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California Association of Toxicologists Annual Meeting (June 9, 2006)
Safety and Efficacy of Antidepressants
and Antipsychotics too
Patrick R. Finley, Pharm.D. BCPP
Professor of Clinical Pharmacy
Psychopharmacology and Behavioral Health
University of California at San Francisco
e-mail: [email protected]
Efficacy of Antidepressants in
Treating Major Depression
100%
80%
60%
65%
40%
35%
20%
0%
Therapeutic Response
>50% decrease sx
Achieve Remission
HAMD < 7
Evaluation of Outcomes with Citalopram for Depression
Using Measurement-Based Care in STAR*D:
Implications for Clinical Practice
Trivedi MH et al. Am J Psychiatry 2006; 163:5-7

Methods
– 2876 depressed patients enrolled from 23 psychiatric, 18 primary care
settings into rigid treatment protocol
– Pts treated initially with citalopram for up to 14 weeks
– Pts randomized to other treatment thereafter if unsuccessful

Results (Level 1)
–
–
–
–
–
Avg of 4.8 visits during tx phase
Avg citalopram dose = 41.8 mg/day
33 % achieved remission ( 5 on QIDS-SR)
47 % had therapeutic response ( 50% decline QIDS-SR)
4.1% had serious adverse effects (no suicides reported)
The majority of patients
prescribed antidepressants
will need a change in their regimen*
* - dosage adjustment, augmentation, or switch antidepressants
Outcomes of Depressed Patients:
Therapeutic Response vs Remission
Pts Maintaining Response
Paykel et al. Psychol Med 1995
1
0.8
Remission
(HAMD<7)
Residual Sx
(HAMD>7)
0.6
0.4
0.2
0
0
2
4
6
Months
8
10
12
Residual Symptoms of Depressed Patients Who
Respond Acutely to Fluoxetine (n=108)
Nierenberg A et al. J Clin Psychiatry 1999;60:221-225.
40
30
20
10
nt
ra
Su
tio
ici
n
da
lI
de
at
io
n
Gu
ilt
Co
nc
e
tig
ue
Fa
ot
or
om
Ps
yc
h
Sl
ee
p
t
W
eig
h
In
te
re
st
oo
d
0
M
Percentage of
Patients
50
Suggestion #1:
Go for the Gold !!
(ie – remission)
Suggestion #2:
Don’t Forget About Psychotherapy
Antidepressant Selection May be
Influenced by the Following:





Family History
Adverse Effects
Medical Co-Morbidities
Psychiatric Co-morbidities
Depression Subtypes
– Anergic/Amotivational
– Anxious/Irritable
– Severe or Tx-Resistant


Gender
Other (drug interactions, cost etc)
SSRI: Common Adverse Effects

Gastrointestinal
–

nausea, diarrhea (fluox, sert), constipation (parox)
Central Nervous System
–
–
headache
insomnia/agitation >>> sedation


Hierarchy: fluox > sert > escital > cital > parox > fluvox
[Prozac > Zoloft > Lexapro > Celexa > Paxil > Luvox}
Sexual Effects
SSRI/SNRI and Sexual Dysfunction
Epidemiology




Approximate incidence (new-onset) = 50 % (range: 2 % - 75 %);
Hierarchy: parox > fluox  sert, cital, escital > fluvox
Incidence slightly higher in men (?)
Severity slightly higher in women (?)
Types of Sexual Dysfunction
–
–
–
libido problems more common with depression
orgasm problems more common with antidepressant
(eg - delayed ejaculation or anorgasmia)
erectile problems uncommon with SSRI
[Patient Counseling:
‘This medication may change your sexual functioning’]
Effect of SSRI Antidepressants on Ejaculation
Waldinger et al. J Clin Psychopharmacol 1998; 18:274-81.

Methods
– Double-blind placebo-controlled RCT
– Compared effects of fluoxetine (20mg), fluvoxamine (100mg), paroxetine
(20mg) and sertraline (50mg) on ejaculatory delay
– Patient Population: men with premature ejaculation (n=60)

Results (increase in ejaculatory latency time from baseline)
–
fluoxetine
paroxetine
sertraline
fluvoxamine
= 117 secs* (p < 0.001)
= 100 secs* (p < 0.001)
= 65 secs* (p = 0.017)
=
9 secs
–
placebo
=
–
–
–
7 secs
* statistically significant difference
SSRI/SNRI and Sexual Dysfunction
Management




Patience
Drug holidays (?)
Reduce dose
Antidotes (ie - augmentation)
–

Examples: bupropion, sildenafil, amantadine, buspirone,
yohimbine, cyproheptadine, nefazodone, stimulants,
granisetron, gingko biloba
Switching antidepressants
–
Examples: bupropion, mirtazapine
SSRI: Other Adverse Effects
Sweating
 Bruxism
 Weight Gain
 Extrapyramidal Side Effects
 SIADH
 GI Bleeds (?)
 Suicide (?)
 Prozac Poop-out (ie – tachyphylaxis)?

