Bipolar disorder: treatment

Treatment of bipolar affective disorder is carried out mainly by normotimic means ("affect stabilizers"), such as lithium preparations, carbamazepine or valproic acid.

But sometimes they resort to relatively new drugs: olanzapine, risperidone, lamotrigine, gabapentin, calcium antagonists. The treatment is divided into several periods: the period of "acute" stabilization, providing for the arrest of a manic episode, sometimes with the help of several drugs; period of stabilization and a period of prolonged preventive therapy in order to prevent new episodes.

[1], [2], [3]

Lithium preparations

Lithium has been used in medicine for a long time, with different successes it has been used for a variety of diseases. In the early 1900s, lithium was often included in popular patented products that help "from all diseases." Preparations containing lithium were recommended for the treatment of various conditions: from malaise to various "dysfunctions of the nervous system". Lithium was also used to treat gout, and in the 1940s it was even used as a salt substitute. In 1949, Cade successfully used lithium to treat a condition that he called "psychotic arousal." This discovery could have revolutionized the treatment of bipolar disorder, which at that time was virtually untreated. However, this happened only in 1970, when the FDA authorized the use of lithium drugs for the treatment of acute mania. Numerous double-blind, placebo-controlled studies have shown that in acute mania lithium preparations are on average effective in 70-80% of patients. However, in recent studies, the effectiveness of lithium was lower, which can be explained by a higher proportion of patients who are resistant to therapy or who have a mixed mania in which lithium monotherapy is not so successful. Nevertheless, lithium remains the most studied drug from the group of normotimic agents.

Lithium is used for bipolar affective disorder and as a preventive agent. As shown by placebo-controlled studies, against the background of prolonged therapy with lithium preparations, in about 70% of patients the number and intensity of affective episodes decreased. Approximately 50% of patients who abruptly stopped the preventive reception of lithium, within 5 months develop a relapse. With a more gradual elimination of lithium, the relapse rate decreases from 94% (over a 5-year period) to 53%.

Some individual features of patients allow predicting the effect of lithium. For example, with classical ("pure") mania, the effectiveness of lithium is significantly higher than with mixed or dysphoric mania. On the other hand, lithium is less effective in the presence of short (fast) cycles. Lithium preparations cause an improvement in 60% of patients with bipolar affective disorder, not having short cycles, and only in 18-25% of patients with similar cycles. The concomitant abuse of psychotropic substances presages the low effectiveness of lithium, but if the drugs were unsuccessful in the past, this does not mean that a new attempt at their use will be ineffective.

Although lithium has one of the lowest therapeutic indices among other psychotropic drugs, it is successfully used by many patients with bipolar affective disorder. The therapeutic concentration of lithium in plasma is usually 0.6-1.2 meq / L, although younger patients sometimes require a higher concentration, and in elderly patients a lower concentration. The most frequent side effects of lithium include thirst, polyuria, memory loss, tremor, weight gain, drowsiness, fatigue, diarrhea. The reason for stopping the drug more often include the following side effects (in decreasing order of frequency): memory loss, weight gain, tremors and coordination disorders, polyuria, drowsiness and fatigue. Tremor caused by lithium can be enhanced by caffeine, which should be paid attention to the patient. Usually the tremor is well removed by beta-blockers. Lithium is capable of causing side effects from the gastrointestinal tract (for example, nausea or an unformed stool), as well as provoke an exacerbation of psoriasis or acne. In addition, lithium often causes benign granulocytosis. On the background of lithium treatment, thyroid function may be impaired, while in 5% of cases clinically obvious hypothyroidism develops, and in 30% of cases an increased level of TSH is revealed. In 15-30% of patients there is an increased titer of antithyroid autoantibodies. Against the background of lithium administration, hyperparathyroidism may also develop, but much less frequently than hypothyroidism.

