The tolerability of antidepressant treatment affects quality of life and medication adherence. There are differences between antidepressants in mode of action, effectiveness and tolerability. Adverse effects frequently associated with antidepressant treatment include sexual dysfunction, discontinuation symptoms, weight gain, gastrointestinal effects, sleep disturbances, and suicidal behavior.
For patients with major depressive disorder (MDD), long-term treatment (6 to 12 months) is recommended in those who have responded to acute treatment to prevent relapse and recurrence. Therefore, long-term tolerability studies are required to determine if there are safety concerns that were not identified in the acute treatment studies.
Vortioxetine is a new antidepressant with multimodal activity: it is an antagonist of 5HT 3 , 5HT 7 and 5HT 1D receptors , a partial agonist of 5HT 1B , a agonist of 5HT 1A and an inhibitor of the serotonin transporter (5-HT). It is licensed for use for the treatment of adults with MDD at approved doses of 5 mg, 10 mg, 15 mg, and 20 mg. Vortioxetine has a low potential for clinically relevant interactions with other drugs.
The present analysis was performed to evaluate the safety and tolerability of vortioxetine using the vortioxetine clinical trials database. All randomized, double-blind, placebo-controlled, open-label studies with vortioxetine for the treatment of MDD, at the recommended therapeutic doses of 5 to 20 mg/day, were included. The analyzes were based on 11 short-term controlled trials and five long-term open-label studies.
Safety and tolerability were based on the nature, incidence, and severity of treatment-emergent adverse events (TEAS), electrocardiogram (ECG) parameters, vital signs, and clinical safety laboratory values during acute treatment.
EASTs were evaluated during the studies through open-ended questions, researcher observations, and patient reports. Suicidal ideation and behavior were assessed with the Columbia Suicide Severity Rating Scale (C-SSRS).
Discontinuation symptoms after abrupt discontinuation of vortioxetine treatment were assessed with the Discontinuation Emergent Signs and Symptoms (DESS) Checklist.
Clinical safety laboratory values included alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, albumin, calcium, creatinine, glucose, hemoglobin, hematocrit, potassium, sodium, bilirubin (total), platelets, and leukocytes.
Cardiovascular safety was assessed by examining changes in patients’ vital signs and ECG parameters and by a comprehensive QT study in healthy subjects. Vital signs, including blood pressure and pulse, were monitored as part of safety assessments in each clinical study.
| Results |
| Short-term placebo-controlled MDD studies |
In the short-term studies, 1,817 patients were treated with placebo, 3,018 with vortioxetine (5-20 mg/day), 113 with venlafaxine XR (225 mg/day), and 753 with duloxetine (60 mg/day).
> Suspension rates by EAST and the number needed to harm (NND). Discontinuation rates due to EAST in short