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Adding antipsychotic meds to depression treatment offers risks, little benefit, Metro State study finds

“In terms of quality of life and how well people were functioning, there was really not much evidence that these drugs did anything,” said researcher Glen Spielmans.

The addition of the antipsychotic medications was associated with adverse side effects, including weight gain, restless leg syndrome, sleepiness and abnormal results from cholesterol and other metabolic-related laboratory tests.

Medications known as atypical antipsychotics, which are widely prescribed in the United States as an add-on therapy for the treatment of depression, are associated with few benefits and significant side effects, such as weight gain and excessive sleepiness, according to a study published Tuesday in the journal PLOS Medicine.

This finding may help patients and their doctors make more informed decisions about the risk-benefit profile of treatments for depression that combine these two types of medications.

Glen Spielmans
Glen Spielmans

Only one-third of patients with depression respond to antidepressant medications, one of the key reasons the add-on use of antipsychotics has become so popular. Aggressive marketing by the pharmaceutical companies that make these drugs is another. In the United States, the estimated number of annual patient visits to doctors in which an antipsychotic medication was prescribed as an adjunct therapy for depression nearly doubled (from 2 million to 3.9 million visits) from the mid-1990s to the late-2000s.

“It’s become pretty clear that antipsychotics are being used at an increased rate for depression over the last few years, so we wanted to see if the evidence supported that practice,” said Glen Spielmans, the new study’s lead author, in a phone interview earlier this week. Spielmans is a researcher and associate professor of psychology at Metropolitan State University in St. Paul. [Full disclosure: I teach writing and editing courses at Metro State.]

Small benefit, significant risks

For the study, Spielmans and his colleagues examined 14 previously published and unpublished randomized clinical trials in which the combined use of an anti-depressant and an antipsychotic medication were compared to the use of an anti-depressant with a placebo. The medications investigated in the studies were aripiprazole (Abilify), olanzapine/fluoxetine (Symbyax), quetiapine (Seroquel) and risperidone (Risperdal).

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A careful analysis of the data from the 14 studies showed a small benefit from the antipsychotic medications on lifting the symptoms of depression. But when the researchers looked at a more meaningful outcome — whether the patients’ quality of life had improved — no benefit was found.

“In terms of quality of life and how well people were functioning, there was really not much evidence that these drugs did anything,” said Spielmans.

The addition of the antipsychotic medications was associated, however, with more adverse side effects, including weight gain, akathisia (a feeling of restlessness often accompanied by an urge to physically move), sleepiness and abnormal results from cholesterol and other metabolic-related laboratory tests.  

“Taken together,” wrote Spielmans and his study’s co-authors, “our meta-analysis found evidence of (1) some improvement in clinician-assessed depressive symptoms, (2) little evidence of substantial benefit in overall well-being, and (3) abundant evidence of potential treatment-related harm.”

Problematic data

Spielmans said that analyzing the data in the 14 studies was challenging because of problems in how the data was collected and reported. For example, most of the studies used clinician ratings of whether a drug had been effective with patients rather than having patients do that rating themselves.

“One can look through a lot of these studies and not even come out with a clear impression of who is actually completing the ratings,” said Spielmans. “Nor is it clear how well they’re trained to administer those ratings.”

The studies also didn’t make it clear if the people who were rating the patients’ depression were the same as those rating their side effects. “These are supposedly double-blind studies,” said Spielmans, “but based on the side effects, [the clinicians] might be able to tell what’s going on and therefore who’s taking the drug. Then it wouldn’t be a doubled-blind study anymore.”

Finding data on the side effects of the drugs was also sometimes a challenge. “Journal articles are generally not a good place to find adverse events,” said Spielmans. “They just don’t get reported in detail.” To find them, Spielmans and his colleagues often had to dig online through clinical trial registry reports — reports that were not available for all of the studies.

Needed: a more meaningful comparison

An even bigger problem with the studies, he added, was the fact that all of them compared the add-on of the antipsychotic medication with a placebo.

“There was no direct comparison of the adding of the antipsychotic with, say, the adding of psychotherapy or some other kind of medication,” Spielmans said.

A comparison with psychotherapy might be particularly useful. Just recently, British researchers found strong evidence that at least one type of talk therapy is an effective adjunct to antidepressants. The study, a randomized controlled trial published online in the Lancet last December, reported that antidepressant-resistant patients who received cognitive behavioral therapy in addition to an antidepressant experienced both a significant reduction in their symptoms of depression and a significant improvement in their quality of life.

If the results from that study hold, said Spielmans, cognitive behavioral therapy “may be a better choice for more people than taking an antipsychotic.”

Right now, Spielmans recommends that patients with depression exercise caution before using antipsychotics as an adjunct to antidepressants. “Look at whatever research is available, and encourage your doctor to do the same,” he said.

PLOS Medicine is an open-access journal, so you can read Spielman’s entire study at the journal’s website.