P.3.d.001 Development of novel antipsychotic drugs based on olanzapine that display reduced weight gain and metabolic side effects

Abstract Background Antipsychotic drugs are the mainstay of the pharmacological treatment of schizophrenia, used in the acute episode of the disorder and for prevention of relapses. Unfortunately, antipsychotics cause side effects. Weight gain is one of the most prominent side effects. In line with weight gain, also alterations of lipid- and glucose homeostasis can occur and increase the risk for cardiovascular disorders. So far, the differences between the multiple antipsychotics in propensity to cause these alterations have not been examined based on data from randomized controlled trial. Therefore, we are conducting a systematic review and network-metaanalysis on metabolic side effects of antipsychotic drugs. Methods Systematic review and network-metaanalysis. Population Patients with schizophrenia. Interventions Antipsychotic drugs and placebo. Comparator In network-metaanalysis all interventions are compared with each other. For presentation of Results:, placebo will be used as reference. Outcomes The primary outcomes will be continuous change of body weight. Additional outcomes will be continuous change of blood glucose, triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol as well as dichotomous values of these outcomes (i.e. number of patients with a clinically relevant increase over pathological thresholds). Study design Randomized controlled trials. Statistical analysis Network-metaanalysis. Planned network-metaregression-, subgroup- and sensitivity-analyses will address the role of the potential effect modifiers baseline weight, study duration, age, gender, ethnicity, previous antipsychotic exposure, antipsychotic dose, sponsorship, and use of enriched-design. Results Funding for this project has been received from the German Ministry of Education and Research. At the time of abstract submission, the project has just started and is currently in the stage of protocol development. Discussion At the time of the conference the protocol of the study will be developed further and the literature search will have started. Thus, on the poster, details of the analytic approach can be presented and challenges discussed. Moreover, results of the search process can be presented.

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A systematic review of metabolic side effects related to the use of antipsychotic drugs in dementia

International Psychogeriatrics ◽

10.1017/s1041610213001658 ◽

2013 ◽

Vol 26 (1) ◽

pp. 19-37 ◽

Cited By ~ 11

Author(s):

A.R. Atti ◽

B. Ferrari Gozzi ◽

G. Zuliani ◽

V. Bernabei ◽

P. Scudellari ◽

...

Keyword(s):

Lipid Metabolism ◽

Weight Gain ◽

Side Effects ◽

Glucose Homeostasis ◽

Older Patients ◽

Antipsychotic Drugs ◽

Old Patients ◽

Metabolic Side Effects ◽

Moderate Dementia ◽

Increased Risk

ABSTRACTBackground:In clinical practice, Second Generation Antipsychotics (SGAs) are often used as first-line treatment for the Behavioral and Psychological Symptoms of Dementia (BPSD) in older adults due to their fewer neurological adverse events and similar effectiveness compared with First Generation Antipsychotics (FGAs). SGAs, however, are associated with more severe metabolic side effects (weight gain, hyperglycemia, diabetes risk, and hyperlipidemia) than FGAs are. In general, older patients, especially those affected by dementia, are at increased risk for malnutrition, and tend to have lower basal metabolism and reduced liver and kidney function. However, little is known about the metabolic side effects of antipsychotic drugs in this population.Methods:A comprehensive review of the literature published between January 1996 and December 2012 investigating the metabolic side effects related to FGAs and SGAs use in old patients affected by dementia.Results:Antipsychotic drugs currently used to treat BPSD in subjects with mild to moderate dementia are associated with weight gain. Currently, there are insufficient data to support a causal relationship between the use of FGAs and SGAs and changes in glucose homeostasis or lipid metabolism in older persons affected by severe dementia (MMSE <14).Conclusion:A possible association between antipsychotic drugs use and weight gain might exist, in particular in subjects with mild to moderate dementia whereas no significant effects are demonstrated regarding glucose homeostasis and lipid metabolism. The antipsychotic drugs potential for causing metabolic abnormalities in older patients requires further specifically designed studies. Clinicians must be aware of this possibility even if the shorter periods of treatment administered in late-life might not be as harmful as it is in younger individuals.

