SNRI List: Serotonin Norepinephrine Reuptake Inhibitors

SNRIs (Selective Serotonin Reuptake Inhibitors) are also known as dual-reuptake inhibitors because they prevent the reuptake of multiple neurotransmitters in the brain. Most of the second-generation antidepressants are classified as “SSRI,” meaning they focus solely on preventing the reuptake of serotonin. SNRI drugs continue to prevent the reuptake of serotonin, but also focus on another neurotransmitter called norepinephrine which is hypothesized to play a role in depression.

The SNRI drugs can be very effective for those suffering from depression and anxiety, but also have been proven to help with other conditions. The combination of reuptake inhibition for both serotonin and norepinephrine is what some experts believe makes the drug effective at reducing physical pain in conditions such as neuropathy (associated with diabetes) and fibromyalgia. Although people are just as prone to developing side effects from using SNRIs as other medications, some people simply respond better to this class of drug than the others.

SNRI List: Serotonin Norepinephrine Reuptake Inhibitors

The class known as SNRIs are more “typical” these days than they were in the past. These days many of these drugs are being grouped with SSRIs because they both work on serotonin. Although they are significantly outnumbered by SSRIs, the production of SNRIs has increased in recent years with new medications like Pristiq and Fetzima.

1. Effexor (Venlafaxine)

Approved in 1993, this is a drug that works as a serotonin-norepinephrine reuptake inhibitor (SNRI). At higher doses, the drug is thought to inhibit the reuptake of dopamine to a small extent, thereby working as an SNDRI. Some evidence suggests that the norepinephrine transporter could be also working to increase dopamine levels in the prefrontal cortex of the brain.

This drug has an interaction with opioid receptors (mu, kappa 1, kappa 3) and the Alpha 2 adrenergic receptor. Many people find that this drug works well for treating cases of severe depression.

2. Cymbalta (Duloxetine)

Approved in 2004, this drug provides relief from depression by working as a serotonin-norpinephrine reuptake inhibitor (SNRI). It has also been found to indirectly increase dopamine in the prefrontal cortex. It is also thought that the pain relieving effects of this drug may be linked to the blockage of sodium ion channels.

This drug is considered the second SNRI antidepressant on the market. When it was released, it differed from Effexor in that it had the ability to provide pain relief. It also had a lower ratio of the degree to which it affected serotonin vs. norepinephrine.

3. Pristiq (Desvenlafaxine)

Approved in 2008, this is a synthetic form of the active metabolite in the drug Effexor. It works by preventing the reuptake of serotonin and norepinephrine. It is considered 10x as potent at inhibiting serotonin reuptake as it is norepinephrine. Effexor differs from this drug in the fact that its reuptake inhibition ratio of serotonin to norepinephrine is 3x that of Pristiq.

4. Fetzima (Levomilnacipran)

Approved in 2013, this is an antidepressant that works as a serotonin-norepinephrine reuptake inhibitor (SNRI). It contains the “levo” enantiomer of the drug milnacipran and has similar effects. In comparison to other drugs, this drug provides a more balanced reuptake of both serotonin and norepinephrine. What makes this drug different from other SNRIs is that its ratio of reuptake inhibition is almost even (1:2).

Ratios of Serotonin to Norepinephrine Reuptake Inhibition

Below are different ratios of serotonin to norepinephrine reuptake inhibition. As you can see, Effexor has the most lop-sided ratio. Newer drugs like Cymbalta and Pristiq slightly bridged the gap, but still focus more on serotonin than norepinephrine. The latest SNRI approved for depression called Fetzima favors the norepinephrine, but has almost an equally balanced ratio.

Effexor – (30:1)
Cymbalta – (10:1)
Pristiq – (10:1)
Fetzima – (1:2)

Non-Antidepressant SNRIs

It should also be noted that there are a couple of SNRI medications on the market that have not been approved to treat depression.

