Bone Status in Obese, Non-diabetic, Antipsychotic-Treated Patients, and Effects of the Glucagon-Like Peptide-1 Receptor Agonist Exenatide on Bone Turnover Markers and Bone Mineral Density

Background: Low bone mineral density (BMD) may constitute an underestimated comorbidity in schizophrenia patients undergoing long-term antipsychotic treatment. Glucagon-like peptide 1 (GLP-1) receptor agonists are antidiabetic drugs, which may also affect bone turnover.Methods: In planned secondary analyses of a 3 months, double-blind, randomized, placebo-controlled trial (n = 45), we explored effects of the GLP-1 receptor agonist exenatide 2 mg once-weekly (n = 23), or placebo (n = 22) on bone turnover markers (BTMs) and BMD in chronic, obese, antipsychotic-treated patients with schizophrenia spectrum disorder. Baseline BTMs were compared to sex- and age-adjusted reference values from a Danish population cohort, and T- and Z-scores were calculated for BMD.Results: In women (n = 24), all baseline BTM measurements of procollagen type I N-terminal propeptide (PINP) and C-terminal cross-linking telopeptide of type I collagen (CTX) were within reference values. In men (n = 21), 5% displayed lower PINP and 14% displayed lower CTX. One patient displayed BMD Z-score < −2, and 23% of patients (17% of women and 29% of men) displayed −2.5 < T-scores < –1 indicating osteopenia, but none had osteoporosis. After treatment, PINP decreased at trend level significance (P = 0.05), and body mass index BMD increased for L2–L4 (P = 0.016). No changes in bone markers were significant after correction for mean prolactin levels.Conclusions: Sex- and age-adjusted measures of bone status in chronic, obese, antipsychotic-treated patients appeared comparable to the reference population. Subtle changes in bone markers during 3 months exenatide treatment may suggest beneficial effects of GLP-1 receptor agonists on bone status in antipsychotic-treated patients, and further studies should consider the potential influence of prolactin

Glucagon-like peptide-1 analogs against antipsychotic-induced weight gain: potential physiological benefits

BACKGROUND: Antipsychotic-induced weight gain constitutes a major unresolved clinical problem which may ultimately be associated with reducing life expectancy by 25 years. Overweight is associated with brain deterioration, cognitive decline and poor quality of life, factors which are already compromised in normal weight patients with schizophrenia. Here we outline the current strategies against antipsychotic-induced weight gain, and we describe peripheral and cerebral effects of the gut hormone glucagon-like peptide-1 (GLP-1). Moreover, we account for similarities in brain changes between schizophrenia and overweight patients. DISCUSSION: Current interventions against antipsychotic-induced weight gain do not facilitate a substantial and lasting weight loss. GLP-1 analogs used in the treatment of type 2 diabetes are associated with significant and sustained weight loss in overweight patients. Potential effects of treating schizophrenia patients with antipsychotic-induced weight gain with GLP-1 analogs are discussed. CONCLUSIONS: We propose that adjunctive treatment with GLP-1 analogs may constitute a new avenue to treat and prevent metabolic and cerebral deficiencies in schizophrenia patients with antipsychotic-induced weight gain. Clinical research to support this idea is highly warranted

The impact of schizophrenia and intelligence on the relationship between age and brain volume

Age has been shown to have an impact on both grey (GM) and white matter (WM) volume, with a steeper slope of age-related decline in schizophrenia compared to healthy controls. In schizophrenia, the relation between age and brain volume is further complicated by factors such as lower intelligence, antipsychotic medication, and cannabis use, all of which have been shown to have independent effects on brain volume. In a study of first-episode, antipsychotic-naïve schizophrenia patients (N = 54) and healthy controls (N = 56), we examined the effects of age on whole brain measures of GM and WM volume, and whether these relationships were moderated by schizophrenia and intelligence (IQ). Secondarily, we examined lifetime cannabis use as a moderator of the relationship between age and brain volume. Schizophrenia patients had lower GM volumes than healthy controls but did not differ on WM volume. We found an age effect on GM indicating that increasing age was associated with lower GM volumes, which did not differ between groups. IQ did not have a direct effect on GM, but showed a trend-level interaction with age, suggesting a greater impact of age with lower IQ. There were no age effects on WM volume, but a direct effect of IQ, with higher IQ showing an association with larger WM volume. Lifetime cannabis use did not alter these findings significantly. This study points to effects of schizophrenia on GM early in the illness, before antipsychotic treatment is initiated, suggesting that WM changes may occur later in the disease process

Bone Status in Obese, Non-diabetic, Antipsychotic-Treated Patients, and Effects of the Glucagon-Like Peptide-1 Receptor Agonist Exenatide on Bone Turnover Markers and Bone Mineral Density

Background: Low bone mineral density (BMD) may constitute an underestimated comorbidity in schizophrenia patients undergoing long-term antipsychotic treatment. Glucagon-like peptide 1 (GLP-1) receptor agonists are antidiabetic drugs, which may also affect bone turnover.Methods: In planned secondary analyses of a 3 months, double-blind, randomized, placebo-controlled trial (n = 45), we explored effects of the GLP-1 receptor agonist exenatide 2 mg once-weekly (n = 23), or placebo (n = 22) on bone turnover markers (BTMs) and BMD in chronic, obese, antipsychotic-treated patients with schizophrenia spectrum disorder. Baseline BTMs were compared to sex- and age-adjusted reference values from a Danish population cohort, and T- and Z-scores were calculated for BMD.Results: In women (n = 24), all baseline BTM measurements of procollagen type I N-terminal propeptide (PINP) and C-terminal cross-linking telopeptide of type I collagen (CTX) were within reference values. In men (n = 21), 5% displayed lower PINP and 14% displayed lower CTX. One patient displayed BMD Z-score Conclusions: Sex- and age-adjusted measures of bone status in chronic, obese, antipsychotic-treated patients appeared comparable to the reference population. Subtle changes in bone markers during 3 months exenatide treatment may suggest beneficial effects of GLP-1 receptor agonists on bone status in antipsychotic-treated patients, and further studies should consider the potential influence of prolactin.</p

