Understanding Antipsychotic Drug Mechanisms Helps Predict Side Effects-and How to Respond

Decades ago, the field of psychiatry presumed that patients with psychotic disorders needed enough medication to produce physical effects called “parkinsonism”—the tremors, rigidity, and shuffling seen in the actual disease—because that meant the therapy was working.

Fortunately, according to Peter Weiden, MD, a professor of psychiatry at the University of Illinois Medical Center in Chicago, it is now understood that “no side effect is required for efficacy in antipsychotics.”

That said, side effects are common and psychiatrists must take them seriously, because otherwise patients may “communicate” by going off their medication, Weiden said. He presented Thursday’s talk, “Reducing the Burden of Antipsychotic Medications: An Integrated Approach to Addressing Adverse Effects,” at the 28th US Psychiatric and Mental Health Congress, being held in San Diego, California.

Weiden reminded his fellow clinicians that the burden of treatment never ends for patients on antipsychotics medication. “Our patients never get a day off.” The good news, he said, is the ability to deal with side effects is vastly improved from 10 years ago.

Arrival of the Atypicals. The arrival of clozapine in the 1970s changed treatment; it ended the idea that neurological effects, known as extrapyramidal symptoms (EPS), are necessary for therapy to work. Unfortunately, clozapine came with a host of other adverse effects, including weight gain and metabolic effects.

Atypical antipsychotics have continued to improve, and today’s drugs offer a “neurological burden that is much lower than the older drugs,” Weiden said. “Unfortunately, none of them are as effective as clozapine.”

Today, there are more than 10 different antipsychotics, each with its own side effect profile; professional meetings devote much more time to issues like weight gain and dyslipidemia. Thus, Weiden asked, as newer antipsychotics become less problematic with these issues, “Will we go back to worrying about EPS and akathisia?”

Understanding the Mechanism. Rather than simply read labels and learn lists of side effects for each therapy, Weiden said, it makes sense to understand the mechanism of action for various receptor affinities, because these are better predictors of adverse effects (and perhaps better than efficacy). “You can make pretty good correlations between receptor affinity and the likelihood of a side effect,” he said.

Then, he reviewed the effects of dopamine, histaminic, muscarinic, and alpha receptor antagonism, paying particular attention to the effects of increased prolactin on sexual function. He also presented a grid with the various modern antipsychotics at low, medium, and high doses, showing the different effect on EPS. Targeting a receptor with more than 1 drug has an additive effect, and withdrawing a drug has separate effects, which are important to understand when switching drugs, Weiden said.

What Side Effects Mean to Patients. Akathisia, the feeling of restlessness and distress that is a separate side effect, can occur with or without parkinsonism, and can occur very quickly. Fortunately, it can be addressed with dose adjustments. Sedation, EPS, and blurred vision also respond well to dose adjustment.

Other side effects don’t respond as well, especially weight gain and dyslipidemia. And patient reactions to some side effects may vary over time, Weiden explained. Sexual dysfunction might not be an issue in the immediate aftermath after a psychotic episode, but if a male patient recovers and finds a girlfriend, suddenly it’s the most important issue.

Weiden referred to this as a paradox: the better the antipsychotics work, the more patients focus on the side effects that remain. “What was once acceptable is no longer acceptable.”

Knowing whether a side effect is truly related to medication requires understanding how common the attribute is in the general population for a patient that age. That’s why obesity is so difficult to address, because it is rising overall. And some side effects that matter to clinicians don’t bother patients at all. Insomnia and sexual function matter a great deal to patients, but few worry enough about high lipids to switch medication.

Patients fear changing medication that is keeping symptoms in check, with good reason. Said Weiden, “It’s not human nature to worry about the heart attack you might have 10 years from now.”