BRINTELLIX film-coated tablets 5 mg No. 28

Vortioxetine (Lu AA21004, trade name Brintellix) is an atypical antidepressant (serotonin modulator and stimulant) developed by Lundbeck in partnership with Takeda. The European College of Neuropsychopharmacology (ECNP) has proposed a classification of psychopharmacological agents, according to which vortioxetine belongs to a new class of antidepressants with multimodal action. By “modality” we mean the “class” of pharmacological targets that are affected by a pharmacological agent. For antidepressants, these are the three classic modalities: inhibition of monoamine reuptake, direct receptor activity and inhibition of monoamine catabolism. Vortioxetine inhibits serotonin reuptake and binds directly to several serotonin receptor subtypes. It is assumed that the consequence of this mechanism of action is increased efficiency, improved tolerability and accelerated onset of therapeutic effects.

Vortioxetine is approved for the treatment of depressive disorder in the United States, Canada, the European Union, the Russian Federation and other countries.

Clinical features of vortioxetine are:

• Own procognitive effect. In many patients who achieve remission, cognitive deficits persist even while taking a unimodal antidepressant. The concept of “cognitive remission” is proposed
• Minimal or no negative impact on sexual function
• Does not cause sleep disturbances
• No significant effect on the ability to drive vehicles
• No significant effect on body weight with long-term use
• Minimal severity of withdrawal syndrome. Immediate withdrawal of vortioxetine is possible. However, in case of long-term use of vortioxetine at a daily dose of 15 and 20 mg, it is recommended to reduce its dose to 10 mg/day a week before complete discontinuation

Mode of application

Brintellix is ​​taken orally, with or without food.

The initial and maintenance dose is 10 mg once daily for adults under 65 years of age.

Depending on the individual sensitivity of the patient, the dose can be increased to a maximum of 20 mg vortioxetine once daily or reduced to a minimum of 5 mg vortioxetine once daily.

After eliminating the symptoms of depression, it is recommended to continue treatment for at least 6 months to strengthen the antidepressant effect.

