Brintellix tablet p/o film 10mg 28 pcs
Pharmacological group:
Antidepressant.
ATX code: N06AX26. Pharmacodynamics:
Mechanism of action The mechanism of action of vortioxetine appears to be related to its direct modulating serotonergic activity and inhibition of the serotonin transporter protein. Preclinical studies show that vortioxetine acts as an antagonist of 5-HT3, 5-HT7 and 5-HT1D receptors, a partial agonist of 5-HT1B receptors and a full agonist of 5-HT1A receptors, and also inhibits the 5-HT transporter, thereby modulating neurotransmission in several systems, primarily serotonergic, but probably also noradrenergic, dopaminergic, neurotransmission mediated by histamine, acetylcholine, GABA and glutamate. This multimodal pharmacological activity appears to underlie the antidepressant and anxiolytic properties of vortioxetine and is also responsible for the improvements in cognition, learning and memory observed in animal studies. However, since the individual contribution of each pharmacological target to the observed pharmacodynamic profile of vortioxetine remains unclear, extrapolation of the reported preclinical data to humans should be done with caution. Two studies using positron emission tomography (PET) in humans to quantify the extent of 5-HT transporter occupancy (using ligands 11C-MADAM or 11C-DASB), at different dosage levels of vortioxetine, found the following data: mean number of transporters 5 -HT associated with vortioxetine was approximately 50% at a dose of 5 mg/day, 65% at a dose of 10 mg/day, and increased to 80% when the dose was increased to 20 mg/day.
Clinical efficacy and safety The efficacy and safety of vortioxetine were studied in a number of clinical studies involving more than 6,700 patients, of which more than 3,700 patients participated in short-term (
Maintenance therapy The persistence of antidepressant effects with maintenance therapy was shown in a relapse prevention study. Patients in remission after initial vortioxetine therapy in a 12-week open-label study were randomized to vortioxetine 5 or 10 mg/day or placebo and monitored for relapse during a double-blind observation period of at least 24 weeks. (from 24 to 64 weeks). Vortioxetine was superior to placebo (p=0.004) in the primary outcome measure of time to relapse of MDD, with a hazard ratio of 2.0; this means that the risk of relapse was twice as high in the placebo group than in the vortioxetine group.
Elderly Patients In a double-blind, placebo-controlled, 8-week, fixed-dose study in elderly patients with depression (over 65 years of age, n=452, 156 of whom were treated with vortioxetine), vortioxetine 5 mg/day was superior to placebo in the evaluation of total score on the MADRS and HAM-D24 scales. The difference between vortioxetine and placebo was 4.7 points on the MADRS at week 8 of treatment (MMRM analysis).
Patients with severe depression or with depression and high levels of anxiety The effectiveness of vortioxetine has also been demonstrated in patients with severe depression (baseline MADRS total score >30) and in patients with depression with concomitant high levels of anxiety (baseline HAM-A total score >20) in short-term studies in adult patients (mean difference from placebo on the MADRS at weeks 6 and 8 ranged from 2.8 to 7.3 points and from 3.6 to 7.3 points, respectively (MMRM analysis)). In a separate study in elderly patients, vortioxetine was also effective in this group of patients. The persistence of the antidepressant effect in this category of patients was also shown in a long-term relapse prevention study. Effect of vortioxetine on the Digit Symbol Substitution Test (DSST), the UC San Diego Life Skills Assessment (UPSA) (objective measures), and the Perceived Deficits Questionnaire score. , PDQ) and scores on the Cognitive and Physical Functioning Questionnaire (CPFQ) (subjective measures). The effectiveness of vortioxetine (at a dose of 5-20 mg/day) in patients with MDD was studied in two short-term placebo-controlled studies in adults and one in elderly patients. Vortioxetine had a statistically significant effect on the Digit Symbol Substitution Test (DSST) compared to placebo, with delta = 1.75 (p = 0.019) to 4.26 (p