Fluoxetine Versus Sertraline and Paroxetine in Major Depressive Disorder:
Changes in Weight with Long-term Treatment
[7 month RCT; n=139]
Fava M et al. J Clin Psychiatry 2000; 61:863-867
30
25
Pct > 7% gain
20
15
10
5
0
Fluoxetine
42 mg/d
Sertraline
94 mg/d
Paroxetine
37 mg/d
Use of Selective Serotonin Reuptake Inhibitors and
Risk of Upper Gastrointestinal Bleeding
Dalton SO et al. Arch Intern Med 2003; 163:59-64
Observed/Expected (O/E) Ratio for GI Bleeds
13
11
9
O/E
Antidepressant
7
5
Antidepressant
+ NSAID
3
1
SSRI
(20/7565)
TCA
(13/4778)
Other
(4/2117)
Antidepressants and Suicide
What’s the Evidence ?

Adults
– 2% of outpatients & 4% of inpatients treated for depression
will commit suicide
– 5-15 % of patients with untreated depression will commit suicide
– Clinical trials:



> 20,000 adult subjects received SSRI in trials
Significant decline in suicidality reported
Study limitations are substantial
–
–
–
–
–
homogenous patient populations
suicidality assessed by 1 item embedded in depression rating scales (eg–HAMD)
inconsistent definition of suicidal behavior
brief follow-up period
distinguish treatment effect from withdrawal effect
Antidepressants and Suicide
What’s the Evidence ?

Children and Adolescents
– Suicide is 3rd leading cause of death in adolescents
– Suicide rate  33% over last 10-14 years
– Clinical trials (Columbia study)



4,250 children in 25 studies of 9 antidepressants
No successful suicides reported
Nonsignificant increase in suicidal behavior (RR=1.78)
– Effexor, Paxil > Celexa, Zoloft  Prozac
Antidepressants and Suicide
Why would risk be greater
in children & adolescents than adults ?





Artifact (ie - preliminary data only)
Depressed children/adolescents are more impulsive
Children are receiving proportionately higher doses
Antidepressants have different PK/PD properties in children
Greater influence/activity of 5HT system in children
Antidepressants and Suicide
Summary





Preliminary data in children and adolescents suggests higher risk of suicidal
behavior after initiation (or dosage change) with ALL antidepressants
Increased suicidal behavior may be attributed to
– lack of response to prescribed antidepressant
– extreme agitation or akathisia
– delayed response (somatic sx better before cognitive)
– misdiagnosis (eg - bipolar depression, personality d/o)
Pharmaceutical manufacturers should be required to disclose ALL results of
clinical trials
Clinical trial methodology is antiquated
– naturalistic element must be integrated into RCT
– more sensitive measures of suicidal behavior needed
– patient population must be more representative
Untreated depression much more likely to induce suicide
than any antidepressant
SSRI Withdrawal Phenomenon

Symptoms:









dizziness
lethargy
nausea
paresthesias
insomnia
Onset: 48-72 hours
Duration: 5-7 days
Worse with paroxetine, venlafaxine
Minimal risk with fluoxetine
Serotonin Syndrome



Rare, idiosyncratic, sometimes fatal
Mechanism: 5HT excess
Symptoms:
–

MS changes, chills/sweating, myoclonus, autonomic instability
( or  BP & HR), fever (malignant hyperthermia)
Medications:
–
Most Commonly Associated: MAOI (Nardil, Parnate)
Commonly Associated: SSRI (all), Clomipramine (Anafranil),
Venlafaxine (Effexor), Tramadol (Ultram), Selegiline,
Sibutramine (Meridia), Detromethorphan
Occasionally Associated: Meperidine (Demerol), Trazodone
–
Rarely Associated: Sumatriptan (Imitrex), St. John’s Wort
–
–
Clinical Significance of
Drug Interactions with SSRI


