Mechanistic aspects and novel biomarkers of responder and non-responder phenotypes in galactosamine-induced hepatitis.

The amino sugar galactosamine (galN) induces alterations in the hepatic uridine nucleotide pool and has been widely used as a model of human viral hepatitis. Histopathological and clinical chemistry analyses of a cohort of rats following administration of galN revealed extreme interindividual variability in the extent of the toxic response which enabled classification of 'responder' and 'non-responder' phenotypes. An integrative metabolic profiling approach was applied to characterize biomarkers of exposure to galN in urine, serum, feces and liver from responders and non-responders. The presence of N-acetylglucosamine and galN in the urine correlated with the occurrence and extent of toxic response. Conversely, the novel identification of galN-pyrazines in the feces of non-responders and their virtual absence in the feces of responders suggests an alternative means of distribution and metabolism of galN in non-responders. The absence of the UDP-hexosamines in the liver of non-responders further supports differential metabolism of galN and suggests an ability of non-responders to avoid UDP-glucose depletion. An observed disturbance of gut microbial derived metabolites in the urine and feces of non-responders may suggest a role of the microflora in reducing the effective dose of galN. This systems level metabonomic approach has provided new mechanistic insights into differential response to galN and is widely applicable to the study of interindividual variation in metabolism for any xenobiotic intervention.

Canine cardiac rhabdomyoma.

A well-circumscribed, expansile, and nonencapsulated cardiac rhabdomyoma composed of tightly arranged, large, variably sized, ovoid to irregular, swollen myocytes with deeply eosinophilic cytoplasm and varying degrees of cytoplasmic vacuolation was detected in an eight- to nine-month-old female beagle dog in a routine toxicology study. By histochemistry, the neoplasm was periodic acid-Schiff positive. By immunohistochemistry (IHC), neoplastic cells were positive for desmin and myoglobin and negative for vimentin and smooth muscle actin. Spontaneous lesions in the heart of young beagle dogs are rare in drug safety studies. On the basis of histopathology, histochemistry, and IHC findings, a diagnosis of cardiac rhabdomyoma was made. Cardiac rhabdomyoma is one of the most frequently occurring primary tumors of the heart and, by far, the most common neoplasm in human infants and children. To our knowledge, this is the first report of the canine cardiac rhabdomyoma.

An immunohistochemical approach to differentiate hepatic lipidosis from hepatic phospholipidosis in rats.

Hepatocellular vacuolation can be a diagnostic challenge since cytoplasmic accumulations of various substances (lipid, water, phospholipids, glycogen, and plasma) can have a similar morphology. Cytoplasmic accumulation of phospholipids following administration of cationic amphiphilic drugs (CAD) can be particularly difficult to differentiate from nonphosphorylated lipid accumulations at the light microscopic level. Histochemical methods (Sudan Black, Oil Red-O, Nile Blue, etc.) can be used to identify both nonphosphorylated and/or phosphorylated lipid accumulations, but these techniques require non-paraffin-embedded tissue and are only moderately sensitive. Thus, electron microscopy is often utilized to achieve a definitive diagnosis based upon the characteristic morphologic features of phospholipid accumulations; however, this is a low throughput and labor intense procedure. In this report, we describe the use of immunohistochemical staining for LAMP-2 (a lysosome-associated protein) and adipophilin (a protein that forms the membrane around non-lysosomal lipid droplets) to differentiate phospholipidosis and lipidosis, respectively in the livers of rats. This staining procedure can be performed on formalin-fixed paraffin embedded tissues, is more sensitive than histochemistry, and easier to perform than ultrastructural evaluation.

Evaluation of suicidal thoughts and behaviors in children and adolescents taking paroxetine.

