A Focus on Vortioxetine – Mechanism of Action and Efficacy

SEROTONIN RECEPTORS

Traditionally, antidepressant research has focused on the development of drugs that bind to the serotonin transporter (SERT). SERT transports serotonin from the synaptic cleft to the presynaptic neuron and inhibition of this transporter causes an increase in serotonin in the synaptic cleft.

However, many antidepressants also act on serotonin receptors, known as 5-hydroxytryptamine (5-HT) receptors.

The 5-HT receptors are a group of receptors found throughout the central and peripheral nervous system.

There are 7 general serotonin receptor classes and another 14 serotonin subtype receptors, the majority of which are implicated in depression and depressive-like behaviours.

Under normal conditions, the serotonin receptors are activated by synaptic serotonin and are involved in both excitatory and inhibitory neurotransmission.

Once activated these receptors modulate the downstream release of other neurotransmitters such as glutamate, dopamine, adrenaline, and GABA.

MECHANISM OF ACTION

Vortioxetine has a unique pharmacological profile and a multimodal mechanism of action. It is considered beneficial in the treatment of depression when pro-cognitive benefits are required [1].

A.) SERT Blockade

Vortioxetine has high affinity for SERT, and SERT blockade increases the availability of serotonin in the synaptic cleft.

B.) 5HT1A Agonist

Vortioxetine acts as an agonist at the 5HT-1A receptor, which is an autoreceptor for serotonergic neurotransmission. An autoreceptor acts as a brake on serotonergic transmission.

Desensitisation of 5HT-1A increases serotonin release, and this is believed to assist in relieving depression.

C.) 5HT-7 Antagonism

Antagonism of the 5HT-7 receptor potentiates the effect of the SERT blockade by increasing the release of serotonin from the raphe nucleus.

D.) 5HT – 1D Antagonism

5HT – 1D receptors are autoreceptors located on the presynaptic axon terminal.

They detect serotonin in the synapse, and when serotonin builds up in the synapse, it binds to the autoreceptors which shut down serotonin release.

By blocking these receptors, vortioxetine increases the release of serotonin.

E.) 5HT-1B Partial Agonism

The partial agonistic activity of vortioxetine at this autoreceptor increases serotonin release.

F.) 5HT-3 Antagonism

5-HT₃ receptors when blocked can lead to increases in serotonin, dopamine, norepinephrine, acetylcholine, and histamine which may explain the pro-cognitive effects of vortioxetine [2].

Together, these serotonergic actions are hypothesised to modulate several downstream neurotransmitters that are implicated in depressive behaviours and the Major Depressive Disorder-associated mood and cognitive dysfunction.

Summary

In summary, vortioxetine blocks 5-HT3, 5-HT1D and 5-HT7 receptors, stimulates 5-HT1A receptor, and partially stimulates the 5-HT1B receptor.

PHARMACOKINETICS

Vortioxetine is approved for Major Depressive Disorder (MDD) with a starting dose of 10 milligrams increasing to 20 milligrams per day.

It has a bioavailability of 75% and reaches peak plasma concentration in seven to eleven hours after administration. Furthermore, food does not appear to affect absorption of vortioxetine.

Daily dosing of vortioxetine has a linear and dose proportional pharmacokinetic profile: raising the dose increases the amount of drug binding to the receptors by 15% for every 5 milligrams.

The half-life is approximately 66 hours, and it is primarily metabolised via multiple cytochrome P450 liver enzymes into inactive metabolites.

DRUG INTERACTIONS AND SIDE EFFECTS

Vortioxetine is a serotonergic drug, and therefore there is a risk of serotonin syndrome if used in combination with drugs that also act on serotonergic pathways.

Symptoms of serotonin syndrome include high body temperature, sweating, tremors, and agitation.

A common side effect of vortioxetine is nausea, which has an incidence of 32% in patients who receive a dose of at least 15 milligrams.

Other common side effects include vomiting, diarrhoea, dry mouth, headaches, sexual dysfunction, and abnormal dreams.

In an analysis of seven placebo-controlled trials, sexual dysfunction was reported by up to a third of men and women taking the 15 mg or 20 mg dose. Sexual problems were, however, also reported in up to 20% of people taking the placebo. (NPS)

An April 2017 paper stated that sexual dysfunction with vortioxetine was not statistically higher when compared with placebo, and was statistically lower compared with other SSRIs or SNRIs.

