Olanzapine-induced Weight Gain Research Articles

Hesperidin Attenuate Olanzapine-Induced Weight Gain, Dysregulation of Lipid and Glucose Metabolism in Rats

Hesperidin Attenuate Olanzapine-Induced Weight Gain, Dysregulation of Lipid and Glucose Metabolism in Rats

Olanzapine-induced weight gain and lipid dysfunction in mice between different gender.

As one of the most common antipsychotics, olanzapine may cause metabolic-related adverse effects, but it is still unknown how olanzapine alters lipid metabolism. In this study, we found that olanzapine-treated mice showed varying degrees of dyslipidemia, which was particularly pronounced in female mice. Based on ultra-performance liquid chromatography-quadrupole time-of-flight-MS (UPLC-Q-TOF-MS) technology and lipid metabolomics, we mapped the changes in lipid metabolism in olanzapine-treated mice and then compared the changes in lipid metabolism between male and female mice. There were 98 metabolic differentiators between the olanzapine-treated and control groups in females and 79 in males. These metabolites were glycerolipids, glycerophospholipids, fatty amides, and sphingolipids, which are involved in glycerolipid metabolism, glycerophospholipid metabolism, and fatty acid metabolism. These results suggest that olanzapine-induced changes in the levels of lipid metabolites are closely associated with disturbances in lipid metabolic pathways, which may underlie lipemia. This lipidome profiling study not only visualizes changes in lipid metabolism in liver tissue but also provides a foundation for understanding the regulatory pathways and mechanisms involved in olanzapine-induced lipid metabolism disorders. Furthermore, this study demonstrates differences in lipid metabolism between males and females, providing a reference for clinical treatment regimen selection.

A Possible Role of Akkermansia muciniphila in the Treatment of Olanzapine-Induced Weight Gain.

Second-generation antipsychotics are mainly used in both acute and long-term treatment of major psychiatric disorders. Although better tolerated than first-generation antipsychotic drugs, they can frequently induce weight gain and metabolic disorders, of these, olanzapine is one of the drugs more likely to induce these side effects. There is consistent evidence of the role of gut microbiota in modulating the gut-brain axis with complex crosstalk with the host involving satiety signaling pathways, food intake behavior, and weight and metabolic regulation. Second-generation antipsychotics induce important gut microbiota modification thus contributing together with the central and peripheral receptors blockade mechanism to weight gain induction and metabolic impairment. These drugs can alter the composition of gut microbiota and induce dysbiosis, often reducing the concentration of Akkermansia muciniphila, a bacterium that is also decreased in patients with diabetes, obesity, metabolic syndrome, or chronic inflammatory diseases. Probiotic administration can be a safe and well-tolerated approach to modulate microbiotaandoffer an integrative strategy in psychiatric patients suffering antipsychotic side effects. Multiple strain probiotics and Akkermansia muciniphila alone have been administered both in mice models and in clinical populations demonstrating efficacy on antipsychotic-induced metabolic impairment and showing a contribution in reducing induced weight gain.Akkermansia muciniphila can improve several parameters altered by olanzapine administration, such as weight gain, insulin resistance, hyperglycemia, liver function, systemic inflammation, and gut barrier function. Although we do not have jet trials in the psychiatric population, this probiotic may be a complementary approach to treating olanzapine-induced weight gain and metabolic side effects.

The effect of continuous theta burst stimulation on antipsychotic-induced weight gain in first-episode drug-naive individuals with schizophrenia: a double-blind, randomized, sham-controlled feasibility trial

