Effects of CYP2C19*17 genetic polymorphisms on plasma and saliva concentrations of diazepam in patients with alcohol withdrawal syndrome.

INTRODUCTION: Diazepam is one of the most commonly prescribed tranquilizers for the therapy of alcohol withdrawal syndrome (AWS). However, diazepam therapy often turns out to be ineffective, and some patients experience dose-dependent adverse drug reactions. Previous studies have shown that the metabolism of diazepam involves the CYP2C19 isoenzyme, whose activity is highly dependent on polymorphism of the encoding gene. OBJECTIVE: The study aimed to investigate the effects of CYP2C19*17 genetic polymorphisms on plasma and saliva concentrations of diazepam as well as its impact on the efficacy and safety rates of therapy in patients with AWS. MATERIAL AND METHODS: The study was conducted on 100 Russian male patients suffering from the AWS who received diazepam injections at a dosage of 30.0 mg/day for 5 days. Genotyping was performed by real-time PCR with allele-specific hybridization. The efficacy and safety assessment was performed using psychometric scales. RESULTS: Based on the results of the study, we revealed differences in the efficacy and safety of therapy in patients with different CYP2C19 -806C>T genotypes. Therapeutic drug monitoring revealed the statistically significant difference in the levels of diazepam plasma concentration: (CC) 251.76 (214.43; 310.61) vs. (CT+TT) 89.74 (54.18; 179.13); P = 0.003, and diazepam saliva concentration: (CC) 3.86 (3.22; 5.12) vs. (CT+TT) 0.79 (0.44; 1.56); P = 0.003. CONCLUSION: Our study showed the effects of CYP2C19*17 genetic polymorphisms on the efficacy and safety rates of diazepam. Furthermore, we revealed the statistically significant differences in plasma and saliva concentration levels of diazepam in patients carrying different genotypes.

Effects of CYP2C19*17 Genetic Polymorphisms on the Steady-State Concentration of Diazepam in Patients With Alcohol Withdrawal Syndrome.

Background: Diazepam is one of the most widely prescribed tranquilizers for the therapy of alcohol withdrawal syndrome (AWS), which includes the symptoms of anxiety, fear, and emotional tension. However, diazepam therapy often turns out to be ineffective, and some patients experience dose-dependent adverse drug reactions, reducing the efficacy of therapy. Aim: The purpose of our study was to investigate the effects of CYP2C19*17 genetic polymorphisms on the steady-state concentration of diazepam in patients with AWS. Materials and Methods: The study was conducted on 50 Russian male patients suffering from the AWS. For the therapy of psychomotor agitation, anxiety, fear, and emotional tension, patients received diazepam in injections at a dosage of 30.0 mg/day for 5 days. Genotyping was performed by real-time polymerase chain reaction. The efficacy and safety assessment was performed using psychometric scales and scales for assessing the severity of adverse drug reactions. Therapeutic drug monitoring (TDM) was performed using the high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method. Results: Based on the results of the study, we revealed the differences in the efficacy of therapy in patients with different CYP2C19 -806C>T genotypes: (*1/*1) -12.0 [-15.0; -8.0], (*1/*17+*17/*17) -7.0 [-14.0; -5.0], P < .001, as well as the results of TDM: (CC) 250.70 [213.34; 308.53] ng/mL (*1/*17+*17/*17) 89.12 [53.26; 178.07] ng/mL, P < .001. Conclusion: Thus, our study enrolling 50 patients with AWS, showed the effects of CYP2C19*17 genetic polymorphisms on the efficacy and safety rates of diazepam. Furthermore, we revealed the statistically significant difference in the levels of plasma steady-state concentrations of diazepam in patients carrying different genotypes.

Impact of CYP2D6 Polymorphism on Equilibrium Concentration of Fluoxetine in Patients Diagnosed With Major Depressive Disorder and Comorbid Alcohol Use Disorders.

