Download Disclosures Objectives: Pharmacists Objectives: Pharmacy

3/9/2016
Disclosures
o I have no personal or financial conflicts of
interest to disclose
o I will be discussing off-label use of medications
Objectives: Pharmacists
Objectives: Pharmacy
Technicians
o Describe four evidence-based clinical pearls of
depression pharmacotherapy
o Identify common medications used to treat
depression
o Explain five ways older medications may be
reformulated into “new” products
o Recognize how older medications may be
reformulated into “new” products
o Identify three compelling comorbid conditions
that my guide antidepressant selection
o Describe medication options for depression
o Develop a rational treatment plan for a patient
with depression
Patient Case
BC is a 60 yo female presenting with:
o ↓ sleep, interest, energy, concentration and weight
(20# over 2 months, not intentional)
o ↑ ‘worrying about everything’
o Off work x 1 week, unable to get out of bed
PMH: hypertension, ‘nerve pain’, and migraines
SH: no tobacco, ‘occasional’ alcohol, works full time
as a retail clerk, financial stressors
Patient Case
o Relevant assessment
o BP 130/55 HR 70 Wt 75 kg (down from 84 kg)
o CMP, CBC and thyroid studies WNL
o Current medications
o Metoprolol, ibuprofen
o PRN hydrocodone/acetaminophen, tramadol and
rizatriptan
o Past medications
o Fluoxetine ‘a long time ago’ – ‘helped a lot’
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Patient Case
Depression Rating Scales
HAM-D 17
QIDS-SR (0-3 each)
Depressed mood (0-4)
o Is this patient depressed?
o If so, what should be our first line treatment
for depression in this patient?
o Is there a role for the ‘new’ antidepressants in
her treatment?
Guilt (0-4)
Suicide (0-4)
Insomnia – early, middle, late (0-2 each)
Work and activities (0-2)
Retardation (0-4)
Agitation (0-4)
Anxiety - psychic (0-4)
Anxiety - somatic (0-4)
Somatic symptoms - GI (0-2)
Somatic symptoms general (0-2)
Genital - libido (0-2)
Hypochondriasis (0-4)
Loss of Weight (0-2)
Insight (0-2)
Based on hx this patient’s score: 21 (severe)
Insomnia – early, middle, late
Total sleep hours
Feeling sad
Appetite
Weight
Concentration
Self-worth/guilt
Thoughts of death/suicide
Interest
Energy
Feeling slowed down
Feeling restless
Based on hx this patient’s score: 17 (severe)
http://www.ids-qids.org
Medications By Class
Medications
Therapeutic Uses
Selective Serotonin Reuptake Inhibitors (SSRIs)
Celexa (citalopram)
Depression
Lexapro (escitalopram)
OCD, GAD, PTSD
Luvox (fluvoxamine)
Social Phobia
Paxil/Paxil CR (paroxetine)
Panic Disorder
Prozac (fluoxetine)
Bulemia
Zoloft (sertraline)
Premenstrual dysphoric
disorder
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
Effexor/Effexor
Depression
XR/venlafaxine extended
GAD
release (venlafaxine)
Social anxiety disorder
Panic disorder
Pristiq (desvenlafaxine)
PTSD
OCD
Cymbalta (duloxetine)
Diabetic neuropathic pain
Chronic musculoskeletal pain
Savella (milnacipran)
Fibromyalgia
Menopausal flushing
Fetzima (levomilnacipran)
Side Effects/Issues
Nausea, diarrhea
Headache
Anxiety upon initiation or dose
increase
Sexual dysfunction
Sweating
Sedation/agitation
Same as SSRIs
Increased blood pressure
Increased heart rate
Liver toxicity (duloxetine)
Side Effects/Issues:
Less sexual dysfunction
than SSRIs and SNRIs
Remeron (mirtazapine)
Depression
Serzone (nefazodone)
Depression, PTSD
Desyrel (trazodone)
Wellbutrin/Zyban
(bupropion)
Depression, insomnia
Depression, Smoking
cessation, ADHD
Sedation, weight gain,
increased triglycerides
Sedation, drug
interactions
Sedation
Agitation, insomnia,
appetite suppression
Viibryd (vilazodone)
Depression
Similar to SSRIs
Depression
Similar to SSRIs
Therapeutic Uses
Side Effects/Issues
Tricyclic Antidepressants (TCAs)
Anafranil (clomipramine)
Elavil (amitriptyline)
Norpramin (desipramine)
Pamelor (nortriptyline)
Sinequan (doxepin)
Tofranil (imipramine)
Vivactil (protriptyline)
Depression
OCD (clomipramine)
Neuropathic Pain
Sleep
Migraine headaches
ADHD (desipramine)
Anticholinergic
Orthostatic hypotension
Arrhythmia
Sedation
Sexual dysfunction
Sweating
Weight gain
Monoamine Oxidase Inhibitors (MAOIs)
Nardil (phenelzine)
Parnate (tranylcypromine)
Emsam (selegiline) patch
A Class of Their Own
Therapeutic Uses
Medications By Class
Medications
Depression
Panic disorder
Other anxiety disorders
Sedation
Sexual dysfunction
Blurred vision
Tachycardia
Serotonin syndrome
Hypertensive crisis
What Is The Best
Traditional Treatment?
