When should you stop an SSRI trial for depression due to lack of efficacy?

30 yo woman with generalized anxiety disorder presents in her first major depressive episode. She is depressed, hopeless, sleeping poorly, exhausted, and losing weight (6 pounds in the last month). She has never taken psychiatric medications before. She would like to try a medication to treat both depression and anxiety (so bupropion is out). 

You prescribe sertraline 50mg daily and increase the dose to 100mg after 4 weeks since her symptoms have not improved. You also refer her to therapy. You see her again after she has been taking sertraline 100mg daily for 6 weeks and has had 4 therapy sessions. Unfortunately, despite rarely missing doses of sertraline, she is not feeling any better. 

What do you recommend? 

  1. Increase the dose of sertraline to 150-200mg daily
  2. Continue sertraline 100mg for 12 weeks total
  3. Switch to another antidepressant

What is an adequate trial of an antidepressant?

An adequate trial requires adequate adherence to an adequate dose of an antidepressant for an adequate duration of time. We want to give a medication a fair chance to work, and we want to switch to another medication as quickly as possible when we know that the medication is unlikely to work. Adequate adherence means taking at least 80% of doses. Adequate duration and adequate dose are not precisely defined, but the adequate duration for a given dose of an antidepressant is somewhere between 4 and 8 weeks. An adequate dose requires at least a minimum therapeutic dose (i.e. the lowest dose that is FDA approved for major depressive disorder (MDD)).

It’s often clearer to define inadequate trials of antidepressants in clinical practice:

  • Escitalopram 5mg daily for 2 months – 5 mg is an inadequate dose
  • Mirtazapine 7.5mg nightly for 7 days, stopped due to oversedation – 7.5 mg is an inadequate dose, and 7 days is an inadequate duration

Returning to our patient who has been taking sertraline 100mg daily for 6 weeks with few missed doses without a response. Is this an adequate trial for MDD? 

Yes, from an adherence and duration perspective. What about the dose? If a patient has not improved on a low-dose of an antidepressant, many current clinical guidelines including those from the American Psychiatric Association (APA), recommend increasing the medication dose as the next step, if the “upper limit” has not been reached. In other words, for MDD, the APA recommends increasing the antidepressant dose until 1) the patient responds, 2) you reach the FDA max dose, or 3) side effects limit titration. While this approach to dose escalation is common, our best data for SSRIs and mirtazapine do NOT support this recommendation. Instead, recent research suggests that an adequate duration of a moderate dose of an SSRI or mirtazapine is an adequate trial for MDD.  

Furukawa and colleagues published a meta-analysis in Lancet in 2019 that looked at the optimal dose of SSRIs, venlafaxine, and mirtazapine in major depression. They included double-blind, randomized controlled trials that compared two or more fixed-dose treatment groups. In fixed dose trials, each group takes a different dose of the same medication, or placebo. If more patients in the group taking a higher dose of medication respond over 4-8 weeks than the group taking the lower dose, there is a dose response for the medication and a rationale to increase the antidepressant dose.

The following figure from Furukawa combines the data from 99 treatment groups in trials that examined fixed doses of SSRIs for adults with MDD. 

If a patient has not improved on a low-dose of an antidepressant, many current clinical guidelines including those from the American Psychiatric Association (APA), recommend increasing the medication dose as the next step, if the “upper limit” has not been reached. In other words, for MDD, the APA recommends increasing the antidepressant dose until the patient responds, you reach the FDA max dose, or side effects limit titration. While this approach to dose escalation is common, our best data for SSRIs and mirtazapine do NOT support this recommendation. Instead, recent research suggests that an adequate duration of a moderate dose of an SSRI or mirtazapine is an adequate trial for MDD.  

Furukawa and colleagues published a meta-analysis in Lancet in 2019 that looked at the optimal dose of SSRIs, venlafaxine, and mirtazapine in major depression. They included double-blind, randomized controlled trials that compared two or more fixed-dose treatment groups. In fixed dose trials, each group takes a different dose of the same medication, or placebo. If more patients in the group taking a higher dose of medication respond over 4-8 weeks than the group taking the lower dose, there is a dose response for the medication and a rationale to increase the antidepressant dose.