Tolerability and Safety The safety and tolerability of vortioxetine have been established in short-term and long-term studies over a dose range of 5 to 20 mg/day. Information about unwanted side reactions is presented in the “Side Effects” section. Vortioxetine did not increase the incidence of insomnia or somnolence compared with placebo. Short-term and long-term placebo-controlled clinical studies have consistently assessed potential withdrawal symptoms following abrupt cessation of vortioxetine treatment. There was no clinically significant difference from placebo in the incidence or quality of withdrawal symptoms after either short-term (6-12 weeks) or long-term (24-64 weeks) vortioxetine therapy. The incidence of spontaneous complaints of sexual adverse reactions was low and similar to placebo in both short-term and long-term studies of vortioxetine. In studies using the Arizona Sexual Function Scale (ASEX), the incidence of treatment-induced sexual dysfunction (TESD) and total ASEX scores were not clinically significantly different from placebo when vortioxetine was used at doses of 5-15 mg/day. When using vortioxetine at a dose of 20 mg/day, an increase in the incidence of sexual dysfunction was observed compared with placebo (difference in frequency 14.2%, CI 95% (1.4, 27.0)). The effect of vortioxetine on sexual function was further assessed in an 8-week, double-blind, flexible-dose comparative study (n=424) compared with escitalopram in patients treated with an SSRI (citalopram, paroxetine, or sertraline) for at least 6 years. weeks, with low levels of depressive symptoms (clinical global assessment-illness severity score at baseline
In short- and long-term studies, vortioxetine had no effect on weight, heart rate, or blood pressure compared with placebo. Vortioxetine did not have a clinically significant effect on parameters of liver and kidney function in clinical studies.
In patients with MDD, vortioxetine had no clinically significant effect on ECG parameters, including QT, QTc, PR and QRS intervals. In a careful study of the QTc interval in healthy subjects, vortioxetine at doses up to 40 mg/day did not affect its duration.
Pharmacokinetics:
Absorption Vortioxetine is slowly but well absorbed after oral administration. The maximum plasma concentration is reached after 7–11 hours. After repeated use in doses of 5, 10 or 20 mg/day, the average maximum plasma concentration (Cmax) is 9–33 ng/ml. Absolute bioavailability is 75%. Food intake does not affect the pharmacokinetics of the drug (see section “Method of administration and dosage”).
Distribution The mean volume of distribution (Vss) is 2600 L, indicating extensive extravascular distribution. The degree of binding to plasma proteins is high (98-99%) and does not appear to depend on the concentration of vortioxetine in plasma.
Biotransformation Vortioxetine is extensively metabolized in the liver, mainly due to oxidation by the CYP2D6 isoenzyme and to a lesser extent by the CYP3A4/5 and CYP2C9 isoenzymes and subsequent conjugation with glucuronic acid. Drug interaction studies did not reveal an inhibitory or inducing effect of vortioxetine on the isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5 (see section “Interaction with other drugs”). Vortioxetine is a weak inhibitor and substrate of P-glycoprotein. The main metabolite of vortioxetine is pharmacologically inactive.
Elimination The average half-life and oral clearance are 66 hours and 33 l/hour, respectively. About 2/3 of the inactive metabolite vortioxetine is excreted in the urine and about 1/3 in the feces. Only a small amount of vortioxetine is excreted unchanged in the feces. Steady-state plasma concentrations are achieved after approximately 2 weeks.
Linearity/nonlinearity Pharmacokinetics are linear and independent of time in the dose range studied (2.5–60 mg/day). Based on the half-life based on AUC0-24h after repeated doses of 5-20 mg/day, the accumulation index is 5 to 6.
Elderly: In elderly healthy subjects (over 65 years of age; n=20), vortioxetine exposure was increased by 27% (Cmax and AUC) compared with younger healthy controls (<45 years of age) following repeated doses of 10 mg/day. The minimum effective dose of vortioxetine 5 mg/day should always be used as an initial dose in patients over 65 years of age (see Dosage and Administration). Vortioxetine should be prescribed with caution to elderly patients at doses above 10 mg/day (see section "Special Instructions").