Antipsychotic intake may induce weight gain in drug-naive individuals with schizophrenia, leading to poor compliance in clinical management. However, there is still a lack of effective approaches to treat or prevent this side-effect. Therefore, we conducted this pilot study to investigate the effect of continuous theta burst stimulation (cTBS), a non-invasive magnetic stimulation technique, on preventing olanzapine-induced weight gain. Thirty-nine first-episode drug-naive individuals with schizophrenia were randomly assigned to receive either the active or sham cTBS intervention for 25 sessions (5 times per day for 5 consecutive days). The primary outcomes were changes in body weight and body mass index (BMI). Secondary outcomes included psychiatric symptoms, eating behavior scales, behavior tasks, and metabolic measures. For the result, the body weight and BMI increased significantly in the sham group but not in the active group, with a significant group effect. The active group exhibited a selective increase in the cognitive restraint domain in the Three-Factor Eating Questionnaire (TFEQ-CR) and a decrease in stop-signal reaction time compared to the sham group. The effect of cTBS on body weight was mediated by TFEQ-CR. Our findings demonstrated the feasibility that cTBS intervention could be a potential method for preventing olanzapine-induced weight gain in drug-naive first-episode schizophrenia patients through enhancing cognitive restraint to food. Trial registration: clinical trial registered with clinicaltrials.gov (NCT05086133).

TAAR1 agonists improve glycemic control, reduce body weight and modulate neurocircuits governing energy balance and feeding

ObjectiveMetabolic Syndrome, which can be induced or exacerbated by current antipsychotic drugs (APDs), is highly prevalent in schizophrenia patients. Recent preclinical and clinical evidence suggest that agonists at trace amine-associated receptor 1 (TAAR1) have potential as a new treatment option for schizophrenia. Intriguingly, preclinical tudies have also identified TAAR1 as a novel regulator of metabolic control. Here we evaluated the effects of three TAAR1 agonists, including the clinical development candidate ulotaront, on body weight, metabolic parameters and modulation of neurocircuits implicated in homeostatic and hedonic feeding. MethodsEffects of TAAR1 agonists (ulotaront, RO5166017 and/or RO5263397) on body weight, food intake and/or metabolic parameters were investigated in rats fed a high-fat diet (HFD) and in a mouse model of diet-induced obesity (DIO). Body weight effects were also determined in a rat and mouse model of olanzapine-, and corticosterone-induced body weight gain, respectively. Glucose tolerance was assessed in lean and diabetic db/db mice and fasting plasma glucose and insulin examined in DIO mice. Effects on gastric emptying were evaluated in lean mice and rats. Drug-induced neurocircuit modulation was evaluated in mice using whole-brain imaging of c-fos protein expression. ResultsTAAR1 agonists improved oral glucose tolerance by inhibiting gastric emptying. Sub-chronic administration of ulotaront in rats fed a HFD produced a dose-dependent reduction in body weight, food intake and liver triglycerides compared to vehicle controls. In addition, a more rapid reversal of olanzapine-induced weight gain and food intake was observed in HFD rats switched to ulotaront or RO5263397 treatment compared to those switched to vehicle. Chronic ulotaront administration also reduced body weight and improved glycemic control in DIO mice, and normalized corticosterone-induced body weight gain in mice. TAAR1 activation increased neuronal activity in discrete homeostatic and hedonic feeding centers located in the dorsal vagal complex and hypothalamus with concurrent activation of several limbic structures. ConclusionThe current data demonstrate that TAAR1 agonists, as a class, not only lack APD-induced metabolic liabilities but can reduce body weight and improve glycemic control in rodent models. The underlying mechanisms likely include TAAR1-mediated peripheral effects on glucose homeostasis and gastric emptying as well as central regulation of energy balance and food intake.

HFD-exacerbated Metabolic Side Effects of Olanzapine Are Suppressed by ER Stress Inhibitor.

