Introduction
Metabolic effect of antipsychotics
Managing metabolic adverse effects
Therapeutic interventions
Pharmacological interventions
Conclusions
References

 

 

 

 

Introduction

The rapid rise in the global prevalence of type 2 diabetes is putting increasing strain on health systems worldwide. An association between schizophrenia and metabolic abnormalities is well described, and patients with schizophrenia have significantly higher rates of cardiovascular disease compared to the general population.1,2 In addition, patients with schizophrenia have higher prevalence of metabolic syndrome and obesity-related illnesses, the cause of which may be multi-factorial, but remains to be fully elucidated.

Psychiatric disease, such as schizophrenia, is frequently associated with poor lifestyle choices, such as diets high in fat, reduced levels of physical activity and high rates of smoking,3 all of which may contribute to the development of metabolic syndrome and insulin resistance.

Atypical or second-generation antipsychotics are increasingly used in the treatment of schizophrenia, due to their reduced extrapyramidal side effects, better concordance and improved quality of life. Such drugs are, however, associated with increased appetite, weight gain, insulin resistance and metabolic abnormalities such as dyslipidaemia.4,5 The molecular mechanisms underlying these metabolic effects are unclear. Weight gain, in particular central adiposity, is widely recognised to predispose an individual to the development of metabolic syndrome and type 2 diabetes. There is emerging evidence that the atypical antipsychotics exert a direct effect on glucose and lipid homeostasis.6 The adverse metabolic effects of these drugs must be recognised when managing a patient with schizophrenia, and risk factors for cardiovascular disease need to be monitored and managed.

There is no clear consensus on screening for metabolic abnormalities in patients receiving atypical antipsychotics and formal guidelines vary greatly.7 Baseline screening and continuous monitoring of patients treated with atypical antipsychotics is essential to prevent, recognise and manage metabolic abnormalities. Additionally, both lifestyle and pharmacological interventions may need to be utilised to prevent these metabolic complications, in a high risk population.8 This article aims to review the management of metabolic complications in patients with schizophrenia.

 

 

Metabolic effect of antipsychotics

Weight gain

Up to 40% of patients with schizophrenia are considered overweight (body mass index [BMI] >25kg/m2).9 Mental illness may itself contribute to changes in energy expenditure versus energy intake due to reduced physical activity, poor diet and lifestyle choices. There is, however, evidence that patients with schizophrenia have increased visceral fat distribution, possibly linked to the use of antipsychotic treatment.10 Visceral adiposity is linked to insulin resistance, dyslipidaemia and increased cardiovascular risk.11

Atypical antipsychotics cause weight gain, although the degree to which they cause weight gain can vary. Clozapine and olanzapine are well recognised as the most weight-inducing, and both exert this adverse effect during short (4–12 weeks) or prolonged periods of treatment.12

Allison and colleagues performed a meta-analysis of antipsychotic-induced weight gain studies in men, and found a mean weight gain of 4.4kg with clozapine, 4.1kg with olanzapine, 2.1kg with risperidone and 0.04kg with ziprasidone over a 12-month period.3

Antipsychotic-induced weight gain in animal models have yielded inconsistent results; Kalinichev and colleagues showed that female rats administered olanzapine for 14 days gained significant weight compared to controls, and this finding correlated with increased food intake.13 A further rat model by Baptista and colleagues showed no significant weight gain nor changes in food intake.14

A postulated mechanism behind antipsychotic-induced weight gain is increased food intake and decreased energy expenditure.15 Therefore, a number of neurotransmitters and neuropeptides have been implicated. Serotonin has been long associated with appetite regulation and appears to be an important satiety signal.16

Atypical antipsychotics are antagonists at both dopamine and serotonin receptors, which may help explain the adverse effect on appetite regulation.17 Dopamine itself has also been implicated in feeding behaviour patterns, and reduced dopamine availability has been associated with obesity.18 Other neurotransmitter receptors under investigation for antipsychotic-induced weight gain/appetite dysregulation include the histamine, cholinergic and cannabinoid systems.

