A meta-analysis, of the efficacy of second generation antipsychotics (SGAs) 142 controlled studies were reviewed 124 studies of SGAs vs FGA, patients 18 studies of SGAs, patients Efficacy differences Clozapine, amisulpiride, risperidone, and olanzapine were more efficacious than FGAS Tolerability differences The meta-analysis could not balance qualitative differences between adverse effects Rare but serious AE vs the frequency and seriousness of more common adverse effects Extrapyramidal AE and/or prolactin elevation vs metabolic effects Davis et al 2003

Atypical antipsychotics and metabolic dysregulation Weight gain, obesity Type II diabetes Lipid abnormalities

What is the prevalence of obesity and type II diabetes in individuals in whom atypical antipsychotics are used? Does schizophrenia per se have an independent role in the development of abnormal glucose metabolism? Preneuroleptic era: Patients with schizophrenia – Impaired fasting glucose tolerance – Type II diabetes – Hyperinsulinemia Kasani 1926, Meduna and Valchoulis 1948, Simon and Garvey 1951

Obesity and body weight gain have been associated with Hypertension Type II diabetes Coronary heart disease Stroke Diseases of gallbladder Osteoarthritis Sleep apnea and respiratory problems Some type of cancer: endometrial, breast, prostate and colon National Institute of Health, USA 1998

The prevalence of both diabetes and obesity among patients with schizophrenia and affective disorders is ~1.5-2 times higher than in the general population The rate of type II diabetes mellitus in family members of patients with schizophrenia is % which is higher that the rate in the population at large: % Adams and Marano 1995 First episode, drug naive patients with schizophrenia had impaired fasting glucose tolerance were more insulin resistant and had higher levels of plasma glucose and insulin than healthy comparisons subjects Ryan et al 2003

Atypical antipsychotics and weight gain Atypical antipsychotics can cause a rapid increase in body weight in the first few months of therapy That may not reach a plateau even after one year of treatment At 10 weeks of therapy estimated average weight gain with AA treatment compared with placebo varies from ~ Kg Allison et al 1999, Wirshing et al 1999, Meyer 2002, Taylor 2003, Nayzulcah 2003

Atypical antipsychotics and weight gain Clozapine +++ Olanzapine +++ Quetiapine ++ Risperidone ++ Ziprasidone +/- Aripiprazole +/- + = increase effect - = no effect Consensus Conferences on psychotic drugs and obesity and diabetes 2004

Amisulpride – weight variations Meta-analysis of 11 randomized controlled trials (2,214 patients) in which amisulpride compared with conventional antipsychotics, risperidone and placebo Short term administration (up to 13 weeks) weight increase > vs baseline Amisulpride16% Placebo11% Haloperidol8% Flupenthixol35%vs amisulpride: p<0.001 Risperidone24%vs amisulpride: p=0.05

Long term administration (up to 12 months) Mean weight increase Amisulpride group+1.2±6.5 Kg Haloperidol group-0.4±5 Kgp<0.001 Coulouvrat and Dondey-Nouvel 1999

Mechanism(s) of action The mechanism(s) of action responsible for weight gain associated with AA therapy are unknown AA possess binding affinities to serotonin (5-HT), dopamine, noradrenaline and particularly histamine H 1 receptors All of these receptors have been implicated in the control of body weight

Risk factors for type II diabetes Age 45 and older High risk ethnicity Gestational diabetes, or delivery of infant weighing >9 lbs Hypertension Dyslipidemia Previous history of impaired fasting glucose or impaired glucose tolerance Jin et al 2004

Number of case reports of normoglycemic patients who developed hyperglycemia offer beginning therapy with Cases Clozapine1994 – 2/ Olanzapine1994 – 2/ Risperidone1994 – 2/ Koller et al 2003 These abnormalities usually resolve with treatment discontinuation and reemerge with reinstitution of the drug