o How do you compare across classes?
o How do you assess efficacy in ‘real world’
environment?
o What do you do if one treatment does not
effectively reduce/eliminate symptoms?
o STAR-D show us the way…
SSRI and partial 5HT1A agonist
Brintellix (vortioxetine)
SSRI, 5HT1A agonist, 5HT3
antagonist
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STAR-D
STAR-D Patient Mix
o Sequenced Treatment Alternatives for
Remission in Depression
o Demographics (N=2,876)
o How do ‘real world’ patients respond/remit?
o How often can we achieve remission vs response?
o Is it better to switch medications or augment with
another medication?
o What do patients prefer?
o Can you use rating scales in practice?
o Do outcomes differ between primary care and
psychiatry specialty clinics?
Trivedi MH, et al. Am J Psych 2006; Gaynes
BN et al. Cleveland Clinic JOM 2008
o Primarily caucasian women aged 31-50
o Psychiatrist 62% and primary care 38%
o Severity: Average HAM-D = 22 at baseline
o Had to be ≥14
o Recurrent depression 75%
o Average 6 episodes lifetime; 15 yr history
o Average duration 2 yrs (25% >2 yrs)
o Comorbid psychiatric disorders 65%
Trivedi MH, et al. Am J Psych 2006
STAR-D Outcomes
Average Dose at Endpoint
Response
QIDS-SR
Remission
QIDS-SR*
Level 1
Citalopram 40 mg
47%
33%
Level 2
switch
Bupropion 282 mg
Sertraline 135 mg
Venlafaxine 194 mg
26%
27%
28%
25%
27%
25%
Level 2
augment
Bupropion 268 mg
Buspirone 41 mg
32%
27%
39%
33%
Level 3
switch
Mirtazapine 42 mg
Nortriptyline 96 mg
13%
17%
8%
12%
Level 3
augment
Lithium 860 mg (level 0.6)
T3 45 mcg
16%
23%
13%
25%
Level 4
Mirt/Venl 36 mg/210 mg
Tranylcypromine 37 mg
24%
12%
16%
14%
Question
Considering STAR-D algorithms, what is the best
option for patient BC?
A. Nortriptyline
B. Sertraline
C. Tranylcypromine
D. Venlafaxine
E. New trick
*: Comparable to HAM-D remission rates
Gaynes BN, et al. Clev Clin JOM 2008
New Tricks
o Combination mechanism
o “Me too” - same mechanism, new chemical
o Active metabolite
o Single isomer
o Extended-release formulation
o Old medication, newly discovered indication
New Tricks – Not So New
o TCAs (active metabolites)
o Amitriptyline and nortriptyline
o Imipramine and desipramine
o MAOIs (similar mechanism)
o Phenelzine
o Tranylcypromine
o SSRIs (same mechanism)
o Fluoxetine, sertraline, fluvoxamine, paroxetine,
citalopram, escitalopram
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One Chemical –
So Many Options
Lesser Known Examples
o Fluoxetine
o Serafem
o Prozac Weekly
o Paroxetine
o Pexeva
o Brisdelle
o Venlafaxine
o VERT (venlafaxine extended release tablets)
VandenBerg AM. Mental Health Clinician 2014
SSRI Single Isomer
o Wellbutrin® IR and generic 75 mg, 100 mg
o Wellbutrin® SR 100 mg, 150 mg, 200 mg
o
o
Generic 100 mg and 150 mg
Wax matrix
o Wellbutrin® XL 150 mg, 300 mg
o
o
Branded generic Budeprion 150 mg only
Diffusion controlled coating
o Aplenzin® 174 mg, 348 mg, 522 mg
o ForfivoTM XL 450 mg (brand only)
VandenBerg AM. Mental Health Clinician 2014
(Es)Citalopram QTc Data
o Citalopram vs. escitalopram
Citalopram
Δ QTc msec (90% CI)
Escitalopram ΔQTc msec (90% CI)
20 mg
8.5 (6.2, 10.8)
10 mg
4.5 (2.5, 6.4)
o Initial claims
40 mg
12.6 (10.9, 14.3)
20 mg
6.6 (5.3, 7.9)
60 mg
18.5 (16.0, 21.0)
30 mg
10.7 (8.7, 12.7)
Mox 400 mg
9.0 (7.3, 10.8)
o Fewer side effects
