Brintellix Mechanism of Action

Pharmacotherapeutic group: Other antidepressants. ATC-code: N06AX26.
Pharmacology: Pharmacodynamics: Mechanism of action: The mechanism of action of vortioxetine is thought to be related to its direct modulation of serotonergic receptor activity and inhibition of the serotonin (5-HT) transporter. Nonclinical data indicate that vortioxetine is a 5-HT₃, 5-HT₇, and 5-HT_1D receptor antagonist, 5-HT_1B receptor partial agonist, 5-HT_1A receptor agonist and inhibitor of the 5-HT transporter, leading to modulation of neurotransmission in several systems, including predominantly the serotonin but probably also the norepinephrine, dopamine, histamine, acetylcholine, GABA and glutamate systems. This multimodal activity is considered responsible for the antidepressant and anxiolytic-like effects and the improvement of cognitive function, learning and memory observed with vortioxetine in animal studies. However, the precise contribution of the individual targets to the observed pharmacodynamic profile remains unclear and caution should be applied when extrapolating animal data directly to man.
In humans, two positron emission tomography (PET) studies have been conducted using 5-HT transporter ligands (¹¹C-MADAM or ¹¹C-DASB) to quantify the 5-HT transporter occupancy in the brain across different dose levels. The mean 5-HT transporter occupancy in the raphe nuclei was approximately 50% at 5 mg/day, 65% at 10 mg/day and increased to above 80% at 20 mg/day.
Clinical efficacy and safety: The efficacy and safety of vortioxetine have been studied in a clinical programme that included more than 6,700 patients, of whom more than 3,700 were treated with vortioxetine in short-term (≤12 weeks) studies of major depressive disorder (MDD). Twelve double-blind, placebo controlled, 6/8-week, fixed-dose studies have been conducted to investigate the short-term efficacy of vortioxetine in MDD in adults (including the elderly). The efficacy of vortioxetine was demonstrated with at least one dosage group across 9 of the 12 studies, showing at least a 2-point difference to placebo in the Montgomery and Åsberg Depression Rating Scale (MADRS) or Hamilton Depression Rating Scale 24-item (HAM-D₂₄) total score. This was supported by clinical relevance as demonstrated by the proportions of responders and remitters and the improvement in the Clinical Global Impression - Global Improvement (CGI-I) score. The efficacy of vortioxetine increased with increasing dose.
The effect in the individual studies was supported by the meta-analysis (MMRM) of the mean change from baseline in MADRS total score at Week 6/8 in the short-term, placebo-controlled studies in adults. In the meta-analysis, the overall mean difference to placebo across the studies was statistically significant: -2.3 points (p = 0.007), -3.6 points (p <0.001), and -4.6 points (p <0.001) for the 5, 10, and 20 mg/day doses, respectively; the 15 mg/day dose did not separate from placebo in the meta-analysis, but the mean difference to placebo was -2.6 points. The efficacy of vortioxetine is supported by the pooled responder analysis, in which the proportion of responders ranged from 46% to 49% for vortioxetine versus 34% for placebo (p <0.01; NRI analysis).
Furthermore, vortioxetine, in the dose range of 5-20 mg/day, demonstrated efficacy on the broad range of depressive symptoms (assessed by improvement in all MADRS single-item scores).
The efficacy of vortioxetine 10 or 20 mg/day was further demonstrated in a 12-week, double-blind, flexible-dose comparative study versus agomelatine 25 or 50 mg/day in patients with MDD. Vortioxetine was statistically significantly better than agomelatine as measured by improvement in the MADRS total score and supported by the clinical relevance as demonstrated by the proportions of responders and remitters and improvement in the CGI-I.
Maintenance: The maintenance of antidepressant efficacy was demonstrated in a relapse-prevention study. Patients in remission after an initial 12-week open-label treatment period with vortioxetine were randomised to vortioxetine 5 or 10 mg/day or placebo and observed for relapse during a double-blind period of at least 24 weeks (24 to 64 weeks). Vortioxetine was superior (p=0.004) to placebo on the primary outcome measure, the time to relapse of MDD, with a hazard ratio of 2.0; that is, the risk of relapse was two times higher in the placebo group than in the vortioxetine group.
Elderly: In the 8-week, double-blind, placebo-controlled, fixed-dose study in elderly depressed patients (aged ≥65 years, n=452, 156 of whom were on vortioxetine), vortioxetine 5 mg/day was superior to placebo as measured by improvement in the MADRS and HAM-D₂₄ total scores. The effect seen with vortioxetine was a 4.7 point difference to placebo in MADRS total score at Week 8 (MMRM analysis).