After one year of therapy with either clozapine or risperidone Significantly greater increase in serum glucose was seen with olanzapine (+10.8 mg/dl) than with risperidone (+0.74 mg/dl) Meyer 2002

Quetiapine, like risperidone, appears to pose a low degree of risk for hyperglycemia than seen with clozapine and olanzapine, although the data are not conclusive Kato and Goodnick 2001 Granfrancesco et al 2003

Ziprasidone appear to be associated with the lowest levels of hyperglycemia Kato and Goodnick 2001 Simpson et al 2004 Risk of hyperglycemia also appears to be low with aripiprazole, but before any conclusion further clinical experience is warranted Taylor 2003

Atypical antipsychotics and diabetes Risk for diabetes Clozapine+ Olanzapine+ RisperidoneD QuetiapineD Ziprasidone- Aripiprazole- + = increased- = no effectD = discrepant results Consensus conference on antipsychotic drugs and obesity and diabetes 2004

Possible mechanism(s) of diabedogenic action of atypical antipsychotics D 2 dopanime receptor blocking in certain areas of the brain e.g. hypothalamus 5-HT IA and 5HTT 2C serotonin receptors and H 1 histamine receptors Body weight gain Chemical structure of the antipsychotic drugs Insulin resistence and inhibition of insulin secretion

Mechanism(s) of diabedogenic action of atypical antipsychotics Increased leptin levels may operate as a compensatory mechanism for the inhibition of insuline secretion or insulin resistance at the receptor level Decrease of insulin-like growth factor-I (IGF-I) Genetic involvement Hyperlipidemia Toxic action of AA on the β cells Liebzeit et al 2001 Mir and Taylor 2001 Ananth et al 2002

Atypical antipsychotic and dislipidemia Changes in serum lipids are concordant with changes in body weight Clozapine and olanzapine are associated with the greatest increases in total cholesterol, LDL cholesterol, triglycerides and with decreased HDL cholesterol

Atypical antipsychotic and dislipidemia Aripiprazole and ziprasidone do not seem to be associated with a worsening of serum lipids Risperidone and quetiapine appear to have intermediate effects on lipids Kato and Goodnick 2001 Review, McIntyre et al 2001 Review Nasrallah and Newcomer 2004 Review, Casey et al 2004 Review Meyer and Coro 2004 Review, Cane et al 2004, Commentary, Consensus Conference, American Diabetes, Association, APA AACE, NAASO 2004

Atypical antipsychotics and dyslipidemia Clozapine+ Olanzapine+ RisperidoneD QuetiapineD Aripiprazole- Ziprasidone- + = inversed effect - = no effect D = discrepant results Consensus conference on antipsychotic drugs and obesity and diabetes 2004

Atypical antipsychotic and dislipidemia All patients with persistent or worsening dislipidemia should be referred for liping- lowering therapy or considered for switch to a less offending agent if possible

Choosing among the antipsychotic medications (risk benefit assessment) The patient’s psychiatric condition Specific target signs and symptoms Past history of drug response Patient’s preference History of treatment adherence Medication effectiveness Comorbidities Cost of medications

Monitoring protocol for patients on SGAs Baseline4 weeks8 weeks12 weeks QuarterlyAnnuallyEvery 5 years Personal /family history XX Weight (BMI) XXXXX Blood pressure XXX Fasting plasma glucose XXX Fasting lipid profile XXXX * More frequent assessments may be warranted based on clinical status ADA, APA 2004

Switching to an AA that has not been associated with significant weight gain or diabetes Referral to a clinician with experience treating people with diabetes Immediate care for patients with severe hyperglycemia glucose values >300 mg/dl or glucose levels <60mg/dl even in the absence of symptoms The presence of symptoms of diabetic ketoacidosis requires immediate evaluation and treatment Initiating interventions aimed at increasing physical activity, improving dietary habits and reducing body weight Nasallah and Newcomer 2004 How should the patients be treated if metabolic disturbances develop?