Normotimics

The secondary preventive action of psychopharmacotherapy implies the ability of a number of drugs, when taken for a long time, to prevent the onset or significantly mitigate the severity of the next affective phase or schizoaffective attack. The concept of secondary drug prophylaxis has been used since the 1960s. To designate such a preventive action of drugs, M. Schou proposed the term "normothymic", i.e. mood-balancing. This term implies the bimodality of the drug's action 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 at a stable level.

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Indications for prescribing normotimics

Preventive 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 neuroleptics, antidepressants or tranquilizers, which are gradually discontinued as remission is established. An indication for prescribing normothymic drugs is the presence of at least two exacerbations of an affective or affective-delusional structure within the framework of the following diagnostic categories of ICD-10 over the past two years:

• schizoaffective disorder (F25);
• bipolar affective disorder (BAD);
• recurrent depressive disorder (RDD);
• o chronic mood disorders;
• cyclothymia (F4.0);
• dysthymia (F34.1).

The algorithms for selecting normothymic therapy taking into account clinical and anamnestic factors for predicting effectiveness are as follows.

Indicated use of carbamazepine:

• early onset of the disease;
• frequent exacerbations (more than 4 times a year);
• o - the presence of “organically defective soil”: dysthymia, dysphoria;
• inverted circadian rhythm;
• resistance to lithium salts;
• schizoaffective disorders;
• prevalence of depression in any form;
• unipolar depressions;
• angry manias;
• absence of vital experiences.

The purpose of lithium salts is shown:

• hereditary burden of affective spectrum disorders;
• low severity of negative symptoms;
• syntonic personality in premorbid;
• absence of "organically defective soil";
• classic bipolar disorder;
• harmonious picture of the attack;
• predominance of manic episodes;
• absence of phase inversions;
• circadian rhythm;
• presence of good remissions.

The indication for valproates is:

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

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

• the need to use normotimics at all stages of treatment;
• as first-line drugs, use of monotherapy with lithium or valproates; if monotherapy is ineffective, use of combinations of these drugs;
• as a second-line drug, use of carbamazepine;
• if 1st and 2nd line normotimics are ineffective, use other anticonvulsants;
• if the clinical picture contains mild depressive states, the first-line drugs are monotherapy with lamotrigine or valproates;
• in more severe depressive states - use a combination of a “standard” antidepressant with lithium or valproate.

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

Classification of normothymic agents

Currently, normothymic drugs include:

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

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Lithium salts

Lithium salts have been used as a preventive therapy since 1963, and by the end of the 1960s it became clear that their prolonged use has a clear preventive effect on patients with recurrent affective disorders. It turned out that lithium prevents pathological phase disorders of mood and mental activity, i.e. stabilizes the background emotional states of a person. This is why lithium salts contributed to the identification of an independent class of psychotropic drugs called normothymics, or thymostabilizers (thymoisoleptics - in accordance with the nomenclature of 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 simpler the syndrome, i.e. the more its psychopathological features approach typical (classical) mania. The advisability of using lithium in the treatment of depression remains controversial. Lithium salts cannot be considered an effective antidepressant. Lithium has a positive therapeutic effect only in shallow depressive states mixed with affect, i.e. retaining inclusions of previous manic phases. Lithium is not indicated for the treatment of severe endogenous depressions, and its use in reactive and neurotic depressions is also inappropriate. At the same time, there are recommendations for the inclusion of lithium in the treatment regimen for resistant depressive states. Preventive therapy is carried out for a long time (sometimes for years). Abrupt cessation of normothymic drugs can lead to the rapid development of affective disorders. Withdrawal of prophylactic therapy should be gradual, over several weeks. The patient should be warned of the possible deterioration of the condition.

Despite the fact that the proven prophylactic 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 incidence of side effects:

• lithium tremor;
• dyspeptic disorders (nausea, vomiting, diarrhea);
• weight gain (mainly due to drinking a lot of fluids);
• renal dysfunction (polyuria with secondary polydipsia, glomerulopathy, interstitial nephritis, renal failure);
• cardiotoxic effect (hypokalemia);
• violation of water-salt metabolism;
• convulsions (which makes its use impossible in patients with epilepsy);
• less often - effect on thyroid function (goiter, exophthalmos, hyperthyroidism).

Difficulty of control: the lithium content in the patient's blood must be determined weekly for the first month, then once every 2 weeks for the second month; after 6 months - every 2 months, and only if the patient's condition on lithium is stable for a year, its level can be monitored 3-4 times a year.

The need for the patient to follow a water-salt diet. Changes in the amount of water in the body and the content of various salts affect the amount of lithium excreted from the body, as a result of which its concentration in the blood either decreases or increases. Excessive consumption of sodium salts causes a decrease in the lithium level, and, conversely, their deficiency can lead to a toxic level of lithium. A decrease in the amount of fluid in the body (for example, with excessive sweating) leads to dehydration and lithium intoxication. Lithium should be used with caution in cases of water-electrolyte metabolism disorders (dehydration, combined use with diuretics, salt-free diet, vomiting, diarrhea).