potent inhibitors of Cytochrome P450
significant differences among SSRI @ potential
– Cyt 1A2:
fluvox >> fluox, parox, sert, cital, escital
substrates: TCA, haldol, clozapine, olanzapine, theophylline
– Cyt 2D6:
fluox, parox, dulox, buprop >> sert, cital, escital
substrates: -blockers, narcotics (codeine, hydrocodone, tramadol), TCA
– Cyt 3A4:
norfluox, fluvox >> fluox, parox, sert, cital, escital
substrates: CCB, estrogen, corticosteroids, statins, protease inhibitors,
alprazolam, triazolam, buspirone, sildenafil


in vitro affinity different than in vivo
wide interpatient variability
Suggestion #3:
Do No Harm
SSRI: Dosing Guidelines for Primary Care*
*note: Dosing may be higher for severe depression or in psychiatric settings

SSRI
–
–
–
–
–
–

Fluoxetine
Sertraline
Paroxetine
Citalopram
Escitalopram
Fluvoxamine
Recommendation:
Initial Dose
Maintenance Dose
10 mg
25 mg
10 mg
10 mg
5 mg
25 mg
10
25
10
10
5
50
– 20 mg/d
– 100 mg/d
– 20 mg/d
– 20 mg/d
– 10 mg/d
– 200 mg/d (divided)
Take with breakfast
exception: take fluvoxamine at HS
VENLAFAXINE (Effexor ®)
Therapeutic Use


MOA: blocks reuptake of 5HT and NE (dose-dependent)
Adverse Effects: similar to SSRI* (including withdrawal)
–

*note: HTN commonly seen with doses > 150 mg/d
Dosing & Administration
–
–
–
–
Initiate treatment at 37.5 mg QD (XR)
Usual therapeutic dose = 75 - 225 mg/d
Maximum Daily Dose XR (package insert) = 225mg/day (?!)
May be preferred if
 Severe or treatment-resistant depression
Incidence of Sustained Hypertension with Venlafaxine* (Effexor
Package Insert, Wyeth 2004)
* - defined as Diastolic BP > 90
AND change in Diastolic BP > 10 x 3 consecutive visits
14%
12%
10%
8%
6%
4%
2%
0%
100 mg/d
300 mg/d
> 300 mg/d
DULOXETINE (Cymbalta®)
Therapeutic Use


MOA: blocks reuptake of 5HT and NE
Adverse Effects: similar to SSRI* (including withdrawal)
– hepatotoxicity (1.0% incidence of 3-fold  in ALT

Pharmacokinetics:
vs 0.2% placebo)
– Plasma Half-life = 12 hrs; linear
– Cytochrome P450 2D6 inhibitor

Dosing & Administration
– Initiate treatment at 30 mg/d
– Usual therapeutic dose = 60 mg/d
– May be preferred if
 severe or treatment-resistant depression
– Other Indications: neuropathic pain
BUPROPION (Wellbutrin® or Zyban ®)
Therapeutic Use


MOA: enhances NE/DA transmission
Adverse Effects: insomnia, HA, nausea, rash, seizures
– Contraindications: h/o eating d/o, seizure d/o

Dosing & Administration
– Sustained-release (SR): initiate with 150mg in AM and increase
to 150mg BID after 3 days; Doses must be separated by  8hrs;
Maximum daily dose = 400mg
– Extended-release (XL): initiate with 150mg in AM and increase
to 300mg in AM after 3 days; Doses must be separated by  24
hrs; Maximum daily dose = 450 mg
– May be preferred if



low energy, predominant anhedonia
pt requests med without sex dysfunction or weight gain
SSRI augmentation
MIRTAZAPINE (Remeron®)
Therapeutic Use



MOA: blocks 2 receptors, 5HT2, 5HT3 receptors
Adverse Effects: sedation, weight gain,  chol/TG
Dosing & Administration
– Initiate treatment with 15mg HS
– Maximum daily dose = 45 mg (?)

note: 30mg associated with less sedation
– May be preferred if



tx-resistant depression
pts with sex dysfunction
weight gain or sedation desirable
Suggestion #3:
Tailor Antidepressant to
Specific Patient
Targeted Treatment of Depression
Medical Comorbidity
 Psychiatric Comorbidity
 Depression Subtype

