treatment-resistant depression

Treatment-Resistant Depression: Some Introductory Tips

Treatment-resistant depression (TRD) has a fairly low barrier of entry. Failure of 2 full antidepressant trials—lasting 6 weeks at a minimally effective dose—is enough to qualify. In this month’s issue of TCPR, we’ll highlight pharmacologic advances that are underutilized and debunk a few that are unlikely to be effective for TRD. But first, we offer the following strategies to guide you in this work.

Rule out bipolar disorder Nonresponse to antidepressants is not enough to diagnose bipolar disorder, but it is a good reason to take a closer look: 40%–60% of TRD cases turn out to have a bipolar diagnosis after structured testing (Francesca MM et al, Clin Pract Epidemiol Ment Health 2014;10:42–47). Other signs pointing that way include the following:
• Family history of bipolar disorder
• History of worsening on antidepressants
• Onset of depression in adolescence

Rescreen for hypomania with a structured interview (see, and dig deeper when patients give ambiguous answers such as, “Not really … not anymore,” or rationalizations such as, “I’m only hyper when I have a lot to do.” Remind patients that hypomania may have been brief, felt normal, or happened long ago.

Patients often answer differently on paper, and the Bipolar Spectrum Diagnostic Scale (see is good at detecting hypomania. Print a copy for a relative to complete and you may get an entirely different set of answers.

Look for depressive subtypes and comorbidities

Subtypes of depression can point the way toward better treatment, such as a lightbox for seasonal depression or MAOIs for atypical features (see page 8 for more on MAOIs). Psychotherapy is often helpful for comorbidities, particularly personality disorders, OCD, addictions, eating disorders, and anxiety disorders. Some of those tend to be veiled in secrecy, such as OCD and addictions, and need a little more probing to diagnose.

Address physical health

Though they are rarely the sole cause of depression, medical problems are frequent contributors, particularly chronic pain, obesity, and inflammatory illnesses. Consult with the primary care physician, check labs, and—for sleep apnea—look for loud snoring, collar size ≥ 17 inches, age ≥ 50, BMI ≥ 35, hypertension, and fatigue. Possible labs to check include thyroid, LFTs, electrolytes, CBC, folate, B12, vitamin D, and testosterone (in men).

Consider pharmacogenetic testing

Pharmacogenetic testing may be useful if treatment resistance has been extensive, though its value is still being debated. While the evidence is mixed, patients who worsen on antidepressants may carry the short allele of the serotonin transporter gene. What’s less controversial is that some patients are slow metabolizers (leading to side effects), whereas others are fast metabolizers (causing low serum levels of antidepressants). Research is ongoing to determine whether commercially available genetic tests are actually valuable for clinicians in the trenches.

Ask about adherence

This article originally appeared in The Carlat Psychiatry Report -- an unbiased monthly covering all things psychiatry.
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Leading questions help here: “Most people don’t take their medications as prescribed, and some don’t take them at all. How many doses do you tend to miss each week?”

Measure your work

This tip may double your remission rates. In a 6-month study that randomized 120 patients to receive treatment with or without routine measurement, remission rates were more than double among those who rated their depression at each visit (29% vs 74%). Both groups were restricted to the same medications (paroxetine and mirtazapine), but the measurement-based group followed an algorithm to adjust the doses based on the self-rated Quick Inventory of Depressive Symptomatology (QIDS) scale (, while the control group based their treatment changes on the physician’s impression (Guo T et al, Am J Psych 2015;172:1004–1013).

I use the Patient Health Questionnaire-9 ( at every visit and have found that graphing the results can reveal long-term patterns I otherwise would have missed. Often a patient will convince me that a new medicine has “done nothing,” until I peek at the patient’s ratings and see that they demonstrate a slow but steady improvement. In the past I would have stopped that medicine, or the patient may have elected to stop it. Now I show the data to the patient, and we decide together whether things are moving in the right direction.

Never give up

Hopelessness is contagious. I keep a long list of options for TRD on my desk to ensure I don’t fall into the counter-transference trap of giving up and doing nothing. I’ve also learned not to cross past medications off that list, even when patients convince me of their futility. Depression, after all, can cloud the recall of past success.

Treatment-Resistant Depression: Some Introductory Tips

This article originally appeared in:

The Carlat Psychiatry Report
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This article was published in print July/August 2018 in Volume:Issue 16:6&7.


APA Reference
Aiken,, C. (2020). Treatment-Resistant Depression: Some Introductory Tips. Psych Central. Retrieved on September 19, 2020, from


Scientifically Reviewed
Last updated: 26 Feb 2020
Last reviewed: By John M. Grohol, Psy.D. on 26 Feb 2020
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