Normotimics

Secondary preventive effect of psychopharmacotherapy means the ability of a number of drugs with long-term administration to prevent an attack or significantly soften the severity of another affective phase or schizoaffective disorder. The concept of secondary drug prevention began to be applied from the 60s. XX century. To denote such a preventive effect of drugs M. Sсhоu proposed the term "normotimic", i.е. Leveling mood. This term implies a bimodal action of the drug in the form of the ability to suppress the development of symptoms of both poles, without causing an inversion of affect, and fixing the patient's condition on a stable

[1], [2], [3]

Indications for the appointment of normotimics

Preventative drug therapy should be started during or immediately after the end of the next schizoaffective attack or affective phase against the background of maintenance treatment with antipsychotics, antidepressants or tranquilizers, which are gradually abolished as remission develops. Indication for the appointment of normotimic drugs - the presence in the last two years of at least two exacerbations of an affective or affective-delirious structure within the following diagnostic categories of ICD-10:

• schizoaffective disorder (F25);
• bipolar affective disorder (FZO);
• recurrent depressive disorder (FZZ);
• o Chronic mood disorders;
• cyclothymia (F4.0);
• dysthymia (F34.1).

The algorithms for choosing normotimic therapy, taking into account the clinical and anamnestic factors of efficacy prognosis, are as follows.

Carbamazepine is indicated:

• early onset of the disease;
• frequent exacerbations (more than 4 times a year);
• o-the presence of "organically inferior soil": dysthymia, dysphoria;
• inverted circadian rhythm;
• resistance to lithium salts;
• schizoaffective disorder;
• prevalence of depression in any form;
• unipolar depression;
• angry mania;
• lack of vital experiences.

The purpose of lithium salts is shown:

• hereditary aggravation of affective spectrum disorders;
• low severity of negative symptoms;
• syntonic personality in premorbid;
• absence of "organically inferior soil";
• classical bipolar disorder;
• a harmonious picture of the attack;
• prevalence of manic episodes;
• absence of phase inversions;
• daily rhythm;
• presence of good remissions.

The appointment of valproate:

• bipolar disorder;
• prevalence of manic episodes;
• chronic affective mood disorders;
• presence of "organically inferior soil";
• dysphoric manifestations in episodes;
• inverted circadian rhythm;
• resistance to lithium salts;
• resistance to carbamazepines.

According to standards developed by the consensus of experts (The Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder, 2000), treatment of bipolar disorder involves:

• the need to use normotimics at all stages of treatment;
• as first-line drugs, the use of monotherapy with lithium or valproate, with monotherapy ineffective - the use of combinations of these drugs;
• as a preparation of the second line, carbamazepine;
• if the normotimics of the 1 st and 2 nd lines are ineffective - use of other anticonvulsants;
• if there are weakly depressed states in the clinical picture as 1st line drugs - appointment of monotherapy with lamotrigine or valproate;
• with more pronounced depressive states - the use of a combination of "standard" antidepressant with lithium or valproate.

Antidepressants are used for 2-6 months after the onset of remission.

Classification of normotimics

Currently, normotimic drugs include:

• lithium salts (lithium carbonate, extended lithium preparations);
• antiepileptic drugs;
• carbamazepine derivatives;
• derivatives of valproic acid;
• antiepileptic drugs of the third generation (lamotrigine);
• calcium channel blockers (verapamil, nifedipine, diltiazem).

[4], [5]

Lithium salts

As a means of preventive therapy, lithium salts have been used since 1963, and by the end of the 1960s, it was found that their long-term use has a clear preventive effect in patients with recurrent affective disorders. It turned out that lithium prevents pathological phase disorders of mood and mental activity, i.e. Stabilizes background emotional states of a person. That is why lithium salts contributed to the isolation of an independent class of psychotropic drugs called normotimics, or timostabilizers (timo-isoleptics - in accordance with the nomenclature Delay J., Deniker P., 1961).

According to modern data, the main indication for the therapeutic use of lithium salts is hypomanic and manic states of moderate severity, and the effectiveness of therapy is higher the easier the syndrome, i.e. The more his psychopathological features approach a typical (classical) mania. The advisability of using lithium in the treatment of depression remains controversial. Lithium salts can not be considered an effective antidepressant. Lithium has a positive therapeutic effect only with shallow depressive conditions mixed with affect, i. E. Retaining the impregnations of the former manic phases. Lithium is not indicated for the treatment of severe endogenous depression, nor is it appropriate for its use in reactive and neurotic depressions. At the same time, there are recommendations for the inclusion of lithium in the curative scheme in the treatment of resistant depressive states. Prophylactic therapy is carried out for a long time (sometimes for years). A sharp discontinuation of taking normotimics can lead to a rapid onset of affective disorders. The abolition of preventive therapy should be gradual, within a few weeks. The patient should be warned about the likely deterioration of the condition.

