Vortioxetine

I have been hearing about the new antidepressant vortioxetine (marketed under the brand name Brintellix).  I decided to post something about it because there have been numerous searches that resulted in hits on this blog looking for information on this medication.  As a consultant, I am probably not in the best position to start prescribing this medication.  The majority of the people I see are already on at least one antidepressant and they have typically tried many.  The  common mistakes of ten years ago like inadequate dosing are not as prevalent.  Augmentation strategies like the addition of bupropion, aripiprazole, and buspirone are common. In primary care settings nobody uses lithium or T3 anymore.  Apart from mood disorder specialists, nobody uses monoamine oxidase inhibitors.  I am just getting to the point where I am seeing people who have responded to vilazodone when nothing else seemed to work.  Even then the numbers are very low.  

What if anything is unique about vortioxetine?

Looking at the package insert, it is approved for the treatment of major depressive disorder and nothing else.  The date of approval was 9/30/2013.  It has the standard contraindications, black box warning and warnings of most antidepressants.  It is a substrate of CYP2D6 and therefore the dose needs to be decreased with inhibitors and increased with inducers of this enzyme.  Other cytochromes CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8, and CYP2B6 also play minor roles in the metabolism.  The metabolite is inactive.   Discontinuation symptoms are also mentioned in the package insert citing headaches and muscle tension following abrupt discontinuation.  The manufacturer states that in anyone taking 15 or 20 mg/day that the dose should be decreased to 10 mg/day for a week before discontinuation is done.  Vortioxetine has a 66 hour half-life.

There is generally more detailed pharmaceutical and pharmacodynamic information in recent FDA approved package inserts and vortioxetine is no exception.  As noted in the graphic below it is a potent inhibitor of serotonin reuptake by 5-HTT (SERT) on the same order of magnitude as escitalopram.  The pharmacology of serotonin receptors (right column) is complex.  I have highlighted the serotonin receptors that vortioxetine binds to with Kis of < 100 nM.  The drug is also an antagonist at 5-HT3, 5-HT1D, 5-HT7, a 5-HT1B partial agonist, and a 5-HT1A receptor agonist. (all values in package insert).

Serotonin pharmacology is complex.  One review (2) written by PharmDs with no financial conflicts of interest described the vortioxetine as a "novel multimodal antidepressant agent with a complex mechanism of action".  They suggest that the pharmacodynamic profile "results in increased levels of serotonin, norepinephrine, dopamine, acetylcholine, and histamine."  Interestingly, there has been no comment that it has a greater binding affinity (113) for the norepinephrine transporter (NET) than SNRI venlaxine (385) but not the SNRI duloxetine (70). (see table below).

Also contained in this package insert is information about serotonin receptor occupancy based on imaging studies.  Two clinical Positron Emission Tomography (PET) studies using 5-HTT ligands showed 50%, 65%, and 80% occupancy at doses of 5, 10, and 20 mg/day respectively.

 

Clinical trials results were also described in the package insert.  There w ere 6-8 week double blind placebo controlled studies using the HAM-D and MADRS as outcome measures.  Six studies are plotted on a mean change from baseline plot and all were better than placebo at week 6 or 8 but in 2/11 measurement the error bar touched or went past the no difference from placebo line.   The results of a maintenance study were also described that looked at the results of  randomizing 396 patients in remission to continuation treatment of vortioxetine 10 mg/day or placebo.  The survival analysis showed significantly longer remission of depression in the vortioxetine group.  Using an effect estimation approach the Number Needed To Treat/Harm (NNT/NNH) was 7 (NNT) for response, 11 (NNT) for remission, and 36 (NNH).  In the review article the authors describe a total of 10 short term clinical trials and 6 with an active comparator.  In 5/6 the active comparator ws duloxetine 60 mg/day and in the other it was venlafaxine extended release 225 mg/day.  All 6 of the comparator trials were run against placebo.

Like other serotonergic agents nausea and diarrhea were the most common reasons for discontinuation and the likelihood was dose dependent at significant rates (21-36% vs 9% on placebo).  Sexual dysfunction was measured in 7 of the clinical trials using the Arizona Sexual experiences Scale (ASEX) after baseline rates were established by other clinical means.  The initial rates were 3-5% for men and 1-2% in women.  Using the ASEX, the rates ranged from 22-34% in women versus 20% placebo and 16-29% in men versus 14% placebo.  The most interesting side effect for me was headaches.  There are seven references to head in the package insert and all of them are in discussions of discontinuation symptoms or as a sign of hyponatremia.  I could not find it listed as a side effect.  In looking at the review (2) this may be an artifact of the high rate of headache (7.6-24.8%) in the placebo group.  Overall rates of discontinuation from the clinical trials compared to placebo were low.

At this point vortioxetine is described as a moderately effective antidepressant with a purported novel mechanism of action.  There has been relatively limited exposure of 2616 people in clinical trials.  I expect the pricing to reflect the usual high price of a novel antidepressant medication and in most managed care and pharmacy systems it will require prior authorization and documentation that other medication trials have failed.  From the clinicians perspective, I will be cautious when using it with other medications that have potential pharmacodynamic and pharmacokinetic effects.  The disclaimer that vortioxetine had an effect of cardiac repolarization that was "below 10 ms the threshold for regulatory concern" will not deter me from doing the necessary evaluation in patients who are taking combinations of medications that affect cardiac conduction or present with new cardiac symptoms.  I will also try to provide some discussion of the unknowns to people who are looking for the next medication that might be effective for chronic depression.  In doing that I am going to renew my membership in the ACS for access to a more detailed discussion of the medicinal chemistry involved (reference 3).

George Dawson, MD, DFAPA

1.  Brintellix (vortioxetine) FDA approved package insert.

2. Pearce EF, Murphy JA. Vortioxetine for the treatment of depression. AnnPharmacother. 2014 Jun;48(6):758-65. doi: 10.1177/1060028014528305. Epub 2014 Mar 27. PubMed PMID: 24676550.

3. Bang-Andersen B, Ruhland T, Jørgensen M, Smith G, Frederiksen K, Jensen KG,Zhong H, Nielsen SM, Hogg S, Mørk A, Stensbøl TB. Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem. 2011 May 12;54(9):3206-21. doi: 10.1021/jm101459g. Epub 2011 Apr 12. PubMed PMID: 21486038.