1. Review of Antidepressants & a look at the newest agent Vortioxetine
Pharmacology Rounds Aug 2015
Sue Corrigan BScPharm, ACPR, PharmD

2. Disclosure
I do NOT have any affiliation (financial or otherwise) with a pharmaceutical, medical device or communications organization
I have not received any funding for speaking or advisory boards from pharmaceutical or medical device organization

3. Outline Pharmacology Review new agent Vortioxetine
Clinical Pearls – what’s the difference between the agents
Review evidence of older agents and vortioxetine

4. Antidepressants Selective Serotonin Reuptake Inhibitors (SSRIs)
Fluoxetine, Fluvoxamine, Sertraline, Paroxetine, Citalopram, Escitalopram
Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs)
Venlafaxine, Desvenlafaxine, Duloxetine
Norepinephrine Dopamine Reuptake Inhibitor (NDRI)
Bupropion
Norepinephrine and Specific Serotonin Antidepressant (NaSSA)
Mirtazapine
Serotonin Modulator and Stimulator
Vortioxetine
Tricyclic Antidepressants (TCA’s)
Monoamine Oxidase Inhibitors (MAOIs)

5. SSRIs, SNRIs, NDRIs and TCAs
are re-uptake inhibitors of 5-HT or NE
aka 5-HT transporter (SERT) blockade …

6. Mirtazapine

7. Clinical Pearls – SSRIs
Pros
Concerns / Comments
Sertraline (Zoloft®)
Safe in CV disease; good efficacy data
FDA analysis – reduction in SI
More diarrhea
High male sexual dysfunction
Citalopram (Celexa®)
Safe in CV disease
Well tolerated
QTc prolongation (40 mg max)
Escitalopram (Cipralex®)
Efficacy data
QTc prolongation
Possibly higher sexual dysfx
Formulary RESTRICTED to pts on PTA
Fluoxetine (Prozac®)
Useful in OCD, eating d/o
No weight gain, stimulating
Very long half-life
Fluvoxamine (Luvox®)
Useful in OCD
MANY MANY drug interactions
Most nausea and sedation
Paroxetine (Paxil®)
Useful in Anxiety
VERY anticholinergic, caution delrium in elderly, High discontinuation rxn,
Highest sexual dysfx and Wt gain in class
FDA analysis – increase in SI
Overall Class Side Effects
N/V/D, sexual dysfunction, SIADH, Risk of GI bleeds, sweating, dry mouth, anxiety (esp early or fast titration), tremor, headache

8. Consider increased Serotonin …
Act on Serotonin 2 receptors (post-synaptically)
Agitation, Insomnia, Anxiety, Akathisia
Panic
Sexual dysfunction
Act on Serotonin 3 receptors (post-synaptically)
Nausea, Diarrhea, GI distress
Headache

9. Clinical Pearls - SNRIs
Pros
Concerns / Comments
Venlafaxine (Effexor®)
Lower sexual dysfunction than SSRIs
Less wt gain
Dual action without the TCA side effects
May help neuropathic pain
High incidence nausea
High discontinuation rxn
Desvenlafaxine (Pristiq®)
Active metabolite of venlafaxine
Increased cost / not covered on Plan G
NOT on hosp formulary
Duloxetine (Cymbalta®)
May be helpful in chronic pain / neuropathy
Possibly less HTN than Venlafaxine
Weaker evidence of efficacy in depr
Increased cost / not covered by Plan G
Overall Class Side Effects
N/V/D, risk of hypertension at higher doses, sexual dysfunction, SIADH, Risk of GI bleeds, sweating, anxiety (esp early or fast titration), tremor, headache, insomnia

10. Clinical Pearls - Others
Drug
Pros
Concerns / Comments
Bupropion (Bupropion®)
Least sexual dysfunction
Least wt gain (may cause wt loss)
Helpful in smoking cessation
Agitation, insomnia, tremor
Caution with seizure hx or eating d/o
Sweating
Mirtazapine (Remeron®)
Available as dissolvable tab
Minimal GI upset or nausea
Sedation (at doses 15 mg or LESS); more activating at higher doses due to NE action
Weight gain
Dry mouth, edema
* Mirtazapine BLOCKS post-synaptic Serotonin 2 and 3 receptors – helpful for anxiety and insomnia, no GI upset
* Trazodone BLOCKS Serotonin 2 receptors – helpful for insomnia