Numerous schizophrenic patients are suffering from obesity primarily attributed to antipsychotic medication and poor dietary habits. This study investigated the progressive deterioration of olanzapine-induced metabolic disorders in the presence of a high-fat diet (HFD) and explored the involvement of endoplasmic reticulum (ER) stress. Female Sprague-Dawley rats fed on a standard chow diet or HFD were treated with olanzapine (3 mg/kg/day) and the ER stress inhibitor 4-phenylbutyric acid (4-PBA, 1 and 0.5 g/kg/day) for 8 days. Changes in body weight, food intake, and plasma lipids were assessed. Hepatic fat accumulation was evaluated using oil red O staining. Western blotting and immunofluorescence assays were employed to examine the expression of ER stress markers, NOD-like receptor pyrin domain-containing protein 3 (NLRP3), and proopiomelanocortin (POMC) in the hypothalamus or liver. Compared to olanzapine alone, olanzapine+HFD induced greater weight gain, increased hyperlipidemia, and enhanced hepatic fat accumulation (P<0.05). Co-treatment with 4-PBA exhibited a dose-dependent inhibition of these effects (P<0.05). Further mechanistic investigations revealed that olanzapine alone activated ER stress, upregulated NLRP3 expression in the hypothalamus and liver, and downregulated hypothalamic POMC expression. The HFD exacerbated these effects by 50%-100%. Moreover, co-administration of 4-PBA dose-dependently attenuated the olanzapine+HFD-induced alterations in ER stress, NLRP3, and POMC expression in the hypothalamus and liver (P<0.05). HFD worsened olanzapine-induced weight gain and lipid metabolic disorders, possibly through ER stress-POMC and ER stress-NLRP3 signaling. ER stress inhibitors could be effective in preventing olanzapine+HFD-induced metabolic disorders.

Salsalate and/or metformin therapy confer beneficial metabolic effects in olanzapine treated female mice

Antipsychotic medications are used in the management of schizophrenia and a growing number of off-label conditions. While effective at reducing psychoses, these drugs possess noted metabolic side effects including weight gain, liver lipid accumulation and disturbances in glucose and lipid metabolism. To counter the side effects of antipsychotics standard of care has typically included metformin. Unfortunately, metformin does not protect against antipsychotic induced metabolic disturbances in all patients and thus additional treatment approaches are needed. One potential candidate could be salsalate, the prodrug of salicylate, which acts synergistically with metformin to improve indices of glucose and lipid metabolism in obese mice. The purpose of the current investigation was to compare the effects of salsalate, metformin and a combination of both drugs, on weight gain and indices of metabolic health in female mice treated with the antipsychotic, olanzapine. Herein we demonstrate that salsalate was equally as effective as metformin in protecting against olanzapine induced weight gain and liver lipid accumulation with no additional benefit of combining both drugs. Conversely, metformin treatment, either alone or in combination with salsalate, improved indices of glucose metabolism and increased energy expenditure in olanzapine treated mice. Collectively, our findings provide evidence that dual therapy with both metformin and salsalate could be an efficacious approach with which to dampen the metabolic consequences of antipsychotic medications.

Comment on "Opioid antagonists to prevent olanzapine-induced weight gain: A systematic review".

Comment on "Opioid antagonists to prevent olanzapine-induced weight gain: A systematic review".

Olanzapine manipulates neuroactive signals and may onset metabolic disturbances

Olanzapine is one of the most prescribed atypical antipsychotics to treat psychiatric illness and is associated with weight gain and metabolic disturbance. The present study investigated the olanzapine-regulated metabolic pathways using functional enrichent analysis including binding affinity with G-protein-coupled receptors (GPCRs). Proteins modulated by olanzapine were retrieved from SwissTargetPrediction, DIGEP-Pred, and BindingDB and then enriched in Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) to assess molecular function, biological process, and cellular components including Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. We used homology modeling to improve the 3D structure for GPCR synapse proteins including dopamine, serotonin, muscarinic, and histamine receptors which were then optimized using molecular dynamics (MD) simulations. The protein-olanzapine binding mechanisms for different GPCR binders were evaluated using molecular docking; later refined by MD simulations. Binding mechanism of olanzapine with D2, 5HT1A, 5HT2A, 5HT2B, 5HT2C, M1, and M2 receptors were created using homology modeling and optimized using MD simulations. In target identification, it was observed that olanzapine majority targeted G-protein coupled receptors. Further, enrichment analysis identified around 76% of the total genes regulated in molecular function, biological process, and cellular components were common including KEGG pathways. Moreover, it was observed that olanzapine had a major potency over the neurotransmitter synapse including neuroactive signals . Olanzapine-induced weight gain and metabolic alterations could be due to the deregulation of multiple synapses like dopamine, serotonin, muscarinic, and histamine at the feeding center followed by cGMP-PKG, cAMP, and PI3K-Akt signaling pathways. HIGHLIGHTS Olanzapine is used in the management of psychiatric illnesses. Olanzapine causes disturbance in lipids and glucosehomeostasis and manipulates energy expenditure. Olanzapine-induced weight gain may occur due to the deregulation of the multiple synapse and cGMP-PKG, cAMP, and PI3K-Akt signaling pathway Communicated by Ramaswamy H. Sarma

