Depression Management

Depression: Optimizing Outcomes
for the Individual Patient

pmiCME Updates
April 11, 2012
Anaheim, California
Faculty:
Rona J. Hu, MD
Educational Partner:
Neuroscience Education Institute
Session 5: Depression: Optimizing Outcomes for the Individual Patient

Learning Objectives
1.
2.
3.
Provide initial evidence-based depression treatment that is specifically suited to the individual patients need.
Monitor patients with depression over time in order to track treatment adherence, response, and side effects.
Make evidence-based treatment adjustments to address residual symptoms and side effects.
Faculty
Rona J. Hu, MD
Clinical Associate Professor
Department of Psychiatry and Behavioral Sciences
Medical Director, Acute Psychiatric Inpatient Unit
Stanford University School of Medicine
Stanford, California
Dr Rona Hu is a clinical associate professor of psychiatry and behavioral sciencepsychopharmacology in the Department
of Psychiatry at Stanford University School of Medicine in Stanford, California. She earned her medical degree from the
University of California, San Francisco (UCSF), School of Medicine in 1990 and completed her residency at the UCSF
Medical Center in 1994. Dr Hu received her certification in psychiatry from the American Board of Psychiatry and
Neurology in 1995 and completed a fellowship with the National Institutes of Health in 1998.
Faculty Financial Disclosure Statement
The presenting faculty reported the following:

Dr Hu is a consultant/advisor for Alexza/Biovail, Beta Healthcare, and Sepracor/Sunovion.
Education Partner Financial Disclosure Statement
The content collaborators at the Neuroscience Education Institute report the following:
Meghan Grady, director of content development at Neuroscience Education Institute in Carlsbad, California, has no
financial relationships to disclose.
Acronym List
Acronym
DSM
MAOI
NDRI
NRI
PHQ-9
Definition
Diagnostic and Statistical Manual
monoamine oxidase inhibitor
norepinephrine dopamine reuptake
inhibitor
norepinephrine reuptake inhibitor
Patient Health Questionnaire9
Acronym
SERT
SNRI
SSRI
TCA
Definition
serotonin transporter
serotonin norepinephrine reuptake
inhibitor
selective serotonin reuptake inhibitor
tricyclic antidepressant
Suggested Reading List

Bostwick JM. A generalists guide to treatment patients with depression with an emphasis on using side effects to tailor
antidepressant therapy. Mayo Clin Proc. 2010;85(6):538-550.
Calonge N, Petitti DB, DeWitt TG, et al.; U.S. Preventive Services Task Force. Screening for depression in adults: U.S.
preventive services task force recommendation statement. Ann Intern Med. 2009;151(11):784-792.
Cascade E, Kalali AH, Kennedy SH. Real-world data on SSRI antidepressant side effects. Psychiatry (Edgemont). 2009;6(2):1618.
Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a
multiple-treatments meta-analysis. Lancet. 2009;373(9665):746-758.
Dallaspezia S, Benedetti F. Chronobiological therapy for mood disorders. Expert Rev Neurother. 2011;11(7):961-970.
Rost K. Disability from depression: the public health challenge to primary care. Nord J Psychiatry. 2009;63(1):17-21.
Session 5
Serretti A, Chiesa A. Treatment-emergent sexual dysfunction related to antidepressants. a meta-analysis. J Clin

