Treatment for schizophrenia

Neuroleptics are the main class of drugs used to treat schizophrenia. They are divided into two main categories: typical neuroleptics and atypical neuroleptics. The pharmacological properties, including side effects, of each of these drug categories are discussed below.

Treatment of schizophrenia with typical neuroleptics

Most patients with schizophrenia find it difficult to implement effective rehabilitation programs without antipsychotic drugs. [ 1 ] Treatment of schizophrenia began in 1952 with the discovery of the antipsychotic properties of chlorpromazine (Delay and Deniker, 1952). After the effectiveness of chlorpromazine was demonstrated in a multicenter, double-blind, placebo-controlled clinical trial, new drugs began to appear for the treatment of schizophrenia. It is extremely important to begin drug treatment promptly, especially within five years of the first acute episode, since this is when most of the disease-related changes in the brain occur. These agents, which belong to the typical (traditional) neuroleptics, are divided into five groups.

The following typical neuroleptics are distinguished:

• Phenothiazines
• Aliphatic (eg, chlorpromazine)
• Piperazines (eg, lerphenazine, trifluoperaein, fluphenazine)
• Piperidines (eg, thioridazine)
• Bouguereauphenones (eg, haloperidol)
• Thioxanthenes (eg thiothixene)
• Dibenzoxazepines (eg, loxapine)
• Dihydroindolones (eg molindone)

Mechanism of action

The antipsychotic effect of all neuroleptics, with the exception of clozapine, closely correlates with their ability to block dopamine D2 receptors. Dopamine D2 receptors are localized in the basal ganglia, nucleus accumbens, and frontal cortex, where they play a leading role in regulating the flow of information between the cerebral cortex and the thalamus. [ 2 ], [ 3 ] Thus, typical neuroleptics can help restore homeostasis of this system. It is assumed that at the cellular level, typical neuroleptics act by blocking the depolarization of nigrostriatal (cell group A9) and mesolimbic (cell group A10) dopaminergic neurons. However, the therapeutic effect appears earlier than the blockade of depolarization occurs, in connection with which it is assumed that this physiological effect can prevent the development of tolerance to neuroleptics. The ability of dopaminomimetic agents such as amphetamine, methylphenidate, L-DOPA to cause paranoid psychosis similar to the manifestations of schizophrenia is an additional argument in favor of the assumption of the key role of the dopaminergic system in the mechanism of action of neuroleptics. However, given the lack of connection between dopamine metabolism and the reaction to neuroleptics, as well as the resistance of a number of patients to typical neuroleptics, it can be concluded that dopaminergic activity is only one of the possible factors involved in the pathogenesis of schizophrenia. [ 4 ]

To reduce the positive symptoms of schizophrenia, at least 60–65% of D2 receptors must be involved. [ 5 ] Typical neuroleptics also act to varying degrees on other receptors: serotonin (5-HT1C and 5-HT2A), muscarinic, alpha- and beta-adrenergic receptors, as well as dopamine D1-, D3- and D4-receptors. Clozapine and new-generation neuroleptics have a higher affinity for some of these receptors than for dopamine D2-receptors.

Side effects of typical neuroleptics

Typical neuroleptics cause a wide range of side effects. High-potency neuroleptics such as fluphenazine and haloperidol are more likely to cause extrapyramidal effects, while low-potency neuroleptics such as chlorpromazine or thioridazine are more likely to cause drowsiness and orthostatic hypotension.[ 6 ]

The spectrum of side effects for each drug depends on the characteristics of its pharmacological action. Thus, neuroleptics with a stronger anticholinergic effect more often cause accommodation disorder, constipation, dry mouth, and urinary retention. A sedative effect is more typical of drugs with a pronounced antihistamine effect, and orthostatic hypotension is typical of drugs that block alpha1-adrenergic receptors. Tolerance usually develops to the effects associated with the blockade of histamine and alpha1-adrenergic receptors. Blockade of cholinergic, noradrenergic, or dopaminergic transmission by neuroleptics can cause a number of disorders in the sexual sphere, including amenorrhea or dysmenorrhea, anorgasmia, lubrication disorder, galactorrhea, swelling and soreness of the mammary glands, and decreased potency. Side effects in the sexual sphere are mainly explained by the cholinergic and adrenergic blocking properties of these drugs, as well as an increase in prolactin secretion due to the blockade of dopamine receptors.

The most serious side effects are associated with the influence of typical neuroleptics on motor functions. They are the most common reason for drug discontinuation. The three main side effects associated with the influence on the motor sphere include early extrapyramidal disorders, tardive dyskinesia and neuroleptic malignant syndrome. [ 7 ]

Main side effects

Central nervous system

• Violation of thermoregulation
• Extrapyramidal disorders
• Neuroleptic malignant syndrome
• Drowsiness
• Epileptic seizures

Cardiovascular system

• ECG changes
• Orthostatic hypotension
• Tachycardia
• "Pirouette" tachycardia

Leather

• Allergic reactions
• Increased sensitivity of the skin to light

Endocrine glands

• Amenorrhea
• Galactorrhea
• Sexual dysfunction
• Weight gain

Gastrointestinal tract

• Cholestatic jaundice
• Constipation

Blood system

• Agranulocytosis
• Leukopenia

Eyes

• Accommodation disorder
• Retinitis pigmentosa

Urinary system

• Urinary retention

Early extrapyramidal syndromes

Early extrapyramidal syndromes include parkinsonism, dystonia, and akathisia. [ 8 ] Parkinsonian symptoms (mask-like face, akinesia, resting tremor, rigidity) are believed to be associated with blockade of dopamine D2 receptors in the basal ganglia. These symptoms occur soon after the start of taking a neuroleptic and, if not corrected, can persist for a long time. It is important to distinguish them from the outwardly similar negative symptoms of schizophrenia, such as emotional alienation, dulling of affect, and apathy. To correct parkinsonian symptoms, an anticholinergic (for example, benzotropine or trihexyphenidyl) is prescribed, the neuroleptic dose is reduced, or it is replaced with a new-generation drug.

Acute dystonic reaction usually manifests itself as sudden contractions of the muscles of the face, neck, or trunk, such as torticollis, oculogyric crisis, or opisthotonos. Like parkinsonism, acute dystonic reaction usually occurs during the first days of treatment. It usually responds well to intramuscular injections of diphenhydramine or benzotropine. Late dystonia usually involves the neck muscles and, unlike acute dystonic reaction, responds less well to anticholinergics.

Akathisia is characterized by a feeling of inner restlessness and a need to move (e.g., pacing) and also usually appears early in treatment. Although akathisia may develop together with other extrapyramidal disorders, it often appears in isolation. [ 9 ] Akathisia is difficult for patients to tolerate and may be the cause of aggressive behavior or suicidal attempts.

