Resistant state. Depression and resistance: how to help the suffering mind? The problem of resistance in the treatment of depression

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

What is resistant depression

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

1. The severity of the disease... The level of resistance increases the protracted nature of the disease. In the chronic form of depression, a "depressive lifestyle" can occur - a decrease in energy potential, weakness of the body, personality changes.
2. Incorrect diagnosis. 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 may not be effective.
3. Parallel disease. The course of depression can 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 the body's defense reaction. Hysterical, paranoid, schizoid personality traits increase immunity to treatment.
4. External factors... The presence of an unfavorable social environment can enhance or form resistance. Experts have established 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 treatments. Changes in the course of depression coincided with the development of mass culture - this factor cannot be ignored. It is generally accepted that depression is a postmodern disease. Cultural factors are considered to be important in the incurability of a mental disorder.
5. Resistance can develop at the genetic level - This is manifested in the body's tolerance to the effects of medications traditionally used to treat depression.

Resistance options

6. Secondary - is a reaction to certain medications that the patient has already taken. It manifests itself as addiction to the drug - this is associated with a decrease in its effectiveness.
7. Pseudo-resistance - a reaction to inadequately prescribed medications may be a manifestation of insufficient treatment or an incorrect diagnosis.
8. 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.



There are several areas of psychotherapy:

9. unloading and dietary;
10. extracorporeal;
11. biological;
12. microwave;
13. medication;
14. electroconvulsive;

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

The most popular treatment method is medication. After diagnosis, the attending physician must determine the effectiveness of the drug. Antidepressant medication should be beneficial.

In the absence of a positive result, a combination treatment is recommended - this is the use of a combination of various medicines. The second drug can be an antidepressant or lithium drugs. A combination therapy option is an antidepressant and ketiapine.

What to do if there are no results. Alternative

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

15. Electrical stimulation method is at the stage of experimental research. 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. This is especially true for cardiovascular diseases and pathologies.

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Resistant depression

Resistant depression is a technical term used to describe the lack of therapeutic effect in the treatment of major depressive disorder. This assumes that at least two courses of adequate antidepressant treatment were carried out. 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. Before that, medications gave a positive result, and there was a stable remission in 50% of patients. Starting from about 1975, the number of patients who were not helped by several courses of antidepressants began to increase. About a third of depressive disorders are now resistant.



Revision of therapy

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

16. The diagnosis was not correct. The patient is being treated for depression, but in fact he has bipolar disorder, schizophrenia, or something similar.
17. The metabolism is disturbed, which does not give the necessary concentration of certain substances.
18. There is a genetic predisposition to an atypical response to antidepressants.
19. There are some side effects that reduce the effectiveness of antidepressants.
20. They are generally chosen incorrectly.
21. Treatment is carried out without complex psychotherapy.
22. Some active stimulus persists. It can be poverty, debt, problems in personal life, and the like.



This is not a complete list of things to consider when depression is refractory to treatment.

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 has disappeared, but anxiety persists, elements of other emotional disturbances may be present.

However, after some time, the patient returns to the medical institution again, and history repeats itself. Outside the walls of the hospital, he is faced with the usual complex of problems for himself and finds himself in the same environment, which makes depression almost incurable.



Pharmacological and other methods

Of course, the analysis of the situation leads to the fact that medicines and the very method of their use are changing. However, often this only starts a new circle, and then the symptoms become the same.

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



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

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

Resistant depression is depression that does not respond to conventional treatment. Experts note that the lack of effectiveness of treatment or its failure during two successive courses are the main signs of resistance.

23. 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 on a person or does not have the required level of effectiveness.
24. Competition of medicines can reduce the effectiveness of treatment or a mutual decrease in their effectiveness. The course of treatment is negatively affected by non-compliance with the patient's regimen of taking medications. In half of the patients with the manifestation of resistance, the drug was prescribed incorrectly, so the course of treatment did not bring the desired results.

What are the prerequisites for suicidal depression? Read the article.

25. Primary or absolute - the 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.

Psychotherapy methods

26. x-ray therapy;
27. psychotherapeutic.

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



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

What is the danger of recurrent depression? Read the article.

What is the diagnosis of depressive conditions? The answer is here.

28. Electroshock method - is highly effective, therefore it has been used for many years.
29. Antipsychotic use... This method of treatment is modern and effective. Effectiveness is noted by research by scientists in the industry.

The key to healing depression is correct diagnosis and timely patient care.

What is resistant depression?

Treatment resistance is a definition denoting that it is depression that does not respond adequately to treatment with at least two standard antidepressants.

However, even such a rather straightforward definition creates several problems, since there is no single point of view on the question of what is meant by adequately performed treatment? In terms of duration or dosage of antidepressants? Moreover, in the part of the definition “does not respond”, there are also variations.

There is only one consistently used criterion - more than a 50% reduction in depression symptomatology on the Hamilton Depression Inventory - seen as a sufficient response to treatment in severely depressed patients.

The time required for an adequate response to treatment is in the range of 6 to 10 weeks, as many studies have found a high level of change in response to treatment only at 2 months of therapy.

The concept of "adequate dose" of an antidepressant does not make much sense after the introduction of new drugs into practice, the level of which in plasma cannot be determined or its definition cannot be interpreted. For example, when different patients receive the same dose of tricyclic antidepressants (TCAs), individual differences in the level of the drug in the blood plasma can reach 10-40 times, so many clinicians are forced to think about determining the level of TCA in plasma when faced with cases of resistance to treatment.

How do patients with treatment-resistant depression differ from other depressed patients?

Patients with resistant depression suffer from depression more often than once in their life, or they have chronic depression.

Depression is also more likely to occur in old age. In elderly patients, CT scans show a decrease in the volume of the cortex and an expansion of the ventricles of the brain. They often show a positive dexamethasone test (DP). They often have concomitant mental and somatic pathology.

What comorbid disorders are found in resistant depression?

Substance abuse (alcohol, drugs), panic disorder, eating disorders (anorexia, bulimia), and personality disorders (psychopathies) are clearly associated with resistant depression.

Substance abusers respond less well for depression treatment, they are more likely to relapse their depression and have a higher suicide rate.

Patients with panic disorder are more likely to have more severe depression and also respond poorly to standard treatment.

Comorbid (concomitant) personality disorders are observed in 40-60% of resistant depressions. These patients are usually characterized by early onset of depression (at a young age), a large number of depressive episodes during life, more often there is a suicidal mood and a reduced response to antidepressant treatment.

What somatic diseases affect resistant depression?

Physical illness can cause, worsen, or potentially complicate the course of depression. Certain medical conditions, such as undiagnosed hypothyroidism (decreased thyroid function), can be the cause of so-called refractory (refractory) depression to treatment.

Other conditions, such as chronic pain, can act reciprocally on each other: an improvement or worsening of one leads to a parallel improvement or worsening of the other. A number of other diseases, such as heart disease, can limit the choice of antidepressants. Therefore, the psychiatrist should seek and treat medical conditions in patients considered resistant to treatment.

What is the most common cause of so-called treatment-refractory depression?

