Causes and variants of resistant depression. Resistant depression Antidepressant combinations for resistant depression

Resistant depression is a special term for the absence therapeutic effect in the treatment of major depressive disorder. This implies that at least two courses of adequate antidepressant treatment have been carried out. And this already means that the scheme was selected taking into account individual features patient and the nature of his symptoms.

General medical statistics shows that the problem is becoming more and more urgent. The problem was first noticed in the second half of the 70s of the 20th century. Prior to this, medications were given positive result, and a stable remission occurred in 50% of patients. Starting around 1975, the number of patients who did not help several courses of antidepressants began to increase. Approximately a third of depressive disorders are now resistant.

Sometimes treatment for depression doesn't work.

In this case, they resort to a completely logical reassessment of previous therapy and a comprehensive analysis of the situation. What can cause it?

The diagnosis is incorrect. The patient is being treated for depression, but in fact he has bipolar affective disorder, schizophrenia or something similar.
Metabolism is disturbed, which does not allow the desired concentration of certain substances to arise.
There is a genetic predisposition to an atypical response to antidepressants.
There are some side effects that reduce the effectiveness of antidepressants.
They are generally chosen incorrectly.
Treatment is carried out without complex psychotherapy.
Some active stimulus remains. It can be poverty, debts, problems in personal life and the like.

Depression can be so severe that even antidepressants don't help.

This is not an exhaustive list of what needs to be considered when depression is not treatable.

Let's pay attention to an important fact. Resistance is often associated with the transition of the disorder to a chronic form.

The patient leaves the clinic in a slightly improved form. For example, the feeling of depression disappeared, but anxiety remained, elements of other emotional disturbances may be present.

However, after some time, the patient returns to the medical institution, and history repeats itself. Outside the walls of the hospital, he faces his usual set of problems and finds himself in the same environment, which makes depression almost incurable.

If you are being treated, and depression is only getting worse, then it makes sense to reconsider the methods of therapy.

Pharmacological and other methods

Of course, the analysis of the situation leads to the fact that medicines and the way they are used change. However, often this only starts a new circle, and then the symptoms become the same.

The latter is divided into the most different types influences that are closer to the physical level and psychotherapy in the understanding of psychoanalysis, gestalt therapy and the like. Not all used physical and related procedures have a high level of scientific evidence of their justification.

Sometimes medication is indispensable in the treatment of depression.

This is sleep deprivation, laser blood irradiation, the use of special light lamps, electroconvulsive effects, and the like.

Resistant depression

05.11.2017

Pozharisky I.

Depression is a dangerous and insidious disease. The basis of his treatment is the correct diagnosis and the correct therapy. However, sometimes even […]

Depression is a dangerous and insidious disease. The basis of his treatment is the correct diagnosis and the correct therapy. However, sometimes even after providing the patient with qualified assistance, the use of drugs, depression does not recede. The person continues to experience symptoms characteristic of his past condition. This untreatable disease is called resistant depression.

Why Resistant Depression Occurs

There are several reasons why resistant depression develops:

Misdiagnosed when the specialist who carried out the treatment prescribed the wrong drugs to the patient, because he did not see the whole picture of the disease, some of the symptoms were ignored or misinterpreted.
During the treatment of depression, the patient violated the regimen and did not take medication, which the doctor prescribed to him, which not only did not improve his condition, but also did not completely eliminate the problem.
The person initially suffered from a severe form of depression, in which there is a decrease in vital energy and a weakening of the body, the longer it lasts, the more difficult it is to treat.
The patient suffers from other diseases and addictions in addition to depression that reduce the effectiveness of treatment, such as emotional dependence .
The effectiveness of the previous treatment was reduced due to the patient's resistance to certain drugs.
The patient is strongly influenced by a social environment that is not conducive to healing., he experiences constant stress and anxiety due to difficult circumstances in life.
The patient was taking other medications during treatment which reduced the effectiveness of the therapy.

All these factors are unfavorable for the patient in their own way, but also increase the risk of resistant depression.

Symptoms characteristic of resistant depression

In patients with prolonged resistant depression, doctors state persistent changes in the psyche. They become closed, gloomy, avoid communication even with people close to them. They have low self-esteem. Often there is anxiety for any reason, even the most insignificant. Those suffering from this form of depression are always dissatisfied with themselves, lonely, try not to be in companies and crowded places. They often abuse alcohol and use drugs.

Resistant depression is characterized by a sharp decrease in appetite or, on the contrary, attempts to calm one's nerves by overeating. Patients constantly feel weakness and weakness, even in the morning when they get out of bed. They often have problems with night rest, as well as insomnia, the daily routine is disturbed and shifted to reverse side. With this form of depression, suicide attempts are frequent, as well as panic disorders, which are difficult to treat with standard methods.

Patients often stop taking medication on their own, and do not report this to their doctor. The course of depression greatly exacerbates the disease thyroid gland and the cardiovascular system.

Treatment for Resistant Depression

Resistant depression is very difficult to treat. To remove patients from this state, various methods are used. The most effective is the use of medications. They are selected for each patient individually. There is no one-size-fits-all treatment for this form of depression. Most likely, the patient will have to try several options at once. After the diagnosis is established, the doctor will prescribe antidepressants, but taking them should give results.

If they are not available, other combinations and combinations of drugs will be chosen for the treatment of depression, prolonging the use of antidepressants, replacing one drug with another, strengthening the action of antidepressants with other medications.

In addition, a variety of psychotherapeutic practices are widely used in the treatment of resistant depression. Short-term therapy is suitable for specific problems. Behavioral, family, group and cognitive therapy also helps in the treatment of depression. These practices help to minimize residual symptoms after patients undergo a course of treatment with medications, and also allow them to quickly return to normal life. The greatest results in the treatment of patients can be achieved through a combination of drug and psychotherapeutic methods of treatment than each of them individually.

When traditional treatment options for resistant depression are ineffective, patients have the opportunity to use other methods. You can try the treatment, which consists in the use of:

electroconvulsive therapy. When treatment of depression is carried out due to the fact that the patient's brain causes seizures with the help of an electric current on the head. This helps to quickly relieve the symptoms of depression.
stimulation vagus nerve. When the treatment of depression is carried out using a special pulse generator, which is connected through the cervical vagus nerve to affect the patient's brain.
Deep brain stimulation. When the treatment of depression takes place due to the direct effect on the human brain of an electric current supplied through the electrodes.
Transcranial magnetic stimulation. When depression is treated with an electromagnetic coil, during which a magnetic field is created and the gray matter of the brain is stimulated.