BRINTELLIX film-coated tablets 5 mg No. 28

Pharmacokinetics Absorption. Vortioxetine is slowly but well absorbed after oral administration and peak plasma concentrations are reached within 7-11 hours. After repeated dosing of 5, 10 or 20 mg per day, an average Cmax of 9-33 ng/ml was observed. Bioavailability is 75%. No effect of food intake on pharmacokinetics was observed. Distribution. The mean volume of distribution (V SS) is 2600 L, indicating voluminous extravascular distribution. Vortioxetine is highly bound to plasma proteins (98-99%) and binding appears to be independent of plasma concentrations of vortioxetine. Metabolism. Vortioxetine is extensively metabolized in the liver, mainly through oxidation and subsequent conjugation with glucuronic acid. In vitro, cytochrome P450 isoenzymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 are involved in the metabolism of vortioxetine. No inhibitory or inducing effects of vortioxetine in vitro on the CYP isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5 were observed. Vortioxetine is a weak P-gp substrate and inhibitor. The main metabolite of vortioxetine is pharmacologically inactive. Elimination The half-life is 66 hours. Approximately 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 in the feces. Steady-state concentrations in blood plasma are achieved after 2 weeks. Linearity/nonlinearity. Pharmacokinetics are linear and independent of time in the dose range studied (2.5-60 mg per day). According to the half-life, the accumulation index is 5 to 6 based on AUC 0-24 after multiple doses of 5 to 20 mg per day. Elderly patients. In older healthy volunteers (age ≥ 65 years, n = 20), exposure to vortioxetine was increased by 27% (Cmax and AUC) compared to young healthy control volunteers (age ≤ 45 years) after multiple doses of 10 mg daily. No dose adjustment is required. Kidney failure. After a single dose of 10 mg vortioxetine, renal impairment (Cockcroft-Gault formula, mild, moderate or severe, n = 8 per group) caused a slight increase in exposure (up to 30%) compared with that in a control group of healthy volunteers. In patients with end-stage renal disease, only a small fraction of vortioxetine was lost during the dialysis process (AUC and Cmax 13% and 27% lower; n = after a single dose of 10 mg vortioxetine. No dose adjustment required. Hepatic failure. After a single dose 10 mg vortioxetine No effect of mild to moderate hepatic impairment (Child-Pugh criteria A and B; n=8 in each group) on the pharmacokinetics of vortioxetine was observed (changes in AUC were less than 10%). No dose adjustment was required. Vortioxetine has not been studied in patients with severe hepatic impairment, and caution should be exercised when prescribing to these patients. Poor metabolizers of CYP2D6. In poor metabolizers of CYP2D6, plasma concentrations of vortioxetine were approximately twice as high as in extensive metabolizers. In the presence of strong CYP3A4/2C9 inhibitors, the effect could potentially be above.Dose adjustment may be required, as for all patients, depending on individual response. Pharmacodynamics Mechanism of action. The mechanism of action of vortioxetine is believed to be related to its multimodal activity, which is a combination of two pharmacological mechanisms: direct modulation of receptor activity and inhibition of the serotonin transporter (5-HT). Preclinical data indicate that vortioxetine is a 5-HT 3, 5-HT 7 and 5-HT 1D receptor antagonist, a partial 5-HT 1B receptor agonist, a 5-HT 1A receptor agonist and a 5-HT transporter inhibitor, causing modulation of neurotransmission in several systems, including serotonin, norepinephrine, dopamine, histamine, acetylcholine, GABA and glutamate. This multimodal activity is believed to provide antidepressant and anxiolytic effects, as well as improvements in cognitive function, learning and memory in preclinical studies of vortioxetine. In addition, preclinical studies indicate that vortioxetine does not cause sexual dysfunction. The precise contribution of each component of this mechanism to the observed pharmacodynamic profile remains unclear, and caution must be exercised when extrapolating preclinical data directly to humans. It was found that the uptake of the serotonin transporter by various daily doses of vortioxetine was approximately 50% with a dose of 5 mg, 65% with a dose of 10 mg, and more than 80% with a dose of 20 mg. Vortioxetine has been clinically shown to have antidepressant effects at 50% 5-HT transporter uptake. Clinical efficacy and safety. The effectiveness of vortioxetine increases with increasing dose. In addition, vortioxetine in doses of 5-20 mg has demonstrated effectiveness in a wide range of depressive (MADRS scale) and anxious (HAM-A scale) depressive symptoms. Relapse prevention. The duration of the antidepressant effect was demonstrated in a relapse prevention study, in which a twice as high risk of relapse was found in the placebo group than in the vortioxetine group. Elderly patients. In the dose range of vortioxetine from 5 to 20 mg per day, efficacy and tolerability in older adults corresponded to the results of studies in the adult population. Patients with severe depression or high levels of anxiety symptoms. Antidepressant efficacy has also been demonstrated in patients with severe depression (MADRS score ≥ 30) and in depressed patients with high levels of anxiety symptoms (HAM-A score ≥ 20) in short-term studies, including studies in older patients, and long-term relapse prevention studies. Patients with an inadequate response to SSRI/SNRI treatment. In a comparative study of flexible doses in patients with depression following an inadequate response to treatment of an existing episode of SSRI/SNRI, vortioxetine at a daily dose of 10-20 mg was statistically significantly more effective than agomelatine at a dose of 25-50 mg (MADRS), clinical significance was demonstrated on the CGI-I and SDS scales. Cognitive dysfunction in depression. In studies of the drug's effect on cognition, the effect of vortioxetine was found to be primarily due to direct effects on cognitive function rather than indirect effects through improvement of depressive symptoms. Quality of life and general functioning. Vortioxetine was superior to placebo on measures of quality of life and clinically significantly improved global health (EQ-5D) and global functioning (SDS-Work, Social and Family) compared with placebo or the active comparator (agomelatine). Moreover, the superior effects compared with placebo on quality of life were maintained throughout the long-term relapse prevention study. Tolerability and safety. The safety and tolerability of vortioxetine were assessed in short- and long-term studies at doses of 5-20 mg per day. Vortioxetine did NOT increase the frequency of insomnia or somnolence compared to placebo. In a systematic assessment of potential withdrawal symptoms, there was no clinically significant difference between vortioxetine and placebo in the frequency or nature of withdrawal symptoms after either short-term (6-12 weeks) or long-term (24-64 weeks) treatment periods. During clinical trials with vortioxetine, the incidence of reported sexual adverse reactions was low and similar to placebo, and rates of treatment-related sexual dysfunction and ASEX total scores were not clinically significant different from placebo for symptoms of sexual dysfunction at the recommended dose of vortioxetine. but high doses were associated with an increased incidence of dysfunction. In clinical trials, vortioxetine had no effect on body weight, heart rate, or blood pressure, similar to placebo. There were no clinically significant changes in liver and kidney function scores during the clinical studies. Vortioxetine did not have any clinically significant effect on ECG parameters, including QT, QTc, PR and QRS intervals, in patients with major depressive disorder. In a rigorous QTc study in healthy volunteers, no potential for QTc prolongation was observed at doses up to 40 mg per day. Childhood. Clinical studies have not been conducted among pediatric patients, hence the safety and effectiveness of the drug. Brintellix has not been established for use in patients under 18 years of age.