Effect of GLP-1 Receptor Agonist Treatment on Body weight in Obese Antipsychotic-treated Patients with Schizophrenia:a Randomized, Placebo-controlled Trial Byline

AIMS: Schizophrenia is associated with cardiovascular co‐morbidity and a reduced life‐expectancy of up to 20 years. Antipsychotics are dopamine D(2) receptor antagonists and are the standard of medical care in schizophrenia, but the drugs are associated with severe metabolic side effects such as obesity and diabetes. Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are registered for treatment of both obesity and type 2 diabetes. We investigated metabolic effects of the GLP‐1RA, exenatide once‐weekly, in non‐diabetic, antipsychotic‐treated, obese patients with schizophrenia. MATERIAL AND METHODS: Antipsychotic‐treated, obese, non‐diabetic, schizophrenia spectrum patients were randomized to double‐blinded adjunctive treatment with once‐weekly subcutaneous exenatide (n = 23) or placebo (n = 22) injections for 3 months. The primary outcome was loss of body weight after treatment and repeated measures analysis of variance was used as statistical analysis. RESULTS: Between March 2013 and June 2015, 40 patients completed the trial. At baseline, mean body weight was 118.3 ± 16.0 kg in the exenatide group and 111.7 ± 18.0 kg in the placebo group, with no group differences ( P = .23). The exenatide and placebo groups experienced significant ( P = .004), however similar ( P = .98), weight losses of 2.24 ± 3.3 and 2.23 ± 4.4 kg, respectively, after 3 months of treatment. CONCLUSIONS: Treatment with exenatide once‐weekly did not promote weight loss in obese, antipsychotic‐treated patients with schizophrenia compared to placebo. Our results could suggest that the body weight‐lowering effect of GLP‐1RAs involves dopaminergic signaling, but blockade of other receptor systems may also play a role. Nevertheless, anti‐obesity regimens effective in the general population may not be readily implemented in antipsychotic‐treated patients with schizophrenia

Tapered discontinuation vs. maintenance therapy of antipsychotic medication in patients with first-episode schizophrenia:Obstacles, findings, and lessons learned in the terminated randomized clinical trial TAILOR

AIM: Evidence is insufficient regarding the consequences of discontinuing vs. maintaining antipsychotic medication in patients with first-episode schizophrenia. Our aim was to examine tapered discontinuation vs. maintenance treatment regarding remission of psychotic symptoms and impact on other areas. METHODS: Patients included had a diagnosis of schizophrenia, were treated with antipsychotic medication, and were in remission of psychotic symptoms. Participants were randomized to tapered discontinuation or maintenance treatment with antipsychotic medication. Assessments were undertaken at baseline and after 1-year. The primary outcome was remission of psychotic symptoms without antipsychotic medication. RESULTS: The trial was terminated due to insufficient recruitment. In total, 29 participants were included: 14 in the tapering/discontinuation group and 15 in the maintenance group. Adherence to maintenance treatment was poor. At 1-year follow-up, remission of psychotic symptoms without antipsychotic medication for 3 months was observed in five participants in the tapering/discontinuation group and two in the maintenance group. CONCLUSION: Due to insufficient recruitment this study does not provide a conclusion on whether unfavorable outcomes or advantages follow tapering of antipsychotic medication. Recruitment and adherence to maintenance treatment encountered obstacles. Based on experiences from this trial, we discussed alternative study designs as consistent evidence is still needed on whether to continue or discontinue antipsychotic medication in remitted patients with first-episode schizophrenia. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-000565-23/DK, EU Clinical Trials Register—EudraCT no. 2016–000565–23

Agents intervening against delirium in the intensive care unit (AID-ICU) - Protocol for a randomised placebo-controlled trial of haloperidol in patients with delirium in the ICU

Background Delirium among patients in the intensive care unit (ICU) is a common condition associated with increased morbidity and mortality. Haloperidol is the most frequently used pharmacologic intervention, but its use is not supported by firm evidence. Therefore, we are conducting Agents Intervening against Delirium in the Intensive Care Unit (AID‐ICU) trial to assess the benefits and harms of haloperidol for the treatment of ICU‐acquired delirium. Methods AID‐ICU is an investigator‐initiated, pragmatic, international, randomised, blinded, parallel‐group, trial allocating adult ICU patients with manifest delirium 1:1 to haloperidol or placebo. Trial participants will receive intravenous 2.5 mg haloperidol three times daily or matching placebo (isotonic saline 0.9%) if they are delirious. If needed, a maximum of 20 mg/daily haloperidol/placebo is given. An escape protocol, not including haloperidol, is part of the trial protocol. The primary outcome is days alive out of the hospital within 90 days post‐randomisation. Secondary outcomes are number of days without delirium or coma, serious adverse reactions to haloperidol, usage of escape medication, number of days alive without mechanical ventilation; mortality, health‐related quality‐of‐life and cognitive function at 1‐year follow‐up. A sample size of 1000 patients is required to detect a 7‐day improvement or worsening of the mean days alive out of the hospital, type 1 error risk of 5% and power 90%. Perspective The AID‐ICU trial is based on gold standard methodology applied to a large sample of clinically representative patients and will provide pivotal high‐quality data on the benefits and harms of haloperidol for the treatment ICU‐acquired delirium