www.mghcme.org

Managing Side Effects: Antipsychotic Agents

David C. Henderson, MD Associate Professor of Psychiatry and Epidemiology

Massachusetts General Hospital Harvard Medical School

Harvard school of Public Health

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David C. Henderson, MD

Forum Pharmaceuticals, Norvartis Research grant

Global Psychiatry CME Speaker Fee

Mclean Hospital Speaker Fee

Reckitt Benckiser Advisory Board

“My spouse/partner and I have the following relevant financial relationship with a commercial interest to disclose:”

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APA Treatment Selection Guide

ARI & ZIP Weight or metabolic

YES Recurrent nonadherence

YES, except RIS Prolactin sensitivity

YES, except RIS EPS sensitivity

YES YES Tardive dyskinesia

YES Hostility/aggression

YES Suicide risk

YES 1st episode

Group 4: Long Acting

Group 3: CLZ

Group 2: 2nd Generation

Group 1: 1st Generation

Patient Profile

Lehman AF et al. Am J Psychiatry. 2004;161(suppl 2):1-51. Reprinted with permission from the American Journal of Psychiatry (Copyright 2004). American Psychiatric Association.

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Usually gradual Incomplete efficacy

Usually fast Usually effective Response to adjunctive therapy?

No* Yes Response to dose lowering?

Low High Specificity to antipsychotic?

Yes Yes Physical findings?

Obesity EPS

*Within doses prescribed for schizophrenia; most studies do not show dose relation; those that do show statistical significance would not usually be clinically significant. Newcomer JW. CNS Drugs. 2005;19(suppl 1):1-93; Weiden PJ. Postgrad Med. 2006 Special Report (September):627-644; Weiden PJ. J Psychiatri Pract. 2007;13-24.

Treatment Approach Varies by Side Effect: Example of EPS Vs Obesity

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Frequency of Side Effects: Atypical Antipsychotics

Side Effect Aripiprazole Clozapine Olanzapine Quetiapine Risperidone Ziprasidone

Weight gain ± +++ +++ + + ±

Extrapyramidal symptoms

± to + ± ± to +* ± ± to +* ± to +*

Tardive dyskinesia ± (?) ± ± (?) ± (?) ± to + ± (?)

Diabetes mellitus ± +++ +++ + + ±

Dyslipidemia ± +++ +++ ++ + ±

QTC prolongation ± ++ + + + ++

Decrease in orthostatic BP

± +++ + ++ ++ ±

Elevated prolactin level

± ± ± ± +++ ±

Somnolence ± +++ + ++ ± ±

McIntyre RS, Konarski JZ. J Clin Psychiatry. 2005;66(suppl 3):28

* = dose related; (?) = not clearly established; ± = no to minimal, + = occasional, ++ = frequent, +++ = substantial occurrence of side effect compared with placebo rates

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Rank Order of Side Effects Eliciting Moderate-to-Severe Distress

4037.3

33.230.8

18.8 18.4

0

10

20

30

40

50

Akinesia Weight Gain Anticho- linergic

Sexual Problems

Muscle Rigidity

Akathisia

Patie

nts R

epor

ting*

(%)

(N=9

9)

*Reporting when side effect is present. Weiden PJ, Miller AL. J Psychiatr Prac. 2001;7:41-47.

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Adverse Events Caused by Blockade of Other, Nondopamine Receptors

Satiety blockade 5-HT2c

[Less EPS] 5-HT2A

Hypotension α1-adrenergic

Sedation, weight gain H1

Dry mouth, constipation, tachycardia blurred vision, urinary retention

M2-5 (peripheral)

Memory, cognition M1 (central)

Adverse Events Receptors

Gardner DM et al. CMAJ. 2005;172:1703-1711; Shayegan DK, Stahl SM. CNS Spectr. 2004;9(10 suppl 11):6-14; McEvoy JP, Freter S. Comp Psychiatry; 1989;30:135-138; Mori K et al. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:659-665; Sweeney JA et al. Psychiatr Res. 1991;37:297-308; Velligan DI et al. Schizophren Res. 2002;53:239-248.