Leptin is an adipokine (a hormone derived from adipose tissue), which has a well characterised role in regulating energy intake and expenditure.19 Leptin acts on receptors in the hypothalmus inhibiting appetite, antagonising the effects of neuropeptide Y and anadamide (appetite stimulants) and promoting the effects of alpha-melanocyte stimulating hormone (a-MSH)—an appetite suppressant.

Zugno and colleagues investigated the effects of olanzapine administration in rats on their leptin levels. They found significantly decreased levels of leptin in the group of rats fed both a normal diet and a high calorie diet, who were administered olanzapine, compared to control groups.20 These findings have been replicated with other second-generation antipsychotics studies, strengthening the association of antipsychotic-induced appetite dysregulation.21,22

 

Insulin resistance and abnormal glucose homeostasis

The prevalence of impaired glucose tolerance (IGT) and type 2 diabetes is significantly higher in patients with schizophrenia, predating the widespread use of atypical antipsychotics. This suggests that the pathophysiology of schizophrenia itself may lead to disturbed carbohydrate metabolism, or there may be a shared genetic predisposition.23 Importantly, however, the incidence of diabetes has significantly increased amongst schizophrenic patients since the introduction of antipsychotic therapy, particularly the second-generation agents.24

Unlike the first generation antipsychotics, atypicals have been associated with new-onset diabetes and diabetic ketoacidosis.25 Cohen and colleagues carried out a review of case reports or case series of new-onset diabetes associated with atypical agents.

He found 27 new cases were associated with clozapine treatment, 39 new cases with olanzapine and three new cases with quetiapine.26 Several cases were not associated with obesity or other strong risk factors such as family history, and interestingly some new-onset cases were reversed after discontinuation of the drug. These observations support the concept that certain antipsychotics may exert a direct adverse effect on glucose homeostasis, independent from drug induced obesity/central adiposity.

The mechanisms underlying antipsychotic-induced diabetes are likely to be multi-factorial. Antipsychotic medication appears to lead to changes in visceral fat distribution via effects on appetite and energy regulation neuropeptides, and to chronic low-grade inflammation in adipose tissue, leading to insulin resistance.

Olanzapine has been associated with higher levels of free-fatty acids which also exacerbate skeletal muscle insulin resistance through decreased muscle glycogen synthesis and glucose oxidation.27 Rodent models have suggested that olanzapine has direct effects on the hepatic insulin action.6 Insulin receptor substrates (IRS) are proteins that are key in the activation of insulin at its receptor leading to glucose uptake, gluconeogenesis and glycogen synthesis. Decreased levels of these IRS proteins are associated with insulin resistance. Mondelli and colleagues showed that olanzapine administration to rats led to a significant reduction in IRS2 levels leading to glucose intolerance. These findings were independent of changes in weight or visceral fat deposition which were found to be non-significant.

 

Dyslipidaemia

Dyslipidaemia is defined as raised serum levels of one or more of total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), and low levels of high-density lipoprotein cholesterol (HDL-C). Central obesity, insulin resistance or glucose intolerance and dyslipidaemia are the cardinal features of metabolic syndrome.

Various studies have shown that the use of second generation antipsychotics results in significantly elevated levels of triglycerides and total cholesterol, with reductions in HDL-C.28,29 Rettenbacher and colleagues found that four weeks administration of clozapine or olanzapine led to increasing BMI and significantly elevated triglycerides, total cholesterol and LDL-C. Interestingly, he found that administration of amisulpride or ziprasidone led to no significant metabolic adverse effects.30 It has been suggested on the basis of these findings that amisulpride or ziprasidone are more desirable antipsychotic treatments for patients with known cardiovascular disease.

 

 

Managing metabolic adverse effects

Screening for metabolic adverse effects

The metabolic adverse effects of antipsychotic treatment should be considered when psychiatrists are formulating a patient’s treatment regime. Pre-existing cardiovascular risk factors should prompt the use of atypical antipsychotics which may have a lower risk of adverse metabolic side effects (Box 1).

