Clinical and pharmacological factors influencing serum clozapine and norclozapine levels.

Background: Clozapine (CLO) is a very effective antipsychotic, whose use is associated with dose-dependent risk of complications. Due to high interindividual variability in CLO metabolism, there is a need to identify factors affecting the blood concentrations of CLO and its active metabolite, norclozapine (NCLO). Methods: A total of 446 blood samples (collected from 233 women and 213 men, aged from 18 to 77 years) were included in this study and analyzed for CLO and NCLO concentrations. The patients were treated at a psychiatric hospital in Warsaw in the years 2016-2021. Serum CLO and NCLO concentrations were determined with high-performance liquid chromatography coupled to UV. Results: The following factors were shown to increase serum CLO and NCLO levels: higher CLO dose (p < 0.001), female sex (p < 0.001), nonsmoker status (p < 0.001), the use of more than two additional psychotropic drugs (only in the case of CLO; p = 0.046), concomitant use of beta-blockers (for CLO p = 0.049; for NCLO p < 0.001), and older age (for CLO p < 0.001; for NCLO p = 0.011). Despite the use of CLO at daily doses within the recommended range (200-450 mg), the evaluated serum CLO and NCLO levels were within the therapeutic ranges in only 37% and 75% of cases, respectively, with 5.6% of cases exceeding the CLO toxicity threshold. Discussion: The use of CLO at recommended doses does not guarantee achieving therapeutic concentrations of CLO or NCLO. Women and nonsmokers were at the highest risk of having toxic CLO levels.

Molecular relapse monitoring reveals the domination of impaired NK cell education over impaired inhibition in missing KIR-ligand recognition in patients after unrelated hematopoietic stem cell transplantation for malignant diseases.

Transplantation of HLA and/or KIR mismatched allogeneic hematopoietic stem cells can lead NK cells to different states of activation/inhibition or education/resetting and change anti-tumor immunosurveillance. In this study, we used molecular relapse monitoring to investigate a correlation between either missing ligand recognition or variation of the cognate iKIR-HLA pairs with clinical outcomes in patients with hematological malignancies requiring allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients (N = 418) with acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS), or lymphoma receiving T-cell repleted graft from HLA-matched or partly mismatched unrelated donors between 2012 and 2020 in our center were included in this study. Missing-ligand recognition was assessed through the presence or absence of recipients' HLA ligand for a particular inhibitory KIR (iKIR) exhibited by the donor. Inhibitory KIR-HLA pair number variation was defined by loss or gain of a new cognate pair of HLA-KIR within the new HLA environment of the recipient, compared with the donor's one. Considering the results of our research, we drew the following conclusions: (i) loss of iKIR-HLA cognate pair for C1, C2, and/or Bw4 groups led to significant deterioration of disease-free survival (DFS), molecular relapse, overall survival (OS) and non-relapse mortality (NRM) for patients undergoing allo-HSCT in the standard phase of the disease. This phenomenon was not observed in patients who underwent transplantation in advanced hematological cancer. (ii) The missing ligand recognition had no impact if the proportion of HLA mismatches was not considered; however, adjustments of HLA mismatch level in the compared groups highlighted the adverse effect of the missing ligand constellation. (iii) The adverse effect of adjusted missing ligand suggests a predominance of lost NK cell education over lost NK cell inhibition in posttransplant recipients' new HLA environment. Our results suggested that donors with the loss of an iKIR-HLA cognate pair after transplantation should be avoided, and donors who provided an additional iKIR-HLA cognate pair should be preferred in the allo-HSCT donor selection process.

Delta resting-state functional connectivity in the cognitive control network as a prognostic factor for maintaining abstinence: An eLORETA preliminary study.

