What is the rationale for an SNRI + SSRI combination ?

[ghost dog]

Hey folks,

I recently saw a pt in consult for chronic pain, and this person was prescribed both an SSRI and an SSRI for their MDD. I'm not sure the rationale for this, as I wasn't able to locate an evidence based reason ( if there is one). In particular, these meds are quite similiar in their mode of action, and they also put the pt at higher risk for serotonin syndrome and other related side effects.

Agree or disgree ?

Comments ?

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[nitemagi]

I don't know of any reason to do this. Better to use one at very high doses.

 

[billypilgrim37]

The only rationales are a) cross-tapering from one agent to another, or b) being really bad at psychopharmacology.

That said, I see people all the time on a low-dose of a TCA for neuropathic pain along with a reasonable dose of an SSRI, and that seems reasonable, or even a dose of amitryptiline prn for sleep with a reasonable dose of an SSRI. In those cases, I just review risks and benefits and run with it if the folks want to continue.

 

[vistaril]

Hey folks,

I recently saw a pt in consult for chronic pain, and this person was prescribed both an SSRI and an SSRI for their MDD. I'm not sure the rationale for this, as I wasn't able to locate an evidence based reason ( if there is one). In particular, these meds are quite similiar in their mode of action, and they also put the pt at higher risk for serotonin syndrome and other related side effects.

Agree or disgree ?

Comments ?

well if you look at the StarD chart, one of the ways you could get that combo is if you're already at Level 2 with Zoloft, one of the level 3 augmentation strategies is to augment with effexor. So even though it't not neccessarily what I do or think of when using StarD, it technically does follow it.....

Honestly though, any real evidence based data on AD combinations/augmentation strategies after initial failure with an SSRI are pretty weak......

the larger question of course is how good are antidepressants for non-severe MDD with obvious clinical manifestations(extreme psychomotor ******ation for example)....the answer is not very good.

 

[dl2dp2]

well if you look at the StarD chart, one of the ways you could get that combo is if you're already at Level 2 with Zoloft, one of the level 3 augmentation strategies is to augment with effexor. So even though it't not neccessarily what I do or think of when using StarD, it technically does follow it.....

Honestly though, any real evidence based data on AD combinations/augmentation strategies after initial failure with an SSRI are pretty weak......

the larger question of course is how good are antidepressants for non-severe MDD with obvious clinical manifestations(extreme psychomotor ******ation for example)....the answer is not very good.

This is false. This is the star*d chart
http://www.nimh.nih.gov/trials/practical/stard/stard-treatment-flowchart.pdf

As u can see. there's no use of an SNRI as an "augment". It's randomized as a switch, not an augmentation.

At this point I'm seriously questioning if you are really a PGY4.

 

[vistaril]

This is false. This is the star*d chart
http://www.nimh.nih.gov/trials/practical/stard/stard-treatment-flowchart.pdf

As u can see. there's no use of an SNRI as an "augment". It's randomized as a switch, not an augmentation.

At this point I'm seriously questioning if you are really a PGY4.

Here is the chart I was looking at.....

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2292431/

under figure 2

I guess the chart I was looking at in this paper is wrong as others are more in line with your chart(where effexor was removed from augmentation under the level 3 guidelines)....

either way, response at that point is very poor anyways abovce placebo no matter what you do.

for routine depression, when pts are telling me they arent getting better on an ssri at therapeutic doses I prefer stopping that AD and switching to another one. The number of depressed non-ocd pts who werent getting any help from Celexa 40mg but will at 60mg is pretty much none....I mean no better than just random chance. That's what the dose response curves say.

Maybe I'll even switch to another medication in the same class first. I've actually stopped Celexa and instead of going to an SNRI or Wellbutrin instead just replaced the Celexa with Zoloft or Paxil or whatever. Doesn't make sense logically, but sometimes pts do improve and I just write it off to placebo....ie pt thought by switching meds they were going to get better.

 

[whopper]

I've seen some patients do better on 60 mg of Citalopram clinically though I am aware of what you brought up Vistaril. There is empiric data showing it the benefit tops off at 40 mg Q daily.

