Atypical antipsychotic examples

At any stage of therapy, either due to exacerbation of the disorder's symptoms or side effects, the adolescent's condition may become threatening to himself or others. It is advisable to hospitalize such a teenager in a psychiatric department. Further selection of antipsychotic therapy for him should be carried out in a safe environment.

In such cases, the question arises: how quickly should we cancel an atypical antipsychotic if, after its short-term use, already at the dose selection stage, we are faced with unacceptable side effects or severe complications? Is it worth it to hospitalize such a child and carry out a gradual withdrawal of the drug in a hospital, or is it more correct to simply immediately stop taking the antipsychotic? nine0005

In pediatric practice, gradual dose escalation, withdrawal, or substitution of the atypical antipsychotic is always preferred. This is not always possible, for example, in the case of acute severe complications or the unilateral decision of some patients or their parents to stop treatment. But when possible, a strategy of phasing out an antipsychotic is always preferable. It is important to be able to explain to the parents of the child that the immediate withdrawal of the drug can lead to an exacerbation of the disorder and be accompanied by no less serious side effects than continuing to take a lower dose of it. nine0005

Side effects associated with the influence of second-generation antipsychotics on the central nervous system

When prescribing atypical antipsychotics to children, drowsiness and sedation are often observed, which are among the most important side effects that should be considered [1–2]. Slow titration is aimed at their detection and prevention in children. We must not allow children in therapy to sleep in class.

During the first week of taking atypical antipsychotics, most children may experience drowsiness, which significantly affects the ability to learn. Children go to bed early, fall asleep during lessons. Reducing a single dose, distributing it over several doses, as a rule, can eliminate or mitigate side effects. Later, many children adapt to the sedation and do not show daytime sleepiness. If the dose of the antipsychotic is increased very slowly in these children, overt sedation and daytime sleepiness can be avoided. nine0005

Can atypical antipsychotics, along with sedation and drowsiness, cause non-sedation-related cognitive impairment in children? This aspect of the clinical action of these drugs remains debatable for both child and adult psychiatric practice. Psychiatrists often describe improvement in cognitive functioning under the influence of atypical antipsychotic therapy in adolescent schizophrenia. At the same time, they often cannot answer the question: to what extent do certain antipsychotics affect the qualitative and quantitative characteristics of thinking and memory in children. This issue is relevant when prescribing antipsychotics to children of preschool and primary school age. The FDA has included information about cognitive impairment caused by atypical antipsychotics in its safety databases. nine0005

Extrapyramidal side effects has traditionally been regarded as a central concern for the safety of classical neuroleptic therapy in adults. It is customary to distinguish between muscle rigidity, tremor, akinesia (manifestations of parkinsonism) and restlessness (akathisia). Extrapyramidal side effects occur, although much less frequently, in the treatment of second-generation antipsychotics.

Children and adolescents are the most susceptible and sensitive to such side effects [2]. They are observed at the use of lower doses compared to adults. Over time, children and adolescents often adapt to taking antipsychotics, which is manifested in the mitigation of extrapyramidal symptoms, increasing doses of antipsychotics, when taking which side effects are not observed. A slow dose increase, a decrease in the peak concentrations of the antipsychotic in the child's blood serum helps to prevent the occurrence of dangerous extrapyramidal side effects. nine0005

How can peak serum concentrations of antipsychotics be reduced? There are two ways: 1) increasing the frequency of administration, while the daily dose of the neuroleptic should be divided into 2–3–4 doses; 2) the use of dosage forms with a slow release of the active substance, for example, slow-release tablets of the active metabolite of risperidone paliperidone (Invega® Extended-Release Tablets) instead of rispolept tablets or rispolept solution for drinking.

At the beginning of antipsychotic therapy, one is more likely to encounter dystonia . It can develop even after a single dose of the first dose of an antipsychotic or during the first days of treatment, it is very painful for the child and can cause his subsequent non-compliance. The risk of developing dystonia is related to the dose used. It can be reduced by slowly and carefully titrating the drug.

The phenomena of drug-induced parkinsonism often develop during the first 7-10 days of antipsychotic therapy.

Akinesia - "feeling of motor stiffness" - is often mistakenly considered as a natural consequence of the psycholeptic action of an atypical antipsychotic. If the dose of neuroleptic is not reduced in a timely manner, akinesia is replaced by akathisia.

