Pharmacokinetics, tolerability, and clinical effectiveness of quetiapine fumarate: an open-label trial in adolescents with psychotic disorders.

BACKGROUND: This is the first investigation of the pharmacokinetics, tolerability, and efficacy of quetiapine fumarate in adolescents with chronic or intermittent psychotic disorders. METHOD: Ten patients with DSM-IV chronic or intermittent psychotic disorders (ages 12.3 through 15.9 years) participated in an open-label, rising-dose trial and received oral doses of quetiapine twice daily (b.i.d.), starting at 25 mg b.i.d. and reaching 400 mg b.i.d. by day 20. The trial ended on day 23. Key assessments were pharmacokinetic analysis of plasma quetiapine concentrations and neurologic, safety, and efficacy evaluations. RESULTS: No statistically significant differences were observed between 100-mg b.i.d. and 400-mg b.i.d. quetiapine regimens for total body clearance, dose-normalized area under the plasma concentration-time curve, or dose-normalized premorning- or postmorning-dose trough plasma values obtained under steady-state conditions after multiple-dose regimens. No unexpected side effects occurred with quetiapine therapy, and no statistically significant changes from baseline were observed for the UKU Side Effect Rating Scale items that were rated. No serious adverse events or clinically important changes in hematology or clinical chemistry variables were reported. The most common adverse events were postural tachycardia and insomnia. Extrapyramidal side effects improved, as evidenced by significant (p < .05) decreases from baseline to endpoint in the mean Simpson-Angus Scale total scores and Barnes Akathisia Scale scores. Quetiapine improved positive and negative symptoms, as shown by significant (p < .05) decreases from baseline to endpoint in the mean Brief Psychiatric Rating Scale total score, the Clinical Global Impressions-Severity of Illness scale, and the Modified Scale for the Assessment of Negative Symptoms summary score. CONCLUSION: Quetiapine pharmacokinetics were dose proportional in adolescents and were similar to those previously reported for adults. Quetiapine was well tolerated and effective in the small number of adolescents studied.

Ongoing and planned clinical trials of anti-arrhythmic drugs: an update.

Anti-arrhythmic drug therapy is frequently used for the control of ventricular arrhythmias in the setting of heart disease. These agents have been used in many randomised clinical trials in an attempt to demonstrate improved survival. However, most studies have been disappointing, showing little or no improvement in survival, and, in some cases, deterioration. This report reviews ongoing clinical trials designed to evaluate survival in specific patient populations.

The microbial alkaloid toxin staurosporine blocks the phorbol ester-induced increase in beta-amyloid precursor protein in PC12 cells.

The amyloid precursor protein (APP) is abnormally cleaved during the progression of Alzheimer's disease, resulting in production of the toxic beta-amyloid peptide, which forms neuritic plaques in the brain. To develop a pharmacological approach for treatment of Alzheimer's disease, natural compounds which may inhibit APP synthesis and/or beta-amyloid production are required. Staurosporine, a toxin isolated from Streptomyces staurospores bacteria, is widely used as a protein kinase C inhibitor in signal transduction research. Using rat pheochromocytoma PC12 sympathetic neurons, which express APP, we characterised staurosporine effect on APP level by western blotting, using an anti-APP monoclonal antibody. PC12 APP levels were increased or decreased upon exposure to either 50-200 nM or 10-20 nM phorbol 12-myristate 13-acetate (PMA, a protein kinase C activator), respectively. An apparent relationship was found between the change in APP level and a differential down regulation process of different PKC isoforms. The PMA-induced increase in intracellular APP level was dose-dependently inhibited by staurosporine (natural alkaloid) or GF 109203X (synthetic analogue), protein kinase C (PKC) inhibitors. This inhibition was mainly observed upon treatment of the cells before the exposure to PMA. These results suggest PKC regulation of APP levels in PC12 cells, and provide staurosporine as a leader compound for the development of drugs to control the expression of APP in Alzheimer's research.

Cerebrospinal fluid neuroendocrinology of alcohol misusers.

Cerebrospinal fluid (CSF) neurohumors reflect central nervous system physiology in a way that peripheral indices can not. We reviewed clinical studies of CSF biogenic amines and neurohormones in alcohol misusers during various stages of withdrawal or abstinence and found them difficult to compare because of highly variable experimental methods, reliance on single time collections (lumbar punctures) that fail to control for potential stress-induced effects of the procedure, lack of control for tobacco use, and a paucity of non-alcoholmisusing controls. However, taken together, the data thus far show that a variety of neuroactive substances are reduced in concentration in the CSF of some alcohol misusers. Low CSF levels of corticotropinreleasing hormone, beta-endorphin, norepinephrine, diazepam-binding inhibitor, 5-hydroxyindoleacetic acid and somatostatin have all been reported. Whether the decreased CSF levels of these neurohormones and neurotransmitters are a cause or consequence of alcoholism has not been determined. In fact, further studies using serial or continuous CSF sampling techniques with homogeneous, better-characterized patients and normal volunteers are still needed to establish the precise CSF neurochemical abnormalities in alcohol misusers.