[ 10 ], [ 11 ], [ 12 ], [ 13 ], [ 14 ], [ 15 ], [ 16 ], [ 17 ], [ 18 ], [ 19 ], [ 20 ], [ 21 ]

Tardive dyskinesia

Tardive dyskinesia (TD) is manifested by involuntary movements that can involve any muscle group, but most often the muscles of the tongue and mouth. In the first 8 years of treatment with neuroleptics, TD occurs in approximately 3-5% of patients. It has been established that 20-25% of young and middle-aged patients treated with typical neuroleptics develop at least mild manifestations of TD, and its prevalence is even higher in elderly individuals. Tardive dyskinesia is usually a complication of long-term use of typical neuroleptics, and the duration of therapy is the main risk factor for its development. However, cases have been described in which TD manifestations occurred in patients who were not treated for schizophrenia. [ 22 ] TD develops more often in elderly women and patients with affective disorders. It is assumed that TD is caused by an increase in the number of dopamine receptors in the striatum, although the GABAergic and other neurotransmitter systems may also be involved in its pathogenesis. The severity of PD varies, but in most cases it is mild. In severe cases, PD can disable the patient and is often irreversible. [ 23 ]

Although a number of agents and methods have been proposed for the treatment of PD, there is no universally effective therapy for PD. It is suggested that vitamin E may have a moderate effect in this condition. The most effective measure for PD is a reduction in the dose of the neuroleptic, but this is not always possible. Therefore, moderate or severe PD may serve as an indication for switching to clozapine or another atypical neuroleptic. [ 24 ]

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome (NMS) is a rare life-threatening complication of neuroleptic therapy. It is characterized by muscle rigidity, hyperthermia, autonomic dysfunction, and changes in mental status. NMS is characterized by leukocytosis and increased serum creatine phosphokinase (CPK) activity. [ 25 ] This condition can lead to rhabdomyolysis and acute renal failure. Risk factors for NMS include infections, dehydration, physical exhaustion, childhood or old age, and rapid changes in the dose of neuroleptics. The incidence of NMS is 0.2% to 3.2%. [ 26 ]

The pathogenesis of this syndrome is unclear, but it is assumed that it develops as a result of excessive blockade of dopamine receptors and decreased activity of the dopaminergic system. NMS should be differentiated from stroke, febrile catatonia and malignant hyperthermia. [ 27 ]

Neuroleptic malignant syndrome is an acute emergency requiring immediate hospitalization and fluid replacement therapy. Any neuroleptics currently being administered to the patient should be discontinued. Dopamine agonists (eg, bromocriptine), amantadine, or muscle relaxants (eg, dantrolene) may be helpful in some cases, but their efficacy has not been systematically studied. Adequate hydration and symptomatic therapy are most important in the treatment of NMS. After the resolution of an episode of NMS, neuroleptics should not be resumed for at least two weeks. Subsequently, a low-potency neuroleptic or a new-generation drug that is less likely to cause extrapyramidal side effects may be prescribed. [ 28 ] The dose of the newly prescribed drug should be increased gradually, with regular monitoring of vital signs, white blood cell count, and CPK levels in the blood.

Toxicity of typical neuroleptics

Typical neuroleptics rarely cause life-threatening complications. The manifestations of drug overdose depend mainly on their antiadrenergic and anticholinergic effects. Since neuroleptics have a strong antiemetic effect, gastric lavage is advisable to remove the drug from the body, rather than prescribing emetics. Arterial hypotension, as a rule, is a consequence of alpha1-adrenergic receptor blockade, it should be corrected by administering dopamine and norepinephrine. In case of cardiac arrhythmia, lidocaine is indicated. Overdose of a neuroleptic with a long-acting effect requires cardiac monitoring for several days. [ 29 ]

Treatment of schizophrenia with clozapine

Clozapine is a dibenzodiazepine first synthesized in 1959. It appeared on the European pharmaceutical market in the 1960s and was almost immediately recognized as more effective than typical neuroleptics. But in 1975, eight patients died in Finland due to infectious complications caused by clozapine-induced agranulocytosis.

As a result, the use of clozapine was limited and it was prescribed only to individual patients for whom other drugs were ineffective. The successful use of clozapine in this category of patients prompted a multicenter study in the United States to determine whether clozapine was more effective than typical neuroleptics in treatment-resistant patients. After receiving positive results, clozapine was approved for use in the United States by the FDA (Food and Drug Administration) in 1990. The drug was approved for use in cases of resistance of positive symptoms to typical neuroleptics or intolerance to them. Clozapine is the only drug whose advantage over typical neuroleptics in treatment-resistant schizophrenia has been firmly proven. In addition, it alleviates manifestations of hostility and aggression, tardive dyskinesia, and reduces the risk of suicide.

Mechanism of action of clozapine

Clozapine modulates the activity of a number of neurotransmitter systems. It is an antagonist of both D1 and D2 dopamine receptors. However, unlike typical neuroleptics, clozapine has the highest affinity for EM receptors, and its affinity for D1 receptors is higher than for D2 receptors. In addition, clozapine is a potent serotonin receptor blocker, its affinity for 5-HT2a receptors is higher than for any type of dopamine receptors. Clozapine also blocks serotonin 5-HT2Ca, 5-HT6 and 5-HT7 receptors, alpha1 and alpha2 adrenergic receptors, cholinergic receptors (both nicotinic and muscarinic), and histamine (H1) receptors. [ 30 ]

Clozapine differs from typical neuroleptics in a number of other properties. In laboratory animals, clozapine does not cause catalepsy, does not block apomorphine- or amphetamine-induced stereotypies, and does not increase serum prolactin levels or dopamine receptor sensitivity. In addition, clozapine blocks depolarization of only A10 dopamine neurons, which is consistent with data obtained when assessing the clozapine-induced increase in c-fos protein expression. Clozapine increases the expression of c-fos (a new marker of cellular activity) in the nucleus accumbens, ventral striatum, anterior cingulate, and medial prefrontal cortex. Unlike clozapine, haloperidol activates c-fos expression in structures innervated by dopaminergic neurons belonging to the A9 group, such as the dorsal striatum. But to this day it remains unclear what pharmacological properties clozapine owes its high antipsychotic activity to.

