Managing Metabolic Side Effects With Combination Therapy ... · antipsychotics, antidepressants, and combination therapy • Highlight common metabolic side effects associated with

© 2019 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD. Lundbeck, LLC

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Managing Metabolic Side Effects With Combination Therapy:

Antipsychotics and AntidepressantsMichael E. Thase, MD

Perelman School of Medicine, University of Pennsylvaniaand Corporal Michael J. Crescenz Veterans Affairs Medical Center

Philadelphia, PA

November 2019 MRC2.CORP.D.00466


Our Featured Speaker

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Michael E. Thase, MDPerelman School of Medicine, University of Pennsylvania School and Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, PA

Dr. Thase is Professor of Psychiatry at the Perelman School of Medicine of the University of Pennsylvania. He is also Director of the Mood and Anxiety Disorders Section, and is a member of the medical staff, of the Corporal Michael J. Crescenz Veterans Affairs Medical Center.

Dr. Thase received his medical degree from the Ohio State University College of Medicine, Columbus, OH.

This program is paid for by Otsuka Pharmaceutical Development &

Commercialization, Inc. and Lundbeck, LLC.

Speakers are paid consultants for Otsuka Pharmaceutical Development & Commercialization, Inc.

The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other health care professional.The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

• Review the mechanisms action and rationales for using antipsychotics, antidepressants, and combination therapy

• Highlight common metabolic side effects associated with antipsychotics, antidepressants, and combination therapy

• Discuss optimal management of metabolic side effects

Objectives

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Combination Therapy

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Mechanisms of Action

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1. Gardner DM et al. CMAJ. 2005;172:1703.2. Chokhawala K and Stevens L. 2019, StatPearls Publishing LLC. 3. Brunner E et al. Neuropsychopharm. 2014;39:2549.

4. Mao YM and Zhang MD. Neuropsych Dis Treat. 2015;11:701.5. Mulder R et al. Bipolar Disorders. 2018;20:17.6. Lenox RH and Frazer A. American College of Neuropsychopharmacology.

2002;1139-1163.

Combination therapy*

Targets multiple systems including DA, 5-HT, ACh,

histamine, and NE to provide enhanced symptom control and

better patient outcomes3,4,5

Antipsychotics Antidepressants

• Can be categorized as2:- First-generation

or “typical” antipsychotics

- Second-generationor “atypical” antipsychotics

• Various drug classes include6:- Selective serotonin

reuptake inhibitors- Tricyclic

antidepressants- Monoamine oxidase

inhibitors

*Refers to the combination of antipsychotics and antidepressants.5-HT, serotonin; ACh, acetylcholine; DA, dopamine; NE, norepinephrine.

• Inhibit a wide range of neurotransmitter receptors including DA, 5-HT, ACh, histamine and NE1

• Block 5-HT and NE reuptake and enhance synaptic transmission6


• The ECNP Consensus Meeting states that the rationale for using combination therapy typically includes 1 of the following1:

– Other treatments have been only partially effective in treating core symptoms– Another treatment is believed to be required to target concurrent symptoms

(outside of the core symptoms)– A combination therapy could be beneficial de novo in some indications– A combination therapy could improve tolerability because the compounds used are

below their individual dose thresholds for side effects

Rationale for Using Combination Therapy

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APA, American Psychiatric Association; ECNP, European College of Neuropsychopharmacology; MDD, major depressive disorder.1. Goodwin G et al. Eur Neuropsychopharmacol. 2009;19:520-532. 2. APA. https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/mdd.pdf. 2010. Accessed November 15, 2019.

• The APA practice guidelines for MDD suggests that combining antidepressants and second-generation antipsychotics couldincrease the rates of response or remission of depressive symptoms in patients who typically have not responded to > 2 medication trials, even when psychotic symptomsare not present2


Indication Typical first-line therapy

Potential disadvantages of first-line therapy

Potential benefits of combination therapy

Schizophrenia* Antipsychotics1,2 Effectively treats positive symptoms, but is less effective in treating negative smptoms3,4

More effective in treating negative symptoms versus

antipsychotics alone5

MDD Antidepressants6 Widely used to treat depressive illness, but a high proportion of

patients fail to respond adequately6

More effective in treating patients with inadequate

responses versus antidepressants alone6

Bipolar disorder Mood stabilizers7 Helps prevents relapse after symptoms are controlled, but is not particularly well tolerated7

More effective in treating both mania and depression

versus monotherapy7

OCD Serotonergic antidepressants9

Approximately 40–60% of patients show partial to no

improvement8

Can be a more effective treatment versus

antidepressants alone8

Benefits of Combination Therapy by Indication

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1. Lally J and MacCabe JH. Br Med Bull. 2015;114:169.2. Muñoz-Negro J et al. J Clin Psychopharmacol. 2016;36:684.3. Moller KH. Psychiatira Danubina. 2016;28:435.4. Stępnicki P et al. Molecules. 2018;23:2087.

