Evaluation of cell proliferation, apoptosis, and DNA-repair genes as potential biomarkers for ethanol-induced CNS alterations.

BACKGROUND: Alcohol use disorders (AUDs) lead to alterations in central nervous system (CNS) architecture along with impaired learning and memory. Previous work from our group and that of others suggests that one mechanism underlying these changes is alteration of cell proliferation, apoptosis, and DNA-repair in neural stem cells (NSCs) produced as a consequence of ethanol-induced effects on the expression of genes related to p53-signaling. This study tests the hypothesis that changes in the expression of p53-signaling genes represent biomarkers of ethanol abuse which can be identified in the peripheral blood of rat drinking models and human AUD subjects and posits that specific changes may be correlated with differences in neuropsychological measures and CNS structure. RESULTS: Remarkably, microarray analysis of 350 genes related to p53-signaling in peripheral blood leukocytes (PBLs) of binge-drinking rats revealed 190 genes that were significantly altered after correcting for multiple testing. Moreover, 40 of these genes overlapped with those that we had previously observed to be changed in ethanol-exposed mouse NSCs. Expression changes in nine of these genes were tested for independent confirmation by a custom QuantiGene Plex (QGP) assay for a subset of p53-signaling genes, where a consistent trend for decreased expression of mitosis-related genes was observed. One mitosis-related gene (Pttg1) was also changed in human lymphoblasts cultured with ethanol. In PBLs of human AUD subjects seven p53-signaling genes were changed compared with non-drinking controls. Correlation and principal components analysis were then used to identify significant relationships between the expression of these seven genes and a set of medical, demographic, neuropsychological and neuroimaging measures that distinguished AUD and control subjects. Two genes (Ercc1 and Mcm5) showed a highly significant correlation with AUD-induced decreases in the volume of the left parietal supramarginal gyrus and neuropsychological measures. CONCLUSIONS: These results demonstrate that alcohol-induced changes in genes related to proliferation, apoptosis, and DNA-repair are observable in the peripheral blood and may serve as a useful biomarker for CNS structural damage and functional performance deficits in human AUD subjects.

Predictors of smoking severity in patients with schizophrenia and alcohol use disorders.

The goal of the present study was to identify predictors of smoking severity in patients with schizophrenia and co-occurring alcohol use disorders (AUD). Our hypothesis was that negative symptoms of schizophrenia, severity of depression, male gender, drinking severity, and recreational drug use were associated with increased smoking. Clinical data, including demographic variables, alcohol and substance use severity, psychiatric medications, severity of depression, positive and negative symptoms of schizophrenia were analyzed in a cohort of 90 patients with schizophrenia or schizoaffective disorder and AUD. Eighty-eight percent of participants were smokers, they smoked an average of 15 cigarettes/day. Zero-inflated negative binomial (ZINB) regression analyses demonstrated that alcohol use severity, gender, and severity of negative symptoms were not predictive of the number of cigarettes smoked. Smoking severity was positively related to Caucasian race, psychosis severity (Positive and Negative Syndrome Scale [PANSS] general score), and medications (conventional antipsychotics). Subjects who used recreational drugs smoked less. In summary, severe, treatment resistant schizophrenia, and conventional antipsychotic treatment is associated with heavy smoking in patients with schizophrenia and AUD regardless of gender or alcohol use.

Psychiatric and substance use disorders among methadone maintenance patients with chronic hepatitis C infection: effects on eligibility for hepatitis C treatment.

We set out to describe the prevalence and severity of psychiatric and substance use disorders (SUDs) in methadone maintenance treatment (MMT) patients with chronic hepatitis C virus (HCV) infection and to measure the impact on HCV-treatment eligibility. Psychiatric disorders, SUDs, and HCV-treatment eligibility were assessed in 111 MMT patients prior to a controlled trial of HCV treatment. Lifetime and current diagnosis rates, respectively, were: any non-SUD Axis I disorder: 82% and 57%, any mood disorder: 67% and 35%, any anxiety disorder: 63% and 22%, any psychotic disorder: 11% and 9%. Antisocial personality disorder was present in 40%. A total of 56% met criteria for current SUDs. A total of 66% received psychiatric medications prior to HCV treatment; over half were receiving antidepressants. Despite psychiatric and substance use comorbidity, only 15% of patients were ineligible for HCV treatment: 10% due to failure to complete the evaluation, and 5% due to psychiatric severity. Substance use did not lead to ineligibility in any participant. Multiple logistic regression showed the Beck Depression Inventory contributed significantly to predicting HCV treatment eligibility. Most MMT patients were eligible [corrected] for HCV treatment despite current SUD and non-SUD diagnoses. Depression severity may be a more significant predictor of HCV treatment eligibility than is substance use.

Hepatitis C treatment eligibility and comorbid medical illness in methadone maintenance (MMT) and non-MMT patients: a case-control study.