BACKGROUND: Cortical regions that support cognitive control are increasingly well recognized, but the functional mechanisms that promote such control over emotional and behavioral hyperreactivity to alcohol in recently abstinent alcohol-dependent patients are still insufficiently understood. This study aimed to identify neurophysiological biomarkers of maintaining abstinence in alcohol-dependent individuals after alcohol treatment by investigating the resting-state EEG-based functional connectivity in the cognitive control network (CCN). METHODS: Lagged phase synchronization between CCN areas by means of eLORETA as well as the Barratt Impulsiveness Scale (BIS-11) and Beck Depression Inventory (BDI) were assessed in abstinent alcohol-dependent patients recruited from treatment centers. A preliminary prospective study design was used to classify participants into those who did and did not maintain abstinence during a follow-up period (median 12 months) after discharge from residential treatment. RESULTS: Alcohol-dependent individuals, who maintained abstinence (N = 18), showed significantly increased lagged phase synchronization between the left dorsolateral prefrontal cortex (DLPFC) and the left posterior parietal cortex (IPL) as well as between the right anterior insula cortex/frontal operculum (IA/FO) and the right inferior frontal junction (IFJ) in the delta band compared to those who later relapsed (N = 16). Regression analysis showed that the increased left frontoparietal delta connectivity in the early period of abstinence significantly predicted maintaining abstinence over the ensuing 12 months. Furthermore, right frontoinsular delta connectivity correlated negatively with impulsivity and depression measures. CONCLUSIONS: These results suggest that the increased delta resting-state functional connectivity in the CCN may be a promising neurophysiological predictor of maintaining abstinence in individuals with alcohol dependence.

COMT and BDNF Gene Variants Help to Predict Alcohol Consumption in Alcohol-dependent Patients.

BACKGROUND: The neurobiology of alcohol dependence (AD) involves alterations in neurotransmitters and the stress response. We hypothesized that an interaction between functional variants of dopaminergic and neurotrophic genes may influence drinking in AD. METHODS: The relationship between alcohol consumption and single-nucleotide polymorphisms, Val66Met in the brain-derived neurotrophic factor (BDNF), and Val158Met in the catechol-O-methyltransferase (COMT), was analyzed among 281 alcohol-dependent individuals. RESULTS: Individuals carrying both the COMT Met158Met genotype and the BDNF Val66Val genotype drank more than those with other variants of these genes (P = 0.039). Those who had a family history of AD also drank more than those without a family history (P = 0.048). Patients with both Met/Met genotype in the COMT Val158Met polymorphism and Val/Val genotype in the BDNF Val66Met polymorphism suffered from more health problems than those carrying other variants (P = 0.030) and had lower motivation to change drinking patterns (P = 0.031). CONCLUSIONS: Patients carrying both the BDNF Val66Val and COMT Met158Met variants had higher alcohol consumption. These effects may be influenced by the effects of BDNF and COMT on dopamine responses to alcohol. Motivation-enhancing strategies might benefit the group of patients identified by genotyping in this study, and also treatment aimed at reducing alcohol consumption.

Relationship between emotional processing, drinking severity and relapse in adults treated for alcohol dependence in Poland.

AIMS: Growing data reveals deficits in perception, understanding and regulation of emotions in alcohol dependence (AD). The study objective was to explore the relationships between emotional processing, drinking history and relapse in a clinical sample of alcohol-dependent patients. METHODS: A group of 80 inpatients entering an alcohol treatment program in Warsaw, Poland was recruited and assessed at baseline and follow-up after 12 months. Baseline information about demographics, psychopathological symptoms, personality and severity of alcohol problems was obtained. The Schutte Self-Report Emotional Intelligence (EI) Test and Toronto Alexithymia Scale (TAS) were utilized for emotional processing assessment. Follow-up information contained data on drinking alcohol during the last month. RESULTS: At baseline assessment, the duration of alcohol drinking was associated with lower ability to utilize emotions. Patients reporting more difficulties with describing feelings drank more during their last episode of heavy drinking, and had a longer duration of intensive alcohol use. A longer duration of the last episode of heavy drinking was associated with more problems identifying and regulating emotions. Poor utilization of emotions and high severity of depressive symptoms contributed to higher rates of drinking at follow-up. CONCLUSIONS: These results underline the importance of systematic identification of discrete emotional problems and dynamics related to AD. This knowledge has implications for treatment. Psychotherapeutic interventions to improve emotional skills could be utilized in treatment of alcohol-dependent patients.

Violent behavior and driving under the influence of alcohol: prevalence and association with impulsivity among individuals in treatment for alcohol dependence in Poland.