Sibutramine

Approved 1998, is an appetite suppressant drug that was initially prescribed to help treat obesity. Due to the fact that it’s been associated with increased risk of strokes and cardiovascular problems, it was pulled from the market in 2010. This drug acted centrally as an SNRI with a distinct mechanism of action, closely resembling amphetamines.

It reduced the reuptake of serotonin by 53%, norepinephrine by 54% and dopamine by 16%. It differs from other appetite suppressants (e.g. amphetamines) because it doesn’t force the release of neurotransmitters, it only prevents their reuptake. It also was considered to act similarly to tricyclic antidepressants (TCAs), but never demonstrated an antidepressant response in studies.

Savella (Milnacipran)

Approved 2009, this drug is utilized for the treatment of fibromyalgia. It has also been approved to treat major depression in countries outside the United States. This drug inhibits the reuptake of serotonin and norepinephrine at a ratio of 1:3. The drug Fetzima (Levomilnacipran) which was approved in 2013 in the United States is very similar to this drug and it inhibits reuptake at a 1:2 ratio – which is slightly more balanced.

Some researchers hypothesize that increasing both neurotransmitters in equal concentration is why certain individuals respond well to this drug. In comparison to the drug Tofranil (Imipramine) with 7 trials, milnacipran was better tolerated with equal efficacy. Recent meta-analyses have shown that there were no significant differences between milnacipran and other antidepressants in terms of efficacy, acceptability, and tolerability.

SNRI Antidepressant Trends: What do you think?

Some people love SNRIs because they experience more relief from depression when norepinephrine levels are increased. There is evidence to support the idea that low norepinephrine could play a role in contributing to a person’s depression. Some people respond very well to the SNRI class, while others experience a backlash of unwanted side effects.

Current trends seem to indicate that many companies are pushing to expand upon the SNRI class and get more of these drugs approved. Pharmaceutical companies also have the ability to essentially hit the jackpot if they are able to get their SNRI approved to treat pain, fibromyalgia, and anxiety. Evidence seems to support this idea too as Cymbalta took the top spot for most prescribed psychiatric drugs of the past year.

What do you think about SNRIs? Do you think that they are a good class of drugs to expand upon? Or do you think that researchers need to stop putting a twist on the same wheel. My thoughts are that companies will continue to essentially “spin” the same drugs until they feel they have made enough money and/or have convincing evidence to pursue another subtype.

I am more in favor of pursuing creative atypical antidepressants like ALKS 5461 and going alternative directions. Even the thought of triple reuptake inhibitors don’t really excite me, as they are just playing a more powerful twist of neurotransmitter roulette. It’s time to start looking past serotonin, norepinephrine, and dopamine in pursuit of a superior class of drug.

Reader discussion (12)

Previously published reader comments are preserved below. New comments are not currently being accepted.

