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Pharmacologic Treatments In Major Depressive Disorder

Otsuka Pharmaceutical Development & Commercialization, Inc. Lundbeck, LLC. © Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD November 2016 MRC2.CORP.D.00174

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 1 or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional. This program was developed with the support of Otsuka Pharmaceutical Development & Commercialization, Inc. and Lundbeck, LLC. The speakers are either employees or paid contractors of 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 2 or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional. MDD: Treatment Practices

*Up to two-thirds of adult patients will not achieve remission with a selective (SSRI); APA Guidelines recommend the first strategy when a treatment change is necessary may be to try to optimize SSRI dose

Combination and Augmentation – Atypical antipsychotics – Mood stabilizers SSRI* SNRI MAOI and TCA NDRI ECT

0 1 2 3 4 5 6 Potential Failed Treatment Attempts • VNS may be an additional option for individuals who have not responded to at least 4 adequate trials of treatment, including ECT

APA=American Psychiatric Association; ECT=electroconvulsive therapy; MAOI=monoamine oxidase inhibitor; NDRI=- reuptake inhibitor; SNRI=serotonin- norepinephrine reuptake inhibitor; TCA=; VNS=vagus nerve stimulations.

1. Gelenberg AJ, et al; on behalf of the Work Group on Major Depressive Disorder. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. Third Edition. 2010. 2. Al-Harbi KS. Patient Prefer Adherence. 2012;6:369-388. 3. Nemeroff CB. J Clin Psychiatry. 2007;68 Suppl 8:17-25. 4. Mojtabai R, Olfson M. J Clin Psychiatry. 2008;69(7):1064-1074.

3 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. © PsychU. All rights reserved. Proposed Mechanisms for Antidepressant Activity1-7

Antidepressants • Reuptake inhibitors – SSRIs, SNRIs, NDRIs – TCAs • MAOIs Mood Stabilizers • Evidence suggests some may enhance

neurotransmission D2 receptor Antipsychotics α1 receptor α2 receptor • All alter D2 neurotransmission 5-HT receptor • Some atypical antipsychotics also 1A 5-HT1B receptor target 5-HT receptors, NE receptors, GABAergic interneuron and a variety of other receptor types Figure adapted from: Blier P, El Mansari M. Philos Trans R Soc Lond B Biol Sci. 2013;368(1615):20120536. Reuptake transporter

GABA=gamma aminobutyric acid; MAOI=monoamine oxidase inhibitor; NDRI=norepinephrine-dopamine reuptake inhibitor; NE=norepinephrine; SSRI=selective serotonin reuptake inhibitor; SNRI=serotonin-norepinephrine reuptake inhibitor; TCA=tricyclic antidepressant. 1. Stahl SM. Chapter 5. In: Stahl SM, ed. Stahl's Essential : Neuroscientific Basis and Practical Application. 4th ed; 2013:129-236. 2. Stahl SM. Chapter 7. In: Stahl SM, ed. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Application. 4th ed; 2013:284-369. 3. Blier P, El Mansari M. Philos Trans R Soc Lond B Biol Sci. 2013;368(1615):20120536. 4. Rang HP, Dale MM. In. Rang and Dale's . 7th ed; 2012:564-583. 5. Nugent AC, et al. J Psychopharmacol. 2013;27(10):894-902. 6. Andrews PW, et al. Front Psychol. 2011;2(159). 7. Artigas F. Pharmacol Ther. 2013;137(1):119-131.

4 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. © PsychU. All rights reserved. Basic Mechanisms of Antidepressant Action: Reuptake Inhibition and Enzyme Inhibition

In general, most function by increasing the availability of monoamines (serotonin, norepinephrine, and/or dopamine) in the , which is thought to be depleted in depression1: • SSRIs, SNRIs and TCAs increase monoamines by blocking one or more of the monoamine transporters thus preventing the from being taken back into the for recycling or degradation1 • MAOIs increase monoamines by inhibiting the activity of the monoamine oxidase enzyme (acting as an ‘enzyme inhibitor’), and thus preventing the breakdown of neurotransmitters1

Adapted from Stahl. 2013

MAO/I=monoamine oxidase (inhibitor); SSRI=selective serotonin reuptake inhibitor; SNRI=serotonin-norepinephrine reuptake inhibitor; TCA=tricyclic antidepressant. 1. Stahl, Stephen M. Stahl's essential psychopharmacology: neuroscientific basis and practical applications. Cambridge University Press, 2013.

