Антипсихотичні препарати

Conventional antipsychotics (see table Conventional Antipsychotics) act primarily by blocking the dopamine-2 receptor (dopamine-2 blockers).

Conventional antipsychotics can be classified as high, intermediate, or low potency. High-potency antipsychotics have a higher affinity for dopamine receptors and less for alpha-adrenergic and muscarinic receptors. Low-potency antipsychotics, which are rarely used, have less affinity for dopamine receptors and relatively more affinity for alpha-adrenergic, muscarinic, and histaminic receptors.

Different drugs are available in tablet, liquid, and short- and long-acting IM preparations. A specific drug is selected primarily based on the following:

• Adverse effect profile

• Required route of administration

• The patient’s previous response to the drug

Conventional antipsychotics may cause significant adverse effects, particularly some related to cognition and extrapyramidal movement disorders (eg, dystonia, tremor, tardive dyskinesia).

About 30% of patients with schizophrenia do not respond to conventional antipsychotics. They may respond to clozapine, an SGA.

About 95% of all antipsychotics prescribed in the US are SGAs.

SGAs block dopamine receptors more selectively than conventional antipsychotics, decreasing the likelihood of extrapyramidal (motor) adverse effects. Greater binding to serotonergic receptors may contribute to the antipsychotic actions on positive symptoms and the adverse effect benefits of SGAs.

SGAs also do the following:

• Tend to alleviate positive symptoms

• May lessen negative symptoms to a greater extent than do conventional antipsychotics (although such differences have been questioned)

• May cause less cognitive blunting

• Are less likely to have extrapyramidal adverse effects (including a much lower risk of tardive dyskinesia)

• Increase prolactin slightly or not at all (except risperidone, which increases prolactin as much as do conventional antipsychotics)

• Can generate a metabolic syndrome, with insulin resistance, weight gain, and hypertension.

SGAs may appear to lessen negative symptoms because they are less likely to have parkinsonian adverse effects than conventional antipsychotics.

Clozapine, the first SGA, is the only SGA shown to be effective in up to 50% of patients resistant to conventional antipsychotics. Clozapine reduces negative symptoms, reduces suicidality, has few or no motor adverse effects, and has minimal risk of causing tardive dyskinesia, but it has other adverse effects, including sedation, hypotension, tachycardia, weight gain, type 2 diabetes, and increased salivation. It also may cause seizures in a dose-dependent fashion. The most serious adverse effect is agranulocytosis, which can occur in about 1% of patients. Consequently, frequent monitoring of white blood cells (done weekly for the first 6 months and every 2 weeks thereafter, then once a month after a year) is required in the US, and clozapine is generally reserved for patients who have responded inadequately to other drugs.

Newer SGAs (see table Second-Generation Antipsychotics) provide some of the benefits of clozapine without the risk of agranulocytosis and are generally preferable to conventional antipsychotics for treatment of an acute episode and for prevention of recurrence. However, in a large, long-term, controlled clinical trial, symptom relief using any of 4 SGAs (olanzapine, risperidone, quetiapine, ziprasidone) was no greater than that with perphenazine, a conventional antipsychotic with anticholinergic effects. In a follow-up study, patients who left the study prematurely were randomized to one of the 3 other study SGAs or to clozapine; this study demonstrated a clear advantage of clozapine over the other SGAs. Hence, clozapine seems to be the only effective treatment for patients who have failed treatment with a conventional antipsychotic or an SGA. However, clozapine remains underused, probably because of lower tolerability and need for continuous blood monitoring.

Lumateperone is the newest SGA for treatment of schizophrenia in adults. It appears to improve psychosocial function with fewer metabolic and motor side effects. It should not be used in older patients with dementia-related psychosis, in whom it carries an increased risk of death. Other side effects include sedation and dry mouth.

Newer SGAs are very similar to each other in efficacy but differ in adverse effects, so drug choice is based on individual response and on other drug characteristics. For example, olanzapine, which has a relatively high rate of sedation, may be prescribed for patients with prominent agitation or insomnia; less sedating drugs might be preferred for patients with lethargy. A 4- to 8-week trial is usually required to assess full efficacy and adverse effect profile. After acute symptoms have stabilized, maintenance treatment is initiated; for it, the lowest dose that prevents symptom recurrence is used. Aripiprazole, olanzapine, and risperidone are available in a long-acting injectable formulation.

