Clozapine was recognized as a clinical curative effect in 1972. The best antipsychotic; especially for refractory schizophrenia, none of the “best efficacy”.
However, with regard to the mechanism of action of clozapine, many people still have the impression that it is simply a “dirty drug”. The advantage is that the receptor mechanism is complex. The understanding of the receptor mechanism and intracellular signaling mechanism of clozapine is limited.
In this context, a recent review published in Pharmacology & Therapeutics (impact factor 13.400) comprehensive The new findings on the efficacy and side effects mechanism of clozapine in recent years were reviewed, aiming to guide the development of innovative treatments for refractory schizophrenia. The full text is 41 pages long. The following briefly introduces the core content-
Fall antipsychotic The apex of the drug “atypical-typical ” spectrum, belonging to the most “atypical” atypical antipsychotics
Clozapine is the first and currently only antipsychotic drug approved for treatment-resistant schizophrenia. Although the exact mechanism remains to be further revealed, recent preclinical and clinical studies have found that clozapine has multiple mechanisms of action that tend to converge at the receptor and intracellular levels (Figure 1).
These mechanisms may, on the one hand, be the basis for the excellent efficacy of clozapine, and, on the other hand, may be the basis for novel therapies. R&D points the way.
Dopaminergic Receptor Effects
Among the numerous mechanisms of action of clozapine, the unique mode of action targeting the dopaminergic system remains highly critical.
For example, clozapine has a weak affinity for the D2receptor (Ki = 431nM) and dissociated rapidly, helping to prevent the upregulation of D2 receptors, and may interact with D2< span>Receptor upregulation associated with therapeutic tolerance, dopamine hypersensitivity psychosis and tardive dyskinesia. In addition, clozapine inhibits both D1 receptors (Ki=189 nM) and D4 receptors (Ki=189 nM). =39nM) with stronger affinity than D2 receptors; D1/D< span>2 receptor affinity ratio may be related to the unique efficacy of clozapine in refractory patients, while D4 receptors may Mediated the modulating effects of clozapine on glutamatergic nerve conduction.
Why is clozapine so effective? May be related to this mechanism | Literature review
2018-07-30
Lipophilicity
An important discovery in recent years is that the particularly strong lipophilicity of clozapine can affect the drug Pharmacokinetics and efficacy. The experimentally derived clozapine lipid-water distribution coefficient LogD(pH 7.4) is 2.754, which is sufficient for clozapine to pass through the blood-brain by passive diffusion barrier and ideal for even distribution of the drug in the central nervous system.
The combination of clozapine and lipoprotein can also form a “physiological warehouse” and prolong the release time of clozapine. Clinical studies have shown that clozapine is more effective in patients with higher blood triglyceride levels, and increased blood triglyceride levels are also significantly associated with improvement in schizophrenia symptoms.
Presynaptic Mechanism
In recent years, it has been observed that the basic part of the clozapine structure preferentially accumulates in presynaptic vesicles, And when it is released, it produces an auto-inhibitory effect on dopamine release, and the final net effect is to reduce the release of dopamine.
This is important for developing newAntipsychotics are valuable. Existing drugs usually block postsynaptic dopamine receptors as the main mechanism of action, and are often criticized as “treating the symptoms but not the root cause”, while the presynaptic mechanism of action is expected to solve the “core” related to the abnormal release of presynaptic neurotransmitters. question. More advantageously, the strong lipophilicity of clozapine facilitated the accumulation of the drug in vesicles.
Challenges and Directions of Antipsychotics | Expert Perspectives
2018-07-01
postsynaptic mechanism
< /p>
Clozapine also has a postsynaptic mechanism of action, but in some unusual ways. For example, clozapine can interact with postsynaptic receptor dimers, “entangle” each other in the recycling of cytoplasmic D2 receptors, affecting The transport and localization of D2 receptors on the membrane surface may prevent D2 receptor up-regulation and a series of adverse consequences.
Cholinergic receptor effects
For a long time, clozapine has been associated with muscarinic cholinergic receptors. Combined with much attention. In particular, clozapine itself is a muscarinic cholinergic receptor antagonist, but its metabolites, norclozapine, are M1 and M4 receptor agonists, these receptors are expected to be effective targets for improving psychotic symptoms and cognitive symptoms in patients with schizophrenia.
A 2020 study supports this idea – M1< span>/M4Receptor agonist xanomeline combined with peripheral anticholinergic trospium in a The primary efficacy endpoint was met in a phase II clinical study in schizophrenia.
11 important advances in the field of antipsychotics (2011 -2020) | Literature Review
2021-12-03
Glutamate effect
Clozapine has a multimodal regulatory effect on the glutamatergic system, which is also a feature of Clozapine is one of the most important features that distinguish it from other antipsychotics and provides supporting evidence for the notion that glutamatergic is involved in the pathophysiological process of treatment-resistant schizophrenia.
Another phase II clinical study showed that sodium benzoate, a commonly used food preservative, could reduce D-amino acid oxidase (DAAO) by inhibiting D-amino acid oxidase (DAAO). Degradation of amino acids, enhancing the function of NMDA receptors, significantly improve symptoms in patients with refractory schizophrenia.
Not just preservatives: sodium benzoate or Help with Treatment-Refractory Schizophrenia | Research Express
2018-01-18
Synaptic plasticity
The pathophysiology of schizophrenia involves altered connectivity within and between different brain regions, while tree Spinal spines are critical for the reception of synaptic inputs and are regarded as sites of synaptic plasticity events.
Compared with other antipsychotics, clozapine has different effects on synaptic plasticity and dendritic spine structure, including significantly increased Expression of the Shank1 gene in primary and secondary dendritic spines of hippocampal neurons (as opposed to haloperidol) may in turn be beneficial for cognitive function. This has been confirmed in both in vitro and in vivo preclinical studies, but corresponding human studies are currently lacking.
Concluding Remarks
A further in-depth understanding of the mechanism of action of clozapine is necessary to find an antipsychotic that is better than blue. The clinical use of clozapine is limited by a variety of side effects that are expected to be free from direct mechanistic links to efficacy.
Bibliography: de Bartolomeis A, Vellucci L , Barone A, Manchia M, De Luca V, Iasevoli F, Correll CU. Clozapine’s multiple cellular mechanisms: What do we know after more than fifty years? A systematic review and critical assessment of translational mechanisms relevant for innovative strategies in treatment-resistant schizophrenia . Pharmacol Ther. 2022 Aug;236:108236. doi: 10.1016/j.pharmthera.2022.108236. Epub 2022 Jun 25. PMID: 35764175.
Click “Read Original” to view and retrieve historical articles.