Evaluation of heterogeneity in pharmacotherapy trials for drug dependence: a Bayesian approach.

AIMS: Difficulty identifying effective pharmacotherapies for cocaine dependence has led to suggestions that subgroup differences may account for some of the heterogeneity in treatment response. Well-attested methodological difficulties associated with these analyses recommend the use of Bayesian statistical reasoning for evaluation of salient interaction effects. METHODS: A secondary data analysis of a previously published, double-blind, randomized controlled trial examines the interaction of decision-making, as measured by the Iowa Gambling Task, and citalopram in increasing longest sustained abstinence from cocaine use. RESULTS: Bayesian analysis indicated that there was a 99% chance that improved decision-making enhances response to citalopram. Given the strong positive nature of this finding, a formal, quantitative Bayesian approach to evaluate the result from the perspective of a skeptic was applied. CONCLUSIONS: Bayesian statistical reasoning provides a formal means of weighing evidence for the presence of an interaction in scenarios where conventional, Frequentist analyses may be less informative. [Supplementary materials are available for this article. Go to the publisher's online edition of The American Journal of Drug and Alcohol Abuse for the following free supplemental resource: Appendix 1].

Attenuation of angiotensin II- and III-induced aldosterone release by prostaglandin synthesis inhibitors.

The effect of two prostaglandin synthesis inhibitors, indomethacin and meclofenamate, on angiotensin II (AII)- and III (AIII)-induced aldosterone release was studied in normal and sodium-depleted conscious rats and in adrenal capsular cell suspensions obtained from normal rats. In normal rats, in vivo AII and AIII were equipotent in causing dose-related increases in serum aldosterone concentrations. Indomethacin decreased the basal serum aldosterone levels by 50% and serum renin levels by 43%. In addition, the steroidogenic effects of AII and AIII were reduced by 45 and 63% with 3 mg/kg of indomethacin and 63 and 73% with 10 mg/kg, respectively. In contrast, meclofenamate failed to alter basal serum levels of aldosterone or AII-stimulated aldosterone release but inhibited serum renin levels by 27% and the aldosterone-stimulating effect of AIII by 99%. Indomethacin (3 mg/kg) and meclofenamate (2 mg/kg) inhibited urinary prostaglandin (PG)E(2) and PGF(2alpha) excretion by 63 and 52% and 37 and 31%, respectively. Both inhibitors significantly decreased the adrenal capsular PGE(2) and PGF(2alpha) content and the conversion of [(14)C]arachidonate to [(14)C]PGE(2) and [(14)C]PGF(2alpha). In sodium-depleted rats, indomethacin produced similar effects reducing the control serum aldosterone levels by 29%, AII-stimulated aldosterone by 47%, and completely suppressing the aldosterone response to AIII without altering serum renin activity. In adrenal cell suspensions, similar results were observed with indomethacin inhibiting basal and AII- and AIII-stimulated aldosterone release by 29, 81, and 93%, respectively. Meclofenamate failed to alter basal and AII-stimulated aldosterone release but inhibited that stimulated by AIII by 86%. The present findings suggest that prostaglandins modulate the effects of the renin-angiotensin system by stimulating the release of renin from the kidney and augmenting the steroidogenic effects of AII and AIII in the adrenal cortex.

Bupropion and naltrexone for smoking cessation: A double-blind randomized placebo-controlled clinical trial.

Combination of non-nicotine pharmacotherapies has been underexamined for cigarette smoking cessation. A randomized, double-blind, parallel-group double-dummy study evaluated two medications, bupropion (BUP) and naltrexone (NTX), in treatment-seeking cigarette smokers (N = 121) over a 7-week treatment intervention with 6-month follow-up. Smokers were randomized to either BUP (300 mg/day) + placebo (PBO) or BUP (300 mg/day) + NTX (50 mg/day). The primary outcome was biochemically verified (saliva cotinine, carbon monoxide) 7-day, point-prevalence abstinence. BUP + NTX was associated with significantly higher point-prevalence abstinence rates after 7-weeks of treatment (BUP + NTX, 54.1%; BUP + PBO, 33.3%), P = 0.0210, but not at 6-month follow-up (BUP + NTX, 27.9%; BUP + PBO, 15.0%), P = 0.09. Continuous abstinence rates did not differ, P = 0.0740 (BUP + NTX, 26.2%; BUP + PBO, 13.3%). Those receiving BUP + NTX reported reduced nicotine withdrawal, P = 0.0364. The BUP + NTX combination was associated with elevated rates of some side effects, but with no significant difference in retention between the groups.