A good effect on the health of patients with resistant depression is physical exercises and walks. They have a strengthening effect on the body and cheer up patients.

When prescribing treatment, the characteristics of the patient's personality, as well as possible concomitant diseases, are taken into account. All appointments are made by a psychiatrist or psychotherapist, consultations and treatment with a cardiologist, endocrinologist, etc. are possible. With resistant depression, it may be necessary to correctly assess the situation by two specialists at once - a psychiatrist and a psychotherapist.

In a significant number of patients after the first course of treatment with antidepressants, there is no effect or a partial effect. In this case, it is important to make sure that the initial diagnosis is correct and to confirm the absence of comorbid disorders (eg, alcoholism or thyroid dysfunction) that may weaken the therapeutic effect. There are three main treatments for resistant depression that can be used sequentially (these treatments are discussed in detail for each drug class):

1.Optimization- checking the individual adequacy of the dosage, which may be higher than the usual doses (for example, fluoxetine - 40-80 mg, desipramine - 200-300 mg). A sufficient duration of treatment (6 weeks or longer) is also checked. It is also necessary to assess the possibility of non-compliance with the therapy regimen, which occurs much more often than most doctors think.

2.Potentiation or combination- potentiation consists in adding to the current treatment drugs that are not antidepressants, but enhance their effect. In particular, the addition of lithium or L-triiodothyronine (T3) to TCAs has been well studied. Combination treatment refers mainly to the prescription of more than one antidepressant. With the advent of the latest drugs, the number of acceptable methods of potentiation and the number of possible combinations has increased significantly. However, only a few of these techniques are well studied and recommended in clinical practice.

3.Changing Therapy- replacement of the main drug with a drug belonging to another class. For example, if the first course was conducted with SSRIs, then the transition is made to bupropion, reboxetine or venlafaxine. However, if the first drug is not suitable for the patient due to side effects, then another drug of the same class, if tolerated, may be effective. For unknown reasons, possibly due to minor pharmacodynamic differences between the individual SSRIs, some patients who do not respond to the first course of therapy may be sufficient to switch to another SSRI. If severe depressive symptoms persist despite the addition or change of therapy, the risk of additional therapy (based on the severity of symptoms and the delay in time of therapeutic effect) should be weighed against the use of ECT.

Continued and maintenance therapy.

In studies with TCAs, it has been shown that when treatment was interrupted during the first 16 weeks of therapy, patients with unipolar depression had a high risk of relapse. As a result, most experts agree that the duration of treatment for responders should be at least 6 months. The need for long-term (several months) treatment for a first depressive episode to prevent relapse has been shown for virtually all of the newer antidepressants. Risk of relapse after 6-8 months is especially high in patients with a long course of the current episode, in patients with residual symptoms or multiple episodes in history (three or more), and also if the first episode of depression developed at a later age. The optimal duration of treatment for such patients has not been established, but it is clear that it should be measured in years. The obvious effect of prophylactic use of antidepressants is observed for at least 5 years. Despite initial expectations that maintenance therapy would be effective at dosages lower than those required for acute acute conditions, today all experts are unanimous in their opinion that effective prevention requires the appointment of full doses of antidepressants. Moreover, in some cases, higher doses are needed to achieve the effect than those used in the acute period.

In the past, there has been a problem with long-term maintenance therapy, as over time, side effects of TCAs such as weight gain and dental caries develop, and discomfort and symptoms such as dry mouth and constipation may increase. With the advent of a new generation of antidepressants, long-term therapy has become easier. SSRIs and other newer antidepressants remain effective for 6 months to 1 year. However, there are patients in whom the therapeutic effect of this class of drugs is depleted over time. In such patients, the methods and methods of treatment described in the paragraph on treatment-resistant depression are used.

In a small number of patients with long-term use of SSRIs, such a side symptom as apathy may develop, which may be mistakenly regarded as a relapse of depression. The appearance of apathy in the absence of other signs of depression should prompt the physician to reduce rather than increase the dose or additional prescription of a drug with noradrenergic or dopaminergic activity.

Amoxapine 32 has some antipsychotic effect and can cause tardive dyskinesia. There are no other specific side effects with long-term use of antidepressants, excluding the risk of withdrawal syndrome with the use of TCAs, MAOIs, SSRIs and venlafaxine. This syndrome is more likely to develop upon sudden discontinuation of long-term treatment, especially if drugs with a short half-life are used.

Treatment-resistant depression (TRD), or resistant depression, refractory depression, is a term used in psychiatry to describe cases of major depression that are resistant to treatment, that is, they do not respond to at least two adequate courses of treatment with antidepressants of different pharmacological groups (or do not respond enough, that is, there is an insufficiency clinical effect). The reduction of depressive symptoms according to the Hamilton scale does not exceed 50%.

Under adequacy of therapy it is necessary to understand the appointment of an antidepressant in accordance with its clinical indications and the characteristics of the spectrum of its psychotropic, neurotropic and somatotropic activity, the use of the required range of doses with their increase in case of failure of therapy to the maximum or with parenteral administration and adherence to the duration of the course of treatment (at least 3-4 weeks ).

The term "treatment resistant depression" was first used in the psychiatric literature with the advent of the concept in 1974. The literature also uses the terms “resistant depression”, “drug-resistant depression”, “drug-resistant depression”, “resistant depression”, “treatment-resistant depression”, “refractory depression”, “treatment-resistant depression”, etc. All these terms are not strictly synonymous and equivalent.

Classification of turbojet engines and its causes

There are a large number of different classifications of turbojet engines. So, for example, I. O. Aksenova in 1975 proposed to distinguish the following subtypes of turbojet engines:

Depressive conditions, initially having lingering course.
Depressive states, acquiring a longer and more protracted course for unknown reasons.
Depressive states with incomplete remissions, that is, with a “partial recovery” (after treatment of which patients still had residual, residual depressive symptoms).

