Cognitive dysfunction affects various domains such as attention, memory, and problem-solving. These cognitive impairments often persist even after the remission of depressive symptoms. The relationship between cognitive dysfunction and psychosocial functioning in MDD is complex and is influenced by the type of depression, severity of symptoms, and cognitive skills.²

Although cognitive complaints are common in patients living with MDD, they are not always subjective and may therefore not align with objective cognitive measurements, emphasising the need for comprehensive cognitive assessments in clinical settings.²

Antidepressants improve cognitive functioning to varying degrees

Various classes of antidepressants have shown some degree of improvement in cognitive tests compared to placebo, with some evidence suggesting that serotonin-norepinephrine reuptake inhibitors (SNRIs) may have greater effects on neurocognitive dysfunction than selective serotonin reuptake inhibitors (SSRIs).³

Bupropion, a noradrenaline and dopamine reuptake inhibitor, has shown promise in improving cognitive measures in depression. Newer agents like vortioxetine, which has a multimodal mechanism of action, have also demonstrated positive effects on cognitive function in MDD.³

Vortioxetine is a novel antidepressant that differs from other antidepressants due to its multi-modal action on serotonin receptors and transporters. Vortioxetine is the first antidepressant that has shown improvements both in depression and cognitive symptoms. It is also the only pharmacological agent approved by the American Food and Drug Administration for the treatment of MDD that specifically targets cognitive dysfunction.^1,3

In a meta-analysis comparing the 21 newest antidepressants for the acute treatment of MDD, vortioxetine was found to be one of the most effective and best tolerated options in head-to-head clinical trials.⁴

Mechanism of action and pharmacokinetics

Preclinical studies suggest that vortioxetine affects multiple neurotransmitter systems, including serotonin, norepinephrine, dopamine, acetylcholine, histamine, glutamate, and gamma-aminobutyric acid. It has demonstrated antidepressant-like effects, stimulating neurogenesis and modulating neurotransmission in various brain regions.³

Vortioxetine's mechanism of action involves binding strongly to the serotonin transporter, enhancing serotonin levels by inhibiting reuptake in the central nervous system. It also exhibits affinity for various serotonin receptors (5-HT), including 5-HT3, 5-HT1A, 5-HT7, 5-HT1D, and 5-HT1B, with varying degrees of binding.⁵

Increasing the dose proportionally increases receptor binding. This results in reuptake blockade of the serotonin transporter, agonistic effects at 5-HT1A, partial agonism at 5-HT1B, and antagonism at 5-HT1D, 5-HT7, and 5-HT3 receptors. While the clinical benefits of these actions are not fully established, they may contribute to enhanced antidepressant effects through increased serotonin release and downstream mechanisms.⁵

Vortioxetine, administered orally at doses of 5mg-20mg, exhibits linear and dose-proportional pharmacokinetics with a bioavailability of 75%. It has a long half-life of about 66 hours, reaching steady-state plasma concentrations in about two weeks, and its absorption is not affected by food.³

It is metabolised mainly by cytochrome P450 enzymes, particularly CYP2D6, but also CYP3A4/5, CYP2A6, CYP2C9, and CYP2C19. Most of the drug is metabolised by the liver, with minimal excretion in urine. Co-administration with alcohol does not lead to significant interactions.³

How does vortioxetine exert its impact on cognitive function?

The impact of vortioxetine on cognitive function is attributed to its blockade of 5-HT3 receptors, enhancing glutamatergic and serotoninergic transmission, pyramidal neuron firing, and facilitating cognitive processing.³

Additionally, its agonism of 5-HT1A receptors, partial agonism of 5-HT1B receptors, and antagonism of 5-HT7 receptors contribute to its pro-cognitive effects. It also influences neurotransmitters like dopamine and norepinephrine and enhances neurogenesis and neurotrophic processes.³

Vortioxetine's distinct spectral changes in quantitative electroencephalography suggest a role in cognitive processing enhancements, setting it apart from other antidepressants. Furthermore, it has shown promise in models of neuropathic pain due to its potent 5-HT3 antagonism, making it a potential option for patients with comorbid depression and neuropathic pain.³

Furthermore, vortioxetine also exhibits immunomodulatory properties, demonstrating antioxidant and anti-inflammatory effects, which could lead to additional clinical benefits, particularly in individuals with inflammatory abnormalities.³ 

Efficacy in other symptom domains and subgroups

Vortioxetine has demonstrated efficacy in addressing specific symptom domains that are crucial in the clinical management of depression, including:³

