Trabecular bone loss after administration of the second-generation antipsychotic risperidone is independent of weight gain

Second generation antipsychotics (SGAs) have been linked to metabolic and bone disorders in clinical studies, but the mechanisms of these side effects remain unclear. Additionally, no studies have examined whether SGAs cause bone loss in mice. Using in vivo and in vitro modeling we examined the effects of risperidone, the most commonly prescribed SGA, on bone in C57BL6/J (B6) mice. Mice were treated with risperidone orally by food supplementation at a dose of 1.25 mg/kg daily for 5 and 8 weeks, starting at 3.5 weeks of age. Risperidone reduced trabecular BV/TV, trabecular number and percent cortical area. Trabecular histomorphometry demonstrated increased resorption parameters, with no change in osteoblast number or function. Risperidone also altered adipose tissue distribution such that white adipose tissue mass was reduced and liver had significantly higher lipid infiltration. Next, in order to tightly control risperidone exposure, we administered risperidone by chronic subcutaneous infusion with osmotic minipumps (0.5 mg/kg daily for 4 weeks) in 7 week old female B6 mice. Similar trabecular and cortical bone differences were observed compared to the orally treated groups (reduced trabecular BV/TV, and connectivity density, and reduced percent cortical area) with no change in body mass, percent body fat, glucose tolerance or insulin sensitivity. Unlike in orally treated mice, risperidone infusion reduced bone formation parameters (serum P1NP, MAR and BFR/BV). Resorption parameters were elevated, but this increase did not reach statistical significance. To determine if risperidone could directly affect bone cells, primary bone marrow cells were cultured with osteoclast or osteoblast differentiation media. Risperidone was added to culture medium in clinically relevant doses of 0, 2.5 or 25 ng/ml. The number of osteoclasts was significantly increased by addition in vitro of risperidone while osteoblast differentiation was not altered. These studies indicate that risperidone treatment can have negative skeletal consequences by direct activation of osteoclast activity and by indirect non-cell autonomous mechanisms. Our findings further support the tenet that the negative side effects of SGAs on bone mass should be considered when weighing potential risks and benefits, especially in children and adolescents who have not yet reached peak bone mass. This article is part of a Special Issue entitled: Interactions Between Bone, Adipose Tissue and Metabolism. (C) 2011 Elsevier Inc. All rights reserved.National Institute Of Arthritis And Musculoskeletal And Skin Diseases [F32AR061932, AR054604]CAPES, Brazil [0102-09-1]MMCRINational Council for Scientific and Technological Development (CNPq), Brazil [201650/2008-8]NIH [P20 RR18789, P20 RR15555, P30 RR030927

Mechanisms Underlying Antipsychotic-Induced NAFLD and Iron Dysregulation: A Multi-Omic Approach

Atypical antipsychotic (AA) medications are widely prescribed for the treatment of psychiatric disorders, including schizophrenia, bipolar disorder and treatment-resistant depression. AA are associated with myriad metabolic and endocrine side effects, including systemic inflammation, weight gain, dyslipidemia and insulin resistance, all of which are associated with increased incidence of non-alcoholic fatty liver disease (NAFLD). NAFLD is highly prevalent in patients with mental illness, and AA have been shown to increase incidence of NAFLD pre-clinically and clinically. However, the underlying mechanisms have not been described. We mined multi-omic datasets from preclinical murine models of sub-chronic risperidone or olanzapine treatment, in vitro exposure of human cells to risperidone and psychiatric patients following onset of aripiprazole therapy focused on pathways associated with the pathophysiology of NAFLD, including iron accumulation, systemic inflammation and dyslipidemia. We identified numerous differentially expressed traits affecting these pathways conserved across study systems and AA medications. We used these findings to propose mechanisms for AA-associated development of NAFLD and dysregulated iron homeostasis

Effects of bovine somatotropin (bST) and ß-adrenergics on lipolysis and hormone-sensitive lipase in lactating cows