Clozapine side effects

Despite its high efficacy, clozapine is used sparingly due to the risk of some side effects, although in many ways this drug is safer than other antipsychotics. Compared with typical neuroleptics, clozapine very rarely causes early or late extrapyramidal complications. Parkinsonism or akathisia rarely occur with clozapine, and cases of acute dystonic reaction have not been reported at all. In addition, clozapine does not seem to cause tardive dyskinesia; although several such cases have been reported, their relationship to clozapine use remains unclear. Moreover, a relationship has been noted between widespread use of the drug and a decrease in the incidence of tardive dyskinesia. Clozapine has also been shown to be useful in the treatment of tardive dystonia and severe akathisia. Due to the low risk of neuroleptic malignant syndrome, clozapine should be considered the drug of choice in patients who have previously experienced this complication. [ 31 ]

However, when using clozapine, a number of serious side effects are possible, the most dangerous of which is agranulocytosis, which occurs in 0.25-1.0% of patients. Most often, it develops during the first 4-18 weeks of therapy, although cases of its occurrence more than a year after the start of treatment have been described. Agranulocytosis can develop quickly or gradually. This complication is more common in elderly women and people taking other drugs that can suppress hematopoiesis. The mechanism of agranulocytosis is unknown, but it is assumed that it develops as a result of direct toxic effects, an immune reaction, or a combined toxic-immune mechanism. There is unconfirmed data on a possible connection between the HLA haplotype and an increased risk of agranulocytosis. [ 32 ] In addition, it is assumed that the clozapine metabolite norclozapine has a toxic effect on bone marrow cells. According to the recommendations developed by the FDA, weekly monitoring of the level of white blood cells is necessary during drug administration. The risk of agranulocytosis is greatest during the first 6 months of treatment, so these recommendations may need to be revised for longer-term treatment. Patients should not be given concomitant drugs that suppress bone marrow function, such as carbamazepine. If the white blood cell count falls below 2000/mm ³ (and the granulocyte count below 1000/mm ³ ), clozapine should be stopped immediately and the patient should be hospitalized in an isolation ward (to prevent infection). During hospitalization, the white blood cell count should be measured at least every other day. Granulocyte colony-stimulating factor filgastrim can be used to enhance granulocyte regeneration. Patients who develop agranulocytosis should not be given clozapine again. There are no data to suggest an increased risk of agranulocytosis due to the influence of other drugs in patients with this complication of clozapine treatment.

Other important side effects that may occur with clozapine include drowsiness, hypersalivation, and weight gain, which is usually already elevated by the time clozapine is prescribed due to previous antipsychotic therapy. [ 33 ], [ 34 ] Other side effects that should be mentioned include tachycardia, orthostatic hypotension, and epileptic seizures. The risk of generalized seizures with clozapine is relatively high (up to 10%); it may also induce myoclonic and atonic paroxysms. Myoclonic jerks often precede the development of a generalized seizure. The likelihood of electroencephalographic (EEG) changes and seizures is dose-dependent. The risk increases significantly with clozapine doses exceeding 600 mg/day. The development of seizures is not a contraindication to further use of clozapine, but requires a reduction in the dose to half the last seizure-free dose. In addition, the use of antiepileptic drugs such as valproic acid should be considered. Carbamazepine should not be used because of the risk of agranulocytosis.

Clozapine toxicity

Clozapine overdose may cause depression of consciousness up to the development of coma, as well as symptoms associated with cholinolytic action (tachycardia, delirium), epileptic seizures, respiratory depression, extrapyramidal disorders. Taking a dose exceeding 2500 mg may result in death.

The high efficacy of clozapine with a low risk of extrapyramidal disorders prompted the development of a new generation of antipsychotic drugs. These drugs were endowed with one or more pharmacological properties - characteristics of clozapine - in order to obtain an equally effective agent, with the use of which the risk of extrapyramidal disorders and agranulocytosis would be minimized. Although new neuroleptics have surpassed clozapine in safety, to date it has not been possible to create a drug that would be as effective as clozapine (Conley, 1997). Clozapine and new generation drugs are called atypical, taking into account the peculiarities of their pharmacological action and the rarity of extrapyramidal complications. [ 35 ]

Manifestations of Clozapine Overdose

• Severe extrapyramidal disorders (including dystonia and severe muscle rigidity), drowsiness
• Mydriasis, decreased deep tendon reflexes
• Tachycardia (low-potential neuroleptics); arterial hypotension (blockade of alpha-adrenergic receptors in the absence of action on beta-adrenergic receptors)
• EEP diffuse slow low-amplitude waves; epileptic seizures (low-potential neuroleptics)
• QT prolongation; atypical ventricular (torsades de pointes) tachycardia with secondary conduction block or ventricular fibrillation

Treatment of schizophrenia with risperidone

Risperidone has been used since 1994. Risperidone is a benzisoxazole derivative with high affinity for 5-HT2a and dopamine D2 receptors, and it blocks serotonin receptors to a greater extent than dopamine receptors. In addition, risperidone effectively blocks alpha1-adrenergic receptors and histamine H1 receptors, but is less active against alpha2-adrenergic receptors. The drug does not have a significant effect on dopamine D1 receptors and cholinergic receptors. Like typical neuroleptics, risperidone blocks the depolarization of dopamine neurons belonging to both the A9 and A10 groups, and in high doses causes catalepsy and muscle dystonia in experimental animals. [ 36 ]

These pharmacological properties of risperidone are reflected in the spectrum of side effects. The risk of developing parkinsonism is dose-dependent - usually parkinsonian symptoms become pronounced at a dose of at least 10 mg/day. Cases of PD and NMS have been reported with risperidone treatment, but the relative risk of PD with this drug (compared with typical neuroleptics) is not clearly established. Other side effects include nausea, vomiting, agitation, anxiety, insomnia, somnolence, increased serum prolactin levels, and weight gain. However, overall, risperidone is relatively well tolerated. [ 37 ]

Overdose may cause somnolence, epileptic seizures, prolongation of the QT interval and widening of the QRS complex, arterial hypotension, and extrapyramidal disorders. Fatal cases caused by overdose of risperidone have been described. [ 38 ]

Treatment with olanzapine

Olanzapine has been used to treat schizophrenia since 1996. In terms of its spectrum of pharmacological action, it is very close to clozapine - olanzapine effectively blocks dopamine (both D1 and D2), as well as serotonin (5-HT2A, 5-HT2C, 5-HT6) receptors, alpha1-adrenergic receptors, histamine (H1) and muscarinic (M1) receptors. However, unlike clozapine, it has a relatively weak effect on serotonin receptors, as well as on alpha2-adrenergic receptors and other cholinergic receptors. Like clozapine, risperidone and other atypical neuroleptics, olanzapine has a higher affinity for 5-HT2A receptors than for dopamine D2 receptors. Like clozapine, it blocks depolarization of dopaminergic neurons of the A10 group, but not of the A9 group. Catalepsy and dystonia in experimental animals are caused only by high doses of the drug. [ 39 ]

Due to its pharmacological properties, olanzapine, even when used in high doses, causes extrapyramidal side effects much less frequently than typical neuroleptics. In addition, olanzapine has virtually no effect on prolactin levels in the blood and apparently does not cause any side effects from the cardiovascular system, including tachycardia. However, olanzapine can cause drowsiness, dizziness, dry mouth, constipation, and moderate weight gain. [ 40 ]

Overdose may result in sedation, toxic anticholinergic effects (including tachycardia and delirium), epileptic seizures, arterial hypotension, and extrapyramidal disorders. There is currently insufficient data to assess the risk of death from overdose. [ 41 ]