Inadequate treatment is perhaps the most common cause of chronicity and recurrence of depression. Approximately 2/3 of patients on outpatient treatment receive therapy inadequate in duration and dose (for example, only for 4-6 weeks).

How important are the subtypes of depressive disorders?

Psychotic, atypical, bipolar, and geriatric depression (depression in the elderly) are important subtypes of depressive conditions, as each of them may require specific therapeutic strategies.

Unrecognized psychotic depression Is a common cause of treatment resistance. Often, psychotic symptoms are subtle and only detectable with careful questioning. Patients with psychotic depression do not respond well to antidepressants and antipsychotic medications if they are used in isolation. However, the combination of these drugs can be very effective, or these patients respond well to electroconvulsive therapy (ECT).

Atypical depression characterized by mobility of mood (mood changes depending on relationships with others), lead fatigue (the patient feels his hands and feet as extremely heavy), sensitivity to rejection (the patient is sensitive even to mild criticism) and constant drowsiness and increased appetite.

These patients respond poorly to tricyclic antidepressants (TCAs) and significantly better to selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs). These patients may benefit from newer antidepressants such as venlafaxine, mirtazamine, and others. A psychiatrist's failure to recognize bipolar depression can lead to cycle changes, mania, or mixed conditions.

Choosing the wrong drugs can be ineffective in treating this disorder and can be detrimental to the course of the disease in the long term.

Patients with geriatric depression more often susceptible to its masked form and have symptoms of anxiety, memory disorders and somatic complaints.

Late depression, which by definition occurs after 65 years of age, is more associated with diseases leading to dementia, impaired perception and somatic diseases that complicate its course.

“Our dreams are a reflection of ourselves”



Depression is a dangerous and insidious disease. The basis of his treatment is the correct diagnosis and 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. Such a disease that does not respond to treatment is commonly referred to as resistant depression.

Why does resistant depression appear?

There are several reasons for the development of resistant depression:

30. Misdiagnosedwhen the specialist conducting 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 interpreted incorrectly.
31. During treatment for depression, the patient violated the regimen and did not take medication, which the doctor prescribed for him, which not only did not improve his condition, but also did not eliminate the problem completely.
32. The person initially suffered from severe 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.
33. In addition to depression, the patient suffers from other diseases and addictionsand reducing the effectiveness of treatment.
34. The effectiveness of the previous treatment was reduced due to the patient's immunity to some drugs.
35. The patient is strongly influenced by the social environment, which is not conducive to healing, he experiences constant stress and anxiety due to difficult circumstances in life.
36. The patient was taking other drugs during treatmentthat reduced the effectiveness of the therapy.

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

Symptoms of Resistant Depression

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

Resistant depression is characterized by sudden decreases in appetite or, conversely, attempts to calm their nerves by overeating. Patients constantly feel weakness and weakness, even from the very morning, when they get out of bed. They often have problems with night rest, as well as insomnia, the daily routine is disrupted and shifted in the opposite direction. With this form of depression, suicide attempts are frequent, as well as panic disorders, which are difficult to treat with standard methods.

Patients often quit taking medication on their own, and do not inform their doctor about it. The course of depression greatly aggravates the disease of the thyroid gland and cardiovascular system.



Treatment of resistant depression

Resistant depression is very difficult to treat. To remove patients from this state, various techniques are used. The most effective is the use of medications. They are selected for each patient individually. No single treatment for this form of depression has been found. Most likely, the patient will have to try several options at once. After the diagnosis is made, the doctor will prescribe antidepressants, but they should be effective.

If they are not there, other combinations and combinations of drugs will be selected for the treatment of depression, prolongation of antidepressant intake, replacement of one drug with another, and strengthening of the effect of antidepressants with other drugs.

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

If traditional treatment options for resistant depression are ineffective, there is an opportunity for patients to use other methods. You can try a treatment that consists of using:

• Electroconvulsive therapy. When the treatment of depression is carried out due to the fact that the patient is exposed to a current on the head to cause seizures. It helps to quickly relieve the symptoms of depression.
• Vagus nerve stimulation. When depression is treated with a special impulse generator that is connected through the cervical vagus nerve to affect the patient's brain.
• Deep brain stimulation. When depression is treated by direct exposure of the human brain to an electric current supplied through electrodes.
• Transcranial magnetic stimulation. When depression is treated with an electromagnetic coil, which creates a magnetic field and stimulates the gray matter of the brain.

Exercise and walking have a good effect on the health of patients with resistant depression. They have a strengthening effect on the body and raise the mood of patients.

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

Despite the emergence of more and more antidepressants, in a significant part of patients with depression (25 ... 30% according to various researchers), the treatment is ineffective or insufficiently effective. Some psychiatrists attribute the unsuccessful therapy to antidepressant resistance. A vast literature is devoted to this issue, although the very concept of therapeutic resistance is not clearly defined and is understood differently by individual authors. We do not dwell on this issue, since it is covered in the work of R. Ya. Bovin and I. O. Aksenova (1982). Everyday clinical experience shows that most of the failures are due not to the therapeutic resistance of depressive conditions, but to inappropriate treatment. N. Lehmann (1977) and many other researchers adhere to this point of view.

Schematically, the reasons for unsuccessful therapy can be divided into 5 groups: 1) difficulties in recognizing and qualifying the depressive state (for example, the so-called "masked" depression) and, as a result, the wrong choice of drug; 2) wrong treatment method; 3) inherent in this psychopathological syndrome, low cure (depressive-depersonalization syndrome); 4) long spontaneous duration of the depressive phase; 5) true resistance to all or individual types of therapy inherent in this patient, regardless of the psychopathological characteristics of the depressive state.

Since the previous sections of this chapter have discussed psychopathological criteria for choosing antidepressants, we do not dwell on them in detail. The use of the drug outside the zone of its indications (see Fig. 1) reduces the effectiveness of therapy and increases the side effect: if an antidepressant is used to the right of its zone (for example, noveril or imipramine for anxiety-depressive syndrome), this can exacerbate anxiety if to the left (for example , amitriptyline with anergic depression) - the antidepressant effect decreases, the treatment is delayed, and if it is still possible to achieve drug remission, then it turns out to be incomplete.

But even with the right choice of the drug, the results of therapy to a large extent depend on the dose of the drug, its distribution during the day, and the method of administration. It is believed that in order to achieve a therapeutic effect, it is necessary that the concentration of antidepressant in the blood is constantly maintained above a certain minimum level. For this, the amount of the drug entering the body must completely replenish its loss, which occurs due to its destruction, mainly in the liver, binding and excretion. The rate of destruction of antidepressants depends on the activity of certain enzymes, which is genetically determined and, in addition, can increase under the influence of taking certain drugs: barbiturates, a number of other anticonvulsants, as well as tricyclic antidepressants themselves. Therefore, patients in whom the destruction and elimination of antidepressants occurs too quickly need large doses and more frequent doses, as well as the parenteral route of administration, bypassing the portal circle and the liver.

