top of page

Beware of labelling depressed people: “treatment resistant” does not mean “untreatable”

What can be done for people who do not respond to antidepressants: current guidelines and new perspectives

I. Prologue: how I ended up being a psychiatrist

Even people who have not suffered from depression themselves most likely have had a friend, a relative or a partner who has been struggling with it.

Actually, the first time I considered becoming a psychiatrist was when I realized that people around me were suffering from mental health problems that they could not name and that they did not know how to seek help for.

Yes, psychiatry can be challenging, as not only are the causes of mental disorders numerous and intertwining, but also patients do not always accept the treatments that we offer. And even if they accept the treatment, it may not help them.

So why on earth did I choose psychiatry? The truth is: the therapeutic relationship with people with mental health problems, even when it is difficult, it is always rewarding and inspiring. And the very complexity of this science makes it intellectually fascinating.

I know that worldwide there is a problem with too few medical doctors entering psychiatry, sometimes for fear of being overwhelmed by the clinical experience. But perhaps, to paraphrase Marie Curie, psychiatry is not to be feared, only to be better understood, and if we understand it more, we will fear it less.

And that’s how I ended up being a shrink.

Now, to the main topic of this blog — and to my main research and clinical interest: depression, and its treatment (especially when standard antidepressants do not work).

The definition of “clinically significant depression”, for which antidepressant prescibing may be indicated, is relatively well known. In addition to persistent sadness, hopelessness and lack of energy, there is usually a clear change in social functioning (for example, people socialise less, or are unable to work or study at the usual level) and physical symptoms like lack of sleep or appetite. This, most people know.

It is important to emphasise that antidepressant medications should not be prescribed for transient sadness in response to life events, and that these medications may have important adverse effects both at the beginning of treatment and when they are stopped. Nevertheless, as many patients have said before, these can be life-saving when prescribed appropriately.

II. Treatment-resistant Depression: (mis)diagnosis and (mis)treatment

However, less clear — sometimes even within the mental health professional community — is the definition of “treatment-resistant depression” (TRD). This is what I have recently discussed in a brief review published on “Cutting Edge Psychiatry in Practice”.

In broad terms, around 50% of patients do not respond to the first antidepressant prescribed; however, TRD is defined as the failure to respond to two or more antidepressants, and, according to this definition, around 20%-30% of people with depression suffer from TRD, resulting in a significant burden for psychiatric services and for economy.

However, before labelling somebody as “treatment resistant”, are we sure that our diagnosis is correct?

For example, some people are diagnosed with major depression when in reality they are suffering from bipolar disorder. In this case, depression is just a phase of a disorder with periods of both low and elevated mood (mania). The standard treatment for bipolar disorder are mood stabilizers (for example, lithium) and antidepressants alone might be ineffective or could even worsen symptoms and trigger an episode of mania.

In other cases, people with depression may seem not to benefit from antidepressants, but they may actually taking these medications at doses that are too low to be effective.

Ideally, a diagnosis of TRD should only be done after an assessment from specialists or secondary care psychiatric services.

III. If you are told that you have treatment-resistant depression, there are still plenty of things to do

What can we do for those people who have an appropriate diagnosis and treatment of TRD, and they do not benefit from antidepressants?

Several alternative strategies are available:

Switching: if people fail to respond to one antidepressant, it does not mean that they cannot respond to others. Antidepressants include more than 30 different medications, with different mechanisms of action. So, trying a different antidepressant if others do not work does help some people.

It is a pity that we still have to use a ‘trial and error’ approach, as we do not have any clinical or blood-test that can tell us in advance which antidepressant works best for the individual person (as, for example, we can do with antibiotics for infections). However, there are promising results in this direction, some from our own research group.

Augmentation: if people fail to respond to more than one antidepressant, they may still respond if a different medication is added — either another antidepressant (combination) or other medications that have been approved specifically for the treatment of TRD (augmentation). Drugs used for this include drugs originally developed for bipolar disorder and later found to be effective in TRD.

Psychotherapy: it is important to emphasise that augmentation with psychotherapy can be as effective as adding another medication, although it may work slower. Cognitive-behavioural therapy is the one most widely used, but other approaches (behavioural activation, interpersonal psychotherapy) are also effective.

Somatic therapies: Finally, for people that failed to improve with numerous antidepressants, after switching and augmentation, there are the so-called “somatic therapies” which are not based on medications. Among these, electroconvulsive therapy (ECT), although historically controversial, is still considered the most effective antidepressant strategy for people whose life is at risk because of severe depression that is not responding to all other interventions.

Another somatic therapy is “Transcranial Magnetic Stimulation”, which stimulates the cerebral cortex through magnetic fields and is better tolerated (but less effective) than ECT.

IV. New frontiers

The future for people with TRD may look brighter than the present, with many possible potential developments.

Last month, an antidepressant of a new class was approved specifically to treat TRD. It represents a new hope for patients with depression who do not respond to anything else, as it has the great advantage of an almost immediate effect on depression. However, as the medication derives from a general anaesthetic that can be abused recreationally, there are concerns that this drug may have severe side effects (similar to other ‘hallucinogenic drugs”) and that it can be used as a drug of abuse. This is why it has to be administered under strict clinical monitoring. If anything, this medication should really be used parsimoniously and only in depressed people who do not benefit with anything else.

There are also new exciting developments in our understanding of the biology of depression, and especially on the role of the immune system and inflammation. In some people, depression might be related to a chronic inflammatory response to stress, involving both the body and the brain.

This new understanding of depression has two very important consequences.

Photo by kyler trautner on Unsplash

First, it reinforces the concept that depression is a medical disorder like all other disorders: not just in the mind, not just in the brain, but in the whole body, with inflammation being the bridge between the body and the brain.

Second, new anti-inflammatory treatment strategies, targeting inflammation through medications, nutritional interventions or lifestyle changes, are currently been developed for the specific subgroup of patients with increased inflammation and who do not respond to antidepressants.

Several clinical trials are trying to do this at the moment, with encouraging results. I am also working on this, thanks to funding from the UK NHS, so watch this space.

V. Who am I really treating?

Lessons that I learnt at my medical school: I never treat a disorder, I treat the people who are affected, and every single person is different.

The clinical guidelines that are described here are only helpful if they are discussed with the patients, and if all the treatment decisions are taken together, collaboratively. It is extremely important to listen carefully to patients, and to understand what they really need.

Of course, TRD is just one of the difficult scenarios in the treatment of depression. What about depression that affects vulnerable people, like adolescents?

Well, this is an interesting story that I will tell you in my next blog.


Disclaimer: My research work, and the work of our research group, is funded mostly by the UK National Health Service, and other governmental and charitable organisations. We also receive some research funding from pharmaceutical companies interested in the development of anti-inflammatory strategies for depression, or involved in the intranasal drug mentioned above; however, this blog, and similar blogs we post on these topics, are completely independent, and only based on the best scientific and clinical evidence.


bottom of page