Managing treatment-resistant depression: A doc’s perspective

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

…it is essential that a doctor prioritize empathetic and collaborative care that empowers patients…

“Resistant to treatment”, when trying to control a disabling disease. That’s hard to accept.

In reality, all emotional and mental disorders are, in some way, resistant to treatment. However, due to the failure of multiple first-line medications, disabling 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 two parts. Here we will review the management of treatment-resistant depression and the factors that contribute to resistance. and evaluation. And we’ll look at treatments, emerging treatments and research in part two.

Come on…


Before we go neck deep, let’s set the table. We’ll start with some interesting statistics about treatment-resistant depression (TRD) from a 2021 study published in Clinic magazine 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, of which $43.8 billion (47.2%) is attributable to TRD.
  • TRD’s share was 56.6% ($25.8 billion) of the healthcare burden, 47.7% ($8.7 billion) of the unemployment burden, and 32.2% ($9. 3 billion) of the productivity burden of drug-treated MDD.

Most of what you are about to read is based on “Managing Treatment-Resistant Depression: Tips for the Outpatient Psychiatrist,” by Lisa Harding, MD. It was published last month in Psychiatric times.

Please note that Dr. Harding addresses psychiatrists. So, if he is dealing with TRD and something he has read is missing from his treatment experience, let his provider know about it.

Management of treatment-resistant depression

In her discussion of management, Dr. Harding begins by encouraging clinicians working with patients with TRD to take a comprehensive approach that includes a thorough understanding of prior treatments, the potential role of interventional therapeutic modalities, and the importance of a patient-centered approach.

Definition of treatment-resistant depression

According to Dr. Harding, TRD is generally defined as failure to respond to two or more trials of antidepressant (AD) medications at an appropriate dose and duration.

TRD manifests in a variety of ways, including partial response, nonresponse, or recurrent depression, despite adequate treatment trials.

Patient-centered approach

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

That being the case, it is essential that a doctor prioritize empathetic and collaborative care that empowers patients, as well as fosters a sense of ownership in the recovery process.

Personally and clinically, “patient-centered” has always been at the top of my priority list.

Factors that contribute to resistance.

“I am depressed, angry and desperate… and I refuse to give up searching for clues and answers.”

You might think it would be unnecessary to say it; Still, Harding encourages doctors to carefully evaluate the factors that contribute to the presentation of depression in each of their patients.

She goes on to mention several…


Most people know that neurotransmitter receptor Structure and function can cause a compromised response to ADs.

That said, patients often demand (and doctors recommend) genetic testing. Harding believes that results are often misinterpreted, so doctors should be aware of the limits of interpretation before ordering genetic testing and discussing the results with patients.


We have heard it millions of times and it is true. Lack of sleep, inadequate nutrition, and lack of physical activity can exacerbate depressive symptoms and hinder positive treatment outcomes.

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


Not surprisingly, lack of social support, family and work stressors, unsafe living conditions, and poor access to quality mental health care (especially evidence-based psychotherapy) play an important role in resistance to treatment.

Comorbid psychiatric and medical conditions.

Comorbid (co-occurring or coexisting) medical and psychiatric conditions, personality traits, and maladaptive coping strategies can complicate TRD treatment. And if they are reported to the doctor or suspected, further evaluation is required.

For example, a patient seen for TRD may have a history of common symptoms of borderline personality disorder. It is crucial that it be ruled out or diagnosed.

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

Evaluation of treatment-resistant depression

The first order of business when working with a patient is to perform a comprehensive evaluation. It should include the patient’s history, including previous treatment trials, response to medication, and any potential contributing factors.

As a former doctor, I cannot overemphasize the importance of a thorough and accurate evaluation.

Consider this: Labs and imaging are useless when it comes to diagnosing emotional and mental disorders. That is why it is crucial to gather all the available information.

If you are a patient, provide as much information as you can to your doctor. That includes calling family and friends, as well as signing authorizations to obtain information from other providers. Managing as much as possible before an appointment really helps.

Medication review

Harding emphasizes that when evaluating a patient’s medication regimen, the primary focus should be determining whether deprescribing could offer benefit.

He goes on to say that if a change or increase with alternative classes of antidepressants is being contemplated, it is essential that a doctor carefully review the current guidelines and how they apply to the patient.

Equally important is to determine whether the patient has a clear and realistic understanding of what aspects of his or her current symptoms can be effectively addressed by antidepressants.

Additionally, exploring antidepressants that target different receptors, for example, from sertraline (Zoloft) to bupropion (Wellbutrin), may be beneficial for patients who are unresponsive to their current Alzheimer’s disease.

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

Why do you recommend this? What are the side effects? How will it interact with my current medications? Will I need blood tests? When and how will I know it is working? What if I don’t want to take it anymore? Is dependency a possibility?

The foundation is laid

Think about it, about nine million people in the US suffer from major depressive disorder treated with medication. And a third of them suffer from treatment-resistant depression.

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

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

Coming to you shortly.

Hey, if you or a loved one is in immediate danger of suffering any form of self-harm, call 988 in the US and here’s a list of international suicide hotlines.

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

And here is 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 want to read more information about Chipur and inspirational articles, check out the titles.

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