Antipsychotic Induced Weight Gain and Metabolic Dysfunction – A Review of Pathophysiology and Management Strategies

ANTIPSYCHOTICS, OBESITY AND DIABETES

Antipsychotics and Weight Gain: 

Second-generation antipsychotics (SGAs) are currently the first-line treatment for psychotic disorders and bipolar disorder. However, these agents are associated with an increase in the risk of adverse cardiometabolic effects. 

This is either directly through metabolic effects or indirectly through clinically significant weight gain. 

The most significant weight gain associated with antipsychotics in previously drug-naive patients with schizophrenia occurs in the first few months.

Their orexigenic weight gain potential is more significant in children and adolescents than in adults. 

Clinically significant weight gain is defined as a 7% or greater increase in total body weight. [Sachs and Guille, 1999]

The European First Episode Schizophrenia Trial (EUFEST) showed that clinically significant weight gain is common in antipsychotic-naïve individuals [Kahn et al., 2008]:

• Olanzapine – 13.9 kg weight gain in 52 weeks with 86% showing a clinically significant ≥7% increase in weight 
• Quetiapine – 10.5 kg weight gain in 52 weeks with 65% showing a clinically significant ≥7% increase in weight 
• Ziprasidone – 4.8 kg weight gain in 52 weeks with 37% showing a clinically significant ≥7% increase in weight 

In another study, the Comparison of Atypicals in First Episode of Psychosis (CAFÉ) trial, long-term antipsychotic use was associated with [McEvoy et al., 2007] : 

• Olanzapine – 7.12 kg after 12 weeks and 11.06 kg after 52 weeks
• Quetiapine – 3.68 kg after 12 weeks and 5.66 kg after 52 weeks
• Risperidone – 4.02 kg after 12 weeks and 6.57 kg after 52 weeks

It is also interesting to note a potential gender-dependent effect of weight gain associated with atypical antipsychotics. Women are more vulnerable to-induced weight gain. [Seeman, 2020]

A recently published ‘real-world’ study examining the newer antipsychotics showed statistically significant increases in weight and BMI over 1 year with brexpiprazole and iloperidone, minimal weight gain with cariprazine and asenapine and a 0.3 kg weight loss with lurasidone. Only asenapine and lurasidone demonstrated statistically lower weight gain than olanzapine. [Greger et al., 2021]

Overall, evidence in the literature suggests that the weight gain potential of different atypical antipsychotics follows this order:

Clozapine/Olanzapine > Risperidone/Quetiapine > Aripiprazole/Ziprasidone

Increased weight gain can set up a cascade toward dyslipidemia and diabetes.

The following diagrams have been simplified from the review by [Pillinger et al., 2020] Confidence intervals have not been included in the below charts. You can view the full article here.

Antipsychotics and Diabetes: 

Schizophrenia is an independent risk factor for type 2 diabetes, and type 2 diabetes has been associated with typical and atypical antipsychotics. [Bushe & Leonard, 2004]

Antipsychotics increase lipids and blood glucose independent of adiposity. Olanzapine and clozapine have the most significant impact in increasing blood glucose and lipids independent of adiposity. [De Leon et al., 2007], [Haupt et al., 2002]

Clinical studies show that atypical antipsychotics induce abnormal glucose metabolism and insulin resistance at baseline and during oral glucose tolerance tests. [Wu et al., 2006]

Disruption of an individual’s energy metabolism is emphasised by the observations of the increased prevalence of diabetes in people with schizophrenia —almost two times greater than in the general population. [Mathews and Muzina, 2007] 

Moreover, the incidence of diabetes is almost 10% higher in patients with schizophrenia who are treated with atypical antipsychotics compared to those treated with typical antipsychotic drugs. [Sernyak et al., 2002] However, it must be noted that there is a higher prevalence of underlying intrinsic parameters associated with these disorders. [Starrenburg and Bogers, 2009]

Antipsychotics and the risk of diabetes. Chart simplified from [Pillinger et al., 2020]