Psychopharmacol. 2009;29(3):259-266.
Serretti A, Mendelli L. Antidepressants and body weight: a comprehensive review and meta-analysis. J Clin Psychiatry.
2010;71(10):1259-1272.
Stahl SM. Stahls Essential Psychopharmacology. 3rd ed. New York: Cambridge University Press; 2008.
Stahl SM. Stahls Essential Psychopharmacology: The Prescribers Guide. 4th ed. New York,: Cambridge University Press; 2011.
Weihs K, Wert JM. A primary care focus on the treatment of patients with major depressive disorder. Am J Med Sci.
2011;342(4):324-330.
Session 5
Drug List
Generic
TK-301
NEU-P11
agomelatine
amitriptyline
amoxapine
aripiprazole
bupropion
citalopram
clomipramine
desipramine
desvenlafaxine
doxepin
duloxetine
escitalopram
eszopiclone
fluoxetine
fluvoxamine*
gabapentin
imipramine
isocarboxazid
lithium
Trade
N/A
N/A
Not in U.S.
Elavil
Asendin
Abilify
Wellbutrin
Celexa
Anafranil
Norpramin
Pristiq
Sinequan
Cymbalta
Lexapro
Lunesta
Prozac
Luvox*
Neurontin
Tofranil
Marplan
various
Generic
l-methylfolate
maprotiline
melatonin
milnacipran
mirtazapine
modafinil
nefazodone
nortriptyline
paroxetine
phenelzine
pregabalin
protriptyline
quetiapine
reboxetine
selegiline
sertraline
tranylcypromine
trazodone
trimipramine
venlafaxine
vilazodone
Depression:
Optimizing Outcomes for the
Individual Patient
Trade
Deplin
Ludiomil
melatonin
Savella
Remeron
Provigil
Serzone
Pamelor
Paxil
Nardil
Lyrica
Triptil
Seroquel
Not in U.S.
EMSAM
Zoloft
Parnate
Desyrel
Surmontil
Effexor
Viibryd
*Off-label
Copyright 2012 Neuroscience Education Institute. All rights reserved.
Learning Objectives
Pretest
A 31-year-old man present complaining of insomnia, constant
fatigue, lack of motivation, and depressed mood. Initial physical
exam is not significant and he is asked to complete the Patient
Health Questionnaire. His score is 14, indicating mild depression.
Based on this, which of the following would be an appropriate
treatment recommendation?
Provide initial evidence-based depression treatment

that is specifically suited to the individual patient's
need
Monitor patients with depression over time in order
to track treatment adherence, response, and side
effects
Make evidence-based treatment adjustments to
address residual symptoms and side effects
1.
2.
3.
4.
5.
6.
Watchful waiting
Antidepressant medication
Psychotherapy
1 or 3
2 or 3
Unsure
Pretest
Pretest
A 48-year-old man who suffers from major depression is currently

taking sertraline, 150 mg/day in the morning. His depressive
symptoms are fairly well controlled, and his chief complaint at this
point is ongoing insomnia. Specifically, he cannot fall asleep until the
early hours of the morning, but then has a very difficult time waking
up for work. This was true prior to his antidepressant treatment as
well. He does not take any other medications. Which of the following
treatment options may be most beneficial for this patient?
Do you establish and monitor markers for patients who are being
treated for major depression?
1. Yes, for all patients who are/have been treated for depression
2. Yes, for patients who have not yet responded to antidepressant
treatment
3. No, I do not use markers
1.Early morning melatonin

2.Evening melatonin
3.Melatonin would not be appropriate for this patient
PHQ-9 Symptom Checklist

1. Over the last two weeks have you been
bothered by the following problems?
Treating Depression in Adults
Not Several
at all days
0
1
a.
Little interest or pleasure in doing things
b.
Feeling down, depressed, or hopeless
c.
Trouble falling or staying asleep, or sleeping too much
More than Nearly

half the every
days
day
2
3
d. Feeling tired or having little energy
Guidelines and Monitoring

Patients
e.
Poor appetite or overeating
f.
Feeling bad about yourself, or that you are a failure . . .
g. Trouble concentrating on things, such as reading . . .

h. Moving or speaking so slowly . . .
i.
Thoughts that you would be better off dead . . .
2. ... how difficult have these problems made

it for you to do your work, take care of things
at home, or get along with other people?
Not difficult at all
Somewhat Difficult
Subtotals:
TOTAL:
Very Difficult
Extremely Difficult
Depression Treatment Guidelines
Guidelines for Management
Severity /
PHQ-9 Initial Strategy
Impairment Score
EDUCATE the patient about depression, management

options, and the limits of confidentiality
DEVELOP a treatment plan with the patient that includes
specific treatment goals in key areas of functioning
(home, work, and social settings)
Severe
20
May start with antidepressant or psychotherapy

but prefer combination
no
Adjust treatment
Antidepressants
and Risk of Suicidality
Medication vs. Psychotherapy
Severe negative thinking
Antidepressant, psychotherapy, or combination
Continue current treatment

Reassess by 46 weeks
yes
no
Full remission?
Weihs K, Wert JM. Am J Med Sci 2011; 342(4):324-30.
Continue to prevent relapse
APA. Practice Guideline... 3rd ed. APA; 2010.
Possible long-termCopyright
maintenance
2012 Neuroscience Education Institute. All rights reserved.
Zuckerbrot RA, et al. Pediatrics 2007;120;e1299-1312.
Severe loss of pleasure