Akathisia is a clinical syndrome characterized by a persistent or recurrent unpleasant feeling of internal motor restlessness, an internal need to move or change position, and manifests itself in the inability of the patient to sit still in one position for a long time or to remain motionless for a long time. Often, akathisia that occurs in the first week of treatment is regarded by a specialist as an increase in anxiety or an exacerbation of manic symptoms. The doctor explains the symptoms that have appeared by the fact that the neuroleptic has not yet had time to act, and the psycholeptic effect of atypical antipsychotics is slightly expressed, and often makes an erroneous decision to increase the dose of the drug more quickly. nine0005

When treating children with atypical antipsychotics, we are often faced with the difficult task of qualifying the primary response to the drug: we must distinguish between overdose-related akathisia and increased anxiety and emotional instability with exacerbation of the underlying condition at therapeutically ineffective doses. Akathisia in the appointment of neuroleptics in children with impaired activity and attention can lead to increased hyperactivity and impulsivity and the appearance of severe emotional instability. nine0005

When conducting a differential diagnosis, it can be important to find out from a child whether he experiences mental discomfort from the need to move a lot or when trying to restrain his restlessness. With anxiety or manic symptoms, children never make such complaints.

Dyskinesia in the form of persistent violent movements of the facial muscles, shoulders, legs, fingers, tongue in patients receiving treatment with neuroleptics is usually associated with the consequences of long-term neuroleptic therapy with classical antipsychotics. It has been shown that dyskinesias significantly reduce the quality of life of patients, stigmatize patients, impede social communications, and create difficulties in finding employment. nine0005

Poor quality of life and stigmatization of patients with schizophrenia are often associated with tardive dyskinesia . There is a point of view that the stigma of public perception of patients with schizophrenia is more associated with this extrapyramidal side effect than with the productive and negative symptoms of the disorder.

Traditional risk factors for the development of tardive dyskinesia are older age, female sex, white race. Adults receiving atypical antipsychotics for more than 1 year have a 6-fold lower risk of developing tardive dyskinesia compared with conventional antipsychotic therapy for a similar period of time. nine0005

Children and adolescents appear to be at a lower risk of developing this complication than adults. In the analysis of case histories of 783 children and adolescents treated with risperidone for more than a year, tardive dyskinesia was registered in 0. 4% of cases [3].

We need to monitor the frequency of this complication. It may increase over time as there is a trend in child psychiatric practice to use higher doses of atypical antipsychotics and to increase the average duration of treatment. nine0005

Tardive dyskinesia in children may be a consequence of the withdrawal of antipsychotics. They occur even after slow discontinuation of atypical antipsychotic therapy.

This clinical phenomenon is easy to explain. Children who stop taking antipsychotics, especially if treatment is stopped abruptly, may have increased levels of dopamine neurotransmission. Blockade of dopamine receptors can cause activation of unblocked parts of the brain's dopaminergic system. Usually these violations, often quite severe, are temporary. We need to explain to parents that motor dyskinesias are likely to decrease over time. In cases where motor tics and vocalizations are excessive, they can be stopped by resuming the use of an antipsychotic at a dose that provides a complete reduction in symptoms, followed by a very slow dose reduction. The FDA recommends a dose reduction of 25% per month. nine0005

It is not always easy to distinguish between neuroleptic withdrawal dyskinesias and the initial manifestations of tardive dyskinesia.

The determining factor is the clarification of the time of their appearance. It is important to find out whether they took place before the start of taking antipsychotics, whether their severity changed with varying doses, if this occurred during treatment. It is also important to confirm the compliance of the child. When dyskinesias appear or worsen, it is important to make sure that he continues to take the medicine. Sometimes, when giving a child a drug, the parents let the child go without making sure that the drug has been swallowed. The child can hide the tablet under the tongue or behind the cheek and then spit it out. In such a case, orally dispersible tablets or drinking solutions can be very helpful. Thus, a clear correspondence between the actual use of drugs and the prescription should first be established, and then the classification of movement disorders should be carried out. nine0005

In pediatric practice, it is very important to distinguish between dyskinesias caused by antipsychotic therapy and dyskinesias due to concomitant neurological and psychiatric disorders. The child before the start of treatment must be carefully examined. It is necessary to distinguish between motor disorders associated with hypoxic-ischemic brain damage and birth trauma, dyskinesia in general developmental disorders (disorders from the autism spectrum), gross and fine motor disorders in children with hyperkinetic disorder. nine0005