Comparison of olanzapine-induced weight gain and metabolism abnormalities between topiramate and vitamin C in patients with schizophrenia: a preliminary study.

Topiramate (TPM) may reduce olanzapine (OLZ)-related weight gain and metabolism abnormalities in patients with schizophrenia. However, differences in the efficacy of OLZ-related weight gain and metabolism abnormalities between TPM and vitamin C (VC) are not clear. This study aimed to investigate whether TPM is more effective than VC in reducing OLZ-induced weight gain and metabolic abnormalities in patients with schizophrenia and explore their patterns. This was a 12-week longitudinal comparison study in OLZ-treated patients with schizophrenia. Twenty-two patients who received OLZ monotherapy plus VC treatment (OLZ + VC group) was matched to 22 patients who received OLZ monotherapy plus TPM treatment (OLZ + TPM group). Body mass index (BMI) and metabolism indicators were measured at baseline and 12-weeks follow-up. A significant difference in triglyceride (TG) levels at different time points (pre-treatment: F = 7.89, p = 0.008; 4-weeks treatment: F = 13.19, p = 0.001; 12-weeks treatment: F = 54.48, p < 0.001) was found. Latent profile analysis demonstrated that a 2-class model for OLZ + TPM group (high vs. low BMI in the first 4 weeks) and OLZ + VC group (high vs. low), respectively. Our findings suggested that TPM could better mitigates OLZ-induced increase in TG levels. The trajectories of change also differed in all metabolic indexes over time between the two groups.

TAAR1 Agonist Ulotaront Improves Glycemic Control and Reduces Body Weight in Rodent Models of Diabetes, Obesity, and Iatrogenic Weight Gain

AbstractIntroductionPreclinical evidence has identified the trace amine-associated receptor 1 (TAAR1) as a novel regulator of metabolic control. Ulotaront is a TAAR1 and 5-HT1A agonist currently in Phase 3 clinical trials for the treatment of schizophrenia. Here we summarize preclinical results assessing the effects of ulotaront on weight and metabolic parameters.MethodsEffects of ulotaront administration were evaluated on oral glucose tolerance (oGTT), gastric emptying, and in rodent models of weight gain (high-fat diet [HFD]-, corticosterone-, and olanzapine-induced).ResultsFollowing 15-day oral administration of ulotaront, rats on HFD showed dose-dependent reduction in body weight, food intake, and liver triglyceride content compared to controls. In addition, a more rapid reversal of olanzapine-induced weight gain and food intake was observed in rats switched to ulotaront (vs. vehicle). Consistent with weight-lowering effects in rats, chronic ulotaront treatment normalized corticosterone-induced weight gain in mice. Assessment of oGTT showed a dose-dependent reduction of glucose excursion in response to acute ulotaront administration in naive and diabetic db/db mice. Ulotaront administration also delayed gastric emptying in mice—a likely mechanism driving reductions in glucose excursions during the oGTT. Whole-brain c-fos imaging of ulotaront-treated mice revealed increased neuronal activity in several brain regions associated with regulation of food intake and metabolic signals.ConclusionsThe data indicate that ulotaront not only lacks metabolic liabilities typically associated with antipsychotics but can reduce body weight and improve glucose tolerance in rodent models. The underlying mechanisms may include TAAR1-mediated peripheral effects on glucose homeostasis and/or direct modulation of homeostatic and hedonic neurocircuits regulating energy balance. The beneficial metabolic effects of ulotaront may suggest a substantially improved risk-benefit profile compared to established antipsychotics.FundingSunovion Pharmaceuticals Inc. and Otsuka Pharmaceutical Development &amp; Commercialization, Inc.

