Question from a Member (slightly edited and emphasis in red added by us):
There is a rationale for combining antidepressants when the second agent has a different mechanism of action. But can SSRIs and SNRIs be combined?
Wouldn’t that be somewhat redundant since they are interchangeable, have similar mechanisms of action, and have a theoretical risk of serotonin syndrome?
We know from clinical experience and a little bit of published data that clinicians do sometimes combine a selective serotonin reuptake inhibitor (SSRI) and a serotonin-norepinephrine reuptake inhibitor (SNRI) for the treatment of major depressive disorder.
Let’s look at what could ever be a reason for combining an SSRI and an SNRI, given that they are both serotonergic and, yes, combining two serotonergic medications could lead to serotonin syndrome.
Case Report: Why an SSRI was added to an SNRI
A published case series reported on four patients with a depressive disorder who had been treated with at least two different classes of antidepressant medications and had only a partial response to a high dose of venlafaxine but then improved after an SSRI was added to the venlafaxine (Gonul et al., 2003).
One of those patients developed a headache after venlafaxine was increased to 375 mg/day, and her blood pressure had gone up. So, venlafaxine was reduced to 300 mg/day, and sertraline 50 mg/day was added. The patient improved significantly with this combination (Gonul et al., 2003).
Think about it. The dose of venlafaxine was reduced by 75 mg and it was replaced by sertraline 50 mg/day. If they had added sertraline 50 mg/day to venlafaxine 375 mg/day, the total dose of sertraline and venlafaxine—and, so, the risk of serotonin syndrome—would have been higher.
Inhibition of norepinephrine reuptake increases when the dose of venlafaxine is higher. In another article on this website, we noted that a large meta-analysis of venlafaxine clinical trials reported that increased sitting diastolic blood pressure in patients on venlafaxine was statistically and clinically significant only when the dose was above 225 mg/day (Thase, 1998). When the dose of venlafaxine was between 300 and 375 mg/day, more than 10% of patients met the criteria for new-onset hypertension (Thase, 1998). For more on this, please see the following article on this website: Key facts about increased blood pressure on venlafaxine
In the case described above, what may have been gained by replacing 75 mg of venlafaxine with 50 mg of sertraline? Equivalent serotonergic activity without an increase in noradrenergic activity or risk of increased blood pressure.
By the way, 75 mg of venlafaxine and 50 mg of sertraline are equivalent (see our article: Antidepressant medications: Dose equivalents.
Is combining an SSRI and an SNRI more efficacious?
I have looked but could not find any published randomized, controlled clinical trial that compared an SSRI or SNRI alone to a combination of an SSRI and an SNRI.
A systematic review and meta-analysis of “Combining Antidepressants vs Antidepressant Monotherapy for Treatment of Patients With Acute Depression” included 39 randomized controlled clinical trials that compared antidepressant combinations to antidepressant monotherapy, but none of them evaluated the combination of an SSRI and an SNRI (Henssler et al., 2022).
Why do some clinicians *think* that the combination may be more efficacious?
If the patient has not yet been treated with a single SSRI or SNRI in the full dose and for long enough, then a second antidepressant is added, and the depression improves, it may be wrongly concluded that it is the combination of the two antidepressants that has worked.
Here’s one example from the same case series that was mentioned above (Gonul et al., 2003). One of the patients they described developed a severe major depressive episode that did not respond to other antidepressant trials (not described here) and so was started on venlafaxine extended-release (XR). This is what happened:
– Venlafaxine XR 225 mg/day for 4 weeks→Partial improvement in depressed mood
– Venlafaxine XR 300 mg/day for another 4 weeks→No further improvement
– Venlafaxine was reduced back to 225 mg/day, and citalopram 20 mg/day was added→Marked improvement
I want to use this abbreviated description of the case to make the point that in situations like this, we don’t know whether the depression would have improved if one of the following things had been done instead of adding citalopram:
– Venlafaxine XR 300 mg/day was given for a full 8 weeks, or
– The dose of venlafaxine XR as monotherapy had been increased to 375 mg/day.
Can combining an SSRI and an SNRI really cause serotonin toxicity (syndrome)?