Now how could this be? Some of it could be placebo effect. The max FDA dosage used to be 60 mg, and those people, stablized on 60 mg and possibly not needing it might've only believed they were better there. Other reasons, studies usually only show the effect on the majority, there are outliers, and several people are overweight and they might have needed a higher dosage.

It's perfectly reasonable to believe an SSRI will not work once the patient is on the maximum or close to the max dosage of a med (e.g. Zoloft 150 mg Qdaily) for at least a month with no benefit whatsoever. At the lower dosages, no, you really got to push the meds up higher.

As for the two meds--the SSRI and SNRI, in general I don't see much justification except for a cross-taper as mentioned above. There are sometimes patients that are stabilized on strange regimens where the regimens that should've worked didn't. E.g. I got a guy whose PTSD, panic disorder, and generalized anxiety disorder is stabilized on Gabapentin (max dosage), a B-blocker, and a small dose of Lyrica. Yes I did try him on several SSRIs and 2 SNRIs with no benefit. Any doctor looking at that guy would, I figure, immediately wonder WTF is going on.

In such cases, I recommend good documentation and patient education so if another doctor takes over, they won't make the patient go through another round of meds that won't work as well as putting the next doctor at ease with an out-of-the-ordinary regimen.

But here I go again with cynicism/realism, I have seen plenty of doctors put patients on bad regimens with no good reason. IF a patient is on a strange regimen, at least ask into why it is what it is, but more often than not, from my experience, there is no good reason. It's really just a doctor prescribing on whim that has no knowledge of basic psychopharmacology.

 

[vistaril]

E.g. I got a guy whose PTSD, panic disorder, and generalized anxiety disorder is stabilized on Gabapentin (max dosage), a B-blocker, and a small dose of Lyrica. Yes I did try him on several SSRIs and 2 SNRIs with no benefit. Any doctor looking at that guy would, I figure, immediately wonder WTF is going on.
.

I *love* Lyrica for GAD.......there is a good paper with a decent n showing that it does better than a lot of the drugs we use 1st line.

what I am more intrigued by are when pts actually carry a formal dx of PTSD, panic d/o, and GAD. While hearing that does give me a pretty good idea of what that pt is going to look like clinically(and thus it may be useful), at some point you have to wonder what symptoms are attributable to what dx. Not that it is really important, but I prefer not to put more than 2 anxiety spectrum dx for any one pt as I don't believe it is really known in most cases what is what......

 

[whopper]

True.

I wondered if he had true GAD. Each DSM diagnosis could not be due to another diagnosis. He did have chronic elevated anxiety but it was usually due to PTSD and fear of another oncoming panic attack. It's possible he only had the other two disorders.

The guy was struck by lightening. Each time it rains, and in southern Ohio it rains quite a bit, his PTSD acts up and he gets panic attacks. When I first saw him, he was placed on excessive amounts of Klonopin and Valium mixed together, sometimes had problems standing due to the meds, and his family told me he hasn't been the same. His concentration was off and he didn't feel well.

We tried him on several SSRIs and SNRIs. My 4th stage med I try is Gabapentin and it worked like a charm. In addition, he had chronic pain in his arm due to nerve pain from the lightening and it significantly lessened it. I know Gapabentin does not have an FDA approval for anxiety but I've seen it work in plenty of patients and there are published articles supporting it's use for anxiety.

I got the guy better to the point where he has no excessive anxiety unless there's an actual full-fledged lightening storm and unfortunately those happen quite a bit here in the summer, and we've tried CBT techniques. During those times I do allow him benzos but he only took about 1-2 pills per storm. I am very confident he is not abusing them because a 30 pill supply could last him all year long except when the storms occur. Even then he only takes about 10 per month. He also harbors a lot of anger towards his previous psychiatrist that doped him up on all those benzos.

A problem with Gabapentin and Lyrica is that they do have some abuse potential though most drug-abusers tend to avoid it. Be careful, however. Meds such as Cogentin too can be abused but most of the drug-abusers would just use things like marijuana because the quality of the high is allegedly not as good on meds like Cogentin and Gabapentin.

