Robert M. Anthenelli

The role of oxygen-free radicals in ischemic tissue injury in island skin flaps.

The contribution of free radical-mediated reperfusion injury to the ischemic damage caused by total venous occlusion of island skin flaps was investigated in a standardized rat model. Control flaps subjected to 8 hours of total venous occlusion showed complete, full thickness necrosis when followed for 7 days following release of the vascular occlusion. Treatment with superoxide dismutase, a scavenger of superoxide radicals, prior to and immediately following the onset of reperfusion, significantly enhanced island flap survival from 0/11 (0%) to 8/15 (53%), p < 0.005, and from 0/9 (0%) to 6/12 (50%), p < 0.02, respectively. These findings are consistent with the hypothesis that oxygen free radicals generated at the time of reperfusion following a period of ischemia contribute significantly to the ultimate damage caused by ischemic injury. Such findings are consistent with similar reported observations on other tissues and suggest a means by which ischemic tissue injury might be therapeutically modified, even after the period of ischemia.

Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial.

BACKGROUND Substantial concerns have been raised about the neuropsychiatric safety of the smoking cessation medications varenicline and bupropion. Their efficacy relative to nicotine patch largely relies on indirect comparisons, and there is limited information on safety and efficacy in smokers with psychiatric disorders. We compared the relative neuropsychiatric safety risk and efficacy of varenicline and bupropion with nicotine patch and placebo in smokers with and without psychiatric disorders. METHODS We did a randomised, double-blind, triple-dummy, placebo-controlled and active-controlled (nicotine patch; 21 mg per day with taper) trial of varenicline (1 mg twice a day) and bupropion (150 mg twice a day) for 12 weeks with 12-week non-treatment follow-up done at 140 centres (clinical trial centres, academic centres, and outpatient clinics) in 16 countries between Nov 30, 2011, and Jan 13, 2015. Participants were motivated-to-quit smokers with and without psychiatric disorders who received brief cessation counselling at each visit. Randomisation was computer generated (1:1:1:1 ratio). Participants, investigators, and research personnel were masked to treatment assignments. The primary endpoint was the incidence of a composite measure of moderate and severe neuropsychiatric adverse events. The main efficacy endpoint was biochemically confirmed continuous abstinence for weeks 9-12. All participants randomly assigned were included in the efficacy analysis and those who received treatment were included in the safety analysis. The trial is registered at ClinicalTrials.gov (number NCT01456936) and is now closed. FINDINGS 8144 participants were randomly assigned, 4116 to the psychiatric cohort (4074 included in the safety analysis) and 4028 to the non-psychiatric cohort (3984 included in the safety analysis). In the non-psychiatric cohort, 13 (1·3%) of 990 participants reported moderate and severe neuropsychiatric adverse events in the varenicline group, 22 (2·2%) of 989 in the bupropion group, 25 (2·5%) of 1006 in the nicotine patch group, and 24 (2·4%) of 999 in the placebo group. The varenicline-placebo and bupropion-placebo risk differences (RDs) for moderate and severe neuropsychiatric adverse events were -1·28 (95% CI -2·40 to -0·15) and -0·08 (-1·37 to 1·21), respectively; the RDs for comparisons with nicotine patch were -1·07 (-2·21 to 0·08) and 0·13 (-1·19 to 1·45), respectively. In the psychiatric cohort, moderate and severe neuropsychiatric adverse events were reported in 67 (6·5%) of 1026 participants in the varenicline group, 68 (6·7%) of 1017 in the bupropion group, 53 (5·2%) of 1016 in the nicotine patch group, and 50 (4·9%) of 1015 in the placebo group. The varenicline-placebo and bupropion-placebo RDs were 1·59 (95% CI -0·42 to 3·59) and 1·78 (-0·24 to 3·81), respectively; the RDs versus nicotine patch were 1·22 (-0·81 to 3·25) and 1·42 (-0·63 to 3·46), respectively. Varenicline-treated participants achieved higher abstinence rates than those on placebo (odds ratio [OR] 3·61, 95% CI 3·07 to 4·24), nicotine patch (1·68, 1·46 to 1·93), and bupropion (1·75, 1·52 to 2·01). Those on bupropion and nicotine patch achieved higher abstinence rates than those on placebo (OR 2·07 [1·75 to 2·45] and 2·15 [1·82 to 2·54], respectively). Across cohorts, the most frequent adverse events by treatment group were nausea (varenicline, 25% [511 of 2016 participants]), insomnia (bupropion, 12% [245 of 2006 participants]), abnormal dreams (nicotine patch, 12% [251 of 2022 participants]), and headache (placebo, 10% [199 of 2014 participants]). Efficacy treatment comparison did not differ by cohort. INTERPRETATION The study did not show a significant increase in neuropsychiatric adverse events attributable to varenicline or bupropion relative to nicotine patch or placebo. Varenicline was more effective than placebo, nicotine patch, and bupropion in helping smokers achieve abstinence, whereas bupropion and nicotine patch were more effective than placebo. FUNDING Pfizer and GlaxoSmithKline.

A Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Varenicline for Smoking Cessation in Patients With Schizophrenia or Schizoaffective Disorder

OBJECTIVE Effective smoking cessation treatments are needed for patients with schizophrenia, who, compared with the general population, have high rates of cigarette smoking and more difficulty quitting. We evaluated the safety and efficacy of varenicline for smoking cessation in outpatients with stable schizophrenia or schizoaffective disorder. METHOD In this 12-week, randomized, double-blind, multicenter trial (May 8, 2008, to April 1, 2010), 127 smokers (≥ 15 cigarettes/d) with DSM-IV-confirmed schizophrenia or schizoaffective disorder received varenicline or placebo (2:1 ratio). The primary outcome was safety and tolerability of varenicline assessed by adverse events frequency and changes in ratings on the Positive and Negative Syndrome Scale and other psychiatric scales from baseline to 24 weeks. Abstinence was defined as no smoking 7 days prior to weeks 12 and 24, verified by carbon monoxide level. RESULTS Eighty-four participants received varenicline; 43, placebo. At 12 weeks (end of treatment), 16/84 varenicline-treated patients (19.0%) met smoking cessation criteria versus 2/43 (4.7%) for placebo (P = .046). At 24 weeks, 10/84 (11.9%) varenicline-treated and 1/43 (2.3%) placebo-treated patients, respectively, met abstinence criteria (P = .090). Total adverse event rates were similar between groups, with no significant changes in symptoms of schizophrenia or in mood and anxiety ratings. Rates of suicidal ideation adverse events were 6.0% (varenicline) and 7.0% (placebo) (P = 1.0). There was 1 suicide attempt by a varenicline patient with a lifetime history of similar attempts and no completed suicides. CONCLUSIONS Varenicline was well tolerated, with no evidence of exacerbation of symptoms, and was associated with significantly higher smoking cessation rates versus placebo at 12 weeks. Our findings suggest varenicline is a suitable smoking cessation therapy for patients with schizophrenia or schizoaffective disorder. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00644969.

Monoamine oxidases and tobacco smoking

Although nicotine has been identified as the main ingredient in tobacco responsible for aspects of the tobacco dependence syndrome, not all of the psychopharmacological effects of smoking can be explained by nicotine alone. Accumulating preclinical and clinical evidence has demonstrated that smoking also leads to potent inhibition of both types (A and B) of monoamine oxidase (MAO). Smokers have 30-40 % lower MAOB and 20-30 % lower MAOA activity than non-smokers. Reduced MAO activity in smokers has been shown by direct measures (platelets, positron emission tomographic studies) or by indirect measures (concentration of monoamine catabolites in plasma or CSF). We examine the hypothesis that chronic habitual smoking can be better understood in the context of two pharmacological factors: nicotine and reduced MAO activity. We speculate that MAO inhibition by compounds found in either tobacco or tobacco smoke can potentiate nicotines effects. Based on this concept, more effective anti-smoking drug strategies may be developed. As a practical consequence of tobacco smokes MAO-inhibitory properties, comparative psychiatric research studies need to screen and control for tobacco use.