Lithium reduces the reabsorption of water in the distal tubules and collecting tubes, which leads to disruption of the concentrating function of the kidneys and the development of polyuria. This, in turn, causes polydipsia and (if patients drink sugary-containing carbonated drinks or juices) increase in body weight. However, there is no conclusive evidence that lithium in therapeutic doses causes irreversible kidney dysfunction.

The influence of lithium on the heart leads to flattening and inversion of the T wave, bradycardia, prolongation of the repolarization period of the sinus node. Since there are currently other normotimic agents that cause fewer side effects from the cardiovascular system, patients with sinus bradycardia or weakness of the sinus node should refrain from using lithium drugs or use them with extreme caution.

In addition to standard lithium preparations (for example, escalite, lytonate, lithotabs), controlled release formulations (eg, escalite CR) or slow release (lithobid) are being produced. These preparations contain lithium carbonate. However, lithium citrate is also available - in the form of syrup (cibalite S). At the same time, 8 mg of lithium is contained in 300 mg of lithium carbonate or 5 ml of lithium citrate. Lithium is fully absorbed when taken orally, its maximum plasma concentration is reached after 1-1.5 hours (with a standard preparation) or 4-4.5 hours (with controlled and slow release forms). Lithium is excreted mainly by the kidneys. The half-elimination period is 18-24 hours.

Non-steroidal anti-inflammatory drugs can increase the concentration of lithium in plasma, except aspirin and sulindac. Diuretics and angiotensin-converting enzyme inhibitors are also capable of increasing serum lithium concentration, enhancing sodium excretion by the kidneys and thereby reducing lithium excretion.

Use of lithium drugs in acute mania

Lithium is still widely used to treat mania, but since its effect appears only after 5-10 days, there is often a need for additional funds. Prior to the appointment of lithium, an ECG is required, an examination of the kidney and thyroid function. Women with a reproductive function should also make a pregnancy test, since lithium has a teratogenic effect. Treatment with lithium usually begins with a dose of 600-1200 mg / day, which is broken down into several doses. The therapeutic concentration of lithium in plasma (0.8-1.2 meq / L) in most patients is achieved at a dose of 1200-1800 mg / day. During the titration period, the concentration of lithium is determined every 4-5 days. Various techniques have been developed to determine the dose of lithium needed to achieve a therapeutic concentration in the serum. According to one of them, the serum concentration of lithium is measured 24 hours after the start of therapy, according to another one at 12, 24 and 36 hours. According to the third, two blood samples, a urine sample must be taken 4 hours after the initiation of therapy and the creatinine clearance is estimated. Despite a variety of techniques, many clinicians still select the dose empirically, given the therapeutic and side effects. Concentration of the drug in the serum is usually evaluated 12 hours after the last dose. If the state of the patient remains stable against the background of prolonged lithium therapy, then the concentration of lithium, as well as the kidney and thyroid function, is usually checked every 6-12 months. In 1 tablet of escalite, lytonate, lithotabs and lithobid contains 300 mg of the drug, in one tablet of escalite CR - 450 mg; 5 ml of a liquid preparation of cibalite-S are equivalent to 300 mg of lithium carbonate.

The toxic effect of lithium may appear at a concentration that is usually considered therapeutic, especially in elderly patients. The first signs of intoxication - ataxia, sweeping tremor, dysarthria. The increased concentration of lithium can have more serious consequences: a change or suppression of consciousness up to the development of coma, fasciculation, myoclonia; possible and fatal outcome. The risk factors for intoxication, which contribute to an increase in serum lithium concentration, include a large dose, a decrease in clearance (with kidney damage, interaction with other drugs, a hypo-salt diet), a decrease in the volume of distribution (dehydration). Factors that increase the susceptibility of the body to the toxic effects of lithium include old age, somatic or neurological diseases. With a mild toxic effect, treatment consists in removing the drug and providing sufficient hydration. In more severe cases, forced diuresis is used to exclude lithium, and hemodialysis if life threatens. If a lithium overdose is suspected, it should be determined at least two times in the plasma with an interval of at least 4 hours, the second measurement should be lower than the first one. However, when taking a cholinolytic drug due to inhibition of the motility of the gastrointestinal tract, lithium absorption may slow down, so the concentration reaches a peak with some delay.

