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The Science and the Art of the Treatment of Depression
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
Page 1
The Science and the Art of the Treatment of Depression Dr. Ellen Jett Wilson, RPh, PhD
PharmCon is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education
This webcast has been supported by PharmCon
Legal Disclaimer: The material presented here does not necessarily reflect the views of Pharmaceutical Education Consultants (PharmCon) or the companies that support educational programming. A qualified healthcare professional should always be consulted before using any therapeutic product discussed. Participants should verify all information and data before treating patients or employing any therapies described in this educational activity.
The Science and the Art of the Treatment of Depression Accreditation:
Pharmacists: 0798-0000-11-071-L01-P Technicians: 0798-0000-11-071-L01-T Nurses: N-701
CE Credits: 1.0 contact hour
Target Audience: Pharmacists, Technicians & Nurses
Program Overview: Before the introduction of fluoxetine (Prozac) in 1987, there were few molecular entities in the treatment arsenal for depression and the drug molecules that were available were limited in use by their side effects. Since 1987, the treatment options for depression has exploded with selective serotonin reuptake inhibitors (SSRI), norepinephrine and dopamine reuptake inhibitors (NDRI), and serotonin norepinephrine reuptake inhibitors (SNRI) among others. With a large number of choices available, it is important to have some criteria to make the best choice of drug molecule to treat a patient’s depressive symptoms. Using knowledge of the positive effects on mood of certain key neurotransmitters can be one tool used in making an appropriate antidepressant choice. Because there are limits to the neurotransmitter theory of depression, it is also important to look to the future and become familiar with alternate theories of depression and the treatment that may soon be available based on these factors.
Objectives: • Identify the key points of neurotransmitter theory of mood and depression • Define the positive effects on moods that are attributed to the neurotransmitters serotonin, norepinephrine, and dopamine • Identify the best antidepressant to match a patient’s depressive symptoms, using the knowledge of mood and neurochemistry • Describe the theories of depression other than the neurotransmitter theory, and discuss future treatments for depression that target these new theories.
This webcast has been supported by PharmCon
The Science and the Art of the Treatment of Depression
This webcast has been supported by PharmCon
Legal Disclaimer: The material presented here does not necessarily reflect the views of Pharmaceutical Education Consultants (PharmCon) or the companies that support educational programming. A qualified healthcare professional should always be consulted before using any therapeutic product discussed. Participants should verify all information and data before treating patients or employing any therapies described in this educational activity.
PharmCon is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education
Speaker: Ellen Wilson is a freelance educator based in Greenville, SC. She received a B.S. in Pharmacy and a PhD in Pharmaceutical Sciences from the University of South Carolina. Her pharmacy practice experiences include retail, hospital, and consulting pharmacy. She also has nearly ten years of collegiate teaching experience at both four-year and two-year institutions. Currently, she teaches online chemistry courses and writes pharmacy continuing education. Ellen lives in Greenville with her husband, two daughters, one cocker spaniel, and a once-stray cat. She is an active volunteer at both church and school, enjoys gardening and backyard birding, and is trying to master the art of French cooking.
Speaker Disclosure: Dr. Wilson has no actual or potential conflicts of interest in relation to this program
The early days of depression treatment were depressing
MAOIs
•Unfavorable side effect profile •Hypertensive crisis •Serotonin syndrome
•Serious interactions •Drug-drug •Food-drug
phenelzine tranylcypromine
isocarboxazid
The Science and the Art of the Treatment of Depression
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
Page 2
The early days of depression treatment were depressing
TCAs
•Effected a variety of neuro-transmitters
•Cholinergic, histaminergic, adrenergic
•Unfavorable side effect profile
amitriptylline, amoxepine
clomipramine, desipramine, doxepin, imipramine,
maprotiline nortriptylline, protriptylline, trimipramine
A Search for “Prozac” and “1987-1990”
The Prozac ® Difference
0
100
200
300
400
500
600
700
1987 1988 1989 1990
Prozac in the US Media
Results
from Health, United States, 1992
0
2
4
6
8
10
12
14
1940 1950 1960 1970 1980 1990 2000
Suicides/100,000 residents
•By 1992, suicide rates had begun to fall •More people suffering from depression were receiving treatment
Overall rate = 7%
Women=10%
Men = 4%
1988-1994
Overall rate = 3%
Women = 3%
Men = 2%
from Health, United States, 2004
1999-2000
The Science and the Art of the Treatment of Depression
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
Page 3
Where are we now?
