Med Check

Regulatory and Legal Briefs

• Modafinil was approved by the U.S. Food and Drug Administration (FDA) for the improvement of wakefulness in patients with excessive sleepiness associated with obstructive sleep apnea or shift-work sleep disorder.

Cephalon, which markets the atypical stimulant under the brand name Provigil, had requested approval for the treatment of all sleep disorders. The agency, however, agreed with of its advisory panel, which had recommended a more narrow indication due to concern that such a broad indication could lead to overprescribing.

The most frequent treatment-emergent adverse events associated with modafinil are headache, nausea, nervousness, stuffy nose, diarrhea, back pain, anxiety, and difficulty in sleeping.

• Olanzapine became the second medication approved by the FDA for the treatment of bipolar disorder. Lithium, approved in 1974, is the only other medication that carries an indication for both bipolar depression and bipolar mania, although many medications are now indicated for the acute treatment of mania alone. Olanzapine gained its mania indication in 2000.

In multiple randomized, placebo-controlled trials for both schizophrenia and bipolar disorder, the most frequent adverse events associated with olanzapine were drowsiness, dizziness, weight gain, dry mouth, constipation, restlessness, low blood pressure, and weakness. Hyperglycemia, in some cases associated with ketoacidosis, coma, or death, has been reported in patients treated with second-generation antipsychotic medications, including olanzapine.

• Quetiapine was approved by the FDA both as a monotherapy and as adjunct therapy with lithium or divalproex for the short-term treatment of acute manic episodes associated with bipolar I disorder. A pooled analysis from two double-blind, placebo-controlled trials showed efficacy and safety in treating acute mania in doses up to 800 mg per day as monotherapy, and a separate analysis of trial data showed efficacy as an adjunct to the two mood stabilizers. The most frequent side effects associated with quetiapine were somnolence, dizziness, dry mouth, constipation, increases in liver enzymes (of unknown clinical significance), and weight gain.

• All patients under the age of 18 taking SSRIs have been urged by Health Canada to contact their prescribing physicians “to confirm that the benefits of the drug still outweigh its potential risks in light of recent safety concerns.” The public health advisory follows hearings in the United States on the potential association of SSRIs with suicidal/self-harming behaviors (see Original article: page 2).

Research Briefs

• Benzodiazepine use can be curtailed with a structured, time-limited intervention in older patients taking the medications for chronic insomnia. In a study of 76 patients with long-term insomnia and medication use, 85 percent of patients who underwent a structured medication taper plus cognitive-behavioral therapy were medication free at seven weeks, compared with 48 percent of those who underwent the same medication taper but did not receive the structured CBT. While CBT appears to alleviate the insomnia, the authors noted, real sleep improvements may not be apparent until several months following benzodiazepine withdrawal.

Am J Psychiatry2004; 161:332-342

• Venlafaxine may be effective for children and adolescents who have ADHD but not comorbid depression. In a small, controlled study, the combined norepinephrine/serotonin reuptake inhibitor was associated with significant reductions in total scores on the Conners parent scale and the Clinical Global Impression severity item after a six-week trial. Treatment-emergent adverse events included gastrointestinal upset, somnolence, and headache, but they were generally transient.

Psychiatry Clin Neurosci2004; 58:92-95

• Tapering of atomoxetine therapy does not appear to be necessary. The medication is not associated with a risk of an exaggerated symptom rebound or adverse events when patients abruptly stop their medication. Effects of abrupt discontinuation were studied in four large clinical trials in both children and adults with ADHD. After nine weeks of continuous therapy with the norepinephrine reuptake inhibitor, abrupt discontinuation, as expected, was followed by a general worsening of symptoms, but not to the pretreatment level. No statistically significant discontinuation-emergent adverse events were found in the study subjects compared with patients taking (and abruptly discontinuing) placebo.

J Clin Psychopharmacol2004; 24:30-35

• Bupropion may be a safe and effective treatment for adolescents with nicotine dependence and comorbid ADHD. In an open-label pilot study with 16 adolescents who smoked, 11 also had ADHD. All of the subjects were titrated to bupropion SR 150 mg twice a day and maintained for six weeks. They also received two brief smoking-cessation counseling sessions.