Depending on the causes, the following types of resistance are distinguished:

Primary (true) therapeutic resistance, which is associated with poor curability of the patient's condition and an unfavorable course of the disease, and also depends on other biological factors (this type of resistance is extremely rare in practice).
Secondary therapeutic (relative) resistance associated with the development of the phenomenon of adaptation to psychopharmacotherapy, that is, formed as a result of the use of the drug (the therapeutic response develops much more slowly than expected, only individual elements of psychopathological symptoms are reduced).
pseudoresistance, associated with inappropriate therapy this species resistance is very common).
Negative therapeutic resistance(intolerance) - hypersensitivity to the development of side effects, which in this case exceed the main effect of the prescribed drugs.

The most common causes of pseudo-resistance are the inadequacy of the therapy (dose and duration of antidepressant intake); underestimation of factors contributing to the chronicity of the condition; lack of control over compliance with the therapy regimen; other reasons are also possible: somatogenic, pharmacokinetic, etc. There is a large number of experimental data confirming the significant role of psychological and social factors in the formation of drug resistance in depression.

Treatment-resistant depression often also develops in patients with hypothyroidism. The prevalence of hypothyroidism in patients with resistant depression is particularly high, reaching 50%. In these cases, it is necessary to treat the underlying disease: both in hypo- and hyperthyroidism, adequately prescribed therapy aimed at normalizing the hormonal balance in most cases leads to a radical improvement in the mental state of patients.

Primary prevention of TRD

Measures primary prevention TRD, that is, measures to prevent the development of therapeutic resistance in the course of treatment depressive states are subdivided into:

diagnostic activities.
Medical activities.
social rehabilitation activities.

Treatment of TRD

To overcome the therapeutic resistance of depression, many methods have been developed, both pharmacological and non-pharmacological. However, the first significant step in the case of ineffectiveness of an antidepressant should be a complete reassessment of previous antidepressant therapy, which consists in clarifying possible causes resistance, which may include, in particular:

insufficient dose or duration of antidepressants;
metabolic disorders affecting the blood concentration of the antidepressant;
drug interactions, which can also affect the concentration of the antidepressant in the blood;
side effects that prevented the achievement of a sufficiently high dose;
comorbidity with others mental disorders or with somatic or neurological pathology;
incorrect diagnosis (if, for example, in reality the patient does not have depression, but 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 move from a depressive to a hypomanic state, or the biological symptoms of depression can be eliminated, and melancholy and anxiety continue to be retained;
adverse life circumstances;
genetic predisposition to a particular reaction to an antidepressant;
lack of control over compliance with the therapy regimen.

In almost 50% of cases, resistant depression is accompanied by latent somatic pathology; psychological and personal factors play an important role in their development. Therefore, only psychopharmacological methods of overcoming resistance without a complex effect on the somatic sphere, influence on the socio-psychological situation and intensive psychotherapeutic correction can hardly be fully effective and lead to stable remission.

In particular, in the treatment of depression caused by hypothyroidism or hyperthyroidism (thyrotoxicosis), in most cases it is sufficient to prescribe adequate therapy to normalize the hormonal balance, which leads to the disappearance of symptoms of depression. Antidepressant therapy for hypothyroidism is usually ineffective; in addition, in patients with impaired thyroid function, the risk of developing undesirable effects of psychotropic drugs is increased: for example, tricyclic antidepressants (and less commonly, MAO inhibitors) can lead to rapid cycling in patients with hypothyroidism; the use of tricyclic antidepressants in thyrotoxicosis increases the risk of somatic side effects.

Drug switching and combination therapy

If the above measures have not led to sufficient effectiveness of the antidepressant, a second step is applied - changing the drug with another antidepressant (usually another pharmacological group). The third step, if the second one is ineffective, may be the appointment of a combination therapy with antidepressants of various groups. For example, you can take bupropion, mirtazapine and one of the SSRI drugs such as fluoxetine, escitalopram, paroxetine, sertraline in combination; or bupropion, mirtazapine, and an SNRI antidepressant (venlafaxine, milnacipran, or duloxetine).

Potentiation

When combined therapy with antidepressants is ineffective, potentiation is used - the addition of another substance, which in itself is not used as a specific drug for the treatment of depression, but can enhance the response to the antidepressant taken. There are many drugs that can be used for potentiation, but most of them do not have the proper level of evidence for their use. Lithium salts, lamotrigine, quetiapine, some antiepileptic drugs, triiodothyronine, melatonin, testosterone, clonazepam, scopolamine, and buspirone are the most evidence-based; they are first-line potentiators. However, drugs that have low level evidence may also be of use in resistant depression when first-line potentiating agents have failed. In particular, benzodiazepines, such as alprazolam, can be used for potentiation, which also reduce the side effects of antidepressants. Some authors recommend the addition of low doses of the thyroid hormone thyroxine or triiodothyronine for therapeutically resistant depression.

In TRD, the addition of lithium or atypical antipsychotics such as quetiapine, olanzapine, and aripiprazole to antidepressant treatment results in about the same improvement in patients with TRD, but treatment with lithium is less expensive. Olanzapine is especially effective in combination with fluoxetine and is produced in combination with it under the name Symbiax for the treatment of bipolar depressive episodes and resistant depression. According to a study of 122 people, additional treatment patients with psychotic depression, quetiapine in combination with venlafaxine gave a significant best level therapeutic response (65.9%) than venlafaxine alone, and the remission rate (42%) was higher compared with imipramine (21%) and venlafaxine (28%) monotherapy. In other data, although the effect on depression when adding antipsychotic drugs to the main drug is clinically significant, it usually does not lead to remission, and patients taking antipsychotics were more likely to leave studies early due to side effects. In general, there are data on the effectiveness of atypical antipsychotics in resistant depression, typical ones are mentioned much less often. In addition, typical antipsychotics themselves have a depressogenic effect, that is, they can lead to the development of depression.

Psychostimulants and opioids

Psychostimulants such as amphetamine, methamphetamine, methylphenidate, modafinil, mesocarb are also used in the treatment of some forms of therapeutically resistant depression, however, their addictive potential and the possibility of developing drug dependence should be taken into account. However, psychostimulants have been shown to be effective and safe means treatment of therapeutically resistant depression in those patients who do not have a predisposition to addictive behavior and who do not have concomitant cardiac pathology that limits the possibility of using psychostimulants.

Also, in the treatment of some forms of resistant depression, opioids are used - buprenorphine, tramadol, NMDA antagonists - ketamine, dextromethorphan, memantine, some central anticholinergics - scopolamine, biperiden, etc.

