Med Check

Eszopiclone won final Food and Drug Administration (FDA) approval last month. It will be the first nonscheduled sedative/hypnotic approved for use for longer than seven to 10 days. To be marketed by Sepracor as Lunesta, the product will not be required to be labeled with the standard FDA warning language, “Hypnotics should generally be limited to 7 to 10 days of use, and reevaluation of the patient is recommended if they are to be taken for more than 2 to 3 weeks.” Eszopiclone was tested in clinical trials for up to one year of continuous use. In contrast, the longest published trial of market leader zolpidem (Ambien) is 12 weeks. Patients showed significant benefits from the drug in reduction of time to sleep onset and an increase in duration of sleep. The drug carries little liability for the “hangover” felt by many patients taking hypnotics, and even after 12 months of use in clinical trials, no evidence was seen of tolerance or withdrawal symptoms after discontinuation.

The FDA approved carbamazepine-extended release last month. To be marketed by Shire as Equetro, it is indicated for the treatment of patients with bipolar disorder. The drug showed efficacy during clinical trials in reduction of mania symptoms, in patients in both manic and mixed states, as early as the first week of treatment. Improvement was also seen in depressive symptoms associated with mixed states. The formulation was not associated with significant weight gain or blood-sugar changes; however, it carries the same potential for blood dyscrasias associated with immediate-release formulations of carbamazepine. The most frequently observed adverse reactions, particularly during the initial phases of therapy, were dizziness, drowsiness, unsteadiness, nausea, and vomiting. The drug is the first carbamazepine formulation to show efficacy in clinical trials in patients with bipolar disorder, though it is not the first extended-release version of carbamazepine. It will be available in 100 mg, 200 mg, and 300 mg strengths for twice-daily dosing.

The National Institutes of Health announced last month, that it was suspending the use of both naproxen and celecoxib in the Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT), sponsored by the National Institute on Aging. The two nonsteroidal anti-inflammatory drugs (NSAIDs) came under heightened scrutiny last fall after the removal of refocoxib from the market due to concerns about increased risk of cardiovascular events. The ADAPT trial was designed to assess the potential benefit of long-term use of NSAIDs in decreasing the risk of developing Alzheimer's in people aged 70 or older who were considered to be at increased risk because of family history, but did not have symptoms of the disease.

Approximately 2,400 patients were enrolled in ADAPT and randomly assigned to naproxen, celecoxib, or placebo for up to three years. While no increased risk was noted in ADAPT associated with celecoxib use, ADAPT data indicated an apparent increase in cardiovascular and cerebrovascular events among the participants taking naproxen, compared with patients taking placebo.

Citalopram may be effective in controlling anxiety disorders among the elderly. The highly selective SSRI is considered to be safer in special populations because of a favorable adverse-effect profile and its relative lack of drug-drug interactions. In a small pilot study of 34 elderly patients, 65 percent of those randomized to citalopram met response criteria, compared with 24 percent of those taking placebo. Response was defined as a 50 percent reduction in score on the Hamilton Anxiety Rating Scale or a Clinical Global Improvement scale score of 1 or 2. The most common adverse effect noted in those taking citalopram was sedation.

Venlafaxine-extended release appears to be an effective treatment for generalized social anxiety disorder. In a 28-week, double-blind trial, 386 adult outpatients were randomized to venlafaxine at a fixed low dose (75 mg per day), a variable higher dose (150-225 mg per day), or placebo. Both groups taking venlafaxine showed statistically significantly greater improvement compared with those on placebo; however, the two venlafaxine groups did not significantly differ from each other. Of those receiving any dose of venlafaxine, 58 percent were deemed responders (Clinical Global Impression–Improvement score of 1, “very much improved” or 2, “much improved”) compared with 33 percent of those on placebo. Nearly twice as many receiving venlafaxine at either dose (31 percent) were judged remitters (Liebowitz Social Anxiety Scale score less than or equal to 30). There were no statistically significant differences in either outcome between the two doses of venlafaxine.

Risperidone may be effective in treating disruptive behavior disorders in children with subaverage intelligence. A one-year, open-label study involved just over 500 patients aged 5 to 14 who received an average of 1.6 mg per day. Scores on the Nisonger Child Behavior Rating Form (NCBRF) Conduct Problem Scale improved significantly as early as week one, and the improvement was maintained through week 52. Improvement was noted on positive social behavior and other NCBRF subscales, as well as on the Aberrant Behavior Checklist and the Clinical Global Impressions scale. In addition, performance on cognitive function tests improved. The most common adverse events were somnolence (30 percent of patients), rhinitis (27 percent), and headache (22 percent). Movement disorder side effects were low, and mean Extrapyramidal Symptom Rating Scale scores actually decreased during continued risperidone treatment. No clinically significant changes were seen in children's lab values, except for transient increases in serum prolactin levels.

Antipsychotic polypharmacy is most commonly used to reduce positive symptoms, according to a survey of Veterans Administration Health System clinicians. Patients with schizophrenia who received prescriptions for more than one antipsychotic were identified, and their clinicians were interviewed using a structured questionnaire. Patterns of prescribing and the rationale underlying polypharmacy were analyzed. Sixty-one percent of clinicians said more than one antipsychotic was prescribed to control positive symptoms, followed by 20 percent who said the goal was controlling negative symptoms. Nine percent said decreasing the total amount of medication was the goal, while 5 percent said the goal of prescribing more than one antipsychotic was to reduce extrapyramidal symptoms.

Clinicians reported that 65 percent of the patients' symptoms were refractory to antipsychotic monotherapy, while 39 percent were reported to be in transition between two antipsychotic regimens. However, in only 46 percent of those patients was the reported transition completed within six to 12 months.

Patients at risk of developing agranulocytosis related to clozapine may be identified using genetic markers discovered recently by Genaissance Pharmaceuticals. Announced last month, the discovery could lead to an easy screening method to determine whether patients can benefit from the unique efficacy of clozapine. The company said in a prepared statement that the findings may apply to other medications associated with blood dyscrasias, but released few details pending the filing of patent applications to protect its discovery. The company did say that “these findings have uncovered new clues to the underlying biological and physiologic mechanisms of drug-induced agranulocytosis and provide a starting point for elucidation of a common mechanism across drugs from different classes that carry this rare, but devastating, side effect.”

Forest Laboratories and Gideon Richter USA announced a collaborative effort to bring Richter's atypical antipsychotic, RGH-188, and related compounds to market. RGH-188 is a novel, potent D₂/D₃ antagonist for oral administration. The compound has a unique receptor-binding profile compared with other atypical antipsychotics and is in clinical development for the treatment of schizophrenia and bipolar disorder. The companies intend to begin phase III clinical trials in the United States before the end of 2006. Patent applications covering RGH-188 have been submitted. If approved, the product would be protected until 2024.

GlaxoSmithKline has released preliminary details on its new antidepressant candidate, known as both NS2359 and GSK372475. The company characterizes the drug candidate as very promising, possessing a“ desired triple mode of action”—that being activity enhancing the function of serotonin, norepinephrine, and dopamine. The company expects the drug will have “a more optimal reduction of depression symptoms together with a faster onset of action. Moreover, clinical study in adult ADHD patients has shown that NS2359 also enhances cognitive functions (concentration, attention, and memory).” GSK plans to initiate clinical phase II dose-finding studies this year in major depressive disorder and start phase III clinical trials by the end of 2006. ▪