more than we bargained for: metabolic side effects …...more than we bargained for: metabolic side...
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More than We Bargained For:Metabolic Side Effects of
Antipsychotic Medications
Michael D. Jibson, MD, PhDProfessor of PsychiatryUniversity of Michigan
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Disclosure
Company Activity AmountUp-to-Date Authorship $3,254
In the past 12 months I have received the following:
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Learning Objectives
Participants will:
• Recognize the specific metabolic risks of antipsychotic medications
• Classify first and second generation antipsychotics according to degree of risk for metabolic side effects
• List potential interventions to reduce metabolic side effects
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Metabolic Side Effects
• Weight gain• Hyperglycemia• Elevated LDL
cholesterol
• Elevated triglycerides• Decreased HDL
cholesterol
Use of all antipsychotics is associated with metabolic dysregulation
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Glucose Dysregulation
Glucose dysregulation associated with antipsychotic medications is not true type 2 diabetes
• Moderately dependent on weight gain
• Not exclusively driven by insulin resistance
• Higher rate of metabolic complications
• Ketoacidosis
• Hyperosmotic coma
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Weight Gain
Weight gain appears to be driven by multiple factors
• Increased appetite
• Dysregulation of glucose metabolism
• Baseline elevated risk
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Baseline Risk
• Prevalence of obesity and diabetes in patients with schizophrenia is 1.5-2.0 times higher than the general population
• No studies on obesity and diabetes in adult drug-naïve schizophrenia patients are available
• Life expectancy with schizophrenia is 20 years less than the general population
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Relative Risk
• Increased risk of weight gain and metabolic complications with antipsychotics are not dependent on diagnosis
• Comparable degrees of weight gain are seen in nonschizophrenic patients
• Schizophrenia patients experience combined risk of the diagnosis and the medication
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Child/Adolescent Risk
• Risks of weight gain and other metabolic complications are at least as great in children and adolescents as in adults
• Stimulants given for ADHD do not reverse the weight gain
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Medication Classes
Risk is not unique to newer medications
• Conventional, low potency antipsychotics (eg, chlorpromazine) carry moderate-high risk
• Conventional , high potency antipsychotics (eg, haloperidol) carry low-intermediate risk
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76543210
-1-2-395
% C
onfid
ence
Inte
rval
for W
eigh
t Cha
nge
Meta-analysis of Antipsychotic-related Weight GainEstimate at 10 Weeksa
Allison DB, et al., Am J Psychiatry 1999;156:1686
Weight (kg)
a Quetiapine weight gain estimated at 6 weeks
15
10
5
0
-5
Weight (lb)
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Metabolic Effect Size (48 wks)
High Risk Low RiskAverage weight gain (lbs) 12.3 1.1
Pts gaining >7% of baseline weight 64% 10%
Average increase in fasting glucose (mg/dl)
4.2 0
Patients developing high fasting glucose (>126 mg/dl)
16.3% 0
Average change in total cholesterol (mg/dl)
+5.6 -5.0
Pts gaining >40mg/dl total cholesterol 32.9% 0
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Risk of Metabolic Complications
Relative risk of medications
• Clozapine/Olanzapine
• Low potency first generation antipsychotics
• Quetiapine/Risperidone/Paloperidone/ Iloperidone/Asenapine
• High potency first generation antipsychotics
• Aripiprazole/Lurasidone/Ziprasidone
Ris
k
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Patient Monitoring
ADA et al., Diabetes Care 2004; 27:596
Baseline 4 wks 8 wks 12 wks Quarterly Annual 5 yrs
Personal/family history X X
Weight (BMI) X X X X X
Waist Circumference X X
Blood pressure X X X
Fasting plasma glucose X X X
Fasting lipid profile X X X
Recommended monitoring for patients on atypical antipsychotics
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Patient Monitoring
Metabolic monitoring
• 46% of adults at high risk for metabolic side effects received a moderate-high risk drug
• Only 45% of adults on moderate-high risk drugs get monitoring
• Only 31% of children on moderate-high risk drugs get monitoring
Essock SM, et al. Psychiatric Serv 2009; 60:1595; Morrato EH et al. Arch Ped Adol Med 2010; 164:344
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Metabolic Syndrome
Men Women
Waist Circumference >40 in >35 in
Fasting Glucose >126 >126
Elevated Triglycerides >150 mg/dl >150 mg/dl
Decreased HDL Cholesterol <40 mg/dl <50 mg/dl
Hypertension >130/85 >130/85
At least 3 of the following:
Adopted from L. John Schloss, MD, with permission
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Treatment Options
Diet and Exercise
• Avoid changes in medication and dose
• Work as effectively as in the general population
but…
• Work no more effectively than in the general population
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Treatment Options
Change Medication
• Wide range of risk among medications
• Benefits have been shown in controlled studies
but…
• Patients respond differentially to the medications
• Switches carry elevated risk of relapse
• Other side effects may be more important
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Treatment Options
Combine Medications
• Combinations of high- and low-risk antipsychotics show moderate risk reduction
• Consider combinations if patient preferentially responds to high-risk medication
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Treatment Options
Reduce Dose
• Moderate evidence of effectiveness
• Avoids medication switch
but…
• Metabolic effects are not entirely dose dependent (eg, olanzapine)
• Relapse is associated with dose reduction
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Treatment Options
Metformin*
• Several small studies show moderate benefit
• Allows continuation of current antipsychotic and dose
• but…
• Larger, population-based studies are lacking
• Effect size is moderate
*Metformin is not FDA approved for weight loss
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Metformin Treatment
Wu, et al. JAMA 1999; 299:185
• 128 first-episode schizophrenia patients
• Clozapine, olanzapine, risperidone, or sulpiridecontinued throughout study
• Patients had gained 10% of body weight in 1st year of treatment
• Compared metformin 750 mg/day, lifestyle change, and placebo
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Metformin Treatment
56
58
60
62
64
66
68
Kgs
Wu et. JAMA 2008; 299:185
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Treatment Recommendations
1. Monitor metabolic parameters
2. Encourage diet and exercise
3. Consider alternative antipsychotic, alone or in combination
4. Consider dose reduction
5. Consider metformin