(Des-Asp1) angiotensin I: a study of its pressor and steroidogenic activities in conscious rats.

The steroidogenic and pressor activities of the nonapeptide (des-Asp1) angiotensin I [(des-Asp)-AI] were tested in conscious rats. (des-Asp)-AI caused dose related increases in mean arterial pressure (MAP), serum aldosterone, and serum corticosterone in doses between 3 and 3,000 ng/kg/min. (des-Asp)-AI was 14% as potent as angiotensin I and angiotensin II and 60% as potent as (des-Asp1) angiotensin II [des-Asp)-AII] in raising MAP. (des-Asp)-AI was less active than AI, AII, or (des-Asp)-AII in causing increased release of aldosterone, possessing only 8%, 11%, and 17% of the potency of AII, (des-Asp)-AII, and AI, respectively. Each of these angiotensin peptides was equally potent in elevating serum corticosterone levels. Infusions of a nonapeptide inhibitor of converting enzyme (CEI, 0.5 mg/kg/min iv) did not alter control MAP or blood pressure responses to AII or (des-Asp-)-AII but inhibited equally the blood pressure effects of AI and (des-Asp)-AI. CEI also inhibited the ability of (des-Asp)-AI (67% inhibition) and AI (34% inhibition) to increase the serum aldosterone concentration, but had no effect on basal aldosterone levels. These data indicate that (des-Asp)-AI has pressor and steroidogenic effects, but requires conversion to (des-Asp)-AII for a major portion of its activity. These results further substantiate the hypothesis that (des-Asp)-AII, recently recognized as a hormone of the renin-angiotensin system, may be produced without the formation of AII as an intermediate and provide in vivo evidence for the conversion of (des-Asp)-AI to (des-Asp)-AII.

Psychiatric aspects of impulsivity.

OBJECTIVE: The authors discuss the relationship of impulsivity to psychiatric disorders and present selected hypotheses regarding the reasons for these relationships. METHOD: Previous research has shown significantly higher levels of impulsivity among patients with conduct disorder, personality disorders, substance use disorders, and bipolar disorder, compared to other psychiatric patients or healthy comparison subjects. A literature review of the theoretical bases of the relationship between these disorders and impulsivity is presented. Measurements of impulsivity and treatment options are discussed in relation to the physiology of impulsivity and the disorders in which it is a prominent feature. RESULTS: Impulsivity, as defined on the basis of a biopsychosocial approach, is a key feature of several psychiatric disorders. Behavioral and pharmacological interventions that are effective for treating impulsivity should be incorporated into treatment plans for these disorders. CONCLUSIONS: The high comorbidity of impulsivity and selected psychiatric disorders, including personality disorders, substance use disorders, and bipolar disorder, is in a large part related to the association between impulsivity and the biological substrates of these disorders. Before treatment studies on impulsivity can move forward, measures of impulsivity that capture the core aspects of this behavior need to be refined and tested on the basis of an ideologically neutral model of impulsivity.

Changes in Helicobacter pylori-induced gastritis in the antrum and corpus during 12 months of treatment with omeprazole and lansoprazole in patients with gastro-oesophageal reflux disease.

BACKGROUND: Several studies have shown that treatment with omeprazole leads to aggravation of Helicobacter pylori gastritis in the corpus. Whether this also applies to lansoprazole, and whether, in comparison with omeprazole, there are differences in therapy-induced gastritis parameter changes remains unclear. METHODS: In 111 patients infected with H. pylori and with gastro-oesophageal reflux disease we investigated the gastritis parameters in antral and corpus mucosa before and after 2, 6 and 12 months of treatment with 15 or 30 mg lansoprazole or 20 mg omeprazole/day. RESULTS: In all groups the different treatments had a similar effect: in both regions of the stomach, suppression or partial elimination of H. pylori was seen. However, improvement in the inflammation was observed only in the antrum, while in the corpus most gastritis parameters worsened significantly. There was no increase in intestinal metaplasia or atrophy. CONCLUSION: In common with omeprazole, lansoprazole aggravates the gastritis parameters in the corpus but improves them in the antrum. Treatment with proton pump inhibitors does not result in any increase in the incidence of atrophy/intestinal metaplasia. However, as gastritis predominating in the corpus seems to be associated with an elevated carcinogenic risk, consideration should be given to prophylactic H. pylori eradication therapy before initiating proton pump inhibitor treatment.