Non-pharmacological methods

Electroconvulsive therapy may also be used in the treatment of treatment-resistant depression. Today, new treatments for these conditions, such as transcranial magnetic stimulation, are being intensively researched. In the treatment of the most refractory forms of depression, invasive psychosurgical techniques, such as electrical vagus nerve stimulation, deep brain stimulation, cingulotomy, amygdalotomy, anterior capsulotomy, can be used.

Vagus nerve stimulation is approved by the US FDA as an adjunctive treatment for long-term treatment of chronic or recurrent depression in patients who have not responded well to 4 or more adequately selected antidepressants. There are limited data on the antidepressant activity of this method.

In 2013, a study published in The Lancet showed that in patients who did not respond to antidepressant treatment, cognitive behavioral therapy used in addition to antidepressant therapy can reduce symptoms of depression and improve the quality of life of patients.

There are efficacy data physical activity as a means of potentiation in treatment-resistant depression.

Literature

Antidepressant Therapy and Other Treatments for Depressive Disorders: A Report working group Evidence Based CINP / Editors T. Bagay, H. Grunze, N. Sartorius. The translation into Russian was prepared at the Moscow Research Institute of Psychiatry of Roszdrav under the editorship of V.N. Krasnov. - Moscow, 2008. - 216 p.
Bykov Yu. V. Treatment-resistant depression. - Stavropol, 2009. - 74 p.
Mosolov S. N. Basic techniques and tactics for the treatment of therapeutically resistant depression // Mosolov S. N. Fundamentals of psychopharmacotherapy. - Moscow: Vostok, 1996. - 288 p.
Mazo G. E, Gorbachev S. E., Petrova N. N. Therapeutically resistant depression: modern approaches to diagnostics and treatment // Bulletin of St. Petersburg University. - Ser. 11. 2008. - Issue. 2.
Podkorytov V.S., Chaika Yu.Yu. Depression and resistance // Journal of Psychiatry and Medical Psychology. - 2002. - No. 1. - S. 118-124.
Bykov Yu. V., Bekker R. A., Reznikov M. K. Resistant depressions. Practical guide. - Kyiv: Medkniga, 2013. - 400 p. - ISBN 978-966-1597-14-2.
Matyukha A.V. Medical treatment resistant depression (brief review) // Bulletin of the Association of Psychiatrists of Ukraine. - 2013. - No. 3.

And this already means that the scheme was selected taking into account the individual characteristics of the patient and the nature of his symptoms.

General medical statistics show that the problem is becoming more and more urgent. The problem was first noticed in the second half of the 70s of the 20th century. Prior to this, medications gave a positive result, and there was a stable remission in 50% of patients. Starting around 1975, the number of patients who did not help several courses of antidepressants began to increase. Approximately a third of depressive disorders are now resistant.

Revisiting Therapy

In this case, they resort to a completely logical reassessment of previous therapy and a comprehensive analysis of the situation. What can cause it?

The diagnosis is incorrect. The patient is being treated for depression, but in fact he has bipolar affective disorder, schizophrenia or something like that.
Metabolism is disturbed, which does not allow the desired concentration of certain substances to arise.
There is a genetic predisposition to an atypical response to antidepressants.
There are some side effects that reduce the effectiveness of antidepressants.
They are generally chosen incorrectly.
Treatment is carried out without complex psychotherapy.
Some active stimulus remains. It can be poverty, debts, problems in personal life and the like.

This is not an exhaustive list of what needs to be considered when depression is not treatable.

Let's pay attention to an important fact. Resistance is often associated with the transition of the disorder to a chronic form.

The patient leaves the clinic in a slightly improved form. For example, the feeling of depression disappeared, but anxiety remained, elements of other emotional disturbances may be present.

Pharmacological and other methods

Of course, the analysis of the situation leads to the fact that medicines and the way they are used change. However, often this only starts a new circle, and then the symptoms become the same.

The latter is divided into a variety of types of influences, which are closer to the physical level and psychotherapy in the understanding of psychoanalysis, Gestalt therapy and the like. Not all used physical and related procedures have a high level of scientific evidence of their justification.

This is sleep deprivation, laser blood irradiation, the use of special light lamps, electroconvulsive effects, and the like.

Causes and Variants of Resistant Depression

Depression is considered one of the most dangerous ailments of the 21st century. Many forms of the disease are recommended to be treated with appropriate methods. Correct diagnosis and adequate prescription of drugs is the main thing in treatment.

In cases of a combination of adverse factors, there is a risk of resistant depression.

What is resistant depression

Resistant depression is called depression, not amenable to treatment by conventional methods. Experts note that the lack of effectiveness of treatment or its insufficiency for two consecutive courses are the main signs of resistance.

Protracted, chronic forms and resistant depression cannot be identified. 6-10 weeks is the period during which the drugs should be at least 50% effective.

The reasons

The severity of the disease. The level of resistance increases the protracted nature of the disease. AT chronic form depression can occur "depressive lifestyle" - a decrease in energy potential, weakness of the body, personality changes.
Misdiagnosis. In case of incorrect diagnosis, not all symptoms are taken into account and interpreted correctly. The stability of heterochromic signs of the disease makes it difficult to establish a true diagnosis and start treatment on time. Inadequately prescribed therapeutic methods of treatment cannot be effective.
parallel disease. The course of depression may be accompanied by other diseases that weaken the body and reduce the effectiveness of treatment. In the presence of cardiovascular, mental, endocrine diseases, resistance is one of the forms of a protective reaction of the body. Increase resistance to treatment hysterical, paranoid, schizoid personality traits.
External factors. The presence of an unfavorable social environment can strengthen or form resistance. Experts found that the development of society and civilization influenced the pathomorphosis of the disease. Studies have shown that the effectiveness of drugs that were successfully used 50 years ago has significantly decreased. This requires the search for new methods of treatment. Changes in the course of depression coincided with the development mass culture This factor cannot be ignored. It is generally accepted that depression is a postmodern disease. Cultural factors are considered important in shaping the incurability of a mental disorder.
Scheme of taking medications. In 11-18% of patients, resistance to the effects of certain drugs is observed. Simply put, a drug does not work or has no effect on a person. required level efficiency.
Resistance can be formed at the genetic level - this is manifested in the body's tolerance to the effects of drugs traditionally used to treat depression.
The effectiveness of treatment can be reduced by the competition of medicines or the mutual decrease in their effectiveness. The course of treatment is negatively affected by non-compliance by the patient with the regimen of taking medications. In half of the patients with manifestation of resistance, the drug was prescribed incorrectly, so the course of treatment did not bring the desired results.