MECHANISMS OF ANTIPSYCHOTIC ASSOCIATED WEIGHT GAIN, METABOLIC DYSFUNCTION AND DIABETES

Analysis of particular receptor occupancy and the propensity of specific medications to weight gain has led to the conclusion that several neurochemical factors are associated with antipsychotic-associated weight gain. In summary, these include: [Manu et al., 2015], [Rege, 2008]

Decreased physical activity: 

• Resting Energy expenditure rates are 20% lower in patients prescribed clozapine. [Sharpe et al., 2006]
• Medications may induce a hypometabolic state that sets up a cycle for weight gain and metabolic dysfunction combined with increased food intake and low activity.
• Individuals with schizophrenia have an impaired capacity to utilise fat with a shift from fat oxidation to glucose oxidation.

Dietary Eating Habits : 

• A recent meta-analysis of 31 studies about dietary patterns in patients with schizophrenia identified a high consumption of saturated fat and a low intake of fruit and dietary fibre. [Dipasquale et al., 2013]
• Patients with schizophrenia had a higher daily intake of calories and protein per kilogram of body weight, independent of BMI. 

Increased Appetite : 

• Obesity can set up a vicious cycle as, despite excessive energy storage, obese individuals continue to consume large amounts of food due to a dysregulated dopaminergic reward system. In the ‘addicted brain’,’ the prefrontal cortex (PFC) and cingulate gyrus (CG) have a reduced ability to regulate compulsive drives, resulting in overeating. 
• Compulsive behaviour is then driven by the relationship between NA and brain memory areas.
• Dopamine which controls appetite is antagonised by antipsychotics which further increase appetite.

Appetite Dysregulation: 

• Abnormal eating behaviours, such as increased food cravings, have been reported. [Kluge et al., 2007]
• Abnormal eating behaviours, such as binge-eating disorder and night eating syndrome, are more prevalent in patients with schizophrenia and may be related to atypical antipsychotic medication. [Lundgren et al., 2010]
• This is likely due to a dysregulation of appetite-regulating hormones such as leptin, ghrelin and adiponectin. 

Leptin: 

• Leptin is part of the anorexigenic pathway in appetite regulation. [Rege, 2008]
• Leptin is a hormonal product synthesised by fat cells (ob gene) and was initially thought to be one of the most important signals for the long-term regulation of weight gain.
• Leptin binds to the hypothalamus’s ventral medial nucleus (VMN) and inhibits neuropeptide Y (NPY), leading to a sensation of satiety. 
• Leptin also suppresses insulin secretion in a negative feedback loop, while adiponectin increases tissue sensitivity to insulin, has antiatherogenic properties, reduces hepatic glucose production, and diminishes gluconeogenesis.
• The role of leptin in antipsychotic-induced weight gain is unclear. Leptin increases in patients on antipsychotics may be due to increased adiposity rather than a direct medication effect. Further complicating the situation is the genetic variability in the leptin receptor, which may predispose some individuals to gain weight on antipsychotics.
• The rise in leptin is clinically significant irrespective of the cause because it increases fat deposition in non-adipose tissues (e.g. blood vessels, liver, heart etc.), increasing the risk of metabolic syndrome.

Ghrelin: 

• Ghrelin has an orexigenic role (increases appetite).
• Ghrelin is synthesised principally in the stomach, and the concentration of circulating ghrelin is negatively correlated with leptin and body fat mass.

• Atypical antipsychotics promote the orexigenic effects of ghrelin, which at the same time renders anorexigenic pathways ineffective.
• Olanzapine is known to directly act on ghrelin secretion and increase appetite, resulting in weight gain. Animal data also indicated that olanzapine increased the orexigenic NPY mRNA, decreased the anorexigenic POMC in the arcuate nucleus, and upregulated ghrelin and ghrelin signalling, leading to hyperphagia. [Zhang et al., 2014] 
• Adiponectin was found to be decreased with clozapine and olanzapine. 

Orexins: 

• A small number of lateral hypothalamic/perifornical area neurons release the orexins, peptides that are critically involved in body weight regulation and arousal. Antipsychotic-induced weight is associated with the activation of distinct orexin neurons. [Rege, 2008]

Prolactin: 

• Hyperprolactinemia can impair insulin sensitivity and affect circulating levels of gonadal hormones, leading to increased adiposity.

