Managing treatment-resistant depression: A doc’s perspective

What’s worse than having a medical condition for which the first-line medication works 50% of the time? How ‘bout one for which at least two different first-line medications don’t work at all. Let’s talk about treatment-resistant depression.

…it’s critical for a clinician to prioritize empathetic and collaborative care that empowers patients…

”Treatment-resistant,” when you’re trying to get a handle on a disabling illness. That’s hard to take.

Really, all of the emotional and mental disorders are in some way treatment-resistant. However, because of the failure of multiple first-line medications, crippling symptoms, and the potential for suicide, treatment-resistant depression is in a class of its own.

We have tons to cover, so we’re going to roll with a two-parter. Here we’ll review managing treatment-resistant depression, factors contributing to resistance. and assessment. And we’ll handle treatments, emerging treatments, and research in part two.

Let’s go…


Before we get neck deep, let’s do some table setting. We’ll start with a few interesting treatment-resistant depression (TRD) statistics from a 2021 study published in the Journal of Clinical Psychiatry…

  • The estimated 12-month prevalence of medication-treated major depressive disorder (MDD) in the United States was 8.9 million adults, and 2.8 million (30.9%) had TRD.
  • The total annual burden of medication-treated MDD among the US population was $92.7 billion, with $43.8 billion (47.2%) attributable to TRD.
  • The share of TRD was 56.6% ($25.8 billion) of the health care burden, 47.7% ($8.7 billion) of the unemployment burden, and 32.2% ($9.3 billion) of the productivity burden of medication-treated MDD.

The bulk of what you’re about to read is based upon “Managing Treatment-Resistant Depression: Tips for the Outpatient Psychiatrist,” by Lisa Harding, MD. It was posted last month on Psychiatric Times.

Keep in mind, Dr. Harding is addressing psychiatrists. So if you’re grappling with TRD and some of what you’ve read is missing from your treatment experience, enlighten your provider.

Managing treatment-resistant depression

In her discussion of management, Dr. Harding begins by encouraging clinicians who work with TRD patients to adopt a comprehensive approach that includes a thorough understanding of past treatments, the possible role of interventional therapeutic modalities, and the importance of a patient-centered approach.

Definition of treatment-resistant depression

According to Dr. Harding, TRD is typically defined as a failure to respond to two or more trials of antidepressant medications (ADs) at an adequate dose and duration.

TRD manifests in various forms, including partial response, nonresponse, or recurrent depression – despite adequate treatment trials.

Patient-centered approach

Harding observes that patients with TRD often feel frustrated, hopeless, and stigmatized because they haven’t responded to conventional treatments. They may even perceive it as a personal failure.

That being the case, it’s critical for a clinician to prioritize empathetic and collaborative care that empowers patients, as well as fostering a sense of ownership in the recovery process.

Personally and clinically, “patient-centered” has always been tops on my priority list.

Factors contributing to resistance

“I’m depressed, angry, and desperate…and I refuse to abandon the search for clues and answers.”

You might think it would go without saying – still, Harding encourages clinicians to thoroughly assess the factors contributing to the presentation of depression in each of their patients.

She goes on to mention several…


Most folks know that neurotransmitter receptor structure and function can cause a compromised response to ADs.

That said, patients often demand – and clinicians recommend – genetic testing. Harding believes the results are often misunderstood, so clinicians need to be aware of interpretation limits before ordering genetic tests and discussing results with patients.


We’ve heard it a jillion times – and it’s true. Poor sleep, inadequate nutrition, and lack of physical activity can exacerbate depressive symptoms and stand in the way of positive treatment outcomes.

Harding mentions neurovegetative symptoms of depression – symptoms leading to dissociation from society as a whole. She believes they deserve the same priority in the overall treatment plan as oral medication.


It’s no surprise that lack of social support, family and work stressors, unsafe living conditions, and poor access to quality mental health care – especially evidence-based psychotherapy – play major roles in treatment resistance.

Comorbid psychiatric and medical conditions

Comorbid – cooccurring or coexisting – psychiatric and medical conditions, personality traits, and maladaptive coping strategies can complicate the treatment of TRD. And if they’re reported to the clinician, or suspected, further assessment is required.

For instance, a patient being seen for TRD may have a history of common symptoms of borderline personality disorder. It’s crucial that it’s ruled out or diagnosed.

Other significant comorbidities include substance abuse, untreated diabetes, and chronic pain.

Assessment for treatment-resistant depression

The first order of business when working with a patient is conducting a comprehensive assessment. It needs to include patient history – including previous treatment trials, medication response, and any potential contributing factors.

As a former clinician, I can’t overemphasize the importance of a thorough and accurate assessment.

Consider this, labs and imaging are of no use when it comes to diagnosing emotional and mental disorders. So gathering every morsel of available information is crucial.

If you’re a patient, provide as much info to your clinician as you can. That includes calling upon family members and friends, as well as signing releases so information can be obtained from other providers. Handling as much as possible before an appointment really helps.

Medication review

Harding emphasizes that when assessing a patient’s medication regimen, the primary focus needs to be on determining whether deprescribing could offer benefits.

She goes on to say that if a switch to, or augmentation with, alternative classes of antidepressants is being contemplated, it’s essential for a clinician to carefully review current guidelines and how they apply to the patient.

Equally important is ascertaining whether the patient has a clear and realistic understanding of which aspects of their current symptoms antidepressants can effectively address.

Additionally, exploring antidepressants that target different receptors – e.g., sertraline (Zoloft) to bupropion (Wellbutrin) – may prove beneficial to patients not responding to their current AD.

Finally, my advice to patients regarding medication: ask questions…

Why are you recommending this? What are the side effects? How will it interact with my current medications? Will I need blood work? When and how will I know it’s working? What happens if I don’t want to take it anymore? Is dependence a possibility?

The foundation is laid

Think about it, some nine million folks in the US are dealing with medication-treated major depressive disorder. And one-third of them have treatment-resistant depression.

That’s a bunch – and the reason we’re talking about it.

I think we’ve laid a good foundation, so be sure to come back for part two for a review of treatments, emerging treatments, and research.

Coming at you shortly.

Hey, if you or someone you care about are in immediate danger of any form of self-harm call 988 in the U.S. And here’s a list of international suicide hotlines.

If you’d like to read Dr. Harding’s piece, here you go: “Managing Treatment-Resistant Depression: Tips for the Outpatient Psychiatrist.”

And here’s the study with the statistics I mentioned: “The Prevalence and National Burden of Treatment-Resistant Depression and Major Depressive Disorder in the United States

If you’d like to read more Chipur info and inspiration articles, review the titles.

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