What are the causes of suicidal depression? Read the article.

Resistance Options

Primary or absolute - a form that occurs in relation to all drugs. This is the basic mechanism of the body, working at the genetic level. The primary form is determined by the clinical picture of the disease.
Secondary - is a reaction to certain drugs that the patient has already taken. It manifests itself as addiction to the drug - this is associated with a decrease in its effectiveness.
Pseudo-resistance - a reaction to inadequately prescribed medications, may be a manifestation of insufficient treatment or an incorrect diagnosis.
Negative is rare. It is a consequence of intolerance and sensitivity to the drug - in this case, the body is protected from the side effects of the drug.

Methods of psychotherapy

There are several areas of psychotherapy:

unloading and dietary;
radiotherapy;
extracorporeal;
biological;
microwave;
medical;
electroconvulsive;
psychotherapeutic.

In the absence of the effectiveness of each method separately, combinations are used. Combining several ways to deal with depression shows great results, even in difficult cases.

Treatment

The most popular treatment is medication. After diagnosis, the attending physician must determine the effectiveness of the drug. The use of antidepressants should have a positive result.

In case of low efficiency or its absence, it is necessary to prescribe another drug. An important condition for treatment is compliance with their regimen.

In the absence of a positive result, it is recommended combined treatment is the use of a combination of different medications. The second drug may be an antidepressant or lithium-containing drugs. A combination therapy option is an antidepressant and ketiapine.

What to do if there are no results. Alternative

A popular method of treatment is psychotherapy. There are two forms - behavioral and rational. Experts recommend starting a course of treatment with this method.

Why is recurrent depression dangerous? Read in the article.

What is the diagnosis of depression? The answer is here.

Gradually, medications are introduced into the course of treatment or several methods are combined with each other in the absence of a positive effect.

The electroshock method is highly effective, so it has been used for many years.
The use of antipsychotics. This method of treatment is modern and effective. Efficiency is noted by research scientists in the industry.
The method of electrical stimulation is at the stage experimental studies. Experts note its effectiveness, but all possible consequences have not yet been studied.

When prescribing treatment, it is necessary to take into account the characteristics of the patient's personality, the presence of contraindications and other diseases. Especially, it concerns cardiovascular diseases and pathologies.

The key to healing from depression is the correct diagnosis and timely assistance to the patient.

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Resistant depression: diagnosis and treatment

Resistant depression, the treatment of which should take place only under the supervision of a specialist, is a rather serious illness. Resistant depression (not treatable) is a type of depression.

Its essence lies in the fact that such depression does not disappear after the standard method of treatment, but resumes after a certain time. This type of depression occurs in people who have experienced the disease more than once in their lives, or people with chronic depression.

Accompanying factors associated with resistant depression

The disease often manifests itself at a young age. Patients do not respond well to antidepressant treatment, and life cycle depression often returns to them.

Poor results in treatment contribute to the heavy use of drugs and alcohol. There is a high chance of relapse. Among these patients, the most common cases of suicide or attempted suicide.

There are disorders of the alimentary tract, patients develop bulimia, anorexia. An indicator of severe depression is panic disorder, which does not respond well to standard methods in the treatment of the disease.

Poor treatment outcome occurs when there is somatic diseases in combination with resistant depression, and sometimes cause depression.

Forms of resistance

Absolute (primary) is due clinical disease and manifests itself to all drugs.

The secondary form of resistance is a negative reaction to some drugs previously taken by the patient. It manifests itself in the form of addiction to drugs, while reducing the effectiveness of treatment.

The negative form is very rare, expressed in intolerance to the prescribed drugs.

Pseudo-resistance is a patient's reaction to an incorrectly prescribed treatment.

Resistance symptoms

Patients have persistent (chronic) depression or psychological pathologies. A sick person becomes closed in himself, communicates less with loved ones. The depressed person is constantly lonely and avoids big noisy companies. There is a feeling of longing, self-esteem is lowered, a person is constantly dissatisfied with himself, a feeling of anxiety appears. Among all these factors, addiction to drugs and alcohol often occurs.

In addition to emotional disorders, accompanying diseases and physiological symptoms. There are disorders in sexual life. The patient's appetite decreases, or vice versa, the patient "seizes" all experiences, that is, suffers from overeating. There is a feeling of fatigue in the morning, as soon as you wake up. There are problems with sleep, rises at night for no reason, constant insomnia. The daily routine is disturbed, and the patient is awake in the middle of the night, and wants to sleep during the day. When the disease worsens, suicide attempts occur.

Causes of the disease

The reasons for resistance are varied:

the diagnosis is incorrect. In this case, the attending physician did not take into account all the symptoms of the disease, and the prescribed treatment is not suitable. Inappropriately prescribed treatment will not give a positive result;
the severity of the disease. When the patient is frequently depressed, is in chronic stage diseases, he develops the so-called "depressive lifestyle". In this case, the body weakens, the energy level decreases;
medication regimen. The patient does not receive the desired result from the treatment due to resistance to certain medications;
external factors. The development and formation of refractory depression is facilitated by the surrounding social environment, which is not always favorable;
the effectiveness of treatment is reduced while taking other medications. In case of non-compliance with the prescribed mode of reception medicines the result of the whole treatment is also reduced;
resistance is formed at the genetic level. The body shows tolerance to medications used in a depressive state of a person;
concurrent disease. Depression occurs simultaneously with other diseases, which leads to a weakening of the body and the ineffectiveness of its treatment.

Treatment of depression

psychotherapeutic;
microwave;
unloading and dietary;
medical;
radiotherapy;
electroconvulsive;
biological.

If one of the methods does not help, they are combined, which gives a good result in treatment even in difficult cases.

The most popular of the methods of treatment is medication. After establishing the diagnosis, the doctor determines the effectiveness of the prescribed drug, often antidepressants. Their reception should show a good result.

Different methods of psychotherapy are used in the treatment of resistant depression. Quite often, short-term therapy is used, aimed at the result, helping to cope with the problem.

If treatment with a course of psychotherapy does not give a positive result, try another course. It can be family or group therapy. Try to address to other psychotherapist.

When psychotherapy and medication do not help you, you can use alternative methods treatments such as neurotherapeutic methods.

Deep brain stimulation (DBS). In this therapy, high-frequency electrical signals are fed into the brain tissue through wires connected to a current through the skull.

