Depression and resistance: how to help a suffering consciousness? Modern methods of overcoming therapeutic resistance in recurrent depression “Our dreams are a reflection of ourselves”

Treatment-resistant patients with schizophrenia, despite ongoing treatment, are characterized by quite pronounced positive and negative syndromes of the disease, noticeable manifestations of cognitive deficits, persistent unusual behavior, distinct affective disorders, and a high risk of suicide.

Criteria for therapeutic resistance:

Symptoms of the disease cannot be treated 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 poor response to antipsychotic therapy. The use of clozapine reverses the condition in half of these patients.

With each subsequent relapse of schizophrenia, the danger of the formation of resistant variants of the disease increases.

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

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

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

Domestic psychiatrists prefer an earlier change of 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 follow especially when an additional prescription of a new drug is planned. It can often be observed that, under external pressure from the patient, and especially from 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 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, version of the disease, is a fairly common phenomenon. It is likely that for a small group of patients (young age, male gender), a reasonable combination of two antipsychotics, for example a typical and an atypical, may still be possible for a limited period of time. We emphasize that modern psychiatry gives absolute preference to monotherapy for schizophrenia.

Currently, the following formal definitions of treatment resistance in schizophrenia are used: persistent positive symptoms in the categories of the BPRS scale, such as hallucinatory behavior, suspiciousness, unusual content of thoughts, moderate 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 established 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 in doses of 400-600 mg per day of chlorpromazine equivalent.

The criteria for the resistance of disease symptoms to treatment were previously considered to be 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 (aminazine).

Other definitions of refractory include absence of a 20% change in BPRS total score or intolerance to a 6-week course of haloperidol 10 to 60 mg per day.

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

Anxiety and depressive conditions increase the resistance of some forms of schizophrenia.

The presence of good compliance significantly reduces refractoriness to therapy. Identifying the patient’s psychological problems with their subsequent correction, studying the characteristics of his family status that 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 develop 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 in them. At the same time, among patients 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 conditions is facilitated by the presence of “pathologically altered soil” in patients - organic failure of the central nervous system. In addition, the latter often causes the early appearance of neuroleptic complications. Treatment of neurological disorders and dysfunction of the autonomic nervous system helps overcome resistance.

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

In treatment-resistant patients, drug compliance is checked first. The main predictors of non-compliance with therapy are: decreased criticism, negative attitude towards medications, a history of episodes of non-compliance with therapy, substance dependence, recent onset of the disease, inadequate therapy after discharge from hospital, unfavorable family environment and lack of compliance between the doctor and the patient. Optional predictors of noncompliance include age, ethnicity, gender, marital status, education, cognitive impairment, severity of positive symptoms, severity of side effects, high drug doses, presence of significant mood disorders, and route of drug administration.

If the psychiatrist does not see the expected effect from the prescribed antipsychotic, then before looking for pharmacokinetic explanations for this fact, whether the patient takes these drugs at all. To identify non-compliance, we can recommend a “short test period”: partial or temporary transfer for long-acting injection forms of the drug.

In patients who do not respond to antipsychotic therapy, clarify the diagnosis of the disease, try to identify hidden somatic disorders.

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

Alcohol or drug abuse should be avoided(cannabis, heroin, amphetamine). 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 should be calculated to relieve psychopathological symptoms.

Methods of intensifying therapy for patients with schizophrenia with therapeutic resistance have always been 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, V.P. Vakhov, R.Ya. Vovin, 1973), various modifications of immediate drug withdrawal (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 (Petrilovich, Baet R., 1970), titration method of administration 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), immunosuppressants (Stukalova L.A., Vereshchagina A.S., 1980), ECT (Rakhmadova L.D., 1985), fasting-dietary 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 antipsychotic with an atypical antipsychotic. If resistance to the latter is detected, you should switch to another atypical antipsychotic.

The most effective drug for the treatment of resistant schizophrenia is considered clozapine. A positive effect when taking this drug was noted in almost half of patients with a resistant type of disease (Kane J. et al., 1988). Let us recall that clozapine is also recommended for use in patients with schizophrenia who express 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 prescribing clozapine can be achieved even after 6-12 months of therapy. However, due to the development severe complications As a result of clozapine use, its use is significantly limited.

As noted above, with long-term therapy with clozapine, the development of myocarditis, neutropenia, agranulocytosis, excessive sedation, hypersalivation, and weight gain is possible.

Numerous studies have not confirmed that the administration of clozapine in the early stages of treatment for schizophrenia can help prevent the formation of 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 that it is ineffective and, on the contrary, leads to a deterioration in the working memory of patients receiving a similar combination of medications.

Olanzapine has been proven effective in the treatment of resistant forms of schizophrenia. Our experience shows the possibility successful treatment resistant forms of schizophrenia with prolonged intramuscular administration of this drug (3-4 weeks).

Lithium or antiepileptic drugs previously prescribed to overcome resistance are no longer recommended. They can be prescribed only if all other methods of therapy have proven ineffective. Some authors report a positive effect when valproate or lamotrigine is added to antipsychotic therapy.

There is no consensus on the use of anaprilin (propranolol) to overcome resistant conditions.

The ineffectiveness of methods of rapid growth and then sharp decline doses of antipsychotics (methods “zigzag”, “break”) (Morozova M.A., 2002).