Treatment with quetiapine

Quetiapine weakly blocks dopamine D1 and D2 receptors, as well as serotonin 5-HT2a and 5-HT1c receptors, but its affinity for 5-HT2a receptors is higher than for dopamine D2 receptors. In addition, it is able to block alpha1 and alpha2 adrenergic receptors, but does not exhibit anticholinergic properties. Quetiapine does not lead to activation of c-fos in the dorsal striatum and, at therapeutic doses, does not cause catalepsy and dystonia in experimental animals. [ 42 ] Significant extrapyramidal disorders, including akathisia, do not occur with quetiapine administration. However, it can cause drowsiness, headache, transient increase in liver transaminases, and weight gain. Quetiapine does not cause an increase in plasma prolactin levels. [ 43 ], [ 44 ]

Treatment with ziprasidone

Ziprasidone has a unique profile of pharmacological action. Being a potent antagonist of 5-HT2a and dopamine D2 receptors, ziprasidone is also an active inhibitor of serotonin and norepinephrine reuptake. Although ziprasidone blocks depolarization of not only A9 but also A10 dopaminergic neurons, in experimental animals at high doses it is capable of causing only catalepsy. No extrapyramidal side effects have been observed with ziprasidone administration. [ 45 ]

There are a number of new antipsychotics currently in early development. Next-generation drugs may have a different mechanism of action (for example, they may be partial agonists of the glycine region of the NMDA receptor complex) and may be able to affect various manifestations of schizophrenia, including negative symptoms. [ 46 ], [ 47 ]

Treatment of the first psychotic episode

A 2010 meta-analysis found that relapse rates were lower in patients taking second-generation antipsychotics than in those taking first-generation antipsychotics. In patients experiencing a first psychotic episode or who have not been treated for more than 1 year, it is advisable to initiate therapy with a new-generation antipsychotic. Currently, the drugs of choice include risperidone, quetiapine, and sertindole. The 2009 PORT (Patients’ Outcomes Study Group) update recommended first-generation antipsychotics at a dose equivalent to chlorpromazine 300–500 mg/day for a first episode and a starting dose of second-generation antipsychotics equal to half the lower end of the dose range needed for patients with a history of multiple episodes. As a major exception, it was noted that the quetiapine dose may need to be increased to 400–500 mg/day. [ 48 ] Risperidone is recommended to be prescribed at a dose of 1-4 mg once daily (at bedtime), with a maximum dose of 6 mg/day. Treatment with olanzapine should be initiated at a dose of 10 mg once daily (at bedtime), then increased to 20-25 mg/day over the course of a week if necessary. Sertindole is initially prescribed at a dose of 12 mg once daily, then increased to 20-24 mg (all doses are taken once at bedtime). Treatment with quetiapine is initiated at a dose of 75 mg, then increased to 150-300 mg twice daily (the daily dose is 300-600 mg/day). Based on the available research results, olanzapine is not recommended as a first-line treatment in adolescents diagnosed with schizophrenia due to the risk of weight gain and diabetes. [ 49 ]

The initial stage of treatment lasts three weeks. If there is a good response to treatment and no complications, the drug is continued at an effective dose for 6-12 months. [ 50 ] At this point, the need for further antipsychotic therapy should be assessed. During this time, the diagnosis can be clarified in newly emerging cases. In chronic schizophrenia, long-term maintenance therapy will most likely be required.

If the patient was previously prescribed a typical neuroleptic that was effective and well tolerated, then this drug should be resumed. Of the typical neuroleptics, haloperidol (5-15 mg/day) and fluphenazine (4-15 mg/day) are most often used; in the indicated doses, they usually do not cause serious side effects. Patients who were previously helped by drugs with a weaker antipsychotic effect (for example, perphenazine or chlorpromazine) can be re-prescribed the same drugs. Due to the high risk of extrapyramidal side effects, typical neuroleptics are currently not considered first-choice drugs in patients with newly diagnosed schizophrenia. [ 51 ]

Treatment algorithms do not mention electroconvulsive therapy (ECT) in first episode. However, it may be considered as a treatment option, especially in patients at risk of harming themselves or others. ECT is used more often in patients with “first episode psychosis,” which includes possible psychotic mania, than in patients with first episode schizophrenia.[ 52 ]

Treatment of agitation and insomnia

Patients often become agitated and hostile immediately after hospitalization. Agitation can usually be reduced by placing the patient in a calm, controlled environment. Additionally, lorazepam (0.5-2 mg), which has an anxiolytic and hypnotic effect, can be prescribed to calm the patient. [ 53 ] Lorazepam is usually used for a short time, necessary to normalize the patient's behavior. Most patients respond favorably to a calm and measured environment; lorazepam is only needed for 1-2 days. If short-acting benzodiazepines are contraindicated, neuroleptics are used in relatively high doses to suppress agitation, such as haloperidol (1-5 mg orally or 1-2 mg intramuscularly) or droperidol (1-2 mg intramuscularly). These drugs should be considered reserve drugs due to the possibility of developing extrapyramidal disorders, including dystonia. Droperidol should be administered only when conditions exist for emergency correction of possible cardiovascular dysfunction, as this drug, although rare, can cause life-threatening collapse. Like lorazepam, these drugs are prescribed for a limited period (the first 1-2 days of hospitalization).

The second complication of an acute psychotic episode that often requires correction is sleep disturbance. The drug of choice in this case is also benzodiazepines (e.g. lorazepam). If they are contraindicated, then diphenhydramine or chloral hydrate can be used as a sleeping pill. The use of sleeping pills should also be limited in time, since normalization of sleep usually occurs within 1-2 weeks after the onset of an acute psychotic episode. [ 54 ], [ 55 ]

Treatment of extrapyramidal disorders

Extrapyramidal disorders are one of the most serious complications of neuroleptic therapy. They can be represented by symptoms of parkinsonism, akathisia and dystonia, which appear quickly or gradually. [ 56 ] When using new generation neuroleptics, the probability of developing drug-induced parkinsonism is reduced to a minimum. However, only clozapine, being an effective antipsychotic drug, almost never causes parkinsonism. Nevertheless, due to the risk of agranulocytosis, it is not recommended to use it as a first-choice drug. Other atypical neuroleptics (risperidone, olanzapine, sertindole and quetiapine), although they cause extrapyramidal disorders less often than typical neuroleptics, can still cause parkinsonism, especially in high doses. Therefore, when using these drugs, it is important not to exceed the usually recommended doses and regularly monitor the condition of patients.

One of the most important advantages of atypical neuroleptics is that the symptoms of drug-induced Parkinsonism can be eliminated by reducing the dose of the drug without sacrificing the antipsychotic effect. [ 57 ] If the increasing symptoms of Parkinsonism significantly limit the patient's life, then fast-acting antiparkinsonian drugs, such as diphenhydramine or benzotropine, should be prescribed to correct them. Their use also reduces the likelihood of developing an acute dystonic reaction. However, the main method of correcting the symptoms of Parkinsonism in a patient taking an atypical neuroleptic is to reduce the dose of the drug, and the antiparkinsonian drug is prescribed only for a limited time. [ 58 ]

Parkinsonism that develops while taking typical neuroleptics is usually more pronounced and persistent. The main method of its correction is also a reduction in the dose of the neuroleptic, which in most cases brings the desired effect. An antiparkinsonian drug can be useful, but, if possible, it should be used only in acute situations. If parkinsonism or another extrapyramidal side effect has developed while taking a typical neuroleptic for a long time and does not decrease when its dose is reduced, then an atypical neuroleptic should be taken. [ 59 ] If persistent parkinsonism has developed while taking an atypical neuroleptic, then another drug from the same group should be taken. If these measures are ineffective, clozapine can be prescribed.

