going into the vortex with vortioxetine...cochrane review 2017 design meta-analysis of 15...

Going into the Vortex with Vortioxetine

Sandy BaptiePharmacy Resident 2019-20

Learning Objectives• By the end of this session:

– Understand vortioxetine unique mechanism of action and binding profile

– Describe potential adverse effects of vortioxetine

– Summarize available evidence behind vortioxetine in Major Depressive Disorder

– Investigate any evidence behind cognitive benefits of vortioxetine

Depression Epidemiology

Can J Psych. 2016;61(9):510-23

Prevalence of major depressive disorder by world region. *WMH, World Health Organization’s World Mental Health Surveys, Canada

Depression Epidemiology

Descriptive epidemiology of Depression in Canada 2012In the past 12 months:Sought treatment 63%Taking an antidepressant 33%With generalized anxiety disorder

25%

Suicide attempts 6.6%With alcohol abuse & dependence

4.8%4.5%

Can J Psych. 2016;61(9):510-23

CANMAT GuidelinesFirst line agents for major depressive episode SSRI SNRI OtherEscitalopram Venlafaxine MirtazapineCitalopram Desvenlafaxine BupropionFluoxetine Duloxetine MianserinFluvoxamine MilnacipranParoxetineSertralineAgomelatineVortioxetine

Can J Psych. 2016;61(9):510-23

Pharmacokinetics• Absorption

– Not affected by food – 75% bioavailable

• Distribution:– Vd 2600L – 98% Protein bound – Time to Peak 7-11h

• Metabolism: – Hepatic (CYP2D6); glucuronic acid conjugation– Half life elimination ~66h

• Excretion:– Urine (59%), feces (26%)

Pharmacodynamics • Serotonin Modulator and Stimulator (SMS)

– SSRI; Ki = 1.6 nM– Inhibits reuptake of serotonin– Agonism at 5-HT1A (Ki=15 nM)– Partial agonism at 5-HT1B (Ki=33 nM)– Antagonism at 5-HT3 (Ki=3.7 nM)– Some antagonist activity at 5-HT1D, 5-HT7

(Ki=19 nM)

Vortioxetine. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: http://online.lexi.com. Accessed Sept 25 2019

European Neuropsyc. 2013; 23(10):1190-98

Serotonin Receptor Binding• 5-HT1A

– Pre-synaptic autoreceptors in raphe nucleus – Post-synaptic neurons in hippocampus, corticolimbic system, septum, amygdala – Receptor abnormalities reported in MDD; established role in MOA of antidepressants

• 5-HT1B– Pre- and postsynaptically on axons, negatively coupled to adenylate cyclase– Antagonists administered alone/ with antidepressants–effective in preclinical models

• 5-HT1D

– Patients with depression impaired sensitivity of postsynaptic 5-HT1D receptors– Higher density of 5-HT1D receptors in the globus pallidus

• 5-HT3– High concentrations in the spinal cord and brainstem– Antagonism leads to reduced nausea

• 5-HT7– Highly expressed in the thalamus, hypothalamus, hippocampus and cortex– Role in circadian rhythm, sleep, mood

• 5-HT2A– Widely distributed at varying densities throughout the brain– Antagonism leads to to anxiolytic action, sedation, reduced sexual dysfunction

Pharmacology and Therapeutics. 2013; 137(1): 119-131

Adverse Effects

Siu, Jacky. CSHP-BC Clinical Symposium 2019

PICOP Patients with Major Depressive DisorderI VortioxetineC Placebo/ other antidepressantsO Major depressive disorder

Literature SearchDatabases Search Terms

Medline, Google Scholar, Clinical Trials database, PubMed, Cochrane Library

(MDD OR major depressive disorder OR depression) AND (vortioxetine OR Trintellix) AND/OR (MADRS OR Hamilton Rating Scale for Depression OR HAM-D24 OR PHQ9) AND/OR adverse events

https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD011520.pub2/epdf/full

Cochrane Review 2017Design Meta-analysis of 15 multicentre RCTs (2 unpublished)

Number N = 7,746 (4134 vortioxetine; 2299 placebo; 1313 to SNRIs (344 venlafaxine, 969 to duloxetine)

Population • Adult inpatient and outpatients with a diagnosis of MDD acute phase (4-12 weeks) taking ≥5mg vortioxetine (on fixed/ flexible dosing)

Selection Criteria • RCTs comparing efficacy, tolerability, or both of vortioxetine VS placebo / any other antidepressant agent in treatment of acute phase depression in adults, up to May 2016

Intervention + Comparator

• 7 studies Vortioxetine VS Placebo• 8 studies Vortioxetine VS SNRI (2 with venlafaxine, 6 duloxetine)• Timeframe for follow up- 6-8 weeks