The use of lithium is complicated by its small therapeutic interval. Often, the clinical effect occurs at those doses of lithium that give pronounced side effects, which leads to lithium intoxication. The interval between therapeutic and toxic concentrations of lithium salts 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, at excessively high concentrations, lithium intoxication may develop. The optimal interval for the manifestation of the prophylactic effect of lithium salts is a lithium concentration 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 the concentration is checked again after a week. Usually, when using average doses of lithium carbonate, its concentration in the blood is maintained within 0.4-0.6 mmol/l. A certain relationship has been noted between the results of therapy and the dose of lithium required to achieve a stable therapeutic concentration: the prognosis is better in cases where small doses of the drug (up to 1000 mg) are sufficient to achieve the required concentration, and, conversely, where the therapeutic concentration is achieved with a dose above 1500 mg, the prognosis is worse.

Low efficiency of lithium salt therapy has been proven in a number of psychopathological disorders. These include:

• rapid alternation of cycles of manic and depressive episodes (more than 3-4 per year); as a rule, it cannot be treated with lithium, since the prophylactic effect of the drug usually occurs 5-6 months after the start of treatment;
• mixed affective states (angry, anxious mania, agitated depression);
• organic brain damage (Parkinsonism, cerebral atherosclerosis, consequences of TBI);
• epilepsy;
• 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 mood disorders

Carbamazepine has been used to treat affective disorders since the 1980s due to its antimanic and thymostabilizing properties. The theoretical basis for the normothymic action of carbamazepine was the hypothesis of amygdala "kindling" put forward by R. Post and J. Ballenger (1982), according to which the existence of prolonged, periodic subthreshold stimuli in affective disorders leads to the depletion of the potential of the GABA-ergic system. The normothymic mechanism of action of carbamazepine was explained both by the blockade of nonspecific stimuli of brain structures and by the blockade of inhibitory functions carried out by the GABA-ergic system (inhibition of transaminases in the hippocampus, basal ganglia and cerebral cortex). According to this theory, the ability of carbamazepine to suppress "kindling 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 effectiveness in relieving manic states, comparable and even superior to traditional antimanic drugs.

The manifestation of the preventive properties of carbamazepine occurs quite quickly. A stable effect with subsequent remission of 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 significantly higher than that of lithium, the preventive effect of which can be judged no earlier than 6 months of treatment. The manic state regresses during carbamazepine therapy, primarily due to the affective and ideomotor components. Persistent manic states, as a rule, lose the severity of symptoms. First of all, the severity of psychopathic manifestations, especially conflict and anger, decreases. The results of therapy for depressive disorders have shown that the affect of anxiety, as well as "classic" depressions, in the structure of which all components of the depressive triad are represented, are subject to the greatest degree of reduction. Vital experiences of melancholy and anxiety lose their dominant position in the complaints of patients and do not have the same painful character. During therapy with this drug, subdepressions change and take on the character of asthenic conditions, in which asthenohypochondriac disorders come to the fore.

Comparative studies of the clinical effect of drugs from the normothymic group have shown that carbamazepine is superior to lithium salts in terms of the severity of the preventive effect on depressive phases, but is somewhat inferior to them in terms of the effect on manic attacks. The effectiveness of carbamazepine in patients with a continuous course of psychosis with a rapid change of phases deserves special attention. High effectiveness of carbamazepine compared to lithium in atypical and schizoaffective psychoses has also been established. Thus, carbamazepine is the drug of choice for normothymic therapy in affective and schizoaffective psychoses, with a predominance of depressive disorders in the course of the disease, as well as in a continuous course with a rapid change of phases.

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

Side effects of carbamazepine - are most pronounced, as a rule, in the early stages of therapy. Their appearance serves as a guideline for selecting an adequate dose for further preventive treatment. The most common are drowsiness, slurred speech, dizziness, mild ataxia, diplopia, leukopenia, dyspeptic disorders, less common - thrombocytopenia, eosinophilia, edema, weight gain, etc. These side effects quickly disappear with an individual rate of dosage increase for each patient and do not require discontinuation of the drug. In most cases, they pass spontaneously, even without reducing the dose. During treatment with carbamazepine, allergic skin reactions are sometimes observed, most often in the form of urticaria or erythema. There is an opinion that the frequency of skin allergic reactions during treatment with carbamazepine is higher in psychiatric patients compared to patients with epilepsy, which is associated with the already existing phenomena of sensitization in these patients to other psychotropic drugs taken earlier. In most cases, they are mild (in the form of maculopapillary erythematous rash), occur mainly at the beginning of therapy and disappear after discontinuation of carbamazepine or use of antihistamines. In some patients taking carbamazepine, short-term leukopenia develops at the first stage of therapy. It is not associated with the level of drug concentration in the blood serum. Changes, as a rule, occur within clinically acceptable limits, are reversible and do not require discontinuation of the drug. In rare cases, agranulocytosis, aplastic anemia, thrombocytopenia develop. Given the risk of developing hematological complications, regular clinical blood tests are recommended during carbamazepine therapy (once every 3 months).

