What is the best antidepressant to take with Effexor? (3 choices)

In this article, we will discuss the best antidepressants to take with Effexor (venlafaxine) – a serotonin-norepinephrine reuptake inhibitor (SNRI). We will also discuss some side effects of such combinations and talk about the antidepressants which should not be taken with Effexor. 

What is the best antidepressant to take with Effexor?

The best antidepressants to take with Effexor are:

  • Selective serotonin reuptake inhibitors (SSRIs)
  • Tricyclic antidepressants (TCAs)
  • Atypical antidepressants

Selective serotonin reuptake inhibitors (SSRIs)

Effexor (venlafaxine) can be combined with SSRIs to manage symptoms associated with major depressive disorder (MDD) or treatment-resistant depression (1). 

One research study indicated that adding sertraline, paroxetine, or citalopram to venlafaxine treatment can enhance the therapeutic effects of the overall treatment regimen and was well-tolerated in the majority of the test participants (2). 

However, it is important to note that doses of such combinations should be carefully adjusted to prevent potential drug-drug interactions. SSRIs primarily work on serotonin levels and do not have affinity for other receptors in your body (1). 

This is why these antidepressants have a good safety profile compared to other classes. SNRIs work on both serotonin and norepinephrine levels, which is why these meds can also be used for different symptoms, such as chronic pain management (3). 

However, the major concern with combining Effexor, an SNRI, with SSRIs is the risk of serotonin syndrome as both meds can inhibit the reuptake of serotonin and increase serotonergic activity in the brain. 

This can lead to serotonin syndrome, which is rare but a life-threatening condition. So, dosage adjustment is crucial when combining SSRIs with Effexor.

Tricyclic antidepressants (TCAs)

TCAs such as clomipramine or imipramine can be combined with Effexor (venlafaxine) for people who do not respond well to TCA monotherapy. It is a known fact that major depressive disorder does not respond well to antidepressant monotherapy. 

This is where such combinations can be beneficial. Research studies have indicated that venlafaxine augmentation to a suitable TCA can be well-tolerated in most individuals and can help manage the stubborn symptoms of MDD or treatment-resistant depression (4). 

However, it is important to note that TCAs do not have a good safety profile. These medications were replaced by newer antidepressants (SSRIs, SNRIs) as the first line of agents because of a poor safety profile. 

So, a combination of Effexor and a TCA should be carefully monitored, and the doses should be carefully adjusted – as not everyone will respond well to it.

Atypical antidepressants

Atypical antidepressants such as bupropion, mirtazapine, etc., can be taken with Effexor to enhance its antidepressant effects and to manage treatment-resistant depression. 

Several research studies have indicated that the combined use of bupropion (Wellbutrin) and venlafaxine (Effexor) can successfully manage chronic depression which does not respond to typical treatment regimens (5). 

Research also suggests that combining venlafaxine with mirtazapine is associated with high remission rates and is well-tolerated (6). Additionally, mirtazapine is a sedative antidepressant that can actively manage insomnia, either linked to depression or presented as a side effect of venlafaxine. 

These studies have shown how Effexor can be paired with atypical antidepressants for better symptomatic management. However, individuals are different and can respond differently to such combinations. 

So, it is important to make sure that you only combine these medications if recommended by your provider. What works for one may not work for another, and such combinations are prescribed based on patient-specific details.

What are the side effects of taking Effexor with another antidepressant? 

Taking Effexor with antidepressants can cause some side effects, including:

Incidence Side effects
Common side effectsNausea 
Upset stomach
Dry mouth
Less common side effectsDilated pupils
Increased heart rate
Urinary retention
Weight changes
Vision changes
Rare side effects Serotonin syndrome 
QTc prolongation

These side effects can vary from person to person and depend on individual-specific factors. Some side effects may require immediate medical attention. 

What antidepressants should not be taken with Effexor?

Effexor should not be taken with monoamine oxidase inhibitors (MAOIs). MAOIs are often prescribed alone as these antidepressants don’t pair well with other classes because of how they work. 

MAOIs block the enzymes which are responsible for the metabolism or breakdown of excitatory monoamine neurotransmitters – such as serotonin, norepinephrine, and dopamine. This increases the availability of these chemicals to manage symptoms associated with depression. 

SNRIs like Effexor increase the availability of serotonin and norepinephrine by simply inhibiting their reuptake back into the presynaptic neuron from where these chemicals are released. 

When combined, MAOIs and typical antidepressants can dangerously increase the levels of these chemicals, including serotonin. Too much serotonergic activity in the brain can lead to serotonin syndrome, which is a life-threatening condition. 

This is why antidepressants should not be paired with MAOIs. Furthermore, Effexor should also not be taken with a fellow SNRI, as these meds work in similar ways, and taking two of these together can increase the risk of additive side effects and serotonin syndrome.

As a pharmacist, I always advise my patients to ensure the safe and effective use of antidepressant combinations. It is also important to closely monitor your side effects, as such combinations might not work for everyone. This helps your doctor make adjustments to your treatment plan if necessary.


  1. Chu A, Wadhwa R. Selective Serotonin Reuptake Inhibitors. 2023 May 1. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 32119293. https://www.ncbi.nlm.nih.gov/books/NBK554406 
  1. 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. https://pubmed.ncbi.nlm.nih.gov/12921926/ 
  1. Sansone RA, Sansone LA. Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison. Innov Clin Neurosci. 2014 Mar;11(3-4):37-42. PMID: 24800132; PMCID: PMC4008300. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4008300/ 
  1. Gómez Gómez JM, Teixidó Perramón C. Combined treatment with venlafaxine and tricyclic antidepressants in depressed patients who had partial response to clomipramine or imipramine: initial findings. J Clin Psychiatry. 2000 Apr;61(4):285-9. PMID: 10830150. https://pubmed.ncbi.nlm.nih.gov/10830150/ 
  1. Fatemi SH, Emamian ES, Kist DA. Venlafaxine and bupropion combination therapy in a case of treatment-resistant depression. Ann Pharmacother. 1999 Jun;33(6):701-3. doi: 10.1345/aph.18249. PMID: 10410184. https://pubmed.ncbi.nlm.nih.gov/10410184/ 
  1. Malhi GS, Ng F, Berk M. Dual-dual action? Combining venlafaxine and mirtazapine in the treatment of depression. Aust N Z J Psychiatry. 2008 Apr;42(4):346-9. doi: 10.1080/00048670701881587. PMID: 18330778. https://pubmed.ncbi.nlm.nih.gov/18330778/ 

Was this helpful?

Thanks for your feedback!