INTRODUCTION: Fluoxetine is used in the treatment of patients with recurrent depressive disorder. Some of these patients do not achieve an adequate response to a treatment regimen containing fluoxetine, and many of these patients experience dose-dependent adverse drug reactions. The cytochrome P450 enzyme CYP2D6 is involved in the biotransformation of fluoxetine, the activity of which is quite dependent on the polymorphism of the gene encoding this enzyme. OBJECTIVE: The objective of the study was to investigate the influence of the 1846G>A polymorphism of the CYP2D6 gene on the concentration/dose indicator of fluoxetine in patients diagnosed with major depressive disorder and comorbid alcohol use disorder. METHODS: Our study included 101 patients with major depressive disorder and alcohol use disorder (average age: 41.3±14.5 y) who were treated with fluoxetine at an average dose of 26.1±8.7 mg/d. Treatment efficacy was assessed using validated psychometric scales, and the safety/tolerability of the therapy was assessed using the Udvalg for Kliniske Undersogelser Side-Effect Rating Scale. Genotyping was done using a real-time polymerase chain reaction. Therapeutic drug monitoring was performed using high-performance liquid chromatography-mass spectrometry. RESULTS: CYP2D6 genotyping by polymorphic marker 1846G>A (rs3892097) in the 101 patients found that there were 81 patients (80.2%) with the GG genotype ("wild-type," normal metabolism), 20 (19.8%) with the GA genotype (intermediate metabolism), and no subjects with the AA genotype (poor metabolism). Statistically significant results in treatment efficacy as evaluated by Hamilton Rating Scale for Depression scores at the end of the treatment course were found: GG 9.0 [confidence interval (CI): 6.0; 12.0] and GA 12.0 (CI: 9.5; 14.0), P=0.005. Statistically significant results were also obtained for the safety profile as measured by scores on the Udvalg for Kliniske Undersogelser Side-Effect Rating Scale: GG 3.0 (CI 2.0; 4.0) and GA 5.0 (CI: 4.0; 5.0), P<0.001. Finally, a statistically significant difference was found in concentration/dose indicators of fluoxetine in patients with the different genotypes: GG 4.831 (CI: 3.654; 6.204) and GA 7.011 (CI: 5.431; 8.252), P<0.001. CONCLUSION: The effect of the genetic polymorphism of the CYP2D6 gene on the efficacy and safety profiles of fluoxetine was demonstrated in a group of 101 patients with major depressive disorder and alcohol use disorder.

Emotional dysregulation features and problem gambling in university students: a pilot study.

Undergraduate students typically cope with various changes in their lives and experience many stressors associated with academic issues. Distress can make them more vulnerable to particular behavioral patterns in order to cope with negative affect. The association of problematic gambling with particular emotion regulation characteristics-some of which are developmentally dependent-becomes a recent focus of research with clinical and preventive implications. We carried out a pilot study enrolling voluntarily young adults of a public university in the Lisbon area, and 117 Portuguese-speaking individuals were interviewed. Participants, mainly female (M = 20.6; SD = 3.9), were investigated taking into consideration their gambling practices, characteristics of impulsivity and alexithymia, along with the symptoms of depression and anxiety. Portuguese versions of the South Oaks Gambling Scale (SOGS) and Short-Version of Impulsive Behavior Scale (S-UPPSP) were prepared (i.e., translation and back-translation of the original versions were performed). The prevalence of gambling problems in this sample is modest, although they were associated with negative urgency and sensation-seeking, as well as with depression symptoms. Multiple correspondence analysis, a particular multivariate model associating gambling problems with socio-demographic and psychological variables, allowed identifying different profiles of individuals. Trace and state emotional dysregulation features are selectively associated with distinctive gambling patterns, according to some previous findings in studies with other groups. Results may address new findings in terms of morbidity, risk factors and the design of future preventive strategies among such individuals.

Changes in sexual behavior patterns due to stimulants use: three case reports.

The paper describes three case reports of changes in sexual behavior patterns in male patients who use stimulants (amphetamine and mephedrone). Two of them demonstrate that the consumption of stimulants may lead to hypersexuality and excessive masturbation. Case report three shows that mephedrone use results in such typical stimulant-related subjective effects as the intensification of sensory experiences and sexual arousal. It leads to the loss of interest in sex without mephedrone. In light of the popularity of sex under the influence of drugs, clinicians should be aware of this phenomenon, since it is associated with high-risk sexual behavior. The description of clinical cases on the link between sex and drugs expands our knowledge in this area, leading to more effective treatment interventions.

How do CYP2C19*2 and CYP2C19*17 genetic polymorphisms affect the efficacy and safety of diazepam in patients with alcohol withdrawal syndrome?

