• A meta-analysis, of the efficacy of second generation antipsychotics (SGAs)142 controlled studies were reviewed 124 studies of SGAs vs FGA, 18.272 patients 18 studies of SGAs, 27.482 patients Efficacy differences Clozapine, amisulpiride, risperidone, and olanzapine were more efficacious than FGASTolerability 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 18-30% which is higher that the rate in the population at large: 1.2-6.3%

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 ~0.5-5.0 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

Amisulpride 16%

Placebo 11%

Haloperidol 8%

Flupenthixol 35% vs amisulpride: p<0.001

Risperidone 24% vs amisulpride: p=0.05

Long term administration (up to 12 months)

Mean weight increase

Amisulpride group +1.2±6.5 KgHaloperidol group -0.4±5 Kg p<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 H1 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

Clozapine 1994 – 2/2002 389

Olanzapine 1994 – 2/2002 289

Risperidone 1994 – 2/2002 138

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 2001Granfrancesco et al 2003

• Ziprasidone appear to be associated with the lowest levels of hyperglycemia

Kato and Goodnick 2001Simpson 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 diabetesClozapine +

Olanzapine +

Risperidone D

Quetiapine D

Ziprasidone -

Aripiprazole -

+ = increased

- = no effect D = discrepant results

Consensus conference on antipsychotic drugs and obesity and diabetes 2004

Possible mechanism(s) of diabedogenic action of atypical

antipsychotics • D2 dopanime receptor blocking in certain

areas of the brain e.g. hypothalamus

• 5-HTIA and 5HTT2C serotonin receptors and H1 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 2001Mir 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 +

Risperidone D

Quetiapine D

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

Baseline 4 weeks 8 weeks 12 weeks

Quarterly Annually Every 5 years

Personal/family history

X X

Weight (BMI) X X X X X

Blood pressure X X X

Fasting plasma glucose

X X X

Fasting lipid profile

X X X X

* 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?