A Focus on Vortioxetine – Psychopharmacology | Mechanism of Action | Clinical Application

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 systems.

There are 7 general serotonin receptor classes and another 14 serotonin subtype receptors, most 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 excitatory and inhibitory neurotransmission.

Once activated, these receptors modulate the downstream release of neurotransmitters such as Glutamate, Dopamine, Adrenaline, and GABA.

MECHANISM OF ACTION OF VORTIOXETINE (BRINTELLIX)

Vortioxetine has a unique pharmacological profile and a multimodal mechanism of action. It is considered beneficial in treating depression when pro-cognitive benefits are required. [D’Agostino et al., 2015]

It is the only drug that can modulate 5-HT receptor activity directly, being a full agonist of 5-HT1A, a partial agonist of 5-HT1B  and an antagonist of the 5-HT3, 5-HT7 and 5-HT1D receptors. [Adamo et al, 2021], [Sowa-Kućma et al., 2017]

The rank order potency of Vortioxetine is 5-HT3> SERT> 5-HT1B> 5-HT1A=5-HT7.

1. SERT Blockade

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

SERT inhibition by vortioxetine at therapeutic doses can be as low as 50%, which may explain the low incidence of sexual dysfunction compared to other SERT inhibitors (SSRIs and SNRIs) that have nearly complete inhibition of SERT at therapeutic doses.

2. 5-HT1A Agonist at presynaptic receptors

• Vortioxetine acts as an agonist at the 5-HT1A receptor, an autoreceptor for serotonergic neurotransmission at the presynaptic end. An autoreceptor acts as a brake on serotonergic transmission.

• Desensitisation of the presynaptic 5-HT1A receptor restores raphe firing to enhance 5-HT release.
• Vortioxetine, a 5-HT1A agonist, accelerates the desensitisation and disinhibition of the 5-HT1A receptor (caused by the 5-HT release), contributing to a reduction in the latency of action of vortioxetine. [Adamo et al., 2021]
• Vortioxetine produces a markedly faster recovery of 5-HT neuronal firing than fluoxetine. [Bétry et al., 2013]

3. 5-HT1A agonist activity at postsynaptic receptors. 

• 5-HT1A agonism inhibits GABAergic interneurons, which results in the release of Glutamate (Glu), Noradrenaline (NA), Dopamine (DA), Acetylcholine (ACh) and Histamine (His) in the prefrontal cortex. [Adamo et al., 2021]
• Activation of 5-HT1A receptors in the medial prefrontal cortex enhances the activity of Ventral tegmental area (VTA) DA neurons and mesocortical DA release. [Díaz-Mataix et al., 2005]

4.  5HT-7 Antagonism

• 5-HT7 receptors innervate GABA neurons in the raphe nucleus and act as negative feedback.
• When 5-HT stimulates these 5-HT7 receptors, inhibitory GABA is released, activating a brake on further 5-HT release.
• Antagonism of the 5-HT7 receptor potentiates the effect of the SERT blockade by increasing the release of serotonin from the raphe nucleus.
• 5-HT7 antagonism increases the acetylcholine and noradrenaline levels in the medial prefrontal cortex. [Sowa-Kućma et al., 2017]
• 5-HT7 antagonism may have antidepressant and pro-cognitive effects through action on circadian rhythms.[Westrich et al., 2015]

5. 5-HT1D Antagonism

• 5-HT1D receptors are autoreceptors located on the presynaptic axon terminal and act as negative feedback on the 5-HT release.
• They detect serotonin in the synapse, and when it builds up, it binds to the autoreceptors, which shut down serotonin release.
• By blocking these receptors, vortioxetine increases the release of serotonin.

6. 5-HT1B Partial Agonism

• The partial agonistic activity of vortioxetine at this autoreceptor increases serotonin release.
• Partial agonism toward the 5-HT1B receptors also increases the release of 5-HT, glutamate, acetylcholine and histamine. It also indirectly increases the release of dopamine and noradrenaline, particularly in the prefrontal cortex and hippocampus. [Sowa-Kućma et al., 2017]

7. 5-HT3 Antagonism

• 5-HT3 antagonism can lead to increases in serotonin, dopamine, norepinephrine, acetylcholine, and histamine, which may explain the pro-cognitive effects of vortioxetine. [Mørk et al., 2012]

8. BDNF:

• Vortioxetine can increase the brain-derived neurotrophic factor (BDNF) levels, promoting neurogenesis in the hippocampus dentate gyrus.  [Adamo et al., 2021]

In summary, vortioxetine is a 5-HT modulator and stimulator which also potentiates the neurotransmission of the noradrenergic, dopaminergic, cholinergic, histaminergic, glutamatergic and gamma-aminobutyric acid (GABA)ergic systems through actions on 5-HT receptors.

These neurotransmitters are implicated in Major Depressive Disorder-associated mood and cognitive dysfunction.