Background Diazepam is one of the most commonly prescribed tranquilizers for therapy of alcohol withdrawal syndrome (AWS). Despite its popularity, there is currently no precise information on the effect of genetic polymorphisms on its efficacy and safety. The objective of our study was to investigate the effect of CYP2C19*2 and CYP2C19*17 genetic polymorphisms on the efficacy and safety of diazepam in patients with AWS. Methods The study was conducted on 30 Russian male patients suffering from the AWS who received diazepam in injections at a dosage of 30.0 mg/day for 5 days. The efficacy and safety assessment was performed using psychometric scales and scales for assessing the severity of adverse drug reactions. Results Based on the results of the study, we revealed the differences in the efficacy of therapy in patients with different CYP2C19 681G>A (CYP2C19*2, rs4244285) genotypes: (CYP2C19*1/*1) -8.5 [-15.0; -5.0], (CYP2C19*1/*2 and CYP2C19*2/*2) -12.0 [-13.0; -9.0], p = 0.021. The UKU scale scores, which were used to evaluate the safety of therapy, were also different: (CYP2C19*1/*1) 7.0 [6.0; 12.0], (CYP2C19*1/*2 and CYP2C19*2/*2) 9.5 [8.0; 11.0], p = 0.009. Patients carrying different CYP2C19 -806C>T (CYP2C19*17, rs12248560) genotypes also demonstrated differences in therapy efficacy and safety rates. Conclusions Thus, the effects of CYP2C19*2 and CYP2C19*17 genetic polymorphisms on the efficacy of diazepam were demonstrated.

Effects of CYP2C19*2 polymorphisms on the efficacy and safety of phenazepam in patients with anxiety disorder and comorbid alcohol use disorder.

Introduction: Phenazepam therapy can often be ineffective and some patients develop dose-related adverse drug reactions. Aim. The purpose of this research was to study the effect of the CYP2C19*2 (681G>A, rs4244285) in patients with anxiety disorders and alcohol dependence taking phenazepam therapy. Materials & methods: Patients (175 males, average age: 37.16 ± 7.84 years) received phenazepam in tablet form for 5 days. Genotyping was performed by real-time polymerase chain reaction. Results: The statistically significant differences in the UKU Side-Effect Rating Scale scores on the fifth day of therapy: (CYP2C19*1/*1) 2.00 [1.00; 2.00), (CYP2C19*1/*2) 7.00 (7.00; 7.00), (CYP2C19*2/*2) 9.00 (8.00; 9.00), p < 0.001. Conclusion: This study demonstrated the different efficacy and safety of phenazepam in patients with different genotypes of CYP2C19*2.

Maturação Orbitofrontal, Marcadores Somáticos e Vulnerabilidade Precoce: para uma Hipótese Compreensiva de "Miopia Emocional" na Toxicodependência / Orbitofrontal Maturation, Somatic Markers and Early Vulnerability: A Comprehensive Hypothesis of "Emotional Myopia" in Drug Addiction

A hipótese de “miopia emocional” constitui uma reflexão teórica de compreensão da vulnerabilidade psicológica identificada em muitos toxicodependentes. Propõe-se uma cooperação, mas não incorporação, de níveis de conhecimento em torno dos determinantes do neurodesenvolvimento, de perspectivas psicanalíticas e de vinculação e de modelos psicobiológicos das toxicodependências. Salientam-se influências ambientais sobre as mudanças na morfologia cerebral, não apenas o trauma precoce ou a privação de cuidados, mas também as decorrentes de consumos abusivos como cernes de vulnerabilidade. Propõe-se que a hipótese Damasiana dos marcadores somáticos participe nessa formulação. A parca qualidade das interações precoces pode sustentar o desligamento afetivo progressivo, a hipomaturação do cérebro social, o incremento de um padrão alexitímico e a procura urgente de sensações, todos potenciais propiciadores da busca do prazer nas drogas.