Renal Impairment Following a single 10 mg dose of vortioxetine, renal impairment as assessed by the Cockcroft-Gault formula (mild, moderate or severe; n=8 per group) resulted in a moderate (up to 30%) increase in vortioxetine exposure compared to healthy control subjects. In patients with end-stage renal disease, dialysis resulted in only a small reduction in exposure (AUC and Cmax decreased by 13% and 27%, respectively; n=8) following a single dose of vortioxetine 10 mg. Depending on renal function, dose adjustment is not required (see sections “Dosage and Administration” and “Special Instructions”).
Hepatic impairment The pharmacokinetics of the drug in patients (N = 6-8) with mild, moderate or severe hepatic impairment (Child-Pugh A, B or C, respectively) were comparable to those in healthy volunteers. Changes in AUC were less than 10% lower in patients with mild or moderate hepatic impairment and 10% greater than in patients with severe hepatic impairment. Changes in Cmax were less than 25% lower in all groups. There is no need for dose adjustment depending on liver function (see sections “Dosage and Administration” and “Special Instructions”).
Types of CYP2D6 genes: Plasma concentrations of vortioxetine were approximately two times higher in patients with reduced CYP2D6 metabolic activity compared to extensive metabolizers. Concomitant use of strong inhibitors of CYP3A4/2C9 isoenzymes in patients with reduced metabolic activity of the CYP2D6 isoenzyme may potentially lead to increased exposure to vortioxetine (see section "Interaction with other drugs"). In patients with extremely rapid metabolism of the CYP2D6 isoenzyme, plasma concentrations of vortioxetine 10 mg/day were within the range of values obtained in extensive metabolizers at doses of 5 mg/day and 10 mg/day. Depending on the patient’s individual response, the possibility of adjusting the dose of the drug should be considered (see section “Method of administration and dosage”).
Preclinical Safety Data In general toxicity studies, vortioxetine administration in mice, rats and dogs was associated with primarily CNS effects that included salivation (rats and dogs), dilated pupils (dogs), and two episodes of seizures in dogs. When the drug was administered at the maximum recommended therapeutic dose of 20 mg/day, no seizure activity was recorded, taking into account that the safety limit was defined as 5%. Organ toxicity was limited to the kidney (rats) and liver (mice and rats). Changes in the kidneys in rats (glomerulonephritis, tubular obstruction, crystals in the renal tubules) and liver in mice and rats (hepatocellular hypertrophy, hepatocyte necrosis, bile duct hyperplasia, crystals in the bile ducts) were observed with exposures greater than 2 times (rats) and 10 times (mice) higher than the human dose at the maximum recommended dose of 20 mg/day. These cases have been associated primarily with rodent-specific crystal obstruction of the renal tubules and bile ducts and are considered unlikely to occur in humans.
Vortioxetine was not genotoxic in a standard battery of in vitro and in vivo tests. Based on standard 2-year carcinogenicity studies in mice or rats, vortioxetine does not appear to have a risk of carcinogenicity in humans.
Vortioxetine had no effect on fertility, mating ability, reproductive organ function, or sperm morphology and motility in rats. Vortioxetine was not teratogenic in rats or rabbits, although effects on fetal weight and delayed ossification were observed in rats with exposure to vortioxetine doses exceeding 10 times the maximum human daily dose of 20 mg/day. Similar effects were observed in rabbits with subtherapeutic exposure.
In pre- and postnatal studies in rats, the use of vortioxetine at doses that did not have a toxic effect on the mother and corresponded to a dose of 20 mg / day in humans was associated with increased mortality of pups, decreased rates of weight gain and slowed development (see section "Use" during pregnancy and breastfeeding").
Vortioxetine penetrated into the milk of lactating rats (see section “Use during pregnancy and breastfeeding”). In juvenile toxicity studies in rats, data obtained from vortioxetine therapy were correlated with those obtained in adult animals.
Environmental risk studies have shown that vortioxetine has the potential for persistence, bioaccumulation and environmental toxicity (risk to fish). However, at recommended patient doses, vortioxetine poses a negligible risk to the aquatic and terrestrial environment.