Patients with severe depression or with depression and high levels of anxiety symptoms: In severely depressed patients (baseline MADRS total score ≥30) and in depressed patients with a high level of anxiety symptoms (baseline HAM-A total score ≥20) vortioxetine also demonstrated efficacy in the short-term studies in adults (the overall mean difference to placebo in MADRS total score at Week 6/8 ranged from 2.8 to 7.3 points and from 3.6 to 7.3 points, respectively, (MMRM analysis)). In the dedicated study in elderly, vortioxetine was also effective in these patients.
The maintenance of antidepressant efficacy was also demonstrated in this patient population in the long-term relapse prevention study.
Effects of vortioxetine on the Digit Symbol Substitution Test (DSST), the University of California San Diego Performance-Based Skills Assessment (UPSA) (objective measures) and Perceived Deficits Questionnaire (PDQ) and Cognitive and Physical Functioning Questionnaire CPFQ (subjective measures) scores: The efficacy of vortioxetine (5-20 mg/day) in patients with MDD has been investigated in 2 adult and 1 elderly short-term, placebo-controlled studies.
Vortioxetine had a statistically significant effect versus placebo on the Digit Symbol Substitution Test (DSST), ranging from Δ = 1.75 (p = 0.019) to 4.26 (p <0.0001) in the 2 studies in adults and Δ = 2.79 (p = 0.023) in the study in the elderly. In the meta-analyses (ANCOVA, LOCF) of the mean change from baseline in DSST number of correct symbols in all 3 studies, vortioxetine separated from placebo (p<0.05) with a standardised effect size of 0.35. When adjusting for the change in MADRS the total score in the meta-analysis of the same studies showed that vortioxetine separated from placebo (p<0.05) with a standardised effect size of 0.24.
One study assessed the effect of vortioxetine on functional capacity using the University of California San Diego Performance-Based Skills Assessment (UPSA). Vortioxetine separated from placebo statistically with results of 8.0 for vortioxetine versus 5.1 points for placebo (p=0.0003).
In one study, vortioxetine was superior to placebo on subjective measures, evaluated using the Perceived Deficits Questionnaire with results of -14.6 for vortioxetine and -10.5 for placebo (p=0.002). Vortioxetine did not separate from placebo on subjective measures when evaluated using the Cognitive and Physical Functioning Questionnaire with results of -8.1 for vortioxetine versus -6.9 for placebo (p=0.086).
Tolerability and safety: The safety and tolerability of vortioxetine have been established in short- and long-term studies across the dose range of 5 to 20 mg/day. For information on undesirable effects, see Adverse Reactions.
Vortioxetine did not increase the incidence of insomnia or somnolence relative to placebo.
In clinical short- and long-term placebo-controlled studies, potential discontinuation symptoms were systematically evaluated after abrupt treatment cessation of vortioxetine. There was no clinically relevant difference to placebo in the incidence or nature of the discontinuation symptoms after either short-term (6-12 weeks) or long-term (24-64 weeks) treatment with vortioxetine.
The incidence of self-reported adverse sexual reactions was low and similar to placebo in clinical short- and long-term studies with vortioxetine. In studies using the Arizona Sexual Experience Scale (ASEX), the incidence of treatment-emergent sexual dysfunction (TESD) and the ASEX total score showed no clinically relevant difference to placebo in symptoms of sexual dysfunction at the 5 to 15 mg/day doses of vortioxetine. For the 20 mg/day dose, an increase in TESD was seen compared to placebo (an incidence difference of 14.2%, 95% CI [1.4, 27.0]).
The effect of vortioxetine on sexual function was further evaluated in an 8-week, double-blind, flexible-dose, comparative study (n=424) versus escitalopram in patients treated for at least 6 weeks with an SSRI (citalopram, paroxetine, or sertraline), with a low level of depressive symptoms (baseline CGI-S ≤ 3) and TESD induced by the prior SSRI treatment. Vortioxetine 10-20 mg/day had statistically significantly less TESD than escitalopram 10-20 mg/day as measured by change in the CSFQ-14 total score (2.2 points, p=0.013) at week 8.
The proportion of responders was not significantly different in the vortioxetine group (162 (74.7%)) compared with the escitalopram group (137 (66.2%)) at week 8 (OR 1.5 p=0.057). The antidepressant effect was maintained in both treatment groups.
