Treatment-resistant depression: How is it different from major depressive disorder (MDD)?



By Tré LaRosa
NeuLine Health


Community understanding of the full scope of any disease is not an easy endeavor. It requires those seeking to understand the disease to research and develop the collective knowledge around the following:

  • Pathophysiology — What the dysfunctional part of the body looks like compared to those without the disease
  • Disease Mechanism — The underlying physical cause of the disease
  • Biomarkers — The biological markers that are indicative of underlying dysfunctional physiology
  • Phenotype/Clinical Presentation — The way the disease presents in a clinical setting, such as symptoms, individually and also community-wide
  • How to diagnose, treat, and prevent the disease
  • Ongoing and future research

And then, even when researchers have developed a strong working knowledge of all the above realms of understanding, ongoing research is still needed to even more deeply understand the scale of considerations and implications of any disease.

Of the above factors, there is one that is of particular interest in this blog: Phenotype. In some diseases, the clinical presentation of the disease can be directly related to the underlying mutation (genotype), type, or form of the disease. Other times, the phenotype can be influenced by several factors; two patients with the same mutation can present entirely differently, and then of course sometimes two patients with different mutations can present very similarly. Altogether, most diseases have risk factors and other factors that influence what exactly causes the disease and how the disease presents.

The overarching subject of this blog is depression where we’ll be exploring the above factors along with the less-commonly discussed and understood treatment-resistant depression. Treatment-resistant depression is not technically a subtype of depression; treatment-resistant depression doesn’t even have an exact or widely agreed upon definition. Typically, treatment-resistant depression is defined as depression that has not improved upon a patient trying two or more antidepressants from different classes of drugs. Studies show that, for the most part, antidepressants are effective at improving symptoms of depression, but 10-30% of patients may indeed have “treatment-resistant depression,” where they continue to struggle with serious depression even while on antidepressants. Other studies show that the figure of patients who still are “inadequately treated” may be closer to 50%. Some studies have shown that only 30% of patients with major depressive disorder reach full remission.

For neuropsychiatric diseases such as depression where there are both physical and mental, visible and invisible, components, the scope of research is even wider. This can also be complicated by social and cultural factors that can present unexpected problems in investigating these diseases. All of this is to say that depression is a fascinating, tragic condition that requires deeper investigation. In the rest of this blog, we’ll be reviewing the pathophysiology, biomarkers, clinical implications, and ongoing research into both traditional and treatment-resistant depression.

Pathophysiology & Clinical Implications

Historically, depression has been viewed as a mental illness as opposed to a physical one. This perspective of reducing complex diseases to a binary physical or mental illness flattens the way we discuss ailments. Evidence suggests that 1 out of 3 people diagnosed with serious illness will experience symptoms of depression, indicating there may be a relationship between non-neurological diseases and the development of depression. Naturally, experiencing a life-changing diagnosis will affect somebody’s mental state, which is why the complexities that overlap chronic disease and depression cannot be overstated; according to the CDC, around 60% of adults in the US, or around 155 million people, have at least one chronic disease. In terms of the relationship between chronic disease and depression, that means more than 50 million American adults may have both depression and a chronic disease.

In terms of the way the brain is altered in those that have depression, the seemingly defining feature in the way the brain changes comes down to changes in grey-matter volume. Grey matter “plays the most significant part in allowing humans to function normally daily” and gets its grey tone (and thus its name) from a “high concentration of neuronal cell bodies.” A decrease in grey matter, as seen in the brains of those who have been diagnosed in depression, can be seen in the hippocampus, the part of your brain utilized in learning, memory, emotions, and stress, and the prefrontal cortex, which is responsible for executive function and planning. There’s also evidence that brain shrinkage occurs in the thalamus, amygdala, and other regions of the brain. These brain changes can happen in as little as eight months during a prolonged episode.

In the past, it was believed that decreased serotonin or norepinephrine levels were responsible for depression. This theory, called the monoamine deficiency hypothesis, has not been disproven but rather expanded upon. Other neurotransmitters including glutamate and GABA are critical messengers that go between the neurons in the “higher centers of the brain involved in regulating mood and emotion,” says Dr. John Krystal of Yale’s Department of Psychiatry. GABA and glutamate are the two most common neurotransmitters in the brain and “they regulate how the brain changes and develops over a lifetime.” Furthermore, from Yale Medicine, “When a person experiences chronic stress and anxiety, some of these connections between nerve cells break apart.” They term these complex interactions the “neurobiology of depression.” Positively, however, Dr. Rachel Katz, also of Yale, says “There are clear differences between a healthy brain and a depressed brain… And the exciting thing is, when you treat that depression effectively, the brain goes back to looking like a healthy brain.”

As for the pathophysiologic differences between depression and treatment-resistant depression, that remains unclear. A review paper published in Neuroscience & Biobehavioral Reviews articulately outlines the state of understanding:

Treatment Resistant Depression (TRD) represents a heterogeneous state with likely multiple causal mechanisms. TRD patients exhibit the same diversity of symptoms, course, history and co-occurring conditions as for treatment-responsive MDD. However, very little is known about what distinguishes patients who do or do not respond to treatment. The extent to which individuals with TRD versus treatment-responsive MDD differ in etiology or pathophysiology remains mostly obscure, although there are several reports that a history of early life stress increases treatment-resistance and that individuals with TRD exhibit differences in brain circuit function. Nevertheless, the underlying mechanisms are not known.

Considering the evidence for whether there is a definitive difference between the pathophysiology of depression and treatment-resistant depression is not clear in one direction or the other, and perhaps even leans in the direction of no clear difference, while there is an increase in papers published studying treatment-resistant depression, there is also a growing number of experts challenging this notion.

In a paper published in The British Journal of Psychiatry, the authors contend:

Treatment-resistant depression is widely defined as non-response to two ‘adequate’ courses of treatment. However, the definitions of treatment and depression are inconsistent reflecting gaps in our understanding. We argue that a failure to respond is often the result of administering inappropriate treatment, which occurs principally because of paradigm failure (emphasis added by author of this blog).

In a 2020 editorial published in the journal Psychotherapy and Psychosomatics, the authors seem to be aligned with the above assessment. These authors argue:

However, current conceptualizations of treatment resistance focus on the characteristics of the patient (whether neurobiological assets, or attitudes, or psychiatric comorbidity) for the insufficient effectiveness of antidepressant drugs and omit any reference to the potential iatrogenic (author note: iatrogenic means “relating to illness caused by medical examination or treatment”) effects of treatment, as if, in the field of infectious disease, treatment resistance were conceptualized independently of the previous use of antibiotics.


In terms of complicated diseases, especially neuropsychiatric ones like depression, the lack of clear understanding is not an indictment of science or medicine but rather to its credit. The brain is a complex organ that itself influences behavior but can also be influenced by external and genetic factors. 

It is clear from the lack of consensus amongst experts that there needs to be deeper investigation into diagnostic tools, biomarkers, neurobiology, the success rate of antidepressants and other treatments such as cognitive-behavioral therapy, as well as more investment and research into alternative therapies. Upon further investigation and understanding of depression and the brain, experts will be able to better delineate whether treatment-resistant depression has its own etiology or whether or not, as some have claimed, treatment-resistant depression is its own disease or just an artifact of an outdated understanding of depression.







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