Brintellix, 28 pcs., 10 mg, film-coated tablets
Mechanism of action
The mechanism of action of vortioxetine appears to be related to its direct modulating serotonergic activity and inhibition of the serotonin transport protein. Preclinical studies show that vortioxetine acts as an antagonist of 5-HT3, 5-HT7 and 5-HT1D receptors, a partial agonist of 5-HT1B receptors and a full agonist of 5-HT1A receptors, and also inhibits the 5-HT transporter , thereby modulating neurotransmission in several systems, primarily serotonergic, but probably also noradrenergic, dopaminergic, neurotransmission mediated by histamine, acetylcholine, GABA and glutamate. This multimodal pharmacological activity appears to underlie the antidepressant and anxiolytic properties of vortioxetine and is also responsible for the improvements in cognition, learning and memory observed in animal studies.
However, since the individual contribution of each pharmacological target to the observed pharmacodynamic profile of vortioxetine remains unclear, extrapolation of the reported preclinical data to humans should be done with caution.
Two studies using positron emission tomography in humans to quantify 5-HT transporter occupancy (using 11C-MADAM
or
11C-DASB
), at different dosage levels of vortioxetine, the following data were obtained: the average number of 5-HT transporters associated with vortioxetine was approximately 50% at a dose of 5 mg/day, 65% at a dose of 10 mg/day and increased to 80 % when increasing the dose to 20 mg/day.
Clinical efficacy and safety
The efficacy and safety of vortioxetine have been studied in a number of clinical studies involving more than 6,700 patients, of which more than 3,700 patients participated in short-term (<12 weeks) studies in major depressive disorder (MDD). Twelve double-blind, placebo-controlled, 6/8-week fixed-dose studies were conducted to determine the short-term effectiveness of vortioxetine for MDD in adult (including elderly) patients.
Efficacy of vortioxetine was demonstrated in at least the single-dose group in 9 of 12 studies showing a change of at least 2 points from placebo on the Montgomery-Åsberg Depression Rating Scales (MADRS)
and Hamilton
(HAM-D24)
.
This was clinically confirmed by the number of patients responding to therapy and achieving remission, as well as improvement on the Clinical Global Impression (CGI-I)
.
The effectiveness of vortioxetine increased with increasing dose. The effectiveness of individual studies was supported by a meta-analysis (MMRM)
MADRS
total score at 6/8 weeks in short-term placebo-controlled studies in adults.
According to the results of a meta-analysis of these studies, the differences from placebo were statistically significant: −2.3 points (p = 0.007); −3.6 points (p<0.001); −4.6 points (p <0.001) at doses of 5, 10 and 20 mg/day, respectively; at a dose of 15 mg/day, statistically significant differences with placebo were not achieved according to the meta-analysis, but the mean differences compared with placebo were −2.6 points. The effectiveness of vortioxetine was also confirmed in the pooled analysis, in which the response rate was 46 to 49% with vortioxetine compared with 34% with placebo (p < 0.01; NRI
).
In addition, vortioxetine in the dose range of 5–20 mg/day has demonstrated effectiveness against a wide range of depressive symptoms (assessed by change in scores on all individual MADRS
).
The effectiveness of vortioxetine at doses of 10 or 20 mg/day was also shown in a 12-week, double-blind, dose-controlled comparative study with agomelatine at doses of 25 or 50 mg/day in patients with MDD. Vortioxetine demonstrated statistically significant superiority over agomelatine on the total MADRS
, which was also clinically significant in the number of patients who responded to therapy, achieved remission and improvement on the
CG1-I
.
Maintenance therapy.
The durability of the antidepressant effect with maintenance therapy was shown in a relapse prevention study. Patients in remission after initial vortioxetine therapy in a 12-week open-label study were randomized to vortioxetine 5 or 10 mg/day or placebo and monitored for relapse for a double-blind observation period of at least 24 weeks (from 24 to 64 weeks). Vortioxetine was superior to placebo (p=0.004) in the primary outcome measure of time to relapse of MDD, with a hazard ratio of 2; this means that the risk of relapse was 2 times higher in the placebo group than in the vortioxetine group.
Elderly patients.
In a double-blind, placebo-controlled, 8-week, fixed-dose study in elderly patients with depression (≥65 years, n=452, 156 of whom were treated with vortioxetine), vortioxetine 5 mg/day was superior to placebo in the global depression score.
