Elizabeth Ralevski

Naltrexone and Disulfiram in Patients with Alcohol Dependence and Comorbid Post-Traumatic Stress Disorder

BACKGROUND Although disulfiram and naltrexone have been approved by the Food and Drug Administration for the treatment of alcoholism, the effect of these medications on alcohol use outcomes and on psychiatric symptoms is still unknown in patients with co-occurring disorders post-traumatic stress disorder (PTSD). METHODS Patients (n = 254) with a major Axis I psychiatric disorder and comorbid alcohol dependence were treated for 12 weeks in a medication study at three Veterans Administration outpatient clinics. Randomization included (1) open randomization to disulfiram or no disulfiram; and (2) double-blind randomization to naltrexone or placebo. This resulted in four groups: (1) naltrexone alone; (2) placebo alone; (3) disulfiram and naltrexone; or (4) disulfiram and placebo. Outcomes were measures of alcohol use, PTSD symptoms, alcohol craving, GGT levels and adverse events. RESULTS 93 individuals (36.6%) met DSM-IV criteria for PTSD. Subjects with PTSD had better alcohol outcomes with active medication (naltrexone, disulfiram or the combination) than they did on placebo; overall psychiatric symptoms of PTSD improved. Individuals with PTSD were more likely to report some side effects when treated with the combination. CONCLUSIONS The results of this study suggest that disulfiram and naltrexone are effective and safe for individuals with PTSD and comorbid alcohol dependence.

Nocturnal melatonin and 24-hour 6-sulphatoxymelatonin levels in various phases of bipolar affective disorder

Nine bipolar patients (2 men and 7 women) and 12 healthy control subjects completed overnight sampling for serum melatonin (MT) and urinary 6-sulphatoxymelatonin (aMT6s). The patients were investigated during manic, depressed, and/or euthymic states. Although serum MT levels did not differ significantly across the bipolar groups, in all cases serum MT levels were significantly lower than in control subjects. Differences in MT levels were also present between bipolar patients who were in a depressed phase and control subjects. There were no statistically significant differences in urinary aMT6s levels among the patients and control subjects, although in all cases nocturnal aMT6s levels were significantly higher than daytime levels. This study provides tentative evidence for decreased serum MT as a trait but not a state marker in bipolar affective disorder.

Noradrenergic vs Serotonergic Antidepressant with or without Naltrexone for Veterans with PTSD and Comorbid Alcohol Dependence

The wars in Iraq and Afghanistan are associated with high rates of post-traumatic stress disorder (PTSD) and comorbid alcohol use disorders. The pharmacotherapy of these comorbid conditions has received relatively little study. The current study compared the serotonin uptake inhibitor, paroxetine, to the norepinephrine uptake inhibitor, desipramine. It also evaluated the adjunctive efficacy of the Food and Drug Administration (FDA)-approved alcoholism pharmacotherapy, naltrexone, relative to placebo. Four groups of predominately male veterans (n=88) meeting current diagnostic criteria for both alcohol dependence (AD) and PTSD were randomly assigned under double-blind conditions to one of four groups: paroxetine+naltrexone; paroxetine+placebo; desipramine+naltrexone; desipramine+placebo. Main outcome measures included standardized scales that assessed symptoms of PTSD and alcohol consumption. Paroxetine did not show statistical superiority to desipramine for the treatment of PTSD symptoms. However, desipramine was superior to paroxetine with respect to study retention and alcohol use outcomes. Naltrexone reduced alcohol craving relative to placebo, but it conferred no advantage on drinking use outcomes. Although the serotonin uptake inhibitors are the only FDA-approved medications for the treatment of PTSD, the current study suggests that norepinephrine uptake inhibitors may present clinical advantages when treating male veterans with PTSD and AD. However, naltrexone did not show evidence of efficacy in this population. This study was registered with ClinicalTrials.gov, registration number NCT00338962 and URL: http://clinicaltrials.gov/ct2/show/NCT00338962?term=desipramine+AND+alcohol+dependence+AND+depression&recr=Closed&rank=1.

Avoidant personality disorder and social phobia : distinct enough to be separate disorders?

