the science and the art of the treatment of depression

The Science and the Art of the Treatment of Depression

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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.




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 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




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



Percent of persons aged 12 and over on antidepressants






Sex and Severity of Symptoms



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)




0 2 4 6

Growth1

Growth2

Growth3

Growth4

Medical Coverage & Growth

Medical Coverage3

Medical Coverage2

Medical Coverage1

Medicare coverage.

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Member resources.

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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




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




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




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




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




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




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?


c

5-HT NEPI, DA

Agitated Depression

• Angry, bitter • Resentful • Despairing • Push others

away

Your Choice?

SSRI or SNRI?


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


5-HT

Anxious Depression

• Fearful • Inadequate • Nervous • Worried •Dependent

Your Choice?




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®)




•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.




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).




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.

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