This is a dangerous form of the disease. Even with qualified help from specialists, taking medications and getting out of a depressive state, the disease occurs again. The person can return to normal life. He functions, marries, works, recovers and makes contacts. But any reason causes a depressive disease.

Depressive states are difficult to notice and distinguish from each other. In the article we will tell you how you can recognize persistent depression and what to do to the patient.

Features and differences of the disorder

A resistant person forgets to take medications or thinks they don't need them. Sometimes he does it on purpose. He is noticeable. They are similar to the bipolar form of neurosis, thyroid disease, chronic fatigue. Therefore, it is important to determine the form of the disease and communicate honestly with the doctor. It is difficult to make a diagnosis.

Sometimes patients hide a return to alcohol and smoking. They use heroin. Depression is aggravated by addictions, diseases of the heart, thyroid gland. Since the doctor prescribes tranquilizers, antidepressants and other drugs, they should not be mixed with alcohol or drugs. It is important to be honest with your doctor about your addiction. Ignoring antidepressants will aggravate a severe mental condition.

If the patient has previously suffered from unfulfillment or a difficult divorce, any negative event or reminder causes a return. He does not want to fight with himself and control reactions.

Reasons for the appearance

A depressed person most often feels unwanted and abandoned. The feeling of irritability arises from a minor disorder, problems in personal life, inability or unwillingness to earn money. The patient is unable to overcome depression and depression. Symptoms become character traits and a way of life. This requires a therapeutic approach and psychological help.

The reasons for the return to resistant depression are the loss of interest in the future and the present, nervous work, inability to please and feel life.

This can lead to improper treatment. A person feels sorry for himself and loses the opportunity to find meaning. He is haunted by thoughts of suicide. As soon as he starts to get depressed, he also has a nervous breakdown. Great importance has what kind of relationship the patient has with others.

Wrong diagnosis or treatment only relieves signs of depression. For a while, the patient calms down. For example, treat depression, not neurosis. Or the manic form of psychosis is referred to as a reaction to stress. Such treatment does not allow the patient to get out of the state. Separating the types of disorders and diagnosing them is very important. A competent psychotherapist and treatment with antidepressants will help to cope with a depressed state.

Forms of depression

There are several forms of resistant conditions.

• If the patient was observed by a non-professional psychologist, he manifests absolute resistant depression. The previous state was taken for another. The reasons remain. The patient again experiences self-doubt, loses life meaning and seeks to hurt himself.
• The secondary form is characterized by a loss of adaptation to treatment. The prescribed drugs do not work for the patient. He is drug resistant.

• The negative form is expressed in the inability to perceive the method of treatment. Hypersensitivity initially causes signs of depression on the physical level. Then provokes frequent breakdowns. Here the reason is in the wrong diagnosis (the fault of the psychologist). Determining the error will help get things going. nervous system.
• Pseudo-resistance is common. Again, the reason is in the wrong treatment. Insufficient study of symptoms, quick consultation, treatment by bad specialists provoke a clear deterioration in health. The disorder did not pass, only the signs became dull for a while.

Why the disorder is difficult to treat

Depression takes on a severe, incurable form. Incorrect diagnosis reinforces symptoms and reveals new ones. Bad habits and low self-control exacerbate the impact of the disorder. Sometimes the patient is so unwilling to get out of this state that he stops taking medication. Unstable and difficult relationship with her husband, difficult financial situation, living in poor conditions affect the treatment.

Patients with schizophrenia resistant to therapy, despite ongoing treatment, are characterized by quite pronounced positive and negative syndromes diseases, marked manifestations of cognitive deficits, persistent unusual behavior, distinct affective disorders, high risk of suicide.

Criteria for therapeutic resistance:

• Symptoms of the disease are not amenable to therapy and persist for a long period of time;
• Unfavorable course of the disease with frequent periods of exacerbation;
• The course of the disease becomes chronic;
• Lack of effect, despite treatment aimed at the main links pathogenesis of the disease;
• Severe side effects of therapy;
• Low level of social and labor adaptation.

In the context of the problem of refractory variants of the course of schizophrenia, it should be borne in mind that there are ethnic, age and gender differences in sensitivity to psychotropic drugs and the characteristics of their metabolism.

Already during the first psychotic episode, approximately 10% of patients with schizophrenia show a weak response to antipsychotic therapy. The use of clozapine makes a difference in half of these patients.