Despite the fact that the proven preventive effect of lithium salts and the introduction of these drugs into clinical practice is one of the most significant achievements of clinical psychopharmacology, the use of lithium is currently limited by the following factors.

High frequency of side effects:

• lithium tremor;
• dyspeptic disorders (nausea, vomiting, diarrhea);
• increase in body weight (mainly due to heavy drinking);
• impaired renal function (polyuria with secondary polydipsia, glomerulopathy, interstitial nephritis, renal failure);
• cardiotoxic effect (hypokalemia);
• violation of water-salt metabolism;
• convulsive seizures (which makes it impossible to use it in patients with epilepsy);
• less often - the effect on the function of the thyroid gland (goiter exophthalmos, hyperthyroidism).

The complexity of control: the content of lithium in the patient's blood should be determined weekly for 1 month, then 1 time in 2 weeks for 2 months. After 6 months - every 2 months, and only if the patient's condition on lithium is stable for a year, you can control its level 3-4 times a year.

The need to comply with patients water-salt diet. The change in the amount of water in the body and the content of various salts affects the amount of lithium removed from the body, as a result of which its concentration in the blood either decreases or rises. Excessive consumption of sodium salts causes a decrease in the level of lithium, and, conversely, their lack can lead to a toxic level of lithium. Reducing the amount of fluid in the body (for example, with excessive sweating) leads to dehydration and intoxication with lithium. Lithium should be used with caution in cases of disturbances in water-electrolyte metabolism (dehydration, combined use with diuretics, salt-free diet, vomiting, diarrhea).

It is difficult for lithium to use its small therapeutic interval. Often the clinical effect occurs at those doses of lithium, which produce significant side effects, which leads to lithium intoxication. In lithium salts, the interval between therapeutic and toxic concentrations is the smallest of all drugs used in psychiatry. The therapeutic effect of lithium salts is due to the constant presence of a certain amount of lithium in the body. At too low concentrations, the effect of the drugs does not appear, with excessively high concentrations - the development of lithium intoxication is possible. The optimum interval for the manifestation of preventive action of lithium salts is the concentration of lithium in the blood plasma of 0.6-1 mmol / l.

Preventive therapy with lithium carbonate begins with minimal daily doses. After a week, the concentration of lithium in the blood is determined, and if it does not reach 0.6 mmol / l, the daily dose of lithium is increased and after a week the concentration is again checked. Usually, when using average doses of lithium carbonate, its concentration in the blood is maintained within the range of 0.4-0.6 mmol / l. There is a definite relationship between the results of therapy and the dose of lithium needed to achieve a stable therapeutic concentration: the forecast is better in those cases where enough small doses of the drug (up to 1000 mg) and, conversely, where the therapeutic concentration is achieved at a dose higher 1500 mg - the forecast is worse.

At a number of psychopathological disorders, the low effectiveness of lithium salt therapy has been proved. Among them are:

• a rapid change in the cycles of manic and depressive episodes (more than 3-4 per year); as a rule, can not be treated with lithium, since the preventive effect of the drug usually occurs 5-6 months after the start of treatment;
• mixed affective states (angry, anxious mania, agitated depression);
• organic brain lesions (Parkinsonism, cerebral atherosclerosis, consequences of CCT);
• epilepsy;
• the debut in the form of a depressive phase of diseases, in the clinical picture of which there are pronounced bipolar affective fluctuations.

Other drugs used to treat affective disorders

Carbamazepine is used to treat affective disorders since the 80's. XX century. In view of the antimanic and thimostabilizing properties found in it. The theoretical justification for the normotimic action of carbamazepine was the hypothesis of amygdal "handling" put forward by R. Post and J. Ballenger (1982), according to which the existence of prolonged, periodic subliminal stimuli in affective disorders leads to depletion of the potential of the GABAergic system. The normotimical mechanism of action of carbamazepine was explained both by blockade of nonspecific stimulations of brain structures and blockade of inhibitory functions performed by GABA-ergic system (inhibition of transaminases in the hippocampus, basal ganglia and cerebral cortex). According to this theory, the ability of carbamazepines to suppress "handling processes", especially expressed in the limbic system, explains its effectiveness in the treatment of affective disorders.

The first studies of the therapeutic effect of carbamazepine in affective and schizoaffective disorders showed its high efficacy in coping manic states, comparable and even superior to traditional antimanic drugs.