Vortioxetine had no effect relative to placebo on body weight, heart rate, or blood pressure in clinical short- and long-term studies.
No clinically significant changes were observed in hepatic or renal assessments in clinical studies.
Vortioxetine has not shown any clinically significant effect on ECG parameters, including the QT, QTc, PR and QRS intervals, in patients with MDD. In a thorough QTc study in healthy subjects at doses up to 40 mg daily, no potential for the prolongation of the QTc interval was observed.
Paediatric population: One randomised, double-blind, placebo-controlled, active-referenced, fixed dose, 8-week study was conducted in adolescent patients with MDD aged 12 to 17 years. The study included a 4-week single-blind placebo lead-in period with standardized psychosocial intervention (N=777); only non-responders from the lead-in period were randomised (N=615). Neither vortioxetine 10 mg/day nor 20 mg/day was statistically significantly superior to placebo based on the Children's Depression Rating Scale-Revised (CDRS-R) total score. The active reference (fluoxetine 20 mg/day) separated statistically from placebo on the CDRS-R total score. In general, the adverse reaction profile of vortioxetine in adolescents was similar to that seen for adults except for higher incidences reported in adolescent than in adults for abdominal pain-related event and suicidal ideation.
Discontinuation due to adverse events (mostly due to suicidal ideation, nausea and vomiting) was highest in patients treated with vortioxetine 20 mg/day (5.6%) as compared to vortioxetine 10 mg/day (2.7%), fluoxetine (3.3%), and placebo (1.3%). The most commonly reported adverse events in the vortioxetine treatment groups were nausea, vomiting and headache. Suicidal ideation and behaviour were reported as adverse events both during the 4-week single-blind lead-in period (placebo 13/777 [1.7%]), and during the 8-week treatment period (vortioxetine 10 mg/day 2/147 [1.4%], vortioxetine 20 mg/day 6/161 [3.7%], fluoxetine 6/153 [3.9%], placebo 0/154 [0%]). Suicidal ideation and behaviour as measured by Columbia-Suicide Severity Rating Scale (C-SSRS) was similar across treatment groups.
The European Medicines Agency has waived the obligation to submit the results of studies in major depressive disorder with vortioxetine in children aged less than 7 years (see Dosage & Administration for information on paediatric use).
The European Medicines Agency has deferred the obligation to submit the results of studies with vortioxetine in one or more subsets of the paediatric population in treatment of major depressive disorder (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: Absorption: Vortioxetine is slowly, but well absorbed after oral administration and the peak plasma concentration is reached within 7 to 11 hours. Following multiple dosing of 5, 10, or 20 mg/day, mean C_max values of 9 to 33 ng/mL were observed. The absolute bioavailability is 75%. No effect of food on the pharmacokinetics was observed (see Dosage & Administration).
Distribution: The mean volume of distribution (Vss) is 2,600 L, indicating extensive extravascular distribution. Vortioxetine is highly bound to plasma proteins (98 to 99%) and the binding appears to be independent of vortioxetine plasma concentrations.
Biotransformation: Vortioxetine is extensively metabolised in the liver, primarily through oxidation catalysed by CYP2D6 and to a minor extent CYP3A4/5 and CYP2C9, and subsequent glucuronic acid conjugation.
No inhibitory or inducing effect of vortioxetine was observed in the drug-drug interaction studies for the CYP isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 (see Interactions). Vortioxetine is a poor P-gp substrate and inhibitor.
The major metabolite of vortioxetine is pharmacologically inactive.
Elimination: The mean elimination half-life and oral clearance are 66 hours and 33 L/h, respectively. Approximately ²/₃ of the inactive vortioxetine metabolites are excreted in the urine and approximately ¹/₃ in the faeces. Only negligible amounts of vortioxetine are excreted in the faeces. Steady-state plasma concentrations are achieved in approximately 2 weeks.
Linearity/non-linearity: The pharmacokinetics are linear and time independent in the dose range studied (2.5 to 60 mg/day).
In accordance with the half-life, the accumulation index is 5 to 6 based on AUC_0-24h following multiple doses of 5 to 20 mg/day.
Special populations: Elderly: In elderly healthy subjects (aged ≥65 years; n=20), the exposure to vortioxetine increased up to 27% (C_max and AUC) compared to young healthy control subjects (aged ≤45 years) after multiple doses of 10 mg/day. The lowest effective dose of 5 mg vortioxetine once daily should always be used as the starting dose in patients ≥ 65 years (see Dosage & Administration). However, caution should be exercised when prescribing to elderly patients at doses higher than 10 mg vortioxetine once daily (see Precautions).
