What Are Atypical Neuroleptics?

Atypical antipsychotics (also known as atypical antipsychotics, AAAs), including clozapine, olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone and other drugs, Compared with traditional antipsychotic drugs, it has the advantages of broad spectrum of action, good curative effect, good safety, etc., and can improve the quality of life of patients.

Although there is currently no clear definition of atypical antipsychotics (AAs), it is generally believed that such drugs should have the following characteristics: good effect on schizophrenia; few adverse reactions, especially little or no extrapyramidal reaction; Has dual effects on serotonin (5-HT2A) and dopamine (D2) receptors.

Chinese name: Atypical antipsychotics

Foreign name: atypical antipsychotics, AAs
Target: Serotonin and dopamine receptors

Introduction to Atypical Antipsychotics

Atypical antipsychotics

The advent of atypical psychiatric drugs has brought dawn to the medical treatment of patients with mental illness. These drugs were developed in the late 1960s and have certain clinical advantages. The main drugs are clozapine, risperidone, olanzapine, quetiapine, aripiprazole, piperopilon, aripiprazole, and iperidone. Compared with traditional antipsychotic drugs, the advantages of new antipsychotic drugs are not only reflected in the treatment of acute episodes of patients with mental illness, but also include small side effects such as extrapyramidal symptoms and tardive dyskinesia, without the need for anticholinergic drugs. ; The treatment is well tolerated and adherent; the treatment has a strong effect in improving positive and negative symptoms and cognitive function, with little or no EPS, and no endocrine adverse reactions due to elevated prolactin levels Wait. Atypical antipsychotic drugs have a good effect on the positive and negative symptoms of schizophrenia, and the incidence of extrapyramidal response (EP) S is low, so they have become the first-line antischizophrenic drugs abroad. ^[1]

Mechanism of atypical antipsychotics

At present, Stahl's hit-and-run theory states that AAs binds rapidly to dopamine (D2) receptors, which can treat schizophrenia in a short period of time, and can cause extrapyramidal reactions in a long period of time. AAs drugs can bind to various receptors such as 5-HT receptor, D receptor, 1 and 2, H1 and M1 receptors, and produce different pharmacological effects.

The details are as follows: The mechanism of treatment of schizophrenia:

a. Combined with 5-HT 2A / D2 receptor to improve positive and negative symptoms;

b. Combined with 5-HT 2C / D2 receptors to improve emotional and cognitive disorders;

c. Binding to 5-HT 1A / D2 receptors, improving negative symptoms and reducing dyskinesias.

Other mechanisms:

a. 5-HT1D binding, inhibiting 5-HT release, can fight anxiety and depression;

b. For 1, H1 and M1 receptors, it has low affinity, so it rarely causes orthostatic blood pressure and constipation;

c. Blocking the D2 receptor can reduce dopamine function and reduce extrapyramidal responses.

Atypical Antipsychotics Common Drugs

clozapine Atypical antipsychotic clozapine

Clozapine was the first atypical antipsychotic to be successfully developed in the late 1960s. Its receptor binding characteristics are very different from traditional antipsychotics. For the dopamine system, most antipsychotic drugs occupy at least 60% of the striatum D2 receptors at the therapeutic dose, while clozapine has an average D2 receptor occupation of only 20%. In vitro experiments show that clozapine has about 10 times stronger affinity for D4 receptor than D2 receptor, and can bind to D1, D3 and D5 receptors. Clozapine also has a wide range of effects on non-dopamine receptors, especially on 5-HT receptors, including 5-HT2, 5-HT3 and the recently discovered 5-HT6 and 5-HT7 receptor subtypes. .

Early comparative studies have shown that clozapine and typical antipsychotics have comparable or better curative effects on positive symptoms in patients with schizophrenia. Although clozapine also has some adverse drug reactions such as sedation, lowering the convulsive threshold, bradycardia, and hepatitis, it rarely causes EPS and is better tolerated than traditional antipsychotics. It was only reported in 1974 that clozapine could cause lethal agranulocytosis in 1% of patients and neutropenia in 10% of patients and was withdrawn from the market.