In fact, the therapeutic effect of antidepressants also depends on a number of factors: on what part of the drug in the blood penetrates into those structures of the brain in which its action is realized, on the sensitivity of receptors and the density of its binding sites in the area of \u200b\u200bnerve endings, etc. Therefore, the beginning treatment with low doses and their slow increase can contribute to the emergence of resistance to this group of antidepressants, since with such a tactic, the activation of antidepressant elimination systems will increase in parallel with the dose increase.

Thus, two forms of resistance can be distinguished: congenital and acquired. However, the border between these forms is relative, since in the second case, the induction of enzyme systems is manifested to a greater extent in those patients who already have a genetically determined increased activity of these enzymes. The rate of development and the magnitude of acquired resistance are the result of two variables: the duration of drug exposure and hereditary predisposition. Therefore, therapeutic resistance to antidepressants occurs during protracted phases, and is also often observed in the treatment of depression in patients with epilepsy who have been taking barbiturates for a long time.

For many years of treatment of patients with depression, we have never met absolute resistance to all types of antidepressant therapy, with the exception of patients with severe and long-term depressive-depersonalization syndrome, and its existence seems to us unlikely, although it is sometimes mentioned in the literature.

Depressive-depersonalization syndrome cannot be regarded only as one of the forms of endogenous depression, since depersonalization is a different register, and not just one of the symptoms of the depressive phase. In cases where it is possible to achieve a reduction in depersonalization, depressive symptoms respond well to therapy. In the presence of severe depersonalization, the effectiveness of therapy and other mental illnesses is sharply reduced.

Sometimes patients with prolonged reactive (neurotic) depression fall into the category of therapeutically resistant ones, but with neurotic (and not reactive-provoked endogenous) depression, one cannot expect a good therapeutic effect from antidepressants, since their action is directed only to the pathogenetic mechanisms of endogenous depression. It is also noted that often therapeutic resistance to antidepressants occurs in depressive-phobic states [Bovin R. Ya., Aksenova I.O., 1982, etc.], however, in a significant part of cases, this syndrome is based on anxiety, and not a mechanism endogenous depression, and therefore antidepressants should be ineffective.

Thus, the reasons for treatment failure in such patients are not due to therapeutic resistance, but to inappropriate treatment. Nevertheless, at our level of knowledge, the reasons for resistance are not well known, and it cannot be ruled out that the low efficiency of various drugs, the action of which is realized through monoaminergic systems, is due to some peculiarities of the response at the receptor level.

The literature describes many ways to combat therapeutic resistance, but their abundance indicates their low effectiveness. To a greater extent, the fight against therapeutic resistance comes down to methods of treating protracted depressive conditions. In cases where the effect of any group of antidepressants, usually tricyclic, was, despite large doses, parenteral administration and the justification of their prescription, from the very beginning, insufficiently effective or gradually decreased in the course of treatment, the first step is to change the drugs, and the new antidepressant must belong to a different group. Thus, tricyclic antidepressants are replaced by MAO inhibitors, "atypical" antidepressants, or (if they are insufficiently effective), ECT. Often this replacement leads to significant improvement that continues until complete remission. However, with especially prolonged depressive phases, the onset improvement gradually decreases again, as a result of which a new drug has to be prescribed again.

In such cases, the assumption is confirmed that antidepressants do not interrupt the spontaneous course of the depressive phase, but only relieve symptoms during the treatment period. Premature withdrawal of therapy, even with a complete regression of the manifestations of depression, leads to its relapse, and it seems that the renewed depression is less responsive to treatment. In order to avoid the possibility of relapses, a careful analysis of the patient's condition is necessary, since in such cases one can often find residual signs of depression: mild daily mood swings, lack of feeling of freshness, "sleepiness" upon waking, constipation, early awakening, etc. Antidepressants should be withdrawn slowly. An additional method for assessing the timeliness of cancellation is the dexamethasone test: if its indicators have not returned to normal, there is a high risk of relapse.

However, such an unambiguous dependence of the course of the depressive phase only on endogenous rhythms does not exist in all cases: often 1-2 sessions of ECT or administration of pyrroxane lead to the onset of intermission. These and other similar observations suggest that the maintenance of the depressive state is carried out by several pathological biological systems, and, despite the spontaneous normalization of one of them (probably the leading one), others continue to keep the protracted pathological process. This assumption is supported by the fact that the rapid stopping effect of single doses of adrenergic blockers, tryptophan, and ECT is usually observed in the second half of the depressive phase.

In any case, the addition of pyrroxane or phentolamine to tricyclic antidepressants according to the previously described method often gives a positive effect. Methods that increase therapeutic sensitivity include a combination of traditional tricyclic antidepressants with chloracizine, while weekly courses of chloracizine (60 ... 90 mg per day) alternate with weekly courses of parenterally administered melipramine; addition of methylphenidate (centedrine); the method of breaks, which was recently described in detail by G. Ya. Avrutskiy and AA Neduva (1981). However, the main way to reduce treatment-resistant depression is by choosing the right treatment.

The main criterion for choosing antidepressant therapy in everyday clinical practice is psychopathological symptoms reflecting the structure of the syndrome. Attempts were made to use mathematical methods, in particular discriminant analysis, to highlight prognostically significant symptoms, and more clearly prognostically unfavorable signs were revealed [Zaitsev SG et al., 1983].

In recent years, pharmacological tests and biological tests have become more widely used to select and predict the effectiveness of drug therapy for depression. Single injections of imipramine were used to predict the results of the subsequent course of treatment with this drug. Despite individual publications on positive results, further studies showed little informational content of the sample. This is to be expected, given the differences between the effect of a single and systematic administration of antidepressants.

SI Pavlovsky (1984) used single loads of tryptophan and DOPA to predict the effectiveness of imipramine and amitriptyline: with a positive reaction to tryptophan, the best results were obtained with amitriptyline treatment. The improvement in the state after taking DOPA and amphetamines indicated the effectiveness of the subsequent use of imipramine.

To select therapy, especially in patients with anxiety depression, we widely use diazepam and dexamethasone tests. An alarming variant of the diazepam test indicates the need for anxiolytic treatment. With the other two options, the degree of symptom reduction makes it possible to judge the proportion of anxiety in the structure of the syndrome and, accordingly, to make a choice between individual antidepressants: with a significant improvement in the process of administering diazepam, amitriptyline or its combination with phenazepam or another anxiolytic should be used; imipramine or another antidepressant that does not have a strong tranquilizing component of action.

A significant advantage of the diazepam test is its simplicity, which allows it to be carried out in any conditions, and the fact that the results can be obtained in 10 ... 20 minutes. The dexamethasone test requires a biochemistry laboratory that can measure cortisol or 11-OCS and takes longer. Therefore, it is less suitable for express diagnostics. However, its value is great in cases where the differential diagnosis between endogenous and neurotic depression, or between depression and anxiety is difficult. Since in these cases the diagnosis also predetermines the therapy, the pathological data of the dexamethasone test indicate the need for the use of antidepressants, and not stimulants or tranquilizers.