Comorbid medical illness is common in patients with chronic hepatitis C (HCV) infection and in methadone treatment (MMT) patients, yet little is known about the impact of medical illness on HCV treatment eligibility. Medical illness and HCV treatment eligibility were compared in a case-control study of 80 MMT patients entering an HCV treatment trial and 80 matched non-MMT patients entering HCV treatment in a gastroenterology clinic. 91% of MMT and 85% of non-MMT patients had chronic medical conditions. Despite similar medical severity ratings, a significantly higher proportion (77%) of non-MMT patients were eligible for HCV treatment than were MMT patients (56%) (p<.01). Specific comorbid medical and psychiatric illness led to ineligibility in only 18% of MMT and 16% of non-MMT patients. However, failure to complete the medical evaluation process was significantly (p<.001) more likely to cause ineligibility among MMT patients (19%) than non-MMT patients (0%).

Methadone maintenance patients' knowledge, attitudes, beliefs, and experiences concerning treatment for hepatitis C virus infection.

Hepatitis C virus (HCV) knowledge, attitudes, beliefs, and experiences (KABE) of 64 HCV antibody positive methadone maintenance treatment (MMT) patients were assessed in conjunction with acceptability of an on-site semi-structured HCV education session, HCV RNA diagnostic testing, HCV treatment motivational assessment, and initiation of HCV treatment. The KABE interviews were conducted in 2006 and 2007 in an urban New York State MMT clinic in affiliation with a NIDA-funded HCV research project. The majority had basic knowledge of HCV disease, but poor understanding of HCV testing and treatment. While the majority of participants expressed fear of HCV treatment side effects, 88% accepted HCV RNA testing and 78% expressed willingness to start HCV treatment with the majority of chronically infected choosing to start HCV treatment medications. Study limitations and implications are discussed.

Health-related quality of life in methadone maintenance patients with untreated hepatitis C virus infection.

OBJECTIVE: To assess health-related quality of life (HRQOL) in methadone maintenance treatment (MMT) patients with untreated chronic HCV infection and to determine the clinical factors that predict HRQOL. METHOD: HRQOL was measured in 100 MMT patients entering an HCV treatment trial. Subjects were mostly male (61%) and white (81%) with a mean age of 43 (+/-10). 57% had a current non-substance use psychiatric disorder. 55% had a current (past 12 months) substance use disorder, including 44% with current opioid or cocaine abuse/dependence. HRQOL in our sample was compared to published reports for the general population as well as for non-MMT HCV patients. To assess predictors of SF-36 HRQOL, hierarchical multiple regression techniques were used to assess model improvement with four blocks of baseline predictors: Demographics, Medical Severity, Addiction Severity, and Depression Severity. RESULTS: HRQOL scores were significantly lower than scores for the general population and were also lower than scores reported for untreated HCV patients not in MMT. Regression analysis demonstrated a consistent pattern whereby Depression Severity increased predictive accuracy for HRQOL measures over simpler models. Beck Depression Inventory scores significantly predicted quality of life across both the mental and physical composite scores and all eight sub-scales of the SF-36. CONCLUSIONS: Untreated HCV patients in MMT had lower HRQOL than HCV patients not in MMT. Depression Severity was associated with significantly lower quality of life measures, suggesting that psychiatric evaluation and intervention prior to the start of HCV treatment may improve overall quality of life and could influence HCV treatment outcomes in MMT patients.

Medical comorbidity in patients with schizophrenia and alcohol dependence.

BACKGROUND: Schizophrenia and alcohol dependence are major risk factors for a variety of medical problems, yet there has been little research on the medical status of patients in whom both conditions coexist. METHODS: We assessed the prevalence and severity of medical illness in 80 patients with schizophrenia or schizoaffective disorder and comorbid alcohol use disorders who entered a controlled trial of monitored naltrexone treatment, and analyzed the relationship between medical illness burden and demographic variables, alcohol and other substance use, and psychosis. Participants underwent physical examination, laboratory tests, medical record review and standardized assessments of medical illness burden, alcohol and other substance use, and psychosis. Nested block multiple regression analyses were used to assess the contribution to illness burden made by demographic variables, alcohol and substance use, and psychosis severity. RESULTS: 83% of participants had at least one chronic medical illness, hypertension being the most common (43%). Medical comorbidity in this cohort was more severe than for schizophrenia patients in the CATIE trial (Chwastiak, L., Rosenheck, R., McEvoy, J.P., Keefe, R.S., Swartz, M.S., Lieberman, J.A., 2006. Interrelationships of Psychiatric Symptom Severity, Medical Comorbidity, and Functioning in Schizophrenia. Psychiatr. Serv., 57(8), 1102-1109.); the prevalence of hypertension, chronic obstructive pulmonary disease, and coronary artery disease, was more than twice greater. Medical illness burden correlated with alcohol use severity, but appeared to be independent of other substance use or psychosis severity. CONCLUSIONS: Patients with co-occurring alcohol use disorder may have significantly more medical illness burden than patients with schizophrenia or schizoaffective disorder alone. Interventions to reduce alcohol use may be necessary to lessen medical morbidity.