It was considered that the reception of lithium during pregnancy dramatically increases the risk of developing fetal abnormalities Ebstein. But, as recent studies have shown, this risk was lower than previously thought. Before prescribing any psychotropic drug during pregnancy, you should carefully weigh the possible benefits and risks. It should be noted that lithium during pregnancy is apparently safer for the fetus than carbamazepine or valproic acid. In pregnancy, the dose of lithium is usually increased due to an increase in the volume of distribution. Since labor is accompanied by significant fluctuations in the volume of liquid media, appropriate dose adjustment is necessary. Many doctors prescribe prophylactic lithium treatment to pregnant patients with bipolar disorder shortly before the planned delivery, since the risk of recurrence is high in the postpartum period.

Valproic acid

In the treatment of bipolar affective disorder, a number of antiepileptic drugs have proved effective, including valproic acid (depakot), carbamazepine (tegretol), lamotrigine (lamictal), gabapentin (neurontin), clonazepam. Valproic acid has now been approved by the FDA for use as a remedy for the management of acute mania in bipolar disorder. Before Meunier discovered its anti-epileptic properties, valproic acid was used as a solvent for medicines. Three years later, in 1966, Lambert first reported its effectiveness in bipolar disorder. For the treatment of bipolar affective disorder in the United States, divalproex sodium (depakot) is most often used, which contains valproate sodium valvalic acid in a 1: 1 ratio. The drug is enclosed in a shell dissolving in the intestine. Valproic acid is also expressed in its pure form (depakin), but this drug more often causes side effects from the gastrointestinal tract than the divalproex sodium.

Valproic acid is almost completely absorbed when taken orally. The maximum concentration is achieved 1-4 h after administration of valproic acid and approximately 3-4 hours after taking divalproex sodium. When using divalproex sodium capsules with small particles encapsulated ("drops" - sprinkles), the concentration reaches a peak about 1.5 hours later. Food intake also delays the absorption of valproic acid. At a serum concentration of 40 μg / ml, 90% of valproic acid binds to plasma proteins, whereas at 82 μg / ml with plasma proteins only 82% of the substance is bound. The binding of valproic acid with proteins is reduced in people with chronic liver, kidney and elderly diseases. Some drugs (eg, aspirin) can displace valproic acid from binding to proteins. Since the drug is mainly metabolized in the liver, with its lesions, the elimination of valproic acid is limited, which requires a dose reduction. The half-elimination period of valproic acid ranges from 6 to 16 hours. The therapeutic effect of valproic acid was associated with various mechanisms, including the enhancement of GABA-ergic transmission, changes in the ion current in the sodium or potassium channels of neuronal membranes, a decrease in the dopamine circulation, and a decrease in the ion current through channels associated with glutamate NMDA receptors.

In controlled studies, it has been shown that in acute mania, valproic acid is superior to placebo in efficacy and not inferior to lithium preparations. In a 3-week, double-blind, placebo-controlled study, the efficacy of valproic acid was shown in patients with acute mania who either did not respond to lithium treatment or did not tolerate it well. Similar results were obtained in another double-blind, placebo-controlled study in which the efficacy of valproic acid and lithium was compared. In this study, hospitalized patients with manic disorder (according to the Research Diagnostic Criteria) were assigned a placebo, valproic acid (initial dose 250 mg, then increased to 2500 mg / day) or lithium carbonate. On the 7th, 14th and 21st days of the study, the average dose of valproic acid was 1116, 1683 and 2006 mg / day, respectively, lithium adenoside - 1312, 1869, 1984 mg / day. The results showed that valproic acid was superior to placebo and was consistent with lithium.