For most people, depression subsides after treatment, and they return to their usual life full of pleasant events. However, in some patients, traditional treatment for depression does not give the desired effect. Even after the treatment, they are not left with a feeling of hopelessness, interest in activities does not appear, and some continue to be haunted by thoughts of suicide.

If you've already been treated for depression but haven't noticed a significant improvement in your well-being, then you have untreatable depression. This depression is called chronic or resistant depression. This article will help you understand the reasons for treatment failure and learn about the possibilities that modern medicine has.

What is resistant depression?

Resistant depression is defined as depression whose symptoms persist after treatment with at least three different drugs. In other words, for many months or even years, you and your doctor have been fighting depression, but all attempts lead to the recurrence of symptoms of the disease. This type of chronic depression and dysthymia are different diseases. Unlike chronic depression, the symptoms of dysthymia are less severe and, although it is also difficult to treat, its symptoms rarely render a person incapacitated and do not significantly affect daily life.

Why is depression sometimes difficult to treat?

Depression may not respond to treatment due to several factors.

• The severity of depression... The more severe the symptoms of depression and the longer they last, the more difficult it is to treat, developing into chronic depression. What to do? Take a close look at your depression history with your doctor. Only by knowing the exact duration and intensity of your symptoms can your doctor prescribe the most effective treatment.
• Incorrect diagnosis... When a patient has an emotional disorder, it can sometimes be difficult to make an accurate diagnosis. For example, depression is often misdiagnosed in bipolar disorder because the manic phase may be much less severe than the depressive phase, and the illness is more like depression than classic bipolar disorder. What to do? Reconsider the diagnosis. Check for blood relatives who have bipolar disorder. Invite a trusted friend or family member to talk to your health care provider. Perhaps he will tell him about the symptoms that you do not notice, and this will help to make the correct diagnosis.
• Another disease... Certain medical conditions can mimic or exacerbate the symptoms of depression. These conditions include thyroid disease, chronic pain, anemia, cardiovascular disease, anxiety disorder, alcohol, tobacco or drug addiction. What to do? Get tested for other medical conditions. Honestly inform your healthcare provider about alcohol, cigarette or drug abuse.
• External factors... If you are under constant stress or anxiety due to life's circumstances, medications are likely not to help you. Such long-term stressful situations can be tense relationships with a loved one, unstable financial situation, poor living conditions. Moreover, a difficult childhood, when a child is often punished or neglected, can lead to serious psychological problems in adulthood and cause depression. What to do? Tell your doctor about the problems in your life that plague you every day so that he understands what you have to deal with. If you have not tried psychotherapy before, then this is exactly what you need. A psychotherapist will teach you the correct behavior in stressful situations, which will allow you to control your mood.
• Scheme of taking medications... Many patients do not adhere to the prescribed medication regimen, which can reduce their effectiveness. They may stop taking the drug, deliberately lower the dosage, reduce the number of doses, or simply forget to take the medicine regularly. But worst of all, such patients rarely report this to their doctor. What to do? If you are one of these patients, then at least do not hesitate to inform your doctor about it. If you find it difficult to remember the doctor's prescriptions, get a pill box with cells for each at the pharmacy. These boxes are filled with tablets once a week in accordance with the treatment regimen drawn up by the doctor and are always carried with them. Modern, more expensive models of such boxes contain a timer that informs about the time of taking the drug with a sound signal.

If you and your healthcare provider can identify at least one of the above factors, then this will give you a chance to develop a more effective treatment strategy.

What to do if it is not possible to identify factors interfering with the treatment process?

It is not always known what factors cause or complicate the course of depression. For example, in your case, the correct diagnosis can be made and there is no concomitant disease. Then you should not stop looking for an effective treatment regimen. Go for a consultation with another specialist, try those methods and drugs that have not been previously used for your treatment. If that doesn't work, look at alternative medicine and experimental treatments for depression.

Which specialist should be involved in treating refractory depression?

It is best to see a doctor who specializes in treating mental illness - a psychiatrist or psychotherapist. If concomitant diseases are detected, specialized specialists may be required - an endocrinologist, a neurologist, a cardiologist, etc. In some cases, simultaneous observation by a psychiatrist and a psychologist may be required so that they can adequately assess your condition and track the course of the treatment process.

What is the goal of treating resistant depression?

It is known that some doctors and, consequently, their patients are not sufficiently motivated to treat depression. However, the goal of treatment for depression should be the complete disappearance of all symptoms of the disease. Studies show that patients who achieve complete remission are much less likely to relapse than those who do not achieve complete remission. That is why it is important to maximize the effectiveness of treatment. Partial improvements should not be a reason to believe that an effective treatment has been found.

What psychotherapies are used to treat resistant depression?

Many psychotherapy methods can be used to treat refractory depression. Nowadays, short-term, result-oriented psychotherapy is often used, which helps to cope with a specific problem. In most cases, this is cognitive behavioral therapy. If your depression does not respond to treatment and you still have not tried it with psychotherapy, do it as soon as possible, if possible.

If you've already been through psychotherapy and it didn't work for you, try the following.

• Change therapist.
• Try a different psychotherapy method, such as group therapy, family therapy, or dialectical behavioral therapy. The latter type of psychotherapy is a type of cognitive behavior therapy that teaches behavioral skills to effectively deal with stress, regulate emotions, and improve relationships with others.
• Give another chance for psychotherapy, as your attitude towards this type of treatment may change for the better.

What medications are used to treat resistant depression?

If you've already tried several antidepressants and other medications prescribed to treat depression, but none of them worked for you, do not lose hope. Perhaps you just haven't found the drug that's right for you yet. Unfortunately, drug selection is still a creative process that is carried out by trial and error.

Even if you've tried a number of medications, there are still several ways to find an effective remedy.

Antidepressant Sensitivity Tests... There are special genetic tests that can determine how the body will react to a particular antidepressant: whether it will be effective, whether side effects will appear. Thus, you can significantly reduce the search time for an effective drug. Moreover, there are tests to identify certain genes that are responsible for the transfer of serotonin between neurons. They allow you to determine whether antidepressants from the serotonin inhibitor class will be effective and at what time they are best used.

Strengthening the action of antidepressants... Certain psychiatric medications that are not commonly used to treat depression can enhance the effect of antidepressants. The enhanced effect is achieved due to the fact that these drugs act on neurotransmitters that are different from those that antidepressants act on. Antidepressants can also be enhanced with anti-anxiety medications. The downside of this treatment is the need for regular monitoring of blood counts and increased side effects. It should be noted that the selection of a "enhancement" drug can also be carried out by trial and error, before a really successful combination is found. This is due to the fact that anticonvulsants, mood stabilizers, beta-blockers, antipsychotic and stimulant drugs can be “enhancers”.

Combination of antidepressants... To enhance the effect, two antidepressants from different classes can be prescribed simultaneously. For example, you may be prescribed a selective serotonin reuptake inhibitor (SSRI) and a selective norepinephrine and dopamine reuptake inhibitor (SSRI) or a tricyclic antidepressant and an SSRI. The meaning of a combination of drugs is the simultaneous effect on different substances - serotonin, norepinephrine and dopamine. In this case, it may also take more than one attempt to identify the most successful combination, and the simultaneous use of two antidepressants can increase the side effects.

