Trintellix (vortioxetine)CODY BLACKPHARM. D CANDIDATE 2018

BTrintellix (vortioxetine) Brintellix (vortioxetine) is now Trintellix

Due to brand name confusion with the antiplatelet Brilinta (ticagrelor)

There are over 50 reported cases of mishaps between Brintellix and Brilinta.

Available as Trintellix, from Takeda, in June 2016

Indicated for Major Depressive Disorder (MDD) by the FDA after six large studiesUnlike other antidepressants, Vortioxetine is not yet FDA

approved for the treatment of bipolar depression but is activating and patients should be screened for BPD prior to administration.

PL Detail-Document, Look-alike, Sound-alike Medications. Pharmacist’s Letter/Prescriber’s Letter. Article; Pharmacist's Letter; June 2016; Vol: 32

Selectively inhibiting the

serotonin transporter

(SERT)

SERT + Multiple actions within the serotonin system

Paradigm Shift In MDD Treatment

Paradigm shift has already begun by combining separate antidepressants

Improves outcomes: Higher remission rates (back to normal) Reduction of residual symptoms (eg. insomnia, anxiety) Reduced side effect burden

Novel drugs are now combining various mechanisms within a single moleculeStephen M. Stahl, Clara Lee-Zimmerman, Sylvia Cartwright and Debbi Ann Morrissette,Serotonergic Drugs for Depression and Beyond,Current Drug Targets, volume 14, issue 5,

pages 578-585, year 2013, issn 1389-4501/1873-5592, doi 10.2174/1389450111314050007, (http://www.eurekaselect.com/node/109205/article) ,5HT1A 5HT1B/D 5HT2A 5HT2C 5HT3 5HT7 NET SERT SNRI SSRI

Serotonin Modulators: A Newer Class Serotonin modulators are distinct from other classes of antidepressants Selective serotonin reuptake inhibitors (SSRIs) Serotonin-norepinephrine reuptake inhibitors (SNRIs) Atypical antidepressants Tricyclics Monoamine oxidase inhibitors (MAOIs) Serotonin modulators

Serotonin modulators: Antagonize postsynaptic serotonin receptors Inhibit reuptake of postsynaptic serotonin to varying degrees Increase synaptic concentrations of 5-HT, NE, DA, ACh, and histamine

-Compiled by Cody Black-Stephen M. Stahl, Clara Lee-Zimmerman, Sylvia Cartwright and Debbi Ann Morrissette,Serotonergic Drugs for Depression and Beyond,Current Drug Targets, volume 14, issue 5, pages 578-585, year 2013, issn 1389-4501/1873-5592, doi 10.2174/1389450111314050007, (http://www.eurekaselect.com/node/109205/article) ,5HT1A 5HT1B/D 5HT2A 5HT2C 5HT3 5HT7 NET SERT SNRI SSRI

Vortioxetine (Trintellix) Multimodal-acting antidepressant

Modulation of several 5-HT receptors Serotonin 5-HT1A/B Receptor Agonist

Coupled to Gi Inhibitory effects initially on 5-HT neurons Leads to downregulation of 5-HT1A over time Increased 5-

HT neuronal activity Serotonin 5-HT3 Receptor Antagonist

Ligand-gated ion channel on GABA interneurons Increased 5-HT & NE neuronal firing.

Present both in the peripheral and central nervous system Involved in GABA and dopamine regulation of neurotransmitter systems

Serotonin 5-HT7 Receptor Antagonist Coupled to Gs located on GABA interneurons which regulate 5-HT neurons. Breaks

taken off of 5-HT neurons. Primarily binds to the serotonin reuptake transporters (SERT)

SERT Antagonism & 5-HT1A Downregulation

Similarly to SSRIs, Vortioxetine blocks the reuptake of serotonin in the presynaptic neuron leading to: Increased serotonin in the synaptic cleft. Initial inhibition of serotonergic neurons via 5-HT1A activation. Long-term downregulation of the inhibitory 5-HT1A receptors Increased 5-HT neuronal activity

5-HT3 & 5-HT7 Antagonism & Disinhibition of GABAergic Interneurons 5-HT3 stimulation leads to

opening of the ion channel and rapid membrane depolarization of GABA interneurons.