• Anhedonia (the diminished ability to experience pleasure): Studies have shown that vortioxetine significantly improves anhedonia, and this improvement is linked to enhanced social functioning and QoL. Furthermore, vortioxetine may also have positive effects on motivation and reward processing.
• Emotional blunting: Vortioxetine has shown promise in reducing emotional blunting, a related symptom characterised by reduced emotional responses. In patients living with MDD who experience emotional blunting and previously did not respond to SSRI or SNRI treatments, vortioxetine led to significant reductions in depressive symptoms and emotional blunting, ultimately improving emotional well-being.
• Physical symptoms and sleep disturbances: MDD often presents with physical symptoms such as fatigue, muscle tension, and sleep disturbances. Vortioxetine has demonstrated broad symptom relief in these areas, including improvements in sleep quality. Its effects on sleep are associated with overall improvements in depressive symptoms and predict antidepressant response. Notably, vortioxetine has a lower risk of causing treatment-emergent insomnia or somnolence compared to other antidepressants like SSRIs or SNRIs.
• Suicidal ideation: Vortioxetine has not been associated with an increased risk of suicidal ideation or behaviour in adults with MDD, according to post-hoc analyses of various studies. This is a critical consideration, given the concerns about the potential for antidepressants to worsen suicidal thoughts, especially in younger populations.
• Anxiety and other psychiatric comorbidities: Vortioxetine has shown efficacy in reducing anxiety symptoms in patients with high levels of anxiety comorbid with MDD. It has also demonstrated effectiveness in addressing MDD when co-occurring with social anxiety disorder and psychological trauma history. Additionally, it appears to be a suitable antidepressant option for patients with both MDD and alcohol use disorder, offering improvements in mood, anxiety, cognitive function, and quality of life.
• Older people, menopause, and non-psychiatric comorbidities: Vortioxetine has been found to be effective and well-tolerated in older adults, addressing concerns about antidepressant efficacy in this population. In peri- and postmenopausal women with MDD, vortioxetine has shown significant improvements in depression, anxiety, climacteric complaints, QoL, and cognitive performance. It may also have potential benefits in comorbid conditions like diabetes, where it improved glycaemic control and metabolic parameters.
• Inadequate response to first-line antidepressant treatment: Vortioxetine has been studied as both a first-line and second-line treatment for MDD. In cases where patients have not adequately responded to SSRIs or SNRIs, switching to vortioxetine has shown advantages in terms of efficacy, functioning, and QoL outcomes.

Safety profile of vortioxetine

Vortioxetine demonstrates favourable safety and tolerability compared to other commonly used antidepressants. One notable distinction is its low incidence of sleep disturbances, sexual dysfunction, weight gain, cardiovascular issues, and discontinuation symptoms.³

Sleep disruptions, like insomnia and poor sleep quality, are infrequent among vortioxetine users. In contrast, it has even shown benefits in improving sleep quality compared to conventional antidepressants.³

Treatment-emergent sexual dysfunction (TESD) is a common issue with antidepressants like SSRIs and SNRIs. Vortioxetine, however, exhibits TESD rates comparable to placebo, making it a more tolerable choice for patients. A study found that switching from SSRIs to vortioxetine improved sexual functioning while maintaining antidepressant efficacy.³

Vortioxetine results in fewer withdrawals due to adverse events compared to other antidepressants. Additionally, it has no significant impact on weight, heart rate, blood pressure, or electrocardiogram parameters.

Nausea is the most common side effect leading to withdrawal, but it is generally mild and transient. Vortioxetine's antagonism of 5-HT3 receptors, which play a role in nausea, provides it with a relatively neutral gastrointestinal profile. Some patients may benefit from splitting doses or combining it with other anti-nausea medications.³

Conclusion

MDD is a global public health concern, impacting millions of lives with its debilitating symptoms. Among the many dimensions of MDD, cognitive dysfunction stands out as a crucial aspect affecting patients' quality of life and overall functioning. Vortioxetine, a novel antidepressant, has emerged as a promising solution to address not only the core symptoms of depression but also the cognitive deficits associated with the condition.

References

1. Zhang X, Cai Y, Hu X, et al. Systematic Review and Meta-Analysis of Vortioxetine for the Treatment of Major Depressive Disorder in Adults. Front Psych, 2022.
2. Lam RW, Kennedy SH, Mclntyre RS, Khullar A. Cognitive dysfunction in major depressive disorder: effects on psychosocial functioning and implications for treatment. Can J Psychiatry, 2014.
3. de Diego-Adeliño J, Crespo JM, Mora F, et al. Vortioxetine in major depressive disorder: from mechanisms of action to clinical studies. An updated review. Expert Opinion on Drug Safety, 2021.
4. Cipriani A, Furukawa TA, Salanti G, et al.Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet,
5. D'Agostino A, English CD, Rey JA. Vortioxetine (brintellix): a new serotonergic antidepressant. PT, 2015.