Switching to a new antidepressant... Switching to a new antidepressant is a common technique when the prescribed antidepressant is not working well enough. You may be prescribed another antidepressant of the same class, such as sertraline, if citalopram is ineffective (both drugs are selective serotonin reuptake inhibitors), or a drug from a different class of antidepressants, such as a selective serotonin norepinephrine reuptake inhibitor (SSRI). The new drug may be more effective.

Prolongation of antidepressant intake... Antidepressants and other mental health medications are fully effective 4 to 6 weeks after they start. The same amount of time is needed to weaken the side effects. Basic antidepressant guidelines recommend that you take these drugs for at least 6 weeks and only then change your antidepressant if it is ineffective. Not all patients survive this period. Some large studies show that antidepressants can be effective 12-14 weeks after they start. Therefore, do not rush to change the drug if it seems ineffective to you. Check with your doctor and try to extend the drug intake for a while.

Alternative treatments for resistant depression

If traditional treatments for depression - medication and psychotherapy - have failed, you may be tempted to use alternative treatments. What methods are neurotherapeutic methods of treatment?

• Electroconvulsive therapy (ECT)... Electroconvulsive therapy is based on inducing seizures in patients by stimulating the brain with an electric current. Many people express great doubts about the safety of this type of therapy, although it is a quick and effective way to relieve symptoms of depression.
• Vagus nerve stimulation... This type of therapy works on the nerves in the brain. The electrode is wrapped around the vagus nerve in the neck and then connected to a pulse generator implanted in the chest wall. The machine is programmed to provide electrical stimulation to the brain.
• Transcranial magnetic brain stimulation... An electromagnetic coil is positioned near the patient's head. Then a powerful and rapidly changing magnetic field penetrates several centimeters deep into the gray matter of the brain, generating an alternating electric current in it.
• Deep brain stimulation (DBS)... This type of therapy involves injecting wires into the brain through the skull and connected to a current source. Then, high-frequency electrical signals are sent to the brain tissue. ...

Articles

Russian medical journal

Alekseev V.V.

Consilium Medicum

IN AND. Maximov

Consilium Medicum

R.V. Akhapkin

Consilium Medicum

V.E. Medvedev, F.Yu. Kopylov, E.A. Makukh

Consilium Medicum

I.Yu.Dorozhenok, E.I. Voronova

Consilium Medicum

Filatova E.G.

Russian medical journal

Kovrov G.V., Lebedev M.A., Palatov S.Yu.

UDC 616.89-008.454: 616-085

G. E. Mazo, S. E. Gorbachev, N. N. Petrova

THERAPEUTIC RESISTANT DEPRESSION:

MODERN APPROACHES TO DIAGNOSTICS AND TREATMENT

St. Petersburg State University, Faculty of Medicine

The problem of therapeutically resistant depression (TRD) remains relevant since the appearance of the first antidepressant and up to the present time at all levels of mental health care. Resistant depression occurs in medical practice more often than the data of clinical trials show, according to which the limit of the effectiveness of antidepressant monotherapy is limited and does not exceed 70%. 20-30% of patients with major depression do not respond to treatment with an antidepressant alone, prescribed in an adequate dose for a period sufficient to obtain a therapeutic effect. In about half of these patients, a favorable reaction to another antidepressant is possible. According to other sources, only 40 to 50% of depressed patients receiving antidepressants remain on this therapy and are sensitive to it after 4-6 weeks of treatment. In addition, some studies claim that up to 60% of patients do not achieve complete reduction of depressive symptoms during antidepressant therapy, and in 20% of patients depressive symptoms persist after 2 years of therapy. 30-60% of patients with pathology related to disorders of the depressive spectrum are resistant to thymoanaleptic therapy.

Differences in the assessment of registration of therapeutic resistance are most likely due to the lack of a single approach for diagnosing this condition.

Definition of therapeutically resistant depression. The definition of therapeutic resistance has changed with the development of therapies for depression. In the period from 1973 to 1983 alone, 15 different definitions of TRD were proposed, which is most likely associated with different methodological approaches to this clinical phenomenon. So, in the 1970s. therapeutically resistant depressions were defined as depressive states, the duration of which cannot be shortened by all known methods, or as depressive states, the indefinite duration of which does not give an effect even with "sufficiently active therapy." The main stages in the development of the concept of therapeutic resistance were: the isolation of primary (genetic) and secondary (arising under the influence of various factors) resistance; separation of therapeutically resistant and chronic depression; isolation of absolute and relative resistance; definition of pseudo-resistance as a response to insufficiently intensive treatment or inadequate prescription of therapy; isolation of negative resistance - the impossibility of prescribing adequate doses of drugs due to side effects.

© G. E. Mazo, S. E. Gorbachev, N. N. Petrova, 2008

The modern systematics of therapeutic resistance shown in the diagram makes it possible to subdivide the absence of the clinical effect of psychopharmacotherapy into primary (true) resistance, secondary resistance, pseudo-resistance, and negative resistance.

Primary resistance is associated primarily with the predicted poor smoking rate of the condition or an unfavorable course of the disease. The absence of an effect due to other biological, including genetically determined, factors, when patients do not respond to certain groups of psychotropic drugs due to a reduced sensitivity of certain neuroreceptors, can also be attributed to the same category.

Secondary resistance is not resistance itself, but is the lack of effect from the treatment used, which develops as its duration increases and is associated with the phenomenon of adaptation to psychopharmacotherapy, especially when it is used routinely.

Pseudo-resistance, to which most cases of resistance belong, is associated with inadequate therapy. According to S.N. Mosolov, the proportion of patients in whom the ineffectiveness of treatment is determined by pseudo-resistance reaches 50-60%. In these cases, the lack of effect can be explained not only by the inaccuracy of the choice of the drug, insufficient dosage or non-compliance with the duration of the course of therapy, but also by other factors (somatogenic, pharmacokinetic, etc.). In such cases, for example, in case of a stomach disease, when the absorption process of the drug is disrupted, in order to achieve a positive response to treatment, a simple change from the oral to parenteral route of administration is sufficient.

With negative resistance, or intolerance, to therapy, we are talking about increased sensitivity to the development of side effects (extrapyramidal, somatic, neurointoxication), the severity of which exceeds the main psychotropic

drug action. The consequence is the impossibility of using adequate doses and the consequent impossibility of achieving the desired therapeutic effect.

All forms of resistance interact. So, in a situation where patients with primary, or true, resistance still managed to achieve a certain positive effect, the results of treatment may turn out to be unsatisfactory due to the addition of the phenomena of adaptation to the drug or intolerance due to the development of signs of allergization of the body.