Overwhelming
neurovegetative
symptoms
Monotherapy psychotherapy or antidepressant
1519
Follow-up (2 weeks):
Symptoms improving (PHQ-9)
Treatment well-tolerated
Adherent
yes
Especially important at diagnosis and during initial treatment
Psychotherapy
1014
Moderate
Psychoeducation and self-management should be provided at all severity levels
ESTABLISH relevant collaboration with mental health

resources
ESTABLISH a safety plan
Medication
Mild
Efficacy, tolerability, and safety of antidepressants

have been studied mostly in individuals between the
ages of 19 to 64
Limited data in children and adolescents suggest
increased risk of suicidality
CBT
Life crisis
Interpersonal therapy
Efficacy not well studied, particularly in younger

children
Data show reduced risk of suicidality for adults ages

65 years and older
Bostwick JM. Mayo Clin Proc 2010;85(6):538-50.
Stone M, et al. BMJ 2009;339:b2880.
Things to Tell Your Patients

About Antidepressants
Monitoring for Response, Adherence, and

Side Effects
Antidepressants only work if taken every day

Antidepressants are not addictive
Benefits from medication appear slowly; some symptoms
may take longer to resolve than others
Mild side effects are common, happen early (before
therapeutic effects), and usually improve with time
Notify you of any late-developing or persistent side
effectsmay require treatment adjustment
Antidepressants should still be taken even after
symptoms abate
Stopping antidepressant treatment abruptly is dangerous
Sometimes it takes a few tries to attain remission
46% of patients stop medication before the chance of

response
A large portion who do respond discontinue once they
feel better
Use10-minute phone calls to identify patients:
With intolerable side effects
Who are not responding or have residual symptoms
Who have discontinued their medication
Who relapse
Focus on tracking most troublesome symptoms rather
than depressed mood per se
Rost K. Nord J Psychiatry 2009;63:17-21.
Monitoring for Response/Remission and

Relapse: Markers
Side Effects
Options to Avoid/Address the
Most Troublesome Side Effects
Stahl, SM. J Clin Psychiatry 2000;61(5):327-8.

Most Troubling Antidepressant Side Effects

Short-term
Longer-term
Nausea
Headache
Activation
Sedation
Sexual dysfunction
Weight gain
SSRI-Induced Activation
SSRIs can be activating upon initiation, causing agitation
and/or increasing anxiety
fluoxetine > sertraline > citalopram/escitalopram/paroxetine
Side effects usually subside in first few weeks of

treatment
Patients experiencing SSRI-induced agitation should
continue taking their medication regularly for several
weeks
Discontinuing or changing dose can prevent stabilization of
therapeutic effects
Therapeutic effects can take several weeks to stabilize
Adding a benzodiazepine short-term can be useful

Cascade E et al. Psychiatry (Edgmont) 2009;6(2):16-8.
Addressing Sedation
Sedation
bupropion
escitalopram
fluoxetine
selegiline
sertraline
vilazodone
citalopram
desvenlafaxine
duloxetine
milnacipran
venlafaxine
amitriptyline
amoxapine
clomipramine
desipramine
doxepin
fluvoxamine
imipramine
isocarboxazid
maprotiline
Dose at night or take larger dose at night

If patient is responding and otherwise tolerating
current treatment
mirtazapine
nefazodone
nortriptyline
paroxetine
phenelzine
protriptyline
tranylcypromine
trazodone
trimipramine
Consider adding modafinil/armodafinil
If patient is not responding, sedation is not

addressed by dosing adjustments, or sedation is
truly intolerable
Switch to a nonsedating antidepressant
Note: clomipramine, fluvoxamine, milnacipran, and low-dose doxepin formulation

are not approved to treat depression
Stahl SM. Stahls essential psychopharmacology: the prescribers guide. 4th ed. 2011.
bupropion
mirtazapine
nefazodone
selegiline
trazodone
vilazodone
Sexual Dysfunction
Addressing Sexual Dysfunction
fluvoxamine
amitriptyline
amoxapine
citalopram
clomipramine
desvenlafaxine
duloxetine
escitalopram
fluoxetine
imipramine
isocarboxazid
Assess sexual function before starting medication

Dont rely on self report
Add high-dose (60 mg/day) buspirone
Switch to agent with less likelihood of sexual
dysfunction (bupropion, vilazodone)
Add phosphodiesterase 5 (PDE-5) inhibitor (e.g.,
sildenafil, vardenafil, tadalafil)
maprotiline
milnacipran
nortriptyline
paroxetine
phenelzine
protriptyline
sertraline
tranylcypromine
trimipramine
venlafaxine
Note: These do not increase desire
For women, consider estrogen creams

