176 - Second generation antipsychotic medications

Second-generation antipsychotic medications

174 The Maudsley® Prescribing Guidelines in Psychiatry CHAPTER 1 Diabetes and impaired glucose tolerance Schizophrenia Schizophrenia is associated with relatively high rates of insulin resistance and type 2 diabetes1,2 – an observation that predates the discovery and widespread use of antipsychotic medication.3–5 Lifestyle interventions (healthy diet, losing weight, regular physical activity) are effective in preventing diabetes6,7 and should be considered for all people with a diagnosis of schizophrenia. Antipsychotic medications The data relating to diabetes and the use of antipsychotic medication are numerous but less than perfect.8–12 The main problem is that while incidence and prevalence studies assume full or uniform screening for diabetes, this is unlikely to be occurring in clinical practice.13 Many studies do not account for other factors affecting the risk of developing diabetes.14 Small differences between medications are therefore difficult to substantiate but may, in any case, be ultimately unimportant: risk is probably increased for all those with schizophrenia receiving any antipsychotic medication. This risk is fairly strongly linked to increased diabetes-­related mortality.11 The mechanisms involved in the development of antipsychotic-­related diabetes are unclear, but may include 5HT2A/5HT2C antagonism, increased plasma lipids, weight gain and leptin resistance.15 Pancreatic insulin secretion is controlled by dopamine16 and this may explain why so many antipsychotics cause impaired glucose tolerance.17 Insulin resistance may occur in the absence of weight gain.18 First-­generation antipsychotic medications Phenothiazine derivatives have long been associated with impaired glucose tolerance and diabetes.19 Diabetes prevalence was reported to have substantially increased following the introduction and widespread use of FGA medications.20 The prevalence of impaired glucose tolerance seems to be higher with the aliphatic phenothiazines than with fluphenazine or haloperidol.21 Hyperglycaemia has also been reported with other FGAs, such as loxapine,22 and other data confirm an association with haloperidol.23 Some studies have suggested that FGAs are no different from SGAs in their propensity to cause diabetes,24,25 whereas others suggest a modest but statistically significant excess incidence of diabetes with SGAs.26 Second-­generation antipsychotic medications Clozapine Clozapine is strongly linked to hyperglycaemia, impaired glucose tolerance and diabetic ketoacidosis.27 The risk of diabetes appears to be higher with clozapine than with other SGAs or FGAs, especially in younger patients,28–31 although this is not a consistent finding.32,33 As many as a third of patients on continuing treatment with clozapine might develop diabetes after 5 years.34 Many cases of diabetes occur in the first 6 months of treatment,

Schizophrenia and related psychoses CHAPTER 1 some within a month,35 and some only after many years.33 Death from ketoacidosis has also been reported.35 Diabetes associated with clozapine is not necessarily linked to obesity or to family history of diabetes,27,36 although these factors greatly increase the risk of developing diabetes on this medication.37 Clozapine appears to increase plasma levels of insulin in a clozapine level-­dependent fashion.38,39 It has been shown to be more likely than FGAs to increase plasma glucose and insulin following oral glucose challenge.40 Testing for diabetes is essential, given the high prevalence of the condition in people receiving clozapine.41,42 Olanzapine As with clozapine, olanzapine has been strongly linked to impaired glucose tolerance, diabetes and diabetic ketoacidosis.43 Olanzapine and clozapine appear to directly induce insulin resistance.44,45 Risk of diabetes has also been reported to be higher with olanzapine than with FGA drugs,46 again with a particular risk in younger patients.29 The time course of development of diabetes has not been established, but impaired glucose tolerance seems to occur even in the absence of obesity and family history of diabetes.27,36 Olanzapine is probably more diabetogenic than risperidone.47–51 Olanzapine is also associated with plasma levels of glucose and insulin higher than those seen with FGAs (after oral glucose load).40,52 Risperidone Risperidone has been linked, mainly in case reports, to impaired glucose tolerance,53 diabetes54 and ketoacidosis.55 The number of reports of such adverse effects is substantially smaller than with either clozapine or olanzapine.56 At least one study has suggested that changes in fasting glucose are significantly less common with risperidone than with olanzapine,47 but other studies have detected no difference.57 Risperidone seems no more likely than FGA drugs to be associated with diabetes,29,46,48 although there may be an increased risk in patients under 40 years of age.29 Risperidone has, however, been observed to adversely affect fasting glucose and plasma glucose (following glucose challenge) compared with the levels seen in healthy volunteers (but not compared with patients taking FGAs).40 Quetiapine Like risperidone, quetiapine has been linked to cases of new-­onset diabetes and ketoacidosis,58–60 and associated with an increased risk of diabetes.61,62 Two studies showed quetiapine to be equal to olanzapine in the incidence of diabetes.57,63 The risk with quetiapine may be dose related, with daily doses of 400mg or more being clearly linked to changes in HbA1C.64 Other SGAs Amisulpride appears not to elevate plasma glucose,65 although there is one reported case of ketoacidosis occurring in a patient given the closely related medication sulpiride.66 Data for aripiprazole67–70 and ziprasidone71,72 suggest that neither drug alters