However, clozapine is effective for symptoms that are currently ineffective with other antipsychotic medications. A multi-center, double-blind trial has shown that treatment with clozapine in refractory schizophrenia, which is ineffective with other antipsychotic drugs, can significantly improve symptoms in one-third of patients. Although many new antipsychotic drugs have similar pharmacological characteristics to clozapine, when these two drugs are compared directly with clozapine in the relief of positive symptoms in patients with refractory schizophrenia in a double-blind trial, No drug was found to be more effective than clozapine. Therefore, under the condition of strict hematological monitoring, the drug is still the first choice for treating such patients with refractory schizophrenia. In addition, clozapine can also improve the cognitive function of patients with schizophrenia, especially for attention, oral expression and learning ability.

risperidone Atypical antipsychotic risperidone

Risperidone is a benzoisoxazole derivative, which is a combination of the chemical structures of haloperidol and risserin. It has stronger affinity for both D2 and 5-HT2 receptors than for clozapine, and also has lower affinity for 1, 2, and H1 receptors. Risperidone improves positive and negative symptoms at lower doses, and it also causes EPS at higher doses. The optimal dose is 6mg · d-1. When the dose is greater than 6-8mg · d-1, the adverse drug reaction becomes significantly worse and it is difficult to tolerate. Risperidone has a moderate effect on refractory schizophrenia, which is similar to traditional Hang psychiatric drugs, but weaker than clozapine. Risperidone can also improve cognitive function in patients with schizophrenia.

olanzapine Atypical antipsychotic olanzapine

Olanzapine is a tribenzodiazepine compound. Its chemical structure and pharmacological characteristics are similar to clozapine, but it does not cause agranulocytosis. It has higher affinity for 5-HT2A and M1 receptors, but also has lower affinity for D1, D2, H1, and 1 receptors. Olanzapine improves both the positive and negative symptoms of schizophrenia, especially the negative symptoms. However, it is effective only for primary negative symptoms and not for secondary negative symptoms. In the long-term efficacy observation, olanzapine has a stronger effect on reducing the long-term recurrence rate of schizophrenia than typical antipsychotic drugs such as fluocalol.

quetiapine Atypical antipsychotic quetiapine

Like clozapine, quetiapine is also a D2 / 5-HT receptor blocker. It also has a multi-receptor effect, but its overall potency is lower than clozapine. The drug has high affinity for 5-HT2A, 1 and H1 receptors, moderate affinity for D2 and 2 receptors, and low affinity for D1 and M1 receptors. Quetiapine has a strong selective effect on the limbic system. Numerous clinical controlled trials have shown that quetiapine is more effective than placebo and haloperidol in treating schizophrenia. Its side effects are similar to placebo, and EPS rarely occurs within the therapeutic dose range, and it rarely causes acute dystonia and Elevated serum prolactin levels have also been reported without agranulocytosis.

amisulpride Atypical antipsychotic amisulpride

Amisulpride is a substitute for benzylamine and has high selectivity for D2 and D3 receptors. Like other atypical antipsychotics, amisulpride is more effective than placebo and haloperidol in treating schizophrenia, and EPS rarely occurs. The most prominent advantage of amisulpride is that it is effective against negative and emotional symptoms. Its effect on schizophrenia negative symptoms is obviously better than haloperidol, and its antidepressant effect is not only stronger than haloperidol, but also better than risperidone. Amisulpride may be effective in treating patients with refractory schizophrenia.

ziprasidone Atypical antipsychotic ziprasidone

Who has marketed azithromycin in the United States and many European countries. Its pharmacological characteristics are similar to other D2 / 5-HT blockers, but it also has 5-HT1A receptor agonistic effects and selective 5-HT reuptake inhibitory effects. The drug is unique in that it reduces weight gain and lowers elevated blood sugar. The effect of this drug in prolonging the QTC interval is stronger than that of other atypical antipsychotics, so it may cause arrhythmia. ECG monitoring should be performed when the drug is used.