With each subsequent relapse of schizophrenia, the risk of developing resistant variants the course of the disease.

Between 20 and 45% of all patients are considered partial responders to treatment. These patients are relatively low level social and labor adaptation, they have a deterioration in the quality of life, frequent relapses diseases, extrapyramidal symptoms.

If a psychotropic drug does not give the expected effect and does not weaken the severity of target symptoms, it should be changed to another medication.

Numerous studies indicate that the change of a psychotropic drug should be carried out no earlier than 6-8 weeks after the appointment of the first medication.

Domestic psychiatrists prefer an earlier change of the drug - 4-6 weeks of therapy. However the patient must receive adequate doses of drugs for a sufficient period of time. This rule is important to observe especially when an additional appointment of a new drug is planned. It can often be observed that under the external pressure of the patient, and especially his relatives, the doctor begins to unreasonably increase the dosage of the drug or adds new medications to monotherapy. However, it should be borne in mind that in most studies, the effectiveness of the combined treatment of schizophrenia with several psychotropic drugs has not been proven. In our opinion, the harmful practice of prescribing several antipsychotics to a patient with schizophrenia in the case of a “resistant”, according to the doctor, variant of the course of the disease is a fairly common phenomenon. It is likely that for a small group of patients (young age, male) a reasonable combination of two antipsychotics, such as a typical and atypical, may still be possible for a limited period of time. We emphasize that modern psychiatry gives unconditional preference to monotherapy for schizophrenia.

Currently, the following formal definitions of therapeutic resistance in schizophrenia are used: persistent positive symptoms in the categories of the BPRS scale, such as hallucinatory behavior, suspicion, unusual content of thoughts, moderately severe disorganization of thinking; moderate severity of schizophrenia (according to BPRS and CGI); lack of a stable period of good social and/or professional functioning for at least 5 years.

Refractoriness to therapy can be ascertained after at least three 4-week periods of therapy with antipsychotics from two or more different chemical groups, one of which must be an atypical antipsychotic used for 5 years at doses of 400-600 mg per day of chlorpromazine equivalent.

Previously, the criteria for the resistance of the symptoms of the disease to treatment were considered the absence of a therapeutic effect during sequential treatment with two antipsychotics of different chemical classes for 6 weeks, at a daily dose corresponding to 700 equivalents of chlorpromazine (chlorpromazine).

Other definitions of refractoriness include no 20% change in total BPRS score or intolerance to a 6-week course of haloperidol 10 to 60 mg daily.

Correlations of refractory states in schizophrenia with the severity of alogia and abulia, morphological changes, and some results of neuropsychological studies were noted.

Anxiety-depressive states increase the resistance of some forms of schizophrenia.

The presence of good compliance markedly weakens the refractoriness to therapy. Identification of the patient's psychological problems with their subsequent correction, the study of the peculiarities of his marital status, which prevent the formation of remission, is an important part of the work of a psychiatrist, psychologist and social worker.

Resistance in schizophrenia does not show a correlation with the duration of the mental disorder.

After the first psychotic episode, resistant states form on average in 11% of cases (Lieberman J., 1989). With each subsequent episode of exacerbation of the disease, the percentage of resistant patients increases. Patients with resistant forms of schizophrenia usually "settle" in psychiatric hospitals or are often hospitalized. At the same time, among patients for a long time in psychiatric hospitals, especially in Russia, there are not so many patients with true resistance.

There is no doubt that the formation of resistant states is facilitated by the presence of "pathologically altered soil" in patients - organic insufficiency of the central nervous system. In addition, the latter often causes the early appearance of neuroleptic complications. Treatment of neurological disorders, dysfunction of the autonomic nervous system helps to overcome resistance.

Insufficient or, conversely, excessively high doses of antipsychotics may be one of the reasons for ineffective treatment.

In treatment-resistant patients, adherence to the drug regimen is checked first. The main predictors of non-compliance with the treatment regimen are considered to be: reduced criticism, negative attitudes towards medications, history of episodes of violation of the therapy regimen in anamnesis, dependence on psychoactive substances, recent onset of the disease, inadequate therapy after discharge from the hospital, unfavorable family environment and lack of compliance between the doctor and the patient. Non-compulsory predictors of non-compliance include: age, ethnicity, gender, marital status, education, cognitive impairment, severity of positive symptoms, severity of side effects, high doses of drugs, presence of significant affective disorders, and route of drug administration.