Studies on the treatment of resistant forms of schizophrenia have shown that combination therapy (antipsychotics, mood stabilizers, antidepressants) does not confirm its effectiveness. It is more often recommended to alternate the use of 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 agents that stimulate or suppress (modulate) the body's immune responses. These drugs increase the body's overall resistance, its nonspecific immunity, and also affect specific immune reactions. In the mid-80s, they wrote about the ability of drugs such as dibazole, methyluracil and pentoxyl to stimulate immune processes (Lazareva D.N., Alekhin E.K., 1985). Considering the fact that these drugs stimulate the processes of regeneration of blood cells (leukopoiesis) and, possibly, neurons of the central nervous system, one could expect their positive effect in schizophrenia. Medicines that can influence immune processes, 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, drugs with the thymus gland and intravenous irradiation of blood with a laser (Mosolov S.N., Zaitsev S.G., 1982; Vasilyeva O.A., Longvinovich G.V., 1995, etc. .).

Immunotherapy is used to overcome the resistance of clinical symptoms to pharmacotherapy in patients with schizophrenia. Before starting immunotherapy, a study of immunological (IS) and interferon (IS) status, leukocyte adhesion inhibition reaction (LAI) in the presence of a number of neuroantigens is carried out. It is 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; environmental immunopathology (Vasilieva 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 thymic peptides specifically affect immunity, increasing the number of cytokine receptors on T cells, increasing the production of cytokines, and the administration of drugs containing interferon leads to more rapid stabilization of the interferon system, helping to stabilize immunological parameters (Butoma B. G., Vasilyeva O.A., 2000).

To treat patients with treatment-resistant forms of schizophrenia, immunosuppressants (cyclophosphamide, cyclophosphamide, azathioprine) were used, which affect the immune status of patients. Despite the temporary exacerbation of the patients’ condition, an improvement in the clinical picture of schizophrenia was ultimately noted (Stukalova L.A. et al., 1981).

A 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 one and have no influence if there is normal reaction(Shaidarov M.Z., 1987). When using levamisole in complex therapy with antipsychotics for unfavorable juvenile 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 the manifestations of depression, hypochondria, a number of signs of negative symptoms, as well as an effect on rudimentary catatonic symptoms. At the same time, the addition of levamisole to antipsychotics 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 and anxiety-depressive syndrome.

When treating resistant schizophrenia, levamisole is usually prescribed 150 mg two days a week for 1.5-2 months.

In psychiatric practice, thymalin, which is a complex of polypeptide factors isolated from thymus gland(thymus). Among the effects of thymalin, the drug’s influence on improving integrative processes in the central nervous system was noted. Timalin also had a psychostimulating effect and reduced the manifestations of depressive spectrum disorders. The effect of thymalin appeared within a few days after the start of use and reached its maximum by the end of the 2nd - 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. Typically, thymalin was prescribed at a dose of 20 mg daily for 8-10 days.

In the 70s of the twentieth century it was opened new class 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 Thymopoietin, 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 1.0 intramuscularly 1 time per day (course of 10 injections).

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

Laser therapy is used to improve the effectiveness of treatment in treatment-resistant patients with schizophrenia. The main mechanism of laser therapy is supposed to reduce the severity of endotoxemia and normalize hemostasis (Saikin M.A., Tsukarzi E.E., 2005). To monitor the effectiveness of laser therapy, it is recommended to pay attention to the activity of platelet monoamine oxidase (MAO), levels of “middle molecules” (MM) in the 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 device (FALM-1), laser irradiation wavelength is 0.63 microns. The radiation power at the output of the light guide is 8 mW. The duration of the session is 15 minutes, the course of therapy is 8-12 sessions. The greatest effectiveness 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 deficiency 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 single irradiation was 12 minutes, the course of treatment was 8-15 sessions once a 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 observed on the 7th day of irradiation. Contraindications for laser therapy are: oncological diseases, active tuberculosis, febrile conditions, pregnancy, cachexia, uncompensated diabetes mellitus, hyperthyroidism (Pletnev S.D., 1981).

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

ECT is used to overcome resistant psychopathological symptoms in schizophrenia.

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

Accompanying factors associated with treatment-resistant depression

The disease often appears at a young age. Patients respond poorly to antidepressant treatment and depression often returns throughout their life cycle.

Excessive use of drugs and alcohol contributes to poor treatment results. There is a high probability of relapse. Among such patients, the most common cases of suicide or attempted suicide occur.

Eating disorders occur, patients develop bulimia and anorexia. Indicators of severe depression are panic disorders, which do not respond well to standard methods in treating the disease.

Poor treatment results occur in the presence of somatic diseases in combination with resistant depression, and sometimes are the cause of depression.

Forms of resistance

Absolute (primary) conditioned clinical disease and occurs with all drugs.

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

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

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

Symptoms of resistance

Patients experience persistent (chronic) depression or psychological pathologies. A sick person becomes withdrawn and communicates less with loved ones. A person suffering from depression is constantly lonely and avoids large noisy companies. There is a feeling of melancholy, self-esteem is low, the person is constantly dissatisfied with himself, and a feeling of anxiety appears. Among all these factors, addiction to drugs and alcohol often occurs.

In addition to emotional disorders, accompanying illnesses and physiological symptoms. Disorders arise in sexual life. The patient’s appetite decreases or, conversely, the patient “eats” all experiences, that is, he suffers from overeating. You feel tired in the morning as soon as you wake up. There are problems with sleep, getting up at night for no reason, constant insomnia. The daily routine is disrupted, and the patient is awake in the middle of the night and wants to sleep during the day. As the disease becomes more complicated, suicide attempts occur.

Causes of the disease

The reasons for resistance are varied:

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

Treatment of depression

psychotherapeutic;
microwave;
fasting and dietary;
medicinal;
X-ray therapy;
electroconvulsive;
biological.

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

The most popular treatment method is medication. After making a diagnosis, the doctor determines the effectiveness of the prescribed drug, often antidepressants. Taking them should show good results.

