Transcript athens-2005-s2-lykouras - World Psychiatric Association

• 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 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
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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 1830% 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
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Quetiapine
Risperidone
Ziprasidone
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+/-
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
Flupenthixol
8%
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 Kg
Haloperidol 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 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
Clozapine
Olanzapine
Risperidone
Quetiapine
Ziprasidone
Aripiprazole
+ = increased
Risk for diabetes
+
+
D
D
- = 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 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
Risperidone
Quetiapine
Aripiprazole
Ziprasidone
+ = inversed effect
- = no effect
D = discrepant results
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+
D
D
-
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 lipinglowering therapy or considered for
switch to a less offending agent if
possible
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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
Weight
(BMI)
X
Blood
pressure
X
X
X
Fasting
plasma
glucose
X
X
X
Fasting
lipid
profile
X
X
X
X
X
X
X
X
X
* More frequent assessments may be warranted based on clinical status
ADA, APA 2004
How should the patients be treated
if metabolic disturbances develop?
• 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