Regulatory and Legal Briefs

• Bristol-Myers Squibb announced in late January that it was voluntarily removing nefazodone (Serzone) from the European market after regulators expressed strong concerns over potentially severe nefazodone-related liver complications, including failure resulting in transplant or death. The drug remains on the market in the United Sates with a black-box warning.

• The Department of Health and Human Services, acting on the joint recommendations of the Food and Drug Administration (FDA) and National Institute of Child Health and Human Development, ordered government-funded pediatric clinical trials of 12 commonly prescribed off-patent medications. Included in the first 12 drugs to be tested are lithium and lorazepam.

• The FDA has issued a draft guidance on the collection of safety and efficacy data during clinical trials for ethnic and racial demographic groups. The FDA requires companies to submit an analysis of data according to age, gender, and race and an analysis of any modifications of dosing for specific groups when a New Drug Application is submitted. To date, those data have not been submitted in any standardized way.

The new guidance instructs companies on the use of specific race and ethnicity categories in reporting of data. In the guidance, the FDA notes that differential metabolic responses to antidepressants, antipsychotics, and anxiolytics have been known for some time. The draft guidance is posted on the FDA Web site at www.fda.gov/cder/guidance/5054dft.doc.

• Last month the FDA approved Wyeth’s Effexor (venlafaxine) and Pfizer’s Zoloft (sertraline) for the treatment of social anxiety disorder. Zoloft became the first selective serotonin reuptake inhibitor (SSRI) approved under this indication, while Zoloft is the only serotonin/norepinephrine reuptake inhibitor (SNRI) approved for social anxiety disorder.

Industry Briefs

• Pfizer announced last month that it will build a $35 million, 60,000-square-foot research unit in New Haven, Conn., where healthy volunteers will receive medications in development. The 50-bed unit will allow Pfizer researchers in collaboration with Yale University faculty to utilize the latest imaging technologies to closely monitor how the developmental medications work in the body. The facility will specifically target research on medications for mental illnesses and Alzheimer’s disease. Pfizer has one other similar research center in the United States, in Michigan, as well as centers in Belgium and Great Britain. Pfizer’s worldwide research program is based in New London, Conn.

• Elan Pharmaceuticals announced last month that it will start testing two new potential treatments for Alzheimer’s disease in the next 12 to 18 months. One phase I/II preclinical study will be a revamped version of the company’s failed vaccine for Alzheimer’s. Clinical trials of that version of the vaccine were abruptly halted when several patients developed an inflammatory encephalopathy after receiving the vaccine. The second phase I/II trial will study an injectible antibody serum that is designed to attack amyloid plaques. Testing in humans for both treatments, the company said, is expected to be years away.

• Renovis announced last month that it has received an NIMH grant supporting the company’s development of novel targets for drug therapy in psychiatric disease. The company develops specialized preclinical models for drug action in living neurons.

• While GlaxoSmithKline was busy defending its patents for Paxil (paroxetine) in federal district court in Chicago, a federal judge in California gave the company a win in a ruling denying class-action certification to numerous parties claiming that GlaxoSmithKline hid serious side effects and withdrawal syndromes from the FDA and the public. The ruling means the suits will have to proceed individually.

• AstraZeneca announced last month that it had submitted an application to European Union regulators for Seroquel (quetiapine) to be granted marketing clearance for the treatment of manic episodes associated with bipolar disorder. A similar application is pending with the FDA.

Research Briefs

• Offspring of women who have prenatal hypertension and are treated with diuretics are four times more likely to develop schizophrenia. Maternal hypertension alone raised the child’s odds ratio of schizophrenia to 1.69, whereas treatment with diuretics without hypertension raised the odds ratio to 2.55. The most significant risk factor among a study population of 7,866 individuals was maternal schizophrenia, which increased the odds ratio of schizophrenia in the child to 11.12.

(Am J Psychiatry 2003; 160:464-468)

• A consensus workshop has produced a set of 14 treatment recommendations on the use of atypical antipsychotics for aggression in youth. The recommendations address evaluation, treatment, stabilization, and maintenance management. The workshop group, which included a number of world-renowned experts in child and adolescent psychiatry, based the recommendations on available research, clinical trials, and clinical experience.