Note: clomipramine, fluvoxamine, and milnacipran are not approved to treat depression
Serretti A, Chiesa A. J Clin Psychopharmacol 2009;29:259-66.
Short-Term Weight Gain:

Meta-Analysis
Weight Gain
bupropion
citalopram
desvenlafaxine
duloxetine
escitalopram
fluoxetine
fluvoxamine
milnacipran
nefazodone
selegiline
sertraline
trazodone
venlafaxine
vilazodone
paroxetine
tranylcypromine
imipramine, paroxetine,
desipramine, clomipramine
amitriptyline
amoxapine
clomipramine
desipramine
imipramine
isocarboxazid
maprotiline
mirtazapine
nortriptyline
phenelzine
protriptyline
trimipramine
Note: clomipramine, fluvoxamine, and milnacipran are not approved to treat depression
Note: clomipramine, fluvoxamine, and moclobemide are not approved to treat depression in the U.S.
Serretti A, Mandelli L. J Clin Psychiatry 2010;71(10):1259-72.
*Filled squares indicate a significant effect.

Long-Term Weight Gain:

Meta-Analysis
Addressing Weight Gain

In meta-analysis, average weight with medications is
small
imipramine, paroxetine,
desipramine, clomipramine
A few patients may gain most of the weight, related to

their own genetic predispostions and other factors
Large weight gain typically occurs gradually over

many months
Monitor patients for weight gain, appetite changes,
and metabolic parameters
If significant weight gain occurs, consider switching
to an agent with less risk of weight change
*Filled squares indicate a significant effect.
Why Remission and Not Just

Response?
Improved social and occupational functioning
Marital discord
Child well-being
Occupational impairment
Residual Symptoms
Physical functioning
Options for Partial/Lack of

Response
Medical comorbidity (morbidity/mortality)
Risk of suicide
Increased risk of relapse
STAR*D: Percent Response and

Remission by Levels
STAR*D Algorithm
Level 1
Citalopram
Level 2 SER BUP VEN CT
Level 2a
Level 3
50%
45%
40%
35%
30%
25%
20%
15%
10%
5%
0%
CIT +: BUP BUS CT
BUP VEN
Mirt
Nortr
Augmentation: Li vs. T3
SER BUP VEN CIT
48.6%
36.8%
30.6%
28.5%
Response
Level 1
Level 4
TCP VEN+MIRT
Fava M, et al.
Psychiatr Clin N Am
2003;26:457-94.
The further along

treatment goes,
the less change
actually occurs
Level 2
16.8%
13.7%
16.3%
13.0%
Level 3
Level 4
Rush AJ, et al. Am J Psychiatry 2006;163:1905-17.

Remission
STAR*D: Increasing Relapse Rates With

Every Treatment Failure
Comparative Efficacy and Acceptability of

12 New-Generation Antidepressants
STAR*D Relapse Rates
After 2 Failures
Patients Relapsing
70%
After 1 Failure
60%
71.7%
64.6%
55.3%
50%
40%
Multiple-treatments meta-analysis
Results/interpretation:
Mirtazapine, escitalopram, venlafaxine, and sertraline were
significantly more efficacious than duloxetine, fluoxetine,
fluvoxamine, paroxetine, and reboxetine
Escitalopram and sertraline showed the best profiles of
acceptability and therefore the lowest rates of
discontinuation (significant vs. duloxetine, fluvoxamine,
paroxetine, reboxetine, and venlafaxine)
Sertraline may be the best choice when initiating treatment
for moderate to severe major depression: best balance
between benefits, acceptability, and cost
After 3 Failures
80%
40.1%
30%
20%
10%
0%
Level 1
Level 2
Level 3
Level 4
Rush AJ, et al. Am J Psychiatry 2006;163:1905-17.
The efficacy and acceptability of buproprion, milnacipran, and citalopram were at intermediate values that were
not significantly different from the other 9 agents. Note: Reboxetine and milnacipran are not approved to treat
depression in the U.S. Cipriani A, et al. Lancet 2009;373:746-758.
Case: When Does It Make Sense

to Increase the Dose?
When Does it Make Sense

to Increase the Dose?
Response
venlafaxine
Response
TCAs
Sasha is a 37-year-old female patient with major

depressive disorder. She is currently taking the
serotonin norepinephrine reuptake inhibitor (SNRI)
venlafaxine 75 mg/day but is only partially
responsive to treatment. Does it make sense to
increase the dose for this patient? Why or why not?
Dose
Dose
SSRIs
Response
Response
tranylcypromine
Dose
Adli M, et al. Eur Arch Psychiatry 2005;255(6):387-400.
Dose
Case: What is the Evidence-Base for Different

