Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effects and the insulin signaling pathway

Abstract

The exact therapeutic mechanism of action of antipsychotic drugs remains unclear. Recent evidence has shown that second-generation antipsychotic drugs (SGAs) are differentially associated with metabolic side effects compared to first-generation antipsychotic drugs (FGAs). Their proclivity to cause metabolic disturbances correlates, to some degree, with their comparative efficacy. This is particularly the case for clozapine and olanzapine. In addition, the insulin signaling pathway is vital for normal brain development and function. Abnormalities of this pathway have been found in persons with schizophrenia and antipsychotic drugs may ameliorate some of these alterations. This prompted us to hypothesize that the therapeutic antipsychotic and adverse metabolic effects of antipsychotic drugs might be related to a common pharmacologic mechanism. This article reviews insulin metabolism in the brain and related abnormalities associated with schizophrenia with the goals of gaining insight into antipsychotic drug effects and possibly also into the pathophysiology of schizophrenia. Finally, we speculate about one potential mechanism of action (that is, functional selectivity) that would be consistent with the data reviewed herein and make suggestions for the future investigation that is required before a therapeutic agent based on these data can be realized.

In male rats, the ability of central insulin to suppress glucose production is impaired by olanzapine, whereas glucose uptake is left intact

“…20,21 Insulin receptors are expressed in many brain areas, and abnormalities in brain insulin signalling have been reported in patients with schizophrenia, with evidence suggesting that antipsychotics may also disrupt these pathways. 22 Linking these disruptions to metabolic dysfunction, it is now well established that insulin, separate from its effects on liver receptors, regulates hepatic glucose production in rodents via hypothalamic insulin receptors. 23,24 Moreover, intranasal insulin administration to healthy humans decreases endogenous glucose production.…”

Involvement of histamine receptors in the atypical antipsychotic profile of clozapine: a reassessment in vitro and in vivo

“…In addition, this interaction may constitute a molecular mechanism involved in many, if not all, side effects of clozapine. Considering the high propensity of clozapine to induce these side effects, correlated with its high antipsychotic properties compared with other atypical neuroleptics, (Leucht et al 2009;Tandon et al 2008), it was recently hypothesized that the therapeutic antipsychotic and adverse effects of antipsychotic drugs might be related to a common pharmacologic mechanism (Girgis et al 2008). The interaction with brain histamine receptors might be a part of this common mechanism.…”

Genetic association and sequencing of the insulin-like growth factor 1 gene in bipolar affective disorder

“…In two recent studies, central administration of IGF1 in mice has shown to have an antidepressant-like effect [Hoshaw et al, 2005;Malberg et al, 2007]. A recent review has linked antipsychotic drug mechanisms and the insulin-signaling pathway which may be abnormal in schizophrenia [Girgis et al, 2008].…”