Treatment-Resistant Depression (A guide)


Author bio

Page last updated: 21/10/2022

Treatment-Resistant Depression

If you have been struggling with depression and tried to treat it using some prescribed antidepressants and/or to go to psychological consultation, however, it did not seem to help, and the symptoms that you had before the treatment, came back, it can mean that you have treatment-resistant depression (TRD).

The name of this type of depression may discourage you. Nevertheless, you should not worry much, as treatment-resistant depression also has its treatment.

In this article, we will talk about treatment-resistant depression, its signs, reasons for development, and the treatment.

What Is Treatment-Resistant Depression?

Treatment-resistant depression (TRD), or resistant depression, is a term used in psychiatry to describe cases of major depression that are resistant to treatment: that do not respond to at least two adequate courses of treatment with antidepressants of different pharmacological groups (or do not respond enough, i.e., there is a lack of clinical effect).

The reduction of depressive symptoms on the Hamilton scale, in this case, does not exceed 50%.

The term “treatment-resistant depression” was first used in the psychiatric literature along with the advent of the concept in 1974.

The terms “resistant depression,” “drug-resistant depression,” “therapeutically resistant depression,” and “refractory depression,” are also used in the literature.

All these terms are not strictly synonymous and equivalent.

Risk Factors of Treatment-Resistant Depression

Research suggested some main risk factors for the treatment of resistant depression:

Duration of a depression episode

If the depression lasts long, it can atrophy some parts of your brain, making cognitive and behavioral changes, which can cause treatment-resistant depression, bringing 

back the symptoms of depression, although you use some ways of treatments.

Treatment-Resistant Depression (A guide)

Comorbid psychiatric disorders

Usually, comorbid psychiatric disorders stay unfound while treating depression.

However, if you want to treat the major depressive disorder without treating the comorbid psychiatric depression, the latter can make it challenging to evaluate and treat depression.

The disorders that can be associated with the treatment-resistant disorder are anxiety disorders, eating disorders, personality disorders, ADHD (attention deficit hyperactivity disorder), as well as an obsessive-compulsive disorder.

The severity of the episode

Most severe and mildest depressions both are supposed to increase the risk of inadequate response: severe depression is associated with biological disbalances, and mild depression, is connected to lower drug versus placebo response.

Frequency of occurrence of TRD and residual symptoms

Researchers have noted new tendencies during depressive disorders: many authors indicate that the course of depression is not as favorable as previously thought.

If, in the 1950s, 80% of patients with depressive disorders recovered, then by the end of the 20th century, about 40% of depressions began to acquire a chronic relapsing character and proceed with protracted episodes of exacerbations.

In many cases, patients with major depression experience an incomplete response to antidepressant therapy or no therapeutic effect at all.

In clinical studies, about one-third of patients achieve complete remission, one third have a partial effect of therapy, and one third are therapeutically resistant.

With partial remission, when there is a lack of therapeutic effect, there are poorly defined residual symptoms, which most often include decreased mood, mental anxiety, sleep disturbances, fatigue, decreased interest or pleasure.

Residual symptoms are associated with suicidal thoughts and attempts, with chronicity, a large number of visits to doctors, including psychiatrists, the need for social assistance and disability benefits.

Patients with residual symptoms have a higher risk of insult and heart attack (infarct).

A significant part of patients with partial remission is traditionally not taken into account when conducting clinical trials of antidepressants.

The Causes of Treatment-Resistant Depression

The most common causes of pseudo-resistance are:

  • The inadequacy of the therapy (dose and duration of antidepressant reception),
  • Underestimation of factors contributing to the chronicity of the condition,
  • Lack of control over compliance with the treatment regimen.

Other reasons are also possible: somatogenic, pharmacokinetic, and others.

There is a large number of experimental data confirming the significant role of psychological and social factors in the formation of treatment-resistant depression.

The first significant step in the case of antidepressant inefficiency should be a complete reevaluation of the previous antidepressant therapy, which consists in finding out the possible causes of resistance, which may include, in particular:

  • Wrong choice of antidepressant;
  • Insufficient dose or duration of antidepressant medication;
  • Metabolic disorders affecting the concentration of antidepressant in the blood;
  • Adverse pharmacokinetic and pharmacodynamic interactions of psychopharmacological drugs with each other and with other taken drugs, reducing the effectiveness of psycho-pharmacotherapy;
  • Side effects that prevent the achievement of a sufficiently high dose;
  • Comorbidity with other mental disorders or with somatic or neurological pathology;
  • The secondary nature of depression to other mental illnesses (for example, OCD or sociophobia), or the presence of somatic or narcological causes of depression, or iatrogenic depression;
  • Incorrect diagnosis – for example, an erroneous diagnosis of a monopolar variant of depressive disorder, while in reality, the patient has a bipolar affective disorder or an erroneous diagnosis of depressive disorder instead of a neurosis or personality disorder;
  • A change in the course of treatment of the structure of psychopathological symptoms: for example, treatment can cause the patient to transit from depressive to hypomanic state, or the biological symptoms of depression can be eliminated, and longing and anxiety continue to be maintained;
  • Adverse life circumstances (unemployment, poverty, unfavorable family conditions);
  • Genetic predisposition to one or another reaction to an antidepressant, individual characteristics of pharmacokinetics;
  • Lack of control over compliance with the treatment regimen, violation of compliance.