Pharmacogenetics: [Rege, 2008]

• An important finding is that patients with lower BMI are at the highest risk of weight gain and that early and rapid weight gain in the first few weeks of treatment appears to be a predictor of long-term weight gain. This weight gain is irreversible in some patients, and discontinuation or switching antipsychotics does not reduce weight. 
• 5HT2C-receptor promoter (759c/t) is identified as an actual genetic susceptibility factor for antipsychotic weight gain. It is hypothesised that the 5-HT2C polymorphism appears to determine circulating leptin levels, providing a potential mechanism underlying the genetic association of the 5-HT2C receptor with weight gain.
• Investigations of serotonin transporter (SERT) gene polymorphisms in olanzapine-induced weight gain found that the SS (short allele) genotype was associated with significantly higher weight gain in those who were non-obese at the time of admission. Incidentally, this genotype is associated with a poorer response to antidepressant treatment. 
• Several other candidate genes are linked (SNAP, adrenergic α2a  receptor, leptin, ghrelin, guanine nucleotide-binding protein, α-1, β-2 and β-3 adrenergic receptor, tumour necrosis factor-a, adiponectin and dopamine D2 receptor genes)

Impaired glucose homeostasis 

• Increased appetite is a crucial driver of insulin resistance. In adipose tissue, decreased lipid storage capacity leads to uncontrolled lipolysis, increasing circulating free fatty acids in systemic and portal circulation.
• This results in increased lipotoxicity (increased VLDL and Triglycerides) and gluconeogenesis in the liver.
• In the skeletal muscle, this results in decreased fatty acid oxidation, insulin action and glucose uptake.
• The accumulation of specific lipid intermediates such as diacylglycerol and gluconeogenesis induces hepatic and muscle insulin resistance  [Holt et al.,  2019]

Antipsychotics may impair glucose homeostasis leading to diabetes through several postulated mechanisms :[Holt et al.,  2019]

1. Direct effect on Insulin sensitivity
2. Effect on pancreatic β cells: D2 receptor antagonism blunts glucose-stimulated insulin release. In contrast, blockade of the 5HT1A and M3 muscarinic receptors decreases the responsiveness of pancreatic β cells to changes in blood glucose.
3. Weight gain
4. Through action on dopaminergic, serotonergic, adrenergic and muscarinic receptors, all of which have a role in regulating insulin secretion​

Path to Type 2 Diabetes and where antipsychotics may be involved: [Padhi et al., 2020], [Meyer & Stahl, 2009] 

1. Reduced secretion of insulin from β cells of islets of Langerhans (Antipsychotic action) 
2. Elevated glucagon secretion from α cells of islets of Langerhans 
3. Increased production of glucose in the liver 
4. Dysfunction of neurotransmitters and resistance of insulin in the brain (Antipsychotic action) 
5. Increase in lipolysis (Antipsychotic action) 
6. Increase in reabsorption of glucose by the kidney 
7. Reduction of effect of incretin in the small intestine 
8. Impairment or decreased uptake of glucose by peripheral tissues like skeletal muscle, liver and adipose tissue 

Neurotransmitters and Receptors: 

• Atypical antipsychotics have been shown to have affinities for a variety of neurotransmitter receptors, including serotonin receptors (5HT1A, 5HT2C, 5HT6, and 5HT7), dopamine receptors (D1, D3, and D4), the histamine receptor H1, muscarinic receptors (M1, M2, M3, M4, and M5) and adrenergic receptors (α1 and α2). [Roth B et al., 2004]
• The two receptors that are most robustly associated with weight gain are the Serotonin 2C (5-HT2C) and Histamine 1 (H1) receptors. [Rege, 2008]
• The M3 receptor muscarinic receptor type 3 (M3), the predominant subtype expressed by pancreatic β-cells, is involved in the pathophysiology of insulin resistance. The M3 receptor is the best predictor of diabetes induced by treatment with atypical antipsychotic medications. [Volpato et al.,2013]

However, many receptors are involved in insulin signalling that may contribute to overall metabolic dysfunction.