(7-Ile) angiotensin III: a relatively selective antagonist of angiotensin steroidogenesis.

The effects of (7Ile) angiotensin III (AIII) and (1-Sar-8-Ile) angiotensin II (AII) on the pressor and steroidogenic effects of angiotensin were compared in conscious rats. (1-Sar-8-Ile) AII (500 ng/kg/min) equally inhibited the pressor responses of AII, AIII and (des-1-Asp) AI by 99% (P less than 0.0001) while (7-Ile) AIII (500 ng/kg/min) was without effect. The steroidogenic effects of AII, AIII and (des-1-Asp) AI (300 ng/kg/min) were inhibited by (1-Sar-8-Ile) AII by 83%, 69% and 50%, respectively, whereas (7-Ile) AIII inhibited their steroidogenic effects by 35%, 62% and 25%. respectively. In contrast, ACTH or potassium stimulated aldosterone release was not altered by either antagonist. In sodium depleted rats, (7-Ile) AII reduced the elevated serum aldosterone levels by 64% without altering the blood pressure, while (1-Sar-8-Ile) AII lowered the blood pressure without altering the concentration of aldosterone present in the serum. Thus, (7-Ile) AIII is relatively selective in its ability to antagonize the adrenal actions of endogenous and exogenous angiontensins when compared to the pressor actions of these peptides. Furthermore, these angiotensin antagonists appear to be useful as pharmacologic tools in assessing the characteristics of the angiotensin receptors in a particular tissue.

Eicosapentaenoic acid alters vascular reactivity and platelet adhesion in Watanabe heritable hyperlipidemic rabbits.

Feeding a diet rich in eicosapentaenoic acid (EPA) to Watanabe heritable hyperlipidemic (WHHL) rabbits resulted in an attenuated aortic contractile response to the vasoconstrictor agent serotonin when compared to responses from WHHL rabbits fed normal rabbit chow. In contrast, only the maximal contractile response to norepinephrine was reduced in EPA-fed rabbit aortas. Additionally, methacholine-induced relaxations were potentiated in aortas obtained from the EPA-fed rabbits. When platelets obtained from EPA-fed rabbits were incubated with arachidonic acid, there was a reduced ability of the platelets to adhere to albumin-coated discs in comparison to control rabbit platelets. These data indicate a potentially beneficial effect of EPA in atherosclerotic WHHL rabbits.

A fine-grained analysis of the role of self-efficacy in self-initiated attempts to quit smoking.

The relation between self-efficacy ratings and smoking behavior was explored among 36 people who were trying to quit smoking on their own. Ss self-monitored high-risk situations, coping efforts to withstand the temptation to smoke, and self-efficacy in coping with similar temptations for 4 weeks after quitting. Self-efficacy ratings were significantly related to the outcome of these situations, with Ss reporting higher efficacy ratings after situations in which they did not smoke as opposed to those in which they did smoke. Self-efficacy was predictive of smoking outcome, but there was considerable intersubject variability in the strength of the relation between efficacy and smoking behavior. Both efficacy and previous smoking behavior predicted smoking outcome equally well, however.

Motivational interviewing with cocaine-dependent patients: a pilot study.

A brief motivational interviewing (MI) intervention was evaluated within the context of an outpatient, cocaine-detoxification program. MI was hypothesized to assist patients in completing the detoxification program and to improve outcomes during subsequent treatment. Participants (N = 105) were randomly assigned to MI or to detox-only conditions. Results indicated that although participants completed the detoxification program at equal rates, completers who received MI increased use of behavioral coping strategies and had fewer cocaine-positive urine samples on beginning the primary treatment. MI patients with lower initial motivation were more likely to complete detoxification.

The effects of high and low doses of methadone on cigarette smoking.