The evolution of the clinical understanding of therapeutically resistant depression has made it possible to define the main key concepts that must be taken into account when registering therapeutically resistant depression. First of all, this is an adequate prescription of antidepressants, which should be based on the pharmacological differences of modern thymoanaleptic drugs. In addition, it is necessary to carefully analyze the usefulness of the therapeutic course and evaluate the effectiveness of antidepressant therapy. According to modern concepts, depression is considered resistant if, during two consecutive courses (3-4 weeks each) of adequate monotherapy with pharmacologically various drugs, there is an absence or insufficiency of the clinical effect (reduction of symptoms according to the Hamilton or Montgomery scale is less than 50%). Evaluation of the effectiveness of antidepressant therapy assumes the following criteria: a decrease in the severity of depressive symptoms according to the Montgomery scale by 50% corresponds to a sufficient effect, by 21-40% - to a moderate effect and less than 21% - to an insignificant effect. An adequate dose of an antidepressant is considered to be the equivalent of 200 mg of imipramine or 200-300 mg of amitriptyline.

Modern classifications also provide for the allocation of stages of therapeutic resistance, depending on which therapeutic effects were ineffective. For the first time such an approach was suggested by Rusch (1997), having developed his own classification of turbojet engines by stages.

Isolation of the stages of therapeutic resistance is of important not only theoretical, but also practical importance, since it allows doctors to orientate doctors to subsequent therapeutic influences when certain methods of therapy are ineffective. However, the scientific literature has criticized this approach to treating therapeutic resistance. This is primarily due to the lack of instructions on the required doses and duration of therapy at each stage of resistance. In addition, this approach declares a higher level of resistance when replacing an antidepressant with an antidepressant from a different class than when replacing an antidepressant from the same class. The author argues the doubtfulness of this assessment and refers to the representative studies by Thase et al. (2001), demonstrating the absence of differences in the anti-resistance effectiveness of these approaches. In addition, the traditional assessment of MAO inhibitors as drugs with more

Stage 1 Failure of at least one adequate antidepressant treatment in one main group

Stage 2 Stage 1 plus failure of adequate treatment with another antidepressant group

Stage 3 Stage 2 plus treatment failure with lithium supplementation

Stage 4 Stage 3 plus failure of monoamine xidase inhibitor treatment

Stage 5 Stage 4 plus failure of electroconvulsive therapy

a pronounced anti-resistant effect, which is not confirmed by either the results of a meta-analysis or a controlled randomized study. Thus, the tiered approach to the assessment of therapeutic resistance does not make it possible to answer the question: which patient is more resistant?

Critically evaluating the tiered approach to assessing resistance, M. Fava in 2003, together with a group of scientists from Massachusetts General Hospital (MGH), proposed another approach to the classification of TRD, which is based on scoring each patient, while the lack of response to an adequate course for each antidepressant is estimated at 1 point, optimization of therapy (increasing the dose, increasing the duration of the course, the use of combined therapy strategies) increases the total point by 5 points, and the use of electroconvulsive therapy (ECT) increases the total point by 3 points. This approach makes it possible to evaluate all adequate anti-resistance measures while minimizing the ideas about different anti-resistant activity of certain antidepressants, which are not always justified from the point of view of evidence-based medicine.

It is advisable to distinguish between therapeutic resistance and protracted course of the disorder. Thus, resistance refers to the reactivity of the organism. This is a fundamental biological characteristic of a living organism, which is understood as the totality of all possible, inherent in the body, ways of responding to changes in the conditions of the external or internal environment. Resistance is a particular case of the organism's reactivity and is understood as the degree of the organism's resistance to one or another pathogenic (conditionally pathogenic) factor. It reflects the individual choice of one or another path of adaptive reactions, a specific protective-adaptive response of the body, while a protracted course reflects the type of course of the most painful process.

Predictors of therapeutically resistant depression. Attempts have been made to identify predictors of therapeutic resistance. So, according to different authors, unfavorable prognostic factors are: melancholic depression, psychotic depression, comorbid mental disorders in the structure of depression, comorbid somatic diseases, atypical structure of depression. Most of the studies to isolate predictors of therapeutic resistance are based on assessing the response to the first antidepressant prescribed, and only a very small number of studies attempt to isolate predictors of resistance to further treatment in patients already assessed as resistant to previous therapy. At the same time, skepticism about the identification of predictors of therapeutic resistance in depression is understandable, since a depressive state of any structure can be therapeutically resistant.

Therapeutic strategies for therapeutic resistance. During the study of the problem of resistance, a large number of different strategies have been proposed for the emergence of therapeutic resistance, which is most likely associated with the pathogenetic heterogeneity of therapeutically resistant depression. The reports of the effectiveness of most methods are based on the results of a small sample of studies or on the descriptions of individual clinical cases and are not confirmed from the modern standpoint of evidence-based medicine.

The main strategies for overcoming therapeutic resistance with pharmacological agents are: replacing an ineffective antidepressant with another antidepressant, combination therapy, which means the simultaneous use of two antidepressants, and augmentation strategies, i.e.

antidepressant therapy with an additional non-antidepressant drug. It should be noted that in the Russian-language scientific literature the term "augmentation" is not widespread and the concepts of "potentiation of the action of antidepressants" or "layering tactics" are mainly used.

Replacing the antidepressant. The strategy of replacing an ineffective antidepressant with another is the most commonly used in the clinic and at the outpatient level. The main question is: what antidepressant should the patient be transferred to if treatment is ineffective - of the same or a different class? Most of the recommendations talk about the need to prescribe an antidepressant of a different class, for example, replacing TCAs with SSRIs. Replacing an antidepressant in one group with an antidepressant in another group can benefit nearly 50% of patients who do not respond to the first drug.

However, there is evidence that substitution with an antidepressant from the same class may be effective, which has been confirmed for selective serotonin reuptake inhibitors. The success of such a replacement is due to the fact that, in addition to the main action, modern SSRIs have a whole range of different pharmacological effects characteristic of individual representatives. In addition, such an approach is advisable, first of all, when registering negative resistance (inability to prescribe adequate therapeutic doses due to intolerance), since additional pharmacological effects primarily determine the spectrum of side effects.

The most proven effectiveness of substitution for drugs that cause a more powerful potentiation of both serotonin and norepinephrine, such as amitriptyline, clomipramine, venlafaxine.

The advantage of the tactics of replacing antidepressants is justified by the fact that the use of a single drug eliminates the risk of drug interactions and associated side effects.

Combined therapy. Combination therapy refers to the combined use of two antidepressants. This strategy is common clinical practice. Approximately 25% of patients with depression who are discharged from the hospital receive more than one antidepressant.

The pharmacological rationale for treatment with a combination of drugs is that the use of two drugs causes a wider spectrum of activity of monoamine pathways than either of them alone. Therefore, the most common therapeutic approach is the combination of antidepressants with predominantly serotonergic and noradrenergic activity.

It must be remembered that in the case of prescribing two antidepressants, the risk of side effects usually increases, unwanted drug interactions are possible - selective serotonin reuptake inhibitors fluoxetine, fluvoxamine and paroxetine can increase the concentration of other psychotropic drugs by suppressing the hepatic cytochrome P450 system, therefore, their use in combination with cardiotoxic tricyclic antidepressants requires special care. For these reasons, the second antidepressant must be added carefully, at a low dose, gradually increasing depending on the tolerance.

