Brief characteristics of the drug
Olanzapine - "Egolanza", "Zyprexa" - is an atypical antipsychotic, characterized by a variety of pharmacological actions. In addition to its affinity for the receptors of the main neurotransmitters, the drug selectively inhibits the excitability of mesolimbic structures. In this case, areas of the brain that regulate motor activity are practically not involved. That is, the substance has all the necessary properties of antipsychotics, but treatment is extremely rarely accompanied by movement (extrapyramidal) disorders.
An antipsychotic drug is indicated for the treatment of patients with schizophrenia, bipolar disorder and other psychoses. Taking olanzapine is associated with an increased risk of metabolic disorders (increased cholesterol levels), obesity, and diabetes mellitus. The second most important side effect for patients is drowsiness and slower reaction speed. “Withdrawal” is one of the main signs of addiction or dependence on a drug.
In modern conditions, it becomes possible for practicing doctors of various specialties to use the widest information field for interdisciplinary interpenetration in the treatment of various diseases. Successful and correct use of specific medications, which include antipsychotics, is impossible without knowledge of not only their formal indications, contraindications and side effects, but also a correct understanding of their mechanism of action and the justification of their prescription. In recent years, olanzapine has found wide use not only in psychiatric hospitals as one of the main antipsychotics, but also in outpatient settings as a frequently used drug for postpsychotic maintenance and preventive treatment [2], as well as in the treatment of borderline neurosis- and psychopathic conditions, for example depersonalization, anxiety, obsessive-compulsive disorders, as well as negative personality disorders with social decline, weakening of motivation, and cognitive impairment. Consequently, cardiologists, neurologists, endocrinologists and other specialists are increasingly faced with patients taking olanzapine or who may need to take it.
Olanzapine is a modern atypical antipsychotic. This group of drugs is characterized primarily by the absence or presence of only dose-dependent extrapyramidal side effects, such as parkinsonism, dystonia, tremor, athetosis, akathisia, tics, myoclonus, stereotypies. Thanks to better tolerability of atypical antipsychotics, and olanzapine in particular, the serious problem of low patient adherence to treatment and prevention of periodic psychoses and endogenous diseases with a continuous course was solved. This is also the reason for the successes in preventing the occurrence of tardive malignant dyskinesias associated with the use of traditional neuroleptics (haloperidol, triftazine, clopixol, etc.), which required a separate approach and were difficult to treat [12].
Another very important feature of atypical antipsychotics, incl. and olanzapine, serves the ability to significantly reduce the severity of negative symptoms (emotional flatness, thinking disorders, decreased social activity, impoverished speech). According to its chemical structure, olanzapine is a derivative of thienobenzodiazepine. Structurally, olanzapine is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2.3-b][1,5]benzodiazepine. The drug was registered in Russia in 1997 (registration certificate P-8-242 No. 009601) and began to be actively used in the 2000s. Doctors and patients first became aware of olanzapine under the commercial name Zyprexa (Eli Lilli). The drug has various forms of release: tablets and liquid in the form of an injection solution. At the moment, in addition to the original drug, there are a considerable number of generics of olanzapine on the Russian market, such as Zyprexa-Zidis, also produced by Eli Lilli, Zalasta and Zalasta-Ku-tab (KRKA), Olanzapine (Teva, Israel; KERN Pharma), Egolanza (EGIS ), parnasan (Gedeon Richter).
Features of the pharmacokinetics and pharmacodynamics of olanzapine
It was found that the drug binds to dopamine receptors type D1, D2, D3, D4 and D5, serotonin receptors type 5HT2A, 5HT2C, 5HT3 and 5HT6, histamine receptors - H1- and α1-adrenergic receptors, as well as muscarinic receptors - M1. The tropism of olanzapine for serotonin receptors exceeds the affinity for dopaminergic receptors of type D2, which is a distinctive feature of all atypical antipsychotics. In general, the comparative antagonistic effect of olanzapine on neuroreceptors can be represented as follows: 5HT2A > H1 > 5HT2C > M1 > D2 > D4 > α1.
