Bipolar Affective Disorder - Treatment

Treatment of bipolar disorder is mainly carried out with mood stabilizers, such as lithium, carbamazepine or valproic acid.

But sometimes they resort to relatively new drugs: olanzapine, risperidone, lamotrigine, gabapentin, calcium antagonists. Several periods are distinguished in the treatment: the period of "acute" stabilization, which involves stopping the manic episode, sometimes with the help of several drugs; the period of stabilization and the period of long-term preventive therapy in order to prevent new episodes.

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Lithium preparations

Lithium has a long history of medical use, and has been tried with varying degrees of success for a wide variety of conditions. In the early 1900s, lithium was often included in popular over-the-counter “cure-all” medications. Lithium-containing preparations were recommended for conditions ranging from the common malaise to all manner of “nervous system dysfunctions.” 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 he called “psychotic agitation.” This discovery could have revolutionized the treatment of bipolar disorder, which at the time had virtually no treatment. However, it was not until 1970 that the FDA approved lithium for use in the treatment of acute mania. Numerous double-blind, placebo-controlled studies have shown that lithium is effective in 70-80% of patients with acute mania. However, in recent studies, lithium has been shown to be less effective, which may be explained by a higher proportion of patients who are resistant to therapy or have mixed mania, in which lithium monotherapy is less successful. Nevertheless, lithium remains the most studied drug from the group of normothymic agents.

Lithium is used in bipolar affective disorder and as a preventive measure. As shown by placebo-controlled studies, with long-term therapy with lithium preparations, the number and intensity of affective episodes decreased in approximately 70% of patients. Approximately 50% of patients who abruptly stop taking lithium for preventive purposes experience a relapse within 5 months. With a more gradual withdrawal of lithium, the relapse rate decreases from 94% (over a 5-year period) to 53%.

Some individual characteristics of patients allow us to predict the effect of lithium. For example, in classical ("pure") mania, the effectiveness of lithium is significantly higher than in mixed or dysphoric mania. On the other hand, lithium is less effective in the presence of short (rapid) cycles. Lithium preparations cause improvement in 60% of patients with bipolar affective disorder who do not have short cycles, and only in 18-25% of patients with such cycles. Concomitant abuse of psychotropic substances predicts low effectiveness of lithium, but if the drugs have been unsuccessful in the past, this does not mean that a new attempt to use them 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 disorder. The therapeutic concentration of lithium in plasma is usually 0.6-1.2 mEq/L, although younger patients sometimes require higher concentrations, and older patients - lower ones. The most common side effects of lithium include thirst, polyuria, memory loss, tremor, weight gain, drowsiness, fatigue, and diarrhea. The following side effects are most often the reason for stopping the drug (in descending order of frequency): memory loss, weight gain, tremor and loss of coordination, polyuria, drowsiness, and fatigue. Tremor caused by lithium may be aggravated by caffeine, which should be brought to the patient's attention. Tremor is usually well relieved by beta-blockers. Lithium can cause gastrointestinal side effects (such as nausea or loose stools) and can exacerbate psoriasis or acne. In addition, lithium often causes benign granulocytosis. Thyroid function may be impaired during lithium treatment, with clinically evident hypothyroidism developing in 5% of cases and elevated TSH levels in 30%. Increased antithyroid autoantibody titers are observed in 15-30% of patients. Hyperparathyroidism may also develop during lithium treatment, but much less frequently than hypothyroidism.

Lithium reduces water reabsorption in the distal tubules and collecting ducts, which leads to impairment of the renal concentrating function and the development of polyuria. This, in turn, causes polydipsia and (if patients drink sugar-containing carbonated drinks or juices) weight gain. However, there is no convincing evidence that lithium in therapeutic doses causes irreversible renal dysfunction.

The effect of lithium on the heart results in flattening and inversion of the T wave, bradycardia, and prolongation of the repolarization period of the sinus node. Since there are currently other normothymic 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 preparations or use them with extreme caution.

In addition to standard lithium preparations (e.g., escalite, litonate, lithotabs), controlled-release (e.g., escalite CR) or slow-release (lithobid) dosage forms are currently produced. These preparations contain lithium carbonate. However, lithium citrate is also produced in the form of a syrup (cibalite S). In this case, 300 mg of lithium carbonate or 5 ml of lithium citrate contain 8 mEq of lithium. Lithium is completely absorbed when taken orally, its maximum concentration in plasma is achieved after 1-1.5 hours (when using the standard preparation) or after 4-4.5 hours (when using controlled-release and slow-release forms). Lithium is excreted mainly by the kidneys. The half-elimination period is 18-24 hours.