The following figure from Furukawa combines the data from 99 treatment groups in trials that examined fixed doses of SSRIs for adults with MDD. 

The x-axis is the fluoxetine-equivalent dose (fluoxetine 40mg = paroxetine 34mg = escitalopram 18mg = citalopram 40mg = sertraline 99mg), and each tick on the x-axis represents a dose examined. 

The y-axis RR is the risk ratio of a response at any given dose compared to placebo. The dotted lines are the 95% confidence intervals. If the RR is 1.0, there is no difference from placebo. Higher RRs suggest increased effectiveness.

The probability of a response was highest for moderate dose SSRIs (fluoxetine-equivalent dose of 30-40mg daily). Higher doses offered a slight decrease in the probability of a response. The data for fixed dose trials of mirtazapine looked similar, with the likelihood of a response increasing from mirtazapine 7.5mg to 30mg and then decreasing at higher doses.  

Returning to our patient and our original question – Is sertraline 100mg daily for 6 weeks with few missed doses an adequate trial for MDD? 

Yes, from an adherence, duration, and dose perspective. If her depressive symptoms haven’t improved at this point, it’s time to switch to another medication.

My approach to titrating SSRIs in major depression is to prescribe a low but therapeutic dose and have the patient break the first 3 pills in half to increase tolerability. Most patients who are going to respond to an SSRI will do so at a low-dose. If there is no improvement after 4 weeks (6 weeks for a geriatric patient), and the patient is tolerating the medication, I increase to a moderate dose. If there is no improvement after 6 weeks on a moderate dose (8 weeks for a geriatric patient), I switch the medication. If a patient partially responds to a given dose, I extend the trial, try a higher dose, or augment with another medication. By switching antidepressants instead of trying a high-dose SSRI, patients with depression may improve 1-3 months earlier.

A few caveats:

  • This data applies to SSRIs prescribed for major depressive disorder, not for anxiety disorders or OCD which may require higher doses or longer trials.  
  • This data applies to SSRIs and mirtazapine. The same Furukawa study looked at fixed-dose trials of venlafaxine and found a significant dose response for depression up to venlafaxine 150mg with more modest continuing increases in efficacy up to venlafaxine 375mg daily. For venlafaxine, I use the FDA max (225mg) as an adequate dose.
  • There are also some recent studies that suggest that there is no added benefit for MDD to SSRIs dosed above the minimum therapeutic dose (i.e. low-dose SSRIs) (Furukawa 2020, Rink 2018).

Key Points

  1. An adequate trial of an antidepressant for the acute treatment of major depressive disorder requires adequate adherence (80% of doses) to an adequate dose (moderate dose of an SSRI or mirtazapine, FDA max dose for venlafaxine) for an adequate duration (4-8 weeks).
  2. A moderate dose is escitalopram 20mg, sertraline 100mg, fluoxetine 40mg, paroxetine 30mg, citalopram 40mg, and mirtazapine 30mg daily. The FDA max for venlafaxine XR is 225mg daily.

Related PsychSnaps:

How do you choose an antidepressant? by Emma Samelson-Jones, May 2023
Which SSRI should I choose? by Emma Samelson-Jones, Feb 2023


References:

Furukawa, Toshi A., et al. “Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis.” The Lancet Psychiatry 6.7 (2019): 601-609.

Furukawa, Toshi A., et al. “No benefit from flexible titration above minimum licensed dose in prescribing antidepressants for major depression: systematic review.” Acta Psychiatrica Scandinavica 141.5 (2020): 401-409.

Rink, Lena, et al. “Dose increase versus unchanged continuation of antidepressants after initial antidepressant treatment failure in patients with major depressive disorder: a systematic review and meta-analysis of randomized, double-blind trials.” The Journal of Clinical Psychiatry 79.3 (2018): 8973.


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