Treatment of akathisia

Akathisia may be combined with other extrapyramidal syndromes. Akathisia is caused by both atypical and typical neuroleptics. This complication is corrected by reducing the neuroleptic dose and additionally prescribing beta-blockers. In some cases, it is necessary to change the drug to a neuroleptic of another class. Clozapine can reduce akathisia that is resistant to other treatment methods.

• Recommendation (Level D) To reduce the risk of developing acute akathisia, clinicians should avoid rapidly increasing the dose of antipsychotic medications.
• Recommendation (Level D) Clinicians should consider dose reduction in patients with persistent akathisia receiving a stable dose of antipsychotic medication, given the potential risk of clinical worsening of mental disorder.
• Recommendation (Level D) When considering the risks and benefits of using combination antipsychotics in a patient, clinicians should take into account the increased risk of akathisia and the lack of evidence for the clinical effectiveness of this strategy.
• Recommendation: (Level D) If antipsychotic polypharmacy is prescribed and persistent, clinically significant akathisia is observed, clinicians should attempt to achieve mono-antipsychotic therapy by gradually tapering and discontinuing one of the antipsychotics or switching to another antipsychotic if this can be achieved without clinical deterioration.[ 60 ]

Maintenance treatment of schizophrenia

Most current guidelines for first-episode psychosis recommend continuing antipsychotic medication for a period of time after remission of the first episode of psychosis to prevent relapse, for example the Australian Clinical Guidelines for Early Psychosis state that antipsychotic treatment can be continued for 12 months or longer, and the National Institute for Health and Care Excellence guideline Adult Psychosis and Schizophrenia: Treatment and Management states: "Advise the patient that there is a high risk of relapse if they stop taking their medication in the next 1–2 years." [ 61 ] Once symptoms have resolved and the patient has stabilized, long-term maintenance therapy is given to prevent symptoms from worsening or relapse. Treatment at this stage is usually provided on an outpatient basis, so it is important to minimise side effects and ensure adherence to treatment recommendations. Quality of life and cost-effectiveness are of particular importance during this phase of treatment. Achieving these goals is possible only with effective psychosocial rehabilitation combined with pharmacotherapy. [ 62 ]

Long-term antipsychotic therapy has long been recognized as the most optimal approach to treating most patients with schizophrenia. Controlled studies show that exacerbations occur three times less frequently with neuroleptics than with placebo. High doses of neuroleptics (equivalent to 600-1200 mg of chlorpromazine) have been used for maintenance therapy for many years. Against the background of this approach, the frequency of relapses and rehospitalizations in the 1960s-80s decreased, but remained quite significant. Attempts were made to increase the effectiveness of treatment by prescribing very high doses. However, controlled studies have shown no advantages to this tactic. In addition, when prescribing high doses, the frequency of tardive dyskinesia increased, and the willingness of patients to cooperate (compliance) decreased. [ 63 ]

To improve compliance, long-acting depot formulations of fluphenazine and haloperidol were introduced in which the active substance was bound to the lipid decanoate. The formulations are administered intramuscularly. A single injection provides stable blood levels of the drug for 4 weeks. In clinical trials, depot formulations provided a higher rate of relapse prevention than oral agents (Davis et al., 1993). As a result, many experts believe that depot formulations are underused in the United States. [ 64 ]

It has been established that if the neuroleptic dose exceeds the value equivalent to 375 mg of chlorpromazine, the effectiveness of maintenance therapy does not increase. At the same time, in about half of the patients, the minimum effective dose is equivalent to about 50-150 mg of chlorpromazine. According to modern recommendations, the standard maintenance dose should be equivalent to 300-600 mg of chlorpromazine.

In the last decade, various methods have been tested to change the risk-effectiveness ratio of maintenance therapy in a more favorable direction. It turned out that with a significant reduction in the maintenance dose, it is possible to reduce the risk of side effects, increase compliance, and at the same time maintain the therapeutic effect for most parameters. The results of these studies have generated wide interest and led to changes in treatment practice. With long-term use of a neuroleptic at a dose of 10% of the standard, the frequency of exacerbations increased, but the degree of social adaptation of the patient was higher, and the risk of side effects was lower. When prescribing a dose of 20% of the standard, the frequency of exacerbations was also higher, but they were less pronounced. Moreover, these exacerbations could be treated on an outpatient basis, additionally prescribing oral administration of the drug. At the same time, other manifestations of the disease, including negative symptoms, were reduced.

Similar results were obtained when patients did not receive maintenance treatment and intensive antipsychotic therapy was started only at the first symptoms of a relapse. However, this scheme turned out to be more burdensome for both patients and psychiatrists, and its results were generally not as convincing as with low-dose maintenance therapy. One study that directly compared the effectiveness of standard- and low-dose maintenance therapy with therapy administered only at the onset of symptoms showed that with continuous use of a low dose, the total drug dose (over the study period) was lower and the frequency of relapses of psychotic symptoms was lower than with treatment of exacerbations only. However, both of these schemes reduced the impact of antipsychotics on the patient and the severity of negative symptoms compared with standard-dose maintenance therapy. However, by the end of the two-year study period, the relapse rate in the alternative treatment groups was higher than in patients receiving standard-dose maintenance therapy, but there were no significant differences in the severity of psychotic symptoms.

The data provided allow us to formulate the following recommendations.

1. For most patients, long-term maintenance therapy with constant doses of neuroleptic is optimal.
2. Doses of typical neuroleptics should be significantly lower than those previously used (600-1000 mg chlorpromazine). Currently, it is common to use doses of 200-400 mg, and in many patients, doses of 150-300 mg (in chlorpromazine equivalent) are effective.
3. Depot preparations improve compliance of patients who agree to this type of treatment. The greatest experience with low-dose maintenance therapy has been obtained using depot preparations. If regular observation of patients is possible, 12.5 mg of fluphenazine decanoate is administered once every 2-3 weeks, and 25-50 mg of haloperidol decanoate - once every 4 weeks, resperidone (consta), 25-75 mg - once every 2 weeks. These doses provide the necessary effect in most patients. In case of periodic exacerbation of psychosis, an additional neuroleptic may be prescribed orally for several weeks.
4. In patients who refuse long-term use of neuroleptics, as well as in long-term remission after a single psychotic episode, therapy is carried out only during an exacerbation.
5. Persistent side effects are an indication for dose reduction.
6. The appearance of the first symptoms of tardive dyskinesia is an indication for discontinuing maintenance therapy (with resumption of neuroleptic administration only in the event of an exacerbation of psychosis), a significant reduction in the dose of neuroleptic, or its replacement with clozapine.