Overdose

Taking vortioxetine in clinical studies in doses ranging from 40 mg to 75 mg caused an exacerbation of the following side effects: nausea, postural dizziness, diarrhea, abdominal discomfort, generalized itching, drowsiness and facial flushing.

Post-marketing experience mainly concerns overdose of vortioxetine up to 80 mg. In most cases, no symptoms were reported. The most common side effects observed are nausea and vomiting.

Experience with vortioxetine overdose above 80 mg is limited. Cases of seizures and serotonin syndrome have been reported following doses several times the therapeutic range.

Treatment should be symptomatic and include appropriate monitoring. Medical supervision in specialized settings is recommended.

Pharmacology

Pharmacodynamic profile in vitro

Inhibits the serotonin transporter (SERT). It has no clinically significant affinity for the norepinephrine transporter (NET, Ki = 113 nM) and dopamine transporter (DAT, Ki > 1000 nM).

It is a full agonist of 5-HT1A receptors, a partial agonist (with low agonist efficiency, Emax) of 5-HT1B receptors and an antagonist of 5-HT1D, 5-HT3 and 5-HT7 receptors.

It should be noted that, according to modern concepts, the clinical “value” of direct 5-HT1A receptor agonists is directly determined by the magnitude of their internal activity (agonist efficiency). The rather low antidepressant and procognitive activity of such partial 5-HT1A agonists as buspirone and tandospirone is due to the fact that the agonism efficiency (Emax) of buspirone is 30% of that of serotonin, and that of tandospirone is 55-85%. Thus, only agents with an agonistic efficiency close to (full and almost full agonists) or greater than that of serotonin (superagonists) at postsynaptic 5-HT1A receptors have the greatest therapeutic potential. Vortioxetine is an almost complete agonist (Emax = 96%) of postsynaptic 5-HT1A receptors.

Pharmacokinetics in humans

Absolute bioavailability when taken orally – 75%

Tmax – 7–8 hours

T1/2 – 57 h

Connection with blood proteins – 99%

Metabolites are not active. Metabolized mainly through isoenzymes of the cytochrome P450 family: CYP2D6, as well as CYP3A4/5, CYP2C9, CYP2C19, CYP2A6, CYP2C8 and CYP2B6.

CYP2D6 inhibitors (eg, bupropion) increase plasma concentrations of vortioxetine, which may require dose adjustment of vortioxetine.

Proposed mechanism of action in vivo

5-HT1 – inhibitory receptors (cause hyperpolarization of the membrane and inhibition of the neuron), that is, they reduce the likelihood of an action potential.

5-HT3 and 5-HT7 are excitatory receptors (cause depolarization of the membrane and increase the likelihood of an action potential).

The fundamental difference between vortioxetine and SSRIs is not only a faster and more pronounced increase in the level of synaptic serotonin, but also an increase in the release of catecholamines (norepinephrine and dopamine) in the cerebral cortex. SSRIs, on the other hand, often reduce catecholamine levels, causing or worsening symptoms of a deficit of positive emotions, decreased motivation, cognitive impairment and sexual dysfunction. One of the mechanisms for the development of such SSRI-induced neurocognitive deficits may be activation by serotonin in the cerebral cortex of inhibitory GABAergic interneurons (through 5-HT3 and 5-HT7 receptors), which regulate the activity of ascending catecholaminergic systems. In this regard, the combined antagonism of vortioxetine at the 5-HT3 and 5-HT7 receptors appears to be synergistic. In addition to increasing the release of all three monoamines, vortioxetine also increases cortical levels of acetylcholine and histamine.

