Robert Finn

Ketamine Infusion Relieves Bipolar Depression Quickly

Smokeless tobacco products are not safer alternatives to cigarette smoking, they do not help smokers quit, and their long-term use can, in fact, increase the risk of fatal heart attack, fatal stroke, and cancer, the American Heart Association warned in a scientific statement. The researchers, led by Mariann R. Piano, Ph.D., examined several international studies to compare smokeless tobacco use and its health risks. Meta-analysis data involving male, Swedish smokers for 1976-2002 showed a significant decrease in cigarette smoking that corresponded with an increase in use of smokeless tobacco products, the investigators wrote in the AHA journal, Circulation. Despite the decline in cigarette use, concern is warranted, Dr. Piano, professor of biobehavioral science at the University of Illinois at Chicago, explained: “Smokeless tobacco products are harmful and addictive – that does not translate to a better alternative,” Dr. Piano, said in a written statement released by the association. “Scientists and policy makers need to assess the effect of ‘reduced risk’ messages related to smokeless tobacco use on public perception, especially among smokers who might be trying to quit,” Dr. Piano and her colleagues wrote. Citing “inadequate evidence of smoking cessation efficacy and safety,” the researchers deemed as inappropriate the promotion of smokeless tobacco as a way to reduce smokingrelated diseases. The American Heart Association does recommend nicotine replacement therapy (nicotine gum or a nicotine-releasing patch placed on the skin) as a safer option for cigarette smokers wanting to quit. “Clinical studies have found no increased risk of heart attack or stroke with either type of nicotine replacement therapy,” the AHA said in the written statement. Metaanalysis data in the association’s scientific statement http://circ.ahajournals.org/cgi /reprint/CIR.0b013e3181f432c3 indicated that smokeless tobacco use was associated with an increased risk of heart disease (relative risk 1.12, n = 8 studies) (Int. J Epidemiol. 2007;36:789804). Additionally, a subanalysis of INTERHEART (a study of 15,152 cases of first myocardial infarction in 52 countries) showed that tobacco chewers had a significantly increased risk of first myocardial infarction (odds ratio 2.23) compared with those who never used tobacco. Two other meta-analyses indicated that smokeless tobacco use was also associated with an increased risk of fatal stroke (RR 1.42, n = 5 studies, and RR 1.40, n = 5 studies). The researchers explained that, like cigarettes, smokeless tobacco (ST) products still contain nicotine of varying concentrations as well as a number of carcinogens that are just as harmful. Cigarettes and oral snuff have similar amounts of nicotine (milligrams per gram of tobacco), while chewing tobacco appears to have “somewhat lower” amounts compared with cigarettes, Dr. Piano and her colleagues wrote. “Even though certain manufacturing techniques are used to reduce the level of these compounds in some products, they remain present in substantial concentrations in ST products, including Swedish snus,” they said. In a comparison of nicotine concentration between three types of smokeless tobacco products (chewing tobacco, dry snuff, and moist snuff ) and cigarettes sold in the United States, all of the smokeless tobacco products had nicotine concentrations that were similar to cigarettes with the highest concentrations (see chart). Dr. Piano and her colleagues found that unlike the aforementioned Swedish cohorts, there was no reduction in smoking rates among people in the United States using smokeless tobacco. (The sale of smokeless tobacco products such as moist snuff or snus is banned in most of the European Union with the exception of Sweden and Norway.) In the United States about 8.1 million people are users of smokeless tobacco and its use is more prevalent in men than women, and people between the ages of 18-25 are the most likely to use smokeless tobacco, the researchers wrote. It also appears that although U.S. chewing tobacco use has been on the decline since the 1980s, snuff consumption and production are increasing, the researchers said. ■ Products could pose increased health