Augmentation Strategies?
Common Augmentation Strategies

for Partial Response in Depression
Lithium
Michelle is a 35-year-old patient who has not

responded to two trials of SSRIs and is only partially
responsive to her current antidepressant (an SNRI),
with multiple residual symptoms. Guidelines often
suggest augmentation of antidepressant treatment
in patients with partial response. What is the
evidence-base for different augmentation
strategies?
One of the best-researched augmentation strategies

Not approved
Thyroid hormone
Relatively little placebo-controlled trial data
Atypical antipsychotics
Aripiprazole and quetiapine XR are approved for patients
failing SNRI therapy
Combining antidepressants
Some data suggest benefits of combining agents with
different mechanisms
Marcus RN, et al. J Clin Psychopharmacol 2008;28(2):156-65. Schwartz TL, Rashid
A. P&T 2007;32(1):28-31. Weisler R, et al. CNS Spectr 2009;14(6):299-313.
Atypical Antipsychotic Augmentation of

SSRIs/SNRIs for Depression
Combination Antidepressant Therapy

to Enhance Response
Most studies of atypical augmentation have shown a

beneficial effect of combined treatment over
monotherapy
But
Advantages
Preserves the response to the first antidepressant
Which may be lost with a switch
Adds mechanisms of action to broaden the

neurochemical actions
Effect sizes have been modest

There is little head-to-head data with other strategies
The adverse event profile of atypical antipsychotics
should put them late in a treatment algorithm
None have been studied systematically for advanced
resistant depression (>2 failure)
Response to Drug A
Response to Drug B (only?)
Response to Drugs A + B
Broadens the clinical actions
Citrome L. Postgrad Med 2010;122(4):39-48.

Symptom-Specific Streategies for Common

Residual Symptoms
Increased Efficacy of Two Antidepressant

Mechanisms Over One: SSRI + NRI (TCA)
SSRI + NRI
SSRI
NRI
major
depressive
disorder
Remission
0%
Remission
7%
NonResponse response
36%
50%
Partial
response
7%
NonRemission response
38%
54%
Response
8%
Partial
response
0%
fatigue
Response
Non17%
concentration
response
33%
psychomotor
Partial
response
50%
depressed
interest/
mood
pleasure
sleep
guilt/
worthlessness
appetite/
weight
suicidality
Adapted from Nelson JC, et al. Biol Psychiatry 2004;55(3):296-300.
Stahl, SM. Stahls Essential Psychopharmacology. 3rd ed. Cambridge University Press; 2008.
Treating Residual Symptoms: Sleep
Treating Insomnia in Depression
fatigue
concentration
depression with insomnia
sleep
Fluoxetine + Fluoxetine alone

eszopiclone 33% remission
42% remission
5-HT/GABA/
histamine
sleep hygiene, CBT

hypnotics (e.g., eszopiclone, zolpidem, zaleplon, ramelteon, doxepin)
sedating antidepressants (e.g., trazodone, mirtazapine, other tricyclics)
treatment
stop activating antidepressant

Fava M, et al. Biol Psychiatry 2006;59:1052-60.

Note: sedating antidepressants are not specifically approved to treat sleep in depression
Investigational Antidepressant Treatments

That Target Circadian Function
Melatonin as Treatment for Depression

Short -life
Prolonged-release melatonin improves sleep but not depression
A preliminary study suggests antidepressant effects of the melatonin
agonist ramelteon
For patients who cant fall asleep and wake up late
Give melatonin in late afternoon/early evening
Advances circadian clock to cause earlier falling asleep and
waking
For patients who fall asleep early and wake early
Give melatonin in the morning
Delays circadian clock to cause later falling asleep and waking
Melatonin and agonists

Chronotherapies
Available elsewhere/under investigation
Agomelatine (Europe)
Melatonin 1 and 2 receptor agonist; 5HT2C antagonist
Few side effects and no discontinuation symptoms
TK-301 (in trials)

Melatonin receptor agonist with 5-HT2B and 5-HT2C
antagonism
Neu-P11 (in trials)

Melatonin receptor agonist with affinity for 5HT1A, 1B, and 2B
Quera Salva MA, et al. Curr Pharm Des 2011;17(15):1459-70;

