VORTIOXETINE- AN

OVERIEW
 MULTIMODAL
ANTIDEPRESSANT
AN EVOLVING CONCEPT?
Modes of Action
Five modes of action for psychotropic drug:

1. Inhibition of transporters

2. Actions at G protein-linked receptors, from stimulation

to blockade
3. Actions at ligand-gated ion channels, from stimulation

to blockade
4. Actions at voltage-gated ion channels

5. Enzyme inhibition
TWO ARE MMAD

Actually 3 modes
Both 2 modes and 5 actions each; [Reuptake + Receptor
(GPCR)]
MMAD is just a Fancy New Name
Multimodal Antidepressant
Multi-modal drugs target more than one mode of

action.
Vortioxetine is an example of such a “multimodal”

agent, since it targets 3 modes of action

1. SERT Inhibition
2. GPCR actions (5HT1A , 5HT1B, 5HT1D and 5HT7
receptors)
3. Inhibition of a ligand-gated ion channel (5HT3)
5HT1B
CUTTING THE BRAKES
SERT BRAKES
1. 5HT1A –SD

2. 5HT1B -TERM

3. 5HT1D -TERM

4. 5HT7-GABA
5HT1A SD- BRAKE & RELEASE
SD 5HT1A receptors inhibit 5HT release, especially immediately

after administration

Eventually downregulate to allow enhanced release by SERT

inhibition with chronic administration.

Simultaneous stimulation of 5HT1A while blocking SERT

more rapid desensitization of the 5HT1A  enhanced release

of 5HT occur faster.
 Simultaneous stimulation 5HT1A +
SERT block rapid desensitization of 5HT1A
AGONISM
the 5HT1A  enhanced release of 5HT
occur faster.

5HT1A agonism
Full or partial antagonism of 5HT1B, 5HT1D,
and/or 5HT7 receptors interferes with their
negative feedback actions, thus “cutting the
brake cable” and thereby disinhibiting 5HT
release
SERT BRAKES
1. 5HT1A –SD

2. 5HT1B -TERM

3. 5HT1D -TERM

4. 5HT7-GABA
DOPAMINE AND SEXUAL
FUNCTION
 Simultaneous stimulation 5HT1A +
SERT block rapid desensitization of 5HT1A
AGONISM
the 5HT1A  enhanced release of 5HT
occur faster.

5HT1A agonism
SERT INHIBITION AND SEX
Post synaptic 5HT1A (1B) increase DA release

Most AD (SERT inhibitors) nearly complete

blockade of the SERT

Vortioxetine  SERT blockade low as 50%.

Apparently lesser amount of sexual dysfunction with

vortioxetine compared to selective SERT inhibitors

RELEASE OF DA-NA-Ach- HA
5HT1A POSTSYNAPTIC
5HT1A receptors are localized on postsynaptic sites,
Do not seem to desensitize over time after the

administration of SSRIs or vortioxetine

Regulate the release of many other neurotransmitters.

5HT1A stimulation-inhibits GABA inhibition of

DA/NA/Ach at presyn terminal Procog

5HT1B POSTSYNAPTIC
5HT1B receptors are localized on postsynaptic sites,
Do not seem to desensitize over time after the

administration of SSRIs or vortioxetine

Regulate the release of many other neurotransmitters.

5HT1B stimulation-inhibits GABA inhibition of

DA/NA/Ach/HA at presyn terminal  Procog

5HT3 POSTSYNAPTIC
5HT3 receptors  facuilitate GABA inhibition on

presynaptic NA and Ach release

Regulate the release of many other neurotransmitters.

5HT3 blockade-inhibits GABA inhibition of

NA/Ach at presyn terminal  Procog

RECEPTORS AND
FUNCTIONS
 RECEPTOR ACTION

5HT1A AGONISM Anxiolytic/ Antidepressant/ Analgesic

Antiemetic/ Procognitive/ ↓Aggression
↓Impulsivity/ ↑Sexual Drive/ ↑Sociability

5 HT1B PARTIAL Antimigraine/ Anxiolytic/ Antidepressant

AGONISM
↓Aggression

5HT1D ANTAGONISM Procognitive/ Migraine

5HT3 ANTAGONISM Antiemetic/ Analgesic/ Anxiolytic/
Antidepressant/ Procognitive/ ↑Sexual Drive

5HT7 ANTAGONISM Procognitive/ Circadian Rhythm

Maintenance/ Thermoregulation
VORTIOXETINE
BASIC INFORMATION
Multimodal AD

Vortioxetine Hydroromide

1-[2-(2,4-Dimethylphenyl

sulfanyl)phenyl] piperazine
C18 H22 N2 S, HBr
vor-tee-OK-sə-teen
Molar weight - 379.36 g/mol
BASIC INFORMATION
Synthesized by Lundbeck

Developed along with Takeda

MDD USFDA -2013

Brintellix (2016) US FDA approved a

name change to Trintellix

PHARMACOKINETICS
Pharmacokinetics- Absorption

Linear and dose-proportional

Absolute bioavailability - 75%

No effect of food on the pharmacokinetics

Pharmacokinetics- Absorption

Cmax = 18 ng/ ml (10 mg)