Prevalence of Depression
with Medical Illnesses*
* - Point prevalence; Mean of range cited when applicable
Finley PR. Rx Consultant 2004; 13 (6):1-8
50%
40%
30%
20%
10%
0%
en
tia
V
HI ons
s
in
rk
Pa
m
De
y
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ile
Ep
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ke
ro
St
l
pu
Po
s
te
be
e
nc
Ca
a
Di
D
CA
l
ra
ne
Ge
n
io
at
Antidepressants and Medical Co-Morbidity

Cardiovascular Disease





Hypertension



SNRI (venlafaxine, duloxetine) - increased blood pressure/heart rate
bupropion - increased blood pressure/heart rate
Cerebrovascular Disease



TCA - increased risk of cardiac events
SSRI – decrease risk of cardiac events (?)
fluoxetine, paroxetine, duloxetine, bupropion - inhibit metabolism of beta blockers
norfluoxetine, fluvoxamine - inhibit metabolism of Ca channel blockers
TCA - superior efficacy vs SSRI (?)
SSRI – preliminary efficacy in prophylaxis
Diabetes


TCA, mirtazapine, paroxetine - weight gain
norfluoxetine, fluvoxamine, nefazodone - inhibit metabolism of sulfonylureas
Antidepressants and Medical Co-Morbidity: Continued

Breast Cancer, Menopause


Parkinson’s Disease


SSRI, SNRI – may increase bleeding risk (?)
Dementia



bupropion - may benefit dopamine transmission
Peptic Ulcer Disease


SSRI, SNRI - may benefit hot flashes
TCA, paroxetine – avoid antidep with antichol effects
SSRI, bupropion – may be less likely to cloud sensorium
AIDS



fluvoxamine, nefazodone - inhibit metabolism of protease inhibitors
TCA, mirtazapine, paroxetine - weight gain may benefit some patients
bupropion, stimulants - may benefit anergic depression
The Epidemiology of Major Depressive Disorder
Results of National Comorbidity Survey Replication
Kessler RC et al. JAMA 2003; 289:3095-3105


Methods: face-to-face household survey; N=9090
Results
– Lifetime prevalence of MDD
– 12 month prevalence
– 12 month  comorbidity prevalence

= 16.2 %
= 6.6 %
= 78.5 %
Note: 51% of depressed pts had comorbid anxiety disorders
– Percent of depressed pts receiving tx
– Percent of treated depressed pts receiving adequate tx
– Percent of all depressed pts receiving adequate tx
= 51.6 %
= 41.9 %
= 21.7 %
FDA Approved Uses of SSRI
and Venlafaxine
SSRI
MDD
Fluoxetine
X
Sertraline
X
Paroxetine
X
GAD
OCD
Social
Phobia
X
X
X
X
X
X
X
X
X
X
X
X
PMDD
X
Escitalopram
Venlafaxine
PTSD
X
Fluvoxamine
Citalopram
Panic
X
X
SSRI in the Management of Anxiety Disorders
General Treatment Considerations





If 1 SSRI is FDA-approved ALL appear to be effective
Start low and go slow
Onset of tx effect slower for anxiety d/o
(vs MDD)
Higher doses required for anxiety d/o: OCD, Panic D/O
Important considerations in choosing SSRI
drug interactions
 tolerability

Relationship of Antidepressant Mechanism to Target Symptoms
Does Selectivity Matter ?


Theory A:
Antidepressants should be tailored to target symptoms

Anxious and/or Irritable

Anergic and/or Amotivational

Severe and/or Melancholic
5HT agents
(SSRI)

NE/DA agents
(bupropion, amantadine, modafinil)

5HT/NE agents (?)
(TCA, high-dose venlafax, duloxetine)

Theory B:
If the antidepressant successfully relieves the depression, all
symptoms will resolve regardless of the mechanism.
Does Pretreatment Anxiety Predict Response
to Either Bupropion SR or Sertraline ?
Rush AJ et al. J Affect Dis 2001; 64:81-87
70
60
50
HAMD 40
Response
30
Rate
20
< 13
13-17
18-23
> 23
10
0
Bupropion
Sertraline
Placebo
Baseline HAMA scores
‘Are you more worried or tired ?’
- Owen Wolkowitz M.D.
- SSRI preferred in worried patients
- Bupropion preferred in tired patients
Comparison of Gender Response Rates:
Sertraline vs Imipramine
Kornstein et al. Am J Psychiatry 2000; 157:1445-1452
70
60
50
62
57
46
45
40
30
20
10
0
women
men
sertraline
imipramine
Minimal Response to Antidepressant Treatment
Alternatives to SSRI