The manifestation of prophylactic properties of carbamazepine occurs rather quickly. Stable effect with the subsequent formation of remission in carbamazepine is noted already in the first 2-3 months of treatment. At the same time, the rate of development of the clinical effect of carbamazepine is much higher than that of lithium, it is possible to judge the preventive effect of which not earlier than 6 months of treatment. The manic state during the therapy with carbamazepine regresses, primarily due to the affective and ideomotor components. The persisting manic states, as a rule, lose the severity of the symptoms. In the first place, the severity of psychopathic manifestations, especially of conflict and anger, falls. The results of treatment of depressive disorders showed that anxiety affects are the most likely to reduce, as well as "classical" depression, in the structure of which all the components of the depressive triad are represented. Vital experiences of anguish, anxiety lose their dominant position in the complaints of patients and do not carry the same excruciating character. Sub-depressants in the process of therapy with this drug are modified and take on the character of asthenic conditions, in which asthenoipochondrial disorders are at the forefront.

Comparative studies of the clinical effect of drugs from the group of normotimics have shown that carbamazepine is superior to lithium salts in terms of preventive action against depressive phases, but it is somewhat inferior to them in influencing manic attacks. Particular attention should be paid to the detected efficacy of carbamazepine in patients with a continual course of psychosis with rapid phase change. The high efficacy of carbamazepine versus lithium in atypical and schizoaffective psychoses has also been established. Thus, carbamazepine is the drug of choice for normotimic therapy for affective and schizoaffective psychoses, with prevalence of depressive disorders during the course of the disease, as well as in continual flow with rapid phase change.

The long-term nature of preventive therapy of affective and schizoaffective seizures determines the importance of the issue of the interaction of carbamazepine with other psychotropic drugs (neuroleptics, antidepressants, tranquilizers). It should be borne in mind that carbamazepine, having a powerful inducing effect on the cytochrome P450 isoenzyme system (ZA4, ZA5, ZA7), enhances the metabolism of all drugs taken with it, metabolized by these enzymes, which leads to a decrease in the concentration of these drugs in serum. In addition, carbamazepine reduces the effectiveness of oral contraceptives.

Side effects of carbamazepine - have the maximum severity, usually in the early stages of therapy. Their appearance serves as a guide for the selection of an adequate dose for further preventive treatment. The most common are drowsiness, blurred speech, dizziness, mild ataxia, diplopia, leukopenia, dyspeptic disorders, less often - thrombocytopenia, eosinophilia, swelling, weight gain, etc. These side effects quickly disappear, and the dosage increase rate is individual for each patient and does not require withdrawal of the drug. In most cases, they pass spontaneously, even without a dose reduction. In the treatment of carbamazepine, allergic skin reactions are sometimes observed, more often in the form of urticaria or erythema. There is an opinion that the incidence of skin allergic reactions in carbamazepine treatment is higher in psychiatric patients compared to epilepsy patients, which is due to the already existing sensitization in these patients to previously taken other psychotropic drugs. In most cases, they are mild (in the form of maculopapillary erythematous rash), occur primarily at the beginning of therapy and disappear after withdrawal of carbamazepine or the use of antihistamines. In some patients taking carbamazepine, short-term leukopenia develops at the first stage of therapy. It is not related to the concentration level of the drug in the blood serum. Changes, as a rule, occur within clinically acceptable limits, are reversible and do not require withdrawal of the drug. In rare cases, agranulocytosis, aplastic anemia, thrombocytopenia develops. Given the risk of developing hematological complications, it is recommended that regular blood tests (1 time per 3 months) be recommended during carbamazepine therapy.

Treatment with carbamazepine begins with small doses, which are prescribed in the evening hours, increasing the dose gradually - by 100 mg every 2-3 days to the maximum tolerated. The daily dose is distributed evenly for a 3-time reception, prolonged forms of carbamazepine are prescribed 2 times a day: in the morning and in the evening. When side effects occur, the dose is reduced, returning to the previous one, which is considered to be the most tolerable for the patient. This dose is left for the entire period of further treatment. If there is no clear preventive effect, then in the process of therapy, doses of carbamazepine are corrected. At the same time, such signs as lack of complete reduction of seizures or positive dynamics in the course of the disease (ie if patients do not have a change in their duration, there is no decrease in the severity of psychopathological symptoms, there is no increase in the duration of remission ). The time period for which the effectiveness of preventive therapy is evaluated by the initially selected doses of carbamazepine is established individually for each patient and is determined on the basis of the features of the course of the disease, the frequency of occurrence of relapses. The indication for correction of dosages is the appearance in patients in the remission of affective fluctuations of the subclinical level in the form of hypomania or subdepression. Dosage is carried out at the same slow pace as at the beginning of therapy.