 

[erg923]

I got the guy better to the point where he has no excessive anxiety unless there's an actual full-fledged lightening storm and unfortunately those happen quite a bit here in the summer,

Why is that bad?

If he doesn't use overly aggressive avoidant behaviors, then he should habituate over time. Encourage him to not use avoidance here. He needs to maintain safety obviously (not outside, not standing by windows), but not running to the basement and cowering in the corner would be a start.

 

[nitemagi]

Here is the chart I was looking at.....

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2292431/

under figure 2

I guess the chart I was looking at in this paper is wrong as others are more in line with your chart(where effexor was removed from augmentation under the level 3 guidelines)....

either way, response at that point is very poor anyways abovce placebo no matter what you do.

for routine depression, when pts are telling me they arent getting better on an ssri at therapeutic doses I prefer stopping that AD and switching to another one. The number of depressed non-ocd pts who werent getting any help from Celexa 40mg but will at 60mg is pretty much none....I mean no better than just random chance. That's what the dose response curves say.

Maybe I'll even switch to another medication in the same class first. I've actually stopped Celexa and instead of going to an SNRI or Wellbutrin instead just replaced the Celexa with Zoloft or Paxil or whatever. Doesn't make sense logically, but sometimes pts do improve and I just write it off to placebo....ie pt thought by switching meds they were going to get better.

Perfect example of why one should think rather than just following charts. If you follow the chart CONCRETELY you could switch to effexor then augment with more effexor.

 

[whopper]

If he doesn't use overly aggressive avoidant behaviors, then he should habituate over time.

True, but it's been years and he still has the problems. He is currently getting CBT and exposure therapy. So far, per him, it hasn't gotten much better and we turned him around, got him off of daily benzos to his current state (GAF or about 41 to about 70) when we did the med switches. From there I thought eventual exposure would've lessened the fear of lightening more and more. Unfortunately, I'll likely not see this guy again since he was one of the last patients I saw in private practice that I just permanently left in May as a stipulation I had to agree with when I joined the university.

Oh and by the way..

There is empiric data showing it the benefit tops off at 40 mg Q daily.

Since I brought this up, several months ago, the FDA dropped the max dosage of Citalopram from 60 mg a day to 40. I wasn't happy with that especially given that I've had patients that swear to me it works better for them at 60 vs 40. I hadn't seen any data supporting this and the FDA gave a response that they felt the benefit/risk ratio wasn't justified at 60 mg without giving the specific evidenced-based data on why. To say I was mad was an understatement because it put me in a position to tell my 60 mg patients to consider switching it when I didn't have much reason to give them other than an FDA regulation where I had no real data to understand the basis of their decision. You know, some docs actually want to understand why they do what they do. Of course it invited questions and I did not have answers to them. Then, of course, came the slew of calls from pharmacists "doctor, don't you know that the new maximum is 40 mg? Why are you continuing them on 60 mg?"

Since then I've seen the data suggesting it and I believe it's probably the same data Vistaril mentioned. Right now, however, I don't know where a link is on the Internet. I read the article off of WebMD sometime ago. I would've been fine with the 40 mg max regulation had they just explained why and provided the evidenced-based data with it. I did a search when the regulation came but did not see anything till several months later.

 

[Slingshot]

I think you have to realize all of these "ssri's" and SNRI's each have a lot more going on in terms of their mechanism of action than simply their classification. I for the most part use their class as a way to classify their side-effect profile but even potentially using two SSRI's if it were not for the risk of SS could potentially provide benefit.

Also keep in mind the affinity of the norepinephrine reuptake activty drastically goes up once past 300mg of effexor and the effect on the SERT continues to go down with higher doses. So a higher dose of effexor at 300 more with a low dose of an SSRI can maximize both serotonin and norepi effects. If you used only effexor at doses above 300 than you would give up maximum serotonergic benefit and if you used cymbalta it is the same thing (lack of serotonergic effect comparatively).

I probably wouldn't bother as there is no evidence and I go with the evidence 99 percent of the time but I can see the theoretical uses.