The effect of methadone dose on the cigarette smoking of five methadone maintenance subjects was studied in a clinical setting. Following a two-week baseline period, daily doses of methadone were either increased (50-80 mg) or decreased (80-50 mg) every two weeks according to an A-B-A-B study design. Continuous self-monitoring was used to collect data on natural smoking behavior, and expired air carbon monoxide (CO) levels were measured at each clinic visit. The predicted methadone dose-related changes in smoking were found in three of the five subjects. Fine-grained analysis of self-monitoring records showed that the proportion of total daily smoking was highest within 4 h after taking methadone for three subjects. CO levels were not significantly associated with smoking rate. The results further support and extend previous reports that methadone may produce dose-related increases in smoking. No reactive effects of self-monitoring were observed, and compliance with this procedure was extremely high, supporting the usefulness of this method for assessing natural smoking behavior in this population.

Treatment outcome of cocaine-alcohol dependent patients.

Cocaine dependent patients (n = 27) with and without concurrent alcohol dependence disorder were compared on measures of substance use, addiction severity (ASI), coping, and psychopathology taken before, during, and after outpatient relapse prevention treatment for cocaine dependence. At pre-treatment, the cocaine-alcohol (CA) group reported more frequent alcohol use, and more severe alcohol and family/social problems compared to the cocaine-only (CO) group. By the end of treatment, both groups reported significantly fewer days of alcohol and cocaine use, with sustained reductions observed at 24 weeks following treatment. On most of the addiction severity and psychiatric symptomatology scales, results indicated overall improvement as a function of time, however scores remained relatively 'worse' in the CA group. Implication of these findings and the need for specific programming in the treatment of dual drug use are explored.

Fluoxetine treatment of cocaine-dependent patients with major depressive disorder.

Sixty-eight male and female individuals with both DSM-IV diagnoses of cocaine dependence and major depressive disorder were randomly assigned to one of two medication conditions (placebo vs. 40 mg per day) as part of a double-blind, placebo-controlled clinical efficacy trial of fluoxetine for the treatment of this dual diagnosis. During the 12-week outpatient treatment phase all participants also received individual cognitive-behavioral psychotherapy targeting both cocaine use and depression. Depressive symptoms remitted as a function of time in treatment, with no significant medication effects found. Fewer cocaine positive urines were found during the first 6 weeks of treatment in the placebo group compared with the 40-mg group. Cocaine use and depressive symptoms during treatment were significantly correlated. The findings fail to support the role of fluoxetine for treatment of cocaine use and depression in dually-diagnosed patients.

Cocaine dependence with and without comorbid depression: a comparison of patient characteristics.

This study compared depressed cocaine dependent patients (CD, N=50) with patients who were cocaine dependent only (CO, N=101) on pre-treatment psychiatric symptomatology, substance use, and psychosocial functioning. Results indicated that the CD group had more overall distress and poorer psychiatric functioning than the CO group. CD individuals scored higher on all subscales of the SCL-90-R, had a higher prevalence of antisocial personality disorder, reported higher craving for cocaine, lower self-efficacy to refrain from drug use, and lower perceived social support. These findings support the need for more intensive treatment approaches for dually-diagnosed patients.

Gastric polyps as precancerous lesions.

Gastric polyps cover a wide range of possible diagnoses. Endoscopically, the nature of the lesions can be diagnosed with a high level of probability. Nevertheless, histopathological diagnosis remains mandatory. The macroscopic appearance of gastric polyps is described together with underlying histopathological diagnoses, which are determinative for subsequent treatment.

Plasma serotonin concentrations: validation of a sampling technique using long catheters.

Serotonin is released by activated platelets and may promote platelet aggregation and epicardial coronary artery constriction in animal models. Serotonin may have similar effects in humans and, thus may be a mediator of certain ischemic syndromes. However, the role of serotonin in human ischemic heart disease has not been studied. Since evaluation of transcardiac serotonin metabolism requires that blood samples be obtained through long catheters, it is possible that artifactual changes in serotonin concentration could occur because of platelet activation in the catheters themselves. Accordingly, to determine if serotonin could be measured through long catheters without artifactual changes, the authors obtained paired blood samples by gentle aspiration through a large bore steel needle and a 100-cm polyurethane catheter placed in the femoral vein of 13 patients. All samples were processed to obtain platelet-poor plasma and then analyzed by a sensitive radioenzymatic assay. Blood sampling through long catheters did not cause a systematic alteration in plasma serotonin concentration. Mean serotonin concentration from the femoral vein through a needle was 22.3 +/- 26.55 ng/ml (mean +/- standard deviation), and that obtained through a long catheter was 20.0 +/- 26.29 ng/ml (p = 0.34). The authors conclude that carefully obtaining blood samples through long catheters does not significantly alter the plasma serotonin concentration and thus the accurate measurement of transcardiac serotonin concentrations is possible using these methods.