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Anticholinergic Load As a Cause of Cognitive Impairment in Schizophrenia

*P<.05; †P<.01. Minzenberg et al. Am J Psychiatry. 2004;161:116-124.

*

† †

0.15 0.16 0.14

0.24

0.35 0.35

0

0.1

0.2

0.3

0.4

Pharmacologic Estimate Clinical Estimate

Corr

elat

ion

"General" IQ

Attention

Memory

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Conventional Antipsychotic Side Effects at Therapeutic Doses

• Extrapyramidal Side Effects (EPS) – Rigidity – Bradykinesia – Tremor – Akathisia

• Tardive Dyskinesia (TD) – Late-onset movements of the tongue, face,

neck, trunk and/or limbs

• Increased Prolactin – Galactorrhea – Amenorrhea

Practice guideline for the treatment of patients with schizophrenia, 2nd edition. APA; 2004. Available at: http://www.psych.org/psych_pract/treatg/pg/SchizPG-Complete-Feb04.pdf. Accessed March 13, 2007.

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Annualized TD Risk With Antipsychotics

Correll CU et al. Am J Psychiatry. 2004;161(3):414 TD = tardive dyskenesia

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Sexual Dysfunction and Antipsychotics

• Antipsychotics can affect sexual dysfunction directly or indirectly, especially in men

• Directly – Binding to dopaminergic, histaminergic,

cholinergic, and α-adrenergic receptors may inhibit motivation and reward, increase sedation, and reduce peripheral vasodilation

• Indirectly – D2 receptor blockade in tuberoinfundibular tract can

increase serum prolactin levels, which in turn can affect sexual function

Baggaley M. Hum Psychopharmacol. 2008;23(3):201

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Prolactin and Sexual Dysfunction During Quetiapine and Risperidone Treatment

Prolactin (ng/mL) 13.8 + 17.9 57.9 + 39.7 .000

Libido 16% 36% .05

Erection 11% 33% .05

Lubrication 6% 38% .05

Orgasm 5% 30% .01

Ejaculatory dysfunction 14% 29% .18

Quetiapine Risperidone (n=25) (n=26) P

Knegtering R et al. J Clin Psychopharmacol. 2004;24(1):56

Query: Prolactin line of chart has odd number placement. Is +17.9 and +39.7 the CI? Editorial

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Mortality in Schizophrenia

Reduced Life Expectancy in Schizophrenia

Antipsychotic-related weight gain and obesity, impaired glucose tolerance and new onset diabetes, hyperlipidemia, and cardiovascular disease

Comorbidities

- Diabetes Mellitus - Cardiovascular disease - Cancer

Lifestyle Choice

- Unhealthy Diet - Lack of physical activity - Excessive Smoking - Alcohol Abuse

High risk of Suicide and accidents

Physical illnesses diagnosed late and

treated insufficiently

The overall mortality rate is two to three times as high for patients with schizophrenia as it is for the general population, resulting in a life expectancy of about 20 years less of the general population* *Laursen TM, et al. Annual review of clinical psychology 2014; 10: 425-48

www.mghcme.org 14

Henderson et al, Lancet Psychiatry 2014

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Cumulative Effect of Small Daily Errors in Energy Balance

Energy expenditure

(kcal/y)

Energy intake (kcal/y)

1 million

1 million

0

Excess intake (% total) Excess intake (kcal/d)

0 0.5 1 5 12 kcal/d 25 kcal/d 125 kcal/d

Change in body fat (kg/year)

0 2 4 6

Rosenbaum M et al. N Engl J Med. 1997;337:396-407.

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Different Metabolic Syndrome Definitions

Metabolic syndrome if *≥3 criteria are met; †≥2 criteria are met in the presence of obligatory waist criterion; or ‡on antihypertensive drugs; or §on antihyperglycemic drugs. ATP = Adult Treatment Panel; ATPA = Adult Treatment Panel–adjusted; IDF = International Diabetes Federation. NCEP ATPIII. JAMA. 2001;285:2486-2497; Grundy SM et al. Circulation. 2004;110:227-239; International Diabetes Federation. Available at: http;//www.idf.org. Accessed April 20, 2007.