(J Am Acad Child Adolesc Psychiatry2003; 42:145-161)

• A prospective open-label trial of olanzapine (Eli Lilly & Co.’s Zyprexa) indicates that the drug is effective in treating adolescents with schizophrenia. The eight-week trial studied 16 outpatients between the ages of 12 and 17 years. Significant improvement was seen on the Positive and Negative Syndrome Scale, the Clinical Global Impression Scale (CGI), and the Children’s Global Assessment Scale. Reductions were seen in both positive and negative symptoms, with sedation and increased appetite the most common side effects.

(J Am Acad Child Adolesc Psychiatry 2003; 42:170-175)

• The translation of a basic-science finding into a clinically significant improvement in treatment options is detailed in a report on the development of the extended-release OROS formulation of methylphenidate (ALZA’s Concerta). Early long-acting forms of the ADHD medication were unsuccessful because of acute tolerance to sustained clinical doses of methylphenidate. The OROS-patented formulation overcame that hurdle, providing both rapid onset and long duration of therapeutic effect through a unique dosing mechanism.

(Arch Gen Psychiatry2003; 60:204-211)

• Methylphenidate appears to be as effective in children with ADHD who also have mental retardation as it is in children who do not have comorbid mental retardation. In a small study of 24 children and adolescents with ADHD and mental retardation, methylphenidate was linked to significant improvements in teacher and parent ratings for attention, hyperactivity, aggression, and asocial behaviors.

(J Am Acad Child Adolesc Psychiatry 2003; 42:209-216)

• A switch to ziprasidone (Pfizer’s Geodon) was associated with a significant decrease in average weight as well as reductions in total cholesterol and triglycerides in patients with mental retardation and maladaptive behaviors who had previously been taking other atypical neuroleptics. The monthly frequency of the maladaptive behavior remained unchanged during the medication switch.

(J Clin Psychiatry 2003; 64:60-62)

• In a review of data from a large national database from the Veterans Affairs health care system, patients with schizophrenia were significantly more likely to see improvements in Global Assessment of Functioning Scores if they continued to take their originally prescribed neuroleptic, rather than switching medications. No significant differences in functioning scores were seen between patients taking typical vs. atypical neuroleptics.

(Am J Psychiatry2003; 160:310-315)

• Clozapine (Novartis’s Clozaril) appears to be an effective atypical neuroleptic for the treatment of psychosis associated with Parkinson’s disease. In a five-year study of 32 patients with Parkinson’s and psychosis, clozapine was associated with significant improvements as measured on the Mini Mental Status Exam (MMSE) and the Parkinsonian Psychosis Rating Scale. No cases of neutropenia occurred, and no exacerbation of motor symptoms was seen in patients taking clozapine.

(Clin Neuropharmacol 2003; 26:8-11)

• In a small study of six patients with comorbid schizophrenia and dementia, the addition of donepezil to existing neuroleptic therapy was found to improve scores on the MMSE, e Alzheimer’s Disease Assessment Scale, Cognitive Subscale, and CGI.

(Clin Neuropharmacol2003; 26:12-17)

• People with impulsive-aggressive behaviors appear to respond well to citalopram (Forest’s Celexa). In an eight-week, open-label, placebo-controlled study, patients taking citalopram showed significant reductions in scores on the Overt Aggression Scale–Modified, the Barratt Impulsiveness Scale, and the Buss-Durkee Hostility Inventory.

(J Clin Psychiatry2003; 64:81-85)

• In a study of 92 patients with treatment-resistant depression, 40 percent responded well to nortriptyline (Mallinckrodt’s Pamelor), while an additional 12 percent achieved remission. Response was defined as a 50 percent reduction in a patient’s score on the 17-item Hamilton Rating Scale for Depression. However, just over one-third of patients were unable to complete the trial, mostly due to side effects.

(J Clin Psychiatry 2003; 64:35-39) ▪