5-HT7 antagonism decreases cAMP levels in 5-HT neurons.

Blockade of pre-synaptic GABA receptors of GABAergic neurons results in neuronal stimulation.

In the periphery, 5-HT3 receptors are located on neurons of the sensory and enteric nervous system.

Stephen M. Stahl (2015). Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): enhancing serotonin release by combining serotonin (5HT) transporter inhibition with actions at 5HT receptors (5HT1A, 5HT1B, 5HT1D, 5HT7 receptors). CNS Spectrums, 20, pp 93-97 doi:10.1017/S1092852915000139

Vortioxetine for Major Depressive Disorder (MDD) Initial PO Therapy:

10 mg once daily Increase to 20 mg once daily as tolerated Consider 5 mg once daily for patients who do not tolerate higher doses.

Maintenance: 5-20 mg once daily

Discontinuation: Doses of 5 or 10 mg/d

Can be discontinued abruptly Dose of 15 or 20mg/d

Reduce to 10mg for 1 week before full discontinuation to prevent withdrawal symptoms

*15% increase in receptor binding / 5 mg Vortioxetine dose increase

https://www-uptodate-com.une.idm.oclc.org/contents/vortioxetine-drug-information?source=search_result&search=vortioxetine&selectedTitle=1%7E8

Pharmacokinetics

Trintellix (vortioxetine) package insert. Deerfield, Illinois: Takeda Pharmaceuticals America, Inc.; Sep, 2013.

60 – 70 hour half-life = low likelihood to cause harsh serotonergic withdrawal or produce problems with taper

Adverse Reactions Black Box Warning: Suicidal thoughts and behaviors DDIs:

Strong inhibitors of CYP2D6 = Reduce TRINTELLIX dose by half Strong CYP Inducers: = Increase TRINTELLIX dose

The maximum recommended dose should not exceed 3 times the original dose. Serotonin syndrome (SS): Avoid co-administration with other serotonergic agents

Sexual Disorder*

Nausea & Diarrhea May lead to SIADH or hyponatremia (BEERS List)

https://www-uptodate-com.une.idm.oclc.org/contents/vortioxetine-drug-information?source=search_result&search=vortioxetine&selectedTitle=1%7E8

Vortioxetine Effect on MADRS Score

McIntyre RS, et al. Int J Neuropsychopharmacol. 2014;17:1557-1567.

Clinically Significant: MADRS is a ten-item diagnostic

questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders.

The higher the score, the more severe the patients depression.

The mean improvement from baseline to week 8 in the MADRS total score was: −10.9 points (placebo) −15.6 points (vortioxetine 10

mg) −17.6 points (vortioxetine 20

mg) **p<0.01; ***p<0.001 vs. placebo

Total Scores From Baseline To Week 8

Vortioxetine Effect on Cognitive Performance

McIntyre RS, et al. Int J Neuropsychopharmacol. 2014;17:1557-1567.

Clinically Significant:

At week 8, separation from placebo (p<0.05) was seen for all other measures of cognitive function with the exception of CRT for vortioxetine 20 mg

Acetylcholine?

Vortioxetine is not FDA approved for pro-cognitive effects, currently.

*p<0.05, **p<0.01, ***p<0.001 vs. placebo.

Where does Trintellix™ fit? Displays efficacy similar to other antidepressants Well tolerated: vortioxetine may have a safer profile

compared with other traditional anti-depressants. Reduced risk of weight gain Reduced risk of sexual dysfunction

The current retail price of vortioxetine is $316.10 for 30 days ($10.53/tablet or day).

Alternative antidepressant if patient cannot tolerate or does not respond to standard generic SSRIs or SNRIs.

http://online.lexi.com.une.idm.oclc.org/lco/action/doc/retrieve/docid/patch_f/4720782?hl=694370

Questions?

https://cdn.psychologytoday.com/sites/default/files/blogs/33760/2013/04/123138-121625.jpg