Association between Fok I vitamin D receptor gene (VDR) polymorphism and impulsivity in alcohol-dependent patients.

Vitamin D appears to have an important role in the modulation of the central nervous system. Vitamin D exerts its biological effects through its interaction with the vitamin D receptor (VDR). Located on chromosome 12 (12q13.1), the VDR gene has many different polymorphisms. Some of them are known to affect the VDR function, such as FokI (rs2228570, T/C) single nucleotide polymorphism. We aimed to explore a potential relationship between FokI VDR polymorphism and impulsiveness in alcohol-dependent (AD) patients. The study population consisted of 148 patients diagnosed with alcohol dependence (DSM-IV criteria) and 212 healthy controls. DNA was extracted from whole blood samples using the standard procedure. Genotypes were analyzed using a real-time PCR method. We found that FokI VDR gene polymorphism was associated with impulsivity [Barratt Impulsiveness Scale (BIS)-11 total score; P = 0.014], and with attentional impulsivity (BIS-11 subscale; P = 0.002) in the male AD patients. Our results suggest that CC FokI genotype of the VDR gene is associated with a higher level of impulsivity in these patients. This finding supports the hypothesis that impulsiveness, which significantly contributes to development of alcohol dependence, has a genetic background.

Association of polymorphisms in HTR2A, HTR1A and TPH2 genes with suicide attempts in alcohol dependence: a preliminary report.

We investigated a relationship between selected polymorphisms: rs6313 in HTR2A, rs6295 in HTR1A and rs1386494 in TPH2, and suicidal behaviour in 150 alcohol-dependent patients. There was a significant association between more frequent C102C genotype in HTR2A and suicide attempts in alcoholic females. No differences in genotype distribution in HTR1A and TPH2 SNPs were found between patients with and without suicide attempts.

Association between Val66Met brain-derived neurotrophic factor (BDNF) gene polymorphism and post-treatment relapse in alcohol dependence.

BACKGROUND: The purpose of this study was to examine relationships between genetic markers of central serotonin (5-HT) and dopamine function, and risk for post-treatment relapse, in a sample of alcohol-dependent patients. METHODS: The study included 154 patients from addiction treatment programs in Poland, who met DSM-IV criteria for alcohol dependence. After assessing demographics, severity of alcohol use, suicidality, impulsivity, depression, hopelessness, and severity of alcohol use at baseline, patients were followed for approximately 1 year to evaluate treatment outcomes. Genetic polymorphisms in several genes (TPH2, SLC6A4, HTR1A, HTR2A, COMT, and BDNF) were tested as predictors of relapse (defined as any drinking during follow-up) while controlling for baseline measures. RESULTS: Of 154 eligible patients, 123 (80%) completed follow-up and 48% (n = 59) of these individuals relapsed. Patients with the Val allele in the Val66Met BDNF polymorphism and the Met allele in the Val158Met COMT polymorphism were more likely to relapse. Only the BDNF Val/Val genotype predicted post-treatment relapse [odds ratio (OR) = 2.62; p = 0.019], and time to relapse (OR = 2.57; p = 0.002), after adjusting for baseline measures and other significant genetic markers. When the analysis was restricted to patients with a family history of alcohol dependence (n = 73), the associations between the BDNF Val/Val genotype and relapse (OR = 5.76, p = 0.0045) and time to relapse (hazard ratio = 4.93, p = 0.001) were even stronger. CONCLUSIONS: The Val66Met BDNF gene polymorphism was associated with a higher risk and earlier occurrence of relapse among patients treated for alcohol dependence. The study suggests a relationship between genetic markers and treatment outcomes in alcohol dependence. Because a large number of statistical tests were conducted for this study and the literature on genetics and relapse is so novel, the results should be considered as hypothesis generating and need to be replicated in independent studies.

Clinical and genetic risk factors for suicide under the influence of alcohol in a Polish sample.