If the psychiatrist does not see the expected effect of the prescribed antipsychotic, then before looking for pharmacokinetic explanations for this fact, whether the patient is taking these drugs at all. To identify non-compliance, a “short test period” can be recommended: a partial or temporary transfer to prolonged injectable forms of the drug.

Patients not responding to antipsychotic therapy should clarify the diagnosis of the disease, try to identify hidden somatic disorders.

It is known that resistance can be associated with a very high activity of liver enzymes, as a result of which even high doses of the drug will give only subtherapeutic plasma concentrations.

Avoid alcohol or drug abuse(cannabis, heroin, amphetamines). In some cases, the cause of resistance may be the use of medications prescribed for the treatment of concomitant diseases.

In all cases of resistance, the target symptoms must be clearly defined. In the case of using two atypical antipsychotics, for each of them, an adequate dose for the relief of psychopathological symptoms should be calculated.

Methods for intensifying the therapy of patients with schizophrenia with therapeutic resistance have always been in the focus of close attention of psychiatrists.

To overcome the resistance of schizophrenia at different times, the following were used: modified versions of insulin shock therapy (Sereysky M.Ya., Zak N.A., 1949; Lichko A.E., 1962; Avrutsky G.Ya. et al.), pyrotherapy (sulfozine, pyrogenal) (Schrodet-Knud, Vakhov V.P., Vovin R.Ya., 1973), various modifications of simultaneous withdrawal of drugs (Avrutsky G.Ya., et al., 1974; Tsygankov B.D., 1979), zigzag method of therapy (Belyakov A.V., 1984), combination of psychopharmacotherapy with atropine (Matvienko O.A., 1985), contrast therapy (Petrilowich, Baet R., 1970), titration method of administration of psychotropic drugs (Donlon P., Tipin J ., 1975; Skorin A.I., Vovin R.F., 1989), beta-blockers and reserpine (Conley R. et al., 1997), autohemotherapy in combination with psychopharmacotherapy (Baranov V.F., et al. , 1967), levamisole (Mosolov S.N., Zaitsev S.G., 1982); thymalin (Krasnov V.N. et al., 1991), prodigiosan (Ezhkova V.A., 1970), immunosuppressors (Stukalova L.A., Vereshchagina A.S., 1980), ECT (Rakhmadova L.D., 1985), unloading diet therapy (RDT) (Nikolaev Yu.S., 1948), plasmapheresis (Malin D.I., Kostitsin N.V., 1994), laser therapy (Kutko I.I., Pavlenko V.V. , 1992), electromagnetic field (Kikut R.P., 1976), EHF-therapy (Muzychenko A.P., Zakhatsky A.N., 1997), acupuncture (Efimenko V.L., 1959, 1982; Gorobets L. N., 1991) and other methods.

One of the first steps to overcome resistance is to replace the traditional neuroleptic with an atypical antipsychotic. If resistance to the latter is found, a switch should be made to another atypical antipsychotic.

Most effective medicine for the treatment of resistant schizophrenia clozapine. A positive effect when taking this drug was observed in almost half of patients with a resistant type of the course of the disease (Kane J. et al., 1988). Recall that clozapine is also recommended for patients with schizophrenia expressing suicidal thoughts.

The effective daily dose of the drug can vary from 100 to 600 mg, with a starting dose of 12.5 mg

A positive result after the appointment of clozapine can be achieved even after 6-12 months of therapy. However, due to the development of severe complications as a result of taking clozapine, its use is significantly limited.

As noted above, with prolonged therapy with clozapine, myocarditis, neutropenia, agranulocytosis, excessive sedation, hypersalivation, and weight gain may develop.

Numerous studies have not confirmed that the appointment of clozapine in the early stages of therapy for schizophrenia can help prevent the formation of its resistant variants (Lieberman J. et al., 2003).

In order to overcome resistance in the treatment of schizophrenia, a combination of clozapine with risperidone was proposed, but it turned out to be ineffective and, on the contrary, leads to a deterioration in the working memory of patients who received such a combination of medications.

The effectiveness of olanzapine in the treatment of resistant forms of schizophrenia has been proven. Our experience indicates the possibility of successful treatment of resistant forms of schizophrenia with prolonged intramuscular injection of this drug (3-4 weeks).

