Mechanisms related with atypical antipsychotics

Atypical antipsychotics indirectly increase the risk of VTE because of their adverse effects such as metabolic syndrome. In addition, AAs may also have prothrombotic effects. Research shows that clozapine can have an impact on the increase in blood platelet aggregation. Also, an interaction between ziprasidone, risperidone and platelet membrane phospholipids has been reported. Patients receiving clozapine and olanzapine were observed to have increased levels of C-reactive protein (CRP) and antithrombin III (AT-III). Also, patients using olanzapine were reported to have increased levels of plasminogen activator inhibitor-1 (PAI1) and leptin. It appears that effects of antipsychotic treatment may not be alone in predisposing an individual toward developing VTE. Having psychosis itself may also play a role. Prior to treatment, patients with acute psychosis were observed to have elevated levels of DD, P-selectin and factor VIII (FVIII) when compared to healthy individuals. Selectins belong to a group of proteins that partake in the inflammatory reaction. P-selectins are found in the alpha granules of platelets and endothelial cells. They reflect their activation state, promote leukocyte adhesion to both activated platelets and endothelial cells. The mentioned parameters have been found to positively correlate with VTE and can be used as markers to evaluate its risk. Patients who failed to undergo treatment after the first episode of schizophrenia have been reported to have higher expression of platelet integrins αIIb and βIIIa versus healthy individuals. The glycoprotein IIb/IIIa and αIIbβ3 complex takes part in ADP-dependent platelet aggregation.
A strong affinity between serotonin 5-HT2A receptors (5-HT2ARs) and AAs such as risperidone may increase coagulation as well as the risk of VTE. Patients receiving antipsychotics were also reported to have elevated antiphospholipid antibody titers, including anticardiolipin antibodies, and lupus anticoagulant. Patients with schizophrenia not using antipsychotic drugs and their healthy relatives have both been observed to have elevated levels of anticardiolipin antibodies. Of these, elevated levels of Immunoglobulin G (IgG) class antibodies were found in both patients and relatives when compared to control groups, while elevated levels of Immunoglobulin M (IgM) class antibodies were only found in patients . Comparable results were also found in subjects with acute psychosis who failed to undergo treatment within a period of three months prior to examination. Increased levels of anticardiolipin IgM antibodies were found in 39.1% of patients and increased levels of IgG antibodies were found in 13% of patients. However, no differences in the levels of these antibodies were shown during periods of no treatment or for periods of up to 42 days after treatment. Subjects taking clozapine were shown to have increased levels of anticardiolipin antibodies, and those taking risperidone had elevated levels of both cardiolipin antibodies and lupus anticoagulants. Antiphospholipid syndrome most commonly manifests as DVT. Regarding antiphospholipid antibodies, an increase in anticardiolipin antibodies was most frequently observed. This is probably because APLs block coagulation inhibitors. Furthermore, there are other adverse effects which result from antipsychotic treatment in addition to (APLs) and hyperhomocysteinemia. Hyperhomocysteinemia is also associated with the risk for CVD, including VTE. The relationship between homocysteine and VTE increases when deficiency in vitamin B12 and folic acid is concurrent with hepatic cirrhosis. Homocysteine shows toxic effects on vascular endothelium by indirectly inhibiting anticoagulant mechanisms that are dependent on CRP and AT-III. Homocysteine levels can be reduced by vitamin B12 and folic acid supplementation. CRP and AT-III activate tissue factor and lead to the formation of inflammatory cytokines and adhesion molecules.
Hyperprolactinemia is another procoagulant adverse effect of AAs. When compared to TAs, AAs represent an advance in the treatment of mental disorders due to high antipsychotic efficacy and have a lower tendency to induce hyperprolactinemia. TAs are full dopamine antagonists and AAs stimulate a mixed dopamine-agonistic/antagonistic activity. Also, partial agonists exert a lower intrinsic activity on receptors than full agonists, which allows them to act either as a functional antagonist or agonist, depending on the surrounding levels of natural neurotransmitters that are full agonists. As a result, an early dissociation from the receptor occurs and it enables normal dopaminergic neurotransmission within the tuberoinfundibular pathway to prevent hyperprolactinemia.
AAs that cause the highest increase in prolactin (PRL) levels include paliperidone, amisulpride and risperidone. However, the manner in which PRL affects the coagulation process is not really known. There is some data suggesting that it may contribute to coagulation disorder. The hemostasis parameters in patients with hyperprolactinemia were significantly different than the hemostasis parameters in healthy individuals. These patients were reported to have an increased blood platelet count, fibrinogen, PAI-1, and decreased tissue factor pathway inhibitor (TFPI). Patients with a history of PE were reported to have increased levels of PRL, FVIII and von Willebrand factor (vWF) within 6 months of the embolic episode. Additionally, a positive correlation was observed between PRL levels and other coagulation activation markers such as D-dimers (DDs) and fibrinogen degradation products (FDP) in males taking antipsychotic drugs such as chlorpromazine and aripiprazole. However, no such correlation was found in females. Other studies have shown the relationship between concentration levels of PRL and coagulation disorders. It was found a simultaneous increase in the levels of PRL, FVIII, vWF, DDs and FDP among males. In a study an increase in PRL levels, particularly within its normal reference range, correlated with a gradual increase in the risk of PE in premenopausal females. Although the procoagulant mechanism of PRL is not precisely known, it seems that its impact is indirect and may be varied. It is also said that PRL increases adenosine diphosphate (ADP)-dependent platelet aggregation. However, it may not do this on its own. Instead, it is likely caused by the combination of PRL and adrenaline, which via protein kinase C, exerts an influence on the Gq protein, which then changes the shape of the activated blood platelets. Also, through the interaction of integrins, PRL promotes leukocyte adhesion to the endothelial cells via chemokine receptors and tyrosine phosphorylation in signaling pathways. Since PRL has proven indirectly related to VTE, it is recommended that patients with other known risk factors for the disease receive medications that do not contribute to an increase in PRL, for example, aripiprazole, asenapine, quetiapine, ziprasidone, as well as low-dose blonanserin.

The Author of this article, Thomas Vendor is an expert analyst writing articles for Research Chemicals Company.



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