The risk of serotonin toxicity (syndrome) is not just a theoretical one.
For example, in one study that compared 60 older adults with serotonin toxicity to a large control group, 8% of those with serotonin toxicity had been on a combination of an SSRI and an SNRI compared to 0.5% of those in the control group (Erken et al., 2022).
(Please note that these numbers cannot tell us what percentage of patients given a combination of an SSRI and an SNRI are likely to develop serotonin syndrome.)
Another finding in this study was that higher antidepressant doses (calculated as equivalent doses of fluoxetine) were also associated with an increased risk of serotonin syndrome.
I was disappointed that this study did not look at what I think is the key question: Was being on a combination of an SSRI and an SNRI associated with an increased risk of serotonin syndrome even if the total antidepressant dose (SSRI plus SNRI) was not higher than the doses taken by those on monotherapy?
Conclusions and Clinical Recommendations
(I should clarify that we are not talking here about patients temporarily on an SSRI and an SNRI due to being cross-tapered from one to the other.)
1. “Are an SSRI and an SSRI being combined?”
The answer is yes, we do see this combination in clinical practice and discussed in some published literature (Palaniyappan et al., 2009; Gonul et al., 2003).
2. “Can an SSRI and an SNRI be combined?” is a question about whether it is safe to do so.
While the combination has been safely used in many cases (for example, Gonul et al., 2003), clinicians should know that this combination has been shown in other cases to be associated with serotonin toxicity (Erken et al., 2022).
I also hope that those combining an SSRI and an SNRI are keeping in mind the possibility that one of the two antidepressants being combined may be increasing the serum levels of the other by inhibiting its metabolism.
3. “Why would an SSRI and an SSRI ever be combined?” is, I think, the most important question we should consider.
There is no good reason to think that the combination of an SSRI and an SNRI is more effective for the treatment of depressive disorders than just increasing the dose of one antidepressant or switching to a different antidepressant.
Clincians who sometimes combine an SSRI and an SNRI must ask themselves WHY they are doing this instead of employing the many alternative strategies open to them.
Except in rare situations where there is a specific reason to do so, I recommend that we should NOT combine an SSRI and an SNRI. It is rarely an example of “rational polypharmacy”.
If, for some reason, an SSRI and an SNRI are to be combined, I would recommend the following:
– Consider getting a consultation with an expert psychopharmacologist and/or an experienced colleague
– Obtain and document informed consent specifically for the combination
– Keep the TOTAL dose of antidepressant medications within therapeutic limits, which can be calculated by using dose equivalents for antidepressant medications as described in the following article on this website: Antidepressant medications: Dose equivalents
Related Pages
Antidepressant medications: Dose equivalents
Depressive Disorders–Treatment–Overview and General Approach
When treating major depression, follow these three steps
All three phases of treatment are very important in major depressive disorder
Tips on the continuation phase of treatment for major depressive disorder
Which persons with major depressive disorder need maintenance (preventive) treatment?
Does improving sleep improve depression too?
How to manage atypical features in depressive and bipolar disorders
Practice guidelines for depressive disorders
References
Bondolfi G, Chautems C, Rochat B, Bertschy G, Baumann P. Non-response to citalopram in depressive patients: pharmacokinetic and clinical consequences of a fluvoxamine augmentation. Psychopharmacology (Berl). 1996 Dec;128(4):421-5. doi: 10.1007/s002130050152. PMID: 8986013.
Dodd S, Horgan D, Malhi GS, Berk M. To combine or not to combine? A literature review of antidepressant combination therapy. J Affect Disord. 2005 Dec;89(1-3):1-11. doi: 10.1016/j.jad.2005.08.012. Epub 2005 Sep 16. PMID: 16169088.
Elgawish MS, Atta AM, Hafeez SM, Abdel Mageed SS, Mahmoud AMA, Moustafa MA, Ali MA. Investigation of Pharmacokinetic and Pharmacodynamic Interactions between Citalopram and Duloxetine: An Integrated Analytical, Computational, Behavioral, and Biochemical Approach. ACS Pharmacol Transl Sci. 2024 Nov 9;7(12):4032-4042. doi: 10.1021/acsptsci.4c00506. PMID: 39698275; PMCID: PMC11650741.