Histaminergic receptors

• The appetite-suppressive action of leptin is mediated through H1-histamine receptors in the ventromedial hypothalamic neurons and the paraventricular nucleus.
• Atypical antipsychotic H1-receptor blockade increases leptin resistance and enhances adiposity.
• Antihistaminergic action also increases the hypothalamic production of AMP-activated protein kinase (AMPK), an enzyme that increases appetite. 

Serotonergic receptors

• Serotonin plays a vital role in regulating energy homeostasis by modulation of appetite and food intake behaviour.
• Antagonism of the serotonin receptor, 5-HT2C (which stimulates anorexigenic POMC neurons and decreases appetite), by antipsychotics can increase food intake, even in the presence of satiety.

Adrenergic receptors

• The metabolic relationship of adrenoreceptors with weight change is suggested to be through the regulation of thermogenesis and lipid mobilisation in adipose tissues.
• However, antipsychotics such as olanzapine have a low affinity for the α2a-adrenergic receptor, and therefore this association with antipsychotic-induced weight gain is controversial.

Muscarinic receptors

• Muscarinic acetylcholine receptors (M3 receptors) in the dorsal vagal complex are activated during feeding and mediate pancreatic insulin release.
• Antipsychotic-related antagonism inhibits insulin secretion leading to hyperglycemia.

Dopaminergic receptors:

• Dopamine is involved in reward pathways and hedonistic appetite control, and dopamine antagonism can increase appetite.

Psychosocial Causes: 

Contribute to obesity through restricting food choices and decreasing energy expenditure

• Social isolation
• Low income and unemployment 
• Decreased physical activity due to negative symptoms of depression
• Deficits in executive function and memory
• Residual psychotic symptoms 
• Substance Use 

MANAGEMENT STRATEGIES - GENERAL RECOMMENDATIONS

Approaching the topic.

Stigma or shame can be a limiting factor in the discussion of weight gain. An open question can facilitate the discussion.

Some people don’t mind talking about their weight; others don’t want to talk about it. How do you feel about this?’

General Guidelines: Monitoring and Psychoeducation: [Jensen et al., 2014], [Rege, 2008]

• Annual measurement of BMI and waist circumference 
• Psychoeducation to overweight and obese adults on the relationship between elevated BMI and the risk of cardiovascular disease, type 2 diabetes, and all-cause mortality. 
• Patients with one or more risk factors (dyslipidemia, arterial hypertension, or hyperglycemia) should be informed that a sustained weight decrease of at least 3%-5% will benefit their health. 

Dietary changes for weight loss (Changes that create an energy deficit (intake < expenditure): 

• Restrict high carbohydrate, and low-fibre food
• Limit foods high in saturated fat and trans-fatty acids; substitute with unsaturated fat from vegetables, fish, legumes, and nuts. 
• Increase fibre intake by consuming fruits, vegetables, grains, pulses and legumes.
• Create deficits of 500–759 kcal/day
• Limit total caloric intake to 1500–1800 kcal/day in males and 1200–1500 kcal/day in females
• Reduce salt intake Limit salt to 6 g / day (2400 mg Na) by choosing foods low in salt and limiting the amount of salt added to food 
• Low carbohydrate and Mediterranean diets led to more significant weight loss than high-protein or low-glycemic index regimens. 
• Low-calorie diets should be avoided in pregnant or lactating women and patients with eating disorders.

Weight loss maintenance : 

• Monthly face-to-face interventions
• Continuation of the reduced caloric intake
• 200–300 min/week of physical activity. Endurance activities are preferable because resistance training does not enhance weight loss. 

For physically inactive patients, 

• Initial physical activity recommendations should be modest, based on the patient’s willingness and ability; after that, the duration and frequency should increase to 30-45 min moderate aerobic activity 3-5 days per week when possible. 
• Greater activity levels of ≥1h per day of moderate (walking) or 30 min per day of vigorous (jogging) activity may be needed to achieve successful long-term weight loss.
• The exercise programme may be started at a lower level, such as walking 2–3 times/week for 30 min.
• Intensive lifestyle interventions reduce body weight and cardiovascular risk factors in obese patients with type 2 diabetes.
• After dietary and behavioural interventions, bariatric surgery should be considered for adults with BMI >40 kg/m2 and patients with obesity-related morbidity with BMI ≥35 kg/m2.