Consistent with the hypothesis that direct modulation of the activity of receptors regulating neural negative feedback systems can increase neurotransmitter release, a single dose of vortioxetine causes a twofold greater increase in extracellular serotonin levels in the hippocampus compared with an equivalent (SERT occupancy) dose of an SSRI. One mechanism for this effect is associated with antagonism of the 5-HT3 and 5-HT7 receptors, since the addition of selective 5-HT3 or 5-HT7 receptor antagonists to SSRIs further increases extracellular serotonin levels.

5-HT1A autoreceptors located on the dendrites and cell bodies of serotonergic neurons of the dorsal raphe nucleus (DRN) are known to reduce the frequency of their spontaneous discharges. Acute administration of SSRIs results in increased levels of synaptic serotonin in the DRN. As a result, the frequency of spontaneous discharges of serotonergic neurons rapidly decreases. 5-HT1A somatodendritic autoreceptors of this localization gradually lose sensitivity to serotonin (desensitize) and the frequency of spontaneous neuronal discharges is restored. Restoration of the frequency of spontaneous discharges of serotonergic neurons with prolonged administration of SSRIs occurs after >7 days. Administration of vortioxetine also, in the first hours, suppresses the bioelectrical activity of DRN neurons, but is characterized by a significantly faster recovery to the initial level - 24 hours. Postsynaptic 5-HT1A receptors located in the cerebral cortex and hippocampus are not subject to desensitization and are responsible for the development of therapeutic effects throughout the administration of the drug.

By blocking 5-HT3 receptors in the medulla oblongata, vortioxetine appears to reduce the inhibitory effect of serotonin on the activity of noradrenergic neurons in the locus coeruleus (LC). Thus, the administration of vortioxetine, in contrast to SSRI(N), is not accompanied by a decrease in the frequency of spontaneous discharges of noradrenergic LC neurons.

Postsynaptic 5-HT1A, as well as 5-HT3 and 5-HT7 receptors, are located on GABAergic interneurons in the prefrontal cortex and hippocampus. It is believed that stimulation of 5-HT1A, as well as blockade of 5-HT3 and 5-HT7 receptors of this localization, reduces the inhibitory effect of GABAergic interneurons (disinhibits) on pyramidal glutamatergic neurons sending descending efferents ending with excitatory synapses on the bodies of dopaminergic neurons of the ventral tegmental area (VTA) and LC noradrenergic neurons. Thus, the level of dopamine and norepinephrine in the prefrontal cortex and ventral hippocampus increases due to an increase in the bioelectrical activity of ascending catecholaminergic structures due to disinhibition of cortical pyramidal neurons.

5-HT1B and 5-HT1D receptors, in particular, are localized on the presynaptic membrane of monoaminergic neurons. Vortioxetine's antagonism at these receptors may also contribute to increased synaptic levels of all three monoamines in the DRN, VTA, and LC neuron projections.

The mechanism of increased levels of acetylcholine and histamine in the prefrontal cortex and hippocampus has not yet been sufficiently studied.

Note!

Description of the drug Brintellix table. p/o 10 mg No. 28 on this page is a simplified author’s version of the apteka911 website, created on the basis of the instructions for use.
Before purchasing or using the drug, you should consult your doctor and read the manufacturer's original instructions (attached to each package of the drug). Information about the drug is provided for informational purposes only and should not be used as a guide to self-medication. Only a doctor can decide to prescribe the drug, as well as determine the dose and methods of its use.

Effects in the preclinic

Preclinical studies have shown that the multimodal pharmacological profile of vortioxetine differentiates it from SSRIs and SNRIs in a number of respects. In particular, vortioxetine is effective in SNRI-unresponsive animal models of depression (acute progesterone withdrawal model). Clinical and preclinical data suggest that acute progesterone withdrawal may cause depression, anxiety, irritability, anhedonia, and social withdrawal. This model is considered SSRI- and SNRI-insensitive. However, a selective 5-HT1A agonist (flesinoxan) and a selective 5-HT3 antagonist (ondansetron) are effective in this model.

Similarly, vortioxetine was effective in a model of cognitive impairment caused by serotonin depletion by a tryptophan hydroxylase inhibitor. Escitalopram and duloxetine were ineffective in this model, unlike the selective 5-HT1A agonist flesinoxan. In addition, administration of vortioxetine for 1 month partially compensated for the impairment of visuospatial memory in 12-month-old mice, while fluoxetine was ineffective.

