaluation of CYP2D6 genotype and debrisoquine metabolic ratio relationship.

The drug-metabolizing cytochrome P450 (CYP) enzyme CYP2D6 is involved in the metabolism of several clinically important drugs. So far more than 50 different CYP2D6 allelic variants have been described, and thus there is an increased need for routine high-performance liquid chromatography (HPLC) methods for the evaluation of the functional implication of CYP2D6 polymorphism. Debrisoquine is metabolized to 4-hydroxydebrisoquine by CYP2D6, and therefore it has been used widely to determine the hydroxylation capacity of the enzyme. The aim of the present study was to develop a simple, accurate HPLC method with ultraviolet detection for the measurement of debrisoquine and 4-hydroxydebrisoquine in urine for evaluation of the relationship between CYP2D6 enzyme activity and genotypes. For the HPLC determination, a C18 extraction column was used with a flow rate of 0.8 mL/min and detection at 210 nm. The compounds were eluted from the column in less than 10 min. Coefficients of variation at all concentrations were less than 4% for both compounds. The debrisoquine/4-hydroxydebrisoquine ratio (debrisoquine metabolic ratio) was determined in a panel of 16 Caucasian healthy volunteers with zero (poor metabolizers), one, two or more than two (ultrarapid metabolizers) CYP2D6 active genes. Significant correlation (p<0.05) between the number of CYP2D6 active genes and the hydroxylation capacity of the enzyme was found. The present HPLC method was simple, fast and accurate, and thus will be useful for the evaluation of CYP2D6 hydroxylation capacity in pharmacogenetic studies.