2017 September-December; 4(3): 50–54. ISSN: 2421-3349
Published online 2017 December 15.

Vortioxetine: efficacy on cognitive symptoms in Major Depressive Disorder

Andrea Escelsior,1 Andrea Aguglia,1,2 Alice Cervetti,1 Jacopo Nebbia,1 Sara Pacella,3 Giulia Piccinini,4 Samantha Visimberga,5 Mario Amore,1 and Davide Prestia1

1Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of Psychiatry, University of Genoa, IRCSS Policlinico San Martino Hospital, Genoa, Italy
2Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy
3Psychiatry Unit, San Giacomo Hospital, Novi Ligure (AL), Italy
4Drug Addiction Service, ASL 4, Genoa, Italy
5“Villa del Principe” Therapeutic Community, Genoa, Italy

Address for correspondence: Davide Prestia, Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), Section of Psychiatry, University of Genoa, IRCCS San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy, E-mail: prestia81@gmail.com

Abstract

In Major Depressive Disorder (MDD), cognitive impairment is frequently associated with depressive symptoms, overlapping them and not being just a consequence; moreover, it persists during remission periods.

Cognitive dysfunctions concern different areas: attention, concentration, executive functions, learning, memory, intellective processing speed, and decision making capacity.

Vortioxetine is a new generation antidepressant with a multimodal action mechanism and a receptor profile that enable it to operate on different neurotransmitter systems. Its administration causes an increase of the glutamatergic, cholinergic, histaminergic and noradrenergic tone, particularly in areas involved in cognitive functions, such as Prefrontal Cortex and Hippocampus.

It also causes increasing neurogenesis, activation of coding genes for dendritic spines, dendritic arborization, increased long-term enhancement of hippocampus.

The aim of our work is to better understand its mechanism of action and to summarize the most recent literature data.

Keywords: vortioxetine, cognitive symptoms, depression, recovery, remission

Introduction

Major Depressive Disorder (MDD) is a chronic, multifactorial disorder, characterized by depressive mood, anhedonia, low self-esteem, feelings of guilt, decreased appetite, sleep-wake rhythm disturbances and altered cognition (1). Lifetime prevalence at 12 months is 16.2% in developed countries, counting more than 300 million people affected worldwide and high levels of mortality; it is furthermore one of the main causes of disability (24).

Individuals with MDD often exhibit impairments in cognitive function, including attention, concentration, executive function, learning, memory, intellective processing speed. The foregoing deficits are key contributors to social and occupational disability, with reduced productivity and an elevated burden of absenteeism, resulting in increased costs caused by the disease (58).

Cognitive symptoms are early features of the disorder, that can be identified during the first episodes of depression as well as in late-life depression and in recurring episodes, which are associated with an increase in cognitive impairment (5, 9).

Cognitive deficits are poorly responsive to pharmacological therapy; they occur in more than 60% of depressed patients, in the 85–94% of the time during acute episodes, and in the 39–44% of the time outside acute episodes, persisting even in symptomatic remission periods (1012).

Vortioxetine: indication, mechanism of action, dosage

Vortioxetine, antidepressant approved by EMA for the treatment of MDD, is on the European market from 2013 and shows efficacy in the treatment of cognitive symptoms in MDD regardless the action on mood symptoms. The efficacy of vortioxetine is established in randomized short-term clinical studies and also in long-term ones until 52 weeks (23, 58, 10, 13, 14).

Broad spectrum effects on cognitive symptoms have been demonstrated on executive functions: attention, concentration, memory and psychomotor activity (14).

Usual dosage range is 5–20 mg/day, recommended starting dosage is 10 mg/day for under 65 years old patients and 5 mg/day for over 65 years old patients (14). The recommended duration treatment is at least six months or more after resolution of depressive symptoms and vortioxetine can be discontinued without tapering (15).

The drug is commonly well tolerated, with poor side effects, mainly on digestive system, and especially concerning sexual dysfunctions (16).

Pharmacokinetics is linear and proportional to the dose in a range between 2.5 mg–60 mg/die, not modified by food intake. It is extensively metabolized by liver through initial oxidation via isoenzymes of citocrome P450, mainly CYP2D6, but also CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8, CYP2B6, then through subsequent glucuronic acid conjugation (7, 14).