Various methods of psychotherapy are used in the treatment of treatment-resistant depression. Quite often, short-term, result-oriented therapy is used to help cope with the problem.

If treatment with a course of psychotherapy does not give a positive result, try another course. This could be family or group therapy. Try seeing a different therapist.

When psychotherapy and medication do not work for you, alternative treatments such as neurotherapies can be used.

Deep brain stimulation (DBS). This therapy sends high-frequency electrical signals into the brain tissue through wires connected to a current through the skull.

Vagus nerve stimulation. Electrical stimulation of the brain occurs using an electrode wrapped around the vagus nerve in the neck.

Electroconvulsive therapy (ECT). Seizures and convulsions are caused by irritating the human brain with electric current. This therapy is effective in relieving symptoms of depression, but many question its safety.

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

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

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Causes and variants of resistant depression

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

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

What is resistant depression

Resistant depression is a depression that cannot be treated with conventional methods. Experts note that the lack of effectiveness of treatment or its insufficiency during two consecutive courses are the main signs of resistance.

It is impossible to equate protracted, chronic forms with resistant depression. 6-10 weeks is the period during which the drugs should be at least 50% effective.

Causes

Severity of the disease. The level of resistance increases the protracted nature of the disease. In the chronic form of depression, a “depressive lifestyle” may occur - a decrease in energy potential, weakness of the body, personality changes.
Incorrect diagnosis. When misdiagnosis, not all symptoms are taken into account and interpreted correctly. The persistence of heterochromic signs of the disease makes it difficult to establish a true diagnosis and begin treatment on time. Inadequately prescribed therapeutic treatments may not be effective.
Parallel disease. The course of depression may be accompanied by other diseases that weaken the body and reduce the effectiveness of treatment. In the presence of cardiovascular, mental, and endocrine diseases, resistance is one of the forms of the body's protective reaction. Hysterical, paranoid, and schizoid personality traits increase resistance to treatment.
External factors. The presence of an unfavorable social environment can enhance or create resistance. Experts have established that the development of society and civilization has influenced the pathomorphosis of the disease. Studies have shown that the effectiveness of drugs that were successfully used 50 years ago has decreased significantly. This requires the search for new treatment methods. Changes in the course of depression coincided with the development of mass culture - this factor cannot be ignored. The generally accepted view is that depression is a postmodern disease. Cultural factors are considered important in determining the intractability of mental disorders.
Regimen for taking medications. In 11-18% of patients, resistance to the effects of certain drugs is observed. Simply put, the drug does not work in humans or does not have the required level of effectiveness.
Resistance can be formed at the genetic level - this is manifested in the body’s tolerance to the effects of medications traditionally used to treat depression.
The effectiveness of treatment can be reduced by competition between medications or a mutual decrease in their effectiveness. The course of treatment is negatively affected by the patient’s non-compliance with the medication regimen. In half of the patients with resistance, the drug was prescribed incorrectly, so the treatment did not bring the desired results.

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

Resistance options

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

Psychotherapy methods

There are several areas of psychotherapy:

fasting and dietary;
X-ray therapy;
extracorporeal;
biological;
microwave;
medicinal;
electroconvulsive;
psychotherapeutic.

If each method is not effective individually, combinations are used. Combining several methods of combating depression shows good results, even in difficult cases.

Treatment

The most popular treatment method 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 effectiveness or its absence, it is necessary to prescribe another drug. An important condition for treatment is compliance with the regimen of taking them.

In the absence of a positive result, combination treatment is recommended - this is the use of a combination of various medications. The second drug may be an antidepressant or lithium-containing drugs. An option for combination therapy is an antidepressant and ketiapine.

What to do if there are no results. Alternative

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

Why is recurrent depression dangerous? Read the article.

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

Gradually, medications are introduced into the course of treatment or several methods are combined with each other if there is no positive effect.

The electroshock method is highly effective and has been used for many years.
Use of antipsychotic drugs. This method of treatment is modern and effective. The effectiveness is noted by research by scientists in the industry.
The method of electrical stimulation 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 patient’s personality characteristics, the presence of contraindications and other diseases. This is especially true for cardiovascular diseases and pathologies.

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

Video: Self-esteem and depressive disorder

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Resistant depression: what to do?

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

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

What is treatment-resistant depression?

Resistant depression is one whose symptoms do not improve after treatment with at least three different medications. In other words, for many months or even years, you and your doctor have been struggling with depression, but all attempts lead to reappearance 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 disable a person and do not have a significant impact on daily life.

Why is depression sometimes resistant to treatment?

Depression may not respond to treatment due to several factors.

Severity of depression. The stronger the symptoms of depression and the longer they last, the more difficult they are to treat, developing into chronic depression. What to do? Carefully review 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, with bipolar disorder, depression is often misdiagnosed, since the manic phase can be much less pronounced than the depressive phase, and the disease is more similar to depression than to classic bipolar disorder. What to do? Reconsider the diagnosis. Check to see if there is anyone in your blood relatives who is suffering bipolar disorder. Encourage a close friend or trusted family member to talk to your doctor. Perhaps he will tell him about the symptoms that you do not notice, and this will help make the correct diagnosis.
Another disease. Some illnesses can mimic or worsen symptoms of depression. These diseases include thyroid disease, chronic pain, anemia, cardiovascular disease, anxiety disorder, alcohol, tobacco or drug addiction. What to do? Get checked for other diseases. Tell your healthcare provider honestly about your alcohol, cigarette, or drug abuse.
External factors. If you are in a constant state of stress or anxiety due to life circumstances, then medications most likely will not help you. Such long-term stressful situations can be a tense relationship with a loved one, an unstable financial situation, or poor living conditions. Moreover, a difficult childhood, when the child was 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 on a daily basis so that he or she understands what you are struggling with. If you haven't tried psychotherapy yet, this is exactly what you need. A psychotherapist will teach you how to behave in stressful situations, which will allow you to control your mood.
Medication regimen. Many patients do not adhere to the medication regimen prescribed by the doctor, which can reduce their effectiveness. They may stop taking the drug, intentionally lower the dosage, reduce the number of doses, or simply forget to take the medication regularly. But the worst thing is that such patients rarely report this to the 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 your doctor's instructions, purchase a box for pills with slots for each pill at the pharmacy. Such boxes are filled with tablets once a week in accordance with the treatment regimen drawn up by the doctor, and are always carried with you. Modern, more expensive models of such boxes contain a timer that indicates the time of taking the drug with an audible signal.