To achieve a more rapid effect in acute mania, treatment can begin with a shock (saturating) dose of 20 mg / kg. In a small open study, it was noted that this technique led to a significant improvement in 53% of patients with good tolerability. Using this technique, the effect occurs as quickly as with the appointment of haloperidol. A quick response makes it possible to use the same drug both for acute treatment and for prevention.

Prospective placebo-controlled studies of the efficacy of valproic acid in the prophylactic treatment of bipolar affective disorder have not yet been conducted. The results of open studies indicate that valproate is effective in long-term treatment and reduces the number and intensity of affective episodes. In a prospectively screened study in which 101 patients with bipolar affective disorder type I or II who had short cycles were included, valproic acid was found to be effective in 87% of cases, both in the treatment of acute manic and mixed conditions, and in prophylactic therapy. Like many other normotimic agents, valproic acid more effectively prevents manic and mixed episodes than depressive episodes. Based on the results of four open trials, only 58 of 195 (30%) patients with a depressive episode had a significant improvement in the treatment with valproic acid.

Valproic acid has advantages over lithium in the treatment of patients with short cycles, mixed or dysphoric mania, secondary mania. It remains unclear whether there are differences in efficacy between valproic acid and lithium in the treatment of patients with "pure" mania, as well as having long cycles.

As a rule, valproic acid is well tolerated. Of the side effects most often occur disorders of the gastrointestinal tract, a slight increase in the level of hepatic transaminases, neurological disorders, such as tremor or sedation. Disturbance of the gastrointestinal tract can be manifested by nausea, vomiting, dyspepsia, anorexia, diarrhea. Usually, these side effects are more pronounced at the beginning of treatment and decrease with time. Side effects from the gastrointestinal tract can be reduced with the use of special capsules of divalproex sodium, and also with the appointment of short-term blockers of histamine H2-receptors or cisapride (propulside). The majority of doctors do not take any other measures 2-3 times higher than the norm with the increase of the level of transaminases, except for the reduction of the dose, and even then only if it is clinically justified. On the background of treatment with valproic acid, transient thrombocytopenia is sometimes observed, which can lead to an increase in bleeding time and the appearance of petechiae and bruising. In patients, it is also possible to increase appetite and increase body weight. It has also been reported about the development of hepatic failure with valproic acid, but the risk of this complication is mainly affected by children under 2 years of age who suffer from epilepsy. The use of valproic acid in the first trimester of pregnancy causes neural tube defects in 1-1.5% of cases. In addition, children, whose mothers were taking valproic acid during pregnancy, also have congenital heart defects. However, most of this information was obtained mainly in the study of women with epilepsy, and this group is characterized by a higher incidence of congenital malformations than the average for the population.

Perhaps the interaction of valproic acid with drugs that bind intensely to plasma proteins. In addition, valproic acid is able to interact with drugs that affect blood clotting. Unlike many other anticonvulsants, valproate is not an inducer of microsomal liver enzymes, although it can inhibit the metabolism of other drugs.

Valproic acid is available in various forms and dosages. One capsule of divalproex sodium, consisting of fine particles in the membrane (depakot sprinkles), contains 125 mg of active ingredient, delayed release divalprox sodium capsules (Depakot) 125, 250 and 500 mg. Valproic acid (depakin) is available in capsules of 250 mg or as a solution (250 mg / 5 ml).