EEG studies have shown large differences in the effects of vortioxetine and SSRI(N) on the bioelectrical activity of the cerebral cortex. In contrast to escitalopram and duloxetine, vortioxetine increased wakefulness in a dose-dependent manner, as did flesinoxan, duloxetine, and ondansetron, but not escitalopram. Quantitative spectral analysis of EEG showed that vortioxetine increases the power of θ (4–8 Hz), α (8–12 Hz) and γ (30–50 Hz) oscillations in the frontal cortex. Duloxetine did not affect the θ- and γ-rhythm, but reduced the power of the α-rhythm, and escitalopram did not cause any changes. Ondansetron (a selective 5-HT3 receptor antagonist) and the selective 5-HT7 antagonist SB-269970 (≈31–35% occupancy) increased the power of the θ rhythm. Flesinoxan (≈41% occupancy) increased the power of the θ- and γ-rhythm. Thus, vortioxetine differs from escitalopram and duloxetine in that it enhances the amplitude of θ-, α- and γ-oscillations in the cortex of the frontal lobes of the brain. The consequence of this is probably the activation of cortical networks responsible for cognitive functions.

Drug interactions

• Irreversible non-selective MAO inhibitors (phenelzine, tranylcypromine) - due to the risk of serotonin syndrome, any combination with drugs in this group is contraindicated. Treatment with vortioxetine should not be started earlier than 14 days after discontinuation of therapy with irreversible non-selective MAO inhibitors. The drug must be stopped at least 14 days before starting treatment with irreversible non-selective MAO inhibitors
• Reversible selective MAO-A inhibitors (eg, moclobemide) are also contraindicated
• Irreversible selective MAO-B inhibitors (selegiline, rasagiline) are not recommended to be combined with vortioxetine, despite the absence of such a warning for SSRIs.
• Medicines that lower the seizure threshold - should be used with caution with other antidepressants (TCAs, SSRIs, SNRIs, bupropion), antipsychotics (phenothiazines, butyrophenones and thioxanthenes), as well as mefloquine and tramadol.
• Electroconvulsive therapy - no studies have been conducted.
• Cytochrome P450 inhibitors - increased frequency of side effects, dose reduction required.
• Omeprazole - The effect of a single 40 mg dose of omeprazole (a CYP2C19 inhibitor) on the pharmacokinetics of vortioxetine in healthy volunteers was not observed.
• Inducers of cytochrome P450 (rifampicin, carbamazepine, phenytoin) - a decrease in the AUC of vortioxetine by 72% is observed; dose adjustment may be required.
• Acetylsalicylic acid - no interaction noted.
• Anticoagulants and antiplatelet agents (including acetylsalicylic acid) - no interaction noted. However, as with other serotonergic agents, caution should be exercised when vortioxetine is used in combination with oral anticoagulants or antiplatelet agents due to a potential increased risk of bleeding.
• Alcohol - no significant effects noted. However, the use of vortioxetine in combination with alcohol is not recommended.
• Benzodiazepines - no significant side effects noted.
• Combined oral contraceptives (COCs) - No effect on sex hormone levels (compared with placebo) was found after concomitant use of vortioxetine with a COC (ethinyl estradiol 30 mcg/levonorgestrel 150 mcg).
• Lithium and tryptophan - There have been reports of increased effects when serotonergic antidepressants are used with lithium or tryptophan, so caution should be exercised when coadministering these drugs.

Contraindications

• Hypersensitivity to the active substance or any component of the drug.
• Concomitant use with non-selective MAO inhibitors or selective MAO-A inhibitors.
• With caution: severe renal and liver failure; mania and hypomania; pharmacologically uncontrolled epilepsy, history of seizures; severe suicidal behavior; cirrhosis of the liver; tendency to bleed; simultaneous use with MAO B inhibitors (selegiline, rasagiline), serotonergic drugs, drugs that lower the seizure threshold, lithium, tryptophan, drugs containing St. John's wort, oral anticoagulants and drugs that affect platelet function, drugs that can cause hyponatremia , electroconvulsive therapy, old age.