Men: <40 Women: <50

Men: <40 Women: <50

Men: <40 Women: <50

HDL-C (mg/dL)

≥100 ≥100 ≥110 Blood glucose (mg/dL)§

≥150 ≥150 ≥150 TG (mg/dL)

≥130/85 ≥130/85 ≥130/85 BP (mm Hg)‡

Men: ≥94/37 Women: ≥80/31

OBLIGATORY

Men: >102/40 Women: >88/35

Men: >102/40 Women: >88/35

Waist (cm/inch)

IDF† ATP III A* ATP III* Criteria

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Subcutaneous Fat

Abdominal Muscle Layer

Intra-abdominal Fat

Visceral Adiposity: The Critical Adipose Depot

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Prevalence of the metabolic syndrome in adults: NHANES III. Arch Intern Med 2003;163:427-436.

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Ethnic Differences in Triglyceride Levels and HDL-Cholesterol

• Black adults and children have a better lipid profile- lower triglyceride and higher HDL

• The effects of insulin resistance on lipid profile were the same in whites and blacks, TG should be higher and HDL lower

• Differences in diet do not account for this • Lipoprotein lipase (LPL) are higher and hepatic lipase are

lower in blacks • Insulin resistance (IR) does not seem to impair LPL in blacks

so can clear triglyceride with IR • May explain the lower rates of metabolic syndrome and

criteria not set to identify high risk for DM and cardiovascular disease.

Sumner AE: J Pediatri 2009; 155:S7.e7-11; Gaillard et al. Ethn Dis 2009 Spring:19:S2-1-7

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Antipsychotic-Associated Differences in Insulin Sensitivity

*P<.001; non-obese patients with schizophrenia, matched on BMI (P=.81), but not leptin (P<.001); hip-waist ratio (P=.04) or subscapular skinfold (P=.049). IVGTT = intravenous glucose tolerance test. Henderson DC et al. Arch Gen Psychiatry. 2005;62:19-28.

Insulin Sensitivity By Medication IVGTT With Minimal-Model Analysis

Insu

lin S

ensi

tivity

(X

10-

4 • min

-1 • m

l-1)

0

5

10

15

CLZ (n=12)

OLZ (n=12)

RIS (n=12)

3.2 4.5

11.7*

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Association of Insulin Resistance With CV Risk Factors and Atherosclerosis

AGEs = advanced glycosylation end products; VCAM = vascular cell adhesion molecule; NO = nitric oxide; PAI = plasminogen activator inhibitor; tPA = adenosine triphosphatase; CRP = C-reactive protein; IL = interleukin.

Atherosclerosis

Glucose Intolerance

•AGEs Hypertension

Dyslipidemia •Low HDL

•Small, dense LDL particles

•Hypertriglyceridemia

Endothelial dysfunction •VCAM, E-selectin

•NO

Impaired thrombosis

•PAI-1 •tPA

Inflammation •CRP • IL-6

Insulin resistance

McFarlane SI et al. J Clin Endocrinol Metab. 2001;86:713-718.

Obesity

www.mghcme.org

.0075 11.2 21.7 .9635 14.2 14.1 Glucose criterion

.0001 26.8 46.9 .0001 31.1 47.2 BP criterion

.0001 36.3 63.3 .0001 31.9 48.9 HDL criterion

.0001 19.6 42.2 .0001 32.1 50.7 Triglyceride criterion

.0001 57.0 76.3 .0001 24.8 35.5 Waist circumference criterion

.0001 25.1 51.6 .0001 19.7 36.0 Metabolic syndrome prevalence

P NHANES III (%) (N=180)

CATIE (%) (N=180) P NHANES (%)

(N=509) CATIE (%) (N=509)

Women Men

CATIE = Clinical Antipsychotic Trials of Intervention Effectiveness; NHANES = National Health and Nutrition Examination Survey. McEvoy JP et al. Schizophr Res. 2005;80:19-32. Copyright Schizophrenia International Research Society 2005.