MADRS
and
HAM-D24
scales .
The difference between vortioxetine and placebo was 4.7 points on the MADRS
at 8 weeks of therapy (
MMRM
).
Patients with severe depression or depression and high levels of anxiety.
The effectiveness of vortioxetine has also been demonstrated in patients with severe depression (baseline
MADRS
≥30) and in patients with depression with concomitant high levels of anxiety (baseline
HAM-A
≥20) in short-term studies of adult patients (mean difference from placebo on the
MADRS
at weeks 6 and 8 ranged from 2.8 to 7.3 points and from 3.6 to 7.3 points, respectively (
MMRM
)). In a separate study in elderly patients, vortioxetine was also effective in this group of patients.
The persistence of the antidepressant effect in this category of patients was also shown in a long-term relapse prevention study.
Effect of vortioxetine on the Digit Symbol Substitution Test (DSST), the UC San Diego Life Skills Assessment (UPSA) (objective measures), and the Perceived Deficits Questionnaire score. , PDQ) and scores on the Cognitive and Physical Functioning Questionnaire (CPFQ) (subjective measures)
. The effectiveness of vortioxetine (at a dose of 5–20 mg/day) in patients with MDD was studied in two short-term placebo-controlled studies in adults and one in elderly patients.
Vortioxetine had a statistically significant effect on DSST
compared with placebo, with Δ = 1.75 (p = 0.019) to 4.26 (p < 0.0001) in two studies in adults and Δ = 2.79 (p = 0.023) in a study in elderly patients.
In a meta-analysis (ANCOVA, LOCF)
baseline in
number of characters correct on
the DSST When adjusted for change in MADRS
, total scores in a meta-analysis of the same studies showed that vortioxetine differed from placebo (p < 0.05) with a standardized effect size of 0.24.
One study assessed the effect of vortioxetine on functional ability using the UPSA
. Vortioxetine was statistically significantly different from placebo with results of 8 points for vortioxetine versus 5.1 points for placebo (p=0.0003).
In one study, vortioxetine was superior to placebo on subjective scores measured by the PDQ
, with results of −14.6 for vortioxetine and −10.5 for placebo (p=0.002).
Vortioxetine did not differ from placebo on subjective scores measured by the CPFQ
, 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-term and long-term studies over a dose range of 5 to 20 mg/day.
Information about unwanted side reactions is presented in the “Side Effects” section.
Vortioxetine did not increase the incidence of insomnia or somnolence compared with placebo.
Short-term and long-term placebo-controlled clinical studies have consistently assessed potential withdrawal symptoms following abrupt cessation of vortioxetine treatment. There was no clinically significant difference from placebo in the incidence or quality of withdrawal symptoms after either short-term (6–12 weeks) or long-term (24–64 weeks) vortioxetine therapy.
The incidence of spontaneous complaints of sexual adverse reactions was low and similar to placebo in both short-term and long-term studies of vortioxetine. In studies using the Arizona Sexual Function Scale (ASEX)
The incidence of treatment-induced sexual dysfunction
(TESD)
ASEX
total score were not clinically significantly different from placebo when vortioxetine was administered at doses of 5–15 mg/day. An increase in the incidence of sexual dysfunction was observed with vortioxetine 20 mg/day compared with placebo (difference in incidence 14.2%, CI 95% (1.4, 27)).
In short- and long-term studies, vortioxetine had no effect on weight, heart rate, or blood pressure compared with placebo.
Vortioxetine did not have a clinically significant effect on parameters of liver and kidney function in clinical studies. In patients with MDD, vortioxetine did not have a clinically significant effect on ECG parameters, including QT, QTc, PR and QRS intervals. In a careful study of the QTc interval in healthy subjects, vortioxetine at doses up to 40 mg/day did not affect its duration.