Safety and Tolerability

The most common adverse reaction observed in clinical trials was nausea. Adverse reactions were mild to moderate in severity and were observed during the first two weeks of therapy. The reactions were usually transient and did not require discontinuation of the drug. Reactions from the digestive system were more often observed in female patients.

Isolated cases of the development of serotonin syndrome have been observed when using SSRIs, SNRIs and other serotonergic antidepressants, including vortioxetine, in monotherapy. The use of serotonergic antidepressants in combination with other serotonergic drugs is known to increase the risk of developing serotonin syndrome. Therefore, concomitant use of vortioxetine in combination with tryptophan, 5-hydroxytryptophan, triptans, tricyclic antidepressants, fentanyl, tramadol, lithium, buspirone and St. John's wort extract should be avoided whenever possible.

There was no risk of QTc prolongation in healthy volunteers when using vortioxetine at a dose of 40 mg per day.

Sexual dysfunction

Determination of the frequency of development of sexual dysfunction (decreased libido, the intensity of sexual arousal, delayed ejaculation, anorgasmia, decreased intensity of orgasm, erectile dysfunction, etc.) that occurs during the use of SSRI(H) [TESD, treatment-emergent sexual dysfunction], based on spontaneous patient reports is not an objective method of assessment, due to the intimacy of complaints. TESD is not usually self-reported by patients, but is often the main reason for not continuing antidepressant treatment, especially among younger patients.

The Arizona Sexual Experience Scale (ASEX) was used in studies of vortioxetine. TESD was defined as sexual dysfunction absent before the start of drug administration (total ASEX score ≥19, with at least 5 for each individual item) but present at at least two consecutive study visits. A pooled analysis of 7 short-term studies of vortioxetine showed that the overall incidence of TESD (excluding dose groups) was not significantly different from placebo (37% vs 32%), while in the duloxetine group (60 mg/day) it was 48.2 %. Taking into account the dose groups of patients, a dependence of frequency on dose was observed. In the vortioxetine 5 mg/day group, the incidence of TESD was significantly lower than in the placebo group and amounted to 25.7%. In the vortioxetine 10 mg/day group, it was similar to placebo – 35.3%. In the vortioxetine 20 mg/day group – 46.1%.

A study of switching patients with TESD in remission on an SSRI to vortioxetine or escitalopram showed a significant improvement in the quality of sexual functioning in most parameters (on the CSFQ-14 scale) across all three phases of intimacy when switching to vortioxetine compared with escitalopram .

One possible explanation for the lack of a significant negative effect of vortioxetine on the quality of sexual functioning may be data from preclinical studies. The addition of an effective 5-HT1A receptor agonist has been shown to reverse SSRI-induced sexual behavior disturbances in animals. Thus, additional stimulation of 5-HT1A receptors, in conditions of increased serotonin levels, may reduce its negative impact on sexual function.

Sleep disorders

In clinical studies, the risk of developing sleep-related adverse reactions (insomnia, early insomnia, moderate insomnia, late insomnia, hyposomnia, dyssomnia, decreased sleep quality) while taking vortioxetine was 2.0 - 5.1% and was not significantly different from placebo (4.4%), as opposed to SSRI(N).

5-HT1A, 5-HT1B, 5-HT3 and 5-HT7 receptors have been shown to play an important role in sleep regulation. Thus, stimulation of 5-HT1A receptors promotes increased levels of wakefulness. In addition, stimulation of 5-HT1A and blockade of 5-HT7 receptors shortens the REM sleep phase.

Animal studies have shown that administration of a selective 5-HT7 receptor antagonist prevents SSRI-induced microarousals (non-REM or REM sleep interrupted by short 10-second epochs of wakefulness), the equivalent of the clinically observed sleep fragmentation with SSRIs. A polysomnographic study of vortioxetine found suppression of REM sleep in healthy volunteers. Compared with paroxetine, at the same level of SERT occupancy, vortioxetine has a significantly lesser effect on REM sleep.

Withdrawal syndrome

Symptoms resulting from acute discontinuation of vortioxetine were studied in three short-term clinical efficacy studies and were similar in frequency and severity to placebo. This may be explained, at least in part, by the long half-life of vortioxetine (57 hours). Immediate withdrawal of vortioxetine is possible. However, in case of long-term use of vortioxetine at a daily dose of 15 and 20 mg, it is recommended to reduce its dose to 10 mg/day a week before complete discontinuation