If you and your doctor can identify at least one of the above factors, 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 which factors cause or complicate the course of depression. For example, in your case the correct diagnosis may be made and there may be no concomitant disease. Then you shouldn't stop searching effective scheme treatment. Go for a consultation with another specialist, try those methods and drugs that have not previously been used for your treatment. If that doesn't help, look into alternative medicine and experimental treatments for depression.

Which specialist should treat treatment-resistant depression?

It is best to consult a doctor who specializes in the treatment of mental illness - a psychiatrist or psychotherapist. When identifying concomitant diseases, specialized specialists may be required - an endocrinologist, neurologist, 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 monitor the progress of the treatment process.

What should be the goal when treating treatment-resistant depression?

It is known that some doctors and, accordingly, 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. Research shows 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 achieve maximum treatment effectiveness. Partial improvements should not be a reason to assume that an effective treatment has been found.

What psychotherapy methods are used to treat treatment-resistant depression?

Many psychotherapies can be used to treat treatment-resistant depression. Today, short-term, outcome-oriented psychotherapy is often used to help cope with a specific problem. In most cases, this is cognitive behavioral therapy. If your depression does not respond to treatment and you have not yet tried to treat it with psychotherapy, do so as soon as possible, if possible.

If you've already had psychotherapy and it hasn't helped you, try the following.

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

What medications are used to treat treatment-resistant depression?

If you have already tried several antidepressants and other drugs prescribed to treat depression, but none of them have helped you, do not lose hope. Perhaps you simply haven’t found the drug that suits you yet. Unfortunately, until now, choosing a medicine is a creative process that is carried out by trial and error.

Even if you have already tried a number of drugs, there are still several ways to find an effective drug.

Tests for sensitivity to antidepressants. There are special genetic tests that can determine how the body will react to a specific antidepressant: whether it will be effective, whether side effects will appear. In this way, you can significantly reduce the time it takes to find an effective drug. Moreover, there are tests to identify certain genes that are responsible for the transmission of serotonin between neurons. They allow you to determine whether antidepressants from the class of serotonin inhibitors will be effective and at what time they are best used.

Strengthening the effect of antidepressants. Some psychiatric drugs that are not usually used to treat depression can enhance the effects of antidepressants. The enhanced effect can be achieved due to the fact that these drugs act on neurotransmitters that are different from those affected by antidepressants. The effects of antidepressants can also be enhanced by 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 an “enhancing” drug can also be carried out by trial and error before a truly successful combination is found. This is because “enhancers” can include anticonvulsants, mood stabilizers, beta blockers, antipsychotics, and stimulant medications.

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 dopamine reuptake inhibitor (SNRI) at the same time, or a tricyclic antidepressant and an SSRI. The meaning of the combination of drugs is to simultaneously influence 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 may increase the side effects.

Switching to a new antidepressant. Switching to a new antidepressant is a common technique when the prescribed antidepressant does not work effectively enough. You may be prescribed a different class of antidepressant, such as sertraline, if citalopram is not effective (both drugs are selective serotonin reuptake inhibitors), or you may be prescribed a drug from a different class of antidepressant, such as a selective serotonin norepinephrine reuptake inhibitor (SNRI). New drug may be more effective.

Extending antidepressant use. Antidepressants and other drugs for the treatment of mental illness become fully effective 4-6 weeks after starting treatment. The same amount of time is needed to reduce side effects. The main guidelines for antidepressants recommend taking these drugs for at least 6 weeks and only after this period changing the antidepressant if it is ineffective. Not all patients survive this period. Some large studies show that antidepressants may be effective weeks after starting. Therefore, do not rush to change the drug if it seems ineffective to you. Consult your doctor and try to continue taking the drug for some more time.

Alternative treatments for treatment-resistant depression

If traditional treatments for depression - medication and psychotherapy - have not been effective, you may want to consider alternative methods. What methods do neurotherapeutic treatments include?

Electroconvulsive therapy (ECT). Electroconvulsive therapy is based on inducing convulsive seizures in patients by irritating the brain with an electric current. Many people have 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 targets 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 wall chest. The device is programmed to provide electrical stimulation to the brain.
Transcranial magnetic stimulation of the brain. The electromagnetic coil is located 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 inserting wires connected to a current source into the brain through the skull. High-frequency electrical signals are then sent to the brain tissue. See details.

Articles

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

Russian Medical Journal

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

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Excellent physical shape in youth is the key to a good mood in old age

Botulinum toxin as a treatment for depression

A third of people caring for a relative with dementia develop depression

On modern stage Medicine doctors can do a lot. Everything is possible. But no one yet knows how to treat old age. Age-related processes are inexorable: the longer a person lives, the greater the likelihood that at some point the brain will also “grow old” and develop dementia (dementia).

