Brintellix Mechanism of Action





Metro Drug
Full Prescribing Info
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. Non-clinical data indicate that vortioxetine is a 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the 5-HT transporter, leading to modulation of neurotransmission in several systems, including the serotonin, 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. In addition, a nonclinical behavioural study in male animals indicates that vortioxetine does not induce sexual dysfunction. 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 specific regions of interest was approximately 50% at 5 mg/day, 65% at 10 mg/day and increased to above 80% at 20 mg/day.
Vortioxetine has shown clinical antidepressant effects at 5-HT transporter occupancies as low as 50%.
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 in 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 both in adults and in the elderly. The efficacy of vortioxetine was demonstrated across 9 of the 12 studies, as measured by improvement in the Montgomery and Åsberg Depression Rating Scale (MADRS) or Hamilton Depression Rating Scale 24-item (HAM-D24) total score, and supported by clinical relevance as demonstrated by the proportions of responders and remitters and the improvement in Clinical Global Impression - Global Improvement (CGI-I) score. The efficacy of vortioxetine increased with increasing dose.
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) and on the anxiety symptoms in depression (assessed using the HAM-A total score).
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 double-blind, placebo-controlled, 8-week, fixed-dose study in elderly (aged ≥65 years) depressed patients, vortioxetine 5 mg/day was superior to placebo as measured by improvement in the MADRS and HAM-D24 total scores.
In the dose range of 5 to 20 mg/day vortioxetine, efficacy and tolerability in the elderly was in line with the results in the adult population.
Patients with severe depression or high levels of anxiety symptoms: Antidepressant efficacy was also demonstrated 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) in short-term studies including the study in the elderly and 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).
Patients with inadequate response to SSRI/SNRI treatment: In a 12-week, double-blind, flexible-dose, comparative study in patients with moderate to severe depression who switched antidepressant treatment after an inadequate response to an SSRI/SNRI for the current episode vortioxetine 10-20 mg/day was statistically significantly better than agomelatine 25-50 mg/day as measured by improvement in the MADRS total score. The clinical relevance was supported by the proportion of remitters and improvement in CGI-I and Sheehan Disability Scale (SDS) scores.
Health-related quality of life and overall functioning: Vortioxetine was superior to placebo in health-related quality of life, as assessed using the SF-36 Mental Component Summary and the Quality of Life Enjoyment Satisfaction Questionnaire total and life satisfaction scores. This was supported by clinically relevant improvements in the overall health rating as measured using EQ-5D (EuroQol index) and in the overall functioning as assessed using the Sheehan Disability Scale (SDS) total score in the areas of work, social life, and family life versus placebo or an active comparator (agomelatine). Furthermore, the superior effects relative to placebo in health related quality of life were maintained in the long-term relapse prevention study.
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 significant difference to placebo in symptoms of sexual dysfunction for doses 5-20 mg/day, however higher doses were associated with a numerical increase in TESD.
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 and 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: Clinical studies on the use of Brintellix (Vortioxetine hydrobromide) in children and adolescents have not been conducted; therefore, the safety and efficacy of Brintellix (Vortioxetine hydrobromide) (see Dosage & Administration). in the paediatric population have not been established.
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 Cmax 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 and subsequent glucuronic acid conjugation.
In vitro, the cytochrome P450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8, and CYP2B6 are involved in the metabolism of vortioxetine.
No inhibitory or inducing effect of vortioxetine was observed in vitro for the CYP isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5. 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 AUC0-24h 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% (Cmax and AUC) compared to young healthy control subjects (aged ≤45 years) after multiple doses of 10 mg/day. No dose adjustment is needed (see Dosage & Administration).
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 Cmax were 13% and 27% lower; n=8) following a single 10 mg dose of vortioxetine. No dose adjustment is needed (see Precautions).
Hepatic impairment: Following a single dose of 10 mg vortioxetine, no impact of mild or moderate hepatic impairment (Child-Pugh Criteria A or B; n=8 per group) was observed on the pharmacokinetics of vortioxetine (changes in AUC were less than 10%). No dose adjustment is needed (see Dosage & Administration). Vortioxetine has not been studied in patients with severe hepatic impairment and caution should be exercised when treating these patients (see Precautions).
CYP2D6 poor metabolisers: The plasma concentration of vortioxetine was approximately two times higher in CYP2D6 poor metabolisers than in extensive metabolisers. In the presence of strong CYP3A4/2C9-inhibitors, the exposure could potentially be higher (see Interactions). Depending on individual patient response, a dose adjustment may be considered (see Dosage & Administration).
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 one episode of convulsions in each of two dogs. 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).
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in