McElroy Sl, et al. Int Clin Psychopharmacol 2011;26(1):48-53;
Galecka E, et al. Psychiatry Res 2011;Epub ahead of print.
Chronotherapies:
Bright Light Therapy
Bright Light Therapy for Depression
Exposure to light alters circadian rhythms and

suppresses melatonin release
10,000 lux (bright light) for 30 min/day
Must be timed with patients circadian phase of
melatonin secretion
Rapid onset of antidepressant action

Hastens the effects of antidepressant drugs
Antidepressant effects mediated through eyes
Extraocular administration shows no antidepressant benefits
Good for bipolar depression but may precipitate mania

Dawn simulation therapy
Administer light 7.5-9.5 hrs after evening melatonin secretion

Approximation of melatonin secretion can be determined using
the Horne-Ostberg Morningness-Eveningness Questionnaire
(MEQ)
Slow incremental light signal at the end of the sleep cycle
Side effects are rare

Headaches, eyestrain, nausea, and agitation
Useful as a non-pharmacological intervention during

pregnancy
Dallaspezia S, Benedetti F. Expert Rev Neurother 2011;11(7):961-70;

Pail G et al. Neuropsychobiol 2009;64:152-62.
Dallaspezia S, Benedetti F. Expert Rev Neurother 2011;11(7):961-70;

Terman M et al. Biol Psychiatry 1989;25(7):966-70.
Chronotherapies:
Sleep Deprivation Therapy
Chronotherapies:
Sleep Phase Advance Therapy
36 hrs of deprivation
Antidepressant effects within hours
Decreases activity of 5-HT2C receptors
Response rates are similar to antidepressants (50-80%)
Response is influenced by some of the same polymorphisms

5-HTTR (serotonin transporter), 5-HT2A, COMT, GSK-3
Advances timing of sleep-wake cycle

Synchronizes sleep with other biological rhythms
Improves effects of antidepressants
Also effective as monotherapy
Improvement doesnt last unless combined with:

Other chronotherapies
Lithium
Antidepressants
Contraindicated for patients with epilepsy

Sleep deprivation increases risk of seizures in patients with epilepsy
Dallaspezia S, Benedetti F. Expert Rev Neurother 2011;11(7):961-70.
Dallaspezia S, Benedetti F. Expert Rev Neurother 2011;11(7):961-70.
Treating Residual Symptoms:

Fatigue and Concentration
Other Common Residual Symptoms of Depression

SSRI/SNRI
MAOI
+ benzo
+
2 antagonist
+ SDA/DPA
fatigue
NE/DA
sleep
NDRI
NRI
SNRI
MAOI
+ modafinil/armodafinil
+ stimulant
+ SDA
+ Li/thyroid/MTH-folate
+ 5-HT1A agonist
dual
5HT/NE
vasomotor
12-126
sexual
dysfunction
pain
DA
SNRI
+ alpha 2 delta
(gabapentin/
pregabalin)
+ estrogen?
SNRI (e.g., desvenlafaxine)
anxiety
5HT
GABA
concentration
NE/DA
dual
5HT/NE
sleepiness/
hypersomnia
DA
NE
histamine
1) NDRI
2)
2 antagonist
3) SARI
4) MAOI
5) 5HT2A/5HT2C
antagonist/
5HT1A agonist
(NDDI)
6) add stimulant
7) stop SSRI/SNRI
+ modafinil
+ stimulant
stop antihistamine,
antimuscarinic,
alpha 1 blockers
Tricyclic Antidepressant (TCA)

Tips and Pearls (1)
Switching Options for Lack of Response

No evidence supporting preference for one agent or one class
over another
Switching within the same class or to another class are both
options
Commonly used: another SSRI/SNRI, bupropion, mirtazapine
Under-used: tricyclic antidepressant (TCA), monoamine oxidase
Can monitor plasma drug levels of many TCAs, especially

nortriptyline, amitriptyline, desipramine, imipramine,
clomipramine/desmethylclomipramine
Most TCAs are CYP2D6 substrates so lower the dose in
genetic poor metabolizers (can now genotype patients for
CYP2D6)
Also, lower the dose if used concomitantly with 2D6 inhibitors
(e.g., fluoxetine, paroxetine, many others)
Tertiary TCAs are metabolized to secondary TCAs by
CYP1A2 (e.g., amitryptyline to nortriptyline; imipramine to
desipramine; clomipramine to desmethylclomipramine) which
can be inhibited by 1A2 inhibitors such as fluvoxamine
inhibitors (MAOIs)
Connolly et al. Drugs 2011;71(7):43-64.