Estudou-se o efeito da somatotropina (bST) na lipase sensível a hormônio (HSL), a enzima reguladora da lipólise. Cinco vacas receberam injeções diárias de 40 mg de bST ou veículo, em delineamento de reversão simples. A bST aumentou a produção de leite (19,2 para 27,9 kg/d; P0,10). A bST não alterou (P>0,10) a atividade ou o grau de ativação da HSL de explantes incubados com isoproterenol (10-5 M) e adenosina deaminase (0,75 U/ml). Embora o balanço energético e o teor de gordura no leite demonstrem aumento na mobilização de gordura, a lipólise e a atividade da HSL não foram alteradas. Os resultados confirmam trabalhos anteriores, indicando que o aumento na mobilização de gorduras por bST é função de diminuição da inibição da lipólise.The effects of bST on hormone-sensitive lipase (HSL), the rate-limiting enzyme in lipid mobilization, were studied. Five multiparous Holstein cows received daily 40 mg injections of n-methionyl-bST or of excipient, in a single reversal design. Treatment with bST increased milk production from 19.2 to 27.9 kg/d (P0.10). Also, bST did not alter (P>0.10) activity or degree of activation of HSL in explants incubated with isoproterenol (10-5 M) and adenosine deaminase (0.75 U/ml). Although energy balance and milk fat content suggest fat mobilization increased, maximal lipolitic rate and HSL, activity were unchanged. Results agree with previous results suggesting the increase in lipid mobilization after bST treatment is the result of a relief of the inhibition of lipolysis

Antipsychotic-induced immune dysfunction: A consideration for COVID-19 risk

Patients with severe mental illness are more susceptible to infections for a variety of reasons, some associated with the underlying disease and some due to environmental factors including housing insecurity, smoking, poor access to healthcare, and medications used to treat these disorders. This increased susceptibility to respiratory infections may contribute to risk of COVID-19 infection in patients with severe mental illness or those in inpatient settings. Atypical antipsychotic (AA) medications are FDA approved to treat symptoms associated with schizophrenia, bipolar disorder, depression and irritability associated with autism. Our team and others have shown that AA may have anti-inflammatory properties that may contribute to their efficacy in the treatment of mental health disorders. Additionally, AA are widely prescribed off-label for diverse indications to non-psychotic patients including older adults, who are also at increased risk for COVID-19 complications and mortality. The aim of this study was to determine if AA medications such as risperidone (RIS) alter the ability to mount an appropriate response to an acute inflammatory or adaptive immune challenge using a preclinical model. Short-term treatment of healthy mice with a dose of RIS that achieves plasma concentrations within the low clinical range resulted in disrupted response to an inflammatory (LPS) challenge compared to vehicle controls. Furthermore, RIS also prevented treated animals from mounting an antibody response following vaccination with Pneumovax23®. These data indicate that short-to intermediate-term exposure to clinically relevant levels of RIS dysregulate innate and adaptive immune responses, which may affect susceptibility to respiratory infections, including COVID-19

The antipsychotic medication, risperidone, causes global immunosuppression in healthy mice.

Atypical antipsychotic medications such as risperidone are widely prescribed for diverse psychiatric indications including schizophrenia, bipolar disorder and depression. These medications have complex pharmacology and are associated with significant endocrine and metabolic side effects. This class of medications also carries FDA black box warnings due to increased risk of death in elderly patients. Clinical reports indicate that patients treated with these medications are more susceptible to infections; however, the underlying mechanisms/pharmacology are unclear. We have previously reported that risperidone and it\u27s active metabolite distributes to the bone marrow in clinically relevant concentrations in preclinical species, leading us to hypothesize that the hematopoietic system may be impacted by these medications. To test this hypothesis, using proteomic and cytokine array technology, we evaluated the expression of genes involved in inflammatory and immune function following short term (5 days) and longer term (4 weeks) treatment in healthy animals. We report that low-dose risperidone treatment results in global immunosuppression in mice, observed following 5 days of dosing and exacerbated with longer term drug treatment (4 weeks). These data are consistent with increased susceptibility to infection in patients administered these medications and have profound implications for the increasing off-label prescribing to vulnerable patient populations including children and the elderly