Lithium or antiepileptic drugs previously prescribed to overcome resistance are no longer recommended. They can only be prescribed if all other therapies have failed. Some authors report a positive effect in the case of joining the antipsychotic therapy with valproate or lamotrigine.

There is no single point of view regarding the use of anaprilin (propranolol) to overcome resistant conditions.

The ineffectiveness of the methods of rapid increase and then a sharp decrease in doses of neuroleptics (“zigzag”, “break” methods) has been proven (Morozova M.A., 2002).

In studies on the treatment of resistant forms of schizophrenia, it has been shown that combination therapy (antipsychotics, mood stabilizers, antidepressants) does not confirm its effectiveness. More often, it is recommended to alternately use different atypical antipsychotics to combat resistance (Davis D., 2006).

For resistant patients with schizophrenia, combination and drug therapy is especially indicated.

In recent decades, much attention has been paid to the development and study of means that stimulate or suppress (modulate) immune reactions organism. These drugs increase the overall resistance of the body, its non-specific immunity, and also affect specific immune responses. In the mid-80s, they wrote about the ability of drugs such as dibazol, methyluracil and pentoxyl to stimulate immune processes (Lazareva D.N., Alekhin E.K., 1985). Given the fact that these drugs stimulate the regeneration of blood cells (leukopoiesis) and, possibly, CNS neurons, one could expect their positive effect in schizophrenia. Medicines that can affect immune processes by specifically activating immunocompetent cells: T- and B-lymphocytes include a number of drugs of microbial and yeast origin, such as prodigiosan and pyrogenal. In psychiatry, the most noticeable effect on the course of schizophrenia was exerted by decaris, thymus preparations and intravenous laser blood irradiation (Mosolov S.N., Zaitsev S.G., 1982; Vasilyeva O.A., Longvinovich G.V., 1995, and others .).

Immunotherapy is used to overcome the resistance of clinical symptoms to pharmacotherapy in patients with schizophrenia. Before the start of immunotherapy, a study of the immunological (IS) and interferon (IS) status, the leukocyte adhesion inhibition reaction (RTAL) in the presence of a number of neuroantigens is carried out. It was noted that three components play a major role in the development of secondary immunological deficiency in CNS pathology: immunogenetic factors, dysregulatory immunodeficiency due to uncompensated disorders of neuroimmune regulation; ecological immunopathology (Vasilyeva O.A., 2000).

Depending on the severity of IS and IFS disorders, thymus preparations or preparations containing interferons are prescribed. This approach to immunotherapy is due to the fact that thymus peptides specifically affect the immune system, increasing the number of cytokine receptors on T-cells, increasing the production of cytokines, and the introduction of drugs containing interferon leads to more rapid stabilization of the interferon system, contributing to the stabilization of immunological parameters (Butoma B. G., Vasilyeva O.A., 2000).

For the treatment of patients with therapeutically resistant forms of schizophrenia, immunosuppressants (cyclophosphamide, cyclophosphamide, azathioprine) were used that affect the immune status of patients. Despite the temporary exacerbation of the condition of patients, in the end, an improvement in the clinical picture of schizophrenia was noted (Stukalova L.A. et al., 1981).

The study of the mechanism of action of levamisole (decaris) showed that it has the effect of an immunomodulator that can enhance a weak reaction cellular immunity, weaken the strong and have no effect in the presence of a normal reaction (Shaidarov M.Z., 1987). When using levamisole in complex therapy with antipsychotics of juvenile unfavorable current schizophrenia, a positive effect was obtained in 50% of cases. The first changes in mental status appeared gradually at 2-3 weeks of therapy. At the syndromic level, there was a tendency to reduce manifestations of depression, hypochondria, a number of signs of negative symptoms, as well as an effect on rudimentary catatonic symptoms. The addition of levamisole to antipsychotics at the same time did not affect hallucinatory and paranoid syndromes. A positive effect of the drug was noted in the treatment of patients with schizophrenia with neurosis-like symptoms, anxiety-depressive syndrome.

In the treatment of resistant schizophrenia, levamisole is usually prescribed 150 mg twice a week for 1.5-2 months.