A multi-site dose ranging study of nalmefene in the treatment of alcohol dependence

Abstract: The opiate antagonist nalmefene has been shown in 2 single-site studies to reduce alcohol consumption and relapse drinking in alcohol-dependent individuals. This safety and preliminary multisite efficacy study evaluated 3 doses of nalmefene (5, 20, or 40 mg) in a double-blind comparison to placebo over a 12-week treatment period in 270 recently abstinent outpatient alcohol-dependent individuals. Participants concomitantly received 4 sessions of a motivational enhancement therapy (with a medication compliance component) delivered from trained counselors. Although more subjects in the active medication groups terminated the study early secondary to adverse events, the rates did not differ significantly from that of placebo. The 20-mg/d group experienced more insomnia, dizziness, and confusion, while the 5-mg group also had more dizziness and the 40-mg group had more nausea than the placebo group. Most of these symptoms were mild and improved over time. Although all subjects had a reduction in heavy drinking days, craving, γ-glutamyl transferase, and carbohydrate-deficient transferrin concentrations over the course of the study, there was no difference between the active medication and placebo groups on these measures. The time to first heavy drinking day was also not significantly different between the placebo and the active treatment groups. This relatively small multisite trial showed that nalmefene was reasonably well tolerated in recently abstinent alcoholics. However, possibly because of variation among the sites or the comparatively small sample size, there was no evidence of superior efficacy outcomes with nalmefene treatment.

Effects of Varenicline on Smoking Cessation in Adults With Stably Treated Current or Past Major Depression: A Randomized Trial

UNLABELLED Chinese translation BACKGROUND Depression is overrepresented in smokers. OBJECTIVE To evaluate smoking abstinence and changes in mood and anxiety levels in smokers with depression treated with varenicline versus placebo. DESIGN Phase 4, multicenter, parallel, 1:1 allocation, double-blind, randomization trial. Randomization, stratified by antidepressant use and depression score at baseline, was blocked in sizes of 4. (ClinicalTrials.gov: NCT01078298). SETTING 38 centers in 8 countries. PARTICIPANTS 525 adult smokers with stably treated current or past major depression and no recent cardiovascular events. INTERVENTION Varenicline, 1 mg twice daily, or placebo for 12 weeks, with 40-week nontreatment follow-up. MEASUREMENTS Primary outcome was carbon monoxide-confirmed continuous abstinence rate (CAR) for weeks 9 to 12. Other outcomes included CARs assessed during nontreatment follow-up and ratings of mood, anxiety, and suicidal ideation or behavior. RESULTS 68.4% versus 66.5% of the varenicline and placebo groups, respectively, completed the study. Varenicline-treated participants had higher CARs versus placebo at weeks 9 to 12 (35.9% vs. 15.6%; odds ratio [OR], 3.35 [95% CI, 2.16 to 5.21]; P < 0.001), 9 to 24 (25.0% vs. 12.3%; OR, 2.53 [CI, 1.56 to 4.10]; P < 0.001), and 9 to 52 (20.3% vs. 10.4%; OR, 2.36 [CI, 1.40 to 3.98]; P = 0.001). There were no clinically relevant differences between groups in suicidal ideation or behavior and no overall worsening of depression or anxiety in either group. The most frequent adverse event was nausea (varenicline, 27.0%; placebo, 10.4%). Two varenicline-group participants died during the nontreatment phase. LIMITATIONS Some data were missing, and power to detect differences between groups was low in rare events. Smokers with untreated depression, with co-occurring psychiatric conditions, or receiving mood stabilizers and antipsychotics were not included. CONCLUSION Varenicline increased smoking cessation in smokers with stably treated current or past depression without exacerbating depression or anxiety. PRIMARY FUNDING SOURCE Pfizer.

Sertraline treatment of co-occurring alcohol dependence and major depression.

Background: Major depressive disorder occurs commonly in association with alcohol dependence, both in clinical samples and in the community. Efforts to treat major depressive disorder in alcoholics with antidepressants have yielded mixed results. This multicenter, double-blind, placebo-controlled trial of sertraline was designed to address many of the potential methodological shortcomings of studies of co-occurring disorders. Method: Following a 1-week, single-blind, placebo lead-in period, 328 patients with co-occurring major depressive disorder and alcohol dependence were randomly assigned to receive 10 weeks of treatment with sertraline (at a maximum dose of 200 mg/d) or matching placebo. Randomization was stratified, based on whether initially elevated scores on the 17-item Hamilton Depression Rating Scale declined with cessation of heavy drinking, resulting in a sample of 189 patients with Hamilton Depression Rating Scale scores ≥17 (group A) and 139 patients with Hamilton Depression Rating Scale scores ≤16 (group B). Results: Both depressive symptoms and alcohol consumption decreased substantially over time in both groups. There were no reliable medication group differences on depressive symptoms or drinking behavior in either group A or B patients. Conclusion: Despite careful attention to methodological considerations, this study does not provide consistent support for the use of sertraline to treat co-occurring major depressive disorder and alcohol dependence. The high rate of response among placebo-treated patients may help to explain these findings. Further research is needed to identify efficacious treatments for patients with these commonly co-occurring disorders.