Ensure completion of therapeutic trial (4-6 wks)
Ensure optimal dose of antidepressant
Partial Response
 
augmentation
– Bupropion
– Other (lithium, T3, lamotrigine, modafinil, other)

Nonresponse
–
–
 
switch
Other SSRI
Other antidepressants (SNRI, bupropion, other)
Suggestion #4:
Optimize Monotherapy
(ie – don’t be afraid to  dose)
Augmentation Strategies
and Other Alternatives











Bupropion
Lithium
Thyroid supplementation (T3)
Buspirone
Pindolol
Lamotrigine
Stimulants
Modafinil
Amantadine, Pramipexole
Atypical Antipsychotics
Other: folic acid, omega 3, inositol, sex hormones, DHEA, SAMe
Medication Augmentation after the Failure of
SSRIs for Depression
Trivedi MH et al (STAR*D). NEJM 2006; 354:1243-1252

Methods
– 2876 depressed patients enrolled from 23 psychiatric, 18 primary care
settings into rigid treatment protocol
– 565 pts failing to achieve remission after 11.9 wks citalopram (55 mg/d)
– Pts randomized to bupropion SR (267 mg/d) or buspirone (41 mg/d)

Results
– Reduction in depressive symptoms (QIDS-SR):
bupropion (25.3 %) vs buspirone (17.1 %) p <0.04
– Rates of Remission (QIDS-SR):
bupropion (39.0%) vs buspirone (32.9%) ns
– Discontinuation due to side effects:
bupropion (12.5 %) vs buspirone (20.6%) p < 0.0009
Switching
within the SSRI Class
Thase M. APA Annual San Francisco 2003






Brown, Harrison (1995)
Zarate (1996)
Thase (1997)
Thase (2001)
Thase (2002)
Calabrese (2003)
Fluox  Sert
71 % (79/112)
Fluox  Sert
42 % (13/31)
Sert  Fluox
63 % (67/106)
Fluox  Cital
62 % (35/57)
Parox  Cital62 % (32/51)
Fluox  Cital
65 % (36/65)
Switching
to an SNRI
Nelson JC. J Clin Psychiatry 2003; 64 [suppl 1]:5-12




Nierenberg (1994)
DeMontigny (1999)
Kaplan (2002)
Poirer (1999)
SSRI  Venlafaxine
SSRI  Venlafaxine
SSRI  Venlafaxine
Various  Venlafaxine
or Parox
33% (28/84)
58% (88/152)
87 % (63/73)
52 % (32/61)
33 % (20/61)
Bupropion-SR, Sertraline or Venlafaxine-XR
after the Failure of SSRIs for Depression
Rush AJ et al (STAR*D). NEJM 2006; 354:1231-1242

Methods
– 2876 depressed patients enrolled from 23 psychiatric, 18 primary care
settings into rigid treatment protocol
– 727 pts failing to achieve remission or couldn’t tolerate citalopram
– Pts randomized to bupropion-SR (283 mg/d), sertraline (135 mg/d) and
venlafaxine-XR (194 mg/d)

Results
– No significant differences between treatments in any primary outcomes
– Reduction in depressive symptoms (QIDS-SR):
bupropion-SR (16.4 %) vs sertraline (21.9 %) vs venlafaxine-XR (16.9%)
– Rates of Remission (QIDS-SR):
bupropion-SR (25.5 %) vs sertraline (26.6 %) vs venlafaxine-XR (25.0%)
– Discontinuation due to side effects:
bupropion-SR (27.2 %) vs sertraline (21.0 %) vs venlafaxine-XR (21.2%)
Atypical or 2nd Generation Antipsychotics (SGA)
Introduction

Empiric Definition:
“Atypical Antipsychotics do NOT…
–
–
–


induce catalepsy (ie - parkinsonism)
increase prolactin
upregulate D2 receptors (ie - tardive dyskinesia)
Working Definition:
“…cause less EPS, TD than conventional agents”
Mechanism
– Dopamine (D2) plus Serotonin (5HT2a) blockade
– D2 blockade in mesolimbic area relieves positive symptoms
– 5HT2 blockade in mesocortical area facilitates DA release to relieve
negative symptoms (esp cognition)
– 5HT2 blockade in nigrostriatum prevents EPS effects
2nd Generation Antipsychotics (SGA)
Relative Advantages

Safety
–
–
–

less extra-pyramidal side effects (EPS)
less tardive dyskinesia (TD)
less cognitive impairment
Efficacy
–
–
–
–
uniquely effective for tx-resistant schizophrenia
more effective vs negative symptoms
more effective for cognitive symptoms
other indications