In psychiatric practice, for the treatment of resistant variants of the course of schizophrenia, thymalin, which is a complex of polypeptide factors isolated from thymus(thymus). Among the effects of thymalin, the effect of the drug on improving integrative processes in the central nervous system was noted. Timalin also had a psychostimulating effect, reduced the manifestations of depressive spectrum disorders. The effect of thymalin manifested itself within a few days after the start of use and reached its maximum by the end of the 2nd - the beginning of the 3rd week of therapy. Researchers noted the ability of thymalin to reduce the severity of extrapyramidal symptoms that arose while taking antipsychotics (Govorin N.V., Stupina O.P., 1990). The addition of thymalin to therapy with psychotropic drugs significantly improved the immunological status of patients with schizophrenia. Attempts have been made to use thymalin in combination with forced diuresis. Usually thymalin was prescribed at a dose of 20 mg daily for 8-10 days.

In the 70s of the twentieth century, a new class of biologically active compounds- thymic peptide hormones of immunity: thymosins, thymopoietins and serum thymic factor (thymulin). Somewhat later, for the treatment of resistant forms of schizophrenia, it was proposed to use imunofan, a synthetic derivative of the hormone Timopoetin, in combination therapy with psychotropic drugs. This medication is able to activate the antioxidant system and eliminate free radical compounds and peroxides. In the combined treatment of schizophrenia, imunofan is administered at a dose of 1.0 intramuscularly 1 time per day (a course of 10 injections).

Recently there have been reports on the effectiveness of non-drug methods of overcoming resistance in patients with schizophrenia - the use of intravenous laser blood irradiation and EHF-therapy (Kutko M.I. et al., 1992; Muzychenko A.P. et al., 2002).

Laser therapy is used to improve the effectiveness of therapy in treatment-resistant patients with schizophrenia. The main mechanism of laser therapy is supposed to reduce the severity of endotoxicosis and normalize hemostasis (Saikin M.A., Tsukarzi E.E., 2005). To control the effectiveness of laser therapy, it is recommended to pay attention to the activity of platelet monoamine oxidase (MAO), the levels of "medium molecules" (SM) of blood plasma and the properties of albumins (Saikin M.A., Tsukarzi E.E., 2005), as well as cytokines (IL -1, IL -2, IL-3, L-6, IL-10) a-TNF and interferons: alpha, beta and gamma INF (Palko O.L., 2005).

Intravenous laser blood irradiation (ILBI) is carried out on a low-intensity helium-neon apparatus (FALM-1), the wavelength of laser irradiation is 0.63 μm. The radiation power at the output of the fiber is 8 mW. The duration of the session is 15 minutes, the course of therapy is 8-12 sessions. The highest efficiency of laser therapy was noted in patients with postpsychotic depression with a predominance of melancholy, apatho-anergic disorders, as well as with a mild degree of deficient disorders. laser therapy significantly reduces the severity of extrapyramidal symptoms (Saikin M.A., Tsukarzi E.E., 2005).

For the treatment of schizophrenia with laser radiation - I.I. Kutko and V.M. Frolov (1996) used radiation power from 0.2 to 1.0 W. The time of a single irradiation was 12 minutes, the course of treatment was 8-15 sessions 1 time per day. The authors noted the most distinct effect in the treatment of depressive-paranoid syndrome; a positive psycho-energizing effect of laser blood irradiation was also recorded. The maximum effect of therapy was noted on the 7th day of irradiation. Contraindications for laser therapy are oncological diseases, active tuberculosis, febrile conditions, pregnancy, cachexia, uncompensated diabetes, hyperthyroidism (Pletnev S.D., 1981).

In the combined treatment of resistant schizophrenia, EHF-therapy is used - electromagnetic radiation of low intensity (Muzychenko A.P., Zakhatsky A.N., 1997).

ECT is used to overcome resistant psychopathological symptoms in schizophrenia.

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.

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

Resistance Options

1. 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.
2. 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.
3. Pseudo-resistance- a reaction to inadequately prescribed medications may be a manifestation of insufficient treatment or an incorrect diagnosis.
4. 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, combined treatment is recommended - this is the use of a combination of various 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.

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

• Electroshock method– is highly effective, so it has been used for many years.
• Use of antipsychotics. This method of treatment is modern and effective. Efficiency is noted by research scientists in the industry.
• 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. Especially, it concerns cardiovascular diseases and pathologies.