Deep brain stimulation for depression

Due to the fact that more than 30% of depression does not respond to traditional treatment, there is growing interest in research aimed at finding alternative treatments.

Treatment of resistant depression

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

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

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

Classification of turbojet engines and its reasons

Exists big number various classifications of turbojet engines. So, for example, I. O. Aksenova in 1975 proposed to distinguish the following subtypes of turbojet engines:

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

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

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

The most common causes of pseudo-resistance are inadequacy of the therapy (dose and duration of antidepressant use); underestimation of factors contributing to chronicity of the condition; insufficient monitoring of adherence to therapy; Other reasons are also possible: somatogenic, pharmacokinetic, etc. There is a large amount of experimental data confirming the significant role of psychological and social factors in the formation of drug resistance of depression.

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

Primary prevention of TRD

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

Diagnostic measures.
Therapeutic measures.
Social rehabilitation measures.

Treatment of TRD

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

insufficient dose or duration of taking antidepressants;
metabolic disorders affecting the blood concentration of an antidepressant;
drug interactions, which can also affect the concentration of antidepressant in the blood;
side effects that prevented the achievement of a sufficiently high dose;
comorbidity with others mental disorders or with somatic or neurological pathology;
incorrect diagnosis (if, for example, in reality the patient does not have depression, but neurosis or a personality disorder);
a change in the structure of psychopathological symptoms during treatment - for example, treatment can cause the patient to transition from a depressive to a hypomanic state, or the biological symptoms of depression can be eliminated, but melancholy and anxiety continue to persist;
unfavorable life circumstances;
genetic predisposition to a particular reaction to an antidepressant;
insufficient monitoring of compliance with the therapy regimen.

In almost 50% of cases, resistant depression is accompanied by hidden somatic pathology; psychological and personal factors play a large role in their development. Therefore, psychopharmacological methods alone to overcome resistance without a comprehensive impact on the somatic sphere, influence on the socio-psychological situation and intensive psychotherapeutic correction are unlikely to be fully effective and lead to sustainable remission.

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

Drug change and combination therapy

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

Monoamine oxidase inhibitors, despite a large number of side effects (because of this, they are best used only if all other drugs have failed to produce a therapeutic effect), continue to be the most effective drugs for the treatment of some forms of depression, which are considered very resistant to traditional antidepressant therapy, in particular atypical depression, as well as depression comorbid with social phobia, panic disorder.

Potentiation

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

According to the results of a meta-analysis, in case of TRD, the addition of lithium or atypical antipsychotics such as quetiapine, olanzapine, aripiprazole to antidepressant treatment leads to an improvement in the patient's condition to approximately the same extent, but treatment with lithium is cheaper. Olanzapine is particularly effective in combination with fluoxetine and is produced in combination under the name Symbiax for the treatment of bipolar depressive episodes and treatment-resistant depression. According to a study that included 122 people, in the adjunctive treatment of patients with psychotic depression, quetiapine in combination with venlafaxine produced a significantly better therapeutic response rate (65.9%) than venlafaxine as monotherapy, and the remission rate (42%) was higher in comparison. with monotherapy with imipramine (21%) and venlafaxine (28%). Other data suggest that although the effect on depression when antipsychotics are added to the main regimen is clinically significant, it does not generally achieve remission, and patients taking antipsychotics were more likely to leave studies early due to side effects. Basically, there is evidence of the effectiveness of atypical antipsychotics in treatment-resistant depression; typical ones are mentioned much less frequently. In addition, typical antipsychotics themselves have a depressogenic effect, that is, they can lead to the development of depression.

Psychostimulants and opioids

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

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

Non-pharmacological methods

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

Vagus nerve stimulation is approved by the US FDA as an adjunctive treatment for the long-term treatment of chronic or recurrent depression in patients who have failed to respond to 4 or more adequately selected antidepressants. Data regarding the antidepressant activity of this method are limited.

In 2013, The Lancet published the results of a study showing that in patients who have failed treatment with antidepressants, cognitive behavioral therapy, used in addition to treatment with these drugs, can reduce symptoms of depression and help improve the patient's quality of life.

There is evidence of effectiveness physical activity as a potentiation agent for treatment-resistant depression.

What does resistant mean?

Resistant is stubborn, uncontrollable, insensitive, resistant, unyielding.

A term with such meanings is widely used in psychology, medicine, technology, and colloquial speech.

Resistant means:

people who are difficult to manage (uncontrollable) and control their behavior;

pathological conditions that do not respond to attempts at therapy;

diseases that are difficult or impossible to cure;

neurons that do not respond to stimulation;

a surface that is difficult to damage by conventional means;

bacteria that are resistant to many antibiotics and so on.

Conducted a survey: “ What is resistant ? I received the answer: “Resistant is the one who resists everything.” Yes, you can say that too!

What does intractable form of epilepsy mean?

Resistant epilepsy – this is an incurable form of epilepsy or resistant to therapy.

Remission of epilepsy, that is, complete cessation of seizures, is usually achieved immediately after starting to take the first correctly selected antiepileptic drug. To do this, first-choice drugs should be used in monotherapy and used in an average therapeutic dose.

But in 30% of cases, epilepsy cannot be cured, despite the efforts of doctors.

Measures to overcome epilepsy resistance:

Treatment with various antiepileptic drugs in monotherapy.
The use of polytherapy - different combinations of two, three or four drugs.
Application of new AEDs.

If all these measures do not lead to seizure control, then it is resistant cases of epilepsy , that is, not treatable.

At resistant epilepsy doctors are forced to consider possible options anticonvulsants, and this does not lead to success.