Outcomes • 1o Outcome: Response• 2o Outcomes:

-Remission-Depressive Symptoms-Drop outs due to adverse events -Drop outs due to inefficacy -Tolerability


Cochrane Review 2017Alvarez 2012; V VS Venlafaxine Vs Placebo N= 315; Double-blind, randomized trial

Baldwin 2012; V Vs Duloxetine Vs Placebo N= 776; Randomized, double-blind, parallel-group fixed-dose study

Boulenger 2014; V Vs Duloxetine Vs Placebo N= 608; Double-blind, randomised, fixed-dose

Henigsberg 2012; V Vs Placebo N= 560; Multicentre, randomised, double-blind, parallel-group, Fixed

Jacobsen 2015; V Vs Placebo N=462; Phase 3, randomised, double-blind, parallel-group, fixed

Jain 2013; V Vs Placebo N= 600; multicentre, randomised, double-blind, parallel-group, fixed-dose study

Katona 2012; V Vs Placebo N= 452; randomised, double-blind, parallel-group, fixed-dose study

Mahableshwarkar 2013; V Vs duloxetine Vs Placebo

N= 611; randomised, double-blind, parallel-group, fixed-dose study

Mahableshwarkar 2015a; V Vs Placebo Vs Duloxetine

N= 463; phase 3, multicentre, randomized, double-blind, parallel-group, fixed

Mahableshwarkar 2015b; V Vs Placebo Vs Duloxetine

N= 602; randomized, double-blind, parallel-group, flexible

Mahableshwarkar 2015c; V Vs Placebo N= 469; phase 3, randomised, double-blind, parallel-group, fixed

McIntyre 2014; V Vs Placebo N= 598; Randomised, double-blind, parallel-group, fixed-dose study

NCT01255787 (2010-2012) V Vs Placebo N= 600; randomised, double-blind, placebo-controlled fixed dose

Takeda 2011; V Vs Placebo N= 366; Randomised, double-blind, parallel-group, phase 3 study

Wang 2015; V Vs Venlafaxine N= 443; randomised, double-blind, parallel-group, fixed dose


Vortioxetine VS Placebo: Response


Results: Vortioxetine VS Placebo


Outcome # of Studies I2 RR (95% CI) P ValueResponse 14 60% 1.35 (1.22 to 1.49) <0.001Drop-outs 14 0% 1.05 (0.93 to 1.19) 0.40Remission 14 58% 1.32 (1.15 to 1.53) <0.001Depressive Symptoms

14 79% MD -2.94, (-4.07 to -1.80)

<0.001

Drop-out due toadverse events

14 0% 1.41 (1.09 to 1.81) 0.008

Drop-out due to inefficacy

14 41% 0.56 (0.34 to 0.90) 0.02

Tolerability 14 8% 1.12 (1.07 to 1.16) 0.001

Vortioxetine VS SNRIs: Response


Results: Vortioxetine VS SNRIsOutcome # of Studies I2 RR (95% CI) P ValueResponse 8 61% 0.91 (0.82 to 1.00) 0.06Drop-outs 8 44% 0.89 (0.73 to 1.08) 0.25Remission 8 57% 0.89 (0.77 to 1.03) 0.11Depressive Symptoms 8 50% MD 1.5

(0.50 to 2.53)0.003

Drop-out due toadverse events

8 55% 0.74 (0.51 to 1.08) 0.12

Drop-out due to inefficacy

8 30% 1.52 (0.70 to 3.30) 0.29

Tolerability 8 0% 0.90 (0.86 to 0.94) <0.001


AMSTAR1. Did the research questions and inclusion criteria for the review include the components of PICO?

Yes

2. Did the report of the review contain an explicit statement that the review methods were established prior to the conduct of the review and did the report justify any significant deviations from the protocol?

Yes

3. Did the review authors explain their selection of the study designs for inclusion in the review?

No

4. Did the review authors use a comprehensive literature search strategy? Yes5. Did the review authors perform study selection in duplicate? Yes6. Did the review authors perform data extraction in duplicate? Yes7. Did the review authors provide a list of excluded studies and justify the exclusions?

Yes

8. Did the review authors describe the included studies in adequate detail? PartialYes

9. Did the review authors use a satisfactory technique for assessing the risk of bias (RoB) in individual studies that were included in the review?

PartialYes

AMSTAR10. Did the review authors report on the sources of funding for the studies included in the review?

Yes

11. If meta-analysis was performed did the review authors use appropriate methods for statistical combination of results?

Yes

12. If meta-analysis was performed, did the review authors assess the potential impact of RoB in individual studies on the results of the meta-analysis or other evidence synthesis?