Vagus nerve stimulation. The brain is electrically stimulated with an electrode wrapped around the vagus nerve in the neck.

Electroconvulsive therapy (ECT). Seizures are caused by electrical stimulation of the human brain. Such therapy is effective in relieving signs of depression, but many question its safety.

Transcranial magnetic stimulation of the brain. Near the patient's head is an electromagnetic coil.

At this moment in gray matter an alternating electric current is generated when a rapidly changing, powerful magnetic field penetrates a couple of cm deep.

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/ !Depressions / Treatment-resistant depression

UDC 616.895.4:615 LBC 56.14-324

Bykov Yu. V. Treatment-resistant depression. - Stavropol, 2009. - 77 p.

The book sets out modern views for the treatment of therapeutically resistant depressive conditions; possible mechanisms of formation of therapeutic resistance to antidepressants are considered, the main classifications and clinical characteristics of resistant states are given. Special attention given to possible therapeutic approaches aimed at overcoming therapeutic resistance in the practice of a doctor. Both medicinal and non-drug effects are described, which have a certain healing effect in the fight against resistant conditions. Separate groups of antidepressants are analyzed, as well as the possibility of their safe interaction with each other.

Reviewer: Doctor of Medical Sciences, Professor, Mazo Galina Elevna

SECTION I. Therapeutic resistance and depression ……9

Some statistics……………………………. 9

The concept of therapeutic resistance…………………10

From history to modern criteria of therapeutic resistance…………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………………

The main classifications of depression resistant to therapy…………………………………………………………….12

Some possible mechanisms for the development of therapeutic resistance (why does the body not respond to an antidepressant?)

Clinic and differential diagnosis protracted depressive states…………………………………………21

SECTION II. Base of medical tactics …………………………. 23

The main tasks, stages and approaches to the treatment of resistant depression………………………………………………………….23

General characteristics of antidepressants……………. ……25

SECTION III. The main stages (steps) of overcoming therapeutic resistance …………………………. 33

Step one: optimization of ongoing therapy (what to do if there is no effect on the primary antidepressant?)…………………………………………………33

Step two: change the antidepressant…………………………38

Step three: combine antidepressants……………. 40 Step Four: Antidepressant + Non-Antidepressant

Step five: non-pharmacological methods of therapy………. 51 1. Classical non-pharmacological methods.……. 51

Electroconvulsive therapy ………………………………. 51 Atropinocomatous therapy ……………………………. 53

Extracorporeal pharmacotherapy ……………………. 56 Intravenous laser blood irradiation …………………….56

2. Recently developed non-pharmacological therapies ……………………………………………………..58

Magnetic convulsive therapy …………………………. 59 Transcranial magnetic stimulation ……………….…60

Vagus Nerve Stimulation ………………………..…..60 Deep Brain Stimulation ……………………………………..61 Light Therapy (Phototherapy) ……………………… ……. 62

Let's draw conclusions (instead of a conclusion)……….. ……………. 63

BOOK REVIEW

The release of a book focused on the coverage of issues of therapeutically resistant depressive states is very timely and important. This is due not only to the steady increase in the prevalence of depression, but also to the fact that, despite the rapid increase in the number of drugs with thymoanaleptic activity on the antidepressant market, the problem of the lack of effect when using them does not approach at least partial resolution.

The concept of therapeutically resistant depression is one of the most controversial and unresolved in modern psychiatry. This is also indicated by the lack of consensus in the definition of this concept and the multitude of author's approaches to classification. Indeed, the selection of this concept is not connected with any clinical characteristics depressive states, nor with the patterns of their development or course. The allocation of treatment-resistant depression is based only on the assessment of response to antidepressant therapy. This is why therapeutically resistant depression is neither diagnostic nor syndromic.

An important aspect of the book is its coverage of therapeutic issues. The modern literature offers a wide variety of methods to overcome therapeutic resistance, the evidence base of which is often insufficient. In addition, in last years describes a large number of non-drug methods to overcome therapeutic resistance in depressive disorder. In clinical reality, a physician faced with a lack of effect or insufficient effect when using an antidepressant must find the answer to the question - what is the next step? The proposed detailed step-by-step presentation of the recommended therapeutic approaches used is undoubtedly an important virtue of the book. This information is clearly presented in a language understandable to practitioners and certainly provides the necessary basis for optimizing the management of patients with antidepressant-resistant depression.

doctor of medical sciences, professor, Mazo Galina Elevna

ACT - atropinocomatous therapy ACTH - adrenocorticotropic hormone

ILBI - intravenous laser blood irradiation GSN - deep brain stimulation HCA - heterocyclic antidepressants

DAST - dopamine stimulating therapy DS - sleep deprivation MAOI - monoamine oxidase inhibitors

MCT - magnetic convulsive therapy MEIVNA - a method of emergency change in the time of prescribing an antidepressant

NaSSA - noradrenergic and specific serotonergic antidepressants OOA - simultaneous withdrawal of antidepressants PA - plasmapheresis

PR - psychoreanimatology PFT - psychopharmacotherapy

RCT - randomized clinical trials RLS - vagus nerve stimulation SNRI - selective norepinephrine reuptake inhibitors

SSRIs - selective serotonin reuptake inhibitors SSRIs - selective serotonin and dopamine reuptake inhibitors SNRIs - selective serotonin and norepinephrine reuptake inhibitors

SSA - specific serotonergic antidepressants T3 - triiodothyronine T4 - tetraiodothyronine

TMS - transcranial magnetic stimulation TRD - therapeutic resistant depression TCA - tricyclic antidepressants UBI - ultraviolet blood irradiation CNS - central nervous system ECT - electroconvulsive therapy

EFT - extracorporeal pharmacotherapy

Dedicated to my teachers - Alexander Ilyich Nelson and Vladimir Alexandrovich Baturin

Raising the issue of treatment-resistant depression is interesting, but far from simple. On the one hand, the relevance of this problem has long been beyond doubt: according to numerous literary sources (both domestic and

and foreign), the frequency of therapeutically resistant depression (TRD) in practice increases from year to year, which is of increasing interest to researchers. On the other hand, despite the accumulated experience in dealing with resistant depression, the boundaries of this problem are very blurred. Thus, the possible mechanisms for the development of TRD are still far from being resolved, and the criteria for diagnosing this difficult condition find more questions than answers. Not always successful attempts to cope with TRD have given rise to more than a dozen anti-resistant methods, many of which have already become history, and those methods that have remained and are being born again often have to reckon with modern canons. evidence-based medicine. The emphasis of this book is on resistance as the cause of the chronification of depression. The description of the classics of the most depressive episode (classification, clinic, diagnosis) remained outside the scope of this material, because There is a huge amount of literature devoted to this today. The only exceptions were the issues of pharmacology and pharmacokinetics of modern antidepressants, which is fully explained by the fact that knowledge in this area gives a decent head start at the stage of choosing tactics to combat TRD. We did not set ourselves the task of writing this monograph in the form of a full-fledged practical guide. Due to the unresolved many issues related to TRD (causality, clinical criteria, therapeutic tactics), this book is more advisory in nature and is a mix of literature review and own practical experience author.

and recommendations for the preparation of this book. The author would appreciate any critical comments on this book and hope that this publication will be of some help to physicians in the treatment of patients with resistant depression.