The maximal plasma concentration is reached within 7–11 hours post-dose, absolute bioavailability is 75%, steady state is reached within about two weeks; the plasma protein binding is 98%–99% (7).

About pharmacodynamics, vortioxetine has a multimodal action on different substrates binded with different affinity: blocks serotonin transporter (SERT) with high affinity (Ki=1.6nM) with an increase of the reuptake, full agonist actions at 5-HT1A (Ki=15nM), partial agonist actions at 5HT1B (Ki=33nM), antagonist actions at 5-HT1D (Ki=54nM), 5-HT3 (Ki=3.7nM) and 5-HT7 (Ki=19nM) (Figure 1).

Figure 1Figure 1
Vortioxetine’s pharmacologic targets. Vortioxetine inhibits the serotonin (5-HT) transporter (SERT) and targets 5 additional 5HT receptors as follows: agonist action at 5-HT1A, partial agonist action 5-HT1B and antagonist action at 5-HT1D, 5-HT3, 5-HT7. (more ...)

Vortioxetine modulates neurotransmitter systems directly and indirectly, increasing glutamate, norepinephrine, dopamine, histamine and acetylcholine, reducing the release of γ-aminobutyric acid GABA (7, 1720).

Effects of Vortioxetine on cognitive symptoms

Although the effects of vortioxetine are relatively well known, the mechanism underlying the improvement on cognitive functions has not yet been fully explained (21).

The 5-HT1A receptor appears especially in the frontal cortex and raphe nuclei. The 5-HT1A agonism, which inhibits GABAergic interneurons that innervate presynaptic terminals of noradrenergic, dopaminergic and cholinergic neurons, seems to induce the release of these neurotransmitters in the prefrontal cortex (19, 22). In rats, the acute and chronic administration of vortioxetine induces an increase in histamine concentration in ventral hippocampus and prefrontal cortex, hypothetically due to the 5-HT1A blocking action, produced by orexina with pro-cognitive effects finally determined by the interaction between histamine and cortical H1 receptors (23).

Partial 5-HT1B agonism seems to mediate the pro-cognitive effects through a sub-population of the same heteroreceptors present on the presynaptic terminals of dopaminergic, noradrenergic, histaminergic and cholinergic neurons, whose cortical occupation would disrupt the release of these neurotransmitters (19). In particular, the effect on cognitive functions of vortioxetine could be explained, at least in part, by blocking 5-HT3, which, unlike SSRIs, would remove the inhibition produced by GABAergic interneurons that inject presynaptic terminals of cholinergic, noradrenergic and dendrites of prefrontal and hippocampal pyramidal neurons. The activation of these last, ultimately, results in glutamatergic tonic activation on subcortical neurotransmitter nuclei (20, 24, 25). Compared to this, it also deserves consideration that 5-HT3 receptors are expressed almost exclusively on GABAergic interneurons, which produced inhibitory control of cortical pyramidal neurons (26) (Figure 2).

Figure 2Figure 2
The indirect regula, on of glutamate release by 5-HT in the prefrontal cortex and hippocampus and how vortioxetine affects it. 5-HT indirectly regulates the glutamate release by modulating GABA concentration. 5-HT acts through two types of GABAergic interneurons (more ...)

In rats, finally, it’s shown how vortioxetine prevents, above all through the 5-HT3 antagonism, serotonin-induced post-synaptic inhibition, particularly at the CA1 region of the hippocampus, and increases the long-term enhancement in the same region (27).

5-HT7 receptors are densely present in the hippocampus and the cortex, though thalamus and hypothalamus are the regions with the highest density (22) (Figure 3).

Figure 3Figure 3
The action of Vortioxetine on the interation between serotonergic and glutamatergic neurons in prefontal and hippocampal cortex. Serotonergic action on the pyramidal neurons can be both excitatory and inhibitory. 5-HT2C, 5-HT4, 5-HT6 and 5-HT7 receptors (more ...)

Preclinical studies

In preclinical studies, the antagonism of 5-HT7 receptor showed to regulate the sleep-wake cycle and to improve impairments of memory function, and it could be considered as a key factor in the mechanism of action due to vortioxetine (28, 29). The antagonism of 5-HT7 could increase the glutamatergic transmission whether its agonism (achieved directly or due to the activation of GABAergic interneurons in dorsal raphe nucleus) seems to decrease it (30, 31).

