Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles

Abstract

Atypical antipsychotic drugs offer several notable benefits over typical antipsychotics, including greater improvement in negative symptoms, cognitive function, prevention of deterioration, and quality of life, and fewer extrapyramidal symptoms (EPS). However, concerns about EPS have been replaced by concerns about other side effects, such as weight gain, glucose dysregulation and dyslipidemia. These side effects are associated with potential long-term cardiovascular health risks, decreased medication adherence, and may eventually lead to clinical deterioration. Despite a greater understanding of the biochemical effects of these drugs in recent years, the pharmacological mechanisms underlying their various therapeutic properties and related side effects remain unclear. Besides dopamine D 2 receptor antagonism, a characteristic feature of all atypical antipsychotic drugs, these agents also bind to a range of non-dopaminergic targets, including serotonin, glutamate, histamine, a-adrenergic and muscarinic receptors. This review examines the potential contribution of different receptors to metabolic side effects associated with atypical antipsychotic treatment for all seven agents currently marketed in the United States (risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone and clozapine) and another agent (bifeprunox) in clinical development at the time of this publication.

Detection of the Moderately Beneficial Cognitive Effects of Low-Dose Treatment with Haloperidol or Clozapine in an Animal Model of the Attentional Impairments of Schizophrenia

“…Compared with the pharmacological profile of haloperidol, the effects of clozapine are diverse and include affinity to a wide array of receptors including dopamine D4, noradrenergic a2, serotonergic 5-HT2, and cholinergic muscarinic M2 receptors (Kinon and Lieberman, 1996;Miyamoto et al, 2005;Nasrallah, 2007;Van Tol et al, 1992). As briefly mentioned in the 'Introduction', our evidence indicates that following AMPH challenges in AMPH-pretreated rats, the cortical cholinergic input system fails to respond to, and thereby to mediate, the performance of this task .…”

Effects of atypical antipsychotic drugs on body weight and food intake in dopamine D2 receptor knockout mice

“…These data suggest D2R involvement in olanzapine activity. Although olanzapine displays slightly lower affinity for D2R than risperidone and ziprasidone [5], olanzapine has similar antagonist efficacy in D2R-mediated signaling, such as reversing dopamine D2R-mediated decreases in cAMP accumulation [32] and other signaling [33].…”

“…Antipsychotics bind to multiple neurotransmitter receptors and may work through different receptor pharmacology [5,6]. Typical antipsychotics are high-affinity dopamine D2 receptor (D2R) antagonists, which includes D2, D3, and D4 receptors, while atypical antipsychotics are antagonists of both serotonin type 2A (5-HT2A) and D2R, with additional affinities for other serotonin and dopamine receptor subtypes as well as histamine, muscarinic, and adrenergic receptors [5,7]. However, the pharmacological mechanisms to explain the particular side effects associated with these drugs are still unclear.…”

“…Because this weight gain is associated with other health complications such as obesity and metabolic syndromes, it is important to understand why these antipsychotics cause these unwanted effects. Antipsychotics bind to multiple neurotransmitter receptors and may work through different receptor pharmacology [5,6]. Typical antipsychotics are high-affinity dopamine D2 receptor (D2R) antagonists, which includes D2, D3, and D4 receptors, while atypical antipsychotics are antagonists of both serotonin type 2A (5-HT2A) and D2R, with additional affinities for other serotonin and dopamine receptor subtypes as well as histamine, muscarinic, and adrenergic receptors [5,7].…”

The role of histaminergic H1 and H3 receptors in food intake: A mechanism for atypical antipsychotic-induced weight gain?

“…However, olanzapine and other atypical antipsychotic drugs such as clozapine can induce significant weight gain and further metabolic disorders including insulin resistance, diabetes and lipid metabolism dysfunction. Among antipsychotics, olanzapine has a higher risk for weight gain than the conventional antipsychotics haloperidol, chlorpromazine and fluphenazine, and its atypical counterparts risperidone, aripiprazole, sertindole, thioridazine, quetiapine, amisulpride, zotepine and ziprasidone (Allison et al, 1999, Nasrallah, 2008. Clozapine, which is also effective for use against treatment-resistant schizophrenia, may induce more weight than olanzapine (4.45kg and 4.15kg, respectively over 10-weeks) (Allison et al, 1999), however a recent study found that high dosages of olanzapine (mean dosage 34mg/day) induced significantly higher weight gain than clozapine (+5.6 ±2.0 kg olanzapine vs clozapine, mean dosage 564mg/day, after 6-months treatment) in patients with treatment-resistant schizophrenia (Meltzer et al, 2008).…”