a meta-analysis, of the efficacy of second generation antipsychotics (sgas) 142 controlled studies...
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• 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?