Before appointing valproic acid, a check should be performed, including liver tests and a clinical blood test (with the determination of the number of platelets). Women with a safe reproductive function should undergo a pregnancy test, since valproate has a teratogenic effect. Treatment usually begins with a dose of 500-1000 mg / day, which is divided into several doses, but sometimes a shock dose of 20 mg / kg is prescribed. During the titration period, the concentration of the drug in the serum should be measured regularly (for example, at intervals of 12 hours). The minimum therapeutic concentration in plasma is usually about 50 μg / ml, the therapeutic range is from 50 to 120 μg / ml. When treated with valproic acid, it is recommended to take multivitamins with zinc and selenium to prevent hair loss, which can be caused by the action of the drug. At the beginning of treatment, it is necessary to conduct a regular blood test (1 time in 1-2 weeks), including a study of platelets, as well as liver tests. With prolonged therapy, after the patient's condition has stabilized, these indicators can be evaluated at an interval of about 6 months. Against the background of treatment, a temporary increase in the level of transaminases is possible, but it is usually not clinically significant. When the drug is abolished, the indicators return to normal. However, the level of transaminases should be regularly examined until the indicators stabilize. The same applies to hematological indicators. The patient should be warned that he should immediately inform the doctor about the appearance of bleeding.

Carbamazepine

Carbamazepine (tegretol, finlepsin) has been used in Europe since the 60s for the treatment of epilepsy and paroxysmal pain syndromes, primarily trigeminal neuralgia. Its effectiveness in the BIPAR first became known in 1971. In 1974, carbamazepine was allowed in the US for the treatment of epilepsy, and later for the treatment of trigeminal neuralgia. To date, the use of carbamazepine for the treatment of bipolar disorder has not been approved by the FDA, although this drug is often used for this purpose.

According to its chemical structure, carbamazepine belongs to the family of iminostilbenes and resembles tricyclic antidepressants in structure. Numerous studies have demonstrated its effectiveness in generalized convulsive and psychomotor epileptic seizures. The anticonvulsant properties of carbamazepine appear to be related to its ability to reduce the polysynagic response and block post-tetanic potentiation. The mechanism of action of carbamazepine in BAPAR remains unclear, although the antimanic effect of the drug has been attempted to explain its effect on sodium channels, the functioning of systems that are associated with acetylcholine, adenosine, aspartate, dopamine, GABA, glutamate, noradrenaline, serotonin, R. Carbamazepine also acts on the system "Second mediator", reducing the activity of adenylate cyclase and guanylate cyclase, as well as the phosphoinositol system.

Absorption of carbamazepine after ingestion is very variable, on average its bioavailability is 75-85%. When taking the drug in the form of a suspension, its concentration in the plasma reaches a peak after 1.5 hours, standard tablets in 4-5 hours, and when taking a slow-release form, from 3 to 12 hours.

About 75% of the absorbed drug binds to plasma proteins. The concentration of carbamazepine in the cerebrospinal fluid is approximately equal to the concentration in the plasma of the free preparation. The metabolism of carbamazepine is mainly carried out in the liver by the cytochrome P450 system. The primary metabolite - 10,11-epoxide is formed with the participation of the CYP3A4 isoenzyme. It has about the same activity as the primary drug, and its concentration is approximately 50% of the concentration of carbamazepine. With the simultaneous administration of valproic acid and carbamazepine, the accumulation of 10,11-epoxide takes place. Like many anticonvulsants, carbamazepine is the inducer of microsomal liver enzymes. Induction of the CYP3A4 isoenzyme may lead to a number of clinically significant drug interactions. Because carbamazepine accelerates its own metabolism, after 3-5 weeks of treatment, its half-elimination period decreases from 25-65 hours to 12-17 hours. This makes it necessary to gradually increase its dose in order to maintain the therapeutic concentration of the drug in the blood achieved at the beginning of treatment. The intensity of carbamazepine metabolism quickly returns to normal if you stop taking the drug. After 7 days of medical "vacation" autoinduction is reduced by more than 65%. Thus, if the patient independently stopped taking the drug, then with the resumption of treatment, he should be assigned a lower dose than that which he took before the drug was discontinued. And in the subsequent it is necessary to gradually increase the dose as the development of autoinduction.