Opioid antagonists to prevent olanzapine-induced weight gain: A systematic review.

IntroductionOlanzapine (OLZ) is a second generation antipsychotic that is approved for the treatment of schizophrenia, bipolar disorder type 1 as monotherapy (acute manic or mixed episodes, maintenance), or as an add-on to lithium or valproate (manic or mixed episodes). It is one of the most effective antipsychotics for the treatment of schizophrenia, but concerns remain due to its significant metabolic adverse effects. Notably, OLZ has one of the highest rates of weight gain among all antipsychotic drugs. Previous studies report on potential mitigation of weight gain with opioid antagonists. A systematic review was conducted to summarize the impact of these agents on weight and BMI when used as adjuncts to OLZ.MethodsA systematic review of randomized controlled trials was conducted with 3 searches between March 2, 2021 and March 27, 2022.ResultsSix studies met inclusion criteria, 5 of which assessed OLZ and samidorphan (SAM) and 1 of which assessed OLZ and naltrexone compared with OLZ monotherapy. A total of 1752 patients were included with 952 receiving SAM and 14 receiving naltrexone as an adjunct to OLZ. SAM was shown to mitigate OLZ-induced weight gain by 1.0 kg. Only 1 study assessed naltrexone with no statistically significant results for weight gain.DiscussionSAM is effective at reducing OLZ-induced weight gain. Naltrexone did not reduce OLZ-induced increases in weight or BMI. However, there is a paucity of data on other opioid antagonists as adjuncts to OLZ treatment to prevent increases in weight or BMI.

Olanzapine/Samidorphan: A New Combination Treatment for Schizophrenia and Bipolar I Disorder Intended to Reduce Weight Gain.

Olanzapine is a second-generation antipsychotic with established efficacy in several psychiatric disease states, but its use is limited because of weight gain and metabolic side effects. Samidorphan is a novel opioid antagonist that binds to mu-opioid, kappa-opioid, and delta-opioid receptors and is hypothesized to reduce cravings for high-calorie foods thus attenuating antipsychotic-induced weight gain. The combination product olanzapine/samidorphan was approved by the US Food and Drug Administration in June 2021 for the treatment of schizophrenia and bipolar I disorder; this article reviews the pharmacological properties of oral olanzapine/samidorphan and its clinical efficacy and tolerability with a focus on mitigation of olanzapine-induced weight gain in these patient populations. In clinical trials, the combination of olanzapine/samidorphan was associated with significantly less weight gain and smaller increases in waist circumference as compared with olanzapine monotherapy. Olanzapine/samidorphan demonstrated similar efficacy as olanzapine monotherapy and was well tolerated. Weight gain and metabolic side effects associated with olanzapine monotherapy can result in tolerability issues and potentially medication nonadherence. Olanzapine/samidorphan is an effective treatment for schizophrenia and bipolar I disorder with less weight gain than olanzapine monotherapy.

Probiotics Plus Dietary Fiber Supplements Attenuate Olanzapine-Induced Weight Gain in Drug-Naïve First-Episode Schizophrenia Patients: Two Randomized Clinical Trials