Although there are no consensus monitoring guidelines, it is good practice to undertake baseline screening and monitoring of metabolic indices during antipsychotic treatment. Thus weight, blood pressure, fasting glucose and lipids are essential parameters to analyse at baseline and during monitoring. More recently, glycated haemoglobin (HbA1c) has been advocated as a screening test for diabetes by the World Health Organization (WHO), with a cut off of 48mmol/mol (6.5%) being the diagnostic threshold for diabetes (although this needs to be confirmed in a second test in asymptomatic patients.31 Importantly, however, use of atypical antipsychotics is suggested as an exclusion for the use of HbA1c in diagnosis of diabetes.

The Lester UK adaptation guidelines recommend that weight should be assessed weekly in the first eight weeks of starting a new antipsychotic, as rapid early weight gain may predict severe weight gain in the long-term. Blood pressure, fasting glucose and lipids should be reviewed every three months for the initial year, then annually thereafter.32 The psychiatrist should consider whether the antipsychotic drug regimen has played a causative role in any metabolic abnormalities and consider whether an alternative regimen should be sought.

 

 

Therapeutic interventions

Diet and physical activity

When commencing antipsychotic therapy, considerable attention should be given to counselling the patient regarding lifestyle. Whilst the patient may not be receptive to advice in the early stages of an acute psychotic illness, the practitioner should always aim to counsel for lifestyle change, perhaps referring to specialists such as dietitians, if the patient becomes more receptive to advice. Thus advice to reduce calorie dense foods, reduce energy intake to prevent weight gain, stop full sugar carbonated drinks and juices and increase fibre intake. Advice should also be given on limitation of salt intake to reduce the chance of high blood pressure developing.

All patients should receive structured advice regarding physical activity. A minimum of 150 minutes of "moderate-intensity" physical activity per week should be advised, although this may depend on the patient’s baseline activity levels, and comorbidities. If the patient is very sedentary, a gradual increase in physical activity should be recommended. A structured physical activity programme may offer significant benefit in reducing potential for weight gain.

 

 

Pharmacological interventions

Pharmacological intervention to treat metabolic indices in patients on antipsychotic therapy may be indicated, particularly if a change of antipsychotic therapy to one less metabolically antagonistic is not feasible. Thus treatment of blood pressure, lipids and hyperglycaemia should follow established local guidelines—in the UK these may be NICE guidelines for each of these risk factors. The management of these metabolic factors is no different in patients on antipsychotic therapy, than those not on such therapy.

A specific role of metformin in treatment of glucose abnormalities should be mentioned. Metformin is generally deemed first line pharmacotherapy for patients with type 2 diabetes who do not achieve adequate glucose control on diet and lifestyle change alone.

Metformin may be particularly useful in anti-psychotic induced metabolic abnormalities, as these are often associated with weight gain and insulin resistance, which is antagonised by metformin. If metformin is commenced, side effects may be limited by slow titration and advising patients to take the medication after meals. If gastrointestinal side effects are problematic, there may be a place for the use of slow release metformin therapy, which may be better tolerated. Metformin should not be used in patients with significant renal disease (estimated glomerular filtration rate under 30mls/min) or significant hepatic disease (fibrosis or cirrhosis).

Specific intervention to aid weight loss, using orlistat, may also be indicated in patients with significant anti-psychotic induced weight gain.

 

 

Conclusions

Schizophrenia is an important mental health condition, and is associated with increased risk of cardiovascular disease and metabolic disease, possibly due to poor health behaviour related to the illness.

Metabolic abnormalities, such as weight gain, dyslipidaemia and abnormal glucose homeostasis can be exacerbated by therapy with atypical antipsychotics, and prescribers should be aware of these adverse effects, and seek to screen for them and minimise their impact.

Metabolic abnormalities should be screened for prior to, and regularly after, commencing antipsychotic therapy, and lifestyle advice and intervention should be offered to reduce the risk of weight gain. Pharmacological intervention may be necessary if lifestyle change is ineffective.

Further research is required on the reasons why these drugs induce such adverse effects, the place of newer antipsychotics which may be more metabolically neutral, in treatment of high risk patients, and the use of interventions to prevent weight gain in patients commencing these drugs.

 

Dr Catherine Gouveia, Dr Tahseen A. Chowdhury

Conflict of interest: none declared

 


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