Antipsychotic-induced bone loss: the role of dopamine, serotonin and adrenergic receptor signalling

Abstract

Antipsychotics are commonly used in treating psychiatric disorders. These medications primarily target dopamine the serotonin receptors, they have some affinity to adrenergic, histamine, glutamate and muscarinic receptors. There is clinical evidence that antipsychotic use decreases BMD and increases fracture risk, with dopamine, serotonin and adrenergic receptor-signalling becoming an increasing area of focus where the presence of these receptors in osteoclasts and osteoblasts have been demonstrated. Osteoclasts and osteoblasts are the most important cells in the bone remodelling and the bone regeneration process where the activity of these cells determine the bone resorption and formation process in order to maintain healthy bone. However, an imbalance in osteoclast and osteoblast activity can lead to decreased BMD and increased fracture risk, which is also believed to be exacerbated by antipsychotics use. Therefore, the aim of this review is to provide an overview of the mechanisms of action of first, second and third generation antipsychotics and the expression profiles of dopamine, serotonin and adrenergic receptors during osteoclastogenesis and osteoblastogenesis.

Keywords: antipsychotics; bone mineral density; dopamine; noradrenaline; osteoblast; osteoclast; schizophrenia; serotonin.

FIGURE 1

Percentage of patients prescribed antipsychotics from 1992–1993 to 2020–2021; Data adopted from mental health services in Australia: Mental health related prescriptions Australian Institute of Health and Welfare (Australian Institute of Health and Welfare, 2022).

FIGURE 2

Signalling cascades regulated by dopamine, serotonin and adrenergic receptors. G-protein coupled receptor stimulation by different neurotransmitters such as dopamine, serotonin and adrenergic receptors regulate different signalling cascades. Activation of G_i receptors such as D₂-like receptors, 5HT_1, 5HT₅ and Adra2 inhibit adenylate cyclase (AC), while activation of G_s receptors such as D₁-like receptors, 5HT₄, 5HT₆, 5HT₇ and Adrb stimulate AC to increase cAMP levels, which in turn activate the PKA/CREB pathway (Zhao et al., 2016; Ramaswamy et al., 2017; Wang et al., 2018; Martel and Gatti McArthur, 2020). G_q/11 receptors activate PLC-IP3 and DAG-PKC signalling pathways, which activate the mitogen-activated protein kinase (MAPK)/ERK signalling cascade (Gustafsson et al., 2006a; Dai et al., 2014; McCorvy and Roth, 2015). Activation of MAPK/ERK also stimulates Runx2 and beta-catenin in osteogenesis while activation of Protein kinase C (PKC) stimulates nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), important in osteoclast differentiation (Abu-Amer, 2013; Zhao et al., 2016; Kim et al., 2019).