Expert lecture hall Lu Jubao: Analysis of the therapeutic advantages of new antipsychotics from the perspective of receptor pharmacology

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The influence of the receptor pharmacological characteristics of antipsychotics on therapeutic practice

The influence of the receptor pharmacological characteristics of antipsychotics on therapeutic practice

Drug therapy is the most important means of treatment of schizophrenia
.

Since the discovery of chlorpromazine more than 50 years ago, almost all clinical antipsychotic drugs have played a role in the treatment of schizophrenia by blocking D2 receptors1

With the in-depth understanding of the treatment of schizophrenia, the control of positive symptoms has gradually become the "basic goal" of drug treatment.
On top of this, there will be more treatment needs to be addressed: such as negative symptoms, cognitive symptoms, and emotional symptoms.
More effective improvement of multi-dimensional symptoms, the avoidance and management of specific drug adverse reactions, and the recovery of neurocognitive/social function and the improvement of quality of life based on the improvement of symptoms
.

SGAs are not a homogeneous drug category: each has its own unique side effects and specific efficacy domains, which involve the different receptor pharmacological mechanisms of the drug (Table 1)
.

Therefore, when prescribing SGAs, best clinical practice requires combining the characteristics of different patient groups, that is, the characteristics of the disease and the degree of susceptibility to adverse reactions, to match the use of drugs and treatment plans

Table 1 Clinical effects related to the intervention of different receptors of antipsychotics

Table 1 The clinical effects related to the intervention of different receptors of antipsychotics Table 1 The clinical effects related to the intervention of different receptors of antipsychotics

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Receptor pharmacological characteristics and drug treatment characteristics of new antipsychotics

Receptor pharmacological characteristics and drug treatment characteristics of new antipsychotics

In the past ten years, several new SGAs have been marketed globally.
Understanding the receptor pharmacological characteristics and clinical treatment characteristics of these drugs can lay the foundation for clinicians to use these drugs more effectively
.

Table 2 Receptor binding characteristics and specific treatment symptom domains of lurasidone, epipiprazole and cariprazine

Table 2 Receptor binding characteristics of lurasidone, epiprazole and cariprazine and specific treatment symptom domains Table 2 Receptor binding characteristics of lurasidone, epiprazole and cariprazine and specific treatments Symptom domain

1.
Lurasidone

1.
Lurasidone

Lurasidone is currently approved in the United States and Europe for the treatment of adolescent/adult schizophrenia and adolescent/adult bipolar depressive episodes.
It will be marketed in China in 2019 for the treatment of adult schizophrenia
.

The unique feature of this drug is its potent antagonism to 5-HT7 receptors (Table 2).

Include 32 antipsychotics, the most comprehensive meta-analysis of antipsychotics at present shows that among the drugs included, lurasidone is the drug with the lowest risk of developing ECG abnormalities, and it is the only 3 drugs that are in the treatment period.
One of the drugs with a risk of weight gain ≥7% comparable to placebo, and is one of the 6 drugs that significantly improves the social function of patients relative to placebo, and one of the 5 drugs that has evidence to significantly improve the quality of life of patients
.

Although compared with other SGAs, the overall improvement effect of lurasidone on PANSS may not be outstanding, but its obvious positive symptom treatment potential, cognitive improvement and improvement of depression symptoms make lurasidone suitable for use in Patients with clinically relevant needs in these areas

2.
Epipiprazole

2.
Epipiprazole

Epipiprazole is currently approved abroad for the acute and maintenance treatment of schizophrenia (FDA, 2015; EMA, 2018) and adjuvant treatment of MDD (FDA, 2015)
.

Epipiprazole has similar partial agonistic effects on 5-HT1A and D2 receptors, and has an antagonistic effect on 5-HT2A and adrenergic α1B/α2C receptors (Table 2)

At present, it is known that at least three kinds of receptors can alleviate akathisia and extrapyramidal side effects (EPS) related to blocking D2 dopamine receptors, namely 5-HT2A antagonism, 5-HT1A agonism and α1B antagonism
.

Compared with epipiprazole and aripiprazole, the binding power of epipiprazole to these three receptors is much greater

In terms of the efficacy of specific symptom domains, animal models have shown that epipiprazole is better than aripiprazole in the treatment of cognitive impairment in schizophrenia6
.

However, to support this view, it is necessary to obtain further clinical trial results with cognition as the primary endpoint

3.
Cariprazine

3.
Cariprazine

Cariprazine is currently approved in the United States and Europe for the acute and maintenance treatment of schizophrenia (FDA, 2015, EMA 2017) and the treatment of mania or mixed episodes associated with bipolar I disorder (FDA, 2015)
.

It is a dopamine D3-preferred D3/D2 receptor partial agonist

Cariprazine seems to be particularly effective in improving negative symptoms, and clinical studies suggest that it can improve functional outcomes while improving negative symptoms
.
In general, cariprazine is a new type of antipsychotic drug that can change clinical decision-making, especially for patients with schizophrenia with negative symptoms
.

4.
Lumeperazone

4.
Lumeperazone

Lumeperidone is a new oral antipsychotic drug.
It is a pioneering synergistic modulator of serotonin, dopamine and glutamate.
It was first approved in the United States in December 2019 for the treatment of adult schizophrenia14
.
The drug is a potent 5-HT2A receptor antagonist (Ki=0.
54nM), and its affinity with the receptor is 60 times that of the dopamine D2 receptor (32nM); this ratio is significantly higher than that of almost all atypicals.
Antipsychotics, such as risperidone (12 times), olanzapine (12.
4 times), aripiprazole (0.
18 times)
.
According to the drug's pharmacodynamic characteristics and preliminary clinical data, depression and negative symptoms and cognitive symptoms may be the dominant treatment symptom domain of lumoperidone, but further research is needed to verify this hypothesis
.

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Concluding remarks

Concluding remarks

With the development and marketing of new drugs, psychiatrists have more and more therapeutic tools
.
Different from previous drugs, new antipsychotic drugs that have been on the market and in the R&D pipeline have begun to show larger and larger differences in receptor pharmacology and clinical action characteristics from previous drugs, which are also beginning to really make up for the past to a large extent.
Treatment needs that cannot be effectively covered by drugs
.
Along with it, the rapid understanding and effective application of new drugs has also become a "sweet burden" for psychiatrists
.
We hope that clinicians can quickly find suitable treatment locations for these new drugs in their clinical practice, so that they can benefit more patients with schizophrenia
.

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