11. Clinical Pearls – TCA’s
Serotonin and NE reuptake inhibitors
ALSO block – Histamine, Muscarinic, Alpha receptors
Tachycardia, hypotension
Weight gain, sexual dysfunction
Sedation
Dry mouth, constipation, confusion/delirium risk, urinary retention, dry eyes, blurred vision
Can be FATAL in overdose – cardiac toxicity, seizures
Also cause sweating, tremors, SIADH, rash
Helpful in OCD (esp Clomipramine) or significant anxiety, atypical depressions
Desipramine and Nortriptyline often tolerated better than Amitriptyline or Imipramine

12. Comparative Efficacy
Systematic Review for treatment of MDD ( )
acute, continuation, maintenance phases; includes unpublished data
Outcomes
Efficacy of response, speed and onset of response, remission, maintenance of remission and QoL
Acute phase treatment of MDD (N=26,349)
80 head-to-head RCTs (at least 6 wks duration), 34 placebo-controlled trials (indirect comparisons, meta-regression)
Across all efficacy trials for acute phase treatment of depression
46% patients achieve remission
62% patients achieve response
No reliable predictors of response
Gartlehner G et al. Ann Int Med 2008;149:

13. Results Acute Phase Treatment Results Comments
Efficacy and Effectiveness
ESC over CIT
SER & VEN over FLX
Similar rates among all agents
Not clinically significant
Onset of Action
MIR over CIT, FLX, SER or PAR
Only fair quality trials
Maintaining Response or Remission
No difference
FLX = SER; FLV = SER;
TRAZ = VEN
Only 3 trials
Treatment Resistant Depression
STAR-D Trial: BUP = SER = VEN
Another fair qual trial: VEN over CIT, FLX, SER, MIR and PAR

14. Assessment of Harm Adverse event profiles similar
VEN: higher incidence of N/V than SSRI’s (33% vs. 22%)
MIR: higher wt gain than SSRI’s
PAR and VEN: highest rates of discontinuation syndrome
Sexual dysfunction (overall 50% incidence)
Bupropion causes significantly less
PAR has highest rates among SSRI’s
Insufficient evidence to draw conclusions about:
Risk of Suicidality
Cardiovascular events
Weak evidence – VEN may increase CV risk

15. Cipriani A. et al. Lancet 2009;373:746-758
Sys review; Acute tx MDD; response rates, N=25928

16. Comments Only about 50-60% pt achieve response in acute tx trials
Efficacy
Escitalopram, Mirtazapine, Sertraline and Venlafaxine possibly more efficacious
Tolerability
Escitalopram, Sertraline, Bupropion and Citalopram possibly better tolerated
Only about 50-60% pt achieve response in acute tx trials
Only about 1/3 pts achieve remission
If don’t respond to first SSRI tried, may respond to a different SSRI (based on STAR-D trial)
Augmentation strategies if partial response …

17. Vortioxetine (Trintellex®)
5-HT reuptake inhibitor
5-HT 1a agonist
5-HT 1b partial agonist
5-HT 1d/3/7 antagonist
In vivo non-clinical studies also demonstrated that vortioxetine enhances levels of 5-HT, NE, DA, Ach and Hist in specific areas of the brain
Modulates glutamate transmission

18. 1A: incr or decr glu; modulates memory; anxiolytic
1B: agonism antidepressant / antagonism memory impr
3: increases glu by reducing GABA; AD activity and memory impr
7: incr or decr glu; AD activity and memory impr

20. Serotonergic modulation of glutamate transmission
Stems from findings that Ketamine’s antidepressant activity is abolished by 5-HT depletion (thus 5-HT dependent)
Glutamate receptors
Ionotropic: NMDA, AMPA, kainate receptors
Metabotropic:
Group I (mGluR1,R5) – potentiates presynaptic GLU release and NMDA currents
Group II (mGluR2,R3) and Group III (mGluR4,6,7 and 8) – suppress glutamate function

21. Glutaminergic agents

22. Vortioxetine Indications and Dosing
Only approved for Major Depressive Disorder
NOT approved for Anxiety … multiple negative trials
Black box warning – increased risk of suicidal thoughts and behavior in children, adolescents and young adults.
Dosing
10 mg once daily (5 mg in elderly); may increase to 20 mg once daily as tolerated

23. Pharmacokinetics Absorption is not affected by food
Very long half-life = 66 hrs
Metabolized by CYP 2D6 and 3A4
Need dose reduction (max 10 mg/d) for
2D6-poor metabolizers
Pts on 2D6 inhibitors: paroxetine, bupropion and fluoxetine
Need dose increase for
Pts on 2D6 inducers for more than 2 weeks (Phenytoin, Rifampin, Carbamazepine)
Wash-out
If changing from MAOI to Vortioxetine = 14 day washout
If changing from Vortioxetine to MAOI = 21 day washout