5 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. © PsychU. All rights reserved. Effective Pharmacologic Treatments for Depression

Class Proposed Mechanism of Action

US Food and Administration-Approved Therapies for Depression Increase synaptic serotonin levels and possibly postsynaptic serotonin receptor Selective serotonin reuptake inhibitors (SSRIs)1 activation Serotonin-norepinephrine reuptake inhibitors Increase synaptic levels and possibly receptor activation of both serotonin and (SNRIs)1 norepinephrine Selective norepinephrine reuptake inhibitors Increases synaptic norepinephrine and postsynaptic receptor activation (NRIs)2 Tricyclic antidepressants (TCAs)3 Inhibit serotonin and norepinephrine reuptake Monoamine oxidase inhibitors (MAOIs)4 Inhibits an enzyme that degrades synaptic monoamines Variable MOAs to increase synaptic monoamine levels. Includes norepinephrine- Atypical/multimodal antidepressants & dopamine reuptake inhibitors (NDRIs), serotonin antagonist/reuptake inhibitors antipsychotics5-7 (SARIs), and serotonin partial agonist/reuptake inhibitors (SPARIs)

Other Potential Therapies for Depression Amphetamines8 Increase extracellular dopamine levels through multiple mechanisms Mood stabilizers9,10 Unknown Other11-13 Variable

1. Gartlehner G et al. 2007. Available at: http://www.ncbi.nlm.nih.gov/books/NBK83442/. 2. Szabo ST et al. Neuropsychopharmacology. 2001;25(6):845-57. 3. Gillman PK. Br J Pharmacol. 2007;151(6):737-48. 4. Remick RA et al. Can Fam Physician. 1990;36:1151-5. 5. Stahl SM. Stahl’s Essential Psychopharmacology. 4th Edition. 2013. 6. Graves SM et al. Brain Res. 2012;1472:45- 53. 7. Katonia CL et al. Neuropsychiatr Dis Treat. 2014;10:349-54. 8. Calipari ES et al. J Neurosci. 2013;33(21):8923-5. 9. Hantouche EG et al. J Affect Disord. 2005;84(2-3):243-9. 10. Schloesser RJ et al. Trends Neurosci. 2011;35(1):36-46. 11. Nemeroff CB. Focus. 2008;6(1):3-14. 12. Wellbutrin PI 2014. 13. Oleptro PI 2010.

6 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. © PsychU. All rights reserved. Differential Actions of Antidepressant Agents on Positive and Negative Affect1

1. Nutt DJ. J Clin Psychiatry. 2008;69 Suppl E1:4-7.

7 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. © PsychU. All rights reserved. Theoretical Receptor-mediated Physiological Effects of Pharmacological Agents: Monoamine Neurotransmitters1-7

Neurotransmitter Receptor Clinical/safety implications target(s)

Dopamine D1-3 Antagonist or partial agonist Antipsychotic; antidepressant; anti-manic

Reduce motor side effects; improve mood and cognition; 5HT Agonist or inverse agonist 2A sleep regulation 5HT , 5HT , Serotonin 1A 1B/D Antagonist or 5HT , 5HT , Possibly contribute to efficacy and tolerability 2C 6 partial agonist 5HT7

5HT1A Partial agonist Anxiolytic; booster of antidepressant action

7 α2A, 2B, 2C Agonist or antagonist Antidepressant; anxiolytic; effects on emotional memories Norepinephrine Improve cognition and reduce behavioral disturbance in α1A, 1B, 1C Agonist ADHD, depression and OCD; cardiac effects. reduce orthostatic hypotension and sedation1,6

1. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th Edition. New York, NY: Cambridge University Press; 2013. 2. Cottingham C et al. J Biol Chem. 2011;286(41):36063-75. 3. Gibbs AA et al. J Neurosci. 2013;33(43):17023-8. 4. Neumeister A et al. Neuropsychopharmacology. 2006;31(8):1750-6. 5. O'Connell TD et al. J Clin Invest. 2003;111(11):1783-91. 6. Doze VA et al. Mol Pharmacol. 2011;80(4):747-58. 7. Schramm NL et al. J Neurosci. 2001;21(13):4875-82.

8 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. © PsychU. All rights reserved. Pharmacologic Treatments In Major Depressive Disorder

Otsuka Pharmaceutical Development & Commercialization, Inc. Lundbeck, LLC. © Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD November 2016 MRC2.CORP.D.00174

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 9 or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.