In recent decades, new drugs for the treatment of epilepsy with previously unused mechanisms of action have been introduced. They gave hope to some resistant patients with epilepsy for reduction, relief of attacks or for remission. The process of creating and registering new AEPs does not stop. Perhaps in the future there will be fewer resistant cases of epilepsy.

Causes of epilepsy resistance

1. There are hereditary mechanisms that determine a negative response to treatment.

For example, initially severe, hereditarily determined, resistant form are Lennox–Gastaut syndrome.

2. Some focal forms of epilepsy, which are based on structural damage to the brain, may also respond poorly to treatment.

An example is malformations of the cerebral cortex. Over time, as a result of this developmental abnormality (such as focal cortical dysplasia, heterotopia), symptomatic focal epilepsy may develop that does not respond to therapy.

In what cases of resistance is it possible?:

if antiepileptic therapy is ineffective,

in the presence of a localized focus of epileptic activity,

with a refined diagnosis established by MRI of the brain.

Surgical treatment of epilepsy is possible only for a small part of the population. resistant patients with epilepsy with careful preoperative selection, specialized training, as well as with the technical equipment and personnel preparedness of specialized medical neurosurgical centers. In recent decades, such operations have become available to a wider range of people, thanks to government support.

An effective method in case pharmacoresistance epilepsy is a specialized ketogenic diet. is now available to patients in Novosibirsk.

Criteria for intractable epilepsy:

Resistant epilepsy - epilepsy, in which the use of two basic antiepileptic drugs in combination with one of the new drugs in an adequate dosage does not provide complete control of seizures.

Seizures in treatment-resistant forms of epilepsy can sometimes be reduced by increasing the number of drugs or increasing their doses above the recommended one. But this leads to increased unwanted side effects and reduces the quality of life of patients. It is necessary to achieve an optimal balance between the effect of therapy and tolerability of the drugs. So that it doesn't turn out like this , that you treat one thing and cripple another . Sometimes it is not necessary to strive for a complete cessation of attacks, but only to reduce and alleviate the attacks.

Resistance may be absolute and relative.

Types of epilepsy resistance:

De nova resistance – in which, from the onset of the disease, remission will never be achieved.

Progressive resistance – evasion from therapy occurs and the remission that has already been achieved is disrupted; the attacks then become uncontrollable.

Wave-like resistance – change of remission for more than 1 year with periods of resumption of attacks.

Overcoming resistance- initially resistant epilepsy, later remission is achieved.

Prescribing highly effective AEDs earlier increases the likelihood of remission and preservation of intelligence.
Treatment should begin with new antiepileptic drugs. Each subsequent drug tried reduces the possibility of remission.
The use of effective combinations of new AEDs: oxcarbazepine, levetiracetam, topiramate, lacosamide and others.
Achieving maximum compliance, including conducting educational work with patients, their loved ones, as well as among professionals on whom the creation of optimal treatment conditions depends.

So, resistant means resistant, unyielding. Resistant epilepsy - this incurable form of epilepsy or treatment-resistant. The article examined the criteria, types, methods of possible overcoming resistance, and gave examples.

Resistant depression, which should be treated only under the supervision of a specialist, is a rather serious illness. Resistant depression (not responding to treatment) is one of the types of depression.

Accompanying factors associated with treatment-resistant depression

The disease often appears at a young age. Patients respond poorly to antidepressant treatment and depression often returns throughout their life cycle.

Excessive use of drugs and alcohol contributes to poor treatment results. There is a high probability of relapse. Among such patients, the most common cases of suicide or attempted suicide occur.

Eating disorders occur, patients develop bulimia and anorexia. An indicator is panic disorders, which do not respond well to standard methods in treating the disease.

Poor treatment results occur in the presence of somatic diseases in combination with resistant depression, and sometimes are the cause of depression.

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Forms of resistance

Absolute (primary) is caused by a clinical disease and manifests itself in all drugs.

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

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

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Symptoms of resistance

In addition to emotional disorders, illness and physiological symptoms are associated. Disorders arise in sexual life. The patient’s appetite decreases or, conversely, the patient “eats” all experiences, that is, he suffers from overeating. You feel tired in the morning as soon as you wake up. There are problems with sleep, getting up at night for no reason, constant insomnia. The daily routine is disrupted, and the patient is awake in the middle of the night and wants to sleep during the day. As the disease becomes more complicated, suicide attempts occur.

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Causes of the disease

The reasons for resistance are varied:

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

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Treatment of depression

Areas of psychotherapy:

psychotherapeutic;
microwave;
fasting and dietary;
medicinal;
X-ray therapy;
electroconvulsive;
biological.

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

The most popular treatment method is medication. After making a diagnosis, the doctor determines the effectiveness of the prescribed drug, often antidepressants. Taking them should show good results.

Various methods of psychotherapy are used in the treatment of treatment-resistant depression. Quite often, short-term, result-oriented therapy is used to help cope with the problem.

If treatment with a course of psychotherapy does not give a positive result, try another course. This could be family or group therapy. Try seeing a different therapist.

When psychotherapy and medication do not work for you, alternative treatments such as neurotherapies can be used.

Neurotherapeutic methods:

Deep brain stimulation (DBS). This therapy sends high-frequency electrical signals into the brain tissue through wires connected to a current through the skull.

Vagus nerve stimulation. Electrical stimulation of the brain occurs using an electrode wrapped around the vagus nerve in the neck.