AIMS: Despite the large number of suicides that occur with intoxication, little is known about the unique predictors of suicide after alcohol consumption. The goal of this study was to examine clinical and genetic risk factors for alcohol-related suicide. METHODS: Data on 162 suicide victims were obtained from post-mortem examinations, police and prosecution inquiries, autopsy protocols and available medical records. Four single nucleotide polymorphisms in the central serotonin system and the renin-angiotensin system related genes previously found to be associated with suicide, alcohol dependence or depression were genotyped. RESULTS: The strongest predictor of suicide under the influence of alcohol was alcohol dependence (OR = 4.63). Those who did not drink alcohol before suicide were more likely to have a diagnosis of major depressive disorder in their medical record and more often had the TT genotype of the tryptophan hydroxylase 2 gene. CONCLUSIONS: Suicide under the influence of alcohol is strongly connected with alcohol dependence. The TPH2 gene may play an important role in suicide vulnerability especially in individuals who did not drink alcohol before suicide.

Ionized magnesium in plasma and erythrocytes for the assessment of low magnesium status in alcohol dependent patients.

BACKGROUND: Studies on the homeostasis of magnesium in alcohol-dependent patients have often been characterized by low hypomagnesemia detection rates. This may be due to the fact that the content of magnesium in blood serum constitutes only 1% of the average magnesium level within the human body. However, the concentration of ionized magnesium is more physiologically important and makes up 67% of the total magnesium within a human organism. There are no data concerning the determination of the ionized fraction of magnesium in patients addicted to alcohol and its influence on mental health status. METHODS: This study included 100 alcohol-dependent patients and 50 healthy subjects. The free magnesium fraction was determined using the potentiometric method by means of using ion-selective electrodes. The total magnesium level was determined by using a biochemical Indiko Plus analyzer. In this study, different psychometric scales were applied. RESULTS: Our results confirm the usefulness of ionized magnesium concentrations in erythrocytes and plasma as a diagnostic parameter of low magnesium status in alcohol-dependent patients. CONCLUSIONS: The lower the concentration of ionized magnesium, the worse the quality of life an alcohol-dependent person might experience. In the case of total magnesium, no such correlation was determined.

Therapeutic tricyclic antidepressant drug monitoring in younger and older depressive patients.

The present study shows the evaluation of clinical state and serum level of tricyclic antidepressants in thirty-eight depressive younger and elderly patients during 8-week observation. We observed no statistically significant differences, neither in psychometric scale scores nor in drug serum levels in both groups of patients.

[Influence of impulsivity, suicidality and serotonin genes on treatment outcomes in alcohol dependence]. / Wplyw impulsywnosci, sklonnosci samobójczych oraz genów ukladu serotoninowego na wyniki leczenia uzaleinienia od alkoholu.

AIM: The aim of the study was to identify risk factors of relapse by investigating relationships among suicidality, impulsivity, genetic markers of serotonin activity, and relapse in alcohol-dependent patients. METHODS: 90 alcohol dependent patients were followed for 12 months after the baseline assessment, which entailed evaluation of suicidality and impulsivity as well as collection of DNA samples. Polymorphisms of genes involved in the synthesis and activity of the serotonin system were analyzed. After 12 months from the first visit, the patients were re-contacted and interviewed for relapse. RESULTS: Relapse rates were significantly higher among patients with the history of suicidal attempts recorded at the baseline assessment. The genetic analysis showed that patients with the G/G genotype in the 5HTR1A gene were more likely to relapse, whereas patients with the C/C genotype were more likely to abstain. Moreover, there was a strong trend for an association between the G/G genotype and a history of suicide attempts. CONCLUSIONS: High level of suicidality may predict relapse in alcoholic patients. Altered serotonergic function increases the risk of a suicide attempt and may contribute to higher risk of relapse in alcohol dependent patients.

The usefulness of monitored therapy using Clozapine concentration in the blood serum for determining drug dose in Polish schizophrenic patients.

BACKGROUND: The aim of the study is to evaluate the advisability of systematic monitoring of clozapine (CLO) concentration in serum during treatment of schizophrenia in Polish psychiatric patients. METHOD: The concentration of CLO and its metabolites: norclozapine (NCLO) and clozapine N-oxide (CLO-NO) in serum obtained from 107 patients suffering from schizophrenia was determined by high performance liquid chromatography (HPLC) method. There were two groups of patients. In the first group of patients (n=95) the concentration of drug and its metabolites was determined by one-time testing. Correlations were tested using the test statistics. In the second group of patients (n=12), 51 samples of serum were provided by the same patient in different time spans (from 6days to 14 months after the beginning of the treatment). RESULTS: Concentrations of CLO and its metabolites in blood serum do not always show a linear dependence on the applied dose for individual patients. CONCLUSION: The high volatility of CLO concentrations in blood serum of patients treated with identical doses of the drug confirmed the validity of the monitored therapy.