Unique properties of Vortioxetine: 

Pro-cognitive effects:

• The pro-cognitive effects of vortioxetine are independent of its impact on depression. [Bennabi et al., 2019]
• The pro-cognitive activity is postulated mainly due to 5-HT3 heteroreceptor antagonism in a subset of the GABAergic inhibitory interneurons.

• 5-HT3 antagonism reduces GABAergic transmission, which can, in turn, disinhibit pyramidal neuronal activity and increase glutamatergic neurotransmission, long-term potentiation (LTP) and neuroplasticity in the prefrontal cortex and the hippocampus.
• In addition, potentiation of histaminergic, cholinergic, noradrenergic and dopaminergic actions via 5-HT1B partial agonism, 5-HT1A postsynaptic agonism and 5-HT3 antagonism may contribute to pro-cognitive effects.

Sleep:[Adamo et al., 2021]

• Vortioxetine improves sleep quality by enhancing non-REM sleep, increasing slow-wave sleep (through 5-HT1A agonism and 5HT-3 antagonism), and suppressing REM sleep (through its 5HT-7 and 5HT1D antagonism).

Pain: [Adamo et al., 2021]

• The synergic increase of the levels of 5-HT, NA and DA contributes to strengthening the function of the descending inhibitory system, which can regulate the ascending nociceptive pathway. [This is one of the reasons why Duloxetine and other SNRIs are indicted in pain disorders].
• Vortioxetine also shows anti-inflammatory effects by inhibiting activated microglia (M1 phenotype), blocking neuroinflammation, and enhancing neurogenesis and neuroplasticity.
• Vortioxetine’s anti-inflammatory profile was superior when compared with amitriptyline and escitalopram.

Summary of Mechanism of Action of Vortioxetine: 

PHARMACOKINETICS AND DOSING

Vortioxetine is approved for Major Depressive Disorder (MDD) with a starting dose of 10 milligrams, increasing to 20 milligrams per day. [Product Information Brintellix]

Vortioxetine (Brintellix) is available as 5 mg, 10 mg and 20 mg tablets and drops.

Doses of 5–20mg were effective, with doses of 20mg exhibiting a greater clinical response.

The recommended starting dose is 5 mg vortioxetine once daily in patients ≥65 years of age.

Pharmacokinetics: 

• It has a bioavailability of 75% and reaches peak plasma concentration seven to eleven hours after administration. Furthermore, food does not appear to affect the absorption of vortioxetine.
• The daily dosing of vortioxetine has a linear and dose-proportional pharmacokinetic profile: raising the dose increases the drug binding to the receptors by 15% for every 5 milligrams.
• The half-life is approximately 66 hours and is primarily metabolised via multiple cytochrome P450 liver enzymes into inactive metabolites.

DRUG INTERACTIONS AND SIDE EFFECTS

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. Generally, the nausea is usually transient, dose-related and more common in women and during the first week of treatment.

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 than placebo and was statistically lower than 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.

Drug Interactions: 

• Vortioxetine is contraindicated in any combination with irreversible non-selective MAOIs due to the risk of serotonin syndrome.
• Vortioxetine is a serotonergic drug; 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.
• Vortioxetine is metabolised by CYP2D6 (amongst other CYP enzymes) and requires an adjustment of the dose when given in combination with CYP2D6 inhibitors (bupropion, fluoxetine or paroxetine).
• Similarly, coadministration with robust CYP inducers (carbamazepine, phenytoin or rifampicin) requires an increased dose of Vortioxetine.

CLINICAL APPLICATION OF VORTIOXETINE

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. [Henigsberg et al., 2012]

Patients were randomly assigned either 1, 5, or 10 mg of vortioxetine, and the results showed a statistically significant reduction in HDRS-24 score for all dosages compared 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. [Boulenger et al., 2014]

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

Both doses of vortioxetine were statistically superior to placebo and were 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).

Cognition:

• Vortioxetine has shown to be beneficial in improving cognitive symptoms as monotherapy and as an adjunct to SSRIs in residual depressive symptoms. [Nierenberg et al., 2019]
• A systematic review showed that only vortioxetine and bupropion have demonstrated procognitive effects in MDD populations relative to selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors.[Blumberg et al., 2020]

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. A significantly lower risk of relapse was also observed with vortioxetine. [Christensen et al., 2020]

Chronic Neuropathic Pain: 

• Vortioxetine has shown efficacy at a dose of 10–20 mg/daily in the short-and long-term treatment of patients with chronic orofacial pain, demonstrating a higher rate of clinical response and remission, better acceptability, safety rate and tolerability, and lower latency of action compared with other antidepressants.
• The analgesic effect is attributed to the enhancement of the serotonergic transmission, the simultaneous inhibition of the 5-HT3 receptors and the modulation of the 5-HT7 receptors. Due to its favourable tolerability profile, it may be particularly useful in elderly patients with concomitant mood disorders and cognitive impairment. [Adamo et al., 2021]

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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