o 10 mg escitalopram = 40 mg citalopram
o R isomer inhibits binding of S isomer
o Final nail
Mox 400 mg 13.4 (10.9, 15.9)
• Clinically significant QTc prolongation generally considered >500 msec or
prolongation of >60 msec
• Actual # of patients with clinically significant prolongation not released
o QTc prolongation warning
http://www.fda.gov/Drugs/DrugSafety/ucm297391.htm
J Psychosocial Nursing 49(11) 2011
Two New Tricks in One:
Levomilnacipran
Duloxetine
o Old dog: milnacipran (SNRI)
o Old dog: SNRI
o New trick: single isomer and extended release
o New trick: equal affinity for both serotonin and
norepinephrine across the dosing range
o Also new indication for MDD
o Limitations
o Cost
o Efficacy similar to other available agents
o The caveats
o Equal affinity ≠ improved efficacy
o Dual mechanism ≠ improved efficacy
Montgomery SA et al. J Clin Psych April 2013
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Duloxetine: The Facts
o FDA approved indications
o MDD, generalized anxiety, chronic pain, diabetic
peripheral neuropathic pain, fibromyalgia
o Recommended dose: 60 mg daily
o Practical pharmacokinetic points:
o Delayed release capsule
o CYP 2D6 moderate inhibitor
o Requires renal dosing
Cymbalta (duloxetine) [PI] accessed January 10, 2014
Duloxetine: The Facts
o Should not be used/avoid use in patients with:
o “evidence of chronic liver disease”
o “Substantial alcohol use”
o Severe renal impairment (GFR<30 mL/min)
o Hepatotoxicity risk
o No definitive study demonstrating benefit over
alternatives for MDD
Cymbalta (duloxetine) [PI] accessed January 10, 2014
Desvenlafaxine
o Old dog: venlafaxine
o New trick: active metabolite
o The spin: Not prone to genetic variability of 2D6
metabolism or 2D6 inhibition interactions
o Caveat
o “venlafaxine and o-desvenlafaxine are
pharmacologically approximately equiactive and
equipotent”
Effexor XR [PI] accessed May 6, 2013
Desvenlafaxine: The Facts
Safer in Poor Metabolizers?
o Venlafaxine primarily metabolized via CYP 2D6
o
o
o
Prone to genetic variability in <10% of population
Rapid/extensive metabolism = “normal”
Poor or ultra-rapid metabolism = genetic variant
o “The differences between the CYP2D6 poor and
extensive metabolizers; however, are not expected
to be clinically important because the sum of
venlafaxine and ODV is similar in the two groups”
Effexor XR [PI] accessed May 6, 2013
Desvenlafaxine Clinical Trials:
MDD
Study Arms
Response
Remission
DeMartinis et al
N=461
placebo
100, 200, 400 mg
35%
51%, 45%, 48%
19%
30%, 28%, 32%
Septien-Velez et al
N=375
placebo
200 and 400 mg
38%
60% and 56%
23%
37% and 34%
Liebowitz et al
N=247
placebo
100 – 200 mg
34%
43%
20%
23%
Boyer P et al
N=485
placebo
50 and 100 mg
50%
65%, 63%
29%
37%, and 45%
o FDA approved indication: MDD
o Recommended dose: 50 mg daily
o Practical pharmacokinetic points:
o t ½ 10 hours
o Absorption 80% with no impact of food
o Metabolism – primarily conjugation
o Minor 3A4
Red results statistically significant compared to placebo
Colvard MD. Mental Health Clinician, 2014
Colvard MD. Mental Health Clinician, 2014
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Desvenlafaxine: The
Verdict
o FDA approved dose is likely subtherapeutic
The Newest New Tricks
o Vilazodone
o Solves a problem that was not there
o Expensive alternative to venlafaxine
o Place in therapy ??