The presence of dyskinesias associated with a neurological disorder is a predictor of poorer tolerance of atypical antipsychotics in children. The severity of motor impairment during the abolition of antipsychotics in these children may be greater than before they were taken. Rapid discontinuation of therapy can lead to an increase in motor disorders, the appearance of motor and vocal tics, and pathological habitual actions. In some cases, heavy violent movements and vocalizations make it impossible to attend school. nine0005

Atypical antipsychotics for tic disorders and de la Tourette's syndrome in children

In transient tics, antipsychotics should be avoided in children. The disease proceeds in waves, and periods of exacerbation of tic symptoms are replaced by regular periods of mitigation of motor disorders and remissions. The duration of the disorder usually does not exceed 12 months. This disorder does not require treatment. If tics are multiple, worse with age, accompanied by echopraxia, which in some patients may be obscene, antipsychotic therapy is indicated. nine0005

Children with chronic motor and vocal tics are characterized by increased levels of dopamine neurotransmission in the motor tracts. This determines the affinity of motor disorders in de la Tourette's syndrome to antipsychotics that act on dopamine receptors of the striopallidar system. When deciding on the pharmacotherapy of Tourette's syndrome, one should always weigh what will affect the child's quality of life to a greater extent - tics or side effects associated with long-term use of antipsychotics or clonidine. nine0005

In 2011, clinical guidelines for the pharmacological treatment of Tourette's syndrome were published in the European Child and Adolescent Psychiatry [4]. Risperidone, aripiprazole, pimozide, sulpiride, tiapride and haloperidol received a positive assessment from the experts.

Due to extrapyramidal side effects and the risk of developing tardive dyskinesias, long-term use of haloperidol and pimozide in pediatric practice is not possible. Tiapride, sulpiride have the largest evidence base, are better tolerated and are the first-line drugs of choice for this disorder. In a number of countries, tiapride is included in clinical protocols for the treatment of Tourette's syndrome. Our data also indicate good efficacy and tolerability of amisulpride. nine0005

Quetiapine, olanzapine, and ziprasidone are not drugs of choice in the treatment of chronic tic disorder.

In Tourette's syndrome, the neuroleptic should be prescribed at doses that stop motor disturbances in children, but do not cause unacceptable side effects. After achieving a clinical effect and therapy for 4-6 months, the antipsychotic is very slowly, over 6-12 months, canceled.

Metabolic and endocrine side effects of the use of atypical antipsychotics in pediatric practice

When using traditional antipsychotics, psychiatrists are more concerned about monitoring extrapyramidal side effects and the risk of developing tardive dyskinesia. They usually have a sufficient level of competence to diagnose neurological side effects early.

Atypical antipsychotics are more associated with cardiometabolic side effects - weight gain, impaired glucose metabolism and lipid metabolism. Psychiatrists, child psychiatrists do not always have sufficient training for the early detection and evaluation of such disorders. nine0005

All antipsychotic drugs can cause metabolic side effects, but their likelihood and severity vary greatly. Clozapine and olanzapine cause metabolic disturbances most frequently. Risperidone and quetiapine have a significant but lower risk than olanzapine and clozapine. To the least extent, ziprasidone and aripiprazole can cause metabolic disorders.

There is some evidence that children are more sensitive to metabolic side effects than adults. One study found that in adults, aripiprazole therapy causes fewer metabolic disorders than in children [5]. Children are more sensitive to therapy with any antipsychotic, such therapy has a greater risk of metabolic disorders, and therefore monitoring of the safety and tolerability of therapy in them should be carried out more strictly. nine0005

Before prescribing an atypical antipsychotic to a child, a family history of obesity, diabetes, and cardiovascular disease should be ascertained. It is necessary to determine the basic level of fasting glucose, lipid profile, evaluating total cholesterol, triglycerides, lipoproteins (low and high density), measure weight, height and blood pressure. It is recommended to monitor the indicators of carbohydrate and lipid metabolism, the weight of the child during treatment every 6 months [2, 6]. nine0005

Many psychiatrists fail to diagnose hyperglycemia, insulin resistance, and dyslipidemia in children taking atypical antipsychotics. They do not always pay attention to the increase in the level of cholesterol and low-density lipoproteins, in particular triglycerides, which are closely associated with insulin resistance.