To reach the goal, you have to go

Honore de Balzac

SECTION I THERAPEUTIC RESISTANCE

It is a well-known fact that the growth of depressive conditions throughout the world is obvious. Statistics confirming this are given in many literary sources and, in order not to repeat ourselves, we will not rewrite the figures for such a gloomy dynamics of depression in the general population, but we will dwell in more detail on “our” problem - resistant states. Here is the data that is of interest to us. According to numerous literature sources, today the biggest problem associated with depressive disorders is that, despite the emergence of a large number of new antidepressants and significant progress in understanding the biological mechanisms of the development of depression, on average, about 30-60% of patients with pathology related to depressive spectrum disorders,

are resistant to ongoing thymoanaleptic (that is, antidepressant) therapy (V. V. Bondar, 1992; E. B. Lyubov

2006; O. D. Pugovkina, 2006). It is not surprising that the progression of protracted and therapy-resistant depression based on these figures has long been a serious clinical problem both in our country and abroad. Today, about 60–75% of patients with depressive disorders after treatment have residual signs of depressive symptoms (C. Ballas, 2002), and 5–10% of such patients, despite repeated attempts to be treated with antidepressants, have no effect at all (M. E. Thase , 1987; A. A. Nierenberg, 1990). The frequently used term “chronic depression” (a concept that largely intersects with resistance) is already found in about 4% of the entire population (O.D. Pugovkina, 2006), and for the period from 1945 to 2000, the total number of protracted depressions lasting up to two years increased from 20 to 45% (Cross-national…, 1999). It is indisputable that the growth of therapeutically resistant conditions causes significant socio-economic difficulties not only for patients, but also for society in

in general. According to foreign authors, significantly increased costs in the treatment of depression occur mainly due to the growth in practice of forms that are resistant to therapy (J. M. Russell, 2004). In addition, the unsuccessful use of antidepressants (and other anti-resistant methods) for depression creates situations that are difficult to tolerate not only by patients, but also by doctors themselves. By the way, among the factors of suicide in patients suffering from prolonged depression, it is the ineffectiveness of their treatment that plays an important role.

THE CONCEPT OF THERAPEUTIC RESISTANCE

To begin with, let us recall the concept of resistance from the standpoint of general pathophysiology. It is believed that resistance is a fundamental biological characteristic of a living organism. Resistance is understood as the degree of resistance of an organism to one or another pathogenic or opportunistic factor, in other words, it is an individual protective and adaptive response of the biosystem. The concept of tolerance is closely related to resistance, which is manifested by the induction of certain enzymes, as well as a decrease in the density of receptors due to the introduction of medicinal substances into the body.

Talk about therapeutic resistance medicines always difficult, since the problem is still far from being resolved, not only in psychiatry, but also in many other areas modern medicine. However, among the diversity of drug insensitivity, PFT resistance is the most frequently discussed due to pharmacological features psychotropic drugs. But, despite this, there are still no generally accepted definitions of therapeutic resistance in psychiatry either in our country or abroad. That is why the decision on insensitivity to psychotropic drugs to this day carries a significant amount of uncertainty. The reason for this, apparently, is too blurred boundaries of the interpretation of this condition, as well as a large arsenal of qualitative characteristics of the very concept of therapeutic resistance in psychiatric practice.

Among the numerous attempts to characterize this condition, the most common opinion in our country (R. Ya. Vovin, 1975; S. N. Mosolov, 2004) is the following:

therapeutically resistant psychiatric patients

these are those patients who do not experience the expected (projected) positive changes in clinical picture with sufficiently active (adequate) PFT. In turn, adequate PFT is commonly understood as the appointment of treatment in accordance with existing clinical indications, that is, when there is a differentiated approach based on correct diagnosis using an effective dosage of prescribed psychotropic drugs.

FROM HISTORY TO MODERN CRITERIA FOR THERAPEUTIC RESISTANCE

Directly define the turbojet engine as a phenomenon, attempts have been made for a long time. Already by the beginning of the 70s of the last century (based on the twenty-year use of antidepressants in psychiatric practice), extensive clinical material was accumulated on the resistance of some endogenous depressive states to antidepressant treatment. By the end of the 1970s, the term “treatment-resistant depression” was increasingly used in the literature. At about the same time, a group of so-called "protracted depressive states" was identified, which included patients in whom, despite the use of all known methods of treatment, depressive manifestations did not disappear completely. There were other definitions of TRD (in the understanding of that time): “protracted depressions”, “chronic depressions”, “irreversible depressions”, “incurable depressions”. At the time, depression was considered therapeutically resistant if it clinical manifestations continued for over a year. However, even then it was believed that the concepts of "resistance" and "protracted course" (with respect to depressive disorders) are not identical, but different biological processes (we will talk about this below, because modern views share this point of view). In 1986, the WHO described TRD as "a condition in which treatment for at least two months, with two consecutive courses of antidepressant therapy, adequate to the condition, did not bring the desired result."

According to modern generally accepted criteria (S.N.

Mosolov, 1995; F. Yanichak, 1999; G. E. Mazo, 2005; M. N. Trivedi, 2003), depression is considered resistant if within two

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Treatment-resistant depression

Treatment-resistant depression (TRD), or resistant depression, refractory depression, is a term used in psychiatry to describe cases of major depression that are resistant to treatment, that is, they do not respond to at least two adequate courses of treatment with antidepressants of different pharmacological groups (or do not respond enough , that is, there is a lack of clinical effect). The reduction of depressive symptoms according to the Hamilton scale does not exceed 50%.