OBJECTIVE: The aim of this study was to summarize results of a blinded review of potential suicidal events and analyses comparing incidence rates between paroxetine- and placebo-treated pediatric patients. METHOD: One thousand one hundred ninety-one (1191) children and adolescents received paroxetine (n = 642) or placebo (n = 549) during placebo-controlled portions of all acute double-blind trials of paroxetine (n = 5). An expert panel blindly reviewed and categorized all identified cases detected by electronic and manual search of adverse events (AEs), serious AEs, and selected cases as suicidal or non-suicidal behavior. Incidence rates were calculated for suicide-related events and for rating scale items assessing suicidality. RESULTS: Suicide-related events occurred more often in paroxetine (22 of 642, 3.4%) than placebo groups (5 of 549, 0.9%); odds ratio (OR) 3.86 (95% CI 1.45, 10.26; p = 0.003). All suicide-related events occurred in adolescents of at least 12 years, except for 1 of 156 paroxetine-treated children. All suicide attempts occurred in major depressive disorder (MDD); few suicide-related events occurred in patients with a primary anxiety disorder. Suicide item analyses did not reveal significant differences between paroxetine and placebo. CONCLUSIONS: Adolescents treated with paroxetine showed an increased risk of suicide-related events. Suicidality rating scales did not show this risk difference. The presence of uncontrolled suicide risk factors, the relatively low incidence of these events, and their predominance in adolescents with MDD make it difficult to identify a single cause for suicidality in these pediatric patients.

Seasonal affective disorder and its prevention by anticipatory treatment with bupropion XL.

BACKGROUND: Seasonal affective disorder (SAD) can cause significant distress and impairment. No antidepressant studies have previously attempted to prevent the onset of autumn-winter depression. METHODS: Three prospective, randomized, placebo-controlled prevention trials were conducted on 1042 SAD patients, enrolled in autumn and treated while still well, across the northern US and Canada. Patients received either bupropion XL 150-300 mg or placebo daily by mouth from enrollment until spring and were then followed off medications for 8 additional weeks. Primary efficacy variables were end-of-treatment depression-free rates and survival distributions of depressive recurrence. RESULTS: Despite a reported average of 13 previous seasonal depressive episodes, almost 60% of patients had never previously been treated for depression. Major depression recurrence rates during the three studies for bupropion XL and placebo groups were 19% versus 30% (p = 0.026), 13% versus 21% (p = 0.049), and 16% versus 31%; yielding a relative risk reduction across the three studies of 44% for patients taking bupropion XL. Survival analyses for depression onset also favored bupropion XL over placebo (p = .081, .057, and <.001). CONCLUSIONS: It is possible to prevent recurrence of seasonal major depressive episodes by beginning bupropion treatment early in the season while patients are still well.

Bupropion SR vs. placebo for weight loss in obese patients with depressive symptoms.

OBJECTIVE: This randomized, double-blind, placebo-controlled study evaluated the efficacy and tolerability of bupropion sustained-release (bupropion SR) in reducing weight and depressive symptoms in obese adults. RESEARCH METHODS AND PROCEDURES: Obese adults (body mass index, 30 to 44 kg/m(2)) not currently meeting criteria for major depression but with depressive symptoms (Beck Depression Inventory score 10-30) received bupropion SR 300 mg/d or placebo for 26 weeks with a 500 kcal/d-deficit diet. Patients who lost <5% of baseline weight at week 12 had bupropion SR dosage or placebo increased to 400 mg/d in a blinded fashion. RESULTS: The bupropion SR group (n = 193) lost an average of 4.4 kg (4.6% of baseline weight) vs. 1.7 kg (1.8% of baseline weight) on placebo (n = 191, p < 0.001, last-observation-carried-forward analysis). More patients in the bupropion SR group than in the placebo group (40% vs. 16% of intent-to-treat sample, 50% vs. 28% of completers, respectively) lost at least 5% of baseline weight (p < 0.05 at week 4, p < 0.001 at weeks 6 to 26). The percentage of patients reporting > or =50% decrease in depressive symptoms did not differ between groups, but depressive symptoms improved more with bupropion SR than with placebo among patients with a history of major depression (p < 0.05, weeks 4 to 26). In the sample as a whole, improvement in depressive symptoms was related to weight loss of > or =5% regardless of treatment (p < 0.0001). Bupropion SR was well-tolerated. DISCUSSION: Bupropion SR in combination with a 500 kcal/d-deficit diet facilitated weight loss. Weight loss of > or =5% may improve mood in obese patients with depressive symptoms.

Continuation phase treatment with bupropion SR effectively decreases the risk for relapse of depression.