Tmax=7-11 hours post dose

T ½ = 66 hours

Steady state = 12 days

Pharmacokinetics - Distribution

Plasma protein binding- 98%

No difference in hepatic (mild, moderate or

severe) or renal (mild, moderate, severe,

ESRD) impairment.
Pharmacokinetics - Metabolism
Extensively metabolized through oxidation and

subsequent glucuronic acid conjugation

Oxidation via CYP2D6, CYP3A4/5,

CYP2C19, CYP2C9, CYP2A6, CYP2C8 and

Pharmacokinetics - Metabolism
Mainly via CYP 2D6

Poor metabolizers of CYP2D6 twice the

plasma concentration of extensive metabolizers

6 inactive metabolites
Pharmacokinetics - Metabolism
Extensively metabolised in the liver

Excreted in urine (59%) and faeces (26%)

Hepatic (mild, moderate or severe) or renal

impairment (mild, moderate, severe and

ESRD) no affect on clearance of vortioxetine

EVIDENCE
ACUTE
•7 published & 5 unpublished short-term (6–12 wk) RCTs

•Vortioxetine was significantly more effective than

placebo

•OR for response and remission of 1.652 and 1.399

respectively.
POSITIVE- 5
NEGATIVE-6
•7 head to head trials
•Did not differ significantly from SNRI/agomelatine
with regard response and remission
•Discontinuation owing to AEs was significantly less
common in the vortioxetine than in the comparator
 VLX

DLX
DLX DLX
VLX
DLX

DLX
DLX

AGO
The place of vortioxetine in the treatment of acute depression
is unclear
Vortioxetine may be more effective than placebo
In comparison to SNRIs, we found no advantage
Major limitation is the lack of comparisons with the SSRIs
May be supplemented by network meta-analyses to define
the role of vortioxetine in the treatment of depression.
 EFFECTIVE INEFFECTIVE

Amitryptiline Fluoxetine

Agomelatine Fluvoxamine

Escitalopram Reboxetine

Paroxetine Trazodone

Mirtzapine

Venlafaxine

Vortioxetine (2.3)
MAINTENANCE
Boulenger JP . J Psychopharmacol. 2012;26(11):1408-1416
MADRS score improved during maintenance therapy.

HAM-A total scores ad CGI improved

Response and remission rates increased over time.

At week 52; Response (75.4%); Remission (60.7%)

Most common adverse event - nausea

SEVERE DEPRESSION
Alvarez. Int J Neuropsychopharmacol. 2012;15(5):589-600
DEPRESSION IN ELDERLY
1508 PATIENTS
DEPRESSION IN CHILD
AND ADOLESCENT
41cases [22 adolescents and 19 children]

This OLE confirms the findings from the lead-in study,

which concluded that a dosing strategy of 5–20 mg/day
is safe, well tolerated, and suitable for future clinical
studies of vortioxetine in pediatric patients.
COGNITION
SEXUAL DYSFUNCTION
ANXIETY
ADVERSE EFFECTS AND
CONTRAINDICATIONS
 Contraindication
Contraindicated in hypersensitivity

At least 14 days should elapse between discontinuation

of a MAOI and starting Vortioxetne

Conversely, at least 21 days should be allowed after

stopping Vortioxtine before starting an MAOI

Warnings
Do not start in a patients on linezolid or

intravenous methylene blue

Symptoms of mania/hypomania were

reported in <0.1% of patients

ADVERSE EVENTS
No significant effect on body weight

Six month, double-blind, placebo-controlled trial -there

was no significant effect on body weight

Risk of bleeding -Concomitant use of aspirin, NSAIDs,

warfarin, and other anticoagulants may add to this risk

ADVERSE EVENTS
Hyponatremia especially in elderly

May trigger an angle closure attack in a patient

with anatomically narrow angles

Cytochrome 2D6 and Interactions
Maximum recommended dose of is 10 mg/day

in known CYP2D6 poor metabolizers.

Reduce the dose by one-half when receiving

a CYP2D6 strong inhibitor (e.g., bupropion,

fluoxetine, paroxetine, or quinidine)

CYP DOSE ADJUSTMENT
Reduce by half when a strong CYP2D6 inhibitor (e.g.,

bupropion, fluoxetine, paroxetine, quinidine) is co-

administered.

Consider increasing the dose when a strong CYP

inducer (e.g., rifampin, carbamazepine, phenytoin) is

co-administered
Cytochrome Interactions
Neither inhibits or induces any of the

cytochrome P 450 enzymes

No change in levels of other medication while

on vortioxetine
Pregnancy and Lactation
Category C drug

Lactation- No information
DOSAGE
DOSAGE
Starting and recommended dose - 10 mg

May be increased to a maximum of 20 mg

Decreased to a minimum of 5 mg vortioxetine once

daily.

May be taken with or without food

SUMMARY
 SUMMARY

Effective FDA approved drug

Favorable cognitive profile

Lesser Propensity to cause Sexual AE

 SUMMARY
Effective in elderly

Safe but needs investigation in children and

adolescents

Easy dosing schedule

 SUMMARY
No effect on levels of other drugs

No dose adjustment in elderly

No dose adjustment in severe renal and

hepatic impairment
THANK YOU