Brintellix
Mechanism of action
The mechanism of action of vortioxetine appears to be related to its direct modulating serotonergic activity and inhibition of the serotonin transporter protein. Preclinical studies show that vortioxetine acts as an antagonist of 5-HT3, 5-HT7 and 5-HT1D receptors, a partial agonist of 5-HT1B receptors and a full agonist of 5-HT1A receptors, and also inhibits the 5-HT transporter, thereby modulating neurotransmission in several systems, primarily serotonergic, but probably also noradrenergic, dopaminergic, neurotransmission mediated by histamine, acetylcholine, GABA and glutamate. This multimodal pharmacological activity appears to underlie the antidepressant and anxiolytic properties of vortioxetine and is also responsible for the improvements in cognition, learning and memory observed in animal studies. However, since the individual contribution of each pharmacological target to the observed pharmacodynamic profile of vortioxetine remains unclear, extrapolation of the reported preclinical data to humans should be done with caution.
Two studies using positron emission tomography (PET) in humans to quantify the extent of 5-HT transporter occupancy (using ligands 11C-MADAM or 11C-DASB), at different dosage levels of vortioxetine, found the following data: mean number of transporters 5 -NT associated with vortioxetine was approximately 50% at a dose of 5 mg/day, 65% at a dose of 10 mg/day and increased to 80% when the dose was increased to 20 mg/day.
Clinical efficacy and safety
The efficacy and safety of vortioxetine have been studied in a number of clinical studies involving more than 6,700 patients, of which more than 3,700 patients participated in short-term (≤12 weeks) studies in major depressive disorder (MDD). Twelve double-blind, placebo-controlled, 6/8-week, fixed-dose studies were conducted to determine the short-term effectiveness of vortioxetine for MDD in adult patients (including elderly patients). Efficacy of vortioxetine was demonstrated in at least the single-dose group in 9 of 12 studies, showing a change of at least 2 points from placebo on the Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HAM-). D24). This was clinically confirmed by the number of patients responding to therapy and achieving remission, as well as improvement on the Clinical Global Impression Scale (CGI-I). The effectiveness of vortioxetine increased with increasing dose. Individual study efficacy was supported by a meta-analysis (MMRM) of mean changes in MADRS total score at 6/8 weeks in short-term placebo-controlled studies in adults. According to the results of a meta-analysis of these studies, the differences from placebo were statistically significant: -2.3 points (p = 0.007); -3.6 points (p<0.001); -4.6 points (p <0.001) at doses of 5, 10 and 20 mg/day, respectively; at a dose of 15 mg/day, statistically significant differences with placebo were not achieved according to the meta-analysis, but the mean differences compared with placebo were -2.6 points. The effectiveness of vortioxetine was also confirmed in the pooled analysis, in which the response rate was 46% to 49% with vortioxetine compared with 34% with placebo (p < 0.01; NRI analysis).
In addition, vortioxetine in the dose range of 5–20 mg/day has demonstrated effectiveness against a wide range of depressive symptoms (assessed by change in scores on all individual MADRS subscales). The effectiveness of vortioxetine at doses of 10 or 20 mg/day was also shown in a 12-week, double-blind, dose-controlled comparative study with agomelatine at doses of 25 or 50 mg/day in patients with MDD. Vortioxetine demonstrated statistically significant superiority over agomelatine in terms of the total MADRS score, which was also clinically significant in the number of patients who responded to therapy, achieved remission and improvement on the CGI-I scale.
Maintenance therapy
The durability of the antidepressant effect with maintenance therapy was shown in a relapse prevention study. Patients in remission after initial vortioxetine therapy in a 12-week open-label study were randomized to vortioxetine 5 or 10 mg/day or placebo and monitored for relapse during a double-blind observation period of at least 24 days. weeks (from 24 to 64 weeks). Vortioxetine was superior to placebo (p=0.004) on the primary outcome measure of time to relapse of MDD, with a hazard ratio of 2.0; this means that the risk of relapse was twice as high in the placebo group than in the vortioxetine group.
Elderly patients
In a double-blind, placebo-controlled, 8-week, fixed-dose study in elderly patients with depression (≥65 years, n=452, 156 of whom were treated with vortioxetine), vortioxetine 5 mg/day was superior to placebo on the total score. according to the MADRS and HAM-D24 scales. The difference between vortioxetine and placebo was 4.7 points on the MADRS at week 8 of treatment (MMRM analysis).
