Med Check

Regulatory and Legal Briefs

• Memantine, after receiving a unanimous vote in favor of approval from the Food and Drug Administration’s (FDA) Peripheral and Central Nervous System Drugs Advisory Committee in September, quickly received final approval on October 17. Forest Labs will market the novel NMDA receptor antagonist to treat moderate to severe Alzheimer’s disease under the brand name Namenda. The drug is expected to be on pharmacy shelves in early January. FDA Commissioner Mark McClellan, M.D., Ph.D., hailed the approval as “good news for Alzheimer’s disease patients” and noted it is the first drug approved for patients with more severe and advanced disease. The drug is presumed to work by blocking the action of glutamate and preventing excitatory overstimulation, leading to toxicity. The most frequently cited adverse effects in clinical trials were dizziness (7 percent), headache (6 percent), and constipation (6 percent).

• Duloxetine received its approvable letter from the FDA last month for treatment of major depression. Eli Lilly’s new, more evenly balanced, serotonin-norepinephrine reuptake inhibitor is believed to offer unique clinical benefits over older medications that target only serotonin or norepinephrine. Currently, only one other combined inhibitor, venlafaxine, is available; however, it exerts a much stronger effect on serotonin than on norepinephrine. To be marketed under the brand name Cymbalta (pronounced sim-BALL-ta), the drug is expected to receive final approval after Lilly resolves manufacturing concerns. In addition, final labeling remains to be approved. The novel agent is expected to gain market share quickly, according to analysts at London-based Datamonitor, which tracks pharmaceutical industry trends. Datamonitor predicts sales of Cymbalta will approach $1 billion in sales within four years of entering the market.

• Escitalopram was issued an approvable letter by the FDA for the treatment of generalized anxiety disorder (GAD). The most selective of the serotonin reuptake inhibitors, it was approved in August 2002 for depression treatment. Final approval of the supplemental application for GAD is expected later this year or early in 2004. Forest Laboratories markets the drug in the U.S. under the brand name Lexapro, holding a license from the Danish pharmaceutical company H. Lundbeck A/S, which developed both escitalopram and its older “sister” citalopram.

• Modafinil received its approvable letter from FDA for treatment of somnolence associated with a prolonged inability to adjust to shift work and with sleep apnea. Cephalon, which markets the stimulant under the brand name Provigil, had requested approval for the treatment of all sleep disorders. However, the FDA’s advisory panel recommended a more narrow indication, expressing concern that such a broad indication could lead to overprescribing. Modafinil is currently indicated only to treat daytime sleepiness associated with narcolepsy.

• The FDA on October 3 issued a report detailing measures it proposes to combat what the agency termed “the growing threat of counterfeit drugs” available in the United States. Recognizing that “there is no single magic bullet” to combat the increasingly sophisticated counterfeiting of medications, the report calls for consideration of multiple methods to authenticate medications, including tiny bar codes, radio-frequency tags, and color-shifting ink for printing on tablets and capsules. The agency has been collecting comments from the public and the pharmaceutical industry and is expected to release a final report in early 2004. The report is posted on the Web at www.fda.gov/oc/initiatives/counterfeit/.

• Quetiapine won approval through the European Union’s Mutual Recognition Procedure to be marketed in 14 countries for the treatment of mania associated with bipolar disorder. Marketed by AstraZeneca as Seroquel, the drug is under review by both the FDA and the United Kingdom’s Medicines Control Agency for the treatment of mania.

• Nefazodone will be removed from the market in Canada on November 27. In discussions with Health Canada, Serzone maker Bristol-Myers Squibb agreed to discontinue the manufacture and distribution of the antidepressant because of significant risks of liver damage and disease associated with the drug. As of December 2002, 51 cases of serious liver damage, including cirrhosis leading to transplant and death, had been reported. The drug remains on the market only in the U.S. and Australia.

Research Briefs

• Isotretinoin does not appear to be associated with new-onset depression and self-injury (including suicidal behaviors), despite well-publicized reports that tried to link the drug to neuropsychiatric side effects. A review of pharmacy claims in a nationwide database looked for connections between prescriptions for the acne drug and prescriptions for antidepressants. Among 2,821 patients who had filled prescriptions for both, 1,439 filled the antidepressant prescription first, and 1,382 filled it after the prescription for the acne drug. The researchers concluded there was no evidence of a causal relationship and noted that both groups were well balanced demographically.