Visit to a Mental Health Professional within 1 Year
CDC National Center for Health Statistics Data Brief Number 76, October 2011
http://www.cdc.gov/nchs/data/databriefs/db76.htm
Race, Ethnicity, and Family Income
CDC National Center for Health Statistics Data Brief Number 76, October 2011
http://www.cdc.gov/nchs/data/databriefs/db76.htm
Percent of persons aged 12 and over on antidepressants
CDC National Center for Health Statistics Data Brief Number 76, October 2011
http://www.cdc.gov/nchs/data/databriefs/db76.htm
The Science and the Art of the Treatment of Depression
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
Page 4
Sex and Severity of Symptoms
CDC National Center for Health Statistics Data Brief Number 76, October 2011
http://www.cdc.gov/nchs/data/databriefs/db76.htm
The Science of Depression Therapy
The Monoamine Theory of Depression
Presynaptic neuron
Postsynaptic neuron synapse
The Monoamine Theory of Depression
Serotonin (5-HT)
Norepinephrine (NEPI)
Dopamine (DA)
The Science and the Art of the Treatment of Depression
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
Page 5
0 2 4 6
Growth1
Growth2
Growth3
Growth4
Medical Coverage & Growth
Medical Coverage3
Medical Coverage2
Medical Coverage1
Medicare coverage.
Aliquam erat volutpat. Donec massa. Integer bium luctus pede. Pellentesque congue aliquam nisi. Nulla faucibus jus to sed est. Donec sit amet augue. Pellentesque habitant morbi tristique senectus et netus et malesuada fames ac turpis egestas. Sed iaculis. Nulla suscipit rhoncus mi. Sed accumsan enim pretium massa. Vivamus at mi.
Member resources.
Donec fringilla pharetra enim. Donec auctor ante ut dolor. Viavst amus leo libero, pret diumonec, cursus regret, lacinia nec, orci. Etiam quis magna in quam pulvinar faucibus. Etiam consta equat nunc at ligula. Donec fringilla pharetra enim. Donec auctor ante ut dolor. Viavst amus leo libero, pret diumonec, cursus regret, lacinia nec, orci. Etiam quis magna in quam pulvinar faucibus. Etiam consta equat nunc at ligula.
Positive Mood Effects By Neurotransmitter
Serotonin NEPI Dopamine
Mood
Panic General anxiety
Compulsion Obsession
Rage PTSD
Mood Alertness
Focus
Anxiety Pain
Mood Concentration
Cravings
Weight
0 2 4 6
Growth1
Growth2
Growth3
Growth4
Medical Coverage & Growth
Medical Coverage3
Medical Coverage2
Medical Coverage1
Medicare coverage.
Aliquam erat volutpat. Donec massa. Integer bium luctus pede. Pellentesque congue aliquam nisi. Nulla faucibus jus to sed est. Donec sit amet augue. Pellentesque habitant morbi tristique senectus et netus et malesuada fames ac turpis egestas. Sed iaculis. Nulla suscipit rhoncus mi. Sed accumsan enim pretium massa. Vivamus at mi.
Member resources.
Donec fringilla pharetra enim. Donec auctor ante ut dolor. Viavst amus leo libero, pret diumonec, cursus regret, lacinia nec, orci. Etiam quis magna in quam pulvinar faucibus. Etiam consta equat nunc at ligula. Donec fringilla pharetra enim. Donec auctor ante ut dolor. Viavst amus leo libero, pret diumonec, cursus regret, lacinia nec, orci. Etiam quis magna in quam pulvinar faucibus. Etiam consta equat nunc at ligula.