Epidemiologic assessment of angina before and after myocardial infarction: The Framingham study.

Angina pectoris before and after MI was evaluated in a sample of 729 men and women from a general population in whom MI developed during a 36-year period of follow-up. Relations of AP to subsequent CHD events and mortality after initial MI were analyzed by proportional hazards regression models and were adjusted for covariates (age, sex, blood pressure, serum cholesterol, body mass index, glucose intolerance, cigarette smoking, and antihypertensive medications) obtained from routine biennial examinations preceding the initial MI. Comparisons of the influence of angina were made between pre-MI angina, post-MI angina, and absence of AP. The sample had 484 men and 245 women (mean ages, 63 and 69, respectively) who survived greater than / equal to 30 days after MI. The initial MI was clinically unrecognized in 165 (34%) men and 115 (47%) women. Data on covariates were complete for 622 subjects, among whom 30% had pre-Ml angina, 18% had post-MI angina, and 52% did not have AP. Angina was half as common in persons with unrecognized MIs as in those with clinically recognized MIs. During an average of 8.7 years of follow-up, 57% of subjects developed subsequent CHD events, including recognized and unrecognized MI, coronary insufficiency, and CHD death, and 74% died. Both pre-MI angina (hazard ratio, 1.49; 95% CI, 1.17 to 1.91) and post-MI angina (hazard ratio, 1.43; 95% CI, 1.06 to 1.94) adjusted for accompanying risk factors were associated with increased risk for subsequent CHD events compared with those without AP. Neither pre-MI nor post-MI angina was associated with excess overall mortality.

An open study of the effects of sertraline on adolescent major depression.

This open study investigated the effects of sertraline in treating 13 adolescents, ages 12 to 18, who were hospitalized for treatment of a major depressive episode. The sample included 7 adolescents with nonendogenous depression and 6 with endogenous depression, as diagnosed by both Research Diagnostic Criteria (RDC) and Kiddie-SADS-P DSM-III-R endogenous subtype criteria. These patients were followed for an inpatient length of stay ranging from 9 to 38 days (mean 19 days), with later outpatient follow-up for a total of 12 weeks. Measures of depression were found to improve significantly, including suicidal ideation and most of the DSM-III-R symptoms of major depression. Sertraline (mean 110 mg or 1.96 mg/kg daily) significantly decreased scores on the 24-item Hamilton Depression Rating Scale and Montgomery-Asberg Depression Rating Scale from premedication baseline to treatment week 12, and also between weeks 1 (after a large week 1 improvement, presumably due to nondrug effects) and 12. There was a small but significant improvement on the Children's Global Assessment Scale between baseline and week 12, but the Family Global Assessment Scale showed no significant change; neither global assessment scale showed significant effects between weeks 1 and 12. Sleep disturbance was common (69%) after 12 weeks of treatment, but clinically significant improvements in sleep patterns were also observed. This open-label prospective study suggests that sertraline might be useful in treating adolescents with major depression. Adverse effects, mainly insomnia and drowsiness, were relatively common but usually manageable. One patient developed mania after 8 days of sertraline treatment at a dose of 100 mg daily.

Minimizing and managing antidepressant side effects.

Side effects often complicate the use of antidepressants for treatment of patients with major depression. Aggressive minimization and management of antidepressant side effects may relieve discomfort and distress, improve quality of life, enable clinicians to use appropriate medications at therapeutic doses, improve compliance, and thus enhance overall outcome. In this article we present recommendations for the management of side effects associated with antidepressant medications. Specifically, strategies are provided for the management of anticholinergic, cardiovascular, sedative, and activating side effects. Strategies for the management of antidepressant-associated insomnia, hypomania and mania, sexual dysfunction, appetite stimulation and weight gain, cognitive impairment, and parathesias are also discussed.

Data monitoring in the cardiac arrhythmia suppression trial.

OBJECTIVE: This report discusses practical aspects of data monitoring in a clinical trial which stopped ahead of schedule due to adverse findings. DESIGN: A review of the considerations and decisions made by the data-monitoring committee of the Cardiac Arrhythmia Suppression Trial (CAST), a randomized, double-blind clinical trial. PATIENTS: CAST consisted of men and women with a recent myocardial infarction, asymptomatic or minimally symptomatic ventricular arrhythmias, and reduced left ventricular ejection fraction. INTERVENTIONS: In CAST, 3 antiarrhythmic agents, encainide, flecainide, and moricizine, were compared against placebo. MAIN OUTCOME MEASURES: The main outcome measures in CAST were arrhythmic death and total mortality. RESULTS: CAST found the 3 agents to be harmful. Encainide and flecainide were stopped first. Subsequently, moricizine was discontinued ahead of schedule. CONCLUSIONS: The complexity of the study design and a midcourse protocol modification raise several data-monitoring issues not previously discussed. These include how to handle apparently dramatic yet unexpected results, the need for flexibility in modifying study design and goals, and the conflict between existing study data and both conventional wisdom and medical practice.

Valproate and carbamazepine in the treatment of panic and posttraumatic stress disorders, withdrawal states, and behavioral dyscontrol syndromes.