J Am Acad Dermatol2003; 49:424-432

• Midazolam is an effective and well-tolerated method for rapid sedation in psychiatric patients who present to emergency rooms with agitation and aggression. In a randomized clinical trial conducted in Brazil, 301 patients received either intramuscular midazolam or a combination of intramuscular haloperidol plus promethazine. Nearly 90 percent of patients who received midazolam were tranquil or asleep at 20 minutes after the injection, compared with 67 percent of those receiving the combination. Midazolam remained significantly better at producing sedation at 40 minutes. By one hour, the two groups were roughly equal. Side effects did significantly differ between the groups, with one patient given midazolam experiencing respiratory depression and one patient receiving the haloperidol/promethazine combination experiencing a grand mal seizure.

BMJ2003; 327:708-713

• Olanzapine may be better than risperidone in controlling negative symptoms in middle-aged patients (aged 50 to 65) with schizophrenia. The two medications were shown to be about equally effective at controlling positive symptoms in a large, international, randomized trial. The Lilly-funded trial lasted 28 weeks. After eight weeks, scores on the Positive and Negative Syndrome Scale were significantly different for the negative subscale, a difference that was maintained at 28 weeks.

J Clin Psychiatry2003; 64:998-1004

• Citalopram augmented by morning light therapy can be more effective in treating depression than the SSRI alone. In a small clinical trial, 30 patients were randomized to either 40 mg citalopram plus 30 minutes of exposure each morning to a particular wavelength of light or citalopram and a “placebo” light that did not contain the phased wavelength in question. The light therapy, which simulated particular wavelengths abundant during early morning hours of natural sunlight, appeared to increase treatment response. Nearly 78 percent of patients exposed to the active light therapy while taking citalopram experienced at least a 50 percent reduction in their Hamilton Depression Rating Scale score, while just 41.6 percent of those patients who took citalopram but were exposed to the placebo light achieved at least a 50 percent reduction.

J Clin Psychiatry2003; 64:648-653

• Methylphenidate appears effective in improving ADHD symptoms in adults, is well tolerated, and has minimal side effects. In a double-blind, crossover trial of placebo versus active medication, 30 adults with documented childhood ADHD and who still showed ADHD symptoms were administered 10 mg of methylphenidate or placebo three times a day for two weeks, then 15 mg of medication or placebo three times a day for two weeks. Following a washout of one week, those who received placebo were crossed over and administered active medication under the same schedule for an additional four weeks. Those who received active medication during the first round received placebo during the second round. All patients showed significantly better self-report ratings and scores on computerized tests when on methylphenidate than on placebo. No differences were noted between the two doses of active medication.

Can J Psychiatry2003; 48:546-554

• Donepezil may have a protective effect in preserving hippocampal volume loss in patients with Alzheimer’s disease. In a double-blind, placebo-controlled trial, 67 patients with mild to moderate Alzheimer’s were given either donepezil or placebo for 24 weeks. Right, left, and total hippocampal volumes were imaged using MRI, and brain concentrations of N-acetylaspartate—a neuronal marker of functionality—were measured using proton magnetic resonance spectroscopy. Donepezil-treated patients at the end of the study had significantly smaller decreases in right and total hippocampal volume than the decreases observed in patients taking placebo. At several interim assessments, levels of N-acetylaspartate were higher in patients treated with donepezil versus placebo; however, these differences were not statistically significant. Patients taking donepezil consistently scored better on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) than patients taking placebo.

Am J Psychiatry2003; 160:2003-2011

• Atypical antipsychotics are being prescribed more commonly than older conventional neuroleptics in American nursing homes, and those prescriptions appear to be appropriately indicated and written for appropriate dosages. In a cross-sectional study of nearly 140,000 nursing-home residents in five states from January 1, 1999, to January 31, 2000, 15 percent (86,514 nursing home residents) received a prescription for an antipsychotic. About 56 percent of those prescriptions were for atypicals, while 39 percent were for a conventional drug. The remainder received combination therapy. According to appropriate-use categories defined by the Centers for Medicare and Medicaid Services, more than 90 percent of antipsychotic prescriptions were either appropriate or potentially appropriate.

J Clin Psychiatry2003; 64:1106-1112

• Duloxetine, nearing FDA final approval for depression, appears to also be an effective treatment for anxiety associated with depression. In a series of Lilly-funded clinical trials used for FDA approval, the combined serotonin-norepinephrine reuptake inhibitor was compared with placebo and either paroxetine or fluoxetine. Duloxetine was significantly better than placebo at reducing symptoms of anxiety, and in three comparisons, duloxetine was superior to paroxetine and fluoxetine. Duloxetine provided rapid relief of symptoms of anxiety and was well tolerated.

Depress Anxiety2003; 18:53-61 ▪