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What is Treatment-Resistant Depression?

With strategies such as Transcranial Magnetic Stimulation (TMS) and Ketamine becoming more prevalent for treatment-resistant depression, it is helpful to take a look at what this entity really means. Not everyone who is being referred for either TMS or treatment with Ketamine may have "true" treatment-resistant depression and then there is what is called "pseudo-resistance."

In simple terms, treatment-resistant depression implies that depression has not reached sufficient remission after an adequate treatment. Remission is defined as clinical improvement with few signs of depression still remaining and a lower likelihood of subsequent exacerbations. About 15% of people with depression may eventually develop treatment-resistant depression (Berlim & Turecki, 2007). Treatment-resistant depression has been variously defined, but the most commonly accepted definition is as below (Souery et al., 2007):

A person with depression is considered to have treatment-resistant depression when consecutive treatments with two antidepressants from two different pharmacologic classes, used for a sufficient length of time at an adequate dose, fail to produce significant improvement. This is further elaborated below:
  • Two different pharmacologic classes means antidepressants having different mechanisms of action. For example, Selective Serotonin Reuptake Inhibitors (SSRIs) versus Serotonin Norepinephrine Reuptake Inhibitors (SNRIs).
  • An adequate length of time is an antidepressant trial lasting at least 4 weeks.
  • An adequate dose is the minimum effective daily dose recommended in the drug package insert.
  • Significant improvement is a score of less than 17 on the 17-item Hamilton Depression Rating Scale.
There are several problems with this definition of treatment-resistant depression. First, it assumes that switch from one class of antidepressant to another may be a more effective strategy than switching within the class. Second, it doesn’t talk about the role of psychotherapy. Third, it is silent on functional improvement and improvement in quality of life and relies only on clinical improvement to define treatment-resistance. Nevertheless, this is the most accepted definition of treatment-resistant depression.

What is Pseudo-Resistance?
Before you jump the gun and diagnose yourself with treatment-resistant depression, first rule out if this is pseudo-resistance. About 60% of people initially classified as having treatment-resistant depression may actually have pseudo-resistance (Berlim & Turecki, 2007). The causes of pseudo-resistance are below (Berlim & Turecki, 2007; Souery et al., 2006):  

  1. Inadequate dosing of the antidepressants: This may be due to staying at a low dose of the antidepressants because of initial side effects that have subsequently abated. Other causes could be drug interactions that are making the antidepressant less effective or an individual having rapid metabolism of the antidepressant. 
  2. Inadequate duration of the antidepressants: Switching medications too soon and concluding that a given medication is ineffective also contributes to pseudo-resistance.
  3. Inadequate adherence: Not taking the antidepressants as prescribed due to side effects or forgetting to take them accounts for about 20% of scenarios that are considered treatment-resistant depression.
  4. Improper diagnosis: This includes:
  • Failure to diagnose an underlying bipolar disorder.
  • Failure to diagnose psychotic symptoms associated with depression.
  • Failure to diagnose melancholic depression. Melancholic depression is a more severe kind of depression characterized by loss of pleasure in all, almost all activities, no emotional response when something good happens, a profound sense of despondency or despair, depression that is worse in the morning, early-morning awakening, appearing markedly slowed down or agitated, poor appetite or weight loss, and excessive or inappropriate guilt (American Psychiatric Association, 2013).
  • Failure to diagnose co-occurring anxiety or personality disorders.
  • Failure to identify underlying medical conditions that may be associated with depression such as hypothyroidism.
If you haven’t responded to a couple of trials of antidepressants, it may be worthwhile to explore the above possibilities in collaboration with your antidepressant prescriber.

What are the Risk Factors for Treatment-Resistant Depression?
While there is no definitive cause as to why some people with depression will develop treatment-resistant depression, research does demonstrate certain risk factors that predispose one to develop treatment-resistant depression. These include the following (Souery et al., 2007):
  • Co-occurring anxiety disorders, particularly panic disorder and social phobia.
  • Having suicidal thoughts during the current episode of depression.
  • Greater severity of depressive symptoms.
  • Presence of melancholic symptoms of depression (described before).
  • History of recurrent episodes of depression.
  • More than one psychiatric hospitalization in the past.
  • Age of onset of depression before 18 years.
  • Non-response to the first antidepressant in one’s lifetime.
  • Co-occurring personality disorder.
Being aware of these risk factors helps an individual plan ahead for treatment as treatment-resistant depression may require a combination of medications or other non-pharmacological strategies.

To learn more about treatment-resistant depression and treatments that work for it, please refer to the the evidence-based comprehensive book The Complete Guide to Self-Management of Depression: Practical and Proven Methods. 



American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Association.

Berlim, M. T., & Turecki, G. (2007). Definition, assessment, and staging of treatment-resistant refractory major depression: a review of current concepts and methods. Canadian Journal of Psychiatry, 52, 46-54.

Souery, D., Oswald, P., Massat, I., Bailer, U., Bollen, J., Demyttenaere, K., Kasper, S., Lecrubier, Y., Montgomery, S., Serretti, A., Zohar, J., & Mendlewicz, J. for the Group for the Study of Resistant Depression (GSRD) (2007). Clinical factors associated with treatment resistance in major depressive disorder: results from a European multicenter study. Journal of Clinical Psychiatry, 68(7), 1062-1070.

Souery, D., Papakostas, G. I., & Trivedi, M. H. (2006). Treatment-resistant depression. Journal of Clinical Psychiatry, 67(suppl 6), 16-22.


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