A number of preclinical studies and preliminary clinical reports, in some cases augmented by controlled studies, suggest that valproate and carbamazepine may have therapeutic effects in the treatment of certain anxiety disorders (panic disorder, post-traumatic stress disorder), alcohol and sedative-hypnotic withdrawal states, and behavioral dyscontrol syndromes. We review the theoretical rationale and available clinical data supporting the potential value of these anticonvulsants in these psychiatric disorders.

Statistical problems in the design of antiarrhythmic drug trials.

Although many aspects of design, monitoring, and analysis in trials of antiarrhythmic drugs are similar to those of other intervention studies, several features are different. These include decisions on how to identify the subjects, timing of the intervention with respect to the disease process, time of randomization, methods for measurement of outcome, and interim monitoring for harm or benefit. The resolution of these issues depends almost entirely on the specification of the question of interest.

Weight changes on fluoxetine as a function of baseline weight in depressed outpatients.

In order to test the hypothesis that weight changes on fluoxetine are a function of baseline weight, we divided a group of 39 depressed outpatients into 3 groups based on the Fogarty table: ideal, underweight, and overweight. Subjects were participants in an open label depression trial that was carried out over 3 years. Doses ranged from 20 mg to 80 mg depending on the patients' response and side effect profile. Demographic data, weights and Hamilton Rating Scale for Depression (HAM-D) scores were collected at baseline. Subsequent Hamilton scores and weights were obtained at monthly intervals until the subjects were terminated from the study. Only those subjects who remained in the study for at least 6 months were included in this analysis. Overweight subjects showed a significant weight loss of 3.3 lbs (p less than .001) in the first 2 months whereas ideal weight subjects gained 4.4 lbs (p = .02) over a 4-month period. All of these changes were maintained throughout the study. The underweight patients showed no consistent trends. All patients examined (those who completed 6 months or more in the trial) had significant decreases in their HAM-D scores (p less than .001).

Classification of deaths after myocardial infarction as arrhythmic or nonarrhythmic (the Cardiac Arrhythmia Pilot Study).

The Cardiac Arrhythmia Pilot Study (CAPS) was a randomized, double-blind trial of antiarrhythmic drugs (encainide, flecainide, moricizine, imipramine and placebo) in 502 patients with at least 10 ventricular premature complexes/hour, 6 to 60 days after acute myocardial infarction. CAPS tested the feasibility of performing a larger study to determine if suppression of ventricular ectopic activity after acute myocardial infarction could improve survival. Patients in CAPS were followed for 1 year. All death or cardiac arrest events were evaluated by at least 2 investigators using a classification scheme that characterized the underlying mechanism as cardiac arrhythmic, cardiac nonarrhythmic or noncardiac. Forty-five patients (9%) died or had cardiac arrest during the 1-year follow-up, 29 (64%) within 1 hour from the onset of symptoms and 16 greater than 1 hour from the onset of symptoms. Twenty-three deaths (51%) were classified as arrhythmic, 19 (42%) as nonarrhythmic and 3 (7%) as noncardiac. Acute myocardial ischemia or infarction was associated with the death/cardiac arrest event in 16 patients (36%), 8 in the arrhythmic death group. Discrepancies in classification among reviewers were particularly common in patients with long-standing symptoms of congestive heart failure, in whom it was frequently difficult to identify the precise moment of the onset of symptoms in the death/cardiac arrest event. Using only the temporal relation of symptoms to categorize deaths or cardiac arrests, the mechanism of 12 (27%) of the 45 patients was in disagreement with the classification based on the Events Committee review. Classification of death as sudden or nonsudden is not equivalent to the classification of death as arrhythmic or nonarrhythmic.

Are 24 hours of ambulatory ECG monitoring necessary for a patient after infarction?

The Beta-Blocker Heart Attack Trial was a randomized clinical trial of propranolol versus placebo in 3837 patients after myocardial infarction. A 24 hour ambulatory ECG was obtained before therapy in 3290 patients 2 to 21 days after myocardial infarction. Sensitivity, specificity, positive and negative predictive values, and prevalence were calculated for four definitions of ventricular arrhythmia with either total or sudden death (death in less than 1 hour of observed symptoms) as an endpoint. These indexes were obtained using the first 1, 2, 4, 6, 12, and 24 hours plus a random hour, a random daytime hour, and a random nighttime hour of the 24-hour ECG of 1336 placebo patients. For both total death and sudden death, as the duration of monitoring increased, (1) prevalence increased, (2) sensitivity increased, (3) specificity decreased, (4) positive predictive value either changed very little or decreased, and (5) negative predictive value was high (greater than 90%) and increased slightly. None of the 3 random hours offered anything beyond the first hour. The Beta-Blocker Heart Attack Trial data, which were based on an average follow-up of 25 months, show that as the number of hours of ambulatory monitoring increase, the percentages of patients identified at risk or not at risk (the positive and negative predictive values) do not change much. Twenty-four hours of monitoring does not appear to be the optimal time duration for deciding whether to treat arrhythmias in patients after infarction.