Nonsteroidal anti-inflammatory drugs may increase plasma lithium concentrations, with the exception of aspirin and sulindac. Diuretics and angiotensin-converting enzyme inhibitors may also increase serum lithium concentrations by increasing renal sodium excretion and thereby decreasing lithium excretion.

Use of lithium preparations in acute mania

Lithium is still widely used to treat mania, but because its effect takes 5 to 10 days to become effective, additional therapy is often needed. An ECG, renal function tests, and thyroid function tests are necessary before lithium is prescribed. Women of normal reproductive function should also have a pregnancy test, as lithium is teratogenic. Lithium therapy is usually initiated at a dose of 600 to 1,200 mg/day, divided into several doses. Therapeutic plasma lithium levels (0.8 to 1.2 mEq/L) are achieved in most patients at a dose of 1,200 to 1,800 mg/day. Lithium levels are measured every 4 to 5 days during titration. Various methods have been developed for determining the dose of lithium needed to achieve therapeutic serum levels. According to one of them, the serum lithium concentration is measured 24 hours after the start of therapy, according to another - after 12, 24 and 36 hours. According to the third, it is necessary to take two blood samples, a urine sample 4 hours after the start of therapy and estimate creatinine clearance. Despite the variety of methods, many clinicians still select the dose empirically, taking into account the therapeutic and side effects. The concentration of the drug in the serum is usually estimated 12 hours after the last dose. If the patient's condition remains stable against the background of long-term lithium therapy, then the lithium concentration, as well as the functions of the kidneys and thyroid gland, are usually checked once every 6-12 months. 1 tablet of escalite, lithonate, lithotabs and lithobide contains 300 mg of the drug, one tablet of escalite CR - 450 mg; 5 ml of the liquid drug cibalit-S are equivalent to 300 mg of lithium carbonate.

The toxic effect of lithium can occur at concentrations that are usually considered therapeutic, especially in elderly patients. The first signs of intoxication are ataxia, sweeping tremor, and dysarthria. Increased lithium concentrations can cause more serious consequences: changes in or depression of consciousness, including coma, fasciculation, myoclonus; death is also possible. Risk factors for intoxication that contribute to an increase in serum lithium concentration include taking a large dose, decreased clearance (with kidney damage, interaction with other drugs, low-salt diet), and a decrease in the volume of distribution (dehydration). Factors that increase the body's susceptibility to the toxic effect of lithium include old age, somatic or neurological diseases. In case of mild toxic effects, treatment consists of discontinuing the drug and ensuring sufficient hydration. In more severe cases, forced diuresis is used to remove lithium, and in life-threatening cases, hemodialysis. If lithium overdose is suspected, its plasma level should be determined at least twice at intervals of at least 4 hours, and the second measurement should be lower than the first. However, when taking an anticholinergic drug, due to inhibition of gastrointestinal motility, lithium absorption may be slowed, so the concentration reaches its peak with some delay.

It was previously believed that taking lithium during pregnancy greatly increased the risk of developing Ebstein's anomaly in the fetus. However, recent studies have shown that this risk is lower than previously thought. Before prescribing any psychotropic drug during pregnancy, the possible benefits and risks should be carefully weighed. It should be noted that lithium during pregnancy appears to be safer for the fetus than carbamazepine or valproic acid. The dose of lithium is usually increased during pregnancy due to the increased volume of distribution. Since labor is accompanied by significant fluctuations in fluid volumes, appropriate dose adjustments are necessary. Many physicians prescribe prophylactic lithium treatment to pregnant patients with bipolar disorder shortly before the planned delivery, since the risk of relapse is high in the postpartum period.

Valproic acid

A number of antiepileptic drugs have proven effective in the treatment of bipolar disorder, including valproic acid (Depakote), carbamazepine (Tegretol), lamotrigine (Lamictal), gabapentin (Neurontin), and clonazepam. Valproic acid is currently FDA-approved for use in the treatment of acute mania in bipolar disorder. Before Meunier discovered its antiepileptic properties, valproic acid was used as a solvent for drugs. Three years later, in 1966, Lambert first reported its effectiveness in bipolar disorder. The most commonly used drug in the United States for the treatment of bipolar disorder is divalproex sodium (Depakote), which contains sodium valproate and valproic acid in a 1:1 ratio. The drug is enclosed in an enteric coating. Valproic acid is also available in pure form (depakine), but this drug more often causes side effects from the gastrointestinal tract than divalproex sodium.