Types of Depression By Neurotransmitter
c
5-HT 5-HT NEPI, DA
5-HT, NEPI, DA
Anxious Depression
• Fearful • Inadequate • Nervous • Worried •Dependent
Agitated Depression
• Angry, bitter • Resentful • Despairing • Push others
away
Melancholic Depression
• Slow, sleepy • Lack concen-
tration, moti-vation
• Ruminate
Limitations of the
Monoamine Theory
Reuptake inhibition and increased NT levels occur
immediately but therapeutic effect takes, on average,
3-8 weeks to occur
Current Treatment Options SSRIs
Generic Trade Year
Approved Equipotent
Starting Dose
fluoxetine Prozac® 1987 20 mg
sertraline Zoloft® 1991 50 mg
paroxetine Paxil® 1992 20 mg
fluvoxamine* Luvox® 1994 50-100 mg
citalopram Celexa® 1998 20 mg
escitalopram Lexapro® 2002 10 mg
*only approved for OCD
The Science and the Art of the Treatment of Depression
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
Page 6
FDA Indications SSRIs
Generic MDD OCD Panic PTSD Social
Anxiety GAD
fluoxetine ✓ ✓ ✓
sertraline ✓ ✓ ✓ ✓
paroxetine ✓ ✓ ✓ ✓ ✓ ✓
citalopram ✓
escitalopram ✓ ✓
Variety of Structures SSRIs
fluoxetine
sertraline
paroxetine
fluvoxamine citalopram
escitalopram
Common Side Effects
17%- Sexual dysfunction & drowsiness
10-12%-Weight gain, insomnia, anxiety, dizziness & headache
6-7%-Dry mouth, blurred vision, nausea, rash & itching
3-5%-Tremor, constipation & upset stomach
SSRIs
OTHER P450s
1A2 2B6
2C9 2C19 3A4
Drug-Drug Interactions SSRIs
• Show the least P450 inhibition
citalopram escitalopra
m
• Inhibits 2D6 at >200mg/day sertraline
• Potent 2D6 inhibitors
fluoxetine paroxetine
The Science and the Art of the Treatment of Depression
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
Page 7
2009 Fluoxetine
and paroxetine
should not be
prescribed with
tamoxifen
SSRIs & Tamoxifen
2010 Paroxetine
risk of death
from breast
cancer when
used with
tamoxifen
Several recent studies have shown an association between SSRI use and an increase in bone loss and fractures.
Bone Loss and Fracture SSRIs
Sex Conclusion
Bone loss in hip, femoral neck & trochanter was
significantly greater in SSRI users
Bone mineral density in the hip was 4-6% lower in
SSRI users
SSRIs QT Prolongation
All have the potential
Risk Factors:
baseline prolongation
HF, MI, LVH
bradycardia
K+, Mg2+
female
advanced age
polypharmacy
www.qtdrugs.org
SSRIs QT Prolongation
8/24/11 FDA Drug Safety Communication:
Escitalopram?
Citalopram should no longer be prescribed at
doses greater than 40mg/day because of the risk of abnormal
heart rhythm
The Science and the Art of the Treatment of Depression
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
Page 8
Several studies show an association between SSRI use and increased
bleeding events. These events range from minor to major.
Increased Risk of Bleeding SSRIs
Evidence
Risk of UGIB with SSRIs
Risk is when NSAIDS are used with SSRIs
SSRI use in post-menopausal women risk
of hemorrhagic stroke
Risk of transfusion has in orthopedic surgery
patients on SSRIs
1.5-3.0 kg
Weight Changes and DM
>24 mths
2x DM
(paroxetine)
mod-high dose
SSRIs
Generic Trade Year
Approved Usual Daily
Dose
venlafaxine Effexor®,
Effexor XR® 1993 75mg
duloxetine Cymbalta® 2004 60mg
desvenlafaxine Pristiq® 2008 50mg
Current Treatment Options SNRIs
Generic MDD OCD
Panic
PTSD
Social Anxiety GAD
venlafaxine ✓ ✓ ✓ ✓
duloxetine ✓ ✓
desvenlafaxine
✓
FDA Indications SNRIs
The Science and the Art of the Treatment of Depression
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
Page 9
Structures SNRIs
venlafaxine desvenlafaxine
duloxetine
Common Side Effects
25-30%--Nausea
15-20%--Dizziness,insomnia
10-15%--Dry mouth, drowsiness, sweating,
constipation
SNRIs
Distinquishing Charactaristics SNRIs
Venlafaxine
• CYP2D6
• generic
Desvenlafaxine
• Active metabolite
• Fewer drug interactions?