Patients with severe depression or depression and high levels of anxiety
The effectiveness of vortioxetine has also been demonstrated in patients with severe depression (baseline MADRS total score ≥30) and in patients with depression with concomitant high levels of anxiety (baseline HAM-A total score ≥20) in short-term studies of adult patients (mean difference from placebo on the MADRS scale at weeks 6 and 8 ranged from 2.8 to 7.3 points and from 3.6 to 7.3 points, respectively (MMRM analysis)). In a separate study in elderly patients, vortioxetine was also effective in this group of patients.
The persistence of the antidepressant effect in this category of patients was also shown in a long-term relapse prevention study.
Effect of vortioxetine on the Digit Symbol Substitution Test (DSST), the UC San Diego Life Skills Scale (UPSA) (objective measures), and the Perceived Deficits Questionnaire score. , PDQ) and scores on the Cognitive and Physical Functioning Questionnaire (CPFQ) (subjective measures)
The effectiveness of vortioxetine (at a dose of 5-20 mg/day) in patients with MDD was studied in two short-term placebo-controlled studies in adults and one in elderly patients.
Vortioxetine had a statistically significant effect on the Digit Symbol Substitution Test (DSST) compared with placebo, with ∆ = 1.75 (p = 0.019) to 4.26 (p < 0.0001) in two studies in adults and ∆ = 2 .79 (p = 0.023) in a study in elderly patients. In a meta-analysis (ANCOVA, LOCF) of mean change from baseline in number of characters correct on the DSST in all three studies, vortioxetine differed from placebo (p < 0.05) with a standardized effect size of 0.35. When adjusted for change in MADRS, total scores in a meta-analysis of the same studies showed that vortioxetine differed from placebo (p < 0.05) with a standardized effect size of 0.24.
One study assessed the effect of vortioxetine on functional ability using the University of California San Diego Life Skills Assessment (UPSA). Vortioxetine was statistically significantly different from placebo with results of 8.0 points for vortioxetine versus 5.1 points for placebo (p = 0.0003).
In one study, vortioxetine was superior to placebo on subjective scores as measured by the Subjective Deficit Questionnaire, with results of -14.6 for vortioxetine and -10.5 for placebo (p = 0.002). Vortioxetine did not differ from placebo on subjective scores measured by the Cognitive and Physical Functioning Questionnaire, with results of -8.1 for vortioxetine versus -6.9 for placebo (p = 0.086).
Portability and safety
The safety and tolerability of vortioxetine have been established in short-term and long-term studies over a dose range of 5 to 20 mg/day. Information about unwanted side reactions is presented in the “Side Effects” section.
Vortioxetine did not increase the incidence of insomnia or somnolence compared with placebo.
Short-term and long-term placebo-controlled clinical studies have consistently assessed potential withdrawal symptoms following abrupt cessation of vortioxetine treatment. There was no clinically significant difference from placebo in the incidence or quality of withdrawal symptoms after either short-term (6-12 weeks) or long-term (24-64 weeks) vortioxetine therapy.
The incidence of spontaneous complaints of sexual adverse reactions was low and similar to placebo in both short-term and long-term studies of vortioxetine. In studies using the Arizona Sexual Function Scale (ASEX), the incidence of treatment-induced sexual dysfunction (TESD) and total ASEX scores were not clinically significantly different from placebo when vortioxetine was used at doses of 5-15 mg/day. When using vortioxetine at a dose of 20 mg/day, an increase in the incidence of sexual dysfunction was observed compared with placebo (difference in frequency 14.2%, DP 95% (1.4, 27.0)).
In short- and long-term studies, vortioxetine had no effect on weight, heart rate, or blood pressure compared with placebo.
Vortioxetine did not have a clinically significant effect on parameters of liver and kidney function in clinical studies.
In patients with MDD, vortioxetine had no clinically significant effect on ECG parameters, including QT, QTc, PR and QRS intervals. In a careful study of the QTc interval in healthy subjects, vortioxetine at doses up to 40 mg/day did not affect its duration.
