Brian V. Broberg

Treatment of antipsychotic-associated obesity with a GLP-1 receptor agonist—protocol for an investigator-initiated prospective, randomised, placebo-controlled, double-blinded intervention study: the TAO study protocol

Introduction Antipsychotic medication is widely associated with dysmetabolism including obesity and type 2 diabetes, cardiovascular-related diseases and early death. Obesity is considered the single most important risk factor for cardiovascular morbidity and mortality. Interventions against antipsychotic-associated obesity are limited and insufficient. Glucagon-like peptide-1 (GLP-1) receptor agonists are approved for the treatment of type 2 diabetes, but their bodyweight-lowering effects have also been recognised in patients with non-diabetes. The primary endpoint of this trial is weight loss after 3u2005months of treatment with a GLP-1 receptor agonist (exenatide once weekly) in patients with non-diabetic schizophrenia with antipsychotic-associated obesity. Secondary endpoints include physiological and metabolic measurements, various psychopathological and cognitive measures, and structural and functional brain MRI. Methods and analysis 40 obese patients with schizophrenia or schizoaffective disorder treated with antipsychotic drugs will be randomised to subcutaneous injection of exenatide once weekly (2u2005mg) or placebo for 3u2005months, adjunctive to their antipsychotic treatment. Ethics and dissemination The trial has been approved by the Danish Health and Medicines Authority, the National Committee on Health Research Ethics and the Danish Data Protection Agency. Trial participation presupposes theoral and written patient informed consent. An external, independent monitoring committee (Good Clinical Practice Unit at Copenhagen University Hospital) will monitor the study according to the GCP Guidelines. Trial data, including positive, negative and inconclusive results, will be presented at national and international scientific meetings and conferences. Papers will be submitted to peer-reviewed journals. Trial registration ClinicalTrials.gov identifier: NCT01794429; National Committee on Health Research Ethics project number: 36378; EudraCT nr: 2012-005404-17; The Danish Data Protection Agency project number: RHP-2012-027.

Effect of GLP-1 receptor agonist treatment on body weight in obese antipsychotic-treated patients with schizophrenia: a randomized, placebo-controlled trial

Schizophrenia is associated with cardiovascular co‐morbidity and a reduced life‐expectancy of up to 20 years. Antipsychotics are dopamine D2 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.

No cognitive‐enhancing effect of GLP‐1 receptor agonism in antipsychotic‐treated, obese patients with schizophrenia

Schizophrenia is associated with profound cognitive and psychosocial impairments. Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) are used for diabetes and obesity treatment, and animal studies have indicated cognitive‐enhancing effects. In this investigator‐initiated, double‐blind, randomized, placebo‐controlled trial, we tested non‐metabolic effects of exenatide once‐weekly (Bydureon™) in obese, antipsychotic‐treated patients with schizohrenia spectrum disorder.

Response to initial antipsychotic treatment in first episode psychosis is related to anterior cingulate glutamate levels: a multicentre 1H-MRS study (OPTiMiSE)

Conventional antipsychotic medication is ineffective in around a third of patients with schizophrenia, and the nature of the therapeutic response is unpredictable. We investigated whether response to antipsychotics is related to brain glutamate levels prior to treatment. Proton magnetic resonance spectroscopy was used to measure glutamate levels (Glu/Cr) in the anterior cingulate cortex (ACC) and in the thalamus in antipsychotic-naive or minimally medicated patients with first episode psychosis (FEP, nu2009=u200971) and healthy volunteers (nu2009=u200960), at three sites. Following scanning, patients were treated with amisulpride for 4 weeks (nu2009=u200965), then 1H-MRS was repeated (nu2009=u200946). Remission status was defined in terms of Positive and Negative Syndrome Scale for Schizophrenia (PANSS) scores. Higher levels of Glu/Cr in the ACC were associated with more severe symptoms at presentation and a lower likelihood of being in remission at 4 weeks (Pu2009<u20090.05). There were longitudinal reductions in Glu/Cr in both the ACC and thalamus over the treatment period (Pu2009<u20090.05), but these changes were not associated with the therapeutic response. There were no differences in baseline Glu/Cr between patients and controls. These results extend previous evidence linking higher levels of ACC glutamate with a poor antipsychotic response by showing that the association is evident before the initiation of treatment.

Glucocorticoids and the risk of schizophrenia spectrum disorder in childhood and adolescence – A Danish nationwide study

Glucocorticoids can have psychosis as a potential side effect, but have also been suggested to yield protective effects due to anti-inflammatory properties. Nonetheless, knowledge is sparse on the association between glucocorticoid treatment and development of psychosis, which we aimed to study in this first large-scale longitudinal study. Among all individuals born in Denmark 1995-2003 (n=597,257), we compared individuals who had redeemed ≥1 prescription for glucocorticoids to an active comparator group and a non-exposed group concerning subsequent development of schizophrenia spectrum disorders until 2013. Hazard rate ratios (HRR) were estimated using Cox regression adjusted for calendar year, age, gender, urbanization, somatic diseases, parental educational level and psychiatric history. The risk for a subsequent diagnosis of early-onset schizophrenia spectrum disorder (N=1141) was increased after exposure to both non-systemic (HRR=1.47; 95%-CI=1.25-1.73; N=371) and systemic glucocorticoids (HRR=1.66; 95%-CI=1.13-2.43; N=34), when compared to non-exposed individuals. Similar elevated risks were observed when comparing to the active comparator group, for schizophrenia and acute psychosis, and within an older cohort. The risk of psychosis was elevated the most within the first year after exposure to glucocorticoids (P<0.001) without any indication for a dose-response association. However, in individuals with asthma, exposure to glucocorticoids did not further increase the risk of psychosis. Glucocorticoid exposure was associated with an increased risk for psychotic disorders, which may be explained by an effect of the underlying somatic disease, such as asthma. A potential beneficial effect of glucocorticoids on psychotic symptoms should be investigated in clinical trials.