After four weeks, 31 percent of the study participants were abstinent, and the remainder experienced significant reductions in the number of cigarettes smoked daily. Bupropion, a weak inhibitor of norepinephrine, serotonin, and dopamine, did not appear to worsen the patients’ ADHD symptoms.

J Am Acad Child Adolesc Psychiatry2004; 43:199-205

• Paroxetine and other SSRIs are associated with hyponatremia in elderly patients. In a prospective, longitudinal study involving 75 seniors who had depression and were treated with paroxetine, 12 percent developed clinically significant hyponatremia within 10 days of beginning SSRI therapy. Lower body mass and lower baseline sodium levels appeared to be significant risk factors for development of hyponatremia.

Symptoms of decreased serum sodium are often mild and nonspecific, including anorexia, fatigue, lethargy, and confusion—all common in elderly patients with depression and likely to be overlooked. Significant, untreated hyponatremia, however, may be fatal.

Researchers suspect enhanced serotonergic tone leads to increased secretion of the hormone ADH. As blood volume increases due to decreased diuresis, sodium concentration falls. Baseline and periodic electrolyte monitoring is recommended.

Arch Intern Med2004; 164:327-332

• Antipsychotics and antidepressants with significant anticholinergic activity can lead to a pattern of cognitive impairment involving decreased complex attention, declarative memory, and auditory and visual memory not related to a patient’s primary mental disorder. Anticholinergic load does not appear to affect intelligence, simple attention, working memory, executive functions, or motor speed. Researchers estimate that as much as one-third to two-thirds of the memory deficit typically seen in patients with schizophrenia is due to anticholinergic load and can be alleviated by better medication management.

Am J Psychiatry2004; 161:116-124

• Not all antipsychotics are created equal, especially in their risk of causing abnormalities in glucose metabolism, including diabetes. A new study screened peer-reviewed publications, as well as oral and poster presentations. Confirming previous reports (Psychiatric News, March 5), Dutch researchers found 27 case reports of treatment-emergent diabetes associated with clozapine, 39 for olanzapine, four for risperidone, and three for quetiapine between 1995 and 2001 in 13 Western countries, Brazil, and Japan. In the majority of cases, risk factors such as family history, obesity, and ethnicity were present in patients developing diabetes while on an antipsychotic. The researchers noted that a slight overrepresentation of cases associated with olanzapine and clozapine may be reported, related to their longer duration on the market. Careful monitoring of weight, body mass index, and glucose levels is advised.

Pharmacopsychiatry2004; 37:1-11

• Risperidone is more effective than haloperidol at improving negative symptoms in patients with schizophrenia. The two drugs, however, are comparable on improving positive symptoms and total rating-scale scores.

A study was conducted of 41 patients with schizophrenia who took either risperidone (1 mg to 12 mg) or haloperidol (2 mg to 20 mg) daily for three months. Tolerability of risperidone was statistically significantly better than haloperidol as well. The most frequent treatment-emergent adverse events for both drugs were tremor and rigidity; however, they were more pronounced in patients taking haloperidol. Serum prolactin levels, elevated in both groups, were the best predictor of extrapyramidal side effects.

Prog Neuropsychopharmacol Biol Psychiatry2004; 28:285-290

• Risperidone–long-acting injection appears to be beneficial for only about half of the patients who received the new long-acting, second-generation antipsychotic. In a case series report of 50 patients followed over six months, 54 percent achieved at least minimal improvement, 4 percent remained unchanged, 24 percent failed to comply with the injection regimen, and 18 percent deteriorated and were switched to alternative antipsychotic medications. Attrition rate at six months was 42 percent. Supplementation with oral medication was often required for longer than three weeks.

Psychiatr Bull R Coll Psychiatr2004; 28:12-14

• Antipsychotic polypharmacy is generally not thought to be safe and effective, and evidence continues to back up that clinical assumption. A case review of 25 patients (18 inpatients and seven outpatients) with schizophrenia who had been treated with high-dose polypharmacy without improvement examined the effect of switching patients to a single second-generation medication at optimal dosing.

