Heeding Cardiometabolic Adverse Effects of Psychotropics · Heeding Cardiometabolic Adverse Effects of Psychotropics Jess G. Fiedorowicz, M.D., Ph.D. Departments of Psychiatry, Epidemiology,

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Heeding Cardiometabolic Adverse Effects of Psychotropics

Jess G. Fiedorowicz, M.D., Ph.D.Departments of Psychiatry,

Epidemiology, and Internal Medicine,François M. Abboud Cardiovascular Research Center,

Obesity Research and Education Initiative,Iowa Neuroscience Institute

The University of Iowa10/13/2017

Disclosures

Dr. Fiedorowicz is supported by the National Heart, Lung, and Blood Institute (2P01HL014388-41A1), the National Center for Advancing Translational Science (U54TR001356 and UL1TR002345), National Institute of Mental Health (R01MH111578), and Myriad Genetics, Inc (research and consulting).

Dr. Fiedorowicz has no conflicts of interest to disclose.

Goals

• To appreciate the associations between psychiatric disorders and cardiovascular disease

• To identify medications associated with metabolic syndrome

• To recognize potential magnitude of these side-effects and clinical relevance thereof

• Begin evidence based treatment when necessary.

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Risk of Heart Disease

Those with mood disorders had twice the risk

of heart disease in the World Mental Health

Surveys.

Ormel et al. General Hospital Psychiatry 2007.

Risk of Heart Disease

Fiedorowicz JG et al. J Psychosom Res 2011.

In the representative NCS-R (N=5,692)

• Vascular disease equivalents and risk factors were more common in those with mood disorders, particularly women with bipolar disorder

• This finding was independent of sociodemographic and clinical variables as well as several traditional risk factors for vascular disease: - diabetes mellitus - family hx of heart disease- high blood pressure - obesity -smoking

Mortality

In representative age samples, patients with schizophrenia and bipolar disorder have approximately twice the risk of dying. Most of the excess mortality occurs secondary to suicide and vascular disease.

Weiner M et al. Annals of Clinical Psychiatry 2010.Saha S et al. Archives of General Psychiatry 2010.

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0

500

1000

1500

2000

2500

Excess Deaths

Infectious

Cancer

Endocrine

Nervous/Mental

Vascular

Respiratory

GI/GU

Urogenital

Accidents

Suicide

Homicide

Undetermined

Mortality

Osby U et al. Archives of General Psychiatry 2001.

VA

SC

UL

AR

54,000 former inpatients with mood disorders from Sweden. All cause mortality SMR 2.6 in bipolar disorder and 2.0 in unipolar major depression. Excess death by cause:

SU

ICID

E

Life Expectancy

• Life expectancy was assessed in national cohort of 6.5 million Swedish adults, 6,618 identified with bipolar disorder from outpatient or inpatient dx.

• Men: -9 years• Women: -8.5 years

• Adjusting for age, sociodemographics and substance use HR 2.1 (95% C.I. 1.9-2.5) for women and 1.7 (95% C.I. 1.5-1.8) for men

Crump C et al. JAMA Psychiatry 2013.

Life Expectancy

• More interesting, elevated risk for risk factors not as high as mortality (diabetes 1.7 women, 1.6 men; CVD 1.3 women, 1.2 men). No ↑ in hypertension, lipid disorders. Suggested risk factors under-identified.

• When stratified by risk factors, mortality risk drops significantly, leading to conclusion: “…better provision of primary care may effectively reduce premature mortality…”

Crump C et al. JAMA Psychiatry 2013.

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Life Expectancy• Life expectancy at 15 y/o was compared for

those hospitalized with serious mental disorders in Denmark, Finland, and Sweden (1987-2006).

• Men: -20 years• Women: -15 years

Wahlbeck K et al. Br J Psychiatry 2011.

Medical Co-morbidity Rx

Patients with psychiatric disorders are less likely to be monitored for and to receive adequate treatment of medical conditions, such as risk factors for vascular disease.

Vahia IV et al. Psychiatric Services 2008.Kreyenbuhl J et al. Journal of Nervous and Mental Disease 2006.Kilbourne AM et al. Journal of Affective Disorders 2007.

Adverse Effects of Treatments

Abosi O et al. Horm Mol Biol Clin Invest Submitted.