The effectiveness of carbamazepine in bipolar disorder has been demonstrated in a number of studies conducted in small groups of patients, where it was compared with the efficacy of placebo, lithium drugs and antipsychotics. According to these studies, monotherapy with carbamazepine was effective in acute mania in 50% of cases, while lithium was effective in 56% of cases, and antipsychotics - in 61% of cases. However, the differences in the efficacy of the drugs were not statistically significant. The effect of carbamazepine appears as quickly as in neuroleptic, but somewhat faster than lithium. Like other normotimic drugs, carbamazepine is less effective in depression, only 30-35% of patients have an improvement. Carbamazepine is particularly effective in the treatment of BPAR with short cycles. The presence of short cycles, mixed or dysphoric mania make it possible to predict a good reaction to carbamazepine. The lack of improvement when taking another anticonvulsant does not mean that carbamazepine will be ineffective.

The most frequent side effects of carbamazepine, due to its effect on the central nervous system, include dizziness, drowsiness, coordination disorder, confusion, headache, fatigue. With a gradual increase in the dose, their probability is minimized. The toxic effect of carbamazepine can be manifested by ataxia, dizziness, dizziness, drowsiness. With a high serum carbamazepine concentration, nystagmus, ophthalmoplegia, cerebellar symptoms, impaired consciousness, convulsions, and respiratory failure may appear. Nausea, vomiting and gastrointestinal upsets occur, but more often - at the very beginning of treatment. In some patients, the number of white blood cells decreases, but it usually does not fall below 4000. And sometimes there is thrombocytopenia. The expressed oppression of hematopoiesis has the character of idiosyncrasy and occurs in 1 out of 10,000-125,000 patients. Carbamazepine can cause a rash - in this situation, many doctors cancel the drug. In the treatment of carbamazepine, hyponatremia sometimes occurs, which is associated with its antidiuretic effect. The frequency of hyponatremia is from 6 to 31%, in the elderly the risk of its development is higher.

Carbamazepine has a teratogenic effect and when used in the first trimester of pregnancy increases the risk of neural tube defects, hypoplasia of the nail plates, facial skull defects and developmental delay.

Carbamazepine interacts with a number of other drugs, which is due to its ability to induce cytochrome P450 (CYP3F4). Particular attention should be paid to the fact that carbamazepine can reduce the effectiveness of oral contraceptives.

Before prescribing carbamazepine, the patient should be examined, including a clinical blood test (with the determination of the number of platelets) and assess the liver function. Women with a reproductive function need a pregnancy test. Treatment usually begins with a dose of 200-400 mg / sug, given in 2-3 doses. But sometimes the treatment starts with a shock (saturating) dose of 20 mg / kg. During the titration period, the serum concentration of the drug should be measured every 12 hours. The therapeutic concentration in plasma is usually from 4 to 12 μg / ml (however, these values are the result of extrapolation of data obtained from patients with epilepsy). The therapeutic dose of carbamazepine usually ranges from 1000 to 2000 mg / day. Since there is no clear correspondence between the response to the treatment and the concentration of the drug in the serum, the dose should be selected, being guided by the effect obtained, and not on the planned serum concentration of the drug. Due to autoinduction of metabolism after 3-5 weeks, an increase in dose may be required (sometimes twice). Carbamazepine is available in the form of 100 mg tablets, 200 mg standard tablets and 100, 200 and 400 mg sustained release tablets, and in the form of a 100 mg / 5 ml suspension.

[4], [5], [6], [7], [8], [9]

Other drugs for the treatment of bipolar affective disorder

Clozapine (clozaril, leponex, azaleptin) and olanzapine (ziprexa) are atypical antipsychotics, which are reported to be effective in acute mania. However, the need to weekly determine the number of leukocytes in the blood (due to the threat of agranulocytosis), as well as possible side effects limit the use of clozapine, and it is prescribed only in treatment-resistant cases of BPAR. Unlike clozapine, olanzapine does not require a weekly blood test and has a more favorable profile of side effects. Currently, placebo-controlled studies assess the effectiveness of monotherapy with olanzapine in acute mania. The therapeutic dose of olanzapine in acute mania is usually 10-20 mg - the entire dose can be taken once before bedtime.

