We have all seen the ads:
“If your depression isn't responding to whatever nonsense oral antidepressant isn't doing the trick,1 maybe you should add this other thing?”
No. Don’t do that:
I have spent years studying these treatment options. I've taken many of them. Here's a list of antipsychotic medication I've personally taken in the context of having bipolar disorder:
Olanzapine (Zyprexa)
Ziprazidone (Geodon)
Quetiapine (Seroquel)
Aripiprazole (Abilify)
Cariprazine2
Whatever the generic is for saphris is…(I looked it up, it's asenepine).
Lurasidone (Latuda)
The following antipsychotics are approved for augmentation of antidepressant response by the FDA:
Aripiprazole (Abilify)
Quetiapine (Seroquel)
Brexpiprazole (Rexulti)
Additionally, people prescribe them for that purpose all the time.
Nobody should ever do this anymore3. The medications have risks that should not be considered acceptable compared to the alternatives.
Which risks? I'm not gonna make you wait. Massive weight gain and metabolic consequences. I didn't make you wait. But they will adversely affect your weight. See what I did there?
There is just no world in which we should be subjecting humans to those risks when we don't have to. There are additional risks:
Tardive Dyskinesia
Dyslipidemia
Diabetes
Akathisia
And more.
Do Antidepressants Work?
Nassir Ghaemi, M.D. and I have had our disagreements when it comes to ADHD4, however this evaluation of antidepressant efficacy is pretty spot on. To quote the good doctor and colleagues on antidepressant efficacy:
The question, therefore, is not about severity of depressive symptoms, but severity of depressive episodes, assuming that someone meets DSM-IV criteria for a major depressive episode.
…
In other words, if one corrects for the statistical floor effect (which was also shown in the data reported by the authors in a regression model correcting for baseline severity of illness), then the claim that antidepressants are only effective in the most extreme depressive conditions is disproven. Antidepressants are also effective in moderate, as well as in severe, depression.
We confuse ourselves when we narrowly focus on the data presented without also representing in our minds the biases inherent in the numbers we’re looking at.
One of my regular complaints is the definition of the term “works”—and the effect size, a.k.a. how big of a difference were talking about.
Imagine discussing a potential partner for a blind date:
Human one: what does he do?
Human two: the potential partner has employment that is statistically significantly different than that of other partners.
Human one: so a good job?
Human two: it’s different. There is only a 5% change than my assurance is due to chance.
Human one: so coffee…
Antipsychotic augmentation is as exciting as a blind date would be with someone who “we have reason to suspect” is “employed enough.” This is why people Netflix and decline chilling opportunities in the real world.
Let’s address the potency of the placebo response. This recent analysis in JAMA is crucial to understand:
Results Fifty RCTs were included involving various types of placebo or sham interventions with a total of 3228 participants (mean [SD] age, 45.8 [6.0] years; 1769 [54.8%] female). The pooled placebo effect size for all modalities was large (g = 1.05; 95% CI, 0.91-1.1); the placebo effect size in RCTs of specific treatment modalities did not significantly differ. …
Three variables were associated with a larger placebo effect size: open-label prospective treatment before double-blind placebo randomization (β = 0.35; 95% CI, 0.11 to 0.59; P = .004), later year of publication (β = 0.03; 95% CI, 0.003 to 0.05; P = .03), and industry-sponsored trials (β = 0.34; 95% CI, 0.09 to 0.58; P = .007).
For general audiences,
The number of failed interventions was associated with the probability a smaller placebo effect size (β = −0.12; 95% CI, −0.23 to −0.01, P = .03).
When we're looking at antipsychotic augmentation, we find that tiny baby doses of things don't do work, AND everything, FDA approved or not, does about the same thing.
All standard-dose atypical antipsychotics were significantly more efficacious than placebo in the efficacy (standardized mean differences [SMDs] ranged from -0.27 to -0.43). There were no significant differences between these drugs. Low-dose atypical antipsychotics were not significantly more efficacious than the placebo
In a network meta- analysis. This is a complicated study design that is pulling a lot of data from people who are enrolled in clinical trials.
Which gets to my actual point.
Effect size is what matters.5
I described this in my recent article on the M-SLo EQE
In short: the augmentation with antipsychotics—if it made you taller by a ratio consistent with its antidepressant effect—would increase height by only 0.67” to 1.175”. The actually weigh gain however…in just 10 weeks…
Which is not ok.
If only there were other options that were more effective and had a better safety profile? Stay tuned That article is coming next.
Live from APA,
—Owen Scott Muir, M.D.
which is gonna be all of them on average,
Do we even care with the brand names for these things are anymore? There's a whole generation of people who are now out of work who used to come up with names for drugs, and GPT4 is going to do that?
I’m making the above definitive
These have been in my head. We haven't met.
Standard mean difference is an effect size