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Weight Gain

Adolescent Data

Meta-analysis of 21 studies (2,455 pts) of drug vs. placebo in children and adolescents:

• Olanzapine 3.45 kg (95% C.I. 2.93-3.98)

• Risperidone 1.77 kg (95% C.I. 1.35-2.20)

• Aripiprazole 0.94 kg (95% C.I. 0.65-1.24)

Mean study duration of 9 weeks.

Almandi NB et al. Pediatric Drugs 2013.

Individual Variability

Antipsychotic naïve youth treated with risperidone for 3 months

Correll CU et al. Trends in Molecular Medicine 2011.

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Antipsychotic Comparisons

Adapted from Lieberman et al. NEJM 2005.

Head-to-head Comparisons

Short-term (≤12 weeks) studies:

Clozapine > Risperidone (MD 3.2 kg)

Olanzapine > Risperidone (MD 2.5 kg)

Olanzapine > Quetiapine (MD 2.7 kg)

Olanzapine > Ziprasidone (MD 2.5 kg)

Rummel-Kluge C. et al. Schizophr Res 2010.


Long-term (>12 weeks) studies:

Clozapine > Risperidone (MD 1.9 kg)

Olanzapine > Risperidone (MD 2.5 kg)

Olanzapine > Quetiapine (MD 2.7 kg)

Olanzapine > Aripiprazole (MD 3.9 kg)

Olanzapine > Ziprasidone (MD 4.4 kg)


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Some Head-to-head Comparisons

Weight gain:

Valproate (1.1 kg) vs. Lithium (0.2 kg) in 12 weeks

Quetiapine (3.3 kg) vs. Lithium (1.0 kg) in 12 weeks

Bowden Cl. et al. J Clin Psychiatry 2005.

Bowden CL et al. Int Clin Psychopharmacol 2010.

Individual Variability Reminder

Even with aripiprazole, 8-11% of patients may gain >7% of baseline weight after four weeks of treatment.

All antipsychotics carry potential for extreme weight gain in vulnerable individuals!

De Hert M et al. et al. Nat Rev Endocrinol 2012.

Gentile S. Drug Saf 2006.

Antidepressants

Mirtazapine greatest risk

TCAs and MAOIs > SSRIs

SSRIs weight loss acutely (< 12 weeks) with some weight gain thereafter.

- In some studies more weight gain with paroxetine than sertraline or fluoxetine

Bupropion associated with weight loss

Masand PS et al. Ann Clin Psychiatry 2002.Fiedorowicz JG et al. Vascular Effects of Treatments 2011.

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Antidepressants – Meta-analysis

Seretti A et al. J Clin Psychiatry 2010.

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Effect on Weight Change During Medium and Long-term Treatment (≥4 mo)

Antidepressants – Long-term

Claims data on 22,610 patients for weight changes 3-12 months.

Blumenthal SR et al. JAMA Psychiatry 2014.



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Psychotropic Propensity for Weight Gain


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Risk for Weight Gain

Greatest risk of weight gain in:

- Those with lower baseline BMI (for short-term, not long-term weight gain)

- Higher BMI in parents

- Higher BMI in patients (long-term)

- Female gender

- Younger age

Gebhardt S et al. J Psychiatr Res 2009.

Clinical Relevance of Weight Changes

Clinical relevance is not straightforward.

Large weight gains (3 to 5 units BMI) in those with Class II or greater obesity associated with 33-53% mortality increase independent of other risk factors.

Myrskyla M et al. Epidemiology 2009.

Identifying Those At Risk

Early weight gain of >5% in 1 month is best predictor of long-term weight gain.

Vandengerghe F et al. J Clin Psychiatry 2015.

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Dyslipidemia

Dyslipidemia Players

Clozapine and olanzapine are known to cause hypertriglyceridemia and hypercholesterolemia (esp. triglycerides).

Olanzapine and quetiapine > risperidone and haloperidol, ziprasidone, aripiprazole (not studied with quetiapine)

Risperidone > aripiprazole and ziprasidone

Olfson M et al. Am J Psychiatry 2006.Duncan EJ et al. Clin Psychopharmcol 2009.

Rummel-Kluge C et al. Schizphr Res 2010.

Dyslipidemia Magnitude

Study of medication-naïve participants x 1 year with haloperidol, risperidone, or olanzapine:

- 36.6 mg/dL increase in triglycerides (2 mmol/L)

- 22.2 mg/dL increase in total cholesterol

Case reports of doubling in triglycerides in 2 weeks!