The “emotional myopia” hypothesis is a theoretical reflection to increase the understanding of the psychological vulnerability showed by many drug addicts Instead of an incorporation, a cooperation is proposed of levels of knowledge on the determinants of the neurodevelopment, psychoanalytical and attachment perspectives and psychobiological models of drug addictions. Environmental inputs that change brain morphology are highlighted, not only early trauma or care deprivation but also others derived from the long-term use of drugs as the core of vulnerability. We propose that Damasio’s hypothesis of somatic markers forms part of this theoretical formulation. The low quality of early social interactions may support an increasing emotional disengagement, a poor maturation of the social brain, an increase of alexithymic patterns and novelty-seeking behaviours, all potential triggers for searching for pleasure in drugs.

Measuring emotional awareness from a cognitive-developmental perspective: Portuguese adaptation studies of the levels of emotional awareness scale.

INTRODUCTION: The Levels of Emotional Awareness Scale (LEAS) was developed to assess the emotional awareness construct, based on a cognitive-developmental perspective and influenced by the Piaget and Werner theories. It is composed of 20 emotion-evoking scenes and has been used in multiple researches related to emotion regulation, alexithymia and psychiatric disorders. It is a well-documented, valid and reliable measure. Due to the extent of LEAS, some investigators have been using one of the parallel forms (LEAS-A), which is a part of the complete version, nevertheless there is a gap of studies concerning LEAS-A psychometric qualities. In the absence of measures for assessing the organization of the emotional experience in Portuguese samples, we developed the Portuguese version of LEAS, characterizing reliability and validity indicators and the same for LEAS-A. MATERIALS AND METHODS: Three different studies were carried out with these versions, two with university students and another with a sample from the general population. RESULTS: The Portuguese version showed high levels of reliability, superior to those found in other adaptation procedures. LEAS-A showed good reliability and indicators of discriminant and concurrent validities. The LEAS-A scores were independent from negative affect and related to the externally-oriented thinking involved in alexithymia. CONCLUSIONS: The Portuguese LEAS and LEAS-A show very adequate qualities, which allow for their scientific use. Implications for clinical and research contexts are discussed.

Introdução: A Escala de Níveis de Consciência Emocional (LEAS) foi desenvolvida para avaliar o constructo consciência emocional, numa perspectiva cognitivo-desenvolvimentista e influenciada pelas Teorias de Piaget e Werner. É composta por 20 situações ou cenários que evocam emoções e tem sido usada em múltiplas investigações nos domínios da regulação emocional, alexitimia e perturbações psiquiátricas. Trata-se de uma medida bem documentada, validada e precisa. Em virtude da sua extensão, alguns investigadores têm vindo a utilizar uma das formas paralelas que compõe a versão completa, a LEAS-A, sendo contudo notória a vacuidade de estudos que descrevam as qualidades psicométricas desta versão. Face à inexistência de uma medida de caracterização da organização da experiência emocional para a população portuguesa, desenvolveu-se a versão portuguesa da LEAS, caracterizaram-se diversos indicadores de precisão e validade, assim como para a versão reduzida LEAS-A. Materiais e Métodos: Foram desenvolvidos três estudos com estas versões, dois deles com recurso a estudantes universitários e um outro com uma amostra da população em geral. Resultados: A versão portuguesa demonstrou níveis elevados de precisão, mais robustos do que os encontrados em estudos de adaptação da escala noutros países. A LEAS-A apresentou bons níveis de precisão e indicadores de validade discriminante e concorrente. As pontuações obtidas na LEAS-A mostraram-se independentes da presença de afecto negativo e associaram-se significativamente a um estilo cognitivo externalizado, próprio do funcionamento alexitímico. Conclusões: As versões portuguesas da LEAS e da LEAS-A apresentam qualidades psicométricas muito adequadas, o que permite o seu uso científico. São discutidas as implicações da sua utilização nos contextos clínico e de investigação.

Feature extraction for psychophysiological load assessment in unconstrained scenarios.

The relevance of psychophysiological measurements for affective computing and emotion analysis applications has been widely recognized. However, and although several authors have studied the informative content of parameters derived from cardiovascular and other modalities, feature extraction remains an open topic in the field. This is particularly relevant in scenarios where the autonomic nervous system triggering stimuli are unknown. In this paper, we analyze a set of features extracted from multimodal biosignal data, applicable to the assessment of psychophysiological load in unconstrained settings. Experimental evaluation is performed on real world data, collected both from control subjects and subjects with a strong clinical background, in a context of questionnaire-based clinical history reporting. The devised feature set has shown promising properties, making it prone to complement the more traditional measurements.