aripiprazole Atypical antipsychotic aripiprazole

Aripiprazole is a compound of fenpropizazine. November 2002 has been approved by the FDA for marketing. The drug has a unique mechanism of action, high affinity for dopamine D2 and D3 receptors and 5-HT1A and 5-HT2A receptors, and dopamine D4 receptor, 5-HT2C and 5-HT7 receptors. , 1-adrenoceptor, histamine H1 receptor, and serotonin reuptake sites have moderate affinity. It is a partial agonist of the dopamine D2 and 5-HT1A receptors and a 5-HT2A receptor antagonist. It has the effect of stabilizing the activity of dopamine system (the increase and decrease of dopamine system activity may be related to the onset of schizophrenia). Clinical trials have shown that aripiprazole is effective for both positive and negative symptoms of schizophrenia. Long-term application can also reduce the recurrence rate of schizophrenia and improve mood and cognitive dysfunction. Its EPS side effects and the effect of increasing serum prolactin levels are less than those of traditional antipsychotics or the aforementioned atypical antipsychotics. Tolerability is similar to placebo.

Atypical antipsychotic adverse reactions

AAs is significantly better than classic antipsychotics in terms of therapeutic efficacy, safety, and tolerance, but there are still some adverse reactions. More researched drugs clozapine, olanzapine, quetiapine, aripiprazole, these drugs have different degrees of impact on the central, metabolic, endocrine, cardiovascular and other systems.

3.1 Effects on the central nervous system AAs blocks dopamine (D2) receptors and serotonin (5-HT) receptors and histamine (H1) receptors. Adverse reactions such as EPS, epilepsy, sedation, insomnia, and drowsiness can occur. The main role in the treatment of schizophrenia is to antagonize (block) the dopamine (D2) receptor. Clozapine is mainly drowsiness, reduced activity, inability to sit still, tremor, muscle tension, torsion spasm, and sudden muscle loss may occur during treatment.

3.2 Effects on Metabolism and Endocrine System Atypical antipsychotics can cause weight gain, blood glucose (fasting blood glucose and postprandial blood glucose), blood lipids (triacylglycerol, cholesterol), fasting insulin, and lower serum triiodothyronine (T3).

3.3 Hyperprolactinemia Hyperprolactinemia is a common adverse reaction with antipsychotic drugs. The mechanism of hyperprolactinemia caused by antipsychotic drugs is mainly to block the funnel-knot of DA in the hypothalamus-pituitary system. D2 receptors in the ganglion pathway reduce DA secretion, promote prolactin elevation, and cause hyperprolactinemia. However, atypical antipsychotic drugs clozapine, risperidone, and quetiathione have no significant effect on blood prolactin . Aripiprazole can significantly improve hyperprolactinemia caused by perphenazine, haloperidol, and risperidone.

3.4 Impact on the blood system The main adverse reaction is neutropenia and the mechanism is unclear.

3.5 Effects on the cardiovascular system The main adverse reactions of AAs drugs are arrhythmia, myocardial ischemia, and can also cause pericardial effusion, drug-induced cardiomyopathy, arrhythmia, including sinus arrhythmia and conduction block.

Other adverse reactions Common adverse reactions of the digestive system are constipation, dry mouth, nausea and vomiting, salivation, liver damage, and anorexia.

Atypical antipsychotic drug interactions

1. Drug Interactions with Clozapine. Clozapine is the most commonly used second-generation antipsychotic drug. The metabolic pathways in the body mainly include oxidative nitrogen metabolism and demethylation metabolism. CYP1A2 inducers can accelerate the metabolism of clozapine. Conversely, inhibitors can delay metabolism. Other metabolic enzyme inducers or inhibitors may also affect the metabolism of clozapine.

2. Drug Interactions with Risperidone Drugs of risperidone are mainly metabolized by CYP2D6 in the body. The blood concentration of risperidone is affected by the CYP2D6 genotype difference. Generally speaking, 7% of white people belong to CYP2D6 slow metabolism, and yellow people <1%. CYP2D6 slow-metabolized populations should consider reducing the amount of drugs when taking risperidone.

3. Olanzapine-Related Drug Interactions Olanzapine's plasma concentration increases linearly in proportion to dose. Oral administration has obvious liver first-pass effects, low bioavailability, peak blood concentration in 5-8 hours, and an average half-life of 33 hours. Gender, age, and smoking status have an effect on the half-life and clearance of olanzapine. Olanzapine is mainly metabolized by CYP1A2. Like clozapine, a CYP1A2 inhibitor or inducer will significantly change the pharmacokinetics of olanzapine.