Renal impairment: Following a single dose of 10 mg vortioxetine, renal impairment estimated using the Cockcroft-Gault formula (mild, moderate, or severe; n=8 per group) caused modest exposure increases (up to 30%), compared to healthy matched controls. In patients with end-stage renal disease, only a small fraction of vortioxetine was lost during dialysis (AUC and C_max were 13% and 27% lower, respectively; n=8) following a single 10 mg dose of vortioxetine. No dose adjustment is needed based on renal function (see Dosage & Administration and Precautions).
Hepatic impairment: The pharmacokinetics in subjects (N = 6-8) with mild, moderate, or severe hepatic impairment (Child-Pugh Criteria A, B, or C, respectively) were compared to healthy volunteers. The changes in AUC were less than 10% lower in subjects with mild or moderate hepatic impairment, and 10% higher in those with severe hepatic impairment. The changes in C_max were less than 25% lower in all groups. No dose adjustment is needed based on hepatic function (see Dosage & Administration and Precautions).
CYP2D6 gene types: The plasma concentration of vortioxetine was approximately two times higher in CYP2D6 poor metabolisers than in extensive metabolisers. Co-administration of strong CYP3A4/2C9 inhibitors to CYP2D6 poor metabolisers could potentially result in higher exposure (see Interactions).
In CYP2D6 ultra-rapid metabolisers, the plasma concentration of vortioxetine 10 mg/day were between those obtained in extensive metabolisers at 5 mg/day and 10 mg/day.
Depending on individual patient response, a dose adjustment may be considered (see Dosage & Administration).
Paediatric population: Pharmacokinetics of vortioxetine in paediatric patients with major depressive disorder following oral administration of 5 to 20 mg once daily was characterized using population modeling analyses based on data from a pharmacokinetic study (7-17 years) and an efficacy and safety study (12-17 years). The pharmacokinetics of vortioxetine in paediatric patients was similar to that observed in adult patients.
Toxicology: Preclinical safety data: Administration of vortioxetine in the general toxicity studies in mice, rats and dogs was mainly associated with CNS-related clinical signs. These included salivation (rat and dog), pupil dilatation (dog), and two incidences of convulsions in dogs in the general toxicity study programme. A no-effect level for convulsions was established with a corresponding safety margin of 5 considering the maximum recommended therapeutic dose of 20 mg/day. Target organ toxicity was restricted to kidneys (rats) and liver (mice and rats). The changes in the kidney in rats (glomerulonephritis, renal tubular obstruction, crystalline material in renal tubule) and in the liver of mice and rats (hepatocellular hypertrophy, hepatocyte necrosis, bile duct hyperplasia, crystalline material in bile ducts) were seen at exposures more than 10-fold (mice) and 2-fold (rats) the human exposure at the maximum recommended therapeutic dose of 20 mg/day. These findings were mainly attributed to rodent-specific vortioxetine-related crystalline material obstruction of the renal tubules and the bile ducts, respectively, and considered of low risk to humans.
Vortioxetine was not genotoxic in a standard battery of in vitro and in vivo tests.
Based on results from conventional 2-year carcinogenicity studies in mice or rats, vortioxetine is not considered to pose a risk of carcinogenicity in humans.
Vortioxetine had no effect on rat fertility, mating performance, reproductive organs, or sperm morphology and motility.
Vortioxetine was not teratogenic in rats or rabbits, but reproductive toxicity in terms of effects on foetal weight and delayed ossification were seen in the rat at exposures more than 10-fold the human exposure at the maximum recommended therapeutic dose of 20 mg/day. Similar effects were seen in the rabbit at sub-therapeutic exposure.
In a pre- and post-natal study in rats, vortioxetine was associated with increased pup mortality, reduced bodyweight gain, and delayed pup development at doses that did not result in maternal toxicity and with associated exposures similar to those achieved in humans following administration of vortioxetine 20 mg/day (see Use in Pregnancy & Lactation).
Vortioxetine-related material was distributed to the milk of lactating rats (see Use in Pregnancy & Lactation).
In juvenile toxicity studies in rats, all vortioxetine treatment-related findings were consistent with those noted in adult animals.
Environmental risk assessment studies have shown that vortioxetine has the potential to be persistent, bioaccumulative and toxic to the environment (risk to fish). However, by recommended patient usage vortioxetine is considered to pose negligible risk to the aquatic and terrestrial environment (see Special precautions for disposal under Cautions for Usage).