I often use nortriptyline and celexa or desipramine and celexa to give a true dual action drug and have good results so I would probably do this to minimize SS risk

 

[nitemagi]

I think you have to realize all of these "ssri's" and SNRI's each have a lot more going on in terms of their mechanism of action than simply their classification. I for the most part use their class as a way to classify their side-effect profile but even potentially using two SSRI's if it were not for the risk of SS could potentially provide benefit.

Also keep in mind the affinity of the norepinephrine reuptake activty drastically goes up once past 300mg of effexor and the effect on the SERT continues to go down with higher doses. So a higher dose of effexor at 300 more with a low dose of an SSRI can maximize both serotonin and norepi effects. If you used only effexor at doses above 300 than you would give up maximum serotonergic benefit and if you used cymbalta it is the same thing (lack of serotonergic effect comparatively).

I probably wouldn't bother as there is no evidence and I go with the evidence 99 percent of the time but I can see the theoretical uses.

I often use nortriptyline and celexa or desipramine and celexa to give a true dual action drug and have good results so I would probably do this to minimize SS risk

Do you have evidence that an SSRI in addition to high dose of effexor does ANYTHING to add serotonergic effect. While both cymbalta and effexor are technically SNRI's, I know of no evidence that you're losing serotonergic benefit at high doses, and those medications are still predominantly serotonergic at no matter the dose (often 10:1).

 

[Slingshot]

This is pretty common knowledge..and there are tons of papers on this but saw them years ago and don't know off the top of my head. Effexor at about 300mg starts to become more and more potent in terms of norepinephrine. SERT effect plateaus just like any other ssri with plateauing curve at a relatively small dose. So its the ratio that drastically changes rather than the actual SERT activity (which I probably described incorrectly).

Cymbalta is not at all more serotergic. Ratio is pretty even from low doses on up

 

[nitemagi]

This is pretty common knowledge..and there are tons of papers on this but saw them years ago and don't know off the top of my head. Effexor at about 300mg starts to become more and more potent in terms of norepinephrine. SERT effect plateaus just like any other ssri with plateauing curve at a relatively small dose. So its the ratio that drastically changes rather than the actual SERT activity (which I probably described incorrectly).

Cymbalta is not at all more serotergic. Ratio is pretty even from low doses on up

Becoming more noradrenergic is different than LOSING serotonergic effect.

 

[ghost dog]

I've seen some patients do better on 60 mg of Citalopram clinically though I am aware of what you brought up Vistaril. There is empiric data showing it the benefit tops off at 40 mg Q daily.

Now how could this be? Some of it could be placebo effect. The max FDA dosage used to be 60 mg, and those people, stablized on 60 mg and possibly not needing it might've only believed they were better there. Other reasons, studies usually only show the effect on the majority, there are outliers, and several people are overweight and they might have needed a higher dosage.

It's perfectly reasonable to believe an SSRI will not work once the patient is on the maximum or close to the max dosage of a med (e.g. Zoloft 150 mg Qdaily) for at least a month with no benefit whatsoever. At the lower dosages, no, you really got to push the meds up higher.

As for the two meds--the SSRI and SNRI, in general I don't see much justification except for a cross-taper as mentioned above. There are sometimes patients that are stabilized on strange regimens where the regimens that should've worked didn't. E.g. I got a guy whose PTSD, panic disorder, and generalized anxiety disorder is stabilized on Gabapentin (max dosage), a B-blocker, and a small dose of Lyrica. Yes I did try him on several SSRIs and 2 SNRIs with no benefit. Any doctor looking at that guy would, I figure, immediately wonder WTF is going on.

In such cases, I recommend good documentation and patient education so if another doctor takes over, they won't make the patient go through another round of meds that won't work as well as putting the next doctor at ease with an out-of-the-ordinary regimen.

But here I go again with cynicism/realism, I have seen plenty of doctors put patients on bad regimens with no good reason. IF a patient is on a strange regimen, at least ask into why it is what it is, but more often than not, from my experience, there is no good reason. It's really just a doctor prescribing on whim that has no knowledge of basic psychopharmacology.

Awesome feedback as always. You guys never let me down; I very much appreciate your expert advice !

Cheers.