MANAGEMENT OF ANTIPSYCHOTIC INDUCED WEIGHT GAIN

Choice of low-risk antipsychotics is critical, and prevention should always be the focus in the management of schizophrenia.[Castle et al., 2021]

Once clinically significant weight gain has occurred, there are three main strategies:

• Switching to a less metabolically adverse antipsychotic
• Adjunctive behavioural treatments
• Adjunctive pharmacologic interventions 

Switching

• One of the most relevant strategies to reduce antipsychotic-related weight gain is to switch to a less orexigenic agent. Analysis of the data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study showed that patients who switched from olanzapine to other antipsychotics gained less weight than those who continued with olanzapine treatment. [Rosenheck et al., 2009]
• However, a review of the data in 2006, from the phase I findings of the CATIE study showed that patients were more likely to discontinue treatment prematurely after switching medications. [Essock et al., 2006] The authors did not look at weight gain or obesity but rather only the effectiveness of switching.

They concluded: 

Unless the clinical situation requires a medication change, prescribers may want to take steps to optimize current medication regimens (e.g., dosage adjustments, behavioral or psychosocial interventions) before switching medications. 

A subsequent randomised controlled efficacy trial in schizophrenia confirmed that weight gain was not associated with clinically relevant efficacy advantages. Switching to agents associated with weight loss was associated with similar efficacy outcomes as switching to more weight gain-promoting agents. [Hermes et al., 2011] 

A meta-analysis showed that switching antipsychotics to agents with lower weight gain potential, notably to aripiprazole and ziprasidone, can improve weight profile and other cardiometabolic outcomes. No significant weight or other cardiometabolic changes were observed when switching to amisulpride, paliperidone/risperidone, quetiapine, or lurasidone. [Siskind et al., 2021]

An Australian Clinical Audit and Survey of Clinical practice showed that ‘simple’ interventions such as switching from moderate or high-risk antipsychotics to lower risk antipsychotics and providing lifestyle advice could reduce metabolic risk profile. [Castle et al., 2021]

Another instructive recent study showed that patients who had gained weight on olanzapine could be switched to lurasidone with beneficial effects for weight and no worsening of psychotic symptom control. [Stahl et al., 2013]

Behavioural 

A meta-analysis and systematic review analysed the effectiveness of cognitive behavioural interventions, nutritional counselling, and a combined nutritional and exercise approach to reduce antipsychotic-related weight gain. [Alvarez-Jimenez et al., 2008]

Although all interventions showed a weight reduction compared to treatment as usual, there was a trend favouring nutritional counselling.

Correll and Carlson proposed in 2006 a 12-step healthy lifestyle program for youths and adults that were currently being treated with antipsychotics. Although over 10 years old, this healthy lifestyle program is as relevant as today: [Correll & Carlson, 2006]

• Family involvement in meal planning
• Drink water instead of soft drinks
• Have 4-6 separate meals/day
• Eat breakfast every day
• Serve small portions
• Eat foods with a low glycaemic index 
• Eat slowly
• Reduce/avoid saturated fat intake
• At least 25-30 grams of soluble fibre
• Avoid snacking while satiated
• Limit fast foods to less than once per week
• Limit sedentary behaviours to less than two hours per day
• Exercise at least 30-60 minutes daily

Behavioural interventions effectively prevented and reduced antipsychotic-associated weight gain and cardiometabolic perturbations, at least in outpatients agreeing to participate in trials to improve physical health. [Caemmerer et al., 2012]

Pharmacological 

The pharmacology of antipsychotic-induced weight gain is likely to be multifactorial, making it difficult to develop targeted pharmacological interventions. The literature on pharmacological agents that have been investigated has produced highly heterogeneous data.

A comprehensive meta-analysis of 32 randomised placebo-controlled trials analysed the efficacy of 15 pharmacological agents to reduce weight gain in patients who experienced weight gain over a mean of 13 weeks. [Maayan et al., 2010]

Only metformin (2.94 kg), fenfluramine (2.6 0kg), sibutramine (2.56 kg), topiramate (2.52 kg), and reboxetine (1.90 kg) were more effective than placebo, with the most evidence being available for metformin. 

