Our next stop in our antidepressant discussion focuses on two of the newer medications, vilazodone and vortioxetine. These medications were developed in the last two decades in an effort to identify novel mechanisms of action and minimize some of the more concerning side effects of the “first line” medications we’ve already discussed (SSRI’s, SNRI’s). Vilazodone and vortioxetine obtained FDA approval for depression in adults in 2011 and 2013, respectively, and have been shown to be viable options for treatment of depression in adults. It is worth noting that their effectiveness and utility in children and adolescents has not been established/shown in research studies thus far.
Vilazodone:
As with trazodone (one of the medications we discussed last blog), vilazodone (or Viibryd) has a complex mechanism of action that is still not fully understood. What we do know is that it works through a myriad of mechanisms that all lead to the enhancement of serotonin transmission and functioning in the brain.
The primary mechanism is through the same serotonin reuptake receptor as SSRIs (SERT), however, unlike SSRIs, vilazodone binds “non-competitively” with serotonin to a different site on the SERT receptor than serotonin (and SSRIs) do. When it binds, vilazodone changes the SERT receptor’s shape and decreases (or inhibits) how readily serotonin is recycled by the SERT receptor. Additionally, vilazodone binds to and “partially” activates both the presynaptic (the neurons that produce/release serotonin) and postsynaptic (the neurons that serotonin binds to and activates) 5-HT₁A “autoreceptors” that also leads to an overall increase in serotonergic neurotransmission.
The combination of SERT blockade and 5-HT₁A partial agonism is theorized to lead to an even bigger increase in serotonin activity than observed with SSRIs. This is thought to contribute to its unique clinical effect, including a notable difference in the timing of the onset of effects (as early as 1 week versus the 2-4 weeks with SSRIs).
Given its primarily serotonin-based effects, vilazodone shares many of the side effects of the SSRIs and SNRIs (GI upset, insomnia, emotional blunting, cognitive slowing), however because of its unique mechanisms of action, vilazodone has a lower incidence of sexual side effects compared to traditional SSRIs.
Vortioxetine:
Vortioxetine (or Trintellix) also acts primarily by modulating and increasing serotonergic activity in the brain. It does this through a complex combination of various pathways/effects, which includes binding to the SERT receptor in the same way SSRIs and SNRIs do (“competively”), leading to increases in serotonin activity/transmission. Additionally, vortioxetine binds to and differentially acts on no less than 5 other serotonin receptors that leads to a net increase in serotonin activity, as well as the modulation of multiple other neurotransmitters that lend vortioxetine its unique clinical and side effect profiles.
In addition to its antidepressant effects, vortioxetine is proposed to have additional “pro-cognitive” effects, meaning it has been shown the capacity to help improve the cognitive dulling and memory/executive functioning issues often seen with depression. The mechanism for this additional benefit is mediated by its unique action on multiple serotonin receptors (5-HT₃, 5-HT7, 5-HT₁D, and 5-HT₁A receptors) that collectively lead to increases in norepinephrine, acetylcholine, and glutamate activity. This also contributes to vortioxetine’s less propensity for GI upset, nausea, insomnia, and vomiting than the SSRIs. Like vilazodone, its partial activation of the 5-HT₁A receptors is thought to contribute to a (somewhat) lower incidence of sexual side effects compared to traditional SSRIs.
Conclusion/Review:
Reading through the above unique mechanisms of action, effects, and the proposed better side effect profile of these two medications, one may ask why these medications are not “first-line” options (like the SSRIs/SNRIs). The answer, very simply, is time. As these are newer medications, they do not have the same amount of robust and extensive evidence base for their efficacy, safety, and tolerability. It is possible that with more long-term, high-quality research vortioxetine and vilazodone may eventually be shown to be just as (or even more) effective and well-tolerated as the SSRIs and SNRI. Nonetheless, these medications are already great options for those patients who cannot tolerate/do not respond to the “first-line” options, as well as in specific clinical scenarios (ex. vortioxetine for depression with significant cognitive impairments). As always, I’ll end the blog by reiterating that you should ALWAYS discuss risks and benefits directly with your mental health clinician before making any decisions so they can help guide you in your mental health journey.
