What change could reduce anxiety in a patient with partial benefit from an SNRI?

A 62 yo woman has a history of chronic pain from osteoarthritis, severe sciatica, recurrent major depression, generalized anxiety, and insomnia. She takes chronic low-dose opioids for pain and an SNRI (duloxetine, titrated to 60mg BID) for pain, depression, and anxiety, with moderate improvement in pain and depression and mild improvement in anxiety.  

She currently has moderate depression, problems with sleep maintenance (she can fall asleep ok, but wakes up after 3-4 hours and can’t go back to sleep), and severe generalized anxiety.  She is most bothered by the uncontrolled anxiety and asks you what medication she can take for it.  

In addition to screening her for PTSD (which can sometimes be missed as a unifying diagnosis in people with anxiety, sleep problems, and low mood), you review her previous treatments:

  • duloxetine has generally been helpful and is well tolerated
  • 2 prior SSRI trials (escitalopram or sertraline) were stopped in the first week because of GI side effects.  
  • clonazepam helped her anxiety in the past, but she understands that she shouldn’t take it now given her age and chronic opioid use
  • she saw 3 prior therapists and never found therapy helpful  
  • she walks a mile daily and thinks this has been helpful for her mood and sleep.

What medication change do you recommend to help manage her anxiety?

A) Switch from duloxetine to fluoxetine (or another SSRI that she has not tried before)

B) Add fluoxetine to duloxetine

C) Add mirtazapine to duloxetine

D) No medication change – she should reconnect with therapy

Answer:  C

SSRIs and SNRIs (specifically venlafaxine and duloxetine) have a response rate of 60-70% for generalized anxiety disorder (GAD) with a Number Needed to Treat (NNT) of 5.  This patient has benefited significantly from duloxetine, which is already at its max dose.  Instead of switching to another medication (which we would do if the duloxetine weren’t helpful), we want to maintain the benefit we have from duloxetine and add in something else.   

Psychotherapy is a first-line treatment for anxiety and as an augmentation agent to an SSRI has a NNT 3.  I would argue that any patient who needs a second medication for anxiety management should have had at least one trial of psychotherapy for anxiety, if it is accessible.   This patient has already tried therapy multiple times without benefit.

SSRIs are typically our first line medications for anxiety, but adding an SSRI to an SNRI that is already at max dose is like adding an ACEi to an ARB for hypertension. It doesn’t make a lot of sense.  SSRIs and SNRIs both inhibit serotonin reuptake from the synapse in the same way, and taking two of these meds at the same time exposes a patient to an increased risk of side effects without an increased likelihood of benefit.  

So for this 62 yo woman with chronic pain (from osteoarthritis and sciatica on opioids),  moderate depression, severe anxiety, and sleep maintenance insomnia on high-dose duloxetine with significant benefit, what additional medication should we offer for anxiety?

Mirtazapine (Remeron) can help anxiety, and is safe to combine with an SSRI or an SNRI like duloxetine.  It is at least as effective as SSRIs for depression, and is also commonly used for anxiety, PTSD, and insomnia, although it doesn’t have the FDA indication for these disorders.  At low doses (3.75-7.5mg), mirtazapine works as a selective histamine blocker, making it helpful for sleep maintenance insomnia.  Higher doses (30-45mg) of mirtazapine are necessary for the antidepressant and anti-anxiety effects of mirtazapine.  Higher doses of mirtazapine can help with sleep as well, but not more so than lower doses do. If this patient is willing to accept the significant risk of weight gain associated with mirtazapine (on average 5.5 lbs in the first 6 months), it would be a good choice for her because it could help her anxiety, depression and sleep maintenance insomnia. In this patient, I would start mirtazapine 15mg at bedtime for a week and then increase to 30mg at bedtime for a 4-6 week trial.

If she is uninterested in mirtazapine due to the potential for weight gain, there are other non-benzo options that could be used to augment an SSRI or SNRI for the treatment of anxiety.  These include gabapentin, pregabalin, buspirone, hydroxyzine, and silexan. Unlike mirtazapine, though, these meds do not treat depression and sleep maintenance in addition to anxiety.  We will cover the use of these other meds for anxiety augmentation in a future PsychSnap.


Cuijpers, Pim, et al. “Adding psychotherapy to antidepressant medication in depression and anxiety disorders: a meta-analysis.” Focus 12.3 (2014): 347-358.

 Serretti, Alessandro, Laura Mandelli, and M. Laura. “Antidepressants and body weight: a comprehensive review and meta-analysis.” The Journal of clinical psychiatry 71.10 (2010): 979.

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