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

UDC 616.89-008.454:616-085

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

THERAPEUTICALLY RESISTANT DEPRESSIONS:

MODERN APPROACHES TO DIAGNOSIS AND TREATMENT

St. Petersburg State University, Faculty of Medicine

The problem of treatment-resistant depression (TRD) has remained relevant since the advent of the first antidepressant to the present day at all levels of care. psychiatric care. Resistant depression occurs in medical practice more often than demonstrated by clinical trial data, according to which the limit of effectiveness of antidepressant monotherapy is limited and does not exceed 70%. 20-30% of patients with major depression do not respond to treatment with a single antidepressant prescribed in an adequate dose for a period sufficient to obtain a therapeutic effect. About half of these patients may respond favorably to another antidepressant. According to other data, 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 treatment. 30-60% of patients with pathology related to depressive spectrum disorders are resistant to thymoanaleptic therapy.

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

Definition of treatment-resistant depression. The definition of treatment resistance has changed along with the development of treatments for depressive conditions. Only in the period from 1973 to 1983, 15 different definitions of TRD were proposed, which was most likely due to different methodological approaches to this clinical phenomenon. So, in the 1970s. Treatment-resistant depression was 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 produce an effect even with “sufficiently active therapy.” The main stages in the development of ideas about therapeutic resistance were: the identification of primary (genetic) and secondary (arising under the influence of various factors) resistance; separation of treatment-resistant and chronic depression; identification of absolute and relative resistance; definition of pseudo-resistance as a response to insufficiently intensive treatment or inadequate treatment; highlighting negative resistance - the inability to prescribe adequate doses of drugs due to side effects.

The modern taxonomy of therapeutic resistance shown in the diagram allows us to subdivide the lack of clinical effect of psychopharmacotherapy into primary (true) resistance, secondary resistance, pseudo-resistance and negative resistance.

Primary resistance is associated primarily with the predicted poor curability of the condition or the unfavorable course of the disease. This category also includes the absence of an effect caused by other biological, including genetically determined, factors, when patients do not respond to certain groups of psychotropic drugs due to the reduced sensitivity of certain neuroreceptors.

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

Pseudo-resistance, which includes most cases of resistance, is associated with inadequacy of therapy. According to S.N. Mosolov, the proportion of patients in whom treatment failure is determined by pseudoresistance reaches 50-60%. In these cases, the lack of effect can be explained not only by inaccuracy in the choice of 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, with stomach disease, when the process of absorption of the drug is disrupted, in order to achieve a positive response to treatment, a simple change from the oral to the 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

effect of the drug. The consequence is the impossibility of using adequate doses and the consequent inability to achieve the desired therapeutic effect.

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

The evolution of the clinical understanding of treatment-resistant depression has made it possible to identify the main key concepts that must be taken into account when recording treatment-resistant depressive conditions. 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 different drugs, there is an absence or insufficient clinical effect (reduction of symptoms on the Hamilton or Montgomery scale is less than 50%). Assessing the effectiveness of antidepressant therapy requires the following criteria: a reduction in the severity of depressive symptoms on 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 a dose equivalent to 200 mg of imipramine or 200-300 mg of amitriptyline.

Modern classifications also provide for the identification of stages of therapeutic resistance depending on which therapeutic interventions were ineffective. This approach was first proposed by Rusch (1997), who developed his classification of TRD by stages.

Identification of the stages of therapeutic resistance is not only important theoretical, but also practical, since it allows, if certain methods of therapy are ineffective, to guide doctors towards subsequent therapeutic interventions. However, there are criticisms of this approach to considering therapeutic resistance in the scientific literature. 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 it with an antidepressant from the same class. The author argues that such an assessment is dubious and refers to representative studies by Thase et al. (2001), demonstrating no difference in the antiresistance efficacy of these approaches. In addition, the traditional assessment of MAO inhibitors as drugs with more

Stage 1 Failure of at least one adequate treatment with an antidepressant from one main group

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

Stage 3 Stage 2 plus treatment failure with lithium addition

Stage 4 Stage 3 plus failure of monoamine oxidase inhibitor treatment

Stage 5 Stage 4 plus failure of electroconvulsive therapy

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

Critically evaluating the leveled approach to assessing resistance, M. Fava in 2003, together with a group of scientists from Massachusetts General Hospital (MGH), proposed another approach to classifying TRD, which is based on assigning a score to each patient, with no response to an adequate course each antidepressant is scored 1 point, optimization of therapy (increasing the dose, increasing the duration of the course, using combined treatment strategies) increases the total score by 5 points, and the use of electroconvulsive therapy (ECT) increases the total score by 3 points. This approach allows us to evaluate all adequate anti-resistant measures while minimizing those that are not always justified from the point of view evidence-based medicine ideas about the different anti-resistant activity of certain antidepressants.

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

Predictors of treatment-resistant depression. Repeated attempts have been made to identify predictors of therapeutic resistance. Thus, according to various 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 studies to identify predictors of treatment resistance are based on assessing the response to the first prescribed antidepressant, and only a very small number of studies attempt to identify predictors of resistance to further treatment in patients already assessed as resistant to previous courses of therapy. At the same time, it is understandable to be skeptical about identifying predictors of therapeutic resistance in depression, 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 due to the pathogenetic heterogeneity of treatment-resistant depression. Reports of the effectiveness of most methods are based on the results of small-sample studies or on descriptions of individual clinical cases and are not confirmed from the modern standpoint of evidence-based medicine.

The main strategies for overcoming therapeutic resistance by 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.

to antidepressant therapy with an additional medicinal agent not belonging to the class of antidepressants. It should be noted that in the Russian-language scientific literature the term “augmentation” is not common and the concepts of “potentiating the action of antidepressants” or “layering tactics” are mainly used.