Bipolar disorder (esp mania)
Dementia (?)
Depression (?)
A Novel Augmentation Strategy
for Treating Resistant Major Depression
Shelton RC et al. Am J Psychiatry 2001; 158:131-134

Methods:
– patients identified with h/o tx-resistance and HAMD > 20
– open label phase consisted of 6 wk escalating dose
fluoxetine (20-60 mg/d)
– responders were excluded
– remainder of patients randomized to 8 week trial of



olanzapine plus placebo
olanzapine plus fluoxetine
fluoxetine plus placebo
– N = 28
2nd Generation Antipsychotics (SGA)
Relative Disadvantages

Safety
–
–

Efficacy
–
–
–
–

metabolic effects (weight gain, diabetes, hyperlipidemia)
other: orthostasis, sedation
limited research data in dementia (behavioral disturbances)
limited research data in bipolar disorder (maintenance treatment)
virtual absence of RCT data in depression
inappropriate prescribing (eg – Seroquel for insomnia)
Cost !!
Weight Gain with Antipsychotic Drugs
[Meta-analysis at 10 weeks]
adapted from Allison et al. Am J Psychiatry 1999;156:1686-1696
12
10
8.7
lbs
9.1
8
8
6
4.6
4
2.9
2.4
2
-1.6
-0.86
0.1
0
-2
ne
pi
za
lo
C
e
in
ap
nz
la
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pi
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ue
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on
C
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op
al
H
e
on
id
as
pr
Zi
M
Pl
Metabolic Effects
of 2nd Generation Antipsychotics
Consensus Statement – Diabetes Care 2004; 27:596-609

Weight Gain
– Increased risk: family hx, underweight, ethnicity
– Dose-dependent (?)
– Effect plateaus at 24-52 weeks (?)

Diabetes
– Case reports of DKA with all SGA
– Not necessarily associated with weight gain

Atherogenic Lipid Profile
–  triglycerides,  LDL,  HDL
2nd Generation Antipsychotics (SGA)
Monthly Cost of Therapeutic Dose
AWP. First Data Bank. Feb 2004
$700
$622
$600
$476
$465
$500
$433
$400 $374
$329
$292
$274
$300
$200
$100
$0
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C
Summary
Recommendations

Target antidepressants to specific populations
– Based on comorbidity and target symptoms



Ensure adequate trial ( 4 weeks)
Optimize Monotherapy ( dose if tolerated)
Partial Response (augmentation)
– Strong Evidence:
– Moderate Evidence
– Preliminary Evidence

lithium, T3, bupropion
buspirone, lamotrigene, modafanil
amantadine
Nonresponse to SSRI (switch)
– Switch to different SSRI (if tolerated)
– Switch to other classes: SNRI, bupropion, mirtazapine
– 3rd line: TCA, MAOI, SGA (?)
Coming Attractions

Generics:
– sertraline (2006 ?), venlafaxine XR (2008 ?)





NK1 or Substance P antagonists (Emend)
Selegiline (Emsam)
Glucocorticosteroid antagonists
(eg - mifepristone, ketoconazole, metyrapone)
CRF antagonists*
BDNF enhancers *
* - denotes product not currently available in United States
Transdermal Selegiline (EMSAM)
Overview
•
MOA
•
Pharmacokinetics
•
Drug/Dietary Interactions
• Nonspecific MAO inhibitor at high doses (eg – MAO-A & MAO-B)
• Transdermal delivery results in minimal MAO inhibition in GI tract
• Plasma half-life of 18-24 hours
• Metabolized via Cyt P450 system (Cyp 2A6, 2B6, 3A4)
• Multiple active metabolites (including methamphetamine)
• Avoid concurrent administration of SSRI, SNRI, TCA, bupropion, mirtazapine, SJW,
sibutramine, tramadol, meperidine, dextromethorphan and cyclobenzaprine
• Washout:
•
•
4 half-lifes after D/C of drugs above
2 weeks after D/C of EMSAM
• Low tyramine diet NOT necessary with 6mg patch
• Low tyramine diet IS recommended with 9mg and 12mg patches
•
Adverse Effects
•
Dosing and Administration
• Application site reactions (31% vs 15% with placebo)
• Other: dizziness, insomnia, sexual dysfunction
• Apply 6mg patch (20mg/cm3) to upper torso every 24 hours