Med Check

Regulatory and Legal Briefs

• Forest Lab’s Lexapro (escitalopram) was approved by the Food and Drug Administration (FDA) December 18 for the treatment of generalized anxiety disorder (GAD) The approval is based on three studies, all of which documented efficacy and safety. The highly selective SSRI is the third antidepressant to be approved for GAD (Paxil and Effexor are the others). Lexapro was approved in 2002 for the treatment of major depressive disorder.

Common adverse effects seen in clinical trials with escitalopram include nausea, ejaculatory disorder, insomnia, fatigue, decreased libido, and anorgasmia.

• Janssen’s Risperdal (risperidone) was approved by the FDA on December 5 for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder. Risperidone was approved as monotherapy as well as in combination with lithium or valproate.

The approval is based on three clinical trials, two as monotherapy and one in combination therapy, in which risperidone was found to be efficacious. Adverse events noted in the trials included weight gain, extrapyramidal symptoms, sleepiness, gastrointestinal upset, and abnormal vision.

• Purdue Pharma’s OxyContin has been the subject of 65 lawsuits in the last several years, claiming the company acted in a manner in which it contributed to injury in patients who became addicted to the controlled-release formulation of oxycodone. As of last month, all 65 suits had been dismissed, many with prejudice, by courts that determined the claims had no foundation. The company maintained that any injury incurred from the drug was the result of improper medical use of the medication.

• The Wellbutrin SR patent fight continues. Wellbutrin SR’s maker, GlaxoSmithKline, filed suit for patent infringement after the FDA approved a generic formulation from Eon Labs in November. Subsequently, Andrx Corporation announced that it had filed a motion for a temporary restraining order to block Eon’s release of a generic version, claiming it was the first to register a generic bupropion SR with the FDA and therefore enjoyed a 180-day period of exclusivity. Both suits resulted in court orders delaying the release of Eon Labs’ generic product.

• Lofexidine, a nonopiate, nonaddictive treatment for the management of withdrawal symptoms in patients undergoing opiate detoxification, may soon be available in the United States. The drug has an excellent safety profile and thus is often prescribed in outpatient settings. It has been available in Europe for many years as BritLofex. Now, US WorldMeds, a private Kentucky-based pharmaceutical specialty company, has partnered with U.K. BritLofex maker, Britannia Pharmaceuticals, to develop and market the compound in this country. US WorldMeds intends to partner with the National Institute on Drug Abuse to conduct the U.S. clinical trials necessary for FDA approval.

Research Briefs

• Levodopa and other dopaminergic drugs appear to spark reinforcing mechanisms in the brain that could lead to addiction, according to an Israeli report. Several case reports now suggest that medications used to treat Parkinson’s disease, aimed at increasing brain dopamine levels, have elicited “withdrawal symptoms” such as impatience, emotional dependence, and craving to receive the next dose. Symptoms of withdrawal in six patients incorrectly diagnosed with Parkinson’s occurred when physicians attempted to stop levodopa, including continued self-administration of the dopaminergic medication after physicians sought to cease therapy.

Neurology2003; 61:1451

• Baclofen, a GABA-A antagonist, appears to be effective in significantly reducing cocaine use when used in conjunction with standard counseling methods, compared with counseling plus placebo.

In a study of 70 outpatients over 16 weeks, those taking baclofen had significantly fewer urine tests positive for cocaine. The effect was larger in patients who entered the study with chronic, heavy rates of crack-cocaine use. An eight-site replication study with larger patient populations is scheduled to begin next month, funded by the National Institute on Drug Abuse.

J Clin Psych2003; 64:1440-1448

• Paroxetine and other SSRIs and antipsychotics may significantly reduce efficacy of tamoxifen, the most common treatment for estrogen-dependent types of breast cancer. In a company-funded study with 12 women, those taking tamoxifen who were also being treated with paroxetine, a potent inhibitor of the CYP2D6 metabolic isoenzyme, had significantly reduced blood levels of tamoxifen’s active metabolites. While this study looked only at paroxetine, research has documented that many psychotropic medications significantly inhibit the CYP2D6 isoenzyme, including bupropion, fluoxetine, fluphenazine, haloperidol, and perphenazine. Fluvoxamine and sertraline also inhibit CYP2D6, but to a lesser extent. The authors note that drug-drug interactions must be carefully looked at in each patient and that possible genetic variations in the cytochrome metabolic enzymes could also play a major role in differences in efficacy and tolerability of many medications.