Primary Prophylaxis of Treatment-Resistant Depression

Primary prophylaxis measures of TRD, the measures to prevent the development of therapeutic resistance in the treatment of depressive conditions, are divided into:

  • Diagnostic measures,
  • Therapeutic activities,
  • Socio-rehabilitation measures.

Treatment for Treatment-Resistant Depression

As we mentioned at the beginning of the article, you should not worry much if you are suffering from treatment-resistant depression, because it can be treated too.

Below you can find some treatments, which can be helpful:


Psychotherapy can help you to deal with the challenges of life, construct healthy relationships, manage your emotions, and other things.

For treatment-resistant depression, it can be useful, especially CBT (cognitive-behavioral therapy), Interpersonal psychotherapy, and family therapy.


If you have used some antidepressants, and they did not help to deal with depression, it can be because of the wrong medication, the wrong dose, or the wrong combination of medications.

So, you should talk to your doctor, and he/she can suggest you other medications, or change the dose of the ones you are currently using (you may have to try some antidepressants until you find the one(s) that works for you), also consider the cytochrome P450 (CYP450) genotyping test, if possible.

You should remember that medication for depression usually takes 4-8 weeks to be effective.

For some people, it takes longer than that. Thus, you should maybe wait for a little and give your current medication sometimes.


ECT or electroconvulsive therapy assumes attachment of small electrodes to head, which sends electrical impulses to the brain, intentionally triggering a brief seizure.

ECT sessions can release the symptoms of depression (although it has side effects like temporary memory loss or temporary confusion).


Repetitive transcranial magnetic stimulation or rTMS is usually used if ECT is not sufficient.

It stimulates nerve cells of the brain with magnetic fields, relieving depression symptoms.

Lifestyle changes:

  • Get enough sleep,
  • Do regular physical exercises,
  • Meditate to manage stress,
  • Do not use alcohol and recreational drugs (if it is hard for you to stop using them, you should talk to your doctor or another medical health professional).
  1. HFNE “Aripiprazole Side Effects”
  2. HFNE “Long Term Depression”
  3. Kaufman’s Clinical Neurology for Psychiatrists (Major Problems in Neurology)
  4. Ketamine for Treatment-Resistant Depression: The First Decade of Progress
  5. Treatment-Resistant Depression
  6. Treatment-Resistant Depression: A Roadmap for Effective Care

FAQs about the topic “Treatment-Resistant Depression.”

Can you become immune to antidepressants?

You can become immune to antidepressants.

It is possible to build up a tolerance to antidepressants and is more common than many people think.

What does treatment-resistant mean?

Treatment-resistant means that the health problem or mental illness does not respond to standard treatments.

For example, treatment-resistant depression, or resistant depression, is a term used in psychiatry to describe cases of major depression that are resistant to treatment: that do not respond to at least two adequate courses of treatment with antidepressants of different pharmacological groups (or do not respond enough, i.e., there is a lack of clinical effect). 

What is a refractory mental illness?

Refractory mental illness is an illness that does not respond to the usual first-line treatments.

It is also called treatment-resistant illness.

An example of such a mental illness is treatment-resistant depression.

How do antidepressants affect the brain?

Research suggested that antidepressants can have a therapeutic effect by stimulating the growth of neurons and the formation of neural connections in these areas of the brain.

Studies have shown that people suffering and not suffering from depression, have differences in the sizes of different areas of the brain.

In patients with depression, the volume of the cingulate cortex and hippocampus is often reduced.

Does major depression ever go away?

Major depression can go away if you follow up on treatment going to psychotherapy sessions, using some medications prescribed by your doctor, and/or some other additional treatment options, such as ECT or rTMS.

What is the strongest antidepressant?

According to the National Institute for Health Research, there are some strongest the most effective antidepressants: escitalopram, paroxetine, sertraline, agomelatine, and mirtazapine.


Treatment-resistant depression (TRD), or resistant depression, is a term used in psychiatry to describe cases of major depression that are resistant to treatment: that do not respond to at least two adequate courses of treatment with antidepressants of different pharmacological groups.

It can be treated by psychotherapy (CBT, interpersonal therapy, or family therapy), medications, ECT or rTMS, as well as some lifestyle changes.

Please feel free to comment on the content or ask any questions in the comments section below.


  1. Factors That Predispose Patients to Treatment-Resistant Depression
  2. Treatment-Resistant Depression