Separately, it should be noted the possibility of using MAO inhibitors in combination therapy. The combination of tricyclic antidepressants and MAO inhibitors has been used since the 1960s, when William Sargent convincingly demonstrated the effectiveness of this method, which was further confirmed by other researchers. The best thing

start treatment with the simultaneous administration of an MAO inhibitor and a tricyclic antidepressant in a low dose or carefully add the first drug to the already achieved adequate dose of the second. However, in clinical practice, such a combination is rarely prescribed due to the high risk of side effects.

Augmentation strategies. Augmentation refers to the addition of another substance that is not in itself used as a specific drug for the treatment of depression, but can enhance the response to an antidepressant being taken. Various drugs of different classes have been proposed as augmentation agents, but only a few have become widespread in clinical practice.

Lithium augmentation. The use of lithium in monopolar depression was first described by de Montigny in 1981. Currently, lithium augmentation is the most commonly used method and has the broadest scientific basis. The effects of lithium in combination with antidepressants have been extensively studied in animal experiments and clinical studies. It was found that the addition of lithium significantly increases serotonergic neurotransmission. In addition, a significant effect of lithium on the hypothalamic-pituitary-adrenocortical system was revealed, consisting in an increase in the production of cortisol and ACTH. The subtle mechanisms of such effects have been studied a lot lately. It is assumed that lithium affects neurotransmission at various levels, in particular, acts at the receptor level, at the level of the secondary messenger system, through the protein kinase C system, and also directly on gene expression. One of the latest findings is a pronounced increase in the level of neuroprotective protein under the influence of lithium, which determines the protection of neurons from proapoptic stimuli.

Lithium augmentation has been shown to be effective with a wide range of antidepressants, including TCAs and SSRIs.

The authors of uncontrolled trials reported that a fairly large number of individuals (60-70%) after the addition of lithium quickly manifested an antidepressant effect (within 48 hours). Data from double-blind, placebo-controlled trials confirm the effectiveness of lithium, but in about 40-50% of patients with depression, the onset of its action is more gradual, over 2-3 weeks.

The concentration of lithium in the blood plasma, necessary to obtain an antidepressant effect in therapeutically resistant patients, has not been precisely established, but, as a rule, concentrations of 0.5-0.8 mmol / L are considered adequate. Usually, lithium treatment is best started with a low dose, for example 200-400 mg per day, especially if patients are taking serotonergic antidepressants, for example, selective serotonin reuptake inhibitors and MAO inhibitors.

The main problems with lithium augmentation are associated with its side effects, which may limit the use of this method of anti-drug therapy.

Augmentation with thyroid hormones. The second main method of augmentation is by adding one of the thyroid hormones, T3 or T4, to the antidepressant.

The potential mechanism of action of thyroid hormones in resistant depression remains poorly understood. There are data, confirmed in animal experiments, that the use of thyroid hormones helps to reduce the activity of autoinhibitory 5-HT1A receptors, and, consequently, to increase the release of serotonin in the cortical structures. In addition, thyroid hormones seem to play an important role in regulating the activity of the central noradrenergic system, and its effect on this system can also enhance

the effect of accelerating the response to antidepressant treatment. It is also assumed that triiodothyronine can act as a cotransmitter of norepinephrine in the adrenergic structures of the nervous system.

The first study of the efficacy of triiodothyronine was published by Prange back in 1969. Since then, there have been numerous reports of the efficacy of triiodothyronine when added to tricyclic antidepressants. There are data from 13 prospective studies (9 open and 4 controlled double-blind studies), confirming the effectiveness of triiodothyronine (T3) at dosages of 25-35.5 μg / day. Convincing data on the effectiveness of T3 in combination with newer antidepressants are not yet available.

T4 results are less clear. Most of the reports noted that when using T4 at a dose of 100 μg / day, that is, at a dose equivalent to 25-35 μg / day of T3, no significant effect was obtained. The use of higher doses of T4 has also been described: for example, according to Bauer (1998), the use of high doses of T4 (the average dose of T4 was 482 μg / day) gave a pronounced therapeutic effect compared to placebo, but this approach raises concerns about safety. Overall, the use of T4 has been much less studied and appears to be less promising than the use of T3.

When analyzing publications on augmentation of thyroid hormones, it remains controversial, the positive effect of this augmentation is associated precisely with the potentiation of the action of antidepressants or with compensation for latent hypothyroidism. In addition, the literature does not pay enough attention to how long patients need to take antidepressants and thyroid hormones.

Antipsychotic Augmentation: The use of typical antipsychotics in the treatment of depression is currently largely limited to cases with severe psychotic symptoms, although there is evidence that the addition of antipsychotics to tricyclic antidepressants can significantly enhance their effect.

The idea of \u200b\u200busing atypical antipsychotics to overcome resistance is much more optimistic. The current focus is on the combined use of atypical antipsychotics and selective serotonergic antidepressants.

The pharmacological mechanisms of action of atypical antipsychotics in patients resistant to selective serotonin reuptake inhibitors require further investigation. It is assumed that the efficacy of atypical antipsychotics in combination with SSRIs may be due to the opposite pharmacological effect of drugs of these classes on noradrenergic activity. The main role is assigned to the effect of atypical antipsychotics on 5-HT2A / 2C receptors. It has been proven that SSRIs can significantly increase serotonergic transmission in the locus ceruleus, thereby suppressing noradrenergic activity in this area. In turn, antipsychotics, acting on 5-HT2A / 2C receptors, stimulate the release of norepinephrine, thereby eliminating the norepinephrine deficiency, which is associated with the development of resistance. A similar mechanism of action was confirmed in experimental work on rats using escitalopram and risperidone.

When atypical antipsychotics are used to enhance the action of SSRIs, lower doses than those usually prescribed in the treatment of schizophrenia may be effective, since blockade of 5-HT2A / 2C receptors is effective at lower doses than blockade of dopamine D2 receptors.

Convincing data to date have been obtained for the combination of olanzapine and fluoxetine and the combination of risperidone with a number of SSRIs.

Drugs such as seroquel, ziprasidone and aripiprazole, which have the highest serotonergic and noradrenergic effects among atypical antipsychotics, are promising in terms of efficacy in therapeutically resistant depression. Clinical trials of the efficacy of these drugs for resistant depression are underway.

With all the promise of using atypical antipsychotics for augmentation, issues related to the specific effect of these drugs on metabolic disorders (hyperprolactinemia, sexual dysfunction, metabolic syndrome) require study.

Other means used for augmentation. Potential augmentation agents include buspirone, pindolol, omega-3 fatty acid, modafinil, psychostimulants (methylphenidate), benzodiazepines, pergolide, lamotrigine, S-adenosyl-methionine (SAMe), zinc, melatonin, inositol and many others. ...

Thus, pindolol, an antagonist of b-andrenergic receptors, has the properties of a 5-HT1A receptor antagonist. The hypothesis of its action is that it enhances the action of SSRIs by blocking the inhibitory action of HT1A autoreceptors in the nucleus of the seam of the brain. The dose of pindolol (7.5 mg per day) commonly used in supplementation studies is probably too low to provide effective blockade of HT1A receptors (Rabiner et al., 2001). It is currently unclear whether higher doses may be more effective.