[Therapeutic drug monitoring in depression--new perspectives]. / Terapia monitorowana depresji--nowe perspektywy.

UNLABELLED: 34 patients with diagnosis of depressive episode (ICD-10) were treated for 8 weeks with tricyclic antidepressants (TCA) 22 patients were treated with clomipramine 75-175 mg daily, 11 with imipramine 75-150 mg and 1 with amitriptyline 150 mg. Following parameters were analysed: plasma concentration (FPIA, HPLC), pharmaco-EEG (spectrum power for delta, theta, alfa1, 2, beta 1, 2, 3 by the use of FFT), clinical improvement (HAMD, HARS, SGI, SERS). 50% reduction in HAMD was regarded as improvement. RESULTS: No relationship between mental state and plasma concentration of TCA was found, initial results in SERS were prognostic for the course of treatment, pharmaco-EEG was typical for antidepressants after two weeks of treatment and reflects clinical improvement and stabilization of plasma concentration. Comparing the plasma concentration of TCA measured by the use of FPIA and HPLC method may be useful for the implementation of monitoring therapy.

The CC genotype in the T102C HTR2A polymorphism predicts relapse in individuals after alcohol treatment.

The serotonin system is hypothesized to contribute to predisposition and course of alcohol dependence. However, the potential association between the T102C polymorphism (rs6313) in the type 2A serotonin receptor (HTR2A) gene and treatment outcomes in alcohol dependence has not been investigated. The aim of the study was to assess the contribution of this genetic polymorphism as a predictor of relapse in relation to other previously identified predictors. A sample of 254 alcohol dependent subjects, were recruited in alcohol treatment centers in Warsaw, Poland and prospectively assessed at baseline and follow-up after 12 months. At baseline, information about demographics, psychopathological symptoms and alcohol problems was obtained. The stop-signal task was performed and blood samples for genetic analysis of HTR2A T102C (rs6313) were collected. Relapse was defined as any drinking during the follow-up period. The statistical analysis showed that the CC genotype was significantly associated with increased relapse. Other significant factors were baseline depressive symptoms, number of drinking days during the 3 months prior to the baseline assessment, severity of alcohol-related problems, and a lifetime history of impulsive suicide attempts. Logistic regression analysis with and without the genetic factor revealed that adding the genetic factor increased the R square value by about 4%, with the CC genotype in the T102C polymorphism being the strongest predictor of relapse (OR = 2.32). The significant influence on relapse of the CC genotype, which is associated with fewer 5-HT2A receptors in the central nervous system, suggests the possibility that this genetic polymorphism could influence response to serotonergic medications.

Vitamin D and the central nervous system.

Vitamin D is formed in human epithelial cells via photochemical synthesis and is also acquired from dietary sources. The so-called classical effect of this vitamin involves the regulation of calcium homeostasis and bone metabolism. Apart from this, non-classical effects of vitamin D have recently gained renewed attention. One important yet little known of the numerous functions of vitamin D is the regulation of nervous system development and function. The neuroprotective effect of vitamin D is associated with its influence on neurotrophin production and release, neuromediator synthesis, intracellular calcium homeostasis, and prevention of oxidative damage to nervous tissue. Clinical studies suggest that vitamin D deficiency may lead to an increased risk of disease of the central nervous system (CNS), particularly schizophrenia and multiple sclerosis. Adequate intake of vitamin D during pregnancy and the neonatal period seems to be crucial in terms of prevention of these diseases.

Serotonin 2A receptor gene (HTR2A) polymorphism in alcohol-dependent patients.

BACKGROUND: The serotonergic (5-HT) dysfunction has been frequently described in subjects with alcohol dependence (AD). In the present study, a potential relationship between T102C polymorphism in the 5-HT receptor subtype 2Agene (HTR2A) and alcohol dependence was examined. METHODS: Genotypes were analyzed in 150 AD patients diagnosed with DSM-IV criteria and in 80 healthy controls. RESULTS: The genetic analysis showed that the frequency of 102C allele and C102C genotype in AD subjects was significantly higher than in controls. Moreover, AD patients homozygous for C allele had significantly lower age at onset of alcohol problems than subjects having at least one T allele. CONCLUSION: The results suggest a potential role of the T102C HTR2A polymorphism in development of alcohol dependence.