Fasting CATIE vs Matched NHANES III Subjects

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Incidence of metabolic disorders in children receiving second-generation antipsychotic vs albuterol treatment

Morrato EH, Nicol GE, Maahs D, Druss BG, Hartung DM, Valuck RJ, Campagna E, Newcomer JW. Metabolic screening in children receiving antipsychotic drug treatment. Archives of Pediatrics & Adolescent Medicine. In press.

CI: confidence interval. * indicates p<0.05 and ** indicates p<0.01 for the comparison between the antipsychotic and albuterol cohorts. Data from California, Missouri, and Oregon state Medicaid programs of children initiating drug treatment in 2005. Antipsychotic and albuterol users had no recognized diabetes or dyslipidemia at the start of therapy. Metabolic disturbances were ascertained for six months after the index start date.

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Henderson DC et al. J Clin Psychiatry. 2007;68:533-541.

New-onset Diabetes Mellitus Known Diabetes Mellitus

New-Onset and Known Diabetes Presenting as Diabetic Ketoacidosis in Schizophrenia Patients Treated With

Atypical Antipsychotics

0

2

4

6

8

10

12

14

16

Mea

n H

bA1c

(%)

0

200

400

600

800

1000

1200

Mea

n G

luco

se (m

g/dL

)

n=11 n=10 n=11 n=10

Mean Glucose Mean HbA1c

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Odds Ratios of Substandard Medical Care in Mentally Ill Outpatients With Diabetes

Data from 313,586 veteran outpatients with diabetes, 25% of whom had mental disorders. SUD = substance use disorder. Frayne et al. Arch Intern Med. 2005;165:2631-2638. Copyright © 2000 American Medical Association. All rights reserved.

Depression

Anxiety

Psychosis

Manic

SUD

Personality

0.8 1.0 1.2 1.4 1.6 0.8 1.0 1.2 1.4 1.6 0.8 1.0 1.2 1.4 1.6 0.8 1.0 1.2 1.4 1.6 0.8 1.0 1.2 1.4 1.6 0.8 1.0 1.2 1.4 1.6 No HbA1c Test Done

No LDL Test Done

No Eye Exam Done

No Monitoring Poor Glycemic Control

Poor Lipemic Control

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Antipsychotic-Induced Weight Gain: A Comprehensive Research Synthesis

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Assessment of Early Weight Gain: A Simple Predictive Tool for Overall Weight-Gain Risk

Age: rapid-weight gain (RWG): 35.6 < non–rapid-weight gain (NRWG): 39.3, P<.0001; BMI: RWG, 23.9 < NRWG, 26.4, P<.0001. Kinon BJ et al. J Clin Psychopharmacol. 2005;25:255-258. Copyright © 2005 Lippincott Williams & Wilkins. All rights reserved.

RWG: ≥7% Δ at 6 weeks NRWG: <7% Δ at 6 weeks NRWG: 0% < Δ< 7% at 6 weeks NRWG: ≤0% Δ at 6 weeks

n=183, 15%

n=615

n=274

n=889, 85%

0 10 20 30 40 50 60

6 Weeks

LS M

ean

Wei

ght Δ

(kg)

Week

14 12 10

8 6

4 2 0

–4

–4

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Weight Gain with Combination Treatments: Quetiapine and Divalproex

0

1

2

3

4

5

Mea

n W

eigh

t Gai

n (k

g)

Group

Quetiapine + divalproex Placebo + divalproex

6-week, double-blind, randomized comparison of quetiapine + divalproex vs divalproex alone in 30 adolescents with bipolar mania.

Weight Gain

4.2

2.5

DelBello MP, et al. J Am Acad Child Adolesc Psychiatry. 2002;41:1216-1223.

www.mghcme.org

0

1

2

3

4

5

6

Wei

ght G

ain

(lb)

Group

Placebo + MS Risperidone + MS Haloperidol + MS

P<0.004 vs placebo.

Sachs GS, et al. J Psychiatry. 2002;159:1146-1154.

0.3

5.3

1.1

3-week, double-blind, randomized comparison of risperidone, placebo, or haloperidol added to mood stabilizer (MS) — divalproex or lithium — in 156 patients with bipolar mania.

