The composer Hector Berlioz described in his Memoirs "the dreadful sensation of being alone in an empty universe." In this state, the musician stopped composing, became inactive and immobile because he had no other capacity "than to suffer". Andrew Solomon says that acute depression is both a destruction (the instinctive functions of life disappear) and a birth (that of a demon). Almost all testimonies speak of being "on the edge of the abyss", which can mean bordering on madness or destruction. For those who haven't experienced it, it's hard to imagine. The bad thing is when this demonic situation persists over time and lasts despite treatment. What to do then?
The first thing to do is to make sure that it really is a treatment-resistant depression. The diagnosis must be adequate, we can never treat blindly. It must be ruled out, for example, that there is anemia, hypothyroidism or some other hormonal disorder that may justify the symptoms. For this reason, every patient undergoing treatment for depression and anxiety should have at least one blood test and a medical assessment done to rule out these factors. We must also ask ourselves: is the patient taking any medication for another pathology that can cause depression? Does the patient consume any toxic substance that favors or perpetuates the condition?
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Within mental pathology, it is necessary to differentiate depression from bipolar disorder, where antidepressants are not only not going to be effective, but can worsen the condition, or differentiate it from an anxiety or personality disorder. We will also have to make sure that the therapeutic attempts have had an adequate duration (with antidepressants it should be six weeks) and with good adherence (between 30 and 50% of patients do not take the treatment well). It will give us clues to ask the patient how they responded to treatment in the past.
In its most widely accepted definition (failure to respond to two therapeutic attempts at appropriate times and doses), treatment-resistant depression (TRD) affects 30% of patients. This figure comes from clinical trials where difficult patients are not admitted and where all confounding variables are controlled. In real life, the percentage reaches at least half of the patients, and some factors seem to be associated with this resistance: older age, greater severity of symptoms, coexistence of other mental disorders, cognitive dysfunction (such as concentration or memory problems), chronic pain, or a history of trauma. According to the algorithms, the next step is to deploy the different pharmacological tactics that have been shown to be effective: associating two antidepressants with different mechanisms of action, substituting one for another from a different family, or boosting the antidepressant with a different substance.
However, it is not an exclusively pharmacological matter. There are many reasons to incorporate psychotherapy into an integrative approach to depression. Firstly, because it is the therapeutic modality that patients usually prefer; second, because it provides possibilities for emotional learning and the management of personal relationships, and fosters resilience and the search for meaning. Third, because meta-analyses show that adding psychotherapy to pharmacological treatment has a modest effect (which is no small thing).
We can try a carousel of antidepressants but it won't work. In the same way that we can uselessly apply multiple approaches to psychotherapy to a patient with severe melancholic depression, in need of a pharmacological approach."
The most studied therapies are cognitive-behavioural, interpersonal and mindfulness, although it seems that the effectiveness does not depend so much on the specific technique as on factors common to the different schools. International guidelines consistently recommend combined pharmacological and psychotherapeutic treatment. Because when did psychiatry leave psychotherapy on the back burner? The great fathers of psychotherapy, such as Sigmund Freud, Carl Jung, Aaron Beck, Otto Kernberg, Alfred Adler, Viktor Frankl, Eric Berne and Joseph Wolpe, were psychiatrists. And now we have the opportunity to work, side by side with clinical psychologists, to achieve the joint implementation of this essential therapeutic tool.
But the concept of treatment resistance is sometimes too focused on treatment and too little on the patient's context. There are depressions that are highly conditioned by the devastating experience of childhood trauma, by oppressive family life that perpetuates suffering, or by unbearable work. We can try a carousel of antidepressants but it won't work. In the same way that we can uselessly apply multiple approaches of psychotherapy to a patient with severe melancholic depression, in need of a pharmacological approach. Broadening the focus is a must.
Finally, there are third- or fourth-line options that can provide great hope for the patient and their families. Electroconvulsive therapy, despite its terrible reputation, has shown robust efficacy in resistant depression. It takes place under anesthesia and in neat and controlled conditions, so you'll have to banish the outdated sequences of One Flew Over the Cuckoo's Nest. Transcranial magnetic stimulation is usually better accepted by patients; It has promising evidence, but it is little available in our country. Recently, drugs such as ketamine or esketamine (marketed in Spain) have appeared, with novel mechanisms of action and rapid and, apparently, sustained efficacy. They are expensive drugs, which should be applied judiciously and responsibly, in patients with a clear indication. Psilocybin, another psychedelic, has just been marketed in Australia and is generating high expectations.
In this sense, the contribution of new tools from the pharmaceutical industry is great news. Perhaps some naïve people still wonder: are pharmaceutical laboratories NGOs? Definitely not. Like Ikea or Zara, they are companies that want to make money. But if they are well regulated and monitored from an ethical point of view, they are essential agents in our health system. In my opinion, it is just as wrong to uncritically buy all their commercial messages as it is to demonize the entire industry as a whole, in a narrative between conspiratorial and anti-capitalist. The pragmatic and reasonable thing to do is to align their legitimate interests with those of society, which urgently needs scientific advances, both in vaccines and drugs.
To the patient, who is the one we care about, we will tell them that we will not stand still, that there are many options and that we will do what we can. From many perspectives, hand in hand with diverse professionals, with a single objective: to glimpse, hand in hand with the famous quote by Albert Camus, that in the middle of winter there is an invincible summer, and not to lose hope.
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