Lamotrigine (lamicatal) and gabapentin (neurontin) are two new anticonvulsants of the new generation, which may be effective in mania, although relevant controlled studies have not yet been carried out. Treatment with these drugs does not require monitoring of their serum concentration. Gabapentin has been used to treat epilepsy since 1993. Despite the fact that in structure it is similar to y-aminobutyric acid, the mechanism of its action is not completely clear. The bioavailability of gabapentin is about 60%, although it decreases with higher doses. Only a small part of the drug binds to plasma proteins (<3%). The half-elimination period is 5-7 hours. Gabapentin is excreted unchanged in urine. The most frequent side effects of gabapentin are drowsiness, dizziness, instability, nystagmus, tremor, double vision. The initial dose of gabapentin is 300 mg / day, then it is increased by 300 mg every 3-5 days. The therapeutic dose in the treatment of BPAR is usually 900-3200 mg / day. Gabapentin, apparently, does not interact with valproic acid or carbamazepine.

Ulamotrigine, used to treat epilepsy since 1994, also found normotimic activity. Like gabapentin, lamotrigine has a favorable spectrum of side effects, but at the moment, data on its effectiveness in bipolar affective disorder is not enough. Lamotrigine acts by inhibiting potential-dependent sodium channels. In addition, it is a weak antagonist of 5-HT3-receptors. The bioavailability of lamotrigine is 98% and does not depend on food intake. Serum concentration reaches a maximum 1.4-4.8 hours after ingestion. The most common side effects of lamotrigine are dizziness, headache, double vision, instability, nausea. Vomiting, disruption of accommodation, drowsiness, and rash are also possible. The appearance of a rash requires special attention, as it may be a harbinger of the development of Stevens-Johnson syndrome and, more rarely, toxic epidermal necrolysis with possible fatal outcome.

Lamotrigine can interact with valproic acid and carbamazepine. In motor therapy, the initial dose of lamotrigine is 25-50 mg / day, then it is increased by 25-50 mg every 1-2 weeks. The therapeutic dose, which is determined by the clinical effect, ranges from 100 to 400 mg / day. Doses exceeding 50 mg / day are prescribed in several doses. When combined with valproic acid, the initial dose of lamotrigine should be lower - 12.5 mg / day, and then gradually increase it. Since valproic acid slows the metabolism of lamotrigine, a rapid increase in lamotrigine dose in this case often causes a rash. But with the simultaneous administration of carbamazepine, which accelerates the metabolism of lamotrigine, the dose of the latter, on the contrary, should be increased more rapidly.

In the treatment of bipolar affective disorder, calcium antagonists are also used, although their role is not fully understood. The greatest experience is accumulated with the use of verapamil. Nimodipine may be useful in patients with ultrashort cycles.

Clonazepam (antelepsin) is a high-potential benzodiazepine that is used in acute mania and as a monotherapy, and as an adjuvant (at the beginning of treatment). In controlled studies, the efficacy of clonazepam was higher than that of placebo and lithium, comparable to that of haloperidol, but inferior to lorazepam. However, the total number of patients included in these studies was extremely small. Having a wide arsenal of normotimic drugs, clinicians today more often use benzodiazepines to enhance the effect of other antimanic drugs than as monotherapy.

Depression in bipolar disorder

The treatment of depression in bipolar affective disorder is not as well understood as the treatment of mania, despite the fact that depressive and mixed episodes often lead to severe maladaptation of the patient. In addition, the effectiveness of treatment of depression in bipolar affective disorder is difficult to estimate because of frequent spontaneous remissions, frequent transition to mania, and simultaneous administration of several drugs, which is now more likely a rule than an exception. The approach to treatment of depression in a patient with BPAR depends on its severity and the therapy received by the time the depressive phase develops. First of all, you should resume taking a normotimic drug or increase its dose up to the upper limit of the therapeutic range (with good tolerability).

