Understanding the Effects of Antipsychotics on Appetite Control

Abstract

Antipsychotic drugs (APDs) represent a cornerstone in the treatment of schizophrenia and other psychoses. The effectiveness of the first generation (typical) APDs are hampered by so-called extrapyramidal side effects, and they have gradually been replaced by second (atypical) and third-generation APDs, with less extrapyramidal side effects and, in some cases, improved efficacy. However, the use of many of the current APDs has been limited due to their propensity to stimulate appetite, weight gain, and increased risk for developing type 2 diabetes and cardiovascular disease in this patient group. The mechanisms behind the appetite-stimulating effects of the various APDs are not fully elucidated, partly because their diverse receptor binding profiles may affect different downstream pathways. It is critical to identify the molecular mechanisms underlying drug-induced hyperphagia, both because this may lead to the development of new APDs, with lower appetite-stimulating effects but also because such insight may provide new knowledge about appetite regulation in general. Hence, in this review, we discuss the receptor binding profile of various APDs in relation to the potential mechanisms by which they affect appetite.

Keywords: antipsychotics; appetite control; hyperphagia; hypothalamus; mechanisms.

Figure 1

Hypothalamic regulation of food intake. The figure shows hypothalamic regulation of food intake involving various hypothalamus regions (ARC, VMH, LHA, PVH, and DMH). The NPY/AgRP pathway increases food intake, while the POMC/CART pathway triggers satiety. Adiponectin/ ghrelin, and cannabinoids all demonstrate food intake regulation by AMPK activation in the ARC or in VMH. Leptin reduces food intake by directly inhibiting AMPK in PVH or indirectly via POMC neurons in ARC. Black dotted arrows and red lines with blunted ends are showing inhibitory signals. Stimulatory signals are represented by blue and green arrows. On the figure, half circles in different colors show the locations of various receptors through which APDs work. ARC, Arcuate nucleus; VMH, Ventromedial hypothalamus; LHA, Lateral hypothalamus area; PVH, Paraventricular nucleus of hypothalamus; DMH, Dorsomedial hypothalamus; NPY/AgRP, Neuropeptide Y/ agouti-related peptide; POMC, Proopiomelanocortin; CART, Cocaine and amphetamine-regulated transcript; AMPK, AMP-activated protein kinase; M3R, Muscarinic 3 receptor; BDNF, Brain-derived neurotrophic factor; GSH-R, Ghrelin receptor; MCR, Melanocortin receptor; CB1R, Cannabinoid receptor; 5HT2cR, 5-hydroxytryptamine 2c receptor (serotonin receptor); Leptin R, Leptin receptor; APDs Antipsychotics.

Figure 2

The regulation of food intake by other brain areas. Vagal afferents bring peripheral signals into the VTA by crossing the brain stem. Dopamine neurons (DA) in the VTA project axons to LHA and NAc. In response to the dopamine neurons projected by VTA, LHA connects higher cortical regions to control food intake. The blue arrows indicate the connections between the different brain areas. The double-sided arrows indicate bidirectional connections. VTA, Ventral tegmental area; NAc, Nucleus accumbens; LHA, Lateral hypothalamus area; DA, Dopamine neurons; DVC, Dorso vagal complex.

Figure 3

Regulation of appetite by APDs. According to the proposed scheme, APDs enhance appetite through different receptor systems activating AMPK-NPY system, metabolic hormonal release via Ach pathway, or mesolimbic pathway. Blunt-ended black lines indicate inhibitions. Black arrows indicate stimulations. The upward arrow represents the upregulation of the NPY/AgRP signals while the downward arrow indicates the downward regulation of POMC. H1, Histamine receptor; M3, Muscarinic receptor; D2, Dopamine receptor; 5HT1a,2a,2c, Serotonin receptors; AMPK, AMP-activated protein kinase; NPY/AgRP, Neuropeptide Y/ agouti-related peptide; POMC, Proopiomelanocortin.

Figure 4

Gut-brain axis and regulation of appetite by APDs. Through impaired stress axis, antipsychotics (APDs) can influence gut microbiota composition, in turn, gut dysbiosis can alter gut-microbiota metabolism, changing the metabolites, leading to increased overeating and weight gain via peripheral (leptin, ghrelin) and vagal afferent signaling.