Regulatory Briefs

• The Food and Drug Administration (FDA) on November 15 granted final approval to market Abilify (aripiprazole) to partners Bristol-Myers Squibb (BMS) and Otsuka America Pharmaceuticals. Indicated for the treatment of schizophrenia, the recommended target dose is 10 mg to 15 mg. Dosing must be adjusted in patients taking other medications that induce or inhibit the cytochrome P450 substrates CYP3A4 and/or CYP2D6.

Clinical testing in more than 5,500 patients worldwide suggests the most common adverse effects are headache, nausea, vomiting, lightheadedness, somnolence, akathisia, and blurred vision. Incidence of extrapyramidal symptoms and neuromalignant syndrome (NMS) were extremely low. Two cases of possible NMS occurred during clinical trials, and the incidence of extrapyramidal symptoms was 6 percent for aripiprazole and 6 percent for placebo. A BMS spokesperson told Psychiatric News that the new medication should be in pharmacies about the first week of this month. Prescribing information is posted on the Web at www.abilify.com.

• The FDA cleared for market in October a new nicotine lozenge as an alternative to existing nicotine-replacement products to help individuals stop smoking. Made by GlaxoSmithKline, the Commit brand lozenge will be available in 72-lozenge packs of either 2 mg or 4 mg strengths. Last spring, the FDA forced off the market a nicotine lollipop, maintaining that nicotine was a drug that it had authority to regulate. Complete prescribing information is posted on the Web at www.commitlozenge.com.

• The FDA has required Roche Laboratories to relabel Accutane (isotretinoin), its drug for severe, recalcitrant nodular acne, to carry stronger warnings about potential psychiatric adverse effects.

The label now warns that the drug “may cause depression, psychosis, and rarely, suicidal ideation, suicide attempts, suicide, and aggressive or violent behaviors. Discontinuation of Accutane therapy may be insufficient; further evaluation may be necessary.” The warning is posted on the Web at www.fda.gov/medwatch/SAFETY/2002/accutane_deardoc_10-2002.htm.

• The FDA also approved the first generic isotretinoin, to be produced by GenPharm Inc. of Toronto. The generic will carry identical safety labeling and be distributed under the same restrictive practices as the brand-name product.

• In regulatory action overseas, the Ministry of Health, Labor, and Welfare in Japan has ordered a Dear Doctor warning for AstraZeneca’s quetiapine (Seroquel) after the ministry received 13 reports of serious side effects, including one death, since the drug’s launch in that country in February 2001. Case reports involved elevated levels of blood glucose, diabetic ketoacidosis, and coma.

Research Briefs

• A small study from McGill University in Montreal reports on eight subjects taking mirtazapine (Remeron), a selective combined norepinephrine/serotonin enhancer, who developed a “norepinephrine syndrome.” The syndrome presented as an “atypical mania” with dysphoria, irritability, insomnia, psychomotor agitation, and abnormal gait, which the authors hypothesize is directly related to a “central norepinephrine hyperactivity.”

(Int Clin Psychopharmacol2002; 17:319-322)

• A Spanish report warns that risperidone (Risperdal), when given in combination with the antiviral medication ritonavir (Norvir, commonly used in patients with HIV infection or AIDS), can lead to a reversible coma. Risperidone is a substrate and weak inhibitor of the cytochrome P450 enzyme, CYP2D6, and a substrate of CYP3A4. When given in combination with other drugs that inhibit one or more of those substrates (ritonavir inhibits both 2D6 and 3A4), metabolism of the drug is significantly slowed, allowing serum concentrations of risperidone to increase dangerously, producing serious side effects. The report warns physicians to reduce dosages of both drugs accordingly.

(Clin Neuropharmacol2002; 25:251-253)

• In a large, multicenter study, researchers have reported that serious skin reactions associated with lamotrigine (Lamictal) are rare. While the rash sometimes associated with the anticonvulsant drug, which is often used as a mood stabilizer, can potentially be life threatening, the report notes, in more than 1,950 patients, the incidence of benign rash associated with the drug was 8.3 percent, and a serious skin reaction occurred in 0.1 percent of patients, with only one case of the most severe, potentially life-threatening type of reaction, Stevens-Johnson syndrome. The study was funded by Lamictal maker, GlaxoSmithKline.

(J Clin Psychiatry2002; 63:1012-1019)

• Japanese researchers report that severe weight gain can be a serious side effect of combination therapy involving atypical antipsychotics and certain SSRIs. In particular, in a retrospective chart review, they identified the combination of risperidone and paroxetine as associated with severe weight gain—as much as 14 kg over four months in one patient—that also resulted in diabetic complications. The authors speculate that the cause is a drug-drug interaction involving inhibitory actions by both drugs on the cytochrome P450 enzyme, CYP2D6.