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

Video: Self-Esteem and Depressive Disorder

In the present work:

• review modern methods treatment of treatment resistant depression (TRD);
• the issues of definition, typology and epidemiology of therapeutic resistance are briefly considered;
• considered the most common clinical guidelines with TRD, including methods of combining psychotropic drugs, replacing antidepressants, their augmentation with atypical antipsychotics, lithium, methylphenidate, triiodothyronine, pindolol and other drugs;
• special attention is paid to modern non-drug methods of treatment of TRD, such as transcranial magnetic stimulation, vagus nerve stimulation, deep brain stimulation, electroconvulsive therapy.

An original algorithm for the treatment of therapeutically resistant depression has been proposed.
According to various researchers, approximately 30-60% of patients with depression remain resistant to adequate thymoanaleptic therapy, while resistance to the first drug reaches 40-60% (Depression Guideline Panel, 1993; Nierenberg A. A., 1994; Any E. B., 2006) . About 10-15% of depressions, regardless of the therapy, acquire a chronic (protracted) course, i.e. last more than 2 years (OlieJ.P., 1987). It should be emphasized that resistance and chronification are not identical, but mutually overlapping concepts.

Tendency to lingering current reflects the features of the course of the disease process, while resistance, from the point of view of general pathology, is a fundamental biological characteristic of the body, which is a special case of reactivity and is understood as an individual set of adaptive reactions or a protective and adaptive reaction of the body in response to internal and external influences ( Zaichik A. Sh., Churilov L. P., 1999).

Among the factors contributing to the emergence of resistance (changes in reactivity), it is necessary to mention advanced age, characteristics of a premorbid personality, an unfavorable social position, a long-term psychotraumatic situation, chronic somatic and neurological diseases, comorbid mental disorders(primarily associated with the use of psychoactive substances), organically defective "soil" (Zhislin S. G., 1965) and others.

In domestic psychiatry, the study of resistance was carried out in the context of the clinical and psychopathological structure of depression. In a number of studies (Vovin R.Ya., Aksenova L.I., 1989; Avrutsky G.Ya., Mosolov S.N. et al., 1991; Tiganov A.S., 1997) it was shown that a high risk of developing resistance (in 50-70% of cases) is associated with the presence of heteronomous depressive syndromes: anesthetic, depressive-phobic and senestohypochondriac. The proportion of resistant cases in sad, anxious, adynamic, somatized and dysphoric variants of the depressive syndrome is 20-40% (Mosolov S.N., 1995; Tiganov A.S., 1997; Mishiev V.D., 1998).

All researchers agree that torpid to antidepressant therapy more often turn out to be conditions other than the classical depressive symptom complex, such as anesthetic, hypochondriacal, obsessive-phobic and atypical depression. In general, it can be noted that the more complex the structure of the depressive syndrome, the more it differs from classical melancholia with a typical daily rhythm, the more symptoms of other psychopathological registers, the higher the likelihood of comorbid anxiety disorder and personality pathology, the more resistant depression is to therapy. Bondar VV (1992) also suggests that a predictor of therapeutic resistance to depression is its syndromic polymorphism.

According to modern generally accepted criteria (Mosolov S.N., 1995; Trivedi M.N., 2003; Mazo G.E., 2004), depression is considered resistant if two consecutive courses of adequate monotherapy (total duration, on average, 6 -8 weeks) pharmacologically different in structure and neurochemical action of antidepressants, there is an absence or insufficient severity clinical effect, i.e. the reduction of symptoms according to the Hamilton scale is no more than 50%. Adequacy is understood as the correct choice of an antidepressant in accordance with the spectrum of psychotropic, neurotropic and somatotropic activity, a dose equivalent to 200-300 mg of amitriptyline, the use of the correct dose escalation scheme and therapy with courses adequate in duration (3-4 weeks, for selective serotonin reuptake inhibitors [SSRI] - 5-6 weeks).

There are the following types of resistance:

• absolute (true, primary) resistance, which is associated with a predictable poor curability and an unfavorable course of the disease. It is conditioned genetic reasons, which determine the individual characteristics of the patient's metabolism, which in turn violate the pharmacokinetics and pharmacodynamics of the drug;
• relative (secondary) resistance due to the phenomenon of adaptation to psychotropic drugs with their long-term use;
• pseudo-resistance caused by inadequate or insufficiently intensive pharmacotherapy (it is believed that up to 60% of all cases of TRD fall into this group);
• negative resistance (intolerance), that is hypersensitivity to the side effects of psychotropic drugs, preventing adequate therapy.