These recommendations may be revised after the results of studies of maintenance therapy with new-generation neuroleptics become available. There is already information on the higher efficacy of clozapine in preventing exacerbations in chronic patients resistant to typical neuroleptics. The relative risk of extrapyramidal side effects allows us to expect that patients will better follow the doctor's recommendations, and this will increase the effectiveness of treatment. However, with regard to new-generation neuroleptics, it is still unclear whether reducing their dose allows optimizing the risk-effectiveness ratio. On the other hand, it is important to compare the results of maintenance therapy with atypical neuroleptics and low doses of typical neuroleptics. Treatment with risperidone at a dose of 4 mg/day will have undoubted advantages over prescribing haloperidol at a dose of 15-20 mg/day. But it remains unclear whether these advantages would be maintained if the comparison were made with haloperidol at a dose of 4-6 mg/day or fluphenazine decanoate at a dose of 12.5 mg once every three weeks. The choice of drug undoubtedly also involves the cost-effectiveness ratio.

Treatment resistance in schizophrenia

Treatment-resistant schizophrenia, the persistence of positive symptoms despite ≥2 studies of adequate dose and duration of antipsychotic medication with documented adherence, is a serious clinical problem with heterogeneous manifestations. Partial or inadequate treatment response is one of the most difficult problems in the pharmacotherapy of schizophrenia. In the past, treatment resistance was overcome by varying the drug dose or by prescribing additional agents such as lithium, anticonvulsants, or benzodiazepines. With the advent of clozapine, newer-generation neuroleptics have become more widely used in the treatment of such patients. This is due to the fact that atypical neuroleptics are more effective or cause significantly fewer side effects than traditional drugs.

Treatment resistance is understood as the persistence of psychotic symptoms (distorted perception of reality and disorganized behavior) and associated disorders, despite adequate pharmacotherapy. [ 65 ]

Typical neuroleptics

Typical neuroleptics have long been the drugs of choice for the treatment of schizophrenia. They are considered equivalent in efficacy. Only one of more than 100 comparative studies found differences in efficacy. In controlled studies, less than 5% of patients resistant to one of the typical neuroleptics were able to achieve success by replacing it with another traditional drug. The choice of drug was guided mainly by the desire to reduce the risk of side effects and to be able to vary the dose. High-potency agents such as haloperidol and fluphenazine are more likely to cause extrapyramidal side effects, but less likely to cause drowsiness and orthostatic hypotension than low-potency agents such as chlorpromazine and thioridazine. Haloperidol and fluphenazine are the only neuroleptics available as depot preparations for parenteral administration. They improve compliance and sometimes achieve a more pronounced effect. [ 66 ]

The choice of neuroleptic for a particular patient depends on the effectiveness and tolerability of the drugs that were prescribed to him/her earlier. In the absence of clinical improvement after three weeks of treatment, it is necessary to check whether the patient is following the prescribed treatment regimen by measuring the drug level in the blood. If the patient is taking the drug conscientiously, then in the absence of noticeable improvement after 4-8 weeks, it is necessary to consider changing the drug.

Atypical antipsychotics

When typical neuroleptics are ineffective, atypical neuroleptics become the drugs of choice. Of this group, four drugs are most often used: clozapine, risperidone, olanzapine, and quetiapine. [ 67 ]

[ 68 ], [ 69 ], [ 70 ], [ 71 ], [ 72 ], [ 73 ], [ 74 ], [ 75 ]

Clozapine

It is recommended for use when typical neuroleptics fail to achieve the desired effect, either due to the drug's low efficacy or severe side effects. Clozapine remains the only drug whose ability to overcome treatment resistance in schizophrenia, established according to strict criteria, is considered proven.

Despite the significant clinical efficacy of clozapine, its use does not improve social adaptation and reduce the costs of patient care in all patients, especially in the first year of therapy. This can be partly explained by the fact that clozapine is usually prescribed to patients who are difficult to treat and spend a long time in psychiatric hospitals. In addition, it is used by a limited number of psychiatrists who are accustomed to working with it. Other studies show that long-term treatment with clozapine is cost-effective.

The optimal strategy for using clozapine is a gradual increase in the dose. The effect can be expected with a dose of 200-600 mg/day. Only if the drug is well tolerated can the dose be increased above 600 mg/day. It is not recommended to increase the dose of clozapine if myoclonic jerks appear, which may serve as harbingers of epileptic seizures. In patients who respond to clozapine, improvement usually occurs within 8 weeks after reaching the optimal dose.

[ 76 ], [ 77 ], [ 78 ], [ 79 ], [ 80 ], [ 81 ]

Risperidone

Risperidone effectively suppresses the positive symptoms of schizophrenia. In addition, when the drug is prescribed at a dose of up to 6 mg / day, the risk of developing extrapyramidal disorders is no higher than that of placebo. However, at a dose of 10 mg / day and above, the drug causes extrapyramidal disorders, and this side effect is dose-dependent. Thus, low and high doses of risperidone can have different clinical effects. There is no evidence that high doses of risperidone (8 mg / day and above) are more effective, so for most patients, a dose of 2 to 6 mg / day is considered optimal.

Although there is evidence that risperidone is more effective than haloperidol, the question remains whether it is superior to conventional antipsychotics in treatment-resistant schizophrenia defined according to clear criteria. Although there have been case reports of risperidone improving previously treatment-resistant patients, these studies have been open-label or retrospective and have not been controlled.

One such study found that risperidone was as effective as clozapine in treating chronic pain. However, the study did not stratify patients based on their resistance to therapy, and the study was not large enough to properly compare the effectiveness of the two drugs.

It is well established that risperidone is ineffective in clozapine-resistant patients. However, there are reports of its ability to improve quality of life and reduce the length of hospitalization in treatment-resistant patients. Because risperidone is significantly safer than clozapine and is better tolerated than typical antipsychotics, risperidone is recommended for treatment-resistant patients before switching to clozapine.

Olanzapine

It is similar to clozapine in its pharmacological action and is effective in schizophrenia that is amenable to treatment with neuroleptics. It causes extrapyramidal disorders less often than typical neuroleptics, and akathisia occurs with the same frequency during treatment with the drug as with placebo. In an open clinical trial, olanzapine was effective in some patients who were significantly resistant to antipsychotic therapy. However, this result could not be confirmed in a double-blind study; only a decrease in anxiety and depression was noted. In the most effective dose (15-25 mg/day), olanzapine is significantly better tolerated than chlorpromazine. Olanzapine can be prescribed to patients resistant to typical neuroleptics, but it is unlikely that it will significantly improve the condition of patients resistant to risperidone.

Quetiapine

It has a higher affinity for serotonin (5-HT1A) than for dopamine receptors. It is a neuroleptic with relatively low activity. It has the greatest effect at a dose of 300-450 mg/day, like clozapine. The drug is safer than typical neuroleptics, and the likelihood of developing extrapyramidal disorders (including akathisia) when using it is no higher than with placebo.

