Hating on Antipsychotics: Are We Going Too Far?

Antipsychotics are not perfect. No drugs are. They can cause weight gain and weird movement side effects and sleepiness. But they have their uses, such as quelling racing thoughts, inner turmoil, and psychosis. There’s nothing inherently good or bad about any class of drugs. It’s up to physicians to understand the data and to prescribe medications judiciously.

With that introduction out of the way, let me describe for you a recent study that was published in the July 11 issue of JAMA. It’s called the VAST-D trial, which stands for “VA Augmentation and Switching Treatments for Improving Depression Outcomes”. In this study, researchers randomly assigned 1522 patients to thee treatments: 1. Switch from the current antidepressant to bupropion; 2. Continue the current antidepressant, and add bupropion; 3. Continue the current antidepressant and add aripiprazole (a second-generation antipsychotic that is FDA approved for adjunctive use in depression). (By the way, the study was not funded by aripiprazole’s makers, and the medication is now available in a low cost generic form).

 After 12 weeks of treatment, the aripiprazole augmentation group fared somewhat better than the others:

Outcome at 12 weeks	Aripiprazole augmentation	Bupropion augmentation	Bupropion switch
Remission rate	29% (statistically superior to bup switch)	27%	22%
Response rate	74% (statistically superior to bup switch and augmentation)	66%	62%

Aripiprazole augmentation yielded a higher remission rate than switching to bupropion, and it produced a higher response rate than either one of the bupropion strategies. But let’s look at side effects—some were more common in the aripiprazole group, others in the bupropion group. Side

Effects Statistically More Common in the Aripiprazole Group:

Side Effects	Aripiprazole augmentation	Bupropion augmentation	Bupropion switch
Akathisia	14.9%	5.3%	4.3%
Somnolence	14.5%	7.9%	7.2%
Weight increased by at least 7% at 12 weeks	9.5%	1.9%	2.3%
Weight increased by at least 7% at 36 weeks	25.2%	5.2%	5.2%

Side Effects Statistically More Common in the Bupropion Groups:

Side Effects	Aripiprazole augmentation	Bupropion augmentation	Bupropion switch
Anxiety	16.6%	22.5%	24.3%
Tremor	3.8%	10.3%	6.1%

Basically, bupropion caused more anxiety and tremor, while aripiprazole caused more weight gain, tiredness, and akathisia (a feeling of inner restlessness often caused by antipsychotics). Now, although aripiprazole caused more side effects, patients seemed to be less bothered by these side effects than those in the other treatment groups—at least as measured by the percentage of patients who withdrew from the study due to side effects. Only 5.3% of the aripiprazole patients withdrew because of side effects, as opposed to 7.3% in the bupropion augmentation group, and 10% in the bupropion switch group.

If you want to quibble with the results, there are a lot of details about the study that you can pick apart. And as is true for just about any large study, these would be reasonable points. But for me as a clinician, the bottom line is that this is the first large truly randomized study comparing antipsychotic augmentation with two other very common strategies for patients who don’t respond to the first antidepressant. And the results pretty clearly show that aripiprazole augmentation is somewhat more effective than the two other methods tested. This doesn’t mean that suddenly all my patients are going to be on aripiprazole. A quarter of patients had significant weight gain after 9 months, and about 15% had akathisia. Those can be problems, but in clinical practice, you monitor for side effects, and if they are bad, you stop the offending medication and try something else. That’s a risk/benefit decision . . . and this study implies that aripiprazole should be high on your options for treatment resistant depression.

But here’s the thing: Nobody seems to want to admit that it works.

 On Medpage Today’s Slow Medicine blog, the focus was on the side effects of aripiprazole, and how this study will definitely not convince them to use aripiprazole.

 Their commentary was titled “No Atypical Antipsychotics for Depression,” and they concluded with: “In the face of uncertainty, our Slow Medicine philosophy favors the safer, more conservative approach. VAST-D will not change our practice. Until we see clear evidence of benefits that outweigh the harms, we don't see a role for antipsychotics for most patients with depression. For now, among patients with an inadequate response to a first antidepressant, we'll try a second antidepressant, consider enhancing behavioral therapy, or think about augmenting with the safer medication, buproprion.”

Given that their philosophy is to avoid quick fixes and take a cautious approach to new treatments, I can understand this coming from Slow Medicine. But even the authors of the original JAMA article took pains to downplay the results. Here’s their conclusion:

 “Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach.”

Really? First, they’re reminding us that we can’t generalize the results beyond the population studied (okay, we got that, it is, after all, a study of vets). Second, they are pretending that response rate was not one of the pre-specified outcome variables (it was a secondary outcome, but based on the same depression scale used for the primary outcome), and therefore they are making believe that there’s no evidence that aripiprazole was better than bupropion augmentation, not just better than switching. And finally, there’s this bizarre indirect way of saying “these results are unimpressive, don’t change your practice.” (I guess that’s what they mean by “net utility”).

 Dudes, this was a major study, and you got an interesting, clinically relevant, result!

It’s okay to brag a little. Let’s go where the data take us, even if we’ve become accustomed to hating on the drugs that come out on top.