Understanding the factors contributing to the formation of resistance allows a differentiated approach to overcoming its various types and using a sequence of anti-resistance measures.

Vovin R.Ya. and Aksenova I. O. (1982) distinguish three levels of true resistance:

1. resistance associated with individual features metabolism of the patient, affecting the pharmacokinetics and pharmacodynamics of the drug (absorption, distribution, metabolism, elimination). To overcome it, it is necessary to switch to parenteral administration of antidepressants;
2. resistance associated with the form of the course of endogenous depression itself, which requires special anti-resistant measures;
3. resistance associated with the fixation of psychopathological manifestations, mediated by personal mechanisms. In this case drug therapy must be combined with psychotherapy and socio-rehabilitation activities.

In theoretical terms, the severity of therapeutic resistance can be ranked according to the degree of its increase as follows:

1. to only one drug or a group of drugs that are similar in chemical structure or action,
2. to two or more antidepressants of different chemical structure and action,
3. to additives that increase the effectiveness of antidepressants,
4. to a combination of two antidepressants,
5. to the combination of an antidepressant with non-drug therapies,
6. to electroconvulsive therapy,
7. to all types of therapy.

In accordance with this scheme, a 5-stage algorithm for the treatment of TRD was proposed (Mosolov S. N., 1995). The first stage involves the use of a tricyclic antidepressant (TCA) with a wide profile of neurochemical action and a powerful thymoanaleptic effect (amitriptyline, imipramine, clomipramine). In the absence of a positive effect of TCA therapy, there is reason to assume pseudo-resistance and proceed to the second stage - the use of an antidepressant of selective action:

• noradrenergic (desipramine, maprotiline, reboxetine and others),
• serotonergic (fluoxetine, sertraline, fluvoxamine and others),
• dopaminergic (bupropion).

If the clinical effect is insufficient, it is considered that the patient is characterized by relative resistance and it is necessary to proceed to the third stage of therapy, that is, the actual anti-resistance measures, which include:

1. combination therapy with several antidepressants;
2. immediate withdrawal with diuretics or cover-up therapy;
3. addition to the antidepressant means of enhancing the effect: lithium, triiodothyronine, L-tryptophan, methylphenidate, L-dopa and other dopamine agonists, immunomodulators, tocopherol, folic acid, as well as non-drug methods (sleep deprivation, phototherapy, plasmapheresis, normobaric oxygenation, laser therapy, reflexology , unloading and dietary therapy and others);
4. MAOI monotherapy for 3-4 weeks.

If these measures are ineffective, after 1-2 weeks of therapy withdrawal, they proceed to the fourth stage - a course of 8-12 procedures of bilateral or unilateral ECT.

In case of ineffectiveness of all the listed stages, one should think about absolute resistance and move on to the fifth stage, which includes long courses of antidepressant therapy, new combination therapy options and anti-resistance measures.

Other algorithms of actions in TRD are also used. As recommended by Cowen P.J. (1998) management of TRD includes the following steps:

1. bringing the dose of the antidepressant to the maximum, depending on tolerance (for depression with psychotic symptoms - the addition of a neuroleptic);
2. replacement of an antidepressant (for example, TCAs for SSRIs, and vice versa);
3. addition of lithium salts;
4. addition of triiodothyronine;
5. connection of MAOIs (can be continued with lithium);
6. other combinations (eg, MAOI + TCA, lithium + MAOI + L-tryptophan, lithium + clomipramine + L-tryptophan).

Interesting is the approach tested in the Department of Biological Therapy of Mentally Ill NIPNI them. V. M. Bekhtereva (Ivanov M. V., Mazo G. E., 2007). The essence of this approach is a consistent algorithm for overcoming TRD with an emphasis on antidepressants from the SSRI group (fluoxetine, paroxetine, sertraline, fluvoxamine, escitolopram). The first step is to register depression resistance after a 4-week course of SSRIs at maximum and submaximal doses. The second step is to clarify the diagnostic affiliation of depression using the ICD-10 rubrics, that is, the exclusion of bipolar affective disorder, schizoaffective disorder, post-attack schizophrenic depression, etc. At the third stage, the clinical structure of resistant depression is determined with the identification of the leading depressive affect and key psychopathological disorders. At the fourth stage, the choice of an effective variant of anti-resistant polypharmacotherapy for depression is performed. Two types of polypharmacotherapy are proposed: combination therapy with antidepressants (SSRIs and TCAs) and SSRI augmentation with an atypical or typical antipsychotic.