Accordingly, in a clinical setting, olanzapine reduces the manifestations of negative symptoms (due to blockade of serotonin receptors of the 5HT2A type), causes a moderate sedative effect and increased appetite (due to blockade of histamine receptors). The relatively weak blockade of dopamine receptors relative to cholinergic muscarinic receptors suggests the absence of adverse neurological effects. Weak blockade of α-adrenergic receptors indicates the absence of inhibition, excessive sedation and effects on vascular tone (orthostatic hypotension and reflex tachycardia). Thus, the profile of psychopharmacological activity of olanzapine is characterized by significant polyvalency, which distinguishes the drug from both classical and some new atypical antipsychotics. When studying and analyzing pharmacokinetics, it was found that the maximum concentration of the drug in the blood plasma after a single oral dose is reached after 5–8 hours. Olanzapine is rapidly absorbed from the gastrointestinal tract regardless of food intake. The concentration of the drug in plasma increases in proportion to the administered dose. Its half-life is on average 33 hours, which allows it to be taken once a day. In persons over 65 years of age, the half-life of olanzapine may be significantly prolonged, so average daily doses of the drug should be lower than usual. Steady-state concentrations of the drug in plasma are achieved after 5–7 days of administration. About 60% of olanzapine is excreted as metabolites in the urine, but in individuals with impaired renal function, the half-life and clearance of olanzapine do not change [10, 11].
It was found that carbamazepine and phenytoin cause induction of the CYP3A enzyme, which may lead to a decrease in olanzapine plasma concentrations in some patients. On the contrary, fluoxetine, fluvoxamine and cimetidine inhibit the activity of CYP1A2 enzymes, which may cause an increase in plasma concentrations of the drug [22, 23].
Against the background of a stable concentration of olanzapine, the pharmacokinetics of ethanol does not change. However, taking ethanol with olanzapine may be accompanied by increased pharmacological effects of olanzapine, such as sedation. Concomitant use of olanzapine with ethanol or diazepam increases the risk of orthostatic hypotension.
In vitro, olanzapine exhibits dopamine antagonism and, like other antipsychotics, could theoretically inhibit the effects of levodopa and dopamine agonists.
From all of the above, we can conclude that olanzapine has a fairly wide range of uses.
According to official information about the indications for use of the drug, these include:
- Treatment of exacerbations; maintenance and long-term anti-relapse therapy for schizophrenia and other psychotic disorders with pronounced productive (including delusions, hallucinations, automatisms) and/or negative (including emotional flatness, decreased social activity, impoverished speech) symptoms, as well as concomitant affective disorders (ICD-10 category F20.0) [13, 15, 18, 19].
- Treatment of acute manic or mixed episodes in bipolar disorder (manic episode F30.0; bipolar disorder F31.0; bipolar disorder, current manic episode without psychotic symptoms F31.1; bipolar disorder, current episode with psychotic symptoms F31.2 [15, 21].
Along with the information obtained from studies on the general effectiveness of this drug, comparative studies with traditional antipsychotics in the treatment of acute psychoses were also conducted. These studies revealed the high effectiveness of olanzapine, which is not inferior to traditional antipsychotics. [5, 7, 14, 20, 24].
The typical dynamics of the antipsychotic action of olanzapine is as follows: as a rule, in the first days of use, a certain sedative effect is observed without pronounced inhibition, which manifests itself in the form of mild drowsiness, reduction of anxiety and psychomotor agitation. As they adapt to the action of the drug, the severity of sedation decreases, patients become more active [1].
In patients with exacerbations of paranoid schizophrenia, from the first days one can note the effect of the drug on the severity of delusional disorders, negativism, aggressiveness and other behavioral disorders, which are reduced almost simultaneously with affective disorders (fear, anxiety, phenomena of confusion). During the first two weeks of therapy, patients become more accessible and open about their experiences, which they willingly begin to share with their doctor. It is significant that quite quickly (within 2-3 weeks) criticism is restored in many patients and partial awareness of the disease arises even in the presence of preserved delusional and hallucinatory disorders [3, 6, 13].
