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Day # 37: Treatment Resistant Depression

Now that we have discussed the different classes of antidepressant medications it will be helpful to take one day to discuss treatment-resistant depression. We will explore the definition of treatment-resistant depression as well as options for treatment.

Today's Content Level: Intermediate; Advanced


Psychotherapy (CBT, IPT, PDP, etc) and SSRI/SNRI medications are first-line treatment for depressive disorders. Many patients will have substantial improvement in depressive symptoms. In the case where patients do not respond, it is helpful to have a framework for these cases.

•Treatment-resistant depression (TRD) is most commonly defined as -> failure of treatment response or remission with two or more treatment attempts of adequate dose and duration.

•Unfortunately there is not a clear consensus about this definition. Specifically, what is an adequate response? 50% reduction in symptoms? Complete resolution of symptoms? Also, what are the specifics regarding the adequacy of both dose and duration of treatment? In a recent lit review only 17% of the studies of treatment resistant depression provided a consensus definition. 1

While not a consensus, the most commonly used definition in research studies regarding response are the following:

  • No response: Improvement <25 percent.

  • Partial response: Improvement 25 to 49 percent.

  • Response: Improvement ≥50 percent but less than the threshold for remission.

  • Remission: Rating scale scores within the normal range.

•TRD is to some extent still informed by results of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. It is the largest study to date (published in 2006) that attempted to characterize a tiered protocol for antidepressant therapy and used remission of symptoms as its main outcome. See previous post for more information.


•Refractory depression is not a uniform entity but a complex spectrum of severity that is different for each patient.

Always reconsider your diagnosis whenever a patient does not respond to multiple attempts at treatment (not just in depression). Many things should be considered, but common confounding conditions include:

  • Comorbid medical disease: hypothyroidism, coronary heart disease, autoimmune, infection, etc. See this post for more info.

  • Medications that may be contributing to depression (ex, glucocorticoids and interferons).

  • Anxiety disorders, personality disorders, substance use disorders.

  • Also, consider that in some patients their apparent treatment resistant depression may in fact be bipolar-type depression which is often unresponsive to standard antidepressants. 2

  • Further screen for psychosocial stressors: traumatic events, marital discord, financial/legal, etc.


Before discussing medication options for TRD, here is a basic algorithm when starting an antidepressant for a depressive disorder.

  • Titrate initial medication (typically SSRI or bupropion) to at least minimum effective dose, assess after 3-4 weeks.

  • If effective, continue for duration of treatment and can titrate as necessary

  • If no effect whatsoever, switch to another antidepressant (can switch to another medication in same class or different class), and wait another ~3-4 weeks at therapeutic dose. A switching sequence may look like this: SSRI -> bupropion -> SNRI -> mirtazapine, TCA, or MAOI.

  • If some effect, consider maximizing dose and/or initial augmentation strategies (SSRI or SNRI + bupropion or mirtazapine)

  • If still no effect with switching or initial augmentation: maximize non-pharmacologic measures, and progress towards “treatment refractory” strategies

•Also, before going down the rabbit hole of medications for TRD it should be emphasized that a large focus should be placed on optimizing psychotherapy if at all possible. Is psychotherapy helping? Could they benefit from a different type of therapy or more frequent visits? How often are they engaging in therapy? Could they benefit from attending individual AND group therapy? These questions and more should be determined to optimize therapy as much as possible.

Here is an overview of some of the options for treatment resistant depression:

  • SSRI or SNRI + bupropion or mirtazapine or buspirone

  • SSRI or SNRI + lithium

  • SSRI or SNRI + second generation antipsychotic (commonly quetiapine, aripirpazole, or risperidone, olanzapine)

  • SSRI or SNRI + lamotrigine

  • SSRI or SNRI + T3 (Triiodothyronine) or T4 (levothyroxine (T4) *questionable evidence*

  • SSRI or SNRI + ketamine

  • SSRI or SNRI + stimulants (example: methylphenidate)

  • Also consider replacing any of the above SSRI/SNRI with a TCA or MAOI.

  • Transcranial Magnetic Stimulation (TMS)

  • Electroconvulsive Therapy (ECT)

  • Deep Brain Stimulation (DBS)

  • Key: SSRI, SNRI, atypical/novel antidepressants, TCA, MAOI, miscellaneous class.

Now we will further divide these options into tiers based on evidence compiled by the authors of the Maudsley Prescribers Guidelines in Psychiatry.

First choices in TRD

  • Buproprion augmentation is well supported, included in the STAR*D trial and typically well-tolerated from a side effect perspective.

  • Mirtazapine augmentation has excellent evidence for its antidepressant effects but be aware of weight gain and sedation.

  • Lithium augmentation is well supported in the literature and is recommended by the NICE guidelines. 3

  • SGA augmentation, particularly quetiapine, aripiprazole, olanzapine, and risperidone (2nd choice) have shown to be effective. Side effects can obviously be problematic.

  • Transcranial Magnetic Stimulation (TMS) may actually be considered as one of the first choices in TRD and the field may move more in this direction as time goes on. Very expensive and time intensive. Not always readily available.

Second choices in TRD (less commonly used that are variably supported by published evaluations)

  • Buspirone augmentation is supported by STAR*D trial. High doses are usually required and poorly tolerated due to dizziness. 4

  • Lamotrigine augmentation is reasonably well researched and possibly the best tolerated augmentation strategy. Appropriate dosing is unclear and requires slow titration due to risk of steven johnson's syndrome.

  • T3 (Triiodothyronine) augmentation has some research support but also has negative studies. Overall mixed results.

  • Electroconvulsive therapy (ECT). Well established and our most effective treatment to date. Usually reserved after multiple treatment failures or if rapid response is needed.

  • Ketamine/Esketamine shows very rapid treatment response. There is some evidence that treatment response can be obtained with repeat dosing but not consistently shown.

  • Remember, also, that TCAs and MAOIs can be used as augmentation or to replace the primary antidepressant (SSRI/SNRI) for any of these options but would definitely be considered later in the treatment algorithm due to significant side effects, food restrictions, and higher lethality in overdose.

Other reported choices in TRD

  • Stimulant (ex: methylphenidate, amphetamines, modafinil) augmentation strategies have had varied outcomes. Mood elevated effects are typically seen within a few hours but are short lived.

  • There are a number of other medications that have been trialed for treatment resistant depression. Here are a few that have shown some potential: buprenorphine, amantadine, atomoxetine, tryptophan, zinc, hyoscine, estrogens, pramipexole, omega 3's, testosterone gel.


I hope you learned something from today's article. This is an advanced topic and deserves more of your attention than just this overview. I highly encourage reading the original research and articles referenced in this post as well as other lit reviews that you find.

Resources for today's post include UpToDate, The Maudsley Prescribing Guidelines in Psychiatry, Pocket Psychiatry, and the articles referenced in the main text.

Bullet Psych is an Amazon Associate and we receive a small commission if you use our links for the purchase of our recommended resources.

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