Treatment with carbamazepine begins with small doses, which are prescribed in the evening hours, the dose is increased gradually - by 100 mg every 2-3 days to the maximum tolerated. The daily dose is distributed evenly into 3 doses, prolonged forms of carbamazepine are prescribed 2 times a day: in the morning and in the evening. If side effects occur, the dose is reduced, returning to the previous one, which is considered the maximum tolerated for the patient. This dose is left for the entire period of further treatment. If there is no clear prophylactic effect, then during the therapy, the doses of carbamazepine are adjusted. In this case, the criteria for insufficient effectiveness are such signs as the absence of a complete reduction in attacks or positive dynamics in the indicators of the course of the disease (i.e. if patients do not observe a change in their duration from attack to attack, there is no decrease in the severity of psychopathological symptoms, there is no increase in the duration of remission). The period of time for which the effectiveness of preventive therapy with initially selected doses of carbamazepine is assessed is set individually for each patient and is determined based on the characteristics of the course of the disease and the frequency of relapses. The indication for dosage adjustment is the appearance of subclinical affective fluctuations in patients in remission in the form of hypomania or subdepression. The dose is increased at the same slow rate as at the beginning of therapy.

In case of ineffectiveness of lithium and carbamazepine monotherapy, sometimes combined treatment with these drugs is carried out. Its use requires caution due to the increased risk of side effects and toxic reactions associated with drug interactions of these drugs. The risk factor in this case is signs of residual organic CNS insufficiency or concomitant metabolic disease. Within the framework of this drug combination, it is necessary to use lower dosages of the drugs, a slower rate of increase in the dose of carbamazepine when adding it to lithium therapy, and maintain the concentration of lithium in the blood at a lower level.

Oxcarbazepine has appeared in clinical practice relatively recently and is similar in chemical structure to carbamazepine. Oxcarbazepine is recommended for use as a drug of choice both as 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. An extremely attractive property of oxcarbazepine is the ability to replace carbamazepine with it within one day in case of ineffectiveness or intolerable side effects.

Valproic acid derivatives

There are many examples in the history of medicine when the value of established treatment methods and previously developed drugs is re-evaluated, which can lead to an expansion of indications for their use. Derivatives of valproic acid illustrate such a pattern. Despite the fact that the antiepileptic effect of valproic acid was discovered back in 1963 and today valproates are the most common antiepileptic drugs that help with all types of seizures, in recent years they have been used as normothymic drugs. The peculiarities of the pharmacokinetics of valproates are that, unlike carbamazepine, they do not induce, but inhibit liver cytochromes, as a result of which the concentration of other drugs taken together with it (neuroleptics, antidepressants, benzodiazepines) in the blood increases, which allows for the wide use of valproates in combination therapy with the above-mentioned drugs.

The advantages of using valproates for the prevention and treatment of bipolar affective disorders are their significantly greater effectiveness compared to lithium salts in the treatment of mixed affective states (primarily angry manias), in the prevention of monopolar depressive disorders, in the treatment of bipolar affective disorders with rapid phase changes (more than 3-4 per year), which are not amenable to treatment with lithium. These drugs are indicated for the prevention of affective disorders in patients with epilepsy, organic brain damage (inflammatory, traumatic, vascular genesis), alcoholism.

Side effects may occur with prolonged use of valproates in the form of tremor, gastrointestinal dysfunction, weight gain, alopecia. Hematological side effects are virtually non-existent. These drugs do not have a sedative effect, do not lead to a decrease in cognitive functions and do not increase tolerance to therapy.

Valproates are used 3 times a day (retarded forms 1-2 times a day). The dose is increased gradually, if side effects appear (dyspepsia), return to the previous dose, which is kept unchanged during the further treatment.

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

In recent years, there have been studies on the use of new antiepileptic drugs as normotimics: topamax, lamotrigine.

A number of modern studies have noted the effectiveness of the combined use of normothymic drugs with atypical antipsychotics as an additional agent in cases of therapeutic resistance to prophylactic monotherapy with normothymic drugs.

Calcium channel blockers

Calcium channel blockers (nifedipipe, verapamil) are non-psychotic drugs with normothymic action. These drugs are mainly used as antianginal agents for ischemic heart disease with angina attacks, to reduce blood pressure in various types of arterial hypertension. According to modern concepts, disturbances in processes in cell membranes associated with calcium play a significant role in the pathogenesis of affective disorders. At the same time, the effectiveness of traditional normothymic drugs is also associated with their effect on calcium-dependent processes. In this regard, a hypothesis was put forward that drugs that directly affect calcium metabolism may have a normothymic 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 use in patients who cannot be treated with lithium, valproates or carbamazepine, including during pregnancy. There are recommendations for the use of these drugs in combination with traditional normothymic agents for the treatment of rapidly cycling variants of bipolar disorders. Nifedipine, unlike verapamil, does not have a depressing effect on the cardiac conduction system and has weak antiarrhythmic activity, with the preferred use of drugs from the SSRI and selective serotonin and norepinephrine reuptake inhibitor groups. In the case of a rapidly cycling variant of the course, valproate monotherapy is the first line. Antipsychotics are recommended for the treatment of psychotic depressions and manias, as well as in combination with normothymic agents as additional preventive measures. Preference should be given to atypical antipsychotics.

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