Sibutramine’s psychiatric application may be limited because it has been known to cause panic, psychosis and mania. 

Topiramate: 

• Topiramate centrally reduces NPY Y1 and Y5 receptors (receptors that increase appetite). Peripherally topiramate reduces leptin mRNA transcription in adipose tissue, which increases energy expenditure.
• There is also speculation that topiramate reduces appetite by altering taste due to its carbonic anhydrase inhibition.[Rege, 2008]

Metformin 

• Metformin is an oral hypoglycaemic agent that reduces hepatic glucose production and increases the peripheral utilisation of glucose. It also improves insulin sensitivity and thus indirectly decreases body weight. 
• A systematic review and meta-analysis showed that metformin effectively reduced BMI and insulin resistance index but not fasting blood sugar. [De Silva et al., 2016]
• Metformin may be more effective in preventing weight gain before the onset of significant insulin resistance and thus shows more efficacy in antipsychotic naïve patients. Once these metabolic changes have occurred, metformin may be less effective in preventing or reversing weight gain.
• The mean weight change was −3.27 kg. Metformin, compared to placebo, resulted in a significant reduction in BMI and insulin resistance index but not fasting blood sugar. [De Silva et al., 2016]

Augmentation with partial dopamine agonists

• Adding the partial dopamine agonist aripiprazole to clozapine is evidence-based and commonly used in clinical practice: an added benefit is the ability, often, to reduce the overall clozapine dose. [Karunakaran et al., 2007]
• Brexpiprazole and aripiprazole have a similar effect on body weight over 1 year (with mean weight increase lower for brexpiprazole than aripiprazole. [Weiss et al., 2018]

GLP-1 Receptor analogues 

• There is emerging evidence about the potential of the glucagon-like peptide-1 receptor (GLP1R) analogues such as liraglutide to reduce weight and reverse glucose intolerance in people who have gained weight on antipsychotics: weight loss is more dramatic than that seen in trials of metformin because of its ability to reduce psychotropic hunger and increase satiety. Glucose tolerance can also be reversed. [Larsen et al., 2017]
• The dose of 3.0mg has been approved in Australia for weight loss and 1.8mg for diabetes.
• A study evaluating 3731 non-mental health patients using a Liraglutide dose of 3.0mg for 52 weeks produced an average weight loss of 8.4 kg, with 33.1% of participants losing more than 10% of their weight. [Pi-Sunyer et al., 2015]
• A 16-week study of once-daily subcutaneous injection of liraglutide significantly improved glucose tolerance, body weight, and cardiometabolic disturbances in patients with schizophrenia spectrum disorders treated with clozapine or olanzapine. [Larsen et al., 2017]
• After stopping liraglutide, the bodyweight reduction was partially sustained for 1 year. However, the improvements in other metabolic parameters returned to baseline levels. [Svensson et al., 2019]
• A 24-week randomised, controlled, open-label pilot trial of once-weekly extended-release subcutaneous exenatide for clozapine-treated obese adults with schizophrenia, with or without T2DM compared to usual care found exenatide was associated with significantly greater weight loss, BMI reduction, reduced fasting glucose and reduced HbA1c levels. [Siskind et al., 2018]
• The post endpoint 12 months follow up showed there were significant increases in weight, BMI and HbA1c in the 12 months post endpoint for the former exenatide group. [Siskind et al., 2020]
• A newer GLP-1 receptor agonist, semaglutide, has shown clinically significant weight loss in patients with overweight or obesity.
• 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with a sustained, clinically relevant reduction in body weight. [Wilding et al., 2021]
• The use of semaglutide in patients on antipsychotics has not yet been studied. In the author’s experience (Dr Sanil Rege), Semaglutide has been successfully used (in conjunction with physician input) in olanzapine-induced weight gain with clinically significant weight loss.
• A study is underway on semaglutide as an adjunct with metformin in patients taking clozapine. [The COaST trial]

SUMMARY