5. Singh SP et al. Br J Psychiatry. 2010;197:174.6. Haddad PM et al. Br Med Bull 2015;115:183.7. Harrison PJ et al. Ann NY Acad Sci. 2016;1366:76.8. Kellner M. Dialogues Clin Neurosci. 2010;12:187.

*Includes delusional disorder. MDD, major depressive disorder; OCD, obsessive compulsive disorder.


Metabolic Side Effects


• Severe mental illness is associated with increased:– Burden of CV mortality and morbidity1

– Prevalence of CV risk factors, such as obesity and T2DM, compared with the general population2,3

• Antipsychotics, antidepressants and mood stabilizers can further adversely affect CV risk in patients with severe mental illness2,4:

Metabolic Comorbidities in Patients With Severe Mental Illness

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1. Abosi O et al. Horm Mol Biol Clin Invest. 2018;20170065.2. Bak M et al. PLoS ONE. 2014;9:e94112.3. Mamakou V et al. Psychiatriki. 2018;29(1):64-73.

4. Correll CU et al. World Psychiatry. 2015;14:119.5. Siafis S et al. Curr Neuropharmacol. 2018;16:1210.

CV, cardiovascular; T2DM, type 2 diabetes mellitus.

– Although some antipsychotics are described as “metabolic neutral,” they are still capable of inducing metabolic side effects5


Metabolic Side Effects: Weight Gain

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1. Correll CU et al. World Psychiatry. 2015;14:119.2. Carey M et al. Pilot and Feasibility Studies. 2018;4:186.3. Hasnain M et al. Postgrad Med. 2012;124:154-167.

4. Brunner E et al. Neuropsychopharm. 2014;39:2549.5. Mao Y and Zhang D. Neuropsychiatry Dis Treat. 2015;11:701-713.

Antipsychotics• Antipsychotics have been associated with clinically relevant weight gain (≥ 7%)1

• The propensity for weight gain differs between antipsychotics, however, no agent should be considered “weight-neutral”2

• Some agents can stimulate appetite3

Antidepressants• Antidepressants have been associated with mild

or moderate weight gain1

• Some agents can stimulate appetite3

Combination therapy• Combination therapy has been associated with weight gain (≥ 7%)4

• The adverse effect of weight gain shared by antipsychotics and antidepressants could be potentially additive5


Metabolic Side Effects: Diabetes

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1. Correll CU et al. World Psychiatry. 2015;14:119.2. Llorente MD and Urrutia V. Clinical Diabetes. 2006;24:18-24.3. Salvi V et al. PLoS ONE. 2017;12:e0182088;

4. Earley WR et al. Psychopharmacol Bull. 2018;48:62.5. Brunner E et al. Neuropsychopharm. 2014;39:2549.6. Berman RM et al. Neuropsychiatric Dis Treat. 2011;7:303.

Antipsychotics• Antipsychotics have been significantly associated with hyperglycemia, which can

result in T2DM, metabolic acidosis or ketosis1,2

• The associated increased risk for diabetes may occur independent of weight gain1

Antidepressants• A meta-analysis showed a significant link between antidepressants and diabetes,

but the strength of this association varied between studies3

Combination therapy• Some studies have reported increased blood glucose levels

with combination therapy versus antidepressants alone4,5

• Other studies, however, have reported no changes in blood glucose levels with combination therapy6

T2DM, type 2 diabetes mellitus.


Metabolic Side Effects: Dyslipidemia

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1. Correll CU et al. World Psychiatry. 2015;14:119.2. Lambert T et al. Aust Prescr. 2011;4:97-99.3. Thase ME et al. J Clin Psychiatry. 2015;76:1224.

4. Earley WR et al. Psychopharmacol Bull. 2018;48:62.5. Brunner E et al. Neuropsychopharm. 2014;39:2549.6. Berman RM et al. Neuropsychiatric Dis Treat. 2011;7:303.

Antipsychotics• Antipsychotics have been associated with varying degrees of dyslipidemia,

which can precede weight gain1

• The most common abnormalities are decreased HDL-C and increased triglyceride levels2

Antidepressants• Antidepressants may not be directly associated with dyslipidemia; however,

weight gain is a risk factor for lipid abnormalities1

Combination therapy• Some studies showed increased lipid levels with combination

therapy versus antidepressants alone3,4

• Other studies, however, have shown no differences in lipid levels after starting combination therapy 5,6

HDL-C, high-density lipoprotein cholesterol.


Metabolic Side Effects: Hypertension

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1. Alves BB et al. SAGE Open Med Case Rep. 2019;7:1-6.2. Licht CMM et al. Hypertension. 2009;53:631-638.3. Ghio L et al. Cas Rep Med. 2011;11:doi.10.1155/2011/856903.