Housing Temperature Influences Atypical Antipsychotic Drug-Induced Bone Loss in Female C57BL/6J Mice

Atypical antipsychotic (AA) drugs, such as risperidone, are associated with endocrine and metabolic side effects, including impaired bone mineral density (BMD) acquisition and increased fracture risk. We have previously shown that risperidone causes bone loss through the sympathetic nervous system and that bone loss is associated with elevated markers of thermogenesis in brown and white adipose tissue. Because rodents are normally housed in sub-thermoneutral conditions, we wanted to test whether increasing housing temperature would protect against bone loss from risperidone. Four weeks of risperidone treatment in female C57BL/6J mice at thermoneutral (28°C) housing attenuated risperidone-induced trabecular bone loss and led to a low-turnover bone phenotype, with indices of both bone formation and resorption suppressed in mice with risperidone treatment at thermoneutrality, whereas indices of bone resorption were elevated by risperidone at room temperature. Protection against trabecular bone loss was not absolute, however, and additional evidence of cortical bone loss emerged in risperidone-treated mice at thermoneutrality. Taken together, these findings suggest thermal challenge may be in part responsible for bone loss with risperidone treatment and that housing temperature should be considered when assessing bone outcomes of treatments that impact thermogenic pathways

Thermoneutral housing does not rescue olanzapine-induced trabecular bone loss in C57BL/6J female mice

Antipsychotic drugs are prescribed to a wide range of individuals to treat mental health conditions including schizophrenia. However, antipsychotic drugs cause bone loss and increase fracture risk. We previously found that the atypical antipsychotic (AA) drug risperidone causes bone loss through multiple pharmacological mechanisms, including activation of the sympathetic nervous system in mice treated with clinically relevant doses. However, bone loss was dependent upon housing temperature, which modulates sympathetic activity. Another AA drug, olanzapine, has substantial metabolic side effects, including weight gain and insulin resistance, but it is unknown whether bone and metabolic outcomes of olanzapine are also dependent upon housing temperature in mice. We therefore treated eight week-old female mice with vehicle or olanzapine for four weeks, housed at either room temperature (23 °C) or thermoneutrality (28-30 °C), which has previously been shown to be positive for bone. Olanzapine caused significant trabecular bone loss (-13% BV/TV), likely through increased RANKL-dependent osteoclast resorption, which was not suppressed by thermoneutral housing. Additionally, olanzapine inhibited cortical bone expansion at thermoneutrality, but did not alter cortical bone expansion at room temperature. Olanzapine also increased markers of thermogenesis within brown and inguinal adipose depots independent of housing temperature. Overall, olanzapine causes trabecular bone loss and inhibits the positive effect of thermoneutral housing on bone. Understanding how housing temperature modulates the impact of AA drugs on bone is important for future pre-clinical studies, as well as for the prescription of AA drugs, particularly to older adults and adolescents who are most vulnerable to the effects on bone

Thermoneutral housing does not rescue olanzapine-induced trabecular bone loss in C57BL/6J female mice

Antipsychotic drugs are prescribed to a wide range of individuals to treat mental health conditions including schizophrenia. However, antipsychotic drugs cause bone loss and increase fracture risk. We previously found that the atypical antipsychotic (AA) drug risperidone causes bone loss through multiple pharmacological mechanisms, including activation of the sympathetic nervous system in mice treated with clinically relevant doses. However, bone loss was dependent upon housing temperature, which modulates sympathetic activity. Another AA drug, olanzapine, has substantial metabolic side effects, including weight gain and insulin resistance, but it is unknown whether bone and metabolic outcomes of olanzapine are also dependent upon housing temperature in mice. We therefore treated eight week-old female mice with vehicle or olanzapine for four weeks, housed at either room temperature (23 °C) or thermoneutrality (28–30 °C), which has previously been shown to be positive for bone. Olanzapine caused significant trabecular bone loss (−13% BV/TV), likely through increased RANKL-dependent osteoclast resorption, which was not suppressed by thermoneutral housing. Additionally, olanzapine inhibited cortical bone expansion at thermoneutrality, but did not alter cortical bone expansion at room temperature. Olanzapine also increased markers of thermogenesis within brown and inguinal adipose depots independent of housing temperature. Overall, olanzapine causes trabecular bone loss and inhibits the positive effect of thermoneutral housing on bone. Understanding how housing temperature modulates the impact of AA drugs on bone is important for future pre-clinical studies, as well as for the prescription of AA drugs, particularly to older adults and adolescents who are most vulnerable to the effects on bone