Valproic acid is almost completely absorbed after oral administration. Peak concentrations are reached 1-4 hours after taking valproic acid and about 3-4 hours after taking divalproex sodium. When using divalproex sodium capsules with small particles enclosed in a shell ("sprinkles"), the concentration reaches its 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 is bound to plasma proteins, while at a concentration of 130 μg / ml, only 82% of the substance is bound to plasma proteins. Binding of valproic acid to proteins is reduced in people with chronic liver disease, kidney disease and in the elderly. Some drugs (eg, aspirin) can displace valproic acid from protein binding. Since the drug is primarily metabolized in the liver, in liver damage, the elimination of valproic acid is limited, which requires a reduction in dosage. The half-life of valproic acid ranges from 6 to 16 hours. The therapeutic effect of valproic acid has been associated with various mechanisms, including increased GABAergic transmission, changes in ionic current in sodium or potassium channels of neuronal membranes, decreased dopamine circulation, and decreased ionic current through channels associated with glutamate NMDA receptors.

Controlled studies have shown that valproic acid is superior to placebo and non-inferior to lithium in acute mania. A 3-week, double-blind, placebo-controlled study demonstrated the efficacy of valproic acid in patients with acute mania who either did not respond to lithium or tolerated it poorly. Similar results were obtained in another double-blind, placebo-controlled study comparing the efficacy of valproic acid and lithium. In this study, hospitalized patients with manic disorder (according to the Research Diagnostic Criteria) were prescribed placebo, valproic acid (initial dose 250 mg, then it was increased to 2500 mg/day) or lithium carbonate. On days 7, 14 and 21 of the study, the average dose of valproic acid was 1116, 1683 and 2006 mg/day, respectively, and the lithium dose was 1312, 1869 and 1984 mg/day. The results showed that valproic acid was superior to placebo and equal to lithium in terms of efficacy.

To achieve a more rapid effect in acute mania, treatment can be started with a loading (saturation) dose of 20 mg/kg. A small open study noted that this technique led to significant improvement in 53% of patients with good tolerability. With this technique, the effect occurs as quickly as with haloperidol. The rapid response makes it possible to use the same drug for both acute treatment and prophylaxis.

Prospective placebo-controlled studies of the efficacy of valproic acid in the prophylactic treatment of bipolar disorder have not yet been conducted. Results of open studies indicate that valproate is effective in long-term treatment and reduces the number and intensity of affective episodes. In a prospective open study that included 101 patients with bipolar disorder types I or II who had short cycles, valproic acid was effective in 87% of cases, both in the treatment of acute manic and mixed states and in prophylactic therapy. Like many other normothymic agents, valproic acid is more effective in preventing manic and mixed episodes than depressive episodes. According to the results of four open studies, only 58 of 195 (30%) patients with a depressive episode experienced significant improvement during therapy with valproic acid.

Valproic acid has advantages over lithium in the treatment of patients with short cycles, mixed or dysphoric mania, and secondary mania. It remains unclear whether there is a difference in efficacy between valproic acid and lithium in the treatment of patients with "pure" mania and those with long cycles.

Valproic acid is generally well tolerated. The most common side effects are gastrointestinal disorders, a slight increase in liver transaminase levels, and neurological disorders such as tremor or sedation. Gastrointestinal disorders may include nausea, vomiting, dyspepsia, anorexia, and diarrhea. These side effects are usually more pronounced at the beginning of treatment and decrease over time. Gastrointestinal side effects can be reduced by using special divalproex sodium capsules, as well as by prescribing short-term histamine H2 receptor blockers or cisapride (propulsid). Most doctors do not take any other measures when transaminase levels increase 2-3 times above normal, except for reducing the dose, and only if clinically justified. Transient thrombocytopenia, which may result in increased bleeding time and the development of petechiae and bruising, is sometimes observed with valproic acid. Patients may also experience increased appetite and weight gain. Liver failure has also been reported with valproic acid, but this complication is mainly seen in children under 2 years of age with epilepsy. Use of valproic acid in the first trimester of pregnancy causes neural tube defects in 1-1.5% of cases. Congenital heart defects have also been reported in children whose mothers took valproic acid during pregnancy. However, most of these reports have been obtained mainly from studies of women with epilepsy, and this group has a higher incidence of congenital defects than the general population.