Dunner DL. Combining antidepressants. Shanghai Arch Psychiatry. 2014 Dec;26(6):363-4. doi: 10.11919/j.issn.1002-0829.214177. PMID: 25642112; PMCID: PMC4311111.
Erken N, Kaya D, Dost FS, Ates Bulut E, Isik AT. Antidepressant-induced serotonin syndrome in older patients: a cross-sectional study. Psychogeriatrics. 2022 Jul;22(4):502-508. doi: 10.1111/psyg.12849. Epub 2022 May 13. PMID: 35562169.
Glezer A, Byatt N, Cook R Jr, Rothschild AJ. Polypharmacy prevalence rates in the treatment of unipolar depression in an outpatient clinic. J Affect Disord. 2009 Sep;117(1-2):18-23. doi: 10.1016/j.jad.2008.11.016. Epub 2008 Dec 21. PMID: 19103462.
Gonul AS, Akdeniz F, Donat O, Vahip S. Selective serotonin reuptake inhibitors combined with venlafaxine in depressed patients who had partial response to venlafaxine: four cases. Prog Neuropsychopharmacol Biol Psychiatry. 2003 Aug;27(5):889-91. doi: 10.1016/S0278-5846(03)00120-9. PMID: 12921926.
Henssler J, Alexander D, Schwarzer G, Bschor T, Baethge C. Combining Antidepressants vs Antidepressant Monotherapy for Treatment of Patients With Acute Depression: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2022 Apr 1;79(4):300-312. doi: 10.1001/jamapsychiatry.2021.4313. PMID: 35171215; PMCID: PMC8851370.
Henssler J, Bschor T, Baethge C. Combining Antidepressants in Acute Treatment of Depression: A Meta-Analysis of 38 Studies Including 4511 Patients. Can J Psychiatry. 2016 Jan;61(1):29-43. doi: 10.1177/0706743715620411. Epub 2016 Jan 1. PMID: 27582451; PMCID: PMC4756602.
Martín-López LM, Rojo JE, Gibert K, Martín JC, Sperry L, Duñó L, Bulbena A, Vallejo J. The strategy of combining antidepressants in the treatment of major depression: clinical experience in spanish outpatients. Depress Res Treat. 2011;2011:140194. doi: 10.1155/2011/140194. Epub 2011 Jun 15. PMID: 21738865; PMCID: PMC3124138. The most common combination was SSRIs and TCAs.
Palaniyappan L, Insole L, Ferrier N. Combining antidepressants: a review of evidence. Advances in Psychiatric Treatment. 2009;15(2):90-99. doi: 10.1192/apt.bp.107.004820
Saah T, Garlow SJ, Rapaport MH. Provide optimized antidepressant monotherapy with multiple drugs before considering antidepressant polypharmacy. Shanghai Arch Psychiatry. 2014 Dec;26(6):360-2. doi: 10.11919/j.issn.1002-0829.214182. PMID: 25642111; PMCID: PMC4311110.
Si T, Wang P. When is antidepressant polypharmacy appropriate in the treatment of depression? Shanghai Arch Psychiatry. 2014 Dec;26(6):357-9. doi: 10.11919/j.issn.1002-0829.214152. PMID: 25642110; PMCID: PMC4311109.
Thase ME. Effects of venlafaxine on blood pressure: a meta-analysis of original data from 3744 depressed patients. J Clin Psychiatry. 1998 Oct;59(10):502-8. doi: 10.4088/jcp.v59n1002. PMID: 9818630.
Copyright © 2024 to 2025, Simple and Practical Medical Education, LLC. All rights reserved. The content on this website may not be reproduced in any form without express written permission.
Disclaimer: The material on this website is provided as general education for medical professionals. It is not intended or recommended for patients or other laypersons or as a substitute for medical advice, diagnosis, or treatment. Patients must always consult a qualified healthcare professional regarding their diagnosis and treatment. Healthcare professionals should always check this website for the most recently updated information.
Leave a Reply