When treating patients resistant to therapy, the following points should be kept in mind.

1. Resistance to therapy is determined by the presence of persistent psychotic disorders or other difficult-to-treat psychopathological manifestations.
2. Treatment resistance is a spectrum of conditions, and patients who are completely resistant (refractory) to treatment constitute the most severe part of this spectrum.
3. Clozapine is the most effective antipsychotic drug in treatment-resistant patients.
4. Although new-generation antipsychotics are safer than clozapine and typical antipsychotics, their effectiveness in treatment-resistant patients has not been definitively determined.

Treatment of schizophrenia with alternative methods

If traditional treatment for schizophrenia is unsuccessful, it should be treated with alternative therapies. These include adjuvant medications, reserpine, and electroconvulsive therapy (ECT). Since the effectiveness of these methods cannot be considered proven, they can only be used in certain situations.

Lithium preparations

Addition of lithium allows some patients with schizophrenia to overcome treatment resistance. A 4-week trial course is sufficient to evaluate the effectiveness of lithium. Although lithium is more effective in patients with affective disorders, its use also produces positive results in other categories of patients. According to some data, lithium reduces hostility in resistant patients and may be especially useful in cases of agitation. [ 82 ]

Although studies of lithium (as an adjuvant) in patients with treatment-resistant schizophrenia have shown positive results, they were conducted on small groups of patients. Therefore, the effectiveness of lithium cannot be considered proven. Caution should be exercised when using lithium in combination with a typical neuroleptic or clozapine due to the risk of delirium and encephalopathy.

Anticonvulsants

Carbamazepine and valproic acid are effective in bipolar affective disorder with psychotic manifestations. However, they are often used as an adjuvant in schizophrenia. Several controlled studies have shown the undoubted effectiveness of carbamazepine as an adjuvant in patients with schizophrenia, but these studies included a small number of patients. Positive changes were generally moderate and concerned more such areas as behavior and social adjustment. Carbamazepine cannot serve as an alternative to neuroleptics, since it is not able to prevent relapses of schizophrenia.

Carbamazepine should be used with caution because it can cause disorientation, ataxia, and agranulocytosis. In addition, carbamazepine can reduce the concentration of haloperidol in the blood by approximately 50%. Due to the risk of toxic hepatitis, caution should also be exercised when prescribing valproic acid.

[ 83 ], [ 84 ], [ 85 ], [ 86 ], [ 87 ]

Benzodiazepines

There are several reports on the use of benzodiazepines as an adjuvant in treatment-resistant schizophrenia. The results are mixed: some double-blind studies have shown a positive effect of benzodiazepines, while others have shown their use to be ineffective. Since irritability and anxiety are common in patients with schizophrenia, it is not surprising that benzodiazepines are often prescribed to them. However, caution should be exercised when prescribing these drugs, as their use may entail persistent drowsiness, fatigue, ataxia, drug dependence, and behavioral disinhibition. In addition, benzodiazepines may potentiate the toxic effect of clozapine. Anxiolytics in schizophrenia are used mainly to relieve agitation or treat prodromal symptoms (early symptoms of relapse) in patients who refuse to take neuroleptics.

[ 88 ], [ 89 ], [ 90 ], [ 91 ], [ 92 ], [ 93 ]

Antidepressants

Many patients with schizophrenia experience depression during the acute episode and are often demoralized during the chronic phase. Neuroleptics may worsen depressive symptoms. In the past, antidepressants were rarely used in schizophrenia for fear that they might trigger psychosis. This is probably unlikely. In general, antidepressants are only moderately effective in most patients with schizophrenia and do not reverse the demoralization. However, patients with persistent depression or a depressive episode occurring separately from psychotic disorders should be given antidepressants in the lowest effective dose. Clozapine has been shown to have a positive effect on depressed mood and reduce the risk of suicide.

[ 94 ], [ 95 ], [ 96 ], [ 97 ], [ 98 ], [ 99 ] , [ 100 ], [ 101 ]

Other treatments for schizophrenia

Although several studies in recent years have shown beneficial effects of beta-blockers and reserpine in treatment-resistant schizophrenia, there have been no controlled trials of these drugs using current diagnostic criteria. Thus, there is little evidence that long-term therapy with either drug is effective.

There are also no controlled trials of ECT in treatment-resistant schizophrenia. Before the introduction of clozapine, several studies of ECT showed that it could be effective in drug-resistant patients, although the effect was greater in patients with a shorter history of illness. Two open studies have shown that ECT may have some benefit in clozapine-resistant patients. However, the durability of the effect and the long-term effectiveness of ECT have not been reported.

To increase the effectiveness of antipsychotic drug therapy, the following principles should be followed.

1. Precise definition of the therapeutic target - the symptoms that the treatment will be aimed at correcting. Neuroleptics are more effective in treating the positive symptoms of schizophrenia, which include hallucinations, delusions, thought disorders and inappropriate behavior. New-generation drugs can also affect negative symptoms, such as social isolation, withdrawal and dulling of affect, especially if they are caused by typical neuroleptics. Clozapine is especially effective in treating hostile, aggressive patients with psychosis. The choice of the therapeutic target allows for a more accurate assessment of the drug's effectiveness.
2. The effectiveness of a neuroleptic can only be assessed after it has been prescribed in optimal doses for a sufficiently long period of time. This rule is especially important to follow before including auxiliary drugs in the treatment regimen. Otherwise, insurmountable difficulties may subsequently arise in selecting the optimal therapy. Typical neuroleptics are often prescribed in too high a dose, which negatively affects the effectiveness of treatment (even in acute psychosis) due to side effects and low patient compliance.
3. It should be borne in mind that the cause of apparent resistance to treatment may be poor drug tolerance, non-adherence to the treatment regimen (non-compliance). Inadequate social support or lack of psychosocial assistance may create the appearance of resistance to treatment. Therefore, before recognizing a particular drug as ineffective, these factors should be excluded. Although the therapeutic dose range for most neuroleptics is not precisely established, measuring the drug concentration in the blood can be useful, as it helps to check whether the patient is taking the drug regularly.
4. It is necessary to accurately assess the effectiveness of monotherapy with a particular drug before moving on to a combination of drugs. The doctor often tries (sometimes under external pressure) to select a treatment that would quickly rid the patient of all his psychopathological manifestations. But it should be remembered that the ability to enhance the effectiveness of neuroleptic therapy has not been proven for any of the auxiliary means. Hostility, irritability, insomnia, isolation can be a consequence of psychosis and can regress only against the background of successful antipsychotic therapy.
5. The choice of the drug is made taking into account the risk of extrapyramidal side effects. New generation neuroleptics are effective in doses that do not cause extrapyramidal complications in most patients. This allows avoiding persistent side effects that are the cause of low treatment effectiveness.
6. It is important to maintain a positive therapeutic attitude. Every year the choice of antipsychotic drugs becomes wider. It is necessary to maintain the patient's belief that even with the most severe mental illness, effective treatment will be found.
7. It is necessary to pay maximum attention to socio-psychological factors, protecting the patient from stress, promoting adequate understanding by the patient and his family of the nature of the disease - this significantly increases the effectiveness of treatment.