BACKGROUND: Driving while intoxicated or under the influence (DUI; for the purposes of this paper, we use the following terms synonymously: driving under the influence, driving while intoxicated, and drunk driving) and engaging in interpersonal violence are two injury-related problems of high public health importance that have both been linked to alcohol consumption. This study sought to estimate the prevalence of DUI and violence in a sample of individuals in treatment for alcohol dependence in Poland. Patient characteristics associated with DUI and violence involvement, with a particular focus on impulsivity, were examined. METHODS: Three hundred and sixty-four patients consecutively admitted to four alcohol treatment programs in Warsaw, Poland participated in this study. Questions concerning history of interpersonal violence as well as those about DUI were derived from the Michigan Alcoholism Screening Test. Impulsivity level was measured using the Barratt Impulsiveness Scale 11, the Revised NEO Personality Inventory, and the stop-signal task. RESULTS: Among all participants in the study, 148 (40.1%) had been arrested in the past for DUI, and 196 (55%) reported involvement in a fight under the influence of alcohol (FUI). The DUI group had a significantly earlier onset of alcohol problems, a longer period of heavy alcohol use, and fewer women in comparison to participants without a DUI history. FUI patients were significantly younger, with a younger average age of onset of drinking problems, longer period of heavy drinking, and lower percentage of women than the non-FUI group. CONCLUSION: Both of the self-reported measures of impulsivity indicated a higher level of impulsivity among participants from the FUI group than those from the non-FUI group.

Impulsivity, risky behaviors and accidents in alcohol-dependent patients.

Impulsivity and alcohol drinking are both considered as important predictors of unintentional as well as intentional injuries. However, relationships of impulsivity with risky behaviors and a history of accidents have not been investigated in alcohol dependence. The aim of this study was to analyze relationships between the frequency of risky behaviors and level of behavioral as well as cognitive impulsivity in alcohol-dependent patients. By means of Barratt's Impulsiveness Scale (BIS) and stop-signal task, the levels of cognitive and behavioral impulsivity among 304 alcohol-dependent patients were measured. Also, patients were asked to answer questions from the Short Inventory of Problems applying to risky behaviors and accidents after alcohol drinking. In addition participants completed a questionnaire to assess frequency of other behaviors from the analyzed spectrum (use of other drugs, driving or aggressive behavior after alcohol drinking). The statistical analysis revealed a significant association between impulsivity and frequency of risky behaviors in alcohol-dependent patients. Individuals with higher scores in BIS behaved more frequently in a risky way and had significantly more accidents after alcohol drinking. The association with risky behaviors was strongest for non-planning and attentional impulsivity subscales, whereas frequency of accidents was particularly associated with motor impulsivity. A multivariate analysis revealed that impulsivity was the most important predictor of risky behaviors, but did not significantly predict a history of accidents. Our study confirms that impulsivity is an important correlate of risky behaviors in alcohol-dependent individuals, along with global psychopathology and severity of alcohol dependence.

Impulsive suicide attempts predict post-treatment relapse in alcohol-dependent patients.

BACKGROUND: The present study was designed to examine the influence of suicidality on relapse in alcohol-dependent patients. Specifically, a lifetime suicide attempt at baseline was used to predict relapse in the year after treatment. Also, the unique contribution of impulsive suicide attempts was examined. METHODS: A total of 154 patients with alcohol dependence, consecutively admitted to four addiction treatment facilities in Warsaw, Poland participated in the study. Of the 154 eligible patients, 118 (76.6%) completed a standardized follow-up assessment at 12 months. RESULTS: Previous suicide attempts were common in adults treated for alcohol dependence with 43% patients in the present sample reporting an attempt at some point during their lifetime. Additionally, more than 62% of those with a lifetime suicide attempt reported making an impulsive attempt. Lifetime suicide attempts were not associated with post-treatment relapse (chi-square=2.37, d.f.=1, p=0.124). However, impulsive suicide attempts strongly predicted relapse (OR=2.81, 95% CI=1.13-6.95, p=0.026) and time to relapse (OR=2.10, 95% CI=1.18-3.74, p=0.012) even after adjusting for other measures of baseline psychopathology, depression, impulsivity, hopelessness and alcohol use severity. CONCLUSIONS: This study is the first to document the relationship between pre-treatment impulsive suicide attempts and higher likelihood of post-treatment relapse in alcohol-dependent patents. Clinicians should routinely conduct an assessment for previous suicide attempts in patients with alcohol use disorders, and when impulsive suicidality is reported, they should recognize the increased risk for relapse and formulate their patients' treatment plans accordingly with the goals of reducing both alcoholic relapse and suicide rates.