Deletion of α-Synuclein in Prrx1-positive cells causes partial loss of function in the central nervous system (CNS) but does not affect ovariectomy induced bone loss

α-Synuclein is a small 140 amino acid polypeptide encoded by the Snca gene that is highly expressed in neural tissue, but it is also found in osteoblasts, erythroblasts, macrophages, and adipose tissue. Previously, using co-expression network analysis we found that Snca was a key regulator of skeletal homeostasis, and its deletion partially prevented bone loss after ovariectomy (OVX). Here we tested the hypothesis that Snca deletion in mesenchymal progenitors using the Prrx1Cre (Prrx1, Paired-related homeobox 1) limb enhancer would protect bone mass after OVX. Prrx1Cre;Snca and littermate controls (Snca) were sham operated or ovariectomized (OVX) at 8 weeks of age and sacrificed at 20 weeks. Independently, eight-week female and male Prrx1Cre;Snca mice and littermate controls were administered a high fat (60% fat) or low fat (10% fat) diet for 15 weeks. Bone loss was not prevented in either genotype after ovariectomy, but the Prrx1Cre;Snca mice were partially protected from weight gain after OVX and high fat diet (HFD). Serum catecholamine levels were lower in the Prrx1Cre;Snca both on a low fat diet (LFD) and HFD versus fl/fl controls. Importantly, mutant mice exhibited a number of physical and behavioral phenotypes that were associated with conditional deletion of Snca in several brain regions. Cells labeled with Prrx1 were noted throughout the central nervous system (CNS). These data support earlier preliminary reports of Prrx1 expression in neural progenitors, and raise a cautionary note about the evaluation of skeletal and body composition phenotypes when using this Cre driver to study osteoprogenitor development

Propranolol attenuates risperidone-induced trabecular bone loss in female mice.

Atypical antipsychotic (AA) drugs cause significant metabolic side effects, and clinical data are emerging that demonstrate increased fracture risk and bone loss after treatment with the AA, risperidone (RIS). The pharmacology underlying the adverse effects on bone is unknown. However, RIS action in the central nervous system could be responsible because the sympathetic nervous system (SNS) is known to uncouple bone remodeling. RIS treatment in mice significantly lowered trabecular bone volume fraction (bone volume/total volume), owing to increased osteoclast-mediated erosion and reduced osteoblast-mediated bone formation. Daytime energy expenditure was also increased and was temporally associated with the plasma concentration of RIS. Even a single dose of RIS transiently elevated expression of brown adipose tissue markers of SNS activity and thermogenesis, Pgc1a and Ucp1. Rankl, an osteoclast recruitment factor regulated by the SNS, was also increased 1 hour after a single dose of RIS. Thus, we inferred that bone loss from RIS was regulated, at least in part, by the SNS. To test this, we administered RIS or vehicle to mice that were also receiving the nonselective β-blocker propranolol. Strikingly, RIS did not cause any changes in trabecular bone volume/total volume, erosion, or formation while propranolol was present. Furthermore, β2-adrenergic receptor null (Adrb2(-/-)) mice were also protected from RIS-induced bone loss. This is the first report to demonstrate SNS-mediated bone loss from any AA. Because AA medications are widely prescribed, especially to young adults, clinical studies are needed to assess whether β-blockers will prevent bone loss in this vulnerable population