J Natl Cancer Inst2003; 95:1758-1764

• Sertraline is associated with clinically meaningful improvement in multiple quality-of-life domains in patients with acute coronary syndrome and depression. Previous studies have shown significant improvement in patients who have either had a myocardial infarction or undergone coronary artery bypass grafting and are then treated with sertraline. The current, company-funded report extends those benefits in a sample of 369 patients hospitalized for heart-related chest pain in the previous month and who met diagnostic criteria for major depression.

J Am Cardiol2003; 92:1271-76

• Sertraline appears to improve depressive symptoms significantly better in women with nonmelancholic depression than does imipramine. However, there appears to be no difference between the two medications in men with nonmelancholic depression. In a study of 239 patients, statistically similar percentages of men (56.5 percent on sertraline vs. 59.3 percent on imipramine) achieved a 50 percent reduction in scores on the Hamilton Depression Rating Scale and the Hamilton Anxiety Rating Scale; however, women on sertraline saw a 72.2 percent response rate, compared with 52.1 percent for those on imipramine.

Prog Neuropsychopharmacol Biol Psychiatry2004; 28:57-65

• Response to antidepressant therapy varies greatly depending on whether depression is unipolar or bipolar. In an analysis of outcomes for 41 patients with bipolar and 37 patients with unipolar depression, short-term nonresponse was more frequent in bipolar (51.3 percent) than unipolar (31.6 percent) depression. Manic switching occurred only in bipolar depression, but was reduced in patients taking concurrent mood stabilizers. Tolerance to medication was 3.4 times more common in bipolar than unipolar depression, and relapse into depression was 4.7 times more common in bipolar depression. No statistically significant differences were seen in rates of negative outcomes in SSRIs, atypical antidepressants, or tricyclics.

Am J. Psychiatry2004; 161:163-165

• All antidepressants are thought to increase availability of serotonin or norepinephrine (or both) through inhibition of reuptake or inhibition of monoamine oxidase. A new study suggests that regardless of the above, all three classes of antidepressants (SSRIs, NRIs, and MAOIs) share the ability to act as functional antagonists at the serotonin type-3 (5-HT3) receptor. Using electrophysiologic recording of 5-HT3 activity, desipramine, imipramine, trimipramine, fluoxetine, reboxetine, and mirtazapine were all shown to block the receptor. The authors concluded that 5-HT3 receptor antagonism may be an unrecognized pharmacologic principle for antidepressant activity.

Mol Psychiatry2003; 8:994-1007

• Risperidone significantly improves scores on the Total Positive and Negative Syndrome Scale as well as the positive symptom subscore, according to a new study. It does not, however, produce significant improvements in negative symptoms in adolescent patients with schizopohrenia. An open-label, prospective study of 11 patients for six weeks showed significant improvements in scores measured by the Brief Psychiatric Rating Scale and the Clinical Global Impression of Severity. Significant adverse effects included extrapyramidal symptoms, somnolence, depression, and weight gain.

J Child Adolesc Psychopharmacol2003; 13:319-327

• Olanzapine appears to be as effective as clozapine in treating patients with schizophrenia who failed to respond to adequate regimens of prior antipsychotic therapy. An 18-week, randomized, double-blind, parallel study found no statistically significant differences in total, positive, or negative scores on the Positive and Negative Syndrome Scale or the Clinical Global Impression of Severity. Response rates were 57.9 percent for those taking olanzapine, compared with 60.8 percent of those taking clozapine. In addition, no significant differences were noted in extrapyramidal symptoms or electrocardiography, vital signs, or laboratory measures.

Prog Neuropsychopharmacol Biol Psychiatry2004; 28:173-180

Industry Briefs

• Risperdal Consta appears to significantly reduce the likelihood of hospitalization due to symptom relapse in patients with schizophrenia. In a study presented at the annual meeting of the American College of Neuropsychopharmacology in San Juan, PR., last month, Lars Eriksson, M.D., head of psychiatry at Sahlgrenska University Hospital in Hisings-Backa, Sweden, retrospectively analyzed hospitalizations prior to and after treatment with Risperdal Consta in 92 patients, followed from two to five years. Patients’ total number of hospitalizations was reduced by 23 percent, while the mean duration of a hospitalization was reduced by 35 percent. Total annual per-patient cost savings to the Swedish health care system averaged $3,631 (USD) for those taking the 50 mg dose to $6,868 (USD) at the 25 mg dose.

The most common side effects noted with Risperdal Consta in the study, which was funded by Janssen Pharmaceutica, were somnolence, akathisia, parkinsonism, dyspepsia, constipation, fatigue, and weight gain. ▪