The adequacy of therapy should be understood as the appointment of an antidepressant in accordance with its clinical indications and the characteristics of the spectrum of its psychotropic, neurotropic and somatotropic activity, the use of the required range of doses with their increase in case of failure of therapy to the maximum or with parenteral administration and compliance with the duration of the course of treatment (at least 3 -4 weeks).

Classification of turbojet engines and its causes

There are a large number of different classifications of turbojet engines. So, for example, I. O. Aksenova in 1975 proposed to distinguish the following subtypes of turbojet engines:

Depressive states, initially having a protracted course.
Depressive states, acquiring a longer and more protracted course for unknown reasons.
Depressive states with incomplete remissions, that is, with a “partial recovery” (after treatment of which patients still had residual, residual depressive symptoms).

Depending on the causes, the following types of resistance are distinguished:

Primary (true) therapeutic resistance, which is associated with poor curability of the patient's condition and an unfavorable course of the disease, and also depends on other biological factors (this type of resistance is extremely rare in practice).
Secondary therapeutic (relative) resistance associated with the development of the phenomenon of adaptation to psychopharmacotherapy, that is, formed as a result of the use of the drug (the therapeutic response develops much more slowly than expected, only certain elements of psychopathological symptoms are reduced).
Pseudo-resistance, which is associated with inadequate therapy (this type of resistance is very common).
Negative therapeutic resistance (intolerance) - hypersensitivity to the development of side effects, which in this case exceed the main effect of the prescribed drugs.

The most common causes of pseudo-resistance are the inadequacy of the therapy (dose and duration of antidepressant intake); underestimation of factors contributing to the chronicity of the condition; lack of control over compliance with the therapy regimen; other reasons are also possible: somatogenic, pharmacokinetic, etc. There is a large amount of experimental data confirming the significant role of psychological and social factors in the formation of drug resistance to depression.

Primary prevention of TRD

Measures for the primary prevention of TRD, that is, measures to prevent the development of therapeutic resistance in the treatment of depressive conditions, are divided into:

diagnostic activities.
Medical activities.
social rehabilitation activities.

Treatment of TRD

To overcome the therapeutic resistance of depression, many methods have been developed, both pharmacological and non-pharmacological. However, the first significant step in the case of ineffectiveness of an antidepressant should be a complete reassessment of previous antidepressant therapy, which consists in finding out the possible causes of resistance, which may include, in particular:

insufficient dose or duration of antidepressants;
metabolic disorders affecting the blood concentration of the antidepressant;
drug interactions, which can also affect the concentration of the antidepressant in the blood;
side effects that prevented the achievement of a sufficiently high dose;
comorbidity with other mental disorders or with somatic or neurological pathology;
incorrect diagnosis (if, for example, in reality the patient does not have depression, but 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 move from a depressive to a hypomanic state, or the biological symptoms of depression can be eliminated, and melancholy and anxiety continue to be retained;
adverse life circumstances;
genetic predisposition to a particular reaction to an antidepressant;
lack of control over compliance with the therapy regimen.

Drug switching and combination therapy

If the above measures did not lead to sufficient effectiveness of the antidepressant, the second step is applied - changing the drug with another antidepressant (usually of a different pharmacological group). The third step, if the second one is ineffective, may be the appointment of a combination therapy with antidepressants of various groups. For example, you can take bupropion, mirtazapine and one of the SSRI drugs such as fluoxetine, escitalopram, paroxetine, sertraline in combination; or bupropion, mirtazapine, and an SNRI antidepressant (venlafaxine, milnacipran, or duloxetine).

Monoamine oxidase inhibitors, despite the large number of side effects (because of this, they are best used only if all other drugs have not given a therapeutic effect), continue to be the most effective drugs for the treatment of certain forms of depression that are considered very resistant to traditional antidepressant therapy, in particular atypical depression, as well as depression comorbid with social phobia, panic disorder.

Potentiation

When combined therapy with antidepressants is ineffective, potentiation is used - the addition of another substance, which in itself is not used as a specific drug for the treatment of depression, but can enhance the response to the antidepressant taken. There are many drugs that can be used for potentiation, but most of them do not have the proper level of evidence for their use. Lithium salts, lamotrigine, quetiapine, some antiepileptic drugs, triiodothyronine, melatonin, testosterone, clonazepam, scopolamine, and buspirone are the most evidence-based; they are first-line potentiators. However, drugs with a low level of evidence may also find use in resistant depression when first-line potentiating agents are ineffective. In particular, benzodiazepines, such as alprazolam, can be used for potentiation, which also reduce the side effects of antidepressants. Some authors recommend the addition of low doses of the thyroid hormone thyroxine or triiodothyronine for therapeutically resistant depression.

In TRD, the addition of lithium or atypical antipsychotics such as quetiapine, olanzapine, and aripiprazole to antidepressant treatment results in about the same improvement in patients with TRD, but treatment with lithium is less expensive. Olanzapine is especially effective in combination with fluoxetine and is produced in combination with it under the name Symbiax for the treatment of bipolar depressive episodes and resistant depression. In a 122-person study, when adjunctive treatment of patients with psychotic depression, quetiapine plus venlafaxine produced a significantly better therapeutic response rate (65.9%) than venlafaxine alone, and the remission rate (42%) was higher in comparison. with monotherapy with imipramine (21%) and venlafaxine (28%). In other data, although the effect on depression when adding antipsychotic drugs to the main drug is clinically significant, it usually does not lead to remission, and patients taking antipsychotics were more likely to leave studies early due to side effects. In general, there are data on the effectiveness of atypical antipsychotics in resistant depression, typical ones are mentioned much less often. In addition, typical antipsychotics themselves have a depressogenic effect, that is, they can lead to the development of depression.

Psychostimulants and opioids

Psychostimulants, such as amphetamine, methamphetamine, methylphenidate, modafinil, mesocarb, are also used in the treatment of some forms of therapeutically resistant depression, but their addictive potential and the possibility of developing drug dependence should be taken into account. Nevertheless, it has been shown that psychostimulants can be an effective and safe treatment for treatment-resistant depression in those patients who do not have a predisposition to addictive behavior and who do not have concomitant cardiac pathology that limits the use of psychostimulants.

Non-pharmacological methods

There is evidence of the effectiveness of physical activity as a means of potentiation in treatment-resistant depression.