Atypical antipsychotics have a different mechanism of action than typical drugs, so doctors should make maximum use of the specific action features of different drug groups when trying to help patients who are resistant to therapy. Clozapine is currently the only drug that can overcome therapeutic resistance. The effectiveness of other new-generation drugs in the treatment of schizophrenia resistant to therapy should be determined in well-designed, double-blind studies with strict patient selection criteria.

Eliminating the negative symptoms of schizophrenia

Although most cases of treatment resistance focus on the persistence of positive symptoms, there is increasing recognition of the importance of problems associated with persistent negative symptoms. Clozapine and other new-generation antipsychotics (risperidone, olanzapine, quetiapine) have been shown to be more effective in reducing negative symptoms than conventional antipsychotics in double-blind studies. However, it remains unclear whether these drugs act directly on the primary negative symptoms of schizophrenia or whether this effect is due to the alleviation of other symptoms.

[ 102 ], [ 103 ], [ 104 ], [ 105 ]

Treatment of comorbid conditions

Depression

Many patients with schizophrenia who are treated with typical antipsychotics develop persistent symptoms of depression after the exacerbation. In these cases, it is necessary to try to identify extrapyramidal side effects in the patient, assess the severity of negative symptoms and the effectiveness of treatment. If these causes of depressed mood are excluded, then "postpsychotic depression" is diagnosed and antidepressants are prescribed. The drugs of choice in these cases are selective serotonin reuptake inhibitors (SSRIs), since, unlike tricyclic antidepressants, they are devoid of cholinolytic action, which can complicate the patient's recovery and care. In addition, with an overdose of SSRIs, the risk of a fatal outcome is lower than with traditional antidepressants.

[ 106 ], [ 107 ], [ 108 ], [ 109 ], [ 110 ]

Addiction

Many patients with long-term schizophrenia or schizophrenia-like psychoses develop drug addiction. These patients need to be recognized and treated promptly. The 12-step program is effective for many of them. It is important to combine it with antipsychotic medications that help maintain remission in patients. Since drug abuse increases the risk of developing tardive dyskinesia, these patients should be prescribed atypical neuroleptics whenever possible.

[ 111 ], [ 112 ]

Psychogenic polydipsia

Patients with chronic psychoses often suffer from psychogenic polydipsia. This disorder appears to arise secondarily due to dysfunction of the brain's thirst-suppressing mechanisms and is often resistant to behavioral therapy. Psychogenic polydipsia is a potentially dangerous complication, as it can lead to renal and cardiac dysfunction. In this case, the drug of choice is a neuroleptic with minimal anticholinergic action, such as risperidone or sertindole. If this is ineffective, clozapine may be prescribed, which may be useful in chronic psychogenic polydipsia, reducing psychotic symptoms on the one hand and water consumption on the other.

Failure of the patient to comply with the doctor's orders (patient non-compliance)

Patients suffering from schizophrenia and schizophrenia-like psychoses for a long time may have difficulty following doctor’s orders. Since many of them are unable to adequately assess their condition, they often stop following doctor’s orders over time. The reasons for non-compliance with orders may be side effects and the absence of an obvious effect of treatment for the patient. If there is a suspicion that the patient has stopped following the treatment regimen, it is necessary to subject him/her to a thorough examination to detect even minimal manifestations of extrapyramidal disorders and akathisia. Often these symptoms, barely noticeable during examination, can greatly disturb the patient. Their active therapy significantly increases compliance. To avoid the development of extrapyramidal disorders, careful adjustment of the neuroleptic dose may be required, allowing to maintain the antipsychotic effect, but minimize side effects. Among the new generation drugs, the lowest risk of extrapyramidal complications, in addition to clozapine, is characteristic of sertindole and quetiapine. Olanzapine and risperidone may cause extrapyramidal disorders (although to a lesser extent than typical neuroleptics), which requires regular monitoring of the patient's condition. In particular, the likelihood of developing extrapyramidal complications when using risperidone becomes significant if its dose exceeds 8 mg/day.

If patients do not follow the recommendations despite the absence of side effects, it is recommended to prescribe a depot drug. Currently, two such drugs are used - haloperidol decanoate and fluphenazine decanoate. Haloperidol decanoate is prescribed at a dose of 25-100 mg intramuscularly once every 4 weeks. Although treatment is sometimes started with a higher dose, the drug is better tolerated if its dose does not exceed 100 mg. Fluphenazine decanoate is prescribed at a dose of 25-50 mg intramuscularly once every 3-4 weeks. When using depot drugs, it is necessary to carefully examine the patient for extrapyramidal disorders and try to find the minimum effective dose (Schooler, 1996).

Persistent side effects

If the patient develops persistent bradykinesia or muscle rigidity, the neuroleptic dose is probably too high and should be reduced. If the symptoms persist after the dose is reduced, the drug the patient is taking should be replaced with a neuroleptic of a different class. If the patient is being treated with a typical neuroleptic, it is recommended to switch to one of the atypical drugs. Bradykinesia and muscle rigidity may regress within a few months after discontinuing the typical neuroleptic, since the drug continues to be slowly released from the "depot". Therefore, it is important to explain to the patient that after switching to a new drug, improvement can be expected only after several weeks.

Similarly, if akathisia persists, an attempt should be made to reduce the dose of the neuroleptic being taken, but first, to find out whether it exceeds the minimum effective dose. If akathisia persists, adding propranolol or another beta-blocker may help. Sometimes it makes sense to switch to an antipsychotic drug of a different class, including from one atypical neuroleptic to another. If akathisia cannot be corrected in this way, then it is advisable to prescribe clozapine.

Patients taking neuroleptics often experience problems in the sexual sphere, for example, they experience lack of lubrication or impotence. Women may experience amenorrhea or dysmenorrhea; men, as well as women, may experience galactorrhea, soreness and swelling of the mammary glands. Decreased erection and impaired lubrication, painful sexual intercourse can also be explained by taking drugs with pronounced cholinolytic activity - these complications can be dealt with by reducing the dose or prescribing a drug with minimal cholinolytic activity. Drugs with pronounced adrenergic blocking properties can also cause disorders in the sexual sphere. Thus, ejaculation disorders have been reported against the background of treatment with thioridazine; probably, the same can be caused by other neuroleptics. In such cases, a reduction in the dose of the drug is also indicated, and if this measure is ineffective, a change of drug. Swelling and tenderness of the mammary glands, menstrual irregularities may be associated with increased prolactin levels, which is caused by taking a neuroleptic that effectively blocks dopamine receptors. Such complications are observed both with the use of typical neuroleptics, especially high-potential drugs, and with the use of risperidone. Although in this case a reduction in the dose of the drug may help, it is often necessary to switch to a drug of a different class.