The co-occurrence of cigarette smoking and bipolar disorder: phenomenology and treatment considerations.

Heffner JL, Strawn JR, DelBello MP, Strakowski SM, Anthenelli RM. The co‐occurrence of cigarette smoking and bipolar disorder: phenomenology and treatment considerations. 
Bipolar Disord 2011: 13: 439–453.

Preliminary evidence for gender-specific effects of topiramate as a potential aid to smoking cessation

AIMS Study aims were threefold: (i) to determine the feasibility, potential efficacy and safety of topiramate as an aid to smoking cessation; (ii) to examine potential predictors of abstinence including gender; and (iii) to explore topiramates effects on tobacco withdrawal and post-cessation weight gain. DESIGN Randomized, double-blind, placebo-controlled, 11-week clinical trial with a 6-week dosage titration period and 5 weeks of maintenance treatment. SETTING Single-site, out-patient, randomized clinical trial. PARTICIPANTS Thirty-eight adult male and 49 female chronic smokers who smoked an average of > 10 cigarettes per day and who were motivated to try to quit smoking. INTERVENTION Random assignment to receive either topiramate (n = 43) up to 200 mg daily in divided doses or placebo (n = 44) orally combined with brief counseling over an 11-week period. MEASUREMENTS Carbon monoxide (CO)-confirmed 4-week prolonged abstinence rate during weeks 8-11. Changes in tobacco withdrawal, body weight and safety parameters were also assessed. FINDINGS Overall, no significant increase in the prolonged abstinence rate was detected, but logistic regression analysis indicated significant gender-specific differences. Men treated with topiramate were nearly 16 times more likely to quit smoking than women on topiramate [37.5% versus 3.7%; odds ratio (OR) = 15.6; P = 0.016] and were roughly four times more likely to quit smoking than placebo-treated men (37.5% versus 13.6%; OR = 3.8; P = 0.098). Topiramate-treated men reported significantly lower tobacco withdrawal scores than both women taking topiramate and men on placebo. On average, male cessators on placebo gained 3.30 kg, whereas topiramate led to a 0.72 kg weight loss (P = 0.03). Study discontinuation rates due to adverse events (AEs) were significantly higher in the topiramate group (topiramate 23% versus placebo 2%). The most commonly reported AEs in the topiramate arm were paraesthesia, fatigue, difficulty with concentration/attention and nervousness. CONCLUSIONS Topiramate produced gender-specific effects on smoking cessation. Male smokers had markedly greater quit rates than female smokers and men were roughly four times more likely to quit smoking when treated with topiramate as compared to placebo. Topiramate was fairly well tolerated, although higher discontinuation rates were seen. Topiramates triple effects aiding smoking abstinence, attenuating nicotine withdrawal and preventing post-cessation weight gain might make it a promising agent for treating tobacco addiction, at least in men.

Platelet monoamine oxidase activity levels in subgroups of alcoholics: Diagnostic, temporal, and clinical correlates

Platelet monoamine oxidase (MAO) activity levels were measured in 47 male inpatient alcoholics to determine whether this biological marker might be useful in differentiating subtypes of alcoholics. Of the subgrouping methods tested, only type 2 alcoholics defined by the criteria of Gilligan et al had significantly lower platelet MAO activity than type 1 alcoholics at intake, but this finding was not stable over time in a subset of subjects. Neither separating male veteran alcoholics into either of two other variations of the type 1/type 2 subtypes, nor classifying the sample into primary alcoholics versus primary ASPD with secondary alcoholism categories, yielded significant differences between subgroups. Generally, enzyme activity levels (Vmax) were higher about 10 days after stopping drinking compared to platelet MAO values determined in thrombocytes obtained after approximately 4 weeks abstinence; these levels remained relatively stable 3 months later in a cohort of subjects. Tobacco smoking was significantly negatively correlated to platelet MAO activity levels.