They also stated that there is evidence that antidepressants that are also 5HT-1A receptor agonists (e.g., vortioxetine and vilazodone) may facilitate sexual performance.

EFFICACY

The RANZCP guidelines for mood disorders typical recommendation for Vortioxetine is second-line treatment; the features for which it is most likely to be useful are melancholia, severe depression and enhancing cognition.

According to the Cochrane review (2017) –

The place of vortioxetine in the treatment of acute depression is unclear. Our analyses showed vortioxetine may be more effective than placebo in terms of response, remission and depressive symptoms, but the clinical relevance of these effects is uncertain.

Furthermore, the quality of evidence to support these findings was generally low. In comparison to SNRIs, we found no advantage for vortioxetine.

Vortioxetine was less effective than duloxetine, but fewer people reported adverse effects when treated with vortioxetine compared to duloxetine. However, these findings are uncertain and not well supported by evidence.

A major limitation of the current evidence is the lack of comparisons with the SSRIs, which are usually recommended as first-line treatments for acute depression.

Studies with direct comparisons to SSRIs are needed to address this gap and may be supplemented by network meta-analyses to define the role of vortioxetine in the treatment of depression.

In the recent largest-ever study on antidepressants by Cipriani et al., Vortioxetine ranked favourably for both efficacy and tolerability.

A post-hoc study showed that Vortioxetine improved anhedonia which correlated with improvement in function and quality of life. [Cao B et al., 2019]

Vortioxetine has been associated with significant improvements in major depressive disorder – associated physical symptoms [Christensen M et al., 2018]

A real-world chart review (32 patients) showed that adjunctive vortioxetine to patients with SSRI treatment-resistance showed a response in 41.7 % and remission in 33% of individuals. [De Berardis D et al., 2020]

Adjunctive vortioxetine may be useful and well-tolerated in stage I treatment-resistant depression.

Heningsberg and colleagues conducted a multicentre, double-blind, placebo-controlled, parallel-group, 8-week trial of 560 patients with a MADRS score of at least 26 [3].

Patients were randomly assigned either 1-, 5-, or 10-mg of vortioxetine and the results showed that there was a statistically significant reduction in HDRS-24 score for all dosages in comparison with placebo.

In another double-blind, randomised, fixed-dose, placebo-controlled, active reference 8-week study, patients with a MADRS score of ≥26 and a minimum CGI-S score of 4, were randomly assigned a daily dose of 15- or 20- mg of vortioxetine, duloxetine 60mg/day or placebo [4].

All three treatments were statistically superior to placebo at reducing total MADRS scores.

Both doses of vortioxetine were statistically superior to placebo, and it was well tolerated.

Emotional Blunting: 

Patients with MDD who experienced a partial response to SSRI/SNRI monotherapy at an adequate dose for ≥6 weeks were switched to 8 weeks of vortioxetine treatment 10-20 mg/day. [Fagiolini et al., 2021]

Vortioxetine was shown to be effective for treating emotional blunting

• Improvement in emotional blunting correlated with improved overall functioning
• Improved emotional blunting also correlated with greater motivation and energy

Anhedonia: 

A pooled post hoc analysis of 11 studies showed efficacy of vortioxetine against anhedonia. This effect was comparable to agomelatine which is efficacious in treating anhedonia. [McIntyre et al., 2021]

It has been hypothesised that the pro-cognitive effects of vortioxetine may be mediated via 5-HT₃ heteroreceptors on GABAergic interneurons, thereby increasing glutamatergic activation which is involved in the pathogenesis of anhedonia (via an effect on nucleus accumbens).

Vortioxetine also shows anti-inflammatory properties which may contribute to its anti-anhedonic effect. (Inflammation is linked to anhedonia).

MDD with Trauma: 

Vortioxetine showed significant short- and long-term efficacy on depressive and anxiety symptoms in patients with MDD and a history of trauma. Significantly lower risk of relapse was also observed with vortioxetine. [Christensen et al., 2020]

Check out our CPD module which summarises mechanisms of actions and side effect profiles of all antidepressants and antipsychotics for further information.

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