Interaction of valproic acid with drugs that intensively bind to plasma proteins is possible. In addition, valproic acid can interact with drugs that affect blood clotting. Unlike many other anticonvulsants, valproate is not an inducer of liver microsomal 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 small particles in a shell (depakote-sprinkles), contains 125 mg of the active substance, capsules of divalproex sodium with a delayed release (depakote) - 125, 250 and 500 mg. Valproic acid (depakine) is available in capsules of 250 mg or as a solution (250 mg / 5 ml).

Before prescribing valproic acid, an examination should be performed, including liver function tests and a complete blood count (including platelet count). Women with intact 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 loading (saturating) dose of 20 mg / kg is prescribed. During the titration of the dose, the concentration of the drug in the serum should be measured regularly (for example, at 12-hour intervals). The minimum therapeutic concentration in plasma is usually about 50 mcg / ml, the therapeutic range is from 50 to 120 mcg / ml. When treating with valproic acid, it is recommended to take multivitamins with zinc and selenium to prevent hair loss, which can be caused by the drug. At the beginning of treatment, it is necessary to regularly (once every 1-2 weeks) conduct a clinical blood test (including a platelet test), as well as liver tests. During long-term therapy, after the patient's condition has stabilized, these indicators can be assessed at intervals of about 6 months. During treatment, a temporary increase in transaminase levels is possible, but it is usually not clinically significant. When the drug is discontinued, the indicators return to normal. However, the transaminase level should be regularly tested until the indicators stabilize. The same applies to hematological indicators. The patient should be warned that he must immediately inform the doctor about the occurrence of bleeding.

Carbamazepine

Carbamazepine (Tegretol, Finlepsin) has been used in Europe since the 1960s to treat epilepsy and paroxysmal pain syndromes, primarily trigeminal neuralgia. Its effectiveness in BPAR was first reported in 1971. In 1974, carbamazepine was approved in the United States 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 received FDA approval, although this drug is often used for this purpose.

Chemically, carbamazepine belongs to the iminostilbene family and is structurally similar to tricyclic antidepressants. Numerous studies have proven its efficacy in generalized convulsive and psychomotor epileptic seizures. The anticonvulsant properties of carbamazepine are apparently associated with its ability to reduce the polysynaptic response and block post-tetanic potentiation. The mechanism of action of carbamazepine in BPAR remains unclear, although attempts have been made to explain the antimanic effect of the drug by its effect on sodium channels, the functioning of systems associated with acetylcholine, adenosine, aspartate, dopamine, GABA, glutamate, norepinephrine, serotonin, substance P. Carbamazepine also acts on the "second messenger" system, reducing the activity of adenylate cyclase and guanylate cyclase, as well as the phosphoinositol system.

The absorption of carbamazepine after oral administration is highly variable, with an average bioavailability of 75-85%. When the drug is taken in suspension form, its plasma concentration reaches a peak after 1.5 hours, standard tablets - after 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 of the free drug in plasma. Carbamazepine is metabolized primarily 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 approximately the same activity as the primary drug, and its concentration is approximately 50% of the carbamazepine concentration. With the simultaneous administration of valproic acid and carbamazepine, 10,11-epoxide accumulates. Like many anticonvulsants, carbamazepine is an inducer of liver microsomal enzymes. Induction of the CYP3A4 isoenzyme can 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 the drug is stopped. After a 7-day drug "vacation", autoinduction decreases by more than 65%. Thus, if the patient independently stopped taking the drug, then when resuming treatment, he should be prescribed a lower dose than the one he took before the drug was discontinued. And then a gradual increase in the dose is necessary as autoinduction develops.