Objective:  Existing evidence from anxiety disorder research indicates that social phobics (SP) with avoidant personality disorder (AVPD) experience more anxiety and show more impairment than patients with SP alone. The purpose of this study was to examine whether in patients diagnosed with AVPD, the co‐occurrence of SP adds to its severity. We hypothesized that the addition of SP will not add to the severity of AVPD alone.

The Role of Personality Factors in the Reporting of Side Effect Complaints to Moclobemide and Placebo: A Study of Healthy Male and Female Volunteers

Although there is good evidence of a relationship between certain personality factors (viz. neuroticism and hypochondriasis) in the reporting of somatic symptoms-both in clinical and in nonclinical research-the recognition of the moderating role of individual differences in the frequency and intensity of side effect reporting is virtually absent from drug trial research. This study was a double-blind moclobemide-versus-placebo trial, the purpose of which was twofold: to investigate the degree of side effect complaints in a sample of healthy nonclinical men and women and to assess the role of personality in symptom reporting. Although there was no overall difference between the groups with respect to side effect complaints, there was a highly significant neuroticism x group x time interaction. In both groups, we found the expected positive relationship between neuroticism and symptom reporting at baseline. At the end of the study, however, this relationship was close to zero in the moclobemide group and had increased to close to 0.60 in the placebo group. These results were essentially replicated when neuroticism was substituted in the regression model by a psychometric measure of hypochondriasis. Our findings provide a striking demonstration of the role of personality factors in the placebo adverse response. As well, they indicate that adverse reactions to the medication were also linked to personality differences. Taken together, our results underscore the importance of considering individual differences in all aspects of pharmacologic research that involve subjective interpretation on the part of patients and subjects.

Naltrexone and disulfiram in patients with alcohol dependence and current depression.

Objective: Although disulfiram and naltrexone have been approved by the Food and Drug Administration for the treatment of alcoholism, no medications have been approved for individuals with alcohol dependence and comorbid psychiatric disorders. In particular, the effect of these medications on alcohol use outcomes and on specific psychiatric symptoms is still unknown in patients with the most common co-occurring disorder, major depression. Method: Two hundred fifty-four patients with a major Axis I psychiatric disorder and comorbid alcohol dependence were treated for 12 weeks in an outpatient medication study conducted at 3 Veterans Administration outpatient clinics. Randomization included (1) open randomization to disulfiram or no disulfiram, and (2) double-blind randomization to naltrexone or placebo. This resulted in 4 groups: (1) naltrexone alone, (2) placebo alone, (3) disulfiram and naltrexone, and (4) disulfiram and placebo. Primary outcomes were measures of alcohol use. Secondary outcomes included psychiatric symptoms assessed by the Hamilton Depression Rating Scale, alcohol craving, γ-glutamyltransferase levels, and adverse events. Results: One hundred thirty-nine subjects (54.7%) met the current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depression. There was no relationship between the diagnosis of depression and medication treatment on alcohol use outcomes, psychiatric symptoms, or the reporting of side effects for these medications. There was a significant interaction between diagnosis, medication group, and craving, where subjects with depression on disulfram reported lower craving over time than subjects with depression on naltrexone. Conclusions: The results suggest that disulfiram and naltrexone are safe pharmacotherapeutic agents for dually diagnosed individuals with depression for the treatment of alcohol use disorders.

Ethyl Glucuronide and Ethyl Sulfate Assays in Clinical Trials, Interpretation, and Limitations: Results of a Dose Ranging Alcohol Challenge Study and 2 Clinical Trials