Therapy with atypical antipsychotics is often accompanied by significant weight gain, requiring special measures to reduce it. The developed phenomena of insulin resistance are associated with type 2 diabetes and require special treatment. nine0005

Physicians who monitor the side effects of atypical antipsychotics in children may overestimate some of the child's complaints, mistakenly regarding them as manifestations of cardiometabolic disorders.

For example, children taking atypical antipsychotics often complain of dry mouth. This symptom can be unreasonably interpreted as a manifestation of diabetes mellitus. With a detailed questioning of most children, it turns out that they complain more about stickiness in the mouth, the viscosity of saliva than the feeling of thirst. An ice cube or chewing gum can eliminate the discomfort that indicates an autonomic imbalance in the early stages of taking antipsychotics, and not the overt symptoms of diabetes. nine0005

Another example of a false-positive diagnosis of cardiometabolic disorders: not every increase in height and weight in children taking atypical antipsychotics is in favor of the metabolic syndrome. It is important to establish not an increase in absolute values, but an excess of age standards. Some general practitioners pay attention not so much to weight as to the waist size of children. An increase in waist circumference is a natural sign of metabolic syndrome, but the American Academy of Pediatrics does not recommend using this indicator as a screening indicator (primarily because it can be very difficult to make reliable measurements in real practice). More reliable is the estimated BMI (body mass index). nine0005

Metabolic syndrome is diagnosed when at least three out of five diagnostic criteria are met in children [7]: 1) the presence of sex- and age-adjusted overweight (obesity) ≥ 95 percentiles; 2) having sex- and height-adjusted high blood pressure (hypertension) ≥ 90 percentiles; 3) triglycerides ≥ 150 mg/dL (1. 7 mmol/L) or more; 4) NSAID cholesterol < 40 mg/dL (1.03 mmol/L) for both sexes; 5) Elevated baseline glucose (hyperglycemia) ≥ 100 mg/dL (5.6 mmol/L) or higher. nine0005

The presence of C-reactive protein is also not among the indicators to be screened when prescribing atypical antipsychotics to children. The appearance of C-reactive protein is closely related not only to the toxic effect of atypical antipsychotics, but also to cardiovascular diseases caused by viral and bacterial infections. This makes it difficult to interpret abnormal readings.

In real clinical practice, it is much easier to follow common indicators of the metabolic syndrome. But it is also important not to ignore dysmetabolic changes that do not reach the criteria of the metabolic syndrome. nine0005

Atypical antipsychotic weight gain

There is a point of view that children with an asthenic constitution are less likely to develop the metabolic syndrome when taking atypical antipsychotics than those with a pycnotic one. These ideas have not found scientific confirmation. It is considered proven that the baseline BMI [7] is not a predictor of greater or lesser weight gain during therapy. It has also been established that there are individuals prone to the manifestation of this side effect and not prone to dysmetabolic disorders when taking any atypical antipsychotics. The best way to predict the risk of weight gain when treated with atypical antipsychotics is to monitor weight during the first four weeks of taking the drug. Height-adjusted weight gain during these four weeks shows a high degree of correlation with weight gain during subsequent therapy. nine0005

Olanzapine causes the greatest weight gain in children, risperidone and quetiapine lead to more moderate weight gain. To the least extent, an increase in BMI is accompanied by therapy with ziprasidone and aripiprazole.

The risk of a significant increase in BMI in children is much higher than in adults. Significant weight gain occurs in 2–6% of adults and in 25–40% of children under 8 years of age. According to our data, a significant increase in weight when prescribing risperidone to children of preschool and primary school age was observed in 42%, in the treatment of olanzapine - in 83% of cases. We have not registered any case of a significant increase in the weight of the child after the appointment of quetiapine and aripiprazole. nine0005

Atypical antipsychotic-induced hyperprolactinemia

The problem of side effects associated with high prolactin levels in antipsychotic therapy was actualized by clinicians several decades ago. When using atypical antipsychotics in adult patients, the risk of such side effects is lower than when treated with conventional antipsychotics. Children and adolescents appear to be at a higher risk of developing side effects associated with high prolactin levels than adults [8]. nine0005

When prescribing atypical antipsychotics to children, we are mainly concerned with the possibility of prolactin reaching levels leading to hypogonadism. High prolactin can lead to suppression of the production of sex hormones and impaired puberty. Along with hypogonadism, long-term high prolactin levels are associated with osteoporosis.