Background and HypothesisAntipsychotic-induced weight gain is associated with alterations to the composition of the gut microbiota. The purpose of this study was to determine the effect of probiotics plus dietary fiber on antipsychotic-induced weight gain.Study DesignTwo sequential, randomized clinical trials were conducted. In Study 1, 90 drug-naïve, first-episode schizophrenia patients were randomized to receive either olanzapine plus probiotics or olanzapine monotherapy for 12 weeks. In Study 2, 60 drug-naïve, first-episode schizophrenia patients were randomly assigned to receive either olanzapine plus probiotics and dietary fiber or olanzapine monotherapy for 12 weeks.Study ResultsIn Study 1, no significant differences in weight gain were observed between the two groups. The insulin resistance index (IRI) was lower in the olanzapine plus probiotics group compared with the olanzapine monotherapy group at week 12 (estimated mean difference, −0.65, [95% confidence interval (CI), −1.10 to −0.20]; p = .005). In Study 2, weight gain was lower in the probiotics plus dietary fiber group than in the olanzapine monotherapy group at week 12 (estimated mean difference −3.45 kg, [95% CI, −5.91 to −1.00]; p = .007). At week 12, IRI increased significantly in the olanzapine monotherapy group (mean, 1.74; standard deviation (SD) = 1.11, p < .001), but not in the olanzapine plus probiotics and dietary fiber group (mean 0.47, SD = 2.16, p = .35) with an estimated mean difference of −0.95 between the two groups [95% CI, −1.77 to −0.14]; p = .022).ConclusionsThese results provide support for the efficacy and safety of probiotics plus dietary fiber in attenuating antipsychotic-induced weight gain in drug-naïve, first-episode schizophrenia patients.

Olanzapine-samidorphan combination tablets for the treatment of schizophrenia and bipolar I disorder - what is it, and will it be used?

ABSTRACT Introduction Although olanzapine remains one of the most efficacious antipsychotic medications for the treatment of schizophrenia, there are significant tolerability concerns related to its weight and metabolic profile. Olanzapine-samidorphan combination tablets (OLZ/SAM), branded as Lybalvi, is a newly FDA approved formulation aimed at attenuating antipsychotic induced weight gain via modulation of the endogenous opioid system with samidorphan, while retaining the robust antipsychotic efficacy of olanzapine. Areas covered We reviewed the published literature of OLZ/SAM for the management of schizophrenia using the US National Library of Medicine’s PubMed.gov resource. Topics covered in this narrative review include the pharmacokinetics, pharmacodynamics, efficacy, and tolerability of OLZ/SAM. Expert Opinion OLZ/SAM is an effective and well-tolerated pharmacologic option in mitigating olanzapine induced weight gain while retaining olanzapine’s efficacy. OLZ/SAM cumulatively tends to attenuate weight gain rather than promote weight loss. Effect on metabolic laboratory variables appears limited. Additional research will be needed to determine its effectiveness compared to alternative strategies to attenuate antipsychotic induced weight gain.

The Case for Clinical Trials with Novel GABAergic Drugs in Diabetes Mellitus and Obesity.

Obesity and diabetes mellitus have become the surprising menaces of relative economic well-being worldwide. Gamma amino butyric acid (GABA) has a prominent role in the control of blood glucose, energy homeostasis as well as food intake at several levels of regulation. The effects of GABA in the body are exerted through ionotropic GABAA and metabotropic GABAB receptors. This treatise will focus on the pharmacologic targeting of GABAA receptors to reap beneficial therapeutic effects in diabetes mellitus and obesity. A new crop of drugs selectively targeting GABAA receptors has been under investigation for efficacy in stroke recovery and cognitive deficits associated with schizophrenia. Although these trials have produced mixed outcomes the compounds are safe to use in humans. Preclinical evidence is summarized here to support the rationale of testing some of these compounds in diabetic patients receiving insulin in order to achieve better control of blood glucose levels and to combat the decline of cognitive performance. Potential therapeutic benefits could be achieved (i) By resetting the hypoglycemic counter-regulatory response; (ii) Through trophic actions on pancreatic islets, (iii) By the mobilization of antioxidant defence mechanisms in the brain. Furthermore, preclinical proof-of-concept work, as well as clinical trials that apply the novel GABAA compounds in eating disorders, e.g., olanzapine-induced weight-gain, also appear warranted.