Serum cortisol concentration in patients with major depression after treatment with fluoxetine.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and elevated cortisol levels is characteristic of the pathophysiology of major depressive disorder (MDD). The aim of this study was to determine whether increased plasma cortisol levels appear in patients with major depression and if effective antidepressant treatment by fluoxetine leads to regulation of cortisol level. This aim was realized by describing and validation of methods of determining fluoxetine and cortisol in serum and searching for correlation between their concentrations in patients with endogenous depression, the therapeutic effect as assessed in Hamilton Depression Rating Scale (HDRS), age and sex of patients. Plasma cortisol and fluoxetine levels were measured using high performance liquid chromatography (HPLC) methods with applying Shimadzu chromatograph with UV detection. Plasma cortisol and fluoxetine levels were measured at time zero (before therapy) and after 6h, 24h, 2, 4, 6 and 8 weeks of fluoxetine administration in patients with major depression qualified for therapeutic drug monitoring (TDM). The study included 21 patients (14 women, 7 men; mean age 29-75 years) and 24 healthy comparison subjects. The patients had a mean score on the 21-item HDRS. As the effect of fluoxetine administration the decrease of the level of cortisol was observed in patients who responded to the therapy (the reduction of points in HDRS scale in at least 50%). The validation parameters of HPLC method of fluoxetine and cortisol determination indicate the possibility of applying them for determination of both: the level of concentration of the drug in therapeutic drug monitoring and the level of cortisol in serum of patients with endogenous depression.

The CC genotype in HTR2A T102C polymorphism is associated with behavioral impulsivity in alcohol-dependent patients.

High levels of impulsivity can increase the vulnerability for development of alcohol dependence. Moreover, impulsivity is considered to be a predictor of poor treatment outcomes. Few studies, however, have directly examined the genetics of impulsivity in alcohol-dependent patients. We analyzed the relationships between a well-recognized genetic marker of serotonin activity and levels of impulsivity as measured by both the Barratt Impulsiveness Scale (BIS-11) and the stop-signal task among 304 alcohol-dependent patients. The stop-signal task was used as an independent, objective method of estimating the level of behavioral impulsivity, and the BIS-11 as a self-report measure of global impulsivity. Blood was collected and analyzed for the T102C (rs6313) polymorphism in the serotonin type 2A receptor gene (HTR2A). Our results indicate a significant association between high levels of behavioral impulsivity and the C/C genotype of rs6313 in alcohol-dependent patients. The CC genotype has been previously found to be associated with a reduction in 5HT2A receptors in the central nervous system. These results support the hypothesis that genetic factors are important determinants of behavioral impulsivity in alcohol-dependent patients, and that the serotonin system plays an important role in establishing its level.

Serum cortisol concentration in patients with major depression after treatment with clomipramine.

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and elevated cortisol (CORT) levels are characteristics of the pathophysiology of major depressive disorder. The aim of this study was to determine whether increased plasma CORT levels appear in patients with major depression and if effective antidepressant treatment by clomipramine (CLO) leads to regulation of CORT level. Plasma CORT levels were measured using high performance liquid chromatography (HPLC) methods in patients with major depression at time zero (before therapy) and after 3 h, 24 h, 4, 6 and 8 weeks of CLO administration. The study included 17 patients (12 women, 5 men; mean age 54.5 years, SD =12.3) and 21 healthy comparison subjects. The patients had a mean score on the 21-item Hamilton Depression Rating Scale (HDRS) of 26.8 (range 22-35). Eight of the patients with major depression recruited for the study showed a 46% increase in CORT concentration compared to the established standard. In 13 patients treated with CLO, serum CLO levels reached a therapeutic range. In recovered depressed patients, antidepressant treatment significantly reduced HDRS scores from the 6th week of treatment. A drop in plasma CORT levels in recovered depressed subjects occurred 0 to 6 weeks after CLO treatment (n = 5, p < 0.046). However, neither subject group exhibited any definitive markers of CORT secretion. In the population studied, patients had distinct profiles of HPA axis dysregulation. Finding a linear correlation between lower CORT secretion and therapeutic plasma CLO levels is the first aim of monitored therapy and may be important for understanding the pathophysiology of major depressive disorder.