High prolactin levels are most commonly seen with risperidone, and the risk of prolactinemia is lower with other antipsychotics. nine0005

It is difficult to say what level of prolactin is unacceptable in terms of the risk of developing hypogonadism and can serve as a basis for reconsidering further therapy.

In prepubertal age, the level of prolactin does not significantly affect the sexual development of a child, and during puberty, even relatively low levels of prolactin can significantly affect the sexual development of a teenager.

Unfortunately, we do not have reliable data on the relationship between the level of prolactin and delayed sexual development in children and adolescents, which does not allow us to predict the risk of these complications by the level of prolactin during antipsychotic therapy. We also do not know subclinical levels of prolactin, which may be potentially harmful to prepubertal child development and puberty. Additional specific studies are needed. However, if we register a prolactin level of 200 ng/dL or higher in a child, then this should be a source of concern. In the presence of high prolactin, not associated with the use of atypical antipsychotics, we must first rule out a pituitary tumor in the child. nine0005

Current recommendations are to look for clinical signs and symptoms of potential hypogonadism in children receiving antipsychotics and, if screening is positive, to monitor prolactin levels.

In the presence of endocrine disorders associated with hyperprolactinemia, it is advisable to consider changing the atypical antipsychotic or reducing its dose.

The presence of amenorrhea or oligomenorrhea in girls with an irregular menstrual cycle is of relative diagnostic value and does not necessarily indicate an imbalance of sex hormones. Galactorrhea is more likely to indicate a high level of prolactin and a violation of estrogen levels. In the case of galactorrhea, even without determining the level of prolactin in the blood serum, it is advisable to reduce the dose of the atypical antipsychotic. Another sign of hypogonadism is gynecomastia, an enlargement of breast tissue. Both galactorrhea and gynecomastia can be diagnosed in both boys and girls. Weight gain in boys can occur in large part through an increase in breast tissue. In these cases, palpation can establish a glandular consistency of the mammary glands. nine0005

It is logical to assume that high prolactin levels and changes in testosterone and estrogen levels are accompanied by changes in sexual behavior and sexual dysfunctions, but screening for such disorders in pediatric practice has no clinical significance. Many teenagers do not know what normal sexual behavior should look like at their age and are unable to objectively assess their sexuality.

The efficacy and safety of the use of atypical antipsychotics in children largely depend on their adherence to a healthy lifestyle and adherence to regimen measures

The effectiveness of antipsychotic therapy in children is largely associated with compliance with a number of regimen measures and the formation of a commitment to a healthy lifestyle. The use of atypical antipsychotics can lead to increased appetite and increased food intake by the child. It is necessary to control the amount of food eaten and its calorie content. With dietary recommendations and sufficient physical activity, it is possible to significantly reduce the risk of metabolic disorders. nine0005

In some patients, the need for smoking increases. Smoking, on the one hand, improves the tolerance of extrapyramidal side effects, on the other hand, it can reduce the antipsychotic activity of clozapine and olanzapine.

The effectiveness of ziprasidone is largely dependent on the caloric content of the diet. Absorption of the drug depends on food intake. If the calorie content of the latter is less than 500 calories, the serum concentration of the drug may be 50% lower. nine0005

A big problem is the interaction of atypical antipsychotics with alcohol. Obviously, adolescents suffering from a mental disorder should be prescribed abstinence from alcohol and drugs. Another question is how to ensure the implementation of these prescriptions. It is difficult to be sure that adolescents who are integrated into a peer group will be able to observe the regime of absolute abstinence from drinking alcohol. Teenagers can stop taking medication if we tell them to never mix medication with alcohol. We need to talk to the teenager about a realistic treatment strategy, including for episodic withdrawal violations. For example, we may recommend that a teenager, in an exclusive case, limit himself to taking only one drink and postpone the medication to a later time, for example, to drink it after returning home from a party. nine0005

Adherence to therapy is a prerequisite for its effectiveness. When prescribing atypical antipsychotics to children, we are always looking for a balance between the severity of the deterioration in social functioning in the case of an untreated mental disorder and the somatic consequences, a reduction in their life expectancy due to cardiometabolic side effects.

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