The above is especially important for developing the patient’s adherence to therapy. As a rule, the patient assesses therapeutic success quite positively and associates this effect with treatment. This reaction is most noticeable in patients with repeated attacks of the disease, when they note the absence of inhibition, “drug load,” and adverse neuroleptic manifestations, which, as a rule, is inevitably associated with therapy with classical antipsychotics. Such a positive attitude allows you to continue therapy and influence negative symptoms in the form of autism, emotional flattening, and difficulties in contact with others. Patients become more and more interested in the world around them, begin to take an interest in the state of affairs in the family, and take warm care of their relatives and friends. At the same time, liveliness, activity, emotionality, naturalness, and openness appear in the external appearance of patients, which were absent in the acute period of the disease. Verbal communication with staff and other patients is normalized. Lastly (after 6–8 weeks), the thinking ability of patients (cognitive sphere) improves.
Experience in treating patients with paranoid schizophrenia with a predominance of negative disorders with olanzapine shows that a stable reduction of negative symptoms on the PANSS (Positive and Negative Syndrome Scale) scale [4, 17] is observed within 6 months and only after that it slows down and in some patients reaches a plateau level. In general, correction of deficiency manifestations (negative and cognitive impairments) occurs extremely gradually and requires long-term (from 3 to 9 months) therapy with olanzapine in combination with adequate psychotherapy, differentiated psychological correction and social and labor rehabilitation [16].
The dynamics of psychotic symptoms during the treatment of schizoaffective disorder and other acute psychoses with olanzapine are harmonious. At the same time, in the 2-3rd week of therapy, there is a uniform reduction of both affective and delusional and hallucinatory disorders with a rapid restoration of criticism to psychosis. All this is accompanied by an increase in the mental activity of patients. In some cases, there is an abrupt termination of the attack with a complete reduction of all productive disorders and criticism of the disease, which resembles the effect of shock methods. This occurs especially often in acute conditions accompanied by intense affects (fear, anxiety, ecstasy, anger, confusion), variability of symptoms, disturbances of consciousness, and oneiric-catatonic disorders.
The effectiveness of the drug in patients with schizoaffective disorder is generally higher than in patients with schizophrenia, which is typical for all antipsychotics. The nature of the reduction of affective symptoms during olanzapine therapy shows that several better treatment results can be achieved in the presence of depressive affect in the picture of acute psychosis, incl. with depressive-paranoid variant. Manic-delusional and especially manic states respond somewhat worse to drug therapy. For faster control of agitation, the addition of sedative neuroleptics is often required. Nevertheless, the drug can be used both for the relief of acute manic-delusional states and for the treatment of psychoses of a more complex structure with distinct manic inclusions [21].
Particular attention should be paid to the nature of the somatotropic effects of olanzapine. The drug is very characterized by the so-called trophotropic effect, which is expressed not only in an increase in body weight [9], but also in the normalization of eating behavior in general, as well as in improving the color of the skin and mucous membranes. This is relevant for depressive-delusional states with a sharp decrease in appetite at the height of the depressive state (F31.5).
The profile of psychotropic activity of olanzapine allows the drug to be used in the treatment of almost all clinical forms of schizophrenia with varying severity of productive and negative symptoms and at different stages of the pathological process, i.e. in the treatment of both acute and subacute, and chronic conditions, incl. with severe deficiency disorders. The use of olanzapine as a maintenance therapy for patients with long-term schizophrenia is justified. In these cases, you can use the drug as monotherapy and count on the development of a persistent preventive (anti-relapse) effect with an improvement in neurocognitive processes in patients. This in turn leads to an increase in the level of their social adaptation and quality of life.
Due to its proven effectiveness in the treatment of negative disorders, olanzapine has been widely used in outpatient therapy for disorders such as neurosis-like (obsessive-compulsive, depersonalization), psychopathic-like and behavioral disorders in low-progressive schizophrenia and schizotypal disorder (F21). Patients in this group note an improvement in performance, cognitive capabilities, an increase in motivation, as well as a significant weakening of depersonalization disorders (alienation, deautomation and mental processes), a reduction in obsessive disorders, and improved communication.