24. Vortioxetine – Side Effects
GI most common nausea (NNH 6), vomiting (NNH 28) and constipation (NNH 64)
Dizziness
Sweating
Headache
Dry mouth
No significant weight gain
Lower sexual dysfunction (20-30%) than SSRIs
May cause hyponatremia rarely but can be severe
Increased risk of GI bleeds when taken with NSAIDs
Caution seizure disorders

25. Vortioxetine Systematic Review
Included 11 RCTs, all placebo-controlled
Trial size range: participants
6 trials included an active comparator arm (5 – duloxetine; 1 venlafaxine)
Included several doses of vortioxetine
4/11 trials considered ‘negative or failed’ by FDA
Baseline MADRS score (moderate-severe depression)
6-8 weeks duration; change in MADRS or HAM-D score; response rates and remission rates
Meeker et al. Systematic Reviews 2015;4:21

26. Response vs. Placebo

27. Remission vs. Placebo
Overall not significant difference from placebo in the short trial duration (6-8 wks) …

28. Response vs. SNRI 5 of 6 trials used duloxetine as active comparator
Individual trials not powered to compare active arms
Pooled comparison show data favors SNRI response rates

29. Remission vs. SNRI NS difference between active arms
Short trial length

30. Considerations Interesting choice of comparator – Duloxetine
Head-to-head vs. Escitalopram … Duloxetine inferior in 2/3 trials
Head-to-head vs. Venlafaxine – favored VEN
Were they trying to pick a “weaker” comparator??? … and yet duloxetine still had better response rates.
Very “clean” patient populations – no other significant co- morbidities; no significant suicide risk; no other meds
Short-term studies

31. Long term trial Enrolled 639 in-pts and out-pts; baseline MADRS 32
Initial 12 week open-label flexible dose – vortioxetine treatment 5 mg daily (could increase to 10 mg) from week 2-8.
76% pts achieved response; 69% achieved remission
Pts who were in remission at both week 10 and 12 – 400 pts (63%) were randomized to Placebo or Vortioxetine for DB, fixed dose phase for 24 weeks
Primary efficacy outcome was time to relapse of MDD with the 24 weeks of DB period
J Psychopharmacol 2012;26:

33. Cognitive Effects
3 of the 11 trials looked at cognitive efficacy measures (one was post-hoc analysis in trial of elderly pts)
Measures
Digit Symbol Substitution Test (DSST)
Rey Auditory Visual Learning Test (RAVLT)
Perceived Deficit Questionnaire
Vortioxetine was superior to placebo for these cognitive measures
Duloxetine inconsistent results vs. placebo; did not show improvement on DSST
Clinically what dose this mean ?????

34. Cost Drug Approx Cost per Month Citalopram $20 Venlafaxine $21-42
Escitalopram
$25
Desvenlafaxine
$85
Sertraline
$24-38
Duloxetine
$74-274
Bupropion
$24-47
Vortioxetine
$100
Mirtazapine
$14-21

35. Final Comments
Vortioxetine has some interesting novel pharmacological properties
Clinical data is very limited at this point; especially long-term use
Studied in moderate-severe depression (easier to show improvements)
Does not appear to be superior to (weaker) active comparators …

36. American Fam Physician 2015;91:5 STEPS New Drug Reviews

37. Final Comments …
Cognitive data is very preliminary – needs to be tested more broadly to determine clinical significance in ‘real world’ trials
“7-year” cautionary window with new drug releases… we’ll know more about the true serious adverse events by the year 2020
Cost – significant (2-5 x cost of our other options except duloxetine)
Glutamate story in Depression … TO BE CONTINUED …

38. Thank-you!!!

39. Atypical Antipsychotic Augmentation
Risperidone, Aripiprazole, Olanzapine and Quetiapine have been studied as augmenting to antidepressant therapy in pts who have not responded to monotherapy
All had a small-modest effect over placebo for improvement in depression severity and remission
Pooled Remission NNT 10 (8-15) … Olanzapine weakest evidence to support
All caused significant side effects
Sedation, Akathisia, EPS, Metabolic changes to glucose and cholesterol, Weight gain
Questionable benefit on quality of life measures
Would reserve for
patients who have depression with psychotic features or atypical features;
patients who have failed multiple trials of mono/dual antidepressant therapy; and
pts who would qualify for ECT but who refuse to consent
PLOS Medicine 2013;10:e