Rush et al. N Engl J Med 2006;354:1231-42.
Note: clomipramine is not approved to treat depression
Tricyclic Antidepressant
Tips and Pearls (2)
TCAs can be sedating, so usually given in a single dose at
bedtime
Doxepin most highly antihistaminic, even at 1-10 mg
In fact, a low-dose formulation of doxepin is now available
for treating insomnia
TCAs may be the best treatment for depression in
Parkinsons disease
Desipramine, nortriptyline, maprotiline are more
noradrenergic
Some TCAs have 5HT2A and 5HT2C antagonist properties
that contribute to their antidepressant action
Novel Treatment Options for

Depression in Adults
Low-dose doxepin formulation is not approved to treat depression.

Stahl SM. Stahls Essential Psychopharmacology. 3rd ed. Cambridge University Press; 2008.
Menza M, et al. Neurology 2009;72(10):886-92.
Vilazodone
Vilazodone: Clinical Data

0
Least-Squares Mean (SE) Change from
Baseline in MADRS Total Score
5HT1A partial agonist and a 5HT transport inhibitor

Like combining an SSRI with buspirone, except
Vilazodones effects at 5HT1A receptors are equal or more
potent than its effects at 5HT transporters
Buspirone is much weaker at 5HT1A receptors
The combined action downregulates presynaptic 5HT1A
autoreceptors over time, eventually increasing 5HT release
into postsynaptic receptors and causing antidepressant
effects
Weeks Receiving Treatment

3
4
5
Placebo (n=232)
Vilazodone (n=231)
-2
-4
-6
-8
-10
-12
P=.051
-14
P=.019
-16
P=.007
Intent-to-treat population. Mixed effects model repeated measures.

Khan A, et al. J Clin Psychiatry 2011;72(4):441-7.
Note: buspirone is not approved to treat depression

Khan A. Expert Opin Investig Drugs 2009;18(11):1753-64.
Vilazodone
L-methylfolate as Augmentation
for Major Depressive Disorder
Usual dose: 40 mg once daily with food

Minimally effective dose not established
Metabolized by CYP450 3A4
Relative lack of sexual dysfunction and weight gain
Most common side effects are diarrhea, nausea,
vomiting, insomnia
Consider for patients with comorbid anxiety
Medical food for suboptimal folate levels in

depressed patients (adjunct to antidepressant)
L-methylfolate is a required co-factor in the
synthesis of all 3 monoamines
L-methylfolate deficiency may be common as a
result of genetic polymorphisms
Two open-label trials support use at the outset of
treatment
One short-term trial supports use as an add-on
therapy
Laughren TP, et al. J Clin Psychiatry 2011;72(9):1166-73.
Up to 70% of MDD Patients Have a Genetic

Polymorphism Impairing Their Ability to
Reduce Folic Acid to L-methylfolate
L-methylfolate Involvement
in Monoamine Synthesis
BH4 activates
the hydroxylase
2 enzymes
to
Tyrosine
and
L-methylfolate
assists
insynthesize
the formation
3 monoamines
tryptophan
hydroxylase
are
of
inactive
in absence of
BH4
tetrahydrobiopterin
(BH4)
MTHFR C677T Polymorphism in Depression

T/T
Polymorphism
14%
C/C
Normal
30%
C/T
Polymorphism
56%
Patients with the C677T

MTHFR polymorphism
have low CNS Lmethylfolate1
Low CNS L-methylfolate is
associated with low
production of serotonin,
norepinephrine, and
dopamine2,3
MTHF
Methylene
THF
BH4
BH2
1. Kelly CB, et al. J Psychopharmacol 2004;18(4):567-71.

2. Bottiglieri T, et al. J Neurol Neurosurg Psychiatry 2000;69:228-32.
3. Surtees R, et al. Clin Sci 1994;86:697-702.
Adapted from Stahl SM. J Clin Psychiatry 2008;69:1352-3.
10
Why Folate Supplementation

Doesnt Work
Summary
Blood
Folate
Many treatment options are available; customize

treatment selection based on the patients
symptoms and concerns
Brain
Folate
Folate
Folate
L-methylfolate
Establish markers and use brief follow-up phone

calls to monitor patients for response, side effects,
and adherence
Adjust treatment by switching or augmenting to

address side effects and residual symptoms
Folate
Folate
Blood-Brain
Barrier
Folate
Folate
Wu D, Pardridge WM. Pharmaceutical Res 1999;16:415-9.