Multiple measures of HPA axis function in ultra high risk and first-episode schizophrenia patients

INTRODUCTIONnAbnormalities within hypothalamus-pituitary-adrenal (HPA) axis might interact with other neurobiological systems to enhance the risk of psychosis. Most of the neurodevelopmental and HPA axis changes occur in adolescence; this is also the period when prodromal and psychotic symptoms occur for the first time. More knowledge about how various stress components interact can advance understanding of the link between psychosis and the HPA axis.nnnMETHODnWe examined 41 ultra high-risk (UHR) patients and 40 antipsychotic-naïve first-episode schizophrenia (FES) patients and compared them with 47 matched controls. The Perceived Stress Scale and the Recent Life Events Questionnaire were used to assess the stress levels. Day-time saliva samples were taken to measure cortisol. The pituitary gland volume was measured manually on the structural MRI using stereology.nnnRESULTSnOnly the UHR patients, had a higher cortisol increase just after awakening (pu202f=u202f0.009) compared to healthy controls. In UHR patients, we found a negative correlation between cortisol increase after awakening and symptom severity (pu202f=u202f0.008). Pituitary gland volume and diurnal cortisol were not significantly different among the three groups. There was no correlation between pituitary gland volume, perceived stress/recent life events and any of the cortisol measures or symptoms.nnnCONCLUSIONnSymptom severity during the very early phase of illness (UHR) seems to be associated with altered cortisol increase. Longitudinal studies in UHR patients would be useful to examine how stress levels affect the course of the illness.

Heritability of cerebral glutamate levels and their association with schizophrenia spectrum disorders: a 1 [H]-spectroscopy twin study

Research findings implicate cerebral glutamate in the pathophysiology of schizophrenia, including genetic studies reporting associations with glutamatergic neurotransmission. The extent to which aberrant glutamate levels can be explained by genetic factors is unknown, and if glutamate can serve as a marker of genetic susceptibility for schizophrenia remains to be established. We investigated the heritability of cerebral glutamate levels and whether a potential association with schizophrenia spectrum disorders could be explained by genetic factors. Twenty-three monozygotic (MZ) and 20 dizygotic (DZ) proband pairs con- or discordant for schizophrenia spectrum disorders, along with healthy control pairs (MZu2009=u200928, DZu2009=u200918) were recruited via the National Danish Twin Register and the Psychiatric Central Register (17 additional twins were scanned without their siblings). Glutamate levels in the left thalamus and the anterior cingulate cortex (ACC) were measured using 1[H]-magnetic resonance spectroscopy at 3 Tesla and analyzed by structural equation modeling. Glutamate levels in the left thalamus were heritable and positively correlated with liability for schizophrenia spectrum disorders (phenotypic correlation, 0.16, [0.02–0.29]; pu2009=u20090.010). The correlation was explained by common genes influencing both the levels of glutamate and liability for schizophrenia spectrum disorders. In the ACC, glutamate and glx levels were heritable, but not correlated to disease liability. Increases in thalamic glutamate levels found in schizophrenia spectrum disorders are explained by genetic influences related to the disease, and as such the measure could be a potential marker of genetic susceptibility, useful in early detection and stratification of patients with psychosis.

Glucagon-like peptide-1 receptor agonists for antipsychotic-associated cardio-metabolic risk factors: A systematic review and individual participant data meta-analysis

To evaluate if glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) reduce antipsychotic‐associated body weight gain in patients with schizophrenia, when compared to controls.

‘No cognitive‐enhancing effect of GLP‐1 receptor agonism in antipsychotic‐treated, obese patients with schizophrenia’: authors' response

To the editor, We read with interest the article by Ishoy et al. entitled ‘No cognitive-enhancing effect of GLP-1 receptor agonism in antipsychotic-treated, obese patients with schizophrenia’ (1). In this analysis, the authors concluded that exenatide did not improve scores on the Brief Assessment of Cognition in Schizophrenia (BACS), Rey-Osterrieth complex figure test (REY), Short-Form Health Survey (SF-36), Personal and Social Performance Scale (PSP), and the Positive and Negative Syndrome Scale (PANSS). As presented in their Discussion section, these conclusions are in contrast to some previous studies. Although impressive, we believe that some methodological issues should preclude the authors from reaching the conclusions they present, namely: (i) ‘Statistical power’: The original sample size calculation (2) was estimated based on a primary outcome of weight loss rather than on any of the secondary endpoints. Also, the power analysis was based on a comparison between both interventions and was therefore not powered for a comparison of change over time between the two arms. The latter will usually require a greater number of subjects. In conclusion, the study is not adequately powered to reach the conclusions provided in the manuscript. (ii) ‘Measurement of change over time’: The authors used repeated measures analysis of variance to compare both groups. When this method was demonstrated to be unreliable, an analysis of covariance was used to control for baseline variables (3).