Perez-Iglesias R et al. Schizphr Res 2009.

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Dyslipidemia Impact

Changes in triglycerides of 1 mmol/L (88 mg/dL) associated with mortality increases of 18% in women and 8% in men independent of other risk factors.

Changes in cholesterol of 36 mg/dL associated with twice the risk of CV mortality.

Nordestgaard BG et al. JAMA 2007.

Stamler J et al. JAMA 2000.

Diabetes Mellitus

Risk with Antipsychotics

Bobo WV et al. JAMA Psychiatry 2013.

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Risk with Antipsychotics

Bobo WV et al. JAMA Psychiatry 2013.

Agents Most Implicated

60% greater risk of new-onset type 2 diabetes mellitus in new users of olanzapine, risperidone, and quetiapine relative to haloperidol

Divalproex consistently associated with insulin resistance.

Pylvanen V et al. Epilepsia 2002.

Lambert BL et al. Am J Epidemiol 2006.


Glucose Change:

Olanzapine > Quetiapine, Risperidone, Aripiprazole, and Ziprasidone


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Diabetes Mechanisms

Indirect Mechanisms

Fig. 2. Central receptor blockade by atypical antipsychotics in the VMHN and the PVN respectively, could cause adiposity by increasing food intake and decreasing energy expenditure. A high SOCS-3 level might lead to leptin resistance. Adiponectin and TNFα influence glucose homeostasis.

Starrenburg FCG et al. Eur Psychiatry 2009.

Direct Mechanisms

Fig. 3. Atypical antipsychotics may inhibit insulin secretion in pancreatic β-cells through inhibition of M3-receptor mediated insulin release. Furthermore antagonism of the 5HT1a-receptor might decrease glucose sensitivity, whereas α2-receptor antagonism might stimulate insulin release, both resulting in disturbance of glycemic control.


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Direct Mechanisms

Fig. 4. Atypical antipsychotics may inhibit glucose uptake in skeletal and liver cells through inhibition of the GLUT glucose transporter.


Elevated Blood Pressure

Agents Implicated

Increases in blood pressure have consistently been reported with:

- Stimulant medications (~4 mm Hg)

- Atomoxetine (~ 2 mm Hg)

- Antidepressants which inhibit norepinephrine reuptake (venlafaxine, duloxetine, tricyclic antidepressants)


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Antipsychotics

Hypertension has been associated several antipsychotics:

- Aripiprazole, clozapine, olanzapine, risperidone



Yasui-Furokori N and Fujii. Neuropsychiatric Disease and Treatment 2013.


Yasui-Furokori N and Fujii. Neuropsychiatric Disease and Treatment 2013.

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Magnitude of ChangeFor venlafaxine and imipramine, a 2-3 mm Hg

difference in systolic blood pressure.

Although small, even within the usual range of blood pressure down to 115/75, changes of this magnitude may be associated with a 15-20% higher risk of CV mortality.

More extreme changes may be seen in vulnerable individuals.

Lewington S et al. Lancet 2002.Thase ME. J Clin Psychiatry 1998.

Monitoring

Divalproex Monitoring

From guidelines: CBC and hepatic function every 6 months.

Data above would suggest:

Consider monitoring BMI and fasting glucose (or hemoglobin A1c)

APA Practice Guidelines.

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Antipsychotic Monitoring

BMI: Baseline, 4, 8, 12 weeks, then quarterly

Fasting glucose: Baseline, 12 weeks, then annually

Lipid profile: Baseline, 12 weeks, every 2-5 years if normal

Prabhakar M et al. www.athero.org 2009.

Conclusions

• Psychotropic medications may have a variety of adverse cardiometabolic effects.• There is considerable individual variability in propensity to have cardiometabolic adverse effects • Routine clinical care should include monitoring of these adverse effects

Management

• To manage may consider- Using lower doses or alternative agents- Address diet, physical activity- Change regimen with early weight gain

(first four weeks for antipsychotics)

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Adjunctive Therapies

Metformin Efficacy

Fiedorowicz JG et al. Current Psychiatr Rep 2012.

Metformin Dosing

Studies in antipsychotic-associated weight gain have used doses of 750-2250 mg/day. Only one study exceed 1700 mg/day (Baptistaet al. 2007).Best results when combined with lifestyle intervention (Wu et al. 2008).