Cyperus rotundus L. reverses the olanzapine-induced weight gain and metabolic changes-outcomes from network and experimental pharmacology

Cyperus rotundus L. is used to treat multiple clinical conditions like inflammation, diarrhea, pyrosis, and metabolic disorders including diabetes and obesity. The present study aimed to predict the interaction of reported bioactives from Cyperus rotundus against obesity via network pharmacology and to evaluate the efficacy of hydroalcoholic extract of Cyperus rotundus against the olanzapine-induced weight gain and metabolic disturbances in experimental animals. Reported phytochemicals of Cyperus rotundus were retrieved from the open-source database(s) and published literature and their targets were predicted using SwissTargetPrediction, enriched in STRING, and bioactives-proteins-pathways network was constructed using Cytoscape. Further, the hydroalcoholic extract of Cyperus rotundus (100, 200, and 400 mg/kg/day, p.o.) was co-administered with olanzapine (2 mg/kg, i.p.) for 21 days in Sprague Dawley rats. During treatment, body weight and food intake were recorded; after the successful completion of 21 days of treatment, animals were fasted to perform oral glucose and insulin tolerance tests. Further, the animals were euthanized; blood and abdominal fat were collected for lipid profiling and histopathological examination respectively. Herein, network pharmacology predicted neuroactive ligand-receptor interaction as a primarily modulated pathway and protein tyrosine phosphatase 1b as a majorly triggered protein via the combined action of bioactives. Further, Cyperus rotundus significantly reversed weight gain, cumulative food intake, ameliorated the lipid and glucose metabolism, and promoted energy expenditure.

Worth the Weight? Olanzapine Prescribing in Schizophrenia. A Review of Weight Gain and Other Cardiometabolic Side Effects of Olanzapine.

About 80% of patients who experience a first episode of psychosis (FEP) will have another within 5 years (1). In a large meta-analysis of randomized controlled trials (RCTs), 12 months of antipsychotic treatment reduced the rate of relapse from 61 to 26% in FEP, and from 64 to 27% in chronic cases (2). Long-term antipsychotic treatment has been associated with a decrease in mortality rates, compared to untreated cases (3). However, compared to the general population, those with schizophrenia still die, on average, 14.5 years earlier (3, 4). Most life years lost relate to poor physical health outcomes—specifically mortality related to cardiovascular disease (CVD) (4). Adverse cardiometabolic side effects of antipsychotics, particularly second-generation antipsychotics (SGA), represent an undeniable contributor to the burden of cardiovascular morbidity and mortality amongst this cohort (5). Olanzapine, a SGA with one of the most significant cardiometabolic side effect profiles (5, 6), continues to be one of the most popular antipsychotics prescribed in schizophrenia (7–9). This commentary will consider some of the most pertinent research assessing the efficacy of olanzapine in schizophrenia management; suggest potential reasons for incongruence observed between guideline recommendations and prescribing practices; and finally, make suggestions as to how olanzapine-induced weight gain—a side effect that often represents the beginning of a series of escalating cardiometabolic derangements–can be recognized and its effects ameliorated. Olanzapine and Weight Gain Amongst those prescribed olanzapine early in psychosis management, 80% experience an increase of ≥7% of their baseline body weight (10, 11). With the exception of clozapine, whether short- or long-term anthropometric outcomes are being assessed, olanzapine is invariably listed as causing the most significant increases amongst users (6). This is not new information–the first review that aggregated data on weight changes following SGA use was published in 1999 (12). In a 2019 meta-analysis of 402 RCTs including data from 53,463 participants with multi-episode schizophrenia, olanzapine remained the antipsychotic most likely to induce clinically significant weight gain after clozapine and zotepine, the latter of which is not licensed in many countries (6). Antipsychotic-induced weight gain (AIWG) is a particularly important side effect, as it mediates cardiometabolic outcomes, including development of type 2 diabetes mellitus (T2DM) and subsequent CVD–the latter being responsible for approximately 60% of the excess mortality amongst those with schizophrenia previously highlighted (13). Aside from drastically reducing life expectancy, such high rates of physical comorbidity increases the personal, social and economic burden on mental illness across the lifespan. Significant weight gain may also influence outcomes related to mental health. AIWG is consistently listed as one of the most distressing side effects of antipsychotic treatment, frequently resulting in partial or complete antipsychotic non-adherence, and future reluctance to engage with treatment (14, 15). Furthermore, research is now emerging suggesting that obesity and metabolic syndrome may be independent predictors of relapse and re-hospitalization amongst those with a Severe Mental Illness (SMI) (16). Due to its significant association with weight gain and other cardiometabolic abnormalities, since 2009 several international guidelines in Europe, the United States, Australia and New Zealand have advised against olanzapine's use as part of first-line psychosis management (17). However, today olanzapine continues to be one of the most popular antipsychotics, extensively prescribed in both FEP and chronic cases, across the spectrum of illness severity and in many jurisdictions (7–9). Considering the cardiometabolic adverse effects of olanzapine are well-documented, what might be the reasons underlying its popularity? Does its prevalent use reflect poor translation of evidence and subsequent guideline recommendations into clinical practice? Or does its popularity reflect an “availability bias”, whereby clinicians ascribe greater efficacy to olanzapine compared to other antipsychotics, simply based on their more familiar and frequent use of olanzapine? It is worth first assessing efficacy data supporting olanzapine, both in symptom reduction and relapse prevention.

