USPSYCH: Vigilance Still Necessary for Atypical Antipsychotics

SAN FRANCISCO, April 25 -- Atypical antipsychotic medications have improved adverse-event profiles compared with the older generation of antipsychotics, but careful attention to major side effects is still required.

The overall medication plan should address the major side effect concerns of each patient, said Daniel E. Casey, M.D., of the Oregon Health and Science University in Portland, in a presentation here at the U.S. Psychiatric and Mental Health Congress regional extension.

"Choose your medications with the principle 'first do no harm' in mind," he said. "Chose the drug with the lowest side effect profile."

The atypical antipsychotics were initially defined as those that reduce neurologic extrapyramidal side effects. But, explained Dr. Casey, the definition has shifted to focus on dopamine. Atypical antipsychotics allow physiologic dopamine function to remain relatively intact despite some dopamine antagonism.

The typical and atypical antipsychotics are all closely linked to effects on the dopamine D₂ receptor, he said.

The typical antipsychotic haloperidol (Haldol), for example, is a D₂ antagonist, which puts the receptor in "neutral." Atypical antipsychotics, however, are for the most part D₂ agonists, which act like the endogenous neurotransmitter to turn on the receptor. "Aripiprazole is the exception to the rule," he said. Aripiprazole (Abilify) is a partial agonist, slowing down receptor activity without stopping it entirely.

Typical and atypical antipsychotics also have varying effects on muscarinic and histamine receptors.

Among the atypicals, stronger H₁ receptor binding is clearly related to increasing weight gain as a side effect. Clozapine (Clozaril) and olanzapine (Zyprexa) have the highest receptor affinity with quetiapine (Seroquel) and risperidone (Risperdal) in the middle and ziprasidone (Geodon) and aripiprazole at the low end. The associated weight gain likewise ranges from about 30% for clozapine to 3% for aripiprazole.

Switching to a different atypical medication may reverse problematic weight gain, metabolic abnormalities and other adverse events.

In one study, patients switching from olanzapine to aripiprazole lost an average of almost 2 kg in two months while those who switched from risperidone to aripiprazole lost a little over 1 kg in the same period.

"Side-effect improvements continue beyond the short-term" and "are very predictable," Dr. Casey added.

The predicted changes in weight when switching between newer antipsychotics include:

•Relative weight equivalence when switching between ziprasidone and aripiprazole.
•A big decrease in weight when switching from olanzapine to aripiprazole.
•A moderate decrease in weight when switching from quetiapine or risperidone to aripiprazole.
•A moderate increase in weight when switching from quetiapine or risperidone to olanzapine.
•A large increase in weight when switching from ziprasidone to olanzapine.
•A modest increase in weight when switching from ziprasidone to quetiapine or risperidone.

The predicted changes for lipid levels followed the same parameters with the exception of relative equivalence in lipid effects when switching between risperidone and aripiprazole.

However, he cautioned that switching is an effective strategy only when patients can be maintained on long-term monotherapy of weight-neutral medication.

To avoid problems with rebound extrapyramidal side effects, insomnia and other withdrawal symptoms when switching to another medication, Dr. Casey suggested that patient education and reassurance are important along with strategies such as delayed tapering of the old drug, holding off on raising the new drug dose, and adding an adjunctive medication.

Primary source: U.S. Psychiatric and Mental Health Congress regional extension Source reference: Casey DE "The Pharmacodynamics of Atypical Antipsychotics" USPSYCH regional extension 2007.