In our previous blog post, we discussed important terminology/concepts for understanding depression and how selective serotonin reuptake inhibitors (Prozac, Zoloft, Lexapro, etc) work. We started with SSRIs as they are considered the “first line” options, and today we will speak about the other “first line” antidepressant group, the SNRIs (Cymbalta, Effexor, Pristiq, etc). As you’ll recall, the two main theories of depression are the monoamine theory and the BDNF theory. The most relevant to the medications in this blog is the monoamine theory, which postulates that depression is caused by (or at least related to) dysfunctional/decreased serotonin, norepinephrine, and (to a lesser extent) dopamine activity in specific areas of the brain responsible for mood and emotion regulation.
Serotonin norepinephrine reuptake inhibitors (abbreviated as SNRI’s) are newer medications also used in the treatment of depressive and most anxiety disorders. Being newer, the evidence base is somewhat less than SSRIs, however they appear to be just as effective overall and are therefore also considered as first-line options. SNRIs work via a similar mechanism as SSRIs and as the name suggests, block the reuptake or recycling of serotonin and norepinephrine from the synaptic cleft/space. SNRIs similarly block serotonin reuptake effects via inhibition of the SERT receptor, which leads to the downstream effect of increased serotonin transmission/activity. However, SNRIs also block norepinephrine reuptake via an analogous NET (norepinephrine transporter) receptor. This blocking of NET receptors causes an increase in norepinephrine (and to a lesser extent, dopamine) concentrations in the prefrontal cortex (and related areas), leading to similar downstream downregulation of inhibitory receptors as seen with SERT inhibition. Given the similarity of their mechanisms of action to SSRIs, SNRIs also typically require weeks to months for their effects to be fully assessed.
To make things just a bit more complex, SNRI’s differ in the extent of serotonin versus norepinephrine reuptake inhibition, with venlafaxine (Effexor) inhibiting serotonin significantly more than norepinephrine, whereas duloxetine (Cymbalta) being more balanced. Additionally, the ratio of inhibition can also change depending on the dose of the medication. Specifically, norepinephrine inhibition increases with the dose of the three main SNRIs (venlafaxine, desvenlafaxine, and duloxetine). SNRIs norepinephrine effects are theorized to also explain why some SNRIs are also effective for treating neuropathic (“nerve”) pain in addition to depression.
As for side effects, SNRIs generally have a very similar side effect profile to SSRIs, with some mild variation in the frequency and intensity of some side effects. However, as SNRIs also exert changes in norepinephrine transmission, they also carry a risk of increasing blood pressure and heart rate, especially at higher doses. As with SSRIs, these mild side effects (if present) tend to occur early in treatment, are relatively manageable/tolerable, and often resolve as the body/brain adjusts to the medication. Lastly, SNRIs also carry the same black box warning regarding the risk of increased suicidal thoughts in individuals under 25yo, as well as the rare risk of the induction of mania/hypomania (primarily in individuals with significant risk factors for bipolar disorder), and lowering of seizure threshold. As always, please discuss risks and benefits directly with your mental health clinician to help guide you in making decisions that are best for you or your loved one.