Metabolomics-based understanding of the olanzapine-induced weight gain in female first-episode drug-naïve patients with schizophrenia

Previous studies have demonstrated that patients with schizophrenia (SZ) have greater rate of metabolic disorder as compared with the control population, which likely be the consequence of use of atypical antipsychotics. Olanzapine is a widely used antipsychotic, which increases the weight of SZ patients. However, the underlying mechanism remains poorly understood. Here we report the metabolomics-based understanding of the weight gain induced by olanzapine. 57 first-episode drug-naïve patients (FEDN) were recruited, of whom 27 patients completed a 4-week clinical trial. We then profiled the metabolomes of their plasma with the LC-MS-based nontargeted metabolomics approach at the baseline and after olanzapine monotherapy for 4 weeks. We observed that the plasma of the olanzapine-treated patient had significantly higher lysophosphatidylcholine (LysoPC), lysophosphatidylethanolamine (LysoPE) and lower carnitine as compared with that of the baseline plasma samples. Moreover, regression analyses indicated that the change of LysoPC(14:0) level was an independent contributor to the olanzapine-induced weight gain. Our study suggests that the metabolomics-based approach may facilitate the identification of biomarkers associated with the metabolic disorder causing by antipsychotic in schizophrenia patients.

Effect of Bifidobacterium on olanzapine-induced body weight and appetite changes in patients with psychosis.

Gut microbiota plays an important role in host metabolism. Antipsychotic drugs can result in metabolic abnormalities. Probiotics may ameliorate the antipsychotic drug-induced metabolic abnormalities by regulating gut microbiota. To determine whether Bifidobacterium intervention can ameliorate olanzapine-induced weight increase. Enrolled patients were assigned to either the olanzapine or olanzapine plus Bifidobacterium group. The following were assessed: body weight, body mass index (BMI), appetite, latency to increased appetite, and baseline weight increase of more than 7%. All assessments were conducted at baseline and at 4, 8, and 12weeks of treatment. We enrolled 70 patients with schizophrenia or schizophrenic affective disorder, and 67 completed the study. Treatment for 4weeks led to between-group differences in weight change (2.4 vs. 1.1kg, p < 0.05) and BMI (0.9 vs. 0.4, p < 0.05). However, this difference disappeared at 8 and 12weeks of treatment (both p > 0.05). The two groups did not differ in appetite increase at any time point (p > 0.05). The mean time from olanzapine initiation to appetite increase was also not significantly different between the two groups (t = 1.243, p = 0.220). Probiotics may mitigate olanzapine-induced weight gain in the early stage of treatment and delay olanzapine-induced appetite increase.