Weight Gain with Combination Treatments: Risperidone and Haloperidol

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• Switch agents: best results to date • Education from the onset of treatment • Diet and nutrition programs • Exercise programs: walking, etc. • Pharmacologic agents (?): prevention vs following

significant weight gain – Sibutramine, orlistat (FDA approved) – Antihistaminic agents (nizatidine) – Amantadine – Topiramate – Buproprion – Metformin

Weight Gain Interventions

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www.mghcme.org Klein DJ, et al. Am J Psychiatry. 2006;163:2072-2079.

Change in Weight and BMI in Children Taking SGAs Plus Placebo or Metformin

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Lifestyle Intervention and Metformin for Treatment of Antipsychotic-Induced Weight Gain: A Randomized

Controlled Trial

-15

-10

-5

0

5

Lifestyle +Metformin

Metformin Lifestyle +Placebo

Placebo

Weight FBS Insulin

N = 128

12-week placebo-controlled trial, metformin 750 mg/day

Chan

ge fr

om B

asel

ine

Wu RR, et al. JAMA 2008;299:185-193

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Predicted Long-Term Changes in Weight When Switching Between Newer Antipsychotics

↑ weight ↑ weight ↑↑ weight ≈ weight ZIP

↓ weight ≈ weight ↑ weight ↓ weight RIS

↓ weight ≈ weight ↑ weight ↓ weight QUE

↓↓ weight ↓ weight ↓ weight ↓↓ weight OLZ

≈ weight ↑ weight ↑ weight ↑↑ weight ARI

ZIP RIS QUE OLZ ARI

Post-switch

Pre-

switc

h

IMPORTANT: Much of the data on weight loss and lipid improvements comes from switch studies with presumably selected patients experiencing mixture of efficacy and tolerability difficulties with prior medication. Weiden PJ. Postgrad Med. 2006 Special Report(September):27-44.

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Predicted Δ in Metabolic Risk Factors When Switching Newer Antipsychotics

?≈ lipids ↑ lipids ↑↑ lipids ≈ lipids ZIP

?≈ lipids ?↑ lipids ↑ lipids ≈ lipids RIS

↓ lipids ?≈ lipids ↑ lipids ↓ lipids QUE

↓↓ lipids ↓ lipids ↓ lipids ↓↓ lipids OLZ

≈ lipids ≈ lipids ↑ lipids ↑↑ lipids ARI

ZIP RIS QUE OLZ ARI

Post-switch

IMPORTANT: Much of the data on weight loss and lipid improvements comes from switch studies with presumably selected patients experiencing mixture of efficacy and tolerability difficulties with prior medication. Weiden PJ. Postgrad Med. 2006;Special Report(September):27-44.

Pre-

switc

h

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Consensus Statement on Antipsychotic Drugs, Obesity, and Diabetes: Monitoring Protocol for Patients on 2nd-

Generation Antipsychotics*

*More frequent assessments may be warranted based on clinical status. Copyright © 2004 American Diabetes Association. From Diabetes Care®, Vol. 27, 2004; 596-601. Reprinted with permission from The American Diabetes Association.

[X] X X X Fasting lipid profile

X X X Fasting plasma glucose

X X X Blood pressure

X X Waist circumference

X X X X X Weight (BMI)

X X Personal/family history

Every 5 y Annually* Quarterly 12 wk 8 wk 4 wk Baseline

Long-Term Short-Term

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Weight Loss/Maintenance Therapy vs Standard of Care

127 146 Total Test for heterogeneity: chi2=69.64, df=8, P=<.0001, I2=88.5% Test for overall effect: z=18.59, P<.00001

Test for heterogeneity: chi2=3.54, df=5, P=.62, I2=0.0% Test for overall effect: z=3.05, P=.002

136 138 Total

Pharmacological Weight Loss Therapy

Pharmacological Weight Gain Prevention Therapy

Cognitive Behavior Weight Loss Therapy

Test for heterogeneity: chi2=0.59, df=1, P=.44, I2=0.0% Test for overall effect: z=4.65, P<.00001

46 58 Total

Test for heterogeneity chi2=1.76, df=2, P=.41, I2=0.0% Test for overall effect z=4.65, P=.002

58 71 Total

Cognitive Behavior Weight Gain Prevention Therapy*

Control Group (n) Tx Group (n) Study

*Medium-term; In 2 studies lasting 6 months: –4.87 [–7.11, –2.64]. Faulkner et al. Cochrane.Database.Syst.Rev. 2007;1:CD005148.