Metaanalysis Shows Stimulant Therapy Inhibits Growth

S A N F R A N C I S C O — The question of whether stimulant therapy for attentiondeficit hyperactivity disorder inhibits a child’s growth has long been controversial, with well-designed studies providing conflicting results. Now, a metaanalysis has indicated that stimulant therapy inhibits both weight gain and expected height gain. Dr. Omar Khwaja reported the results of this metaanalysis in a poster presentation at the annual meeting of the Pediatric Academic Societies. Twenty-two studies including 2,383 patients were selected for the metaanalysis. The children, aged 0-18 years, were treated with either dextroamphetamine or methylphenidate for a mean duration of 1.5 years. The metaanalysis included clinical trials, observational cohort studies, and casecontrol studies. The effect sizes, as measured by a statistic called Cohen’s d, were statistically significant for both weight and height, but greater for weight. However, the metaanalysis found that the effect size favoring weight gain restriction was –0.63, and the effect size favoring restriction in expected height gain was –0.41. Standard interpretations of the Cohen’s d statistic describe an effect size of –0.41 as small to medium, and an effect size of –0.63 as medium to large. The effect was more pronounced for dextroamphetamine than for methylphenidate, wrote Dr. Khwaja, of Children’s Hospital, Boston, and his colleagues. Their meta–regression analysis evaluated the relative effects of the study’s duration, medication type, the study’s outcome metric, and the child’s age at treatment. The authors found that medication type proved to be the only statistically significant variable. “Physicians should continue to be vigilant in monitoring growth parameters in stimulant-treated children,” the authors wrote. —Robert Finn Consider Three Variables in ADHD Prescribing

Latency Test Costly, but Best in Daytime Sleepiness

INDICATIONS AND USAGE: Bipolar Mania: SEROQUEL is indicated for the treatment of acute manic episodes associated with bipolar I disorder, as either monotherapy or adjunct therapy to lithium or divalproex. The efficacy of SEROQUEL in acute bipolar mania was established in two 12-week monotherapy trials and one 3-week adjunct therapy trial of bipolar I patients initially hospitalized for up to 7 days for acute mania. Effectiveness has not been systematically evaluated in clinical trials for more than 12 weeks in monotherapy and 3 weeks in adjunct therapy. Therefore, the physician who elects to use SEROQUEL for extended periods should periodically re-evaluate the longterm risks and benefits of the drug for the individual patient. Schizophrenia: SEROQUEL is indicated for the treatment of schizophrenia. The efficacy of SEROQUEL in schizophrenia was established in short-term (6-week) controlled trials of schizophrenic inpatients. The effectiveness of SEROQUEL in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use SEROQUEL for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient . CONTRAINDICATIONS: SEROQUEL is contraindicated in individuals with a known hypersensitivity to this medication or any of its ingredients. WARNINGS: Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. SEROQUEL (quetiapine) is not approved for the treatment of patients with dementia-related psychosis (see Boxed Warning). Neuroleptic Malignant Syndrome (NMS). A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including SEROQUEL. Rare cases of NMS have been reported with SEROQUEL. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored since recurrences of NMS have been reported. Tardive Dyskinesia: A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, SEROQUEL should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient on SEROQUEL, drug discontinuation should be considered. However, some patients may require treatment with SEROQUEL despite the presence of the syndrome. Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including SEROQUEL. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (eg, obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the suspect drug. PRECAUTIONS: General: Orthostatic Hypotension: SEROQUEL may induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α1-adrenergic antagonist properties. Syncope was reported in 1% (23/2567) of the patients treated with SEROQUEL, compared with 0% (0/607) on placebo and about 0.4% (2/527) on active control drugs. SEROQUEL should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction abnormalities), cerebrovascular disease or conditions which would predispose patients to hypotension (dehydration, hypovolemia and treatment with antihypertensive medications). The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 25 mg bid. If hypotension occurs during titration to the target dose, a return to the previous dose in the titration schedule is appropriate. Cataracts: The development of cataracts was observed in association with quetiapine treatment in chronic dog studies (see Animal Toxicology). Lens changes have also been observed in patients during long-term SEROQUEL treatment, but a causal relationship to SEROQUEL use has not been established. Nevertheless, the possibility of lenticular changes cannot be excluded at this time. Therefore, examination of the lens by methods adequate to detect cataract formation, such as slit lamp exam or other appropriately sensitive methods, is recommended at initiation of treatment or shortly thereafter, and at 6 month intervals during chronic treatment. Seizures: During clinical trials, seizures occurred in 0.6% (18/2792) of patients treated with SEROQUEL compared to 0.2% (1/607) on placebo and 0.7% (4/527) on active control drugs. As with other antipsychotics SEROQUEL should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer’s dementia. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older. Hypothyroidism: Clinical trials with SEROQUEL demonstrated a doserelated decrease in total and free thyroxine (T4) of approximately 20% at the higher end of the therapeutic dose range and was maximal in the first two to four weeks of treatmen