Taking Mirtazapine With Venlafaxine And Nortriptyline

In our latest question and answer, the pharmacist discusses drug interactions between venlfaxine, mirtazapine and nortriptyline.

Taking Mirtazapine With Venlafaxine And Nortriptyline
Apr 14, 2019

Charley asked

I am currently taking mirtazapine 60mg/day with venlafaxine 225mg/day for neuropathic pain, PTSD, and depression. My physician would also like to add a low dose of nortriptyline for pain and insomnia. Please advise.

At a glance

  • There are a few potential interactions between mirtazapine, venlafaxine and nortriptyline. Use together could result in increases in blood pressure, increased risk of cardiac events and an increased risk of serotonin syndrome. There may be situations where taking all three is the best therapy for a particular individual, but it is important to be aware of, and be monitored for, side effects.


Pills Pointing Towards Another With Text - Interaction Between venlafaxine, mirtazapine and nortriptyline

There certainly is some concern with taking mirtazapine, venlafaxine, and nortriptyline together.

Although they are all technically in different classes of drugs, they have very similar mechanisms of action and work on many of the same neurotransmitters.

While therapy with all three may be beneficial for some, based on the particular medication situation, it is important to be aware that there may be an increased risk of side effects with combined use.

I'll give a general overview of each in the next sections below, and then revisit their use together.

About Mirtazapine

Mirtazapine is an antidepressant that is in its own unique class, as it is not chemically related to other antidepressants.[1]

In addition to its antidepressant effects, studies show that it also possesses an anti-anxiety effect and therefore may be a useful drug choice for treating depression and coexisting anxiety.[2]

Mirtazapine has a somewhat complex mechanism of action when compared to other antidepressants.

It works primarily by antagonizing alpha2-receptors, which has the overall resulting effect of enhancing the release of serotonin and norepinephrine.

Interestingly, it also antagonizes certain serotonin receptors (e.g. 5-HT2), which may be why it acts as an effective anti-anxiety medication.[3]

Additionally, mirtazapine is known to be a potent antihistamine, as it blocks H1-receptors. The antihistamine effects can also help with anxiety and sleep disorders.[4]

About Venlafaxine

Venlafaxine (brand name Effexor) is classified as an SNRI or serotonin-norepinephrine reuptake inhibitor. SNRI drugs are also known as 'dual inhibitors'

As the name suggests, it inhibits the reuptake of two neurotransmitters, serotonin, and norepinephrine, increasing their overall concentrations in the brain.[5]

At high doses, it may also slightly increase concentrations of dopamine as well.[6]

SNRI drugs like venlafaxine are used for a wide range of indications, from depression to neuropathic pain.

About Nortriptyline

Nortriptyline is a tricyclic antidepressant or TCA.

Tricyclic antidepressants are comparatively older than other antidepressant classes, like SSRIs (e.g. Zoloft) and SNRIs (e.g. Effexor).

Tricyclic antidepressants work mainly by blocking the reuptake of norepinephrine and serotonin (similar to SNRIs).[7]

Unfortunately, they are often associated with significantly more side effects, as they are generally sedating and have strong anticholinergic effects, which can cause dry mouth, dry eyes, constipation, and confusion (among much else).

Due to the side effect profile of tricyclic antidepressants, they aren't generally used solely as antidepressants but more often for other indications like neuropathic pain, migraine prevention and insomnia (since they can be very sedating).[8]

Using All Three

As you can see from the descriptions above, all three drugs (mirtazapine, venlafaxine, and nortriptyline) have an effect on neurotransmitters, mainly serotonin, and norepinephrine.

It can be difficult to predict the effects of using all three together. You likely will experience the benefits of the drugs in terms of their antidepressant, pain relieving and sleep effects, but there will also be an increased risk of side effects.

Perhaps the three most notable side effects you should be aware of are changes to blood pressure, risk of cardiac events and the risk of serotonin syndrome.

Blood Pressure

Drugs that increase norepinephrine levels are well known to cause increases in blood pressure. Generally, increases in blood pressure are small but using multiple drugs that affect norepinephrine could cause a significant elevation.[9]

You should certainly be sure to monitor your blood pressure while taking all three.

Cardiac Events

Many antidepressants, in general, are associated with a small increase in the risk of QT prolongation and torsade de pointes, a type of arrhythmia.[10][11][12]

The risk is generally considered to be low with any single antidepressant drug unless you have additional risk factors.

However, taking three antidepressants may increase the risk more but unfortunately, there isn't much data available to definitively know.

Serotonin Syndrome

Drugs that can increase serotonin have a risk of causing a rare, but serious disorder is known as serotonin syndrome. The risk is well-documented to be increased if you are taking multiple serotonergic drugs.[13][14]

If serotonin syndrome occurs, the symptoms generally occur rapidly, and include:[15]

  • Sweating
  • Shivering
  • Muscle rigidity
  • Mental status changes
  • Seizures

Serotonin syndrome, although rare, is a serious medical condition and needs to be treated immediately.

Final Words

Be sure to discuss the potential risks and benefits of using these three drugs together with your doctor. It would be prudent to start the nortriptyline at a low dose and titrate up if necessary.

While taking all three drugs, you should be monitored for improvement in your medical conditions, as well as side effects, and adjust doses/medication accordingly.

  1. ^ Elsevier ClinicalKey: Mirtazapine Monograph. ClinicalKey
  2. ^ Mirtazapine Prescribing Information. AccessFDA
  3. ^ A Review of Therapeutic Uses of Mirtazapine in Psychiatric and Medical Conditions. PubMed
  4. ^ A review of the pharmacological and clinical profile of mirtazapine. PubMed
  5. ^ Elsevier ClinicalKey: Venlafaxine Monograph. ClinicalKey
  6. ^ Displacement of serotonin and dopamine transporters by venlafaxine extended release capsule at steady state: a [123I]2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane single photon emission computed tomography imaging study. PubMed
  7. ^ Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. PubMed
  8. ^ Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. PubMed
  9. ^ A meta-analysis of effects of selective serotonin reuptake inhibitors on blood pressure in depression treatment: outcomes from placebo and serotonin and noradrenaline reuptake inhibitor controlled trials. PubMed
  10. ^ A comparison of the risk of QT prolongation among SSRIs. PubMed
  11. ^ Evaluating the risk of QTc prolongation associated with antidepressant use in older adults: a review of the evidence. PubMed
  12. ^ Cardiovascular Considerations in Antidepressant Therapy: An Evidence-Based Review. PubMed
  13. ^ Serotonin Syndrome. PubMed
  14. ^ Recognition and treatment of serotonin syndrome. PubMed
  15. ^ Overview of serotonin syndrome. PubMed

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