Non-drug augmentation: Non-drug augmentation methods include ECT (50-65% of cases), plasmapheresis (65% of cases), transcranial magnetic stimulation (TMS), vagal stimulation (VNS), partial sleep deprivation, hypobaric oxygenation, intravascular laser irradiation of blood , acupuncture, etc.

The most common method - ECT - is recommended for use when all other methods of overcoming resistance are ineffective or in the case of severe depressive conditions, psychotic level, with suicidal tendencies. Anamnestic data on drug resistance may be a predictor of low therapeutic response to ECT.

Adequate pharmacological treatment (taking TCAs at a dose of at least 200 mg per day for at least four weeks) before ECT (64%) is a predictor of 50% of the rate of therapeutic response to ECT. If patients have not received adequate drug therapy, the response rate to ECT reaches 86%.

The development of an appropriate pharmacological continuous therapy after ECT is urgent, since the typical clinical practice of continuing the same drug therapy that was given to the patient before ECT, as a rule, is ineffective.

Discussion. Currently, there is no standard algorithm for detecting resistant depression. The main difficulty in compiling such algorithms is the lack of reliable data on the comparative effectiveness of one or another method. In addition, it is necessary to once again focus on the complexity of the task, since therapeutically resistant depression is a heterogeneous group, united only on the basis of response to therapy and including clinically and pathogenetically heterogeneous states.

The proposed algorithms (Thase, Triverdi, Mosolov, Kennedy) generally recommend the consistent use of various strategies to increase the effectiveness of antidepressant therapy, ranging from optimization of current treatment to the use of the most powerful methods of general biological influence. Of interest are algorithms that offer a differentiated approach to treatment depending on the nature of the response to an antidepressant. In case of complete ineffectiveness, preference is given to replacing the antidepressant, if there is a partial response to therapy - it is more advisable to use a combination of antidepressants or one of the augmentation methods. Most authors consider the use of lithium as the first step in augmentation.

Further research is needed on the effectiveness of methods and remedies for overcoming TRD, such as the ongoing trials of sequential treatment of depression (STAR \u200b\u200b* D; Rush et al., 2004), funded by the National Institute of Mental Health (USA). The result of these studies could be the development of a more differentiated algorithm of actions for therapeutic depression, taking into account both the characteristics of the response to certain therapeutic influences and the psychopathological characteristics of depressive states.

Mazo G. E., Gorbachev S. E., Petrova N. N. Modern strategies of diagnostic and management for antidepressant nonresponse.

This article reviews treatment options (augmentation, etc) for depressed patients with suboptimal clinical responses to an antidepressant. Approximately one third of depressed patients treated with antidepressants exhibit suboptimal or delayed clinical response to these medications. In such cases, alternative options include switching to another antidepressant or adding a second antidepressant. Augmentation strategies include addition of lithium carbonate, atypical antipsychotics, psychostimulants, thyroid hormone (triiodothyronine), pindolol, or buspirone. In approximately half of all antidepressant-resistant cases of major depressive disorder, controlled clinical trials have indicated that augmentation with lithium or thyroid hormone is effective. Pindolol therapy has been shown to accelerate clinical response in some but not all studies.

Key words: depression, olinical strategies for antidepressant nonresponse.

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Today, depressive and anxiety disorders are one of the leading mental illnesses. ... At the beginning of this century, they accounted for about 40% of the total number of mental disorders registered in the world. At the same time, it is noted that the resistance (resistance) of depression to certain drugs is growing.

What is depression

Depression is a mental disorder that is accompanied by depressed, melancholy, and depressed moods, combined with disturbances in thinking, movement, and internal organs. Depression belongs to a group of affective disorders, which are characterized by pathological changes in mood. Depression occurs in almost all mental illness, but it manifests itself in different ways.

Depression has a tendency to recur, therefore, negatively affect the quality of life of patients. Depression is based on a decrease in the activity of the brain due to the development of transcendental inhibition with extreme depletion of the subcortex and inhibition of all instincts.

How does depression manifest?

Simple forms of depression are characterized by the following symptoms: decreased mood, motor and mental inhibition. Initially, patients develop fatigue, sadness, increased fatigue, and sometimes anxiety or a spiteful sullenness. Gradually, dissatisfaction with oneself and one's actions joins them. On them "laziness rolls over", they "do not want to move either an arm or a leg." Patients consider themselves "unfit for anything worthwhile", they are abandoned by the feeling of joy and happiness, they strive for loneliness. Sleep becomes restless, the process of falling asleep is disturbed, patients do not eat well, they are worried about constipation and constant headaches.

With increasing severity of the disease, the mood worsens even more and turns into "black melancholy". A feature of this melancholy is its physical sensation in the chest, in the heart, in the head in the form of “heartache” or “heavy stone”.

In severe depression, patients are immobile, depressed, and mournful or completely absent. The eyes are sad, the eyelids are half-closed, the voice is quiet, monotonous, they speak softly, in monosyllables, and as if with difficulty. Gradually, thoughts about their inferiority and sinfulness can lead them to thoughts of suicide. These states can be suddenly interrupted by an explosion of feelings of despair, hopelessness with groaning, self-harm, and suicidal tendencies. Patients lose weight, they have a decrease in blood pressure, hormonal imbalance (impotence in men and cessation of menstrual function in women) and so on.

In addition to typical depression, there are other manifestations of it: "tearful", "smiling", anxious depression, and so on.

Depression treatment

Depression is treated with drugs called antidepressants. The choice of an antidepressant depends a lot on the form of depression. There are three groups of antidepressants:

• with a predominantly psychostimulating (exciting) effect;
• with a broad spectrum of action, but with a predominance of thymoleptic effect (improve mood);
• predominantly with a sedative-thymoleptic or sedative effect (soothes and improves mood, or simply soothes).

Depending on the predominance of certain signs in depression, antidepressants are selected with a certain effect.

The problem of resistance in the treatment of depression

During the treatment of depression, many patients show resistance (immunity) to one or another drug, and sometimes to all antidepressants. Such resistance is quite common and sometimes a serious problem. Currently, resistance to antidepressants is well understood and is divided into:

• for primary or true resistance - about immunity, which is associated with the genetic characteristics of the patient (for example, with reduced sensitivity of nerve endings to them) or with a severe course of the disease;
• on secondary resistance - the effect of addiction (adaptation of the body) to a particular drug with its long-term use;
• for pseudo-resistance, which is associated with the inadequacy of the treatment prescribed for this patient (inaccuracy in the choice of the drug, its insufficient dose, the dose calculated without taking into account other diseases, for example, those that impair the absorption of the drug);
• negative resistance - an increased sensitivity to the development of side effects when taking antidepressants, the severity of which is so high that the drug has to be canceled.

All types of resistance interact. For example, even if a positive effect has been achieved in patients with primary resistance, this effect may subsequently decrease due to the addition of negative resistance phenomena due to the development of allergies to this drug.