The efficacy of carbamazepine in bipolar disorder has been proven in a number of studies conducted on small groups of patients, where it was compared with the efficacy of placebo, lithium preparations and neuroleptics. According to these studies, carbamazepine monotherapy was effective in acute mania in 50% of cases, while lithium was effective in 56% of cases, and neuroleptics - in 61% of cases. However, the differences in the efficacy of the drugs were not statistically significant. The effect of carbamazepine manifests itself as quickly as that of a neuroleptic, but somewhat faster than that of lithium. Like other normothymic drugs, carbamazepine is less effective in depression, with improvement noted in only 30-35% of patients. Carbamazepine is especially effective in the treatment of BPAR with short cycles. The presence of short cycles, mixed or dysphoric mania allows one to predict a good response to carbamazepine. Failure to improve with another anticonvulsant does not mean that carbamazepine will also be ineffective.

The most common side effects of carbamazepine due to its effect on the central nervous system include dizziness, drowsiness, coordination disorder, confusion, headache, and fatigue. With a gradual increase in the dose, their likelihood is reduced to a minimum. The toxic effect of carbamazepine can manifest itself as ataxia, dizziness, double vision, and drowsiness. With high serum concentrations of carbamazepine, nystagmus, ophthalmoplegia, cerebellar symptoms, impaired consciousness, seizures, and respiratory failure may occur. Nausea, vomiting, and gastrointestinal disorders, if they occur, are more often at the very beginning of treatment. In some patients, the number of leukocytes decreases, but it usually does not fall below 4,000. And thrombocytopenia is sometimes observed. Severe suppression of hematopoiesis is idiosyncratic in nature and occurs in 1 out of 10,000-125,000 patients. Carbamazepine can cause a rash - in this situation, many doctors cancel the drug. Hyponatremia sometimes occurs during treatment with carbamazepine, which is associated with its antidiuretic effect. The incidence of hyponatremia ranges from 6 to 31%, with the risk of its development being higher in the elderly.

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

Carbamazepine interacts with a number of other drugs 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 determination of the platelet count) and an assessment of liver function. In women with intact reproductive function, a pregnancy test is necessary. Treatment is usually started with a dose of 200-400 mg/day, administered in 2-3 doses. However, sometimes treatment is started with a loading (saturating) dose of 20 mg/kg. During the titration period, the serum concentration of the drug should be measured every 12 hours. The therapeutic plasma concentration is usually from 4 to 12 μg/ml (however, these values are the result of extrapolation of data obtained in 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 treatment and the concentration of the drug in the serum, the dose should be selected based on the effect obtained, and not on the intended serum concentration of the drug. Due to autoinduction of metabolism, an increase in the dose (sometimes doubling) may be required after 3-5 weeks. Carbamazepine is available as chewable tablets of 100 mg, standard tablets of 200 mg, and sustained-release tablets of 100, 200, and 400 mg, as well as a suspension with a concentration of 100 mg/5 ml.

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Other medications for treating bipolar disorder

Clozapine (Clozaril, Leponex, Azaleptin) and olanzapine (Zyprexa) are atypical antipsychotics that have been shown to be effective in acute mania. However, the need for weekly white blood cell counts (due to the risk of agranulocytosis) and potential side effects limit the use of clozapine and it is reserved for treatment-resistant cases of BPD. Unlike clozapine, olanzapine does not require weekly blood counts and has a more favorable side effect profile. Olanzapine monotherapy is currently being evaluated in placebo-controlled trials for acute mania. The therapeutic dose of olanzapine for acute mania is usually 10–20 mg, the entire dose may be taken as a single dose at bedtime.

Lamotrigine (Lamictal) and gabapentin (Neurontin) are two new-generation anticonvulsants that may be effective in treating mania, although controlled studies have not yet been conducted. Treatment with these drugs does not require monitoring of their serum concentrations. Gabapentin has been used to treat epilepsy since 1993. Although it is structurally similar to γ-aminobutyric acid, its mechanism of action is not fully understood. Gabapentin has an approximate bioavailability of 60%, although it decreases at higher doses. Only a small portion of the drug binds to plasma proteins (< 3%). The half-life is 5-7 hours. Gabapentin is excreted unchanged in the urine. The most common side effects of gabapentin include drowsiness, dizziness, unsteadiness, nystagmus, tremor, and 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 for the treatment of BPAR is usually 900-3200 mg/day. Gabapentin does not appear to interact with valproic acid or carbamazepine.

