Friday, 29 April 2011

Metabolic Effects of Atypical Antipsychotics

Metabolic Effects of Atypical Antipsychotics—Implications on Weight Gain and Glucose and Lipid Metabolism

Cindy PY Chiu, MBBS, MRCPsych (UK), FHKCPsych, FHKAM (Psych); Eric YH Chen, MB ChB (Edin), MA (Oxon), MRCPsych (UK), FHKCPsych, FHKAM (Psych), MD (Edin)

Antipsychotic medication is crucial in the treatment of schizophrenia spectrum disorders and bipolar disorders. It is also widely used in the treatment of conditions with behavioural disturbance, such as dementia and learning disability, as well as tic disorder. In line with the growing emphasis on minimizing potentially disabling side effects, contemporary antipsychotic prescription practice favours atypical agents over conventional antipsychotics.1–3 Conventional antipsychotics, despite their value in terms of clinical efficacy, have a generally higher incidence of side effects, including extrapyramidal symptoms, hyperprolactinaemia and tardive dyskinesia. This poses tolerability problems that affect compliance and, hence, hinder recovery. However, atypical antipsychotics are not without drawbacks. The newer drugs are significantly more expensive, and there is concern over their different profile of side effects. In view of their own advantages and disadvantages, the choice between conventional and atypical antipsychotics cannot simply be a dichotomized exercise.

Clinical observation has aroused concern over the development of a metabolic syndrome consisting of weight gain, hyperglycaemia and hyperlipidaemia, which implies an elevated risk of morbidity and mortality. This article attempts to review recent literature on atypical antipsychotics and their relationship with the metabolic syndrome.

Metabolic Risk in Schizophrenia

Individuals suffering from schizophrenia have a two- to threefold excess in morbidity and mortality when compared with the general population,4 of which physical co-morbidity accounts for 60% of non-suicide premature deaths.5 Such an increase in risk is likely related to a multitude of lifestyle factors, such as lack of exercise, low-fibre diets, excessive alcohol consumption and smoking; social factors, such as unemployment and disadvantaged social conditions; and a higher likelihood of accidents and injuries. A study of Scottish patients with schizophrenia living in the community showed a diet lower in fruit and vegetables, heavier smoking and a higher likelihood of obesity compared with the general population. Cardiovascular risk was also increased to an extent that warranted active intervention.6 In the United States, the prevalence of the metabolic syndrome amongst patients with schizoaffective disorder was higher than that in the general population.7 A case-controlled study comparing drug-naive/drug-free schizophrenic patients and healthy controls showed higher body mass index (BMI) and 3.4 times more intra-abdominal fat in patients than in normal controls, despite comparable total body fat and subcutaneous fat.8 General health status is, therefore, compromised with increased cardiovascular events,9 obesity, hypertension and diabetes mellitus in schizophrenic patients. Family history is also of relevance, as the prevalence of diabetes can be as high as 33% in those patients with a positive family history versus 10% in those without. Thus, even before medication effects become involved, schizophrenia per se predisposes patients to increased risks of cardiovascular morbidity and the metabolic syndrome. Care should be taken in the choice of antipsychotics to achieve maximum benefit and minimal metabolic risk.
Metabolic Syndrome

The metabolic syndrome is characterized clinically by central obesity, dyslipidaemia, hypertension and elevated fasting sugar. The operational definition of metabolic syndrome according to the National Cholesterol Education Program requires three out of the five criteria of abdominal obesity, elevated fasting triglycerides, decreased high-density lipoprotein, elevated blood pressure and elevated fasting glucose.10
Antipsychotics and the Metabolic Syndrome
Baseline data of subjects with chronic schizophrenia treated with various antipsychotics from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) showed a prevalence of metabolic syndrome of 42.7%, doubling that seen in the general population.1
Weight gain and dyslipidaemia are relatively limited with most conventional antipsychotic drugs. Amongst the various conventional drugs in use, weight gain and impaired glucose tolerance have been recognized predominantly with low-potency agents, such as chlorpromazine.12 Despite the relatively lower incidence of neurological side effects, such as extra-pyramidal effects and tardive dyskinesia, there is an increasing awareness of the metabolic effects of atypical antipsychotics, which seem to be more substantial than with conventional agents.13,14
Hyperglycaemia, Diabetic Ketoacidosis and Diabetes Mellitus

Current findings are suggestive of an association between atypical antipsychotic use and impaired glucose tolerance, worsening of diabetic control, and higher incidence of diabetes mellitus and diabetic ketoacidosis.15 Amongst outpatients with schizophrenia and major mood disorders receiving antipsychotic treatment, there was a trend towards a higher prevalence of diabetes in those receiving atypical antipsychotics versus those receiving decanoate medication.14 Atypical anti- psychotics may worsen metabolic control in type 2 diabetes mellitus, as reflected by a higher rate of initiation of insulin therapy (‘secondary failure’) in an elderly outpatient population.16 Of the atypical drugs, clozapine and olanzapine are more often found to have an adverse effect on glucose metabolism.17,18