o Vortioxetine
Colvard MD. Mental Health Clinician, 2014
Vilazodone
o Old dog
o
o
SSRI activity + 5HT1A partial agonist
Similar to SSRI + buspirone or pindolol
o New trick
o
o
Combine mechanisms into one medication
5HT1A partial agonist activity →↓ sexual dysfunction
o Caveat
o
o
Dual mechanism ≠ better efficacy or faster response
“…the net result of this action on serotonergic transmission
and its role in vilazodone’s antidepressant effect are
unknown”
Viibryd [PI]; accessed January 10, 2016
Vilazodone: Trials
Vilazodone: The Facts
o FDA approved indication: MDD
o Recommended dose: 40 mg daily with need for
2 week titration
o Practical pharmacokinetic points:
o t ½ 25 hours
o Absorption increased 2-fold with food
o Metabolism CYP 3A4 (major), 2D6/2C19 (minor)
o Dose adjustment required with 3A4 inhibitors
and inducers
Viibryd [PI]; accessed January 10, 2016
Vilazodone: Results
o Four DB, PC efficacy trials; 6-10 weeks each
o Response rates 44-59 %
o Standard MDD inclusion/exclusion criteria
o Remission rates <30% not significantly
different from placebo
o Montgomery-Asberg Depression Rating Scale
(MADRS) change from baseline primary endpoint
o Demographics
o
o
o
o
Primarily caucasian women ~40 yrs of age
Average duration current episode ~6 months
Average of 3 lifetime episodes of depression
MADRS average 30 baseline (just below severe)
Deardorff WJ. Expert Opin Pharmacother 2014
o Nausea /diarrhea 25-35%
o Sexual dysfunction 1-2%
o However comparable to active control duloxetine
Deardorff WJ. Expert Opin Pharmacother 2014
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Vilazodone: The Verdict
o No studies to demonstrate better efficacy or
tolerability than SSRI/SNRIs
o High rates of nausea/vomiting
o Outcomes comparable to currently available $4
antidepressant medications
o Drug interactions
o Place in therapy:
o
??
Vortioxetine
o Old dog
o
o
SSRI + 5HT1A partial agonist + 5HT3 antagonist
Similar to SSRI + buspirone + ondansetron
o New tricks
o
o
o
o
o
Multiple mechanisms
5HT3 antagonist to minimize nausea/vomiting
5HT1A and 5HT1B partial agonist activity
5HT7 antagonist
5HT1D antagonist
o Caveat
o
Multiple mechanisms ≠ better efficacy or faster response
Brintellix [PI]; accessed January 10, 2016
Vortioxetine: The Facts
Vortioxetine: The Studies
o FDA approved indication: MDD
o Twelve DB, PC efficacy trials; 6-10 weeks each
o Recommended dose: 10 mg daily (5-20 mg)
o Standard MDD inclusion/exclusion criteria
o Practical pharmacokinetic points:
o MADRS or HAMD change from baseline used for
primary endpoint
o t ½ 66 hours
o Absorption 75% with no impact of food
o Metabolism CYP 2D6, 3A4 and others
o Max 10 mg with 2D6 inhibitors or poor
metabolizers
o Increase dose with potent inducers
Viibryd [PI]; accessed January 10, 2016
Vortioxetine Results
o Four studies demonstrating no difference from
placebo on primary outcome
o Limited comparative response/remission data
o Higher dose of 10 mg appears more effective
with higher rates of side effects
o Two studies with no difference in primary
outcome for active control (duloxetine)
o Demographics
o
o
o
o
Primarily caucasian women ~40 yrs of age
Average duration current episode ~6 months
Average of 3 lifetime episodes of depression
MADRS average variable
Deardorff WJ. Expert Opin Pharmacother 2014
Vortioxetine: The Verdict
o Unique mechanisms
o No demonstrated benefit over older agents
o Question regarding optimal dose
o High rates of nausea and sexual dysfunction
o Drug interactions
o Place in therapy ??