BACKGROUND The ethanol metabolites, ethyl glucuronide (EtG) and ethyl sulfate (EtS), are biomarkers of recent alcohol consumption that provide objective measures of abstinence. Our goals are to better understand the impact of cutoff concentration on test interpretation, the need for measuring both metabolites, and how best to integrate test results with self-reports in clinical trials. METHODS Subjects (n = 18) were administered, 1 week apart, 3 alcohol doses calibrated to achieve blood concentrations of 20, 80, and 120 mg/dl, respectively. Urinary EtG/EtS was measured at timed intervals during a 24-hour hospitalization and twice daily thereafter. In addition, participants from 2 clinical trials provided samples for EtG/EtS and drinking histories. Cutoffs for EtG/EtS of 100/50, 200/100, and 500/250 ng/ml were evaluated. RESULTS Twelve hours following each challenge, EtG was always positive at the 100 and 200 cutoffs, but at 24 hours sensitivity was poor at all cutoffs following the low dose, and poor after 48 hours regardless of dose or cutoff. Similarly, in the clinical trials EtG sensitivity was good for detecting any drinking during the last 24 hours at the 2 lowest cutoffs, but under 40% during the last 24 to 48 hours. Sensitivity was reduced at the 500 ng/ml cutoff. Discrepancies between EtG and EtS were few. Comparison of self-reports of abstinence and EtG-confirmed abstinence indicated underreporting of drinking. CONCLUSIONS Any drinking the night before should be detectable the following morning with EtG cutoffs of 100 or 200 ng/ml. Twenty-four hours after drinking, sensitivity is poor for light drinking, but good for heavier consumption. At 48 hours, sensitivity is low following 6 drinks or less. Increasing the cutoff to 500 ng/ml leads to substantially reduced sensitivity. Monitoring both EtG and EtS should usually be unnecessary. We recommend EtG-confirmed self-reports of abstinence for evaluation of outcomes in clinical trials.

Assessment of personality disorders in anorexia nervosa and bulimia nervosa. A comparison of self-report and structured interview methods.

Interest in assessing Personality Disorders (PDs) in association with anorexia nervosa (AN) and bulimia nervosa (BN) has been accompanied by the development of several structured interview and self-report measures. In an attempt to see how the self-report Millon Clinical Multiaxial Inventory (MCMI-II) compared with the Structured Clinical Interview for DSM-III-R (SCID-II) in the assessment of PDs, we gave both instruments to 43 inpatients with a diagnosis of AN or BN. Correlation coefficient values for both categorical and dimensional comparisons were generally less than .4. Although comparable rates of positive PDs occurred for each of the three clusters (A: 30.2% vs. 34.9%, B: 25.6% vs. 18.6%, and C: 62.8% vs. 81.4% for SCID-II vs. MCMI-II), agreement for individual diagnosis and individual subjects was poor. In conclusion, the MCMI-II did not prove to be a reliable instrument for assessing axis II PDs in patients with AN and BN when compared with the SCID-II.

The Impact of Personality Disorders on Alcohol‐Use Outcomes in a Pharmacotherapy Trial for Alcohol Dependence and Comorbid Axis I Disorders

Although antisocial and borderline personality disorders frequently co-occur with alcohol dependence and other Axis I disorders, their effect on alcohol use outcomes in context of pharmacotherapy remains unclear. Patients with Major Axis I disorders, including alcohol dependence, and diagnosis of antisocial (ASPD) or borderline personality disorder (BPD) were enrolled in a 12-week medication trial for treatment of their alcohol dependence. Everyone was randomized to one of four cells: naltrexone alone, placebo alone, open label disulfiram and naltrexone, or open label disulfiram and placebo. Outcome measures included scales for alcohol use and craving. Data were analyzed comparing patients with ASPD vs. those without, and patients with BPD vs. those without. Diagnosis of personality disorder did not adversely affect alcohol outcomes, and patients with ASPD or BPD did not have a poorer response to medication than patients without diagnosis of ASPD or BPD. The findings suggest that naltrexone and disulfiram can be safely and effectively used with patients who have comorbid diagnoses of Axis I and Axis II disorders.

The effects of moclobemide on sexual desire and function in healthy volunteers.

Decreased sexual desire is a recognized symptom of major depression (MD). Disturbances in sexual function, although reported in drug = free patients, have more often been viewed as adverse drug effects during antidepressant treatment with established classes of antidepressants (TCA, MAOI, SSRI). However, it is difficult to draw conclusions about the effects of antidepressants on sexual desire and function for two reasons: lack of standardised assessments for sexual function; inability to distinguish depression-related symptoms from drug-induced sexual disturbances. The purpose of this study was to examine the effects of moclobemide (a RIMA antidepressant) on sexual function in healthy male and female volunteers. Sixty male and female volunteers were randomly assigned to either moclobemide 300 mg or placebo for 3 weeks. They were seen at weekly intervals to assess drug compliance and to complete a 10-item sexual function questionnaire (SFQ). In both men and women there were no differences between moclobemide and placebo on measures of sexual desire and function. However, men and women differed in the levels of reported interest and sexual performance.