Weight Gain

Weight gain may occur to a certain extent with all atypical agents and is most prominent in the first 4 to 6 months of treatment.19 Weight gain with atypical antipsychotics has been recognized, especially with olanzapine and clozapine and to a lesser extent with quetiapine, risperidone and amisulpiride. Ziprasidone may have some reversal effect on weight gain.18,19 Hyperprolactinaemia, 5-HT2c and H1 antagonism and leptin insensitivity are some of the proposed mechanisms,20 as suggested by increased levels of insulin and leptin as well as obesity in mutant mice without functional 5-HT2c receptors.21 Leptin, produced by adipose tissue, is involved in the regulation of food intake by a negative feedback mechanism via receptors at the hypothalamus. High levels of leptin correlate with obesity; proposed mechanisms include leptin deficiency and dysfunctional leptin receptors. Chronic schizophrenic patients with initial leptin levels comparable to those of healthy controls were found to have higher serum leptin as well as weight gain at the end of a period of antipsychotic treatment. Amongst those on atypical antipsychotics, leptin levels were significantly higher in those on olanzapine, intermediate with clozapine and lower with risperidone.22 Drug-naive Chinese patients with first-episode schizophrenia were found to have a threefold increase in leptin and significant increases in both subcutaneous and intra-abdominal fat on MRI after 10 weeks of either risperidone or chlorpromazine treatment.23

As obesity brings considerable morbidity and mortality, weight management is important to prevent and ameliorate the undesirable effects related to weight gain. Attendees of a weight-training programme focusing on nutrition, exercise and motivation had significant reductions of body weight and BMI at the end of 1 year when compared to other patients who received usual care.24 Switching to another antipsychotic with less effect on weight may curb further weight gain and, in some cases, reverse the effect. Agents such as topiramate, orlistat, metformin and reboxetine may be useful in selected cases but are not without side effects of their own.


Amongst atypical antipsychotics, olanzapine and clozapine were more often found to be related to an increase of blood lipid levels.11,25 Clozapine and olanzapine were associated with increased blood cholesterol by the fourth month of treatment. Ziprasidone, risperidone and zotepine, however, had no apparent effect on lipid levels. It was proposed that lipoprotein lipase was involved through a direct drug effect or via down-regulation by hyperinsulinaemia. In some cases at least, antipsychotic-induced hyperlipidaemia is reversible upon withdrawal of the drug.26 Hyperlipidaemia is closely associated with cardiovascular events and should be actively prevented.
Awareness and Management

Psychiatrists are generally aware of the potential metabolic side effects from atypical antipsychotics. Despite such knowledge and concern, disparity occurred between guideline recommendations for routine monitoring and actual clinical practice. In the Atypical Antipsychotic Therapy and Metabolic Issues Survey, more than 80% of the respondents recognized the increased metabolic risk of patients receiving atypical antipsychotic treatment, but less than half of the patients received regular monitoring of blood pressure, body weight, waist circumference, and lipid and glucose levels.27

Expert groups worldwide have made consensus recommendations for the detection and management of the metabolic syndrome.28 In short, there should be baseline data on body weight, waist circumference, blood pressure, fasting sugar and lipids, and a personal medical history as well as family history. Close monitoring of the physical parameters within the first few months is warranted and is to be repeated at regular intervals thereafter. Prompt referrals should be made for patients who develop metabolic side effects.

Various factors account for the increased risk of developing metabolic syndrome in patients with schizophrenia. The metabolic syndrome of weight gain, hyperglycaemia and hyperlipidaemia contributes significantly towards cardiovascular disease, bringing about considerable morbidity and mortality, not to mention medical emergencies such as diabetic ketoacidosis. Non-medication factors such as a low-fibre diet, lack of physical exercise, smoking and alcohol consumption are also important. Atypical antipsychotics, in particular olanzapine and clozapine, have a higher predisposition to metabolic effects when compared with typical agents.

Management of the metabolic syndrome starts with a physical and personal history; baseline measurements of body weight, BMI, blood pressure, fasting glucose and lipids; and, with that in mind, an appropriate choice of antipsychotic medication. Patients should be counselled prior to the commencement of treatment, with education on a balanced diet and recommendations for dietary restrictions. A healthy lifestyle encouraging exercise should be advocated, and smoking and sedentary habits should be discouraged. Weight-monitoring programmes give structure and quantify changes regularly, which may help with patient perseverance.

Physical measurements and blood investigations should be repeated within the first 6 months and performed annually thereafter. The presence of metabolic syndrome warrants adequate intervention. The decision of whether or not to change the antipsychotic agent is dependent upon weighted variables such as clinical response, tolerability of other side effects and response of the metabolic syndrome to treatment. Above all, clinician and patient awareness of the metabolic syndrome is essential for its prevention and amelioration.

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