No

13. Did the review authors account for RoB in individual studies when interpreting/ discussing the results of the review?

Yes

14. Did the review authors provide a satisfactory explanation for, and discussion of, any heterogeneity observed in the results of the review?

Yes

15. If they performed quantitative synthesis did the review authors carry out an adequate investigation of publication bias (small study bias) and discuss its likely impact on the results of the review?

Yes

16. Did the review authors report any potential sources of conflict of interest, including any funding they received for conducting the review?

Yes

Risk of Bias


Limitations • Methodological

– Quality of evidence low to moderate– High heterogeneity within studies – Was only compared to SNRI or placebo– Outcomes varied markedly across studies– Unclear risk of bias of selective reporting and other biases– Did not include cognition as an outcome – Only evaluated acute phase of depression – Varying doses of vortioxetine– Reporting of adverse effects varied markedly– All studies were sponsored by the pharmaceutical companies that manufactures vortioxetine

• Clinical– Unclear if vortioxetine advantage in specific side effects (eg sexual dysfunction)– Cannot conclude outcomes compared to SSRIs

Conclusion: No firm conclusion on vortioxetine can be made. Was effective in treating MDD; no clear advantage over SNRIs


McIntyre, et al 2014

Int J of Neuropsychopharmacol. 2014:17(10);1557–67

McIntyre, et al 2014


Method • Randomized, double-blind, parallel-group, placebo-controlled, fixed-dose study, December 2011 – May 2013

Participants • 598 patients with Recurrent MDD according to DSM-IV-TR criteria; Current MDE confirmed using MINI; MADRS total score ≥26; reported duration of current MDE ≥ 3 months

• 79 psychiatric inpatient and outpatient settings in 12 countries• Age range 18-65, mean age 45, 66% female, no comorbidities

Duration • 8 weeks treatment, 4 weeks follow up

Intervention & Comparator

Participants were randomly assigned to 1 of 3 treatments:• Vortioxetine 10 mg/day; 195 participants• Vortioxetine 20 mg/day; 207 participants• Placebo; 196 participants • 8-week double-blind treatment period • Participants seen at baseline and weeks 1, 4 and 8

Outcomes • Change from baseline to week 8 in the composite z-score defined as the equally weighted sum of the z-scores in the DSST (executive function, speed of processing, attention) and RAVLT (learning, memory)

McIntyre, et al 2014 Results


Outcome Mean Difference 95% CI P Value1o efficacy endpoint- Vortioxetine 10mg- Vortioxetine 20mg

0.360.33

0.22 – 0.550.19 – 0.47

<0.0001<0.0001

DSST Score- Vortioxetine 10mg- Vortioxetine 20mg

4.204.26

2.50 – 5.90 2.57 – 5.94

<0.001<0.001

RAVLTacquisition- Vortioxetine 10mg - Vortioxetine 20mg

1.020.59

0.11 – 1.93−0.31 –1.50

0.0290.199

RAVLTdelayed recall - Vortioxetine 10mg- Vortioxetine 20mg

0.710.65

0.24 – 1.19 0.17 –1.12

0.0030.007

McIntyre, et al 2014 Results


Outcome Mean Difference from placebo

95% CI P Value

MADRS Total Score - Vortioxetine 10mg- Vortioxetine 20mg

-4.7-6.7

-6.4; −3.0 -8.4;-5.0

<0.001<0.001

CGI-I Score - Vortioxetine 10mg- Vortioxetine 20mg

-0.61-0.86

-0.81; -0.40 -1.1; -0.65

<0.001<0.001

- CGI-S Score- Vortioxetine 10mg - Vortioxetine 20mg

-0.65-0.85

-0.88; -0.42-1.1; -0.62

<0.001<0.001

Limitations


• Methodological– Did not make sample size calculation– Study was for short period of time – Funded by maker of vortioxetine (Lundbeck)– Eligible patients may not be representative of adults with MDD who are seen in

normal clinical practice – Exclusion of individuals presenting with milder baseline severity – Results only pertain to the two doses evaluated

My conclusion: Could trial in otherwise healthy patient with primarily cognitive symptoms in major depressive disorder, but unsure of long term benefit

Vortioxetine: Bottom line• Recommendation:

– Patients with acute phase depression who display cognitive symptoms (executive function, speed of processing, attention) in either an inpatient or outpatient setting

Monitoring

Efficacy Safety SleepInterestGuilt/hopelessnessEnergyConcentrationAppetite Psychomotor retardation/ agitation Suicidal Ideation

Nausea/ vomitingDizziness/ abnormal dreams/ suicidal ideation/ serotonin syndromeDry mouth Sexual dysfunction Diarrhea, constipation

going into the vortex with vortioxetine...cochrane review 2017 design meta-analysis of 15...

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