–5.0 0 –7.5 2.5 5.0 –2.5 7.5

Favors Tx Favors Control

Weighted Mean Difference (Fixed)

[95% CI]

Weighted Mean Difference (Fixed)

[95% CI]

–3.38 [–4.81, –1.96]

–1.69 [–2.77, –0.61]

–1.16 [–1.90, 0.41]

–3.85 [–4.25, –3.44]

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Weight Loss study (Daumit et al. , New England J Med, 2013)

• 291 participants who underwent randomization, – 58.1% had schizophrenia or a schizoaffective disorder,

22.0% had bipolar disorder, and 12.0% had major depression.

– At baseline, the mean was 36.3; mean weight was 225.9 lb). Data on weight at 18 months were obtained from 279 participants.

– At 18 months, the mean between-group difference in weight (change in intervention group minus change in control group) was −3.2 kg (−7.0 lb, P=0.002); 37.8% of the participants in the intervention group lost 5% or more of their initial weight, as compared with 22.7% of those in the control group (P=0.009).

38

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12-Step Healthy Lifestyle Program

• Skip breakfast • Consume fast food >1 per wk • Consume saturated or processed fat-free food • Watch TV, play computer games

≥2 hours/day

• Replace sugar-containing drinks with water

• Eat 4 to <6 meals, with <2 meals in the evening or night

• Serve small meal portions • Eat slowly, drink water, take seconds only

after delay • Eat food with a low glycemic index (<55) • Consume >25–30 grams of soluble fiber per

day • Snack only when hungry and use fruit or

vegetables • Perform moderate physical activity for >30–

60 min/day

Do Not’s Do’s

Correll CU, Carlson HE. J Am Acad Child Adolesc Psychiatry. 2006;45: 771-791.

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Effect of Interventions to Reduce CHD Risk

-8-14

-27-30 -30

-45 -45

-60

-80

-60

-40

-20

0

CH

D R

isk

(%)

BMI by 1 pt

Smoking Cessation

DBP by 6 mm Hg (>140/90)

TC by 10% (TC 180–

200 mg/dL Weight by 4–10 kg

LDL by 30 mg/dL (any LDL)

Healthy Weight

(BMI 18.5–25)

Active Lifestyle (≥20 min

walk)

Li TY et al. Circulation. 2006;113:499-506; Hennekens CH. Circulation. 1998;97:1095-1102; Rich-Edwards JW et al. N Engl J Med. 1995;332:1758-1766; Bassuk SS, Manson JE. J Appl Physiol. 2005;99:1193-1204; Grundy SM. Circulation. 2004;110:227-239; Critchley JA, Capewell S. JAMA. 2003;290:86-97..

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AE Prevention/Management

• Careful choice of drug (based on history, individual risk profile, pharmacologic characteristic of medications)

• Information provided to px/so’s (psychoeducation—individual, groups, etc.)

• Monitoring (include baseline status!)

• Dose reduction • Add-on treatment

(eg, anticholinergics, statins, sildenafil, etc.) • Switching antipsychotic • Making risk/benefit profile a regular topic • Lifestyle interventions

Psychopharmacology Friday, September 28 – Sunday, September 30, 2012

The Westin Copley Place

39th Annual Psychopharmacology Conference Thursday – Sunday, October 22– 25, 2015

The Westin Copley Place MGHCME.ORG

Massachusetts General Hospital Department of Psychiatry

Presents

39th Annual Psychopharmacology

Conference

THURSDAY-SUNDAY, OCTOBER 22-25, 2015 THE WESTIN COPLEY PLACE

BOSTON, MA