Preclinical studies showed how vortioxetine can promote the expression of genes which code for dendritic spines proteins, and how it induces more dendritic arborisation when compared to fluoxetine in vivo (32).

Clinical Studies

There are many clinical studies that demonstrate the efficacy of vortioxetine on cognitive impairments. In a study on depressed patients undergoing N-back-task vs placebo and scanned with Functional Magnetic Resonance, vortioxetine has been shown to reduce neural activity in the Right Dorsolateral Prefrontal Cortex, Hippocampus and in Temporal-Parietal Areas. These results could explain the effects of the drug in the improvement of executive functions (10). In particular, three trials, named FOCUS, CONNECT and ELDERLY, investigated in a large sample the efficacy of vortioxetine on cognitive symptoms (3, 7, 33, 34).

The FOCUS trial, a randomized, double-blind, placebo controlled trial, included 602 MDD patients with self-reported cognitive deficits, aged between 18 and 65 years, to whom placebo or vortioxetine was administered at the flexible dose of 10–20 mg/day for 8 weeks; finally, to a group of patients, a comparison was made with duloxetine 60 mg/day (3). In order to measure cognitive performance, the Digit Symbol Substitution Test (DSST) and the University of San Diego Performance-based Skills Assessment (UPSA), that allow to measure various cognitive functions including executive functions, attention, processing speed, visual scanning and spatial perception, the Trail Making Test -A/B, and finally the Perceived Deficit Questionnaire (PDQ) for a subjective evaluation of cognitive functions, were used. The results showed a statistically significant superiority of vortioxetine vs placebo for: DSST (p <0.05), PDQ, (p <0.01), TMT-A (p=0.446), TMT-Bv (p <0.001), Clinical Global Impression-Improvement (CGI-I, p <0.001), Montgomery-Asberg Depression Rating Scale (MADRS, p <0.05) and UPSA (p <0.001). With a path analysis, it has also been shown as 75.7% of the vortioxetine effect on cognitive performance corresponding to the DSST performance, would be attributed to a direct effect of treatment, rather than an improvement in depressive symptoms (3).

The CONNECT trial, a multi-national double blind study, included 602 patients with MDD, aged 18 to 65, randomized (1:1:1) for: vortioxetine 10 mg/day, vortioxetine 20 mg/day or placebo for a period of 8 weeks. The Authors used the following tests for outcomes on cognitive functions: DSST, Rey Auditory Verbal Learning Test (RAVLT, Instant Memory and Learning), TMT-A/B, Simple Response Time Tasks (SRT, processing speed), Choice Reaction Time task (CRT, attention) and PDQ; MADRS and CGI-I were also administered to evaluate the outcome of depressive symptoms. Vortioxetine vs placebo showed statistically significant superiority to: DSST/RAVLT (p <0.001), TMT-B (p <0.001), SRT (p=0.016), PDQ (p <0.001), MADRS (p <0.001) and CGI-I (p <0.001).

There is, however, a clear divergence between the two studies in the results of the Congruent Stroop Test (FOCUS, p=0.016, CONNECT, p=0.002), and Incongruent (FOCUS, p=0.980, CONNECT, p=0.001) (3, 33).

The ELDERLY study, a blinded and placebo-controlled study, on elderly patients (mean age = 70 years) with MDD, included 452 randomized (1:1:1) for 5 mg/day vortioxetine, duloxetine 60 mg/day or placebo for 8 weeks. It has been verificated the pro-cognitive effect of vortioxetine (DSST, p <0.05; RAVLT, p <0.05) compared to duloxetine (DSST, p >0.05, RAVLT, p <0.01) (34).

Conclusions

In conclusion, it can be affirmed that vortioxetine may represent a good choice for treating persisting cognitive symptoms in Major Depressive Disorder, which often cause a great functional impairment and which are frequently resistant to conventional antidepressants.

Further studies are needed to better understand the underlying mechanisms and the neurobiological effects involved in the functioning of this new drug.

Acknowledgments

None

Footnotes

Disclosure statement

The Authors report no conflicts of interest.

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