(Clin Neuropharmacol2002; 25:269-271)

• A Spanish report indicates that olanzapine (Zyprexa) may be considered as a first-line treatment for severely psychotic inpatients with schizophrenia. In a sample of 483 patients treated with olanzapine compared with 421 treated with typical antipsychotics, overall improvement in symptomatology was significantly greater with olanzapine, as measured by BPRS positive and negative scores and the CGI. Zyprexa maker Eli Lilly partially funded the study.

(Int Clin Psychopharmacol2002; 17:287-295)

• A review of the England- and Wales-based General Practice Research Database, which holds clinical records of more than 3.5 million subjects, suggests a strong association between olanzapine exposure and hyperlipidemia in patients with schizophrenia. Researchers found 1,268 cases between June 1, 1987, and September 24, 2000, and matched those with 7,598 medication-naïve control subjects with schizophrenia. Patients on olanzapine had a fivefold increase in odds of developing hyperlipidemia compared with controls, and a threefold increase compared with patients taking typical antipsychotics. Risperidone, the only other atypical studied, was not found to be associated with an increased incidence of hyperlipidemia. The study was partially funded by unrestricted funds from BMS, maker of the novel antipsychotic, aripiprazole (Abilify).

(Arch Gen Psych2002; 59:1021-1026)

• Topiramate (Topamax) appears to effectively block SSRI-induced weight gain in patients with anxiety disorders, according to a new study. The report looked at a small cohort of 15 patients, who prior to adding topiramate to their drug regimen, had gained an average of 13 kg. After adding topiramate (at an average dose of 135 mg per day), by the end of 10 weeks the cohort had lost an average of 4.2 kg. The study was partially funded by Janssen–Ortho McNeil, maker of Topamax.

(J Clin Psychiatry2002; 63:981-984)

• Galantamine (Reminyl), an acetylcholinesterase inhibitor commonly used in Alzheimer’s disease and other dementias, may be beneficial in improving negative symptoms in patients with treatment-refractory schizophrenia. Adding galantamine at 12 mg twice a day to a patient’s existing antipsychotic regimen was associated with a clinically significant improvement in negative symptoms within one week of starting the medication, according to a case report. In addition, within a few days of discontinuing the drug, negative symptoms worsened, returning to baseline. Positive symptoms were unchanged during galantamine therapy.

(Clin Neuropsychopharmacol2002; 25:272-275)

• A report from Brookhaven National Laboratories indicates that for a drug to be associated with dopamine-driven reward and addiction, the drug must cause increases in striatal dopamine levels rapidly. Using PET imaging during drug intoxication, researchers verified a long-held hypothesis that increases in dopamine that occur more slowly do not lead to addictive potential.

(Behav Pharmacol2002; 13:355-366)

• Researchers at Eli Lilly have produced further evidence that their new ADHD medication, atomoxetine (Strattera), works through increasing extracellular levels of norepinephrine (NE). In a study in rats, the medication was shown to have very high affinity for norepinephrine transporters, less affinity for serotonin transporters, and relatively low affinity for dopamine transporters. The high affinity for the NE transporter blocks reuptake of NE, increasing availability of the neurotransmitter in synapses in the prefrontal cortex of the rats.

(Neuropsychopharmacology2002; 27:699-711)

Industry Briefs

• A new report from Decision Resources, an independent pharmaceutical research and advisory company, forecasts that Lilly’s new antidepressant duloxetine (Cymbalta) will be the most promising drug launched between 2001 and 2011. The report projects that the new drug will make up 20 percent of all antidepressant sales by 2011. Duloxetine, a combined serotonin/norepinephrine reuptake inhibitor that is more equally balanced in its inhibition of serotonin vs. norepinephrine reuptake than venlafaxine (Wyeth’s Effexor), received its approvable letter from the FDA earlier this year, and Lilly hopes to receive final marketing clearance in the first quarter of next year. The report notes that the drug’s favorable safety profile is especially appealing to general practitioners who have been slow to accept venlafaxine because of its potential to cause cardiac side effects (notably, high blood pressure).

• New data on duloxetine, released by Lilly last month at the U.S. Psychiatric and Mental Health Congress, further indicate that the drug is not only safe (a 52-week, open-label study), but that patients exhibit clinically significant improvements in key mood and anxiety symptoms by the end of the first week of drug therapy, as well as improvements in all depressive symptoms by the end of the second week (two separate nine-week studies).

• Two company-funded studies presented at the recent annual meeting of the American Academy of Child and Adolescent Psychiatry find that both Concerta (McNeil Pharmaceuticals’ methylphenidate) and Adderall XR (amphetamine mixed salts manufactured by Shire Pharmaceuticals Group) are effective and safe, as well as comparable to traditional multiple daily dose regimens. The Adderall study looked at nearly 3,000 children (aged 6 to 12) with ADHD, concluding that the drug was associated with significant improvements in relationships with family and friends, as well as scholastic, emotional, and physical functioning of the children. The Concerta study looked at 177 children (aged 13 to 18) with ADHD and concluded that the drug is effective and safe and not statistically significantly different from twice-daily dosing of short-acting methylphenidate. ▪