A menu of potential reinforcers in a methadone maintenance program.

This study demonstrates the use of paired comparisons and interval scaling techniques for measuring the relative priority of program privileges available at a methadone maintenance clinic. Fifteen methadone program privileges were combined in all possible pairs (N = 105) on a reinforcer menu and administered to a group of 12 methadone patients and a second group of counselors (N = 4). Data were converted to interval scales using the law of comparative judgment to form a quantitative continuum from least to most preferable. Free methadone, free dental service, and more take-homes were ranked highest in both groups; however, patients showed less differentiation in their preference for these privileges. Dose decreases were least preferred. Results are discussed in terms of their clinical applicability in identifying privileges for potential use in modifying the behavior of drug abusers. The method of paired comparisons has excellent psychometric properties and may offer some advantages over other response scale formats.

The impact of impulsivity on cocaine use and retention in treatment.

To determine whether impulsivity was related to severity of drug use and treatment outcome, 50 cocaine dependent subjects underwent baseline measures of severity of current cocaine use and the Barratt Impulsiveness Scale (BIS-11). The hypothesis of the study was that there would be a significant correlation between impulsivity and cocaine use severity. As predicted, there was a significant correlation between BIS-11 total scores and self-reported average daily cocaine use as well as cocaine withdrawal symptoms. A subset of 35 patients underwent a 12-week double-blind placebo controlled trial of buspirone and group therapy. Subjects with high baseline impulsivity remained in the study a significantly shorter period than did subjects with lower baseline impulsivity. This study shows that impulsivity is a significant predictor of cocaine use and treatment retention, and suggests the need for targeting impulsivity in cocaine dependence treatment.

Comparison of different algorithms for evaluation of respiratory sinus arrhytmia: cross-correlation function histogram analysis and regression analysis.

Three algorithms for assessment of respiratory sinus arrhythmia (RSA) have been evaluated: cross-correlation function, histogram analysis and regression plot. The algorithms were tested experimentally in a group of 11 subjects. A cross-correlation function with a high time resolution (1 ms) was used for investigation of the time lag between instantaneous heart rate and respiration (CTL). This time lag was not affected by the breathing rate in a range of 8 to 29 breaths per minute. A mathematical model of CTL compared with experimental results indicates that respiratory sinus arrhythmia is probably modulated directly by the respiratory network in the brainstem rather than by a baroreflex in the range of breathing rate investigated. Histogram analysis reflects the impact of inspiration and expiration on respiratory sinus arrhythmia. For this purpose heart rate changes were separated into two distributions (inspiration-expiration). The result value (U-VAL) of the Mann-Whitney U-test reflects the impact of respiration on heart rate variability. Regression analysis of heart rate versus respiration shows that the heart rate increase is more closely coupled to inspiration than the heart rate decrease to expiration. Both, CTL and U-VAL are thought to be useful parameters for clinical investigation of RSA.

Medication take-home doses and contingency management.

Two studies examined contingent take-home medication doses during treatment of opiate or cocaine dependence. In the first study, methadone maintenance patients were randomly assigned to one of two 8-week baseline take-home (TH) conditions differing in frequency of clinic visits per week. This was followed by a 12-week contingency management (CM) procedure in which frequent THs resulted from drug-free urines. Participants receiving more frequent THs during baseline had lower illicit drug use during the first 6 weeks of CM. In the second study, fluoxetine (0-, 20-, 40-mg) TH doses were similarly contingent in treatment of cocaine dependence. The 40-mg group used less cocaine during contingency than did other groups. The combination of fluoxetine and environmental contingencies may produce benefit where neither alone is sufficient.