Antipsychotics-induced metabolic alterations: Recounting the mechanistic insights, therapeutic targets and pharmacological alternatives

Singh, Raghunath; Bansal, Yashika; Medhi, Bikash; Kuhad, Anurag

doi:10.1016/j.ejphar.2018.12.003

Cited by 66 publications

(51 citation statements)

References 136 publications

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“…According to their findings, this was not the case for histamine H1 antagonism [91]. Similarly, while studying the dynamics of serum leptin level and some anthropometric values in patients with schizophrenia and treated by risperidone, olanzapine and clozapine, Gorobets and collaborators' results suggested that leptin resistance contributes to the pharmacogenetic increment of body weight [87,92]. Piao and collaborators studied the effects of risperidone on leptin-stimulated STAT3 and found that this drug inhibits leptin signalling in the human SH-SY5Y neuroblastoma cell line through the induction of suppressor of signalling of cytokine 3 and 6 [93].…”

Section: Leptin and Antipsychotics-induced Weight Gainmentioning

confidence: 99%

Leptin and psychiatric illnesses: does leptin play a role in antipsychotic-induced weight gain?

et al. 2020

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Antipsychotic-induced weight gain is the most prevalent somatic adverse event occurring in patients treated by antipsychotics, especially atypical antipsychotics. It is of particular interest because of its repercussion on cardiovascular morbidity and mortality especially now that the use of second-generation antipsychotics has been extended to other mental health illnesses such as bipolar disorders and major depressive disorder. The mechanism underlying antipsychotics-induced weight gain is still poorly understood despite a significant amount of work on the topic. Recently, there has been an ongoing debate of tremendous research interest on the relationship between antipsychotic-induced weight gain and body weight regulatory hormones such as leptin. Given that, researchers have brought to light the question of leptin's role in antipsychotic-induced weight gain. Here we summarize and discuss the existing evidence on the link between leptin and weight gain related to antipsychotic drugs, especially atypical antipsychotics.

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Section: Leptin and Antipsychotics-induced Weight Gainmentioning

confidence: 99%

Leptin and psychiatric illnesses: does leptin play a role in antipsychotic-induced weight gain?

et al. 2020

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“…Antipsychotic therapy prevails as a standard and fundamental component for major psychiatric disorders like acute episode of psychoses and the maintenance phase of schizophrenia and schizoaffective disorders (21). These drugs do not act exclusively on the CNS, and the more evident problem related with AAP treatment is the higher risk of developing hyperphagia, hyperglycemia, dyslipidemia, weight gain, diabetes mellitus, and insulin resistance (22), which further develops metabolic and cardiac complications with subsequent reduction in life expectancy, poor patient compliance, and sudden death (4).…”

Section: Why Is It Important To Make Evident the Neuroendocrine Effecmentioning

confidence: 99%

“…Atypical (AAP) or second-generation antipsychotics (SGA) are effective against positive and negative symptoms and improve some domains of cognition of schizophrenia. AAP are the first clinical option to treat various psychiatric conditions because they produce significantly fewer EPS and pose a lower risk of pseudo-parkinsonism and catalepsy in comparison to typical antipsychotics (3,4).…”

Section: Introductionmentioning

confidence: 99%

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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“…Notably, S20 with the privileged structure of Aripiprazole had the strongest activity for the D 2 receptor (IC 50 = 1.3 nM), even higher than that of Brexpiprazole. [25][26][27] Therefore, further in vitro pharmacological characterization of S6 is essential. Interestingly, the alkenyl-containing compound S22 retained high potency for D 2 R but the effect on 5-HT 1A R and 5-HT 2A R was weakened (S22 vs S4).…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Biological Evaluation of Five‐Atom‐Linker‐Based Arylpiperazine Derivatives with an Atypical Antipsychotic Profile

Wang

Yang

et al. 2019

ChemMedChem

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Herein we describe a focused set of new arylpiperazine derivatives as potential broad-spectrum antipsychotics. The general structure contains a quinolinone-like moiety, an arylpiperazine moiety, and a five-atom linker. Among them,isothiazol-4-yl)piperazin-1-yl)pentyl)quinolin-2(1H)-one (S6) shows a promising preclinical profile. Compound S6, characterized by partial D 2 R agonism, 5-HT 1A R agonism, 5-HT 2A R antagonism, and blockade of SERT activities, was found to decrease psychosis-and depressive-like symptoms in rodents. The polypharmacological profile of S6 could provide opportunities for the treatment of various other central nervous system disorders such as anxiety, depression, and psychoses associated with dementia. Furthermore, S6 demonstrated acceptable safety, toxicology, and pharmacokinetic profiles, and has been selected as a preclinical candidate for further evaluation in schizophrenia.[a] Dr.previous SAR studies on antipsychotic drugs indicated that an appropriate linker is of great importance for desired multireceptor activity, we also explored the influence of linker flexibility of the new derivatives on receptor function profiles. [18] Among the derivatives prepared, compound S6 manifested a unique polypharmacological antipsychotic profile. It displayed much higher potency for the desired targets (D 2 , 5-HT 1A , 5-HT 2A , and SERT) than other off-target receptors (α 1A , H 1 , 5-HT 2C , M 3 , hERG). Thus, compound S6 was developed as an atypical antipsychotic candidate to treat schizophrenia based on the D 2 R, 5-HT 1A R, 5-HT 2A R and SERT multi-target profile. 2 3 4 5 6 7 8

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Antipsychotics-induced metabolic alterations: Recounting the mechanistic insights, therapeutic targets and pharmacological alternatives

Cited by 66 publications

References 136 publications

Leptin and psychiatric illnesses: does leptin play a role in antipsychotic-induced weight gain?

Leptin and psychiatric illnesses: does leptin play a role in antipsychotic-induced weight gain?

Immunoendocrine Peripheral Effects Induced by Atypical Antipsychotics

Synthesis and Biological Evaluation of Five‐Atom‐Linker‐Based Arylpiperazine Derivatives with an Atypical Antipsychotic Profile

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