Ellen NicholsMay 1, 2015
Brief background: Dysthymia for forty years, interspersed with a few major depressive episodes, plus SAD. Have used a half dozen SSRI's, one tricyclic (1979), and two forms of MAOI. I have also used Effexor and Cymbalta. At some times, I have been prescribed Wellbutrin, Trazodone, and Risperdal (but not all at once, of course.) The only medications that really moved the needle past the mid-line, that is to say truly brightened my mood, were Trazodone added to others, and Parnate (MAOI) by itself. However, the first made me too groggy and the second interfered with sleep. But for the last 7 weeks I have been taking Fetzima in addition to Wellbutrin, mostly at 40 mg, although I tried a week at 80 mg and was too tired. Finally, I feel good. Some typical side effects, but all can be dealt with or tolerated. In answer to your question, I think that there may be room in the market for one or two more SNRI's with a ratio of less than 10:1. There is such individual response to medications that more than one alternative is needed. And thank you GLOOM for your research on this matter. It helps me to understand why "this time is different," and not chalk it up to the passing of short daylight hours.
KarenAugust 19, 2015
Day one of 80mg Fetzima. Although I am sweating profusely and my BP is alittle high my Pdoc upped me from 40mg. I am anxious, cannot sleep. I have tried them all and still no relief. Had DNA testing and it shows low dopamine. I seriously wonder if any of these meds can help.
LesOctober 29, 2015
Hi Karen, curious about what DNA test you did. In my research I have found the only drugs that can actually increase dopamine levels are amphetamines. Amphetamines are not like reuptake inhibitors, they actually cause your brain to produce more dopamine not prevent reuptake.
MichaelDecember 29, 2015
I have been on SSRI/SSNRI for a long while. What you described does not really match symptoms of low Dopamine. Nevertheless, what has worked the best for me has been taking SSRI in conjunction with Bupropion XL 150mg (Wellbutrin) which increases Dopamine level (more energy, increased happiness... but can increase anxiety as well). Best...
Ivy BAugust 20, 2015
Tramadol is also an SNRI.
JohnOctober 29, 2015
Fetzima was horrible, I had all the worst side effects. I've taken Wellbutrin since diagnosed 15 yrs ago. My gripe is the damn manufacturing companies; until they all produce these meds uniformly, especially the generics, it won't matter what type of meds do what!
Tammy HostetlerDecember 2, 2015
I have a curious case. 50 y/o female has been moody since adolescence, after menopause decided to try antidepressants for increased SI and rage. Cymbalta worked well but due to side effects had to be D/C. Pt tried Statterra, Effexor, with no results. Any suggestions?
DaveDecember 4, 2015
I discovered the SNRI properties of tramadol after being prescribed it for a shoulder injury and found it to be a good fit for my mental health, albeit with sleep disruption and other common side effects (sweating & nausea). I noticed a profound improvement in my mood which I suspect was related to norepinephrine re-uptake. I had used citalopram in the past and was familiar with serotonin increases, too much of which gave me headaches and a distinct inability to concentrate. However the balance of the SNRI properties in Tramadol seem more suitable for me. I no longer need the pain relief from Tramadol and I would like to ask my GP if I can replace citalopram with a more suitable SNRI. Does anyone know the seretonin / norepinephrine ratio of Tramadol so I may discuss this further with my GP to determine the correct SNRI replacement? -Dave
CarolJanuary 19, 2016
Dave, I have found Tramadol works well also for depression and anxiety. It is a synthetic opiate and that is probably one of the reasons that it is helping.
markSeptember 18, 2016
I would be nice if the drug companies came out with very low dose SNRIs. I start to get manic at the current doses. For instance it would be nice if they came out with a 5 or 10 mg Cymbalta. The SNRIs really help me but end up going to far and I get manic. The lowest dose you can currently get for Cymbalta is 20 mg.
JustinJanuary 24, 2017
I have had a similar experience! And the drug was really working beautifully, better than anything I'd ever experienced for anxiety. But I just felt like I needed to be taking like a 10mg dose.
JimDecember 9, 2016
I survived a TBI 14.5 years ago and used SSRIs for years. 4 years ago, a routine follow up MRI showed scar tissue causing degeneration from the original TBI. Am currently being treated for CTE, though only an autopsy will show what disease will eventually kill me. Neurologist switched me from an SSRI to an SNRI for several reasons, one of them to retard rapid degeneration. Currently taking Fetzima x3 years, 120 mg, works great. Only side effect that stayed with me was the excessive sweating, which sucks since I'm already a heavy sweater. The benefits outweigh the side effects by a large margin.

SNRI List: Serotonin Norepinephrine Reuptake Inhibitors

1. Effexor (Venlafaxine)

2. Cymbalta (Duloxetine)

3. Pristiq (Desvenlafaxine)

4. Fetzima (Levomilnacipran)

Non-Antidepressant SNRIs

Sibutramine

Savella (Milnacipran)

SNRI Antidepressant Trends: What do you think?

Reader discussion (12)

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