Haloperidol affects bones while clozapine alters metabolic parameters - sex specific effects in rats perinatally treated with phencyclidine

Nikolić, Tatjana; Petronijević, Milan; Sopta, Jelena; Velimirović, M.; Stojković, T.; Dožudić, Gordana Jevtić; Aksić, Milan; Radonjić, Nevena V.; Petronijević, Nataša

doi:10.1186/s40360-017-0171-4

Cited by 11 publications

(7 citation statements)

References 106 publications

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“…In studies carried out in animal models, similar effects to those described above in cell cultures have been observed in MQs. In a perinatal phencyclidine rat model, the administration of clozapine increased IL-6 and TNF-α with sex-specific changes (91), which can fit in the theory of "cytokine signature" observed in blood leukocytes from healthy volunteers incubated with clozapine (1 µM) (92). It has also been reported that, in Wistar rats, clozapine (45 mg/kg/day) induced myocarditis related with lymphocytic infiltrates, which induced the release of reactive oxygen species (ROS), cytokines, and TNF-α (93).…”

Section: Clozapinesupporting

confidence: 57%

Immunoendocrine Peripheral Effects Induced by Atypical Antipsychotics

et al. 2020

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Atypical antipsychotics (AAP) or second-generation antipsychotics are the clinical option for schizophrenia treatment during acute psychoses, but they are also indicated for maintenance during lifetime, even though they are being used for other psychiatric conditions in clinical practice such as affective disorders and autism spectrum disorder, among others. These drugs are differentiated from typical antipsychotics based on their clinical profile and are a better choice because they cause fewer side effects regarding extrapyramidal symptoms (EPS). Even though they provide clear therapeutic benefits, AAP induce peripheral effects that trigger phenotypic, functional, and systemic changes outside the Central Nervous System (CNS). Metabolic disease is frequently associated with AAP and significantly impacts the patient's quality of life. However, other peripheral changes of clinical relevance are present during AAP treatment, such as alterations in the immune and endocrine systems as well as the intestinal microbiome. These less studied alterations also have a significant impact in the patient's health status. This manuscript aims to revise the peripheral immunological, endocrine, and intestinal microbiome changes induced by AAP consumption recommended in the clinical guidelines for schizophrenia and other psychiatric disorders.

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Section: Clozapinesupporting

confidence: 57%

Immunoendocrine Peripheral Effects Induced by Atypical Antipsychotics

et al. 2020

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“…In our previous research, clozapine (1 mg/kg) administration for two consecutive weeks could up-regulate rat serum IL-6 levels but had no effect on serum TNF-α (Liu et al 2015). Some evidence suggests that the cytokines secretion upon chronic administration of clozapine (20 mg/kg/day) is gender dependent: serum IL-6 and TNF-α increased in female rats, but only serum TNF-α level increased in male rats (Nikolić et al 2017). Additionally, acute administration of clozapine inhibited the increase of serum TNF-α and IL-6 in lipopolysaccharidetreated mice (Sugino et al 2009).…”

Section: Discussionmentioning

confidence: 91%

Do proinflammatory cytokines play a role in clozapine-associated glycometabolism disorders?

Zhao

Zhang

et al. 2021

Psychopharmacology

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Rationale and objective Clozapine (CLZ) is the most effective drug for treatment-resistant schizophrenia but is associated with many side effects, including glycometabolism disorders. Immunological mechanisms may be involved in the development of clozapine side effects. Research relating the immunomodulatory effects of clozapine and its early markers to clinically relevant adverse events is needed to reduce the harmful side effects of clozapine. This study aimed to investigate the role of proinflammatory cytokines in clozapine-associated glycometabolism disorders. Methods We measured the effect of a range of doses of clozapine on glycometabolism-related parameters and proinflammatory cytokines levels in mice peripheral blood. We also examined the differences between these indicators in the peripheral blood of clozapine-treated schizophrenia patients and healthy controls. Furthermore, we detected proinflammatory cytokines expression in mice pancreatic tissue. Results Following clozapine administration, glucagon significantly decreased in mouse serum, and proinflammatory cytokine IL-β levels markedly increased. Clozapine reliably increased proinflammatory cytokines (IL-1β, IL-6, and TNF-α) expression in murine pancreatic tissue. Compared with healthy controls, clozapine-treated patients’ BMI, blood glucose, and proinflammatory cytokines (IL-1β, IL-6, and TNF-α) increased significantly. In clozapine-treated patients, a higher clozapine daily dosage was associated with higher levels of the proinflammatory cytokines IL-1β and IL-6, and a significant positive correlation was observed between blood glucose levels and the proinflammatory cytokines IL-6 and TNF-α. Conclusion Findings from animal experiments and clinical trials have shown clear evidence that clozapine has a regulatory effect on immune-related proinflammatory cytokines and influences glycometabolism indicators.

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“…As aforementioned, clozapine may be able to protect BMD by activating NMDARs; however, other mechanisms deserve attention too. A recent animal study showed that clozapine had protective effect on bones possibly via causing sex-specific increase in pro-inflammatory cytokines 30 . It will be interesting to explore the effect of clozapine on bone mass and other related parameters.…”

Section: Discussionmentioning

confidence: 99%

Long-term Use of Clozapine is Protective for Bone Density in Patients with Schizophrenia

Lin

Wang

et al. 2019

Sci Rep

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Low bone mineral density (BMD) prevails among patients with schizophrenia. Antipsychotics use plays an important role in BMD. Previous cross-section study suggests that clozapine treatment may benefit BMD of women with schizophrenia. However, the effect of long-term clozapine therapy on BMD remains unknown. This prospective study compared clozapine and non-clozapine antipsychotics in long-term effects on BMD among both men and women with schizophrenia. Patients with schizophrenia and age-matched healthy individuals were enrolled from two centers. All patients, including clozapine receivers and non-clozapine antipsychotics recipients, kept clinically stable with unchanged antipsychotics and doses for at least 6 months at enrollment and during the follow-up period. BMD was examined by dual-energy X-ray absorptiometer upon enrollment and at 1- or 3-year follow-up. Thorough clinical and laboratory variables were measured too. The mean BMD of patients receiving clozapine was higher than that of the non-clozapine patients at both enrollment and follow-up. Overall, the patients in the clozapine group gained BMD, while those in the non-clozapine group lost BMD after 1–3 years (p = 0.015). There was no significant difference of BMD change between clozapine-treated patients and healthy controls. Factors associated with BMD change in the clozapine group included calcium level (B = −0.607, p = 0.021) and T3 level (B = −0.077, p = 0.007). This longitudinal study suggests that long-term clozapine treatment may protect BMD compared to prolactin-raising and non-clozapine prolactin-sparing antipsychotics among patients with schizophrenia. Future prospective studies are warranted to testify whether switching from non-clozapine antipsychotics to clozapine can rescue BMD.

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Haloperidol affects bones while clozapine alters metabolic parameters - sex specific effects in rats perinatally treated with phencyclidine

Cited by 11 publications

References 106 publications

Immunoendocrine Peripheral Effects Induced by Atypical Antipsychotics

Immunoendocrine Peripheral Effects Induced by Atypical Antipsychotics

Do proinflammatory cytokines play a role in clozapine-associated glycometabolism disorders?

Long-term Use of Clozapine is Protective for Bone Density in Patients with Schizophrenia

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