Duloxetine
hepatic insufficiency
renal insufficiency
• Pain?
Current Treatment Options Misc
Generic Trade Year
Approved Usual Daily
Dose
bupropion Wellbutrin, SR & XL® 1985/1989 300 mg
mirtazapine
Remeron® 1996 30-45 mg
vilazodone Viibryd® 2011 40 mg
The Science and the Art of the Treatment of Depression
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
Page 10
FDA Indications Misc
Generic MDD OCD
Panic
PTSD
Social Anxiety GAD
bupropion ✓
mirtazapine
✓
vilazodone ✓
Structures Misc
bupropion
trazodone
vilazodone mirtazapine
Distinquishing Charactaristics Misc
Bupropion
DA, NEPI
• Mild stimulant
• Appetite suppression
sexual dysfunction
Mirtazapine
5HT, NEPI
• Potent antihistamine
• Sedation>low dose
• Dry mouth
• Weight gain appetite
Vilazodone
• SSRI & 5HT agonist
• Take with food
• NVD
• insomnia
The Art of Depression Therapy
The Science and the Art of the Treatment of Depression
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
Page 11
SSRI or SNRI?
Matching the Rx to the Pt
RA is a 45 yo male presenting with symptoms of agitated depression Angry and bitter Ruining relationships Past response to citalopram 80mg/day
Your Choice?
SSRI
What dose of citalopram?
Matching the Rx to the Pt
c
5-HT NEPI, DA
Agitated Depression
• Angry, bitter • Resentful • Despairing • Push others
away
Your Choice?
SSRI or SNRI?
Matching the Rx to the Pt
RA is a 55 yo female presenting with symptoms of anxious depression Nervous and worried Fearful that husband will leave Hx of breast cancer, on tamoxifen
Your Choice?
SSRI Avoid fluoxetine and paroxetine
Matching the Rx to the Pt
5-HT
Anxious Depression
• Fearful • Inadequate • Nervous • Worried •Dependent
Your Choice?
The Science and the Art of the Treatment of Depression
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
Page 12
Alternate Theories and
Related Drug Treatments
Much research into novel
antidepressants focuses on glutamate balance in the brain
NMDA AMPA
BDNF Glial cell Glial cell
Na
t Rev D
rug
Disco
v. 20
08 Ma
y; 7(5):426-437
•Riluzole and glutamate
•Glutamate and MDD
•Downstream effects
•Well tolerated
•>12 clinical trials for depression
Riluzole
(Rilutek®)
•NMDA receptor antagonists
•amt of Glu through NMDA
•Newer agents needed with more practical drug profile
Ketamine
Memantine(Namenda®)
The Science and the Art of the Treatment of Depression
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
Page 13
•AMPA potentiators
•amt of Glu through AMPA
•Several novel compounds in clinical and pre-clinical trials
Ampalex
aniracetam
•Glial gluatmine transporter enhancers
b-lactams
ceftriaxone
Many effective
treatments for MDD
Efficacy is similar among
all agents
Side effect profiles differ
New agents are needed
Glutamate system is a
novel target
Bibliography
Cipriania A, et al. "Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta analysis." Lancet 373, no. 9665 (Feb 2009): 746-758. Desmarais, JE, and KJ Looper. “Interactions between tamoxifen and antidepressants via cytochrome P450 2D6.” Journal of Clinical Psychiatry 70, no. 12 (2009): 1688. Diem SJ, Blackwell TL, Stone KL, et al. “Use of antidepressants and rate of hip bone loss in older women; the study of osteoporotic fractures.” Archives of Internal Medicine 167 (2007): 1240. Emmons, Henry. The Chemistry of Joy: A Three-Step Program for Overcoming Depression Through Western Science and Eastern Wisdom. New York, New York: Simon & Schuster, 2006.