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Metabolomic profiles associated with a mouse model of antipsychotic-induced food intake and weight gain

Scientific Reports ◽

10.1038/s41598-020-75624-2 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Rizaldy C. Zapata ◽

Sara Brin Rosenthal ◽

Kathleen Fisch ◽

Khoi Dao ◽

Mohit Jain ◽

...

Keyword(s):

Weight Gain ◽

Side Effects ◽

Food Intake ◽

Palmitoleic Acid ◽

Antipsychotic Drugs ◽

Plasma Metabolites ◽

Plasma Citrulline ◽

Metabolic Side Effects ◽

Psychiatric Conditions ◽

Underlying Mechanisms

Abstract Antipsychotic drugs (AP) are used to treat a multitude of psychiatric conditions including schizophrenia and bipolar disorder. However, APs also have metabolic side effects including increased food intake and body weight, but the underlying mechanisms remain unknown. We previously reported that minocycline (MINO) co-treatment abrogates olanzapine (OLZ)-induced hyperphagia and weight gain in mice. Using this model, we investigated the changes in the pharmacometabolome in the plasma and hypothalamus associated with OLZ-induced hyperphagia and weight gain. Female C57BL/6 mice were divided into groups and fed either i) control, CON (45% fat diet) ii) CON + MINO, iii) OLZ (45% fat diet with OLZ), iv) OLZ + MINO. We identified one hypothalamic metabolite indoxylsulfuric acid and 389 plasma metabolites (including 19 known metabolites) that were specifically associated with AP-induced hyperphagia and weight gain in mice. We found that plasma citrulline, tricosenoic acid, docosadienoic acid and palmitoleic acid were increased while serine, asparagine and arachidonic acid and its derivatives were decreased in response to OLZ. These changes were specifically blocked by co-treatment with MINO. These pharmacometabolomic profiles associated with AP-induced hyperphagia and weight gain provide candidate biomarkers and mechanistic insights related to the metabolic side effects of these widely used drugs.

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Psychotropic drug-induced genetic-epigenetic modulation of CRTC1 gene is associated with early weight gain in a prospective study of psychiatric patients

Clinical Epigenetics ◽

10.1186/s13148-019-0792-0 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Aurélie Delacrétaz ◽

Anaïs Glatard ◽

Céline Dubath ◽

Mehdi Gholam-Rezaee ◽

Jose Vicente Sanchez-Mut ◽

...

Keyword(s):

Weight Gain ◽

Side Effects ◽

Prospective Study ◽

Psychotropic Drugs ◽

Energy Homeostasis ◽

Psychiatric Patients ◽

Metabolic Disturbances ◽

Drug Induced ◽

Metabolic Side Effects ◽

Early Weight Gain

Abstract Background Metabolic side effects induced by psychotropic drugs represent a major health issue in psychiatry. CREB-regulated transcription coactivator 1 (CRTC1) gene plays a major role in the regulation of energy homeostasis and epigenetic mechanisms may explain its association with obesity features previously described in psychiatric patients. This prospective study included 78 patients receiving psychotropic drugs that induce metabolic disturbances, with weight and other metabolic parameters monitored regularly. Methylation levels in 76 CRTC1 probes were assessed before and after 1 month of psychotropic treatment in blood samples. Results Significant methylation changes were observed in three CRTC1 CpG sites (i.e., cg07015183, cg12034943, and cg 17006757) in patients with early and important weight gain (i.e., equal or higher than 5% after 1 month; FDR p value = 0.02). Multivariable models showed that methylation decrease in cg12034943 was more important in patients with early weight gain (≥ 5%) than in those who did not gain weight (p = 0.01). Further analyses combining genetic and methylation data showed that cg12034943 was significantly associated with early weight gain in patients carrying the G allele of rs4808844A>G (p = 0.03), a SNP associated with this methylation site (p = 0.03). Conclusions These findings give new insights on psychotropic-induced weight gain and underline the need of future larger prospective epigenetic studies to better understand the complex pathways involved in psychotropic-induced metabolic side effects.

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Metabolic Side-Effects of the Novel Second-Generation Antipsychotic Drugs Asenapine and Iloperidone: A Comparison with Olanzapine

PLoS ONE ◽

10.1371/journal.pone.0053459 ◽

2013 ◽

Vol 8 (1) ◽

pp. e53459 ◽

Cited By ~ 19

Author(s):

Heidi N. Boyda ◽

Ric M. Procyshyn ◽

Catherine C. Y. Pang ◽

Erin Hawkes ◽

Daniel Wong ◽

...