BACKGROUND: This was the first controlled continuation phase study (up to 1-year total treatment) to evaluate the safety and efficacy of bupropion SR for decreasing the risk for relapse of depression in patients who responded to bupropion SR. METHODS: Patients with recurrent major depression were treated with bupropion SR 300 mg/day during an 8-week open-label phase. Responders (based on Clinical Global Impressions Scale for Improvement of Illness scores) entered a randomized, double-blind phase where they received bupropion SR 300 mg/day or placebo for up to 44 weeks. After randomization, relapse was defined as the point at which the investigator intervened by withdrawing the patient from the study to treat depression. RESULTS: Four hundred twenty-three patients were randomized. A statistically significant difference in favor of bupropion SR over placebo was seen in the time to treatment intervention for depression when survival curves were compared (log-rank test, p =.003). Statistically significant separation between bupropion SR and placebo began at double-blind week 12 (p <.05). Adverse events in bupropion SR-treated patients accounted for 9% and 4% of discontinuations from the open-label and double-blind phases, respectively. CONCLUSIONS: Bupropion SR was shown to be effective and well tolerated in decreasing the risk for relapse of depression for up to 44 weeks.

Prevalence of sexual dysfunction among newer antidepressants.

BACKGROUND: Sexual dysfunction commonly occurs during antidepressant treatment. However, the reported rates of sexual dysfunction vary across antidepressants and are typically underreported in product literature. The objectives of this study were (1) to estimate the prevalence of sexual dysfunction among patients taking newer antidepressants (bupropion immediate release [IR], bupropion sustained release [SR], citalopram, fluoxetine, mirtazapine, nefazodone, paroxetine, sertraline, venlafaxine, and venlafaxine extended release [XR]) and (2) to compare physician-perceived with patient-reported prevalence rates of antidepressant-associated sexual dysfunction. METHOD: This cross-sectional, observational study was conducted in 1101 U.S. primary care clinics. Adult outpatients (4534 women and 1763 men) receiving antidepressant monotherapy were enrolled. The prevalence of sexual dysfunction was measured using the Changes in Sexual Functioning Questionnaire. RESULTS: In the overall population, bupropion IR (22%) and SR (25%) and nefazodone (28%) were associated with the lowest risk for sexual dysfunction, whereas selective serotonin reuptake inhibitor (SSRI) antidepressants, mirtazapine, and venlafaxine XR were associated with higher rates (36%-43%). In a prospectively defined subpopulation unlikely to have predisposing factors for sexual dysfunction, the prevalence of sexual dysfunction ranged from 7% to 30%, with the odds of having sexual dysfunction 4 to 6 times greater with SSRIs or venlafaxine XR than with bupropion SR. Physicians consistently underestimated the prevalence of antidepressant-associated sexual dysfunction. CONCLUSION: Ours is the first study to assess sexual dysfunction across the newer antidepressants using consistent methodology and a validated rating scale. Overall, SSRIs and venlafaxine XR were associated with higher rates of sexual dysfunction than bupropion or nefazodone. Because antidepressant-associated sexual dysfunction is considerably underestimated by physicians, greater recognition and education are imperative when prescribing antidepressant treatment.

Effect on body weight of bupropion sustained-release in patients with major depression treated for 52 weeks.

BACKGROUND: Short-term studies have demonstrated a modest weight-reducing to weight-neutral effect among patients receiving bupropion sustained-release (SR) for the treatment of depression. OBJECTIVE: This study was conducted to evaluate the long-term effects of bupropion SR on body weight in patients with depression. METHODS: This analysis was conducted within a long-term relapse-prevention study in patients with major depression. Those whose depression had responded to open-label treatment with bupropion SR were randomized to 44 weeks of double-blind treatment with bupropion SR 300 mg/d or placebo. Patients were categorized by body mass index (BMI) as follows: BMI < 22, BMI 22 to 26, BMI > or = 27, and BMI > or = 30. RESULTS: Four hundred twenty-three patients were enrolled in the double-blind phase of the study, 210 receiving bupropion SR and 213 receiving placebo. At the end of the open-label phase, the following mean weight losses were seen in the 4 BMI groups: BMI < 22, 0.5 kg; BMI 22 to 26, 1.1 kg; and BMI > or = 27 and BMI > or = 30, 1.8 kg each. At the end of double-blind treatment, mean change-from-baseline weights were as follows: BMI < 22, -0.1 kg; BMI 22 to 26, -0.6 kg; BMI > or = 27, -1.4 kg; and BMI > or = 30, -2.4 kg. The rate of change in body weight during the double-blind phase was statistically significant compared with baseline BMI (P < 0.001, analysis of covariance). CONCLUSIONS: Modest mean weight losses that increased with increasing baseline body weight were observed with long-term bupropion SR treatment. The findings of this analysis suggest that bupropion SR may be an appropriate therapeutic option in normal-weight or overweight patients with depression who are concerned about weight gain.