Ulamotrigine, which has been used to treat epilepsy since 1994, has also been found to have normothymic activity. Like gabapentin, lamotrigine has a favorable spectrum of side effects, but at present there is insufficient data on its efficacy in bipolar disorder. Lamotrigine acts by inhibiting voltage-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 concentrations reach a maximum 1.4-4.8 hours after oral administration. The most common side effects of lamotrigine are dizziness, headache, double vision, unsteadiness, and nausea. Vomiting, accommodation disorder, 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, less commonly, toxic epidermal necrolysis, which can be fatal.

Lamotrigine may interact with valproic acid and carbamazepine. In motonotherapy, the initial dose of lamotrigine is 25-50 mg/day, subsequently 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 it is gradually increased. Since valproic acid slows down the metabolism of lamotrigine, a rapid increase in the dose of lamotrigine in this case more often causes a rash. But with the simultaneous use of carbamazepine, which accelerates the metabolism of lamotrigine, the dose of the latter, on the contrary, should be increased faster.

Calcium antagonists are also used in the treatment of bipolar disorder, although their role is not completely clear. The greatest experience has been gained with verapamil. Nimodipine may be useful in patients with ultrashort cycles.

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

Depression in Bipolar Disorder

Treatment of depression in bipolar affective disorder has not been studied as well as treatment of mania, despite the fact that depressive and mixed episodes often lead to significant maladjustment of the patient. In addition, the effectiveness of treatment of depression in bipolar affective disorder is quite difficult to assess due to frequent spontaneous remissions, frequent transition to mania, and simultaneous administration of several drugs, which is currently the rule rather than the exception. The approach to treating depression in a patient with BPD depends on its severity and the therapy received by the time the depressive phase develops. First of all, it is necessary to resume taking the normothymic drug or increase its dose up to the upper limit of the therapeutic range (if well tolerated).

If a depressive episode develops while taking lithium, it is necessary to measure the plasma drug level and examine the thyroid function to exclude hypothyroidism, which can be caused by lithium. Prescribing lithium as an antidepressant for bipolar affective disorder is successful in about 30% of cases - valproic acid and carbamazepine cause improvement in about the same percentage of patients. Antidepressants are also effective in the depressive phase of BPAR. In double-blind placebo-controlled studies, antidepressants caused improvement in 48-86% of patients. Imipramine, desipramine, moclobemide, bupropion, tranylcypromine, and fluoxetine effectively reduced the manifestations of depression in patients with BPAR.

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

In some patients, antidepressants shorten the cycles of bipolar disorder. Wihr (1988) evaluated the effect of antidepressants in 51 patients with short cycles and 19 patients with long cycles, the vast majority of whom were women. In 73% of patients with short cycles, the first episode of hypomania or mania occurred during antidepressant treatment, while in patients with long cycles such a relationship was observed in only 26% of cases. In about half (51%) of patients with short cycles, the cycles accelerate during antidepressant treatment and slow down after their withdrawal. TCAs more often provoke a transition to mania and are less effective than SSRIs or MAO inhibitors. A recent controlled double-blind study demonstrated the effectiveness of paroxetine, prescribed against the background of suboptimal lithium levels, in depression in patients with BPD. At the same time, in patients with optimal plasma lithium levels, the addition of parkosetin 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 the risk of developing mania or hypomania, as well as possible acceleration of the change of cycles. In this regard, first of all, when depression develops, in bipolar affective disorder, it is necessary to optimize therapy with normothymic agents, and also to evaluate the thyroid function. If these measures are unsuccessful, then antidepressants or ECT can be used. SSRIs and bupropion are less likely to cause mania or hypomania than MAO inhibitors and TCAs. Keeping special charts that display the dynamics of cycles and the effectiveness of treatment measures allows for more effective treatment of this disease, which accompanies most patients throughout their remaining lives.

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Algorithms for the treatment of acute mania

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

Successful treatment significantly improves the quality of life of a patient with major depression or bipolar disorder. This chapter has focused on drug treatments for these conditions, but for most patients, a combination of drug therapy and psychotherapy is optimal. For example, psychotherapy may be aimed at normalizing the patient's relationships with others and creating a mood for strict adherence to doctor's orders.

Although doctors currently have a large number of effective means for treating affective disorders, the psychopharmacological method of treatment appeared in their arsenal relatively recently. For thousands of years, sympathy for the patient, communication with him, care were the main tools in the hands of the doctor. And today, despite the fact that pharmacotherapy can save the life of a patient with an affective disorder, it is only one component of the overall treatment system.

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