Method of use of olanzapine and dosing features
Doses of the drug are selected empirically depending on the clinical picture of psychosis. The drug can be taken once a day, regardless of meals. The standard starting dose of olanzapine is 5–10 mg/day. If necessary, the dose is gradually increased, but increasing the daily dose above 15 mg is recommended no earlier than 4 days after starting the drug.
It should be borne in mind that improvement can be achieved at low to medium doses. The maximum daily dose is 20 mg. Although increasing the dosage is not accompanied by an increase in the number of side effects, there is also no noticeable increase in the clinical effect. Therefore, exceeding a dose of 20 mg/day is not recommended. When treating elderly and senile people, as well as people with severe somatic pathology, the drug should be used in doses 1.5–2.0 times less.
In the treatment of schizophrenia and similar psychotic disorders, lower doses of olanzapine (about 5–10 mg/day) can be recommended for patients with a low progression of the process, and for more progressive forms (paranoid continuous, juvenile malignant and paranoid paroxysmal forms) - medium and high doses of the drug (15–20 mg/day). In forms with a large proportion of affective and sensory-delusional symptoms, i.e. in cases of obvious paroxysmal forms and schizoaffective disorder, the effective dose should be selected empirically, but usually it rarely exceeds 15 mg / day. With the so-called chronic delusional psychoses (paranoid disorders), the dose should be maximum, i.e. 20 mg/day [1]. Treatment of patients prone to developing sedation can begin with a dose of 5 mg/day.
The period of stabilization of the mental state lasts at least 2–3 months. With complete control of the condition, the dose of olanzapine is gradually reduced and is usually 10–15 mg/day. The development of side effects is a signal to reduce the dose or discontinue the drug.
Maintenance (anti-relapse) therapy is usually carried out in doses worked out at the previous stage. It is recommended to maintain the dose level for several months, after which an attempt can be made to reduce the dose. In good condition (without psychotic symptoms and with minimal severity of the defect), the question of stopping the drug can be considered no earlier than after 1.5–2.0 years of continuous use. In newly diagnosed patients with schizophrenia, i.e. who have experienced a first psychotic episode, the duration of continuous maintenance therapy with olanzapine should also be at least 2 years [2]. The duration of continuous use of the drug in patients with a history of a greater number of episodes increases by another 2–3 years.
Transferring from classical antipsychotics to olanzapine is possible at any stage of patient treatment, especially in cases of severe extrapyramidal side effects or resistance to therapy [8]. As a rule, cross-use of drugs is carried out, followed by a gradual reduction in doses of previous therapy. The initial dose and rate of increase in the dose of olanzapine depend on the clinical condition of the patient. Despite the fact that olanzapine extremely rarely causes side extrapyramidal disorders and even, according to some studies, can have a positive effect on their dynamics, in the presence of pronounced neuroleptic manifestations due to previous therapy, anticholinergic correctors should be continued for some time.
Side effects, precautions and complications
Side effects during therapy with olanzapine are of a special nature and differ significantly from those of classical antipsychotics. One of the most common side effects (observed in at least 30–50% of patients) is weight gain. This is associated with the high antihistamine activity of the drug, which stimulates appetite and, accordingly, leads to an increase in body weight.
On average, the increase in body weight is about 2 kg over 6 weeks of therapy. In approximately one third of patients taking olanzapine, body weight gain is more than 7% of the initial weight [9]. In order to correct this side effect, the patient is first recommended to diet with a reduced calorie content; if ineffective, the daily dose of the drug may be reduced. It has been established that in most patients, the increase in body weight as olanzapine treatment continues reaches a plateau in the 2nd–3rd month and no longer progresses.
The second most common side effect, developing in almost a third of patients, is drowsiness, which is also associated with the antihistamine properties of the drug. Drowsiness is usually more pronounced in the first days of taking olanzapine, and disappears as treatment continues and adaptation to the action of the drug.