Deardorff WJ. Expert Opin Pharmacother 2014
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Atypicals as Adjunct
o Old dog: atypical antipsychotics
Atypicals as Adjunct
Agent
FDA approval
Clinical Trial Outcomes
o New trick: indication for MDD as adjunct
Olanzapine/
fluoxetine
3-12/25-50 mg
Treatment resistant
depression
Most: No difference from mono tx
One trial and pooled analysis
OFC>fluoxetine monotherapy
o Limitations
Quetiapine XR Adjunct to
150-300 mg
antidepressants
Addition of quetiapine XR > placebo
with MADRS score change
Response/remission improved in
some studies
Aripiprazole
2-15 mg
Improved response and remission
compared to placebo
o Definition of ‘non-response’ was as little as 6 weeks
on antidepressant
o No head to head with other augmentation options
o Metabolic syndrome risk
Adjunct to
antidepressants
Wright BM et al. Pharmacotherapy 2013
Patient Case: New Tricks
Pros
Cons
What Else Do We Need To
Consider for This Patient?
Vilazodone
Less sexual dysfunction?
$$, must take with food, GI
upset dose limiting
o Propensity for drug interactions
Vortioxetine
Less GI upset?
$$, drug interactions
Duloxetine
May help with pain
Need more EtOH hx
Interacts with metoprolol,
hydrocodone
o Common side effects
Desvenlafaxine
?
$$, risk of underdosing
Quetiapine
Helps insomnia, anxiety
Metabolic syndrome,
urinary incontinence,
hypotension
Aripiprazole
?
Metabolic syndrome,
akathisia
Olanzapine/
fluoxetine
?
METABOLIC
SYNDROME, interactions
Levomilnacipran
?
$$
o Serious side effects
o Cost
Drug Interactions
The Safe Ones
The Risky Ones
o
Citalopram
o
Fluoxetine (2D6>>3A4)
o
Escitalopram
o
Fluvoxamine (1A2, 3A4)
Sertraline
o
Paroxetine (2D6)
o
Mirtazapine
o
Duloxetine (2D6)
o
Venlafaxine
o
Bupropion (2D6)
o
Nefazodone (3A4)
o
Vilazodone (3A4 substrate)
o
Vortioxetine (2D6 and 3A4)
o
o
o
Desvenlafaxine
Milnacipran
Question
Which of BC’s current medications potentially
interact with fluoxetine?
A.
B.
C.
D.
Hydrocodone/acetaminophen
Tramadol
Metoprolol
All of the above
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Common Side Effects
Antidepressant Class
Serious Side Effects
Antidepressant Class
SSRIs
Anxiety, GI, headache, sexual dysfunction
SSRIs
Hyponatremia, bleeding, movement disorders
SNRIs
SSRI + sweating
SNRIs
SSRI + hypertension, hepatotoxicity
Bupropion
Insomnia; no sexual dysfunction
Bupropion
Seizures (?)
Vilazodone
SSRI, GI may be worse; less sexual dysfunction?
Same as SSRIs
Vortioxetine
Similar to vilazodone
Vilazodone/
vortioxetine
Mirtazapine
Sedation, weight gain, hyperlipidemia (?); less sexual
dysfunction
Mirtazapine
Minimal
TCAs
Cardiac toxicity
TCAs
Sedation, anticholinergic, orthostasis
MAO inhibitors
Orthostasis, serotonin toxicity, hypertensive urgency
MAO inhibitors
Sedation
Cost
Generic Available $4 to $40
Citalopram
Escitalopram
Fluoxetine
Fluvoxamine
Paroxetine
Sertraline
Venlafaxine (IR, XR tablets)
Bupropion (IR, SR, XL)
Mirtazapine
Patient Case
>$40 per month
Desvenlafaxine
Duloxetine (in transition phase)
Levomilnacipran
Vilazodone
Vortioxetine
Compelling Patient
Specific Target
Symptoms
Treatment considerations
Low energy
SNRI or bupropion (still need to treat insomnia)
Insomnia,  appetite,
anxiety
Mirtazapine
Lipids, overweight
AVOID mirtazapine
Polypharmacy
Choose from the ‘safe list’
Pain, migraines
SNRI
Financial issues
Choose generic
My Recommendation
Venlafaxine XR + temporary sedative hypnotic and
alternatives for pain
Final Thoughts
o Antidepressants have similar efficacy
o Newest agents do not appear to have efficacy or
tolerability benefits over older agents
o Base treatment on
o
o
o
Past history of response
Drug interactions
Side effects
Questions?
o Remind patients that medications take 8-12 weeks
to have optimal effect
o
Devise safety plan and coping strategies for the interim
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