Keyword(s):

Side Effects ◽

Antipsychotic Drugs ◽

Second Generation ◽

The Novel ◽

Metabolic Side Effects ◽

Second Generation Antipsychotic

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Structural contributions of antipsychotic drugs to their therapeutic profiles and metabolic side effects

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2011.07590.x ◽

2011 ◽

Vol 120 (3) ◽

pp. 371-384 ◽

Cited By ~ 34

Author(s):

Somayeh Jafari ◽

Francesca Fernandez-Enright ◽

Xu-Feng Huang

Keyword(s):

Side Effects ◽

Antipsychotic Drugs ◽

Metabolic Side Effects

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Examining side effect variation of antipsychotic treatment in schizophrenia spectrum disorders

10.1101/2020.07.27.20162727 ◽

2020 ◽

Author(s):

Maria S. Neumeier ◽

Stephanie Homan ◽

Stefan Vetter ◽

Erich Seifritz ◽

John M. Kane ◽

...

Keyword(s):

Weight Gain ◽

Side Effects ◽

Precision Medicine ◽

Side Effect ◽

Antipsychotic Drugs ◽

Schizophrenia Spectrum Disorders ◽

Schizophrenia Spectrum ◽

Second Generation Antipsychotics ◽

Spectrum Disorders ◽

The Right

Background: Side effects of antipsychotic drugs play a key role in non-adherence and discontinuation of treatment in schizophrenia spectrum disorders (SSD). Precision medicine aims to minimize such side effects by selecting the right treatment for the right patient. However, to determine the extent of precision medicine that is required, we need to (1) show that there is indeed variation in side effects and (2) estimate the amount of variation in those side effects between patients. While clinical observations suggest that such variation may be considerable, a statistical comparison of side effect variation between active and control treatments is required to confirm this. Here, we hypothesized to find larger side effect variation in treatment compared with control in patients treated with first and second generation antipsychotics. Methods: We included double-blind, placebo-controlled, randomized controlled trials (RCTs) of adults with a diagnosis of SSD and prescription for licensed antipsychotic drugs. Standard deviations of the pre-post treatment differences of weight gain, prolactin levels,and corrected QT (QTc) times were extracted. Data quality and validity were ensured by following the PRISMA guidelines. The outcome measure was the overall variability ratio of treatment to control across RCTs. Individual variability ratios were weighted by the inverse-variance method and entered into a random-effects model. Results: We included N = 16578 patients for weight gain, N = 16633 patients for prolactin levels, and N = 10384 patients for QTc time. Variability ratios (VR) were significantly increased for weight gain (VR = 1.08; 95% CI: 1.02 - 1.14; P = 0.004) and prolactin levels (VR = 1.38; 95% CI: 1.17 - 1.62; P < 0.001) but did not reach significance for QTc time (VR = 1.05; 95% CI: 0.98 - 1.12; P = 0.135). Conclusion: We found increased variability in major side effects in patients with SSD under treatment with second generation antipsychotics, suggesting that subgroups of patients or even individual patients may benefit from improved treatment allocation through stratified or personalized medicine, respectively.

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Risperidone-induced Enuresis in a 12-year-old Child

Journal of Neurosciences in Rural Practice ◽

10.4103/0976-3147.193530 ◽

2017 ◽

Vol 08 (01) ◽

pp. 122-123

Author(s):

Reetika Dikshit ◽

Sagar Karia ◽

Avinash De Sousa

Keyword(s):

Weight Gain ◽

Side Effects ◽

Urinary Bladder ◽

Behavior Problems ◽

Conduct Disorder ◽

Metabolic Side Effects

ABSTRACTRisperidone has been documented to be effective in the management of behavior problems, aggression, and conduct disorder in children. While metabolic side effects like weight gain and obesity have been attributed to Risperidone use in children, side effects of the drug related to the urinary bladder are rare. We present a case of Risperidone-induced enuresis in a 12-year-old boy with conduct disorder that resolved completely after stopping the medication.

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