Another significantly common side effect in patients receiving olanzapine (about a third) is a slight increase in plasma prolactin concentrations. Clinical manifestations of hyperprolactinemia associated with olanzapine (gynecomastia, galactorrhea and breast enlargement) are rare. In most patients, normalization of prolactin levels is observed without discontinuation of the drug. However, periodic screening for hyperprolactinemia is recommended during long-term use of olanzapine [10]. Side effects associated with anticholinergic effects (dizziness, akathisia, tremor, dyspeptic disorders, peripheral edema, orthostatic hypotension, dry mouth, constipation, urinary retention), although they develop quite rarely, should be kept in mind by persons with clinically significant prostate hypertrophy, angle-closure glaucoma, paralytic ileus and similar conditions.
Compared to classical antipsychotics, olanzapine practically does not cause extrapyramidal side effects such as drug-induced parkinsonism, acute and tardive dyskinesias [24]. However, it should be remembered that as the daily dose of the drug and the duration of use increase, the likelihood of their occurrence increases and some patients may experience drug-induced akathisia during olanzapine therapy (about 5%). In these cases, it is advisable to prescribe antiparkinsonian correctors, benzodiazepine tranquilizers or β-blockers.
In laboratory studies, a transient, asymptomatic increase in liver transaminases, an increase in plasma glucose levels of more than 200 mg/dL (suspicious of diabetes), as well as from 160 to 200 mg/dL (suspicious of hyperglycemia) in patients with initial levels are rarely observed. glucose less than 140 mg/dl. Therefore, for patients at increased risk, it is advisable to consult an endocrinologist and undergo multiple blood tests for sugar levels. If ketoacidosis develops and the diagnosis of diabetes mellitus is confirmed, olanzapine therapy should be discontinued immediately.
After prolonged treatment, withdrawal syndrome may develop (so-called cholinergic rebound symptoms). Its risk when discontinuing this drug (as well as clozapine) is significantly higher than when discontinuing traditional antipsychotics. The reasons for its occurrence are presumably related to the development of hypersensitivity of cholinergic and dopaminergic receptors when taking an antipsychotic, as well as the fact that the serotonergic, noradrenergic, GABAergic and serotonergic systems are involved. Abrupt withdrawal of olanzapine is permissible only in the presence of serious clinical indications, and it is not advisable to discontinue the drug without consulting a doctor and without gradually reducing the dose.
When using the drug in patients with dementia of the Alzheimer's type, gait disturbances may occur.
Olanzapine withdrawal syndrome can include symptoms ranging from physical discomfort to severe psychosis. When olanzapine is discontinued, insomnia, anxiety, agitation, and irritability may develop. Despite the low risk of extrapyramidal disorders while taking olanzapine, these disorders may worsen if this drug is abruptly discontinued.
Thus, taking into account all the features of this drug, correct prescription, careful monitoring of adverse events and correction of somatic effects, the possibility of its successful use both in a psychiatric hospital and in an outpatient setting is created.
Description of withdrawal syndrome
Withdrawal syndrome, or withdrawal reaction, is a set of clinical manifestations associated with stopping taking a drug. The severity of the patient’s condition depends on the treatment regimen (dose, regimen, duration), but the main role is played by the individual characteristics of the person. All other things being equal, the severity of symptoms will vary from person to person.
Causes of withdrawal
The pharmacokinetics of olanzapine largely depends on age, activity of the underlying disease, condition of internal organs and gender. The following risk factors for the development of neuroleptic withdrawal syndrome are identified:
- abruptly stopping the drug
- long course of therapy with one drug
- dose reduction not agreed with the doctor
- violation of the treatment regimen
- short duration of pharmacotherapy, especially when using maximum daily doses - less than 6 months, sometimes 2 weeks are enough
- simultaneous discontinuation of other medications that correct mental status
- replacing one antipsychotic with another due to stabilization of the patient’s condition, or vice versa, the appearance of new symptoms
