Glucose and lipid metabolism of long‐term risperidone monotherapy in patients with schizophrenia

Abstract

Risperidone has a relatively low risk of causing obesity and diabetes mellitus and is a first-line treatment for schizophrenia. The aim of the present study was to investigate glucose and lipid metabolism, and feeding-control parameters in schizophrenia patients treated with long-term risperidone monotherapy. Fifteen patients with paranoid-type schizophrenia who had been treated with risperidone and had Global Assessment of Function (GAF) scores >70 were selected and compared with healthy volunteers (n = 25). Single assessments of psychotic symptoms, side-effects, Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) score, bodyweight, body fat percentage and blood sampling were performed. Fasting blood glucose, insulin, hemoglobin A1c, homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol, triglyceride, high density lipoprotein (HDL)-, low density lipoprotein-cholesterol, adiponectin, prolactin and feeding-control parameters (ghrelin and leptin) were analyzed. The body fat percentage (P = 0.0018), body mass index (BMI) (P = 0.0150), fasting blood glucose (P = 0.0358), triglyceride (P = 0.0377), leptin (P = 0.0243), total ghrelin (P = 0.0067), active ghrelin (P = 0.0241) and prolactin (P < 0.0001) levels of patients treated with risperidone were significantly higher than those of healthy volunteers, while the HDL-cholesterol level (P = 0.0222) was significantly lower. Although the patients had very mild psychiatric symptoms and maintained functionally high levels, the glucose and lipid parameters were significantly impaired compared to healthy volunteers. A high level of plasma ghrelin might increase appetite, leading to exacerbation of metabolic impairment.

The role of ghrelin signalling in second-generation antipsychotic-induced weight gain

“…Furthermore, the majority of longer-term studies reporting on ghrelin levels after more than 6 months of SGA treatments showed an upregulation effect of SGAs on circulating total (Esen-Danaci et al, 2008;Murashita et al, 2007a;Murashita et al, 2005), active (Murashita et al, 2007a;Murashita et al, 2005;Palik et al, 2005) or desacyl (Perez-Iglesias et al, 2008) ghrelin levels, with the exception of two studies (Chen et al, 2011;Kim et al, 2008) (see details in Table 1). Interestingly, both of these two studies reported on total ghrelin levels only (Chen et al, 2011;Kim et al, 2008); while the three long-term studies reported on active ghrelin levels all indicated that SGAs can increase ghrelin levels (Murashita et al, 2007a;Murashita et al, 2005;Palik et al, 2005). Since acyl ghrelin (noctanoyl ghrelin) is the biologically active form of ghrelin which binds to the GHS-R1a receptor to exert its orexigenic effect (as mentioned earlier in section 2.1), it might be more relevant in the context of SGA-induced body weight gain compared to total ghrelin, although SGAs, as suggested by another study, also increase desacyl (inactive) ghrelin levels in the long-term (Perez-Iglesias et al, 2008).…”

“…Clinical data has indicated ghrelin production and signalling is upregulated, at least in a subpopulation of patients under SGA treatments (Esen-Danaci et al, 2008;Murashita et al, 2007a;Murashita et al, 2005;Palik et al, 2005;Perez-Iglesias et al, 2008), which was supported by the majority of acute and chronic animal studies (Murashita et al, 2007b;van der Zwaal et al, 2012;Weston-Green et al, 2011). Although ghrelin signalling is only indirectly related to SGAs, and therefore other mechanisms (for example, antagonism of H1, H3, 5-HT2a, M3 receptors) cannot be excluded, the majority of data as discussed above indicate that the altered ghrelin signalling under SGA treatments can at least partly explain the weight gain sideeffects induced by SGAs.…”

“…Ghrelin could increase food intake and lead to body weight gain in humans (Adachi et al, 2010;Druce et al, 2005), which coincides with clinical observations that patients on antipsychotics often experience increased appetite and food intake. In addition, clinical (Basoglu et al, 2010;Chen et al, 2011;Esen-Danaci et al, 2008;Hosojima et al, 2006;Kim et al, 2008;Murashita et al, 2007a;Murashita et al, 2005;Palik et al, 2005;Perez-Iglesias et al, 2008;Roerig et al, 2008;Tanaka et al, 2008;Togo et al, 2004;Vidarsdottir et al, 2010) and animal studies (Albaugh et al, 2006;Davey et al, 2012;Weston-Green et al, 2011) suggest that SGA treatments modulate circulating ghrelin levels. Moreover, rats treated with olanzapine, an SGA with significant weight gain liabilities, have elevated hypothalamic ghrelin receptor (also called growth hormone secretagogue receptor 1a; GHS-R1a) expression (Davey et al, 2012;Zhang et al, 2012), indicating that ghrelin signalling may play a role in antipsychotic-induced obesity.…”

Impact of atypical antipsychotic therapy on leptin, ghrelin, and adiponectin

“…In another human vitro study with 7-day olanzapine exposure had no effect on adiponectin (Murashita et al, 2005) 7 olanzapine Prospective 6-month study Compared to baseline, no significant change in adiponectin levels although body fat significantly increased at month 6. (Murashita et al, 2007) 15 risperidone 25 controls…”

The Effects of Atypical Antipsychotic Usage Duration on Serum Adiponectin Levels and Other Metabolic Parameters

“…The effects of atypical antipsychotics, as well as other symptoms of metabolic syndrome, on serum adiponectin levels are increasingly becoming the subject of research. Previous studies investigating the relationship between serum adiponectin levels and the usage of atypical antipsychotics have focused more on short-term effects [9,[13][14][15][16][17]. In this study, our purpose was to investigate the effects of atypical antipsychotic usage on serum adiponectin levels and metabolic parameters based on their association with long-and short-term atypical antipsychotic usage.…”