Pharmacologic Considerations in
the Treatment of Major Depressive
Disorder
Presented by: Ann M. Hamer, PharmD, BCPP
Date: 10/30/2014
Disclosures and Learning Objectives
• Learning Objectives
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Be able to identify common adverse
effects of newer antidepressants
Be able to discuss differences between
the newer antidepressants
Be able to define the goals of
antidepressant treatment
Disclosures: Dr. Ann Hamer has nothing to disclose.
Pharmacologic Treatment of MDD
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Review summary of evidence
Review adverse effects
Review antidepressant withdrawal
Review drug interactions
Review antidepressant costs
Review goals of treatment
• Next Week's Topic
Treatment Guidelines
American Psychiatric Association
Choosing an Initial Antidepressant
Because there is comparable efficacy between and within
classes of medications, the initial selection of antidepressants
is based largely on the following considerations:
•Anticipated side effects
•Safety and tolerability of side effects for individual patients
•Patient preference
•Quantity and quality of clinical trial data
•Cost
www.psych.org
OHSU Drug Effectiveness Review Project—CEBP
Summary of the Evidence
• Effectiveness and efficacy were similar
between all second generation
antidepressants.
• Roughly a 60% overall response rate
• Discontinuation rates and response and
remission rates did not differ substantially.
www.ohsu.edu/drugeffectiveness/reports/final.cfm
Available Antidepressants
SSRIs
Brintellix (vortioxetine) B
Celexa (citalopram) G
Lexapro (escitalopram) G
Luvox (fluvoxamine) G
Paxil (paroxetine) G
Prozac (fluoxetine) G
Viibryd (vilazodone) B
Zoloft (sertraline) G
Selectively inhibit the
reuptake of serotonin (5HT)
at the presynaptic neuronal
membrane
G=Generic; B=Brand
SNRIs
Cymbalta (duloxetine) B
Effexor (venlafaxine) G
Fetzima (levomilnacipran) B
Pristiq (desvenlafaxine) B
Others
Wellbutrin (bupropion) G
Bupropion is a weak
inhibitor of DA, NE and 5HT
reuptake
Remeron (mirtazapine) G
Inhibit serotonin and
norepinephrine reuptake
Mirtazapine ↑central
noradrenaline and 5HT
activity by antagonizing
central presynaptic α2
adrenergic autoreceptors
and heteroreceptors
Common Adverse Effects
SNRIs
SSRIs
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Nausea
Vomiting
Dizziness
Insomnia
Agitation
Headache
Sexual dysfunction
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Nausea
Vomiting
Dizziness
Insomnia
Anxiety
Headache
Somnolence
Decreased appetite
Sexual dysfunction
Others
Bupropion:
• Headache
• Agitation,
• Weight loss
• Insomnia
• Nausea
Mirtazapine:
• Dizziness
• Diarrhea
• Increased appetite
(weight gain)
• Drowsiness,
• Dry mouth
ATD Induced Sexual Dysfunction
Antidepressant
Type of Sexual Dysfunction
Incidence*
Venlafaxine
Impaired ejaculation, delayed/absent orgasm
12%
Paroxetine
Impaired ejaculation, delayed/absent orgasm
13-28%
Fluvoxamine
Impaired ejaculation, delayed/absent orgasm
2-8%
Sertraline
Impaired ejaculation, delayed/absent orgasm
14%
Citalopram
Impaired ejaculation, delayed/absent orgasm,
decreased libido
1-6%
Fluoxetine
Impaired ejaculation, delayed/absent orgasm,
decreased libido, and erectile impairment
2-11%
Mirtazapine
Decreased libido
2-6%
Bupropion
Decreased libido
1-3%
*Based on spontaneous report in clinical trials
ATD Induced Sexual Dysfunction
Key Points
• Serotonergic antidepressant incidence may
be as high as 50-70%.
• Lowest level of sexual dysfunction with nonserotonergic antidepressants.
• Patients should be routinely asked about
sexual adverse effects. May affect ATD
adherence.
• Best way to avoid is the use of nonserotonergic antidepressants.
ATD Sexual Dysfunction
Treatment
• Use non-serotonergic antidepressant (e.g.
bupropion) first.
• Wait it out
• Only useful in a minority of patients
• Carefully switch to non-serotonergic
antidepressant
Drug Interactions
Drug Interactions
• Citalopram—least likely SSRI to cause CYP450
drug interactions
• Venlafaxine—less likely than duloxetine to
cause drug interactions; duloxetine more highly
protein bound and 1A2 substrate
• Bupropion—can lower the seizure threshold
ATD Withdrawal
Occurs with most antidepressants if the dose is
not tapered.
Serotonin discontinuation syndrome
F = flu-like symptoms
I = insomnia
N = nausea
I = imbalance
S = sensory disturbances
H = hyperarousal
ATD Withdrawal
• May be difficult to distinguish from depression
relapse.
• Antidepressant withdrawal syndrome is
characterized by the time-locked emergence of
new, defined and quantifiable signs and
symptoms, which develop on cessation or
reduction of an antidepressant that has been
taken for more than a few weeks.