If the depressive episode develops against the background of lithium intake, you need to measure the plasma level of the drug, as well as examine the function of the thyroid gland to exclude hypothyroidism, which can cause lithium. The appointment of lithium as an antidepressant in bipolar affective disorder is successful in about 30% of cases - approximately the same percentage of patients are caused by the improvement of valproic acid and carbamazepine. Effective in the depressive phase of BPAR and antidepressants. In double-blind, placebo-controlled trials, antidepressants caused an improvement in 48-86% of patients. Effectively reduced manifestations of depression in patients with BPAR imipramine, desipramine, moclobemide, bupropion, tranylcypromine, fluoxetine.

However, the use of antidepressants in BPAR hinders the possibility of inducing mania. A retrospective review of the results of clinical trials showed that the transition from depressive to manic phase occurs in 3.7% of patients taking sertraline or paroxetine in 4.2% of patients taking placebo and 11.2% of patients taking TCAs. In the registration studies of SSRIs in the treatment of major depression, obsessive-compulsive disorder and panic disorder, induction of mania was noted in 1% of cases.

In some patients, antidepressants help to shorten cycles of bipolar affective disorder. Wihr (1988) evaluated the effect of antidepressants in 51 patients with short cycles and 19 patients with long cycles, the overwhelming majority of whom were women. In 73% of patients with short cycles, the first episode of hypomania or mania occurred against the background of antidepressant medication, while in patients with long cycles this relationship was observed only in 26% of cases. Approximately half (51%) of patients with short cycles on the background of treatment with antidepressants change the cycles, and after their withdrawal - slows down. TCAs often provoke a transition to mania and are less effective than SSRIs or MAO inhibitors. A recent controlled double-blind study demonstrated the efficacy of paroxetine, administered at a suboptimal lithium level, in depression in patients with BPAR. At the same time, in patients with an optimal level of lithium in plasma, the addition of parcosine did not lead to an increase in the antidepressant effect.

Thus, the use of antidepressants for the treatment of depression in bipolar affective disorder is associated with a risk of developing mania or hypomania, as well as the possible acceleration of cycle changes. In this regard, primarily in the development of depression, with bipolar affective disorder, it is necessary to optimize therapy with normotimic agents, as well as evaluate the function of the thyroid gland. If these measures are not successful, then you can use antidepressants or ECT. SSRIs and bupropion rarely cause mania or hypomania than MAO and TCA inhibitors. The maintenance of special maps showing the dynamics of cycles and the effectiveness of treatment measures allows more effective treatment of this disease that accompanies the majority of patients throughout their remaining life.

[10], [11], [12]

Algorithms for the treatment of acute mania

The effectiveness of acute mania treatment depends on the correctness of the diagnosis of bipolar affective disorder (which is especially difficult in the III stage of mania), the features of the dynamics of cycles (short or long cycles), such as mania (classical or mixed). The correct choice of treatment requires consideration of all these factors.

Successful treatment significantly improves the quality of life of a patient with major depression or bipolar affective disorder. In this chapter, the focus has been on the medicinal methods of treating these conditions, but for most patients the combination of pharmacotherapy and psychotherapy is optimal. For example, psychotherapy can be aimed at normalizing the relationship of patients with others and creating a mood for him to clearly fulfill the doctor's appointments.

Although currently doctors have a large number of effective tools for the treatment of affective disorders, the psychopharmacological method of treatment has appeared in their arsenal relatively recently. For millennia, sympathy for the patient, communication with him, caring was the main tool in the hands of the doctor. And today, despite the fact that pharmacotherapy can save a life for a patient with an affective disorder, this is only one of the components of the overall system of treatment.

[13], [14], [15]