Antipsychotics• Case reports suggest that hypertension, although rare, is a potential adverse

event with some antipsychotic treatments1

Antidepressants• A large-scale cohort study found that patients with MDD have significantly lower

systolic blood pressure and were less likely to have isolated hypertension2

• The use of certain antidepressants, however, was associated with high diastolic and systolic blood pressure, as well as hypertension2

Combination therapy• A case series in patients with MDD and hypertension,

indicated that treatment with combination therapy appeared to have no impact on blood pressure3

MDD, major depressive disorder.


• The benefits of antipsychotics can sometimes be obscured by adverse effects and medical risks1

• The benefits of a particular medication, however, could outweigh potential risks, even if those risks include diabetes or dyslipidemia2

• Risk-benefit assessments for prescribing a particular antipsychotic medication should be based on1:– The specific drug, as opposed to the generation or class of drug– The specific situation, including the actual and expected harms experienced

by an individual

• The APA-ADA guidelines suggest monitoring patients on second-generation antipsychotics for3:

Risk-Benefit Assessments

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1. Stroup TS and Gray N. World Psychiatry. 2018;17:341.2. Llorente MD and Urrutia V. Clin Diabetes. 2006;24:18-24.3. Abosi O et al. Horm Mol Biol Clin Invest. 2018; 20170065.

– History of CV factors– BMI– Waist circumference

– Fasting blood glucose– Blood pressure– Lipid profile

ADA, American Diabetes Association; APA, American Psychiatric Association; BMI, body mass index; CV, cardiovascular.


Managing Metabolic Side Effects

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• Obese patients with severe mental disease report worse general HRQoL and weight-related HRQoL versus non-obese patients1

– Weight reduction strategies in patients receiving antipsychotics can improve QoL2

• Weight gain can result in nonadherence with antipsychotics and is a common reason for discontinuation of combination therapy3,4:– Maximizing safety and tolerability of medications can improve adherence to

treatment and enhance clinical outcomes in patients with bipolar depression, as well as improve their general medical health5

• Diagnosis of diabetes can lead to increased anxiety, depressive symptoms and lower self-esteem, especiallyin patients with underlying psychiatric disorders6

• Successful management of side effects associated with antipsychotics is essential for treatment optimization2

Importance of Managing Metabolic Side Effects

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1. Kolotkin RL et al. Obesity. 2008;16:749.2. Stroup TS and Gray N. World Psychiatry. 2018;17:341.3. Garcia S et al. J Clin Psychopharmacol. 2016;355-371.

4. Brunner E et al. Neuropsychopharm. 2014;39:2549.5. Kemp DE. J Affective Disord. 2014;169:S34-S44.6. Llorente MD and Urrutia V. Clin Diabetes. 2006;24:18-24.

HRQoL, health-related quality of life; QoL, quality of life


• Behavioral interventions for weight loss in patients receiving antipsychoticsor antidepressants can lead to1,2:– Significant improvements in CV risk– Reduced weight gain– Improved lipid profiles– Improved glucose profiles

• Lifestyle interventions include guidance on healthy diets and eating habits, encouraging regular exercise,2 and CBT3

Lifestyle Interventions

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1. Lambert T et al. Aust Prescr. 2011;4:97-99.2. Hasnain M et al. Postgrad Med. 2012;124:154-167.

3. Dayabandara M et al. Neuropsychiatric Dis Treat. 2017;13:2231.4. Naslund JA et al. Psychiatry Res. 2016;244:139.

*Includes schizophrenia, bipolar disorder and major depressive disorder.CBT, cognitive behavioral therapy; CV, cardiovascular.

• Wearable sensors and smartphone apps can be valuable tools for supporting weight-loss efforts in patients with severe mental illness4*


• For patients experiencing clinically relevant weight gain, a switch in treatment regimen may be considered1:– For example, switching a second-generation antipsychotic or an antidepressant

to agents with lower metabolic liability is a strategy frequently used to address associated side effects2

• Treatment with antidiabetic medications, with or without lifestyle interventions, in patients with schizophrenia also receiving antipsychotics has been associated with decreased3:

• Pharmacological options can be used to symptomatically treat metabolic problems associated with antipsychotic therapies:– For example using statins to treat dyslipidemia or

antihypertensive medications to treat hypertension4

Pharmacological Options

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1. Kemp DE. J Affective Disord. 2014;169:S34-S44.2. Hasnain M et al. Postrgrad Med. 2012;124;154-167.

3. Wu R et al. JAMA. 2008;299:185-193.4. Stroup TS and Gray N. World Psychiatry. 2018;17:341.

– Weight– BMI– Waist circumference

– Fasting glucose– Insulin– Insulin resistance index

BMI, body mass index.

© 2019 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD. Lundbeck, LLC


Managing Metabolic Side Effects With Combination Therapy:

Antipsychotics and AntidepressantsMichael E. Thase, MD

Perelman School of Medicine, University of Pennsylvaniaand Corporal Michael J. Crescenz Veterans Affairs Medical Center

Philadelphia, PA

November 2019 MRC2.CORP.D.00466

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Managing Metabolic Side Effects With Combination Therapy ... · antipsychotics, antidepressants, and combination therapy • Highlight common metabolic side effects associated with