ATD Withdrawal
Symptoms
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Typically start 24 to 72 hours after the last antidepressant
dose (peaking at 1 week).
Typically resolve within 1 to 3 weeks.
Severe and disabling withdrawal syndrome seen in 5% of
patients.
Treatment
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Tapering the dose can decrease the symptoms.
Restarting the antidepressant will make the symptoms go
away.
Slower tapers may then be necessary
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Depends on drug and patient
Patient Preference
Patient Responses
Common Side Effects
Precautions
MD experience
Uncommon serious s.e.
DC problems
Time in market
Dosing schedule
Cost
Blood test
Common other uses
Pill appearance
GP Responses
Common side effects
Cost
Precautions
MD experience
Dosing schedule
DC problems
Uncommon serious s.e.
Time in market
Blood test
Common other uses
Pill appearance
Antidepressants Costs
Drug
Average Dose
Average Cost*
Comment
Brintellix (vortioxetine)
20mg QD
$253
Brand only
Bupropion XL
150mg BID
$28
Citalopram
20mg QD
$5
LCA, $
Cymbalta (duloxetine)
30mg QD
$39
Brand only
Escitalopram
10mg QD
$12
Fetzima (levomilnacipran)
40mg QD
$201
Brand only
Fluoxetine
20mg QD
$5
LCA
Fluvoxamine
100mg BID
$14
Mirtazapine
30mg QD
$13
Paroxetine
20mg QD
$9
LCA, $
Pristiq (desvenlafaxine)
100mg QD
$157
Brand only
Sertraline
100mg QD
$9
LCA
Venlafaxine XR
150mg QD
$17
Viibryd (vilazodone)
40mg QD
$176
Brand only
*GoodRx.com price comparison; LCA=low cost alternative; $=Walmart $4/$10 generic
Defining the Goals of Treatment
Response = a clinically significant degree of depressive
symptom reduction following treatment initiation.
When used clinically, response implies that the treatment
has caused the response
Response criteria must be met for 3 consecutive weeks
Remission = the virtual absence of depressive symptoms.
3 consecutive weeks must pass, during which each week
is characterized by the virtual absence of depressive
symptoms, before remission can be ascribed.
Remission may end with either relapse or recovery.
Progressive ATD Treatment (STAR*D)
Level
Treatment
Choices
1
Monotherapy
2
3
4
Remission
Rate
Relapse
Rate
SSRI
30%
33.5%
Switch
Different SSRI, bupropion SR or
venlafaxine XR
25%
47.4%
Augment
Bupropion SR
30%
Switch
Mirtazapine or nortriptyline
Augment
Lithium or
thyroid (T3)
Switch
MAOI or
venlafaxine + mirtazapine
12-20%
42.9%
16%
25%
6.9%
13.7%
>50%
Switching Strategies
Drug switching to
Initial drug
Fluoxetine Other SSRI
SNRI
Mirtazapine Nefazodone Bupropion MAOI
Fluoxetine
3
1
2
3
1
3
Other SSRI
1
1
1
2
3
2
3
SNRI
1
1
1
2
2
2
3
Mirtazapine
2
2
2
2
2
3
Nefazodone
3
3
2
2
2
3
Bupropion
1
1
1
2
2
3
MAOI
3
3
3
3
3
3
Key: (1) direct switch probably safe; (2) cross-taper recommended; (3) washout period advisable
ATD Comparison
Summary of Comparative Data with Newer ATDs (Moderate to High Level Evidence)
Comparative Benefits
•Similar efficacy, effectiveness, and QOL
•Onset of action
•Mirtazapine > citalopram, fluoxetine,
paroxetine, & sertraline
•Response rates similar after 4 weeks of tx
Comparative Adverse Effects
•Nausea and vomiting: Venlafaxine has a 52%
higher incidence than SSRIs as a class
•Weight gain: Mirtazapine > citalopram,
fluoxetine, paroxetine, sertraline (1.8 – 6.6 lbs
after 6-8 wks)
•Efficacy does not differ in older adults
•Diarrhea: Sertraline > bupropion, citalopram,
fluoxetine, fluvoxamine, mirtazapine,
nefazodone, paroxetine & venlafaxine
•Fluoxetine daily = fluoxetine weekly (response
and remission rates)
•Discontinuation Rates: Duloxetine & venlafaxine
> SSRIs
•Paroxetine IR = paroxetine CR (response and
adherence rates)
•Withdrawal Symptoms: Paroxetine &
venlafaxine > other SSRIs; Lowest with
fluoxetine
•Remission rates similar
•Similar efficacy for treating anxiety and
depression in MDD with anxiety sx
•Paroxetine=duloxetine (pain scores for patients
with depression
•Sexual Dysfunction: Bupropion < escitalopram,
fluoxetine, paroxetine, and sertraline; Paroxetine
> other SSRIs
Summary
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Best chance for success (remission) with
antidepressant tx may be with first trial
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Use at an adequate dose for an adequate
duration
Similar efficacy between newer
antidepressants with minor differences
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Adverse effects, drug interactions, patient
preference and cost are all important
considerations
The End!
Next Week's
Topic:
Pharmacologic
Treatment of
Bipolar
Disorder