Replacing an antidepressant. The strategy of replacing an ineffective antidepressant with another is the most commonly used one both in the clinic and on an outpatient basis. The main question: which antidepressant should the patient be switched to if treatment is ineffective - the same or another class? Most recommendations suggest the need to prescribe a different class of antidepressant, for example, replacing TCAs with SSRIs. Replacing an antidepressant from one class with an antidepressant from another may benefit nearly 50% of patients who are refractory to the first drug.

However, there is evidence that replacing it with an antidepressant from the same class can also be effective, which has been confirmed for selective serotonin reuptake inhibitors. The success of such a replacement is explained by 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 primarily when registering negative resistance (the 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 replacement with drugs that cause a more powerful potentiation of both serotonin and norepinephrine, such as amitriptyline, clomipramine, venlafaxine.

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

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

The pharmacological rationale for treatment using a combination of drugs is that the use of two drugs causes a wider range of monoamine pathway activity than either drug alone. Therefore, the most common therapeutic approach is to combine antidepressants with predominantly serotonergic and noradrenergic activity.

It must be remembered that when two antidepressants are prescribed, the risk of side effects usually increases, and 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, so their use in combination with Cardiotoxic tricyclic antidepressants require special caution. For these reasons, a second antidepressant should be added cautiously, at a low dose, and gradually increased based on 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 later confirmed by other researchers. The best thing

begin 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 this combination is prescribed very rarely due to the high risk of side effects.

Augmentation strategies. Augmentation refers to the addition of another substance that is not itself used as a specific drug for the treatment of depression, but can enhance the response to the antidepressant being taken. A variety of drugs from different classes have been proposed as augmentation agents, but only a few have gained acceptance into clinical practice.

Lithium augmentation. The use of lithium for unipolar depression was first described by de Montigny in 1981. Currently, lithium augmentation is the most commonly used method and has the widest scientific basis. The effects of lithium in combination with antidepressants have been studied in detail in animal experiments and clinical studies. It has been established 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. Recently, the subtle mechanisms of such effects have been studied a lot. Lithium is thought to affect neurotransmission at various levels, particularly at the receptor level, the second messenger system, the protein kinase C system, and 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 proapoptotic stimuli.

The effectiveness of lithium augmentation has been found with a wide range of antidepressants, including TCAs and SSRIs.

Authors of uncontrolled trials reported that a fairly large number of individuals (60-70%) experienced rapid antidepressant effects (within 48 hours) after lithium supplementation. Data from double-blind, placebo-controlled trials support the effectiveness of lithium, but in about 40-50% of patients with depression, its onset of action is more gradual, over 2-3 weeks.

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

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

Augmentation with thyroid hormones. The second main method of augmentation is the addition of one of the thyroid hormones - T3 or T4 - to the antidepressant.

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

effect of accelerating the response to treatment with antidepressants. It is also suggested that triiodothyronine may act as a cotransmitter of norepinephrine in the adrenergic structures of the nervous system.

The first study on the effectiveness of triiodothyronine was published by Prange back in 1969. Since then, there have been numerous reports of the effectiveness 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) in dosages of 25-35.5 mcg/day. There is no convincing data on the effectiveness of T3 in combination with new antidepressants.

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

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

Augmentation with antipsychotics 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 adding an antipsychotic to tricyclic antidepressants can significantly enhance their effect.

The idea of using atypical antipsychotics to overcome resistance is much more optimistic. Currently, the main 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 study. It is hypothesized that the effectiveness of atypical antipsychotics in combination with SSRIs may be due to the opposing pharmacological effects of drugs of these classes on noradrenergic activity. The main role is given to the influence of atypical antipsychotics on 5-HT2A/2C receptors. It has been shown 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 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 effects of SSRIs, lower doses than those typically prescribed in the treatment of schizophrenia may be effective because effective 5-HT2A/2C receptor blockade occurs at lower doses than dopamine D2 receptor blockade.

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

Promising drugs for effectiveness in treatment-resistant depression include quetiapine, ziprasidone, and aripiprazole, which have the greatest serotonergic and noradrenergic effects among atypical antipsychotics. Clinical studies of the effectiveness of these drugs in treatment-resistant depression are currently being conducted.

Although the use of atypical antipsychotics for augmentation is promising, issues related to the specific effect of these drugs on metabolic disorders (hyperprolactinemia, sexual disorders, metabolic syndrome) require study.

Other means used for augmentation. Possible 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 an antagonist of 5-HT1A receptors. The hypothesis of its action is that it enhances the action of SSRIs by blocking the inhibitory action of HT1A autoreceptors in the raphe nucleus of the brain. The dose of pindolol (7.5 mg per day) commonly used in add-on studies is probably too low to provide effective HT1A receptor blockade (Rabiner et al., 2001). It is not currently established whether higher doses may be more effective.

Non-drug augmentation. Non-drug augmentation methods include ECT (in 50-65% of cases), plasmapheresis (in 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 states, psychotic level, with suicidal tendencies. Anamnestic information about resistance to drug therapy may serve as a predictor of poor therapeutic response to ECT.

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

It is important to develop appropriate pharmacological continuous therapy after ECT, since the typical clinical practice Continuing the same drug therapy that was administered to the patient before ECT usually turns out to be ineffective.

Discussion. Currently, there is no standard algorithm for identifying 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 emphasize the complexity of the task, since treatment-resistant depression is a heterogeneous group, united only on the basis of response to therapy and including clinically and pathogenetically heterogeneous conditions.

The proposed algorithms (Thase, Triverdi, Mosolov, Kennedy) generally recommend the sequential 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 into the effectiveness of treatments for DDD is needed, such as the ongoing Sequential Treatment Trials for Depression (STAR*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 interventions 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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