Of two minds: New research finds atypicals are just a modest improvement in schizophrenia treatment

April 16, 2007

Antipsychotic agents have long been integral to the management of schizophrenia. First-generation, "conventional" antipsychotics are high-affinity antagonists of dopamine D2 receptors. Although they are effective against antipsychotic symptoms, they are also associated with a high rate of neurologic adverse effects. Such effects include tardive dyskinesia and extrapyramidal symptoms (EPS).

Clinicians hoped that the introduction of second-generation, "atypical" anti-psychotics would bring increased efficacy and safety. Compared with conventional agents, the atypical agents have a lower affinity for dopamine D2 receptors and a greater affinity for serotonin (5-HT1A, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7) and norepinephrine receptors (alpha-1 and alpha-2).

The latest approval

The Food & Drug Administration recently approved paliperidone (Invega, Janssen), an atypical antipsychotic, for the treatment of schizophrenia. It is the first new treatment for schizophrenia to be approved since 2003.

Paliperidone, the active metabolite of risperidone, is delivered once daily through Alza's OROS osmotic drug technology. This extended-release system consists of an osmotically active trilayer core surrounded by a subcoat and semipermeable membrane. The membrane controls the rate at which water enters the tablet core, which in turn determines the rate of drug delivery.

Akathisia and EPS were among the treatment-emergent adverse events reported in 5% or more of patients treated with paliperidone and at least twice the placebo rate for at least one dose, according to the manufacturer. The company also said that discontinuation rates due to adverse events were 5% for both the paliperidone and placebo groups. As with other atypical antipsychotics, the package insert includes a black box warning regarding the increased risk of death in elderly patients with dementia-related psychosis compared with placebo.

Janssen advised that paliperidone causes a modest increase in the corrected QT interval (QTc), so it should be avoided in patients with congenital long QT syndrome, history of cardiac arrhythmias, and in combination with other drugs that prolong QTc.

Carnahan said that paliperidone could be a second-or third-line agent for most patients. He pointed out, however, that it does have potential advantages for some patients, such as those with liver disease or hepatitis C. The lack of clinically significant CYP450 inhibition or induction could make paliperidone especially good for slow metabolizers, he said. According to the manufacturer, no dose adjustment is needed in patients with mild to moderate hepatic impairment.