The authors also offer a differentiated approach to the choice of anti-resistant measures depending on the clinical structure of the depressive syndrome. So, with the predominance of melancholy and ideomotor retardation, the most effective method is a combination of SSRIs and TCAs, with a predominance of anxiety disorders- augmentation of SSRIs with triftazine or risperidone, in the presence of difficult-to-treat hypochondriacal and obsessional disorders in the structure of depression, augmentation of SSRIs with atypical antipsychotics (quetiapine or risperidone) is recommended, in the presence of insomnia disorders - SSRIs with typical antipsychotics.

Instant cancellation

Simultaneous cancellation is a powerful means of overcoming therapeutic resistance and in half of the patients leads to a sharp break in depressive symptoms or phase inversion (Avrutsky G. Ya., Neduva A. A., 1981; Mosolov S. N., 1996). "Saturation" stage medicines when carrying out simultaneous cancellation, it involves increasing the doses of TCAs and cholinergic correctors to the maximum tolerated (i.e., until side effects appear) and lasts 10-14 days. The regimen also includes a classic antipsychotic (usually trifluoperazine). Then one-stage cancellation of therapy is performed. Diuretics, heavy drinking, intravenous infusion of saline are sometimes used to enhance the withdrawal effect. Critical reduction of depressive symptoms usually occurs on the 5-10th day after withdrawal. For the correction of pronounced somato-vegetative disorders during this period, symptomatic agents and benzodiazepine tranquilizers are prescribed. Lithium salts, carbamazepine and sodium valproate are used as "cover" therapy (prevention of phase inversion), and neurometabolic agents are used in patients with organically defective "soil".

Change to an antidepressant with a different mechanism of action

If an antidepressant is not effective, a switch to another drug within the same class (i.e., to a drug with an identical mechanism of action, for example, switching from one SSRI to another SSRI) or switching to a drug with a different mechanism of action (for example, switching from an SSRI to a norepinephrine reuptake inhibitor) may be possible. , MAOI, TCA, or heterocyclic antidepressant). In a meta-analysis by Papakostas G. I. et al. (2008) showed a small but statistically significant advantage of switching to a drug with a different mechanism of action (SSRIs were used as first-line drugs) - see fig. 2.

In a large randomized, multicentre, prospective STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study conducted by NIMH ( National Institute Mental Health, USA), investigated various stages and strategies for the treatment of major depressive disorder in an outpatient setting. In Phase 1, 2876 participants received citalopram for 14 weeks. At Stage 2, participants who did not achieve remission were randomized to one of 3 augmentation groups (N=565) for 14 weeks (citalopram + bupropion, citalopram + buspirone, citalopram + CBT [cognitive behavioral therapy]) or one of the 4 replacement therapy groups (N=727) (bupropion, venlafaxine, sertraline, CBT as monotherapy). The remission rate at stage 2 in the buspirone and bupropion groups was approximately 30%. The remission rate at stage 2 in the replacement therapy groups was 17.6% for sertraline, 24.8% for venlafaxine, and 21.3% for bupropion. At Stage 3, participants who did not achieve remission were randomized to one of 2 augmentation groups (current BP + triiodothyronine, BP + lithium) or to one of 2 replacement therapy groups (nortriptyline or mirtazapine monotherapy).

The remission rate at stage 3 after 14 weeks in the lithium and triiodothyronine augmentation groups was 15.9% and 24.7%, respectively. The 14-week remission rate at Stage 3 in the switchover groups (N=235) was 12.3% for mirtazapine and 19.8% for nortriptyline. Finally, at the last 4th stage, nonresponders (N=58) were included in the combination of venlafaxine with mirtazapine or in the tranylcypromine monotherapy (MAOI) group. After 14 weeks, the remission rate in the tranylcypromine group was 6.9% and in the venlafaxine plus mirtazapine group it was 13.7%. At each subsequent stage, the number of respondents decreased. Thus, in the STAR*D study (Mathys M., Mitchell B.G., 2011; Rush A.J., Trivedi M. H. et al., 2003,2006), substitution for an antidepressant with a different mechanism of action (in particular, SSRIs for SNRIs) was more effective, than switching to an antidepressant with the same mechanism of action (SSRI to SSRI).