Review of Antidepressants & a look atthe newest agent Vortioxetine

Pharmacology Rounds Aug 2015Sue Corrigan BScPharm, ACPR, PharmD

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

Outline• Pharmacology• Review new agent

Vortioxetine• Clinical Pearls – what’s

the difference between the agents• Review evidence of

older agents and vortioxetine

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)

SSRIs, SNRIs, NDRIs and TCAsare re-uptake inhibitors of 5-HT or NE

aka 5-HT transporter (SERT) blockade …

Mirtazapine

Clinical Pearls – SSRIsSSRI Pros Concerns / Comments

Sertraline (Zoloft®) Safe in CV disease; good efficacy dataFDA analysis – reduction in SI

More diarrheaHigh male sexual dysfunction

Citalopram (Celexa®) Safe in CV diseaseWell tolerated

QTc prolongation (40 mg max)

Escitalopram (Cipralex®)

Well toleratedEfficacy data

QTc prolongationPossibly higher sexual dysfxFormulary RESTRICTED to pts on PTA

Fluoxetine (Prozac®) Useful in OCD, eating d/oNo weight gain, stimulatingFDA analysis – reduction in SI

Very long half-life

Fluvoxamine (Luvox®) Useful in OCD MANY MANY drug interactionsMost nausea and sedation

Paroxetine (Paxil®) Useful in Anxiety VERY anticholinergic, caution delrium in elderly, High discontinuation rxn, Highest sexual dysfx and Wt gain in classFDA 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

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

Clinical Pearls - SNRIsSNRI Pros Concerns / Comments

Venlafaxine (Effexor®) Lower sexual dysfunction than SSRIsLess wt gainDual action without the TCA side effectsMay help neuropathic pain

High incidence nauseaHigh discontinuation rxn

Desvenlafaxine (Pristiq®)

Active metabolite of venlafaxine Increased cost / not covered on Plan GNOT on hosp formulary

Duloxetine (Cymbalta®)

May be helpful in chronic pain / neuropathyPossibly less HTN than Venlafaxine

Weaker evidence of efficacy in deprIncreased cost / not covered by Plan GNOT on hosp formulary

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

Clinical Pearls - OthersDrug Pros Concerns / Comments

Bupropion (Bupropion®)

Least sexual dysfunctionLeast wt gain (may cause wt loss)Helpful in smoking cessation

Agitation, insomnia, tremorCaution with seizure hx or eating d/oSweating

Mirtazapine (Remeron®)

Least sexual dysfunctionAvailable as dissolvable tabMinimal GI upset or nausea

Sedation (at doses 15 mg or LESS); more activating at higher doses due to NE actionWeight gainDry 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

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

Comparative Efficacy• Systematic Review for treatment of MDD (1980-2007) • 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;149:734-750

ResultsAcute Phase Treatment

Results Comments

Efficacy and Effectiveness

ESC over CIT

SER & VEN over FLX

Similar rates among all agentsNot clinically significant

Onset of Action MIR over CIT, FLX, SER or PAR

Only fair quality trials

Maintaining Response or Remission

No differenceFLX = SER; FLV = SER; TRAZ = VEN

Only 3 trials

Treatment Resistant Depression

STAR-D Trial: BUP = SER = VENAnother fair qual trial: VEN over CIT, FLX, SER, MIR and PAR

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

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

Comments• 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 …

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

1A: incr or decr glu; modulates memory; anxiolytic1B: agonism antidepressant / antagonism memory impr3: increases glu by reducing GABA; AD activity and memory impr7: incr or decr glu; AD activity and memory impr

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

Glutaminergic agents

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

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

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

Vortioxetine Systematic Review• Included 11 RCTs, all placebo-controlled• Trial size range: 429-779 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 30-34 (moderate-severe

depression)• 6-8 weeks duration; change in MADRS or HAM-D score;

response rates and remission ratesMeeker et al. Systematic Reviews 2015;4:21

Responsevs. Placebo

Remissionvs. Placebo

Overall not significant difference from placebo in the short trial duration (6-8 wks) …

Responsevs. 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

Remissionvs. SNRI

• NS difference between active arms

• Short trial length

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

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;26:1408-1416

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 ?????

Cost Drug Approx

Cost per Month

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

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 …

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

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 …

Thank-you!!!

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:e1001403