The Science and the Art of the Treatment of Depression
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
Page 14
Bibliography
Haney EM, Chan BK, Diem SJ, et al. “Association of low bone mineral density with selective serotonin reuptake inhibitor use by older men.” Archives of Internal Medicine, no. 167 (2007): 1246. Hirsch, Michael, and Robert J Birnbaum. “Selective serotonin reuptake inhibitors (SSRIs) for treating depressed adults.” In UpToDate, edited by Denise S. Basow. Waltham, MA: UpToDate, 2011. Hirsh, Michael, and Robert J. Birnbaum. "Serotonin-norepinephrine reuptake inhibitors (SNRIs) and other antidepressants for treating depressed adults." In UpToDate, edited by Denise S. Basow. Waltham, MA: UpToDate, 2011.
Bibliography
Jin, Yan et. al. “CYP2D6 Genotype, Antidepressant Use, and Tamoxifen Metabolism During Adjuvant Breast Cancer Treatment.” Journal of the National Cancer Institute 97, no. 1 (Jan 2005): 30-39. Kelly, CM et al. “Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study.” British Journal of Medicine 340 (2010): c693. Krystal, John H, Sanjay J. Mathew, and et al. "Potential psychiatric applications of metabotropic glutamate receptor agonist and antagonists." CNS Drugs 24, no. 8 (2010): 669-693. National Center for Health Statistics. Health, United States, 1992. Report, Hyattsville, MD: U.S. Department of Health and Human Services, 1993.
Bibliography
National Center for Health Statistics. Health, United States, 2004. Report, Hyattsville, MD: U.S. Department of Health and Human Services, 2005. Pittenger, Christopher, Vladimir Coric, and et al. "Riluzole in the Treatment of Mood and Anxiety Disorders." CNS Drugs 22, no. 9 (2008): 761-786. Pratt LA, Brody DJ, Gu Q. Antidepressant use in persons aged 12 and over: United States, 2005-2008. NCHS data brief, no 76. Data Brief, Hyattsville, MD: National Center for Health Statistics, 2011. Sanacora, Gerard, Carlos A. Zarate Jr, John Krystal, and Husseini Manji. "Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders." National Review of Drug Discovery 7, no. 5 (May 2008): 426-437.
Bibliography
The Centers for Disease Control and Prevention. “Office of Enterprise Communication Press Release.” www.cdc.gov. 2004 2-Dec. http://www.cdc.gov/media/pressrel/r041202.htm (accessed 2011 19-Oct). The National Institute of Mental Health. "Questions and Answers about the NIMH Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study--All Medication Levels." www.nimh.nih.gov. Nov 2006. http://www.nimh.nih.gov/trials/practical/stard/allmedicationlevels.shtml (accessed Nov 23, 2011). U.S. Department of Health and Human Services. Mental Health and Mental Disorders. 2011 29-Sept. http://www.healthypeople.gov/2020/topicsobjectives2020/objectiveslist.aspx?topicid=28 (accessed 2011 25-Oct).
The Science and the Art of the Treatment of Depression
© 2010 Pharmaceutical Education Consultants, Inc. unless otherwise noted. All rights reserved.
Reproduction in whole or in part without permission is prohibited.
Page 15
Bibliography
U.S. Food and Drug Administration. FDA Drug Safety Communication: Abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide). Drug Safety Communication, Washington, DC: U.S. Department of Health and Human Services, 2011. Wehrenberg, Margaret. The 10 Best-Ever Depression Management Techniques. New York, New York: W.W Norton & Company, 2010.
Notes
Notes Notes