Posttest
Posttest
A 31-year-old man present complaining of insomnia, constant

fatigue, lack of motivation, and depressed mood. Initial physical
exam is not significant and he is asked to complete the Patient
Health Questionnaire. His score is 14, indicating mild depression.
Based on this, which of the following would be an appropriate
treatment recommendation?
1.
2.
3.
4.
5.
6.
Do you now plan to establish and monitor markers for patients

who are being treated for major depression?
1. Yes, for all patients who are/have been treated for depression
2. Yes, for patients who have not yet responded to antidepressant
treatment
3. No, I do not use markers
Watchful waiting
Antidepressant medication
Psychotherapy
1 or 3
2 or 3
Unsure
Posttest
A 48-year-old man who suffers from major depression is currently
taking sertraline, 150 mg/day in the morning. His depressive
symptoms are fairly well controlled, and his chief complaint at this
point is ongoing insomnia. Specifically, he cannot fall asleep until the
early hours of the morning, but then has a very difficult time waking
up for work. This was true prior to his antidepressant treatment as
well. He does not take any other medications. Which of the following
treatment options may be most beneficial for this patient?
1.Early morning melatonin
2.Evening melatonin
3.Melatonin would not be appropriate for this patient
11

Depression Management

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Depression: Optimizing Outcomes

for the Individual Patient

Session 5: Depression: Optimizing Outcomes for the Individual Patient

Faculty Financial Disclosure Statement

The presenting faculty reported the following:

Education Partner Financial Disclosure Statement

Suggested Reading List

Serretti A, Chiesa A. Treatment-emergent sexual dysfunction related to antidepressants. a meta-analysis. J Clin

Provide initial evidence-based depression treatment

Copyright 2012 Neuroscience Education Institute. All rights reserved.

A 48-year-old man who suffers from major depression is currently

1.Early morning melatonin

PHQ-9 Symptom Checklist

Treating Depression in Adults

Little interest or pleasure in doing things

Feeling down, depressed, or hopeless

Trouble falling or staying asleep, or sleeping too much

More than Nearly

d. Feeling tired or having little energy

Guidelines and Monitoring

Poor appetite or overeating

Feeling bad about yourself, or that you are a failure . . .

g. Trouble concentrating on things, such as reading . . .

Thoughts that you would be better off dead . . .

2. ... how difficult have these problems made

Copyright 2012 Neuroscience Education Institute. All rights reserved.

Depression Treatment Guidelines

Guidelines for Management

EDUCATE the patient about depression, management

Copyright 2012 Neuroscience Education Institute. All rights reserved.

May start with antidepressant or psychotherapy

Medication vs. Psychotherapy

Severe negative thinking

Antidepressant, psychotherapy, or combination

Continue current treatment

Zuckerbrot RA, et al. Pediatrics 2007;120;e1299-1312.

Severe loss of pleasure

Monotherapy psychotherapy or antidepressant

Especially important at diagnosis and during initial treatment

Psychoeducation and self-management should be provided at all severity levels

ESTABLISH relevant collaboration with mental health

Efficacy, tolerability, and safety of antidepressants

Efficacy not well studied, particularly in younger

Data show reduced risk of suicidality for adults ages

Bostwick JM. Mayo Clin Proc 2010;85(6):538-50.

Stone M, et al. BMJ 2009;339:b2880.

Copyright 2012 Neuroscience Education Institute. All rights reserved.

Copyright 2012 Neuroscience Education Institute. All rights reserved.

Things to Tell Your Patients

Monitoring for Response, Adherence, and

Antidepressants only work if taken every day

46% of patients stop medication before the chance of

Copyright 2012 Neuroscience Education Institute. All rights reserved.

Copyright 2012 Neuroscience Education Institute. All rights reserved.

Monitoring for Response/Remission and

Stahl, SM. J Clin Psychiatry 2000;61(5):327-8.

Most Troubling Antidepressant Side Effects

Side effects usually subside in first few weeks of

Bostwick JM. Mayo Clin Proc 2010;85(6):538-50.

Copyright 2012 Neuroscience Education Institute. All rights reserved.

Dose at night or take larger dose at night

Consider adding modafinil/armodafinil

If patient is not responding, sedation is not

Note: clomipramine, fluvoxamine, milnacipran, and low-dose doxepin formulation