Fiedorowicz JG et al. Current Psychiatr Rep 2012.v

Baptista T et al. Schizophr Res 2007.

Wu RR et al. JAMA 2008.

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Metformin Tolerability

Common side-effects include:- GI: Diarrhea, N/V, abdominal discomfort- Weakness

Less common- Metallic taste in mouth

Fiedorowicz JG. Unpublished Review.

Metformin Monitoring

Periodic monitoring of renal function, glucose and CBC.

Rare risk of lactic acidosis (contraindicated if serum creatinine ≥ 1.4 in women or 1.5 mg/dL in men, CHF).

Vitamin B12


Topiramate Efficacy


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Topiramate Dosing

Can titrate in 25-50 mg increments to 100 mg bid. Doses in obesity studies range from 50-200 mg/day.


Topiramate Tolerability

As of 2013, more than 9,000 subjects have been enrolled in RCTs of topiramate, alone or in combination, for weight loss or binge eating associated with obesity. 10% more w/d on topiramate than placebo.- Paresthesias (metabolic acidosis), sedation,

decreased concentration- Acute angle closure glaucoma and

nephrolithiasis (Micromedex 1-3%), Stevens-Johnsons


Naltrexone and Bupropion

Greenway FL et al. J Clin Endocrinol Metab 2009.

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References (40)Abosi O, Lopes S, Schmitz S, Fiedorowicz JG. Cardiometabolic effects of

psychotropic medications. Hormone Molecular Biology and Clinical Investigation, Submitted.

American Psychiatric Association Practice Guideline for the Treatment of Patients with Bipolar Disorder, 2nd Edition, 2002.

Baptista T, Rangel N, Fernandez V et al. Metformin as an adjunctive treatment to control body weight during olanzapine administration: a multicentric, double-blind, placebo-controlled trial. Schizophr Res 2007; 93(1): 99-108.

Blumenthal SR, Castro VM, Clements CC et al. An electronic health records study of long-term weight gain following antidepressant use. JAMA Psychiatry 2014; 71(8): 889-896.

Bobo WV, Cooper WO, Stein CM, et al. Antipsychotics and risk of Type 2 Diabetes Mellitus in Children and Youth. JAMA Psychiatry 2013; 70(10): 1067-1075.

Bowden CL, Mosolov S, Hranov L, et al. Efficacy of valproate versus lithium in mania or mixed mania: a randomized, open 12-week trial. Int ClinPsychopharmacol 2010;25(2):60-67.

Bowden CL, Grunze H, Mullen J, et al. A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J Clin Psychiatry 2005;66(1):111-121.

Correll CU, Lencz T, Malhotra AK. Antipsychotic drugs and obesity. Trends in Molecular Medicine 2011; 17(2): 97-107.

Crump C, Sundquist K, Winkleby M, Sundquist J. Comorbidities and mortality in bipolar disorder: A Swedish national cohort study. JAMA Psychiatry 2013; 70(9): 931-939.

Duncan EJ, Woolson SL, Hamer RM, Dunlop BW. Risk of lipid abnormality with haloperidol, olanzapine, quetiapine, and risperidone in a Veterans Affairs population. Int Clin Psychopharmacol 2009;24(4):204-213.

Fiedorowicz JG, Metz NS, Prabhakar M. Adverse vascular effects of medications used in the treatment of bipolar disorder (book chapter) in Plunkett JM (ed.) Bipolar disorders: Causes, Diagnosis, and Treatment. Nova Science Publishers, 2011, ISBN: 978-1-61122-955-4.

Fiedorowicz JG, He J, Merikangas KR. The association between mood and anxiety disorders with vascular disease and risk factors in a nationally-representative sample. J of Psychosom Res 2011; 70(2): 145-154.

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Gebhardt S, Haberhausen M, Heinzel-Gutenbrunner M, et al. Antipsychotic-induced body weight gain: predictors and a systematic categorization of the long-term weight course. J Psychiatr Res 2009;43(6):620-626.

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Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. Jama 2007;298(3):299-308.

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Heeding Cardiometabolic Adverse Effects of Psychotropics · Heeding Cardiometabolic Adverse Effects of Psychotropics Jess G. Fiedorowicz, M.D., Ph.D. Departments of Psychiatry, Epidemiology,