Patients were followed for 12 weeks after the switch. Eleven of the 18 inpatients improved enough on second-generation monotherapy to be discharged, while four were close to discharge at 12 weeks. Average antipsychotic dose was reduced from 2203 mg (chlorpromazine equivalents) to 619 mg per day. The average number of antipsychotic medications decreased from 3.5 to 1.1, while the overall number of psychotropic medications was reduced from nearly seven to 2.6.

Prog Neuropsychopharmacol Biol Psychiatry2004; 28:361-369

• Olanzapine provides significantly more improvement than fluphenazine for long-term treatment of patients with schizophrenia. A 22-week, double-blind, parallel trial compared the two drugs with multiple rating measures for safety and efficacy. Patients taking olanzapine showed greater improvement from baseline to endpoint on the Brief Psychiatric Rating Scale score, the Positive and Negative Syndrome Scale total and positive scores, and the Clinical Global Impression severity score. In addition, patients taking olanzapine showed greater decreases in extrapyramidal side effects compared with patients taking fluphenazine. Weight gain was the most frequent treatment-emergent adverse event in the olanzapine group, while akathisia and insomnia were most common in those taking fluphenazine.

Prog Neuropsychopharmacol Biol Psychiatry2004; 28:311-318

Industry Briefs

• Risperidone–long-acting injection is reportedly a safe and effective alternative for young adults with schizophrenia who are stable on their oral antipsychotic medication. In a presentation at the 12th Biennial Winter Workshop on Schizophrenia in Davos, Switzerland, Professor Hans-Juergen Moller from Ludwig-Maximilians-Universität in Münich reported preliminary data from the Switch to Risperidone Microspheres (StoRMi) clinical trial. These data conflict with a British report (above) in which only half of patients improved.

Nearly 120 young adults aged 18 to 30 were switched from their oral medication to the long-acting risperidone in the German study. More than half had been taking oral new-generation antipsychotics, while 28 percent were on a first-generation medication. Both positive and negative symptoms improved significantly for the majority of patients within the first month and continued to improve over six months.

• Danish neuropsychopharm giant Lundbeck A/S and Merck and Co. announced an agreement to develop and commercialize gaboxadol in the U.S. market. Gaboxadol is a novel, direct-acting GABA-A receptor agonist currently in Phase III clinical trials for the treatment of sleep disorders. To date, the compound has shown sleep-inducing as well as sleep-maintaining properties that have resulted in improvements such that sleep patterns appear to normalize. Under the agreement, Lundbeck will co-promote gaboxadol to psychiatrists following introduction to the U.S. market, which is thought to be at least 18 to 24 months away.

• Akzo-Nobel’s Organon unit has announced that it is continuing its collaboration with Pfizer on the development and commercialization of asenapine, a 5HT2/D2 antagonist. The new-generation antipsychotic is in Phase III trials for the treatment of schizophrenia and bipolar disorder. Early clinical data suggest that asenapine is well tolerated and shows statistically superior efficacy when compared with placebo.

• An extended-release formulation of zaleplon is under development for the treatment of insomnia by King Pharmaceuticals. A Phase II clinical trial program will begin by the end of April, designed to select the most effective extended-release formulation of the short-acting, nonbenzodiazepine hypnotic. The immediate-release formulation of zaleplon is effective in patients who experience difficulty in onset of sleep; however, it has not been shown to increase total sleep time or reduce the potential for premature awakening. In clinical trials to date, the most frequent treatment-emergent adverse events associated with zaleplon were headache, dizziness, and somnolence.

• A rapidly dissolving form of donepezil could make administering that medication to patients with Alzheimer’s disease easier, contributing to improved compliance. A Supplemental New Drug Application was filed by Eisai/Pfizer in Japan nearly a year ago and has now been filed in the U.S. and the European Union through its mutual-recognition procedure. The FDA is expected to make a preliminary decision on the application by late 2004 or the first quarter of 2005. ▪