Weight gain, hyperlipidemia, and elevated risk of type 2 diabetes are the major adverse effects of SGAs. Thus, before treatment with SGAs is begun, all patients should be screened for risk factors, including personal or family history of diabetes, weight, waist circumference, blood pressure, and fasting plasma glucose and lipid profile. Those found to have or be at significant risk of metabolic syndrome may be better treated with ziprasidone or aripiprazole than the other SGAs. Patient and family education regarding symptoms and signs of diabetes, including polyuria, polydipsia, weight loss, and diabetic ketoacidosis (nausea, vomiting, dehydration, rapid respiration, clouding of sensorium), should be provided. In addition, nutritional and physical activity counseling should be provided to all patients when they start taking an SGA. All patients taking an SGA require periodic monitoring of weight, body mass index, and fasting plasma glucose and referral for specialty evaluation if they develop hyperlipidemia or type 2 diabetes.

Sometimes, combining an antipsychotic with another drug is beneficial (1). These drugs include

• Antidepressants/selective serotonin-norepinephrine reuptake inhibitors

• Another antipsychotic

• Lithium

• Benzodiazepines

Investigational new drugs that antagonize the dopamine receptor are under development, including ABT-925, BL1020, ITI 007, JNJ-37822681, and other novel drugs (2).

Some conventional and second-generation antipsychotics (SGAs) are available as long-acting depot preparations (see table Depot Antipsychotic Drugs). These preparations are useful for eliminating drug nonadherence. They may also help patients who, because of disorganization, indifference, or denial of illness, cannot reliably take daily oral drugs.

Conventional antipsychotics have several adverse effects, such as sedation, cognitive blunting, dystonia and muscle stiffness, tremors, elevated prolactin levels (causing galactorrhea), weight gain, and lowered seizure threshold in patients with seizures or at risk of seizures (for treatment of adverse effects, see table Treatment of Acute Adverse Effects of Antipsychotics). Akathisia (motor restlessness) is particularly unpleasant and may lead to nonadherence; it can be treated with propranolol.

Second-generation antipsychotics are less likely to cause extrapyramidal (motor) adverse effects, including tardive dyskinesia, but these may occur. Metabolic syndrome (excess abdominal fat, insulin resistance, dyslipidemia, and hypertension) is a significant adverse effect with many SGAs.

Tardive dyskinesia is an involuntary movement disorder most often characterized by puckering of the lips and tongue, finger movements, writhing of the arms or legs, or more. For patients taking conventional antipsychotics, the incidence of tardive dyskinesia is about 5% each year of drug exposure and incidence is considerably lower with SGAs. In about 2%, tardive dyskinesia is severely disfiguring. In some patients, tardive dyskinesia persists indefinitely, even after the drug is stopped. Because of this risk, patients receiving long-term maintenance therapy should be evaluated at least every 6 months. Rating instruments, such as the Abnormal Involuntary Movement Scale, should be used to more precisely track changes over time. Patients who have schizophrenia and who continue to require an antipsychotic drug may be treated with clozapine or quetiapine, which are SGAs. Valbenazine, a vesicular monoamine transporter-2 inhibitor, has recently been approved for treatment of tardive dyskinesia. Starting dose is 40 mg once a day and, in the absence of liver dysfunction, after 1 week is increased to 80 mg once a day. The most important adverse effects are hypersensitivity, somnolence, QT prolongation, and parkinsonism.

Neuroleptic malignant syndrome, a rare but potentially fatal adverse condition, is characterized by rigidity, fever, autonomic instability, and elevated creatine kinase.

1. 1. Correll CU, Rubio JM, Inczedy-Farkas G, et al: Efficacy of 42 pharmacologic cotreatment strategies added to antipsychotic monotherapy in schizophrenia: Systematic overview and quality appraisal of the meta-analytic evidence. JAMA Psychiatry 74(7):675-684, 2017. doi: 10.1001/jamapsychiatry.2017.0624

2. 2. Wang SM, Han C, Lee SJ: Investigational dopamine antagonists for the treatment of schizophrenia. Expert Opin Investig Drugs 26(6):687-698, 2017. doi: 10.1080/13543784.2017.1323870