In the case of inefficiency of monotherapy with lithium and carbamazepine, a combined treatment with these drugs is sometimes performed. Its use requires caution in connection with an increased risk of side effects and toxic reactions associated with drug interactions of these drugs. Risk factors are signs of residual organic insufficiency of the central nervous system or a concomitant metabolic disease. Within this drug combination it is necessary to use lower dosages of drugs, slower rate of escalating the dose of carbamazepine upon adherence to lithium therapy and to maintain the concentration of lithium in the blood at a lower level.

Oxcarbazepine comparatively recently appeared in clinical practice and is similar in chemical structure to carbamazepine. Oxcarbazepine is recommended to be used as a drug of choice both in the form of monotherapy and as part of combined treatment regimens. It is also possible to switch to oxcarbazepine therapy from other drugs if they are poorly tolerated. The extremely attractive property of oxcarbazepine is the ability to replace carbamazepine in one day in case of ineffectiveness or intolerable side effects.

Valproic acid derivatives

In the history of medicine, there are many examples where the value of established methods of treatment and previously developed drugs is re-evaluated, which may lead to an expansion of the indications for their appointment. Valproic acid derivatives are an illustration of this pattern. Despite the fact that in 1963 an antiepileptic effect of valproic acid was found and to this day valproate - the most common antiepileptic drugs that help with all types of seizures, in recent years they have been used as normotimics. The peculiarities of the pharmacokinetics of valproates are that unlike carbamazepine, they do not induce but inhibit the liver cytochromes, as a result of which the concentration of other drugs taken together with it (neuroleptics, antidepressants, benzodiazepines) increases in the blood, which makes it possible to widely use valproate in combination therapy with the above means.

The advantages of using valproate for the prevention and treatment of bipolar affective disorders are significantly more effective than lithium salts in the treatment of mixed affective conditions (primarily angry mania), in the prevention of unipolar depressive disorders, in the treatment of bipolar affective disorders with rapid phase change (more 3-4 per year), which are not amenable to treatment with lithium. These funds are shown for the prevention of affective disorders in patients with epilepsy, organic brain lesions (inflammatory, traumatic, vascular genesis), alcoholism.

Side effects can be with long-term administration of valproates in the form of a tremor, a violation of the function of the digestive tract, weight gain, alopecia. Hematological side effects practically do not arise. These drugs do not have a sedative effect, do not lead to a decrease in cognitive functions and an increase in tolerance to therapy.

Valproates are applied 3 times a day (retard forms 1-2 times a day). Dose build-up is gradual, with the appearance of side effects (dyspepsia) return to the previous dose, which remains unchanged during the further treatment.

Thus, valproate can also be used as an effective means of preventing recurrent emotional disorders, and their use in the treatment of epilepsy patients is a means of preventive therapy of a wide range of affective disorders.

In recent years, work has appeared on the use of new protivo-epileptic drugs as normotimics: topamax, lamotrigine.

A number of modern studies have noted the effectiveness of the combined use of normotimics with atypical antipsychotics as an additional tool in cases of therapeutic resistance to preventive monotherapy with normotimics.

Calcium channel blockers

Calcium channel blockers (nifedipip, verapamil) refer to non-psychotic drugs, which have a normotimic effect. These drugs are mainly used as antianginal drugs for ischemic heart disease with angina attacks, to reduce blood pressure in various types of hypertension. According to modern concepts in the pathogenesis of affective disorders, an important role is played by violations of processes in cell membranes that are associated with calcium. At the same time, the effectiveness of traditional normotimics is also associated with their effect on calcium-dependent processes. In connection with this, a hypothesis was advanced that drugs directly acting on calcium metabolism may have a normotimic effect. Clinical studies have shown that the use of calcium channel blockers does have a preventive effect in bipolar disorders, including acute mania. Calcium channel blockers are recommended for patients who can not be treated with lithium, valproate or carbamazepine, including during pregnancy. There are recommendations for the use of these drugs in combination with traditional normotimics for the therapy of rapid cyclic variants of bipolar disorder. Nifedipine, unlike verapamil, does not have a depressing effect on the conduction system of the heart and has a weak antiarrhythmic activity and with the preferred use of drugs from SSRIs and selective serotonin and noradrenaline reuptake inhibitors. In the case of a rapidly cyclic variant of the course, monotherapy with valproate is used as the first line. Antipsychotics are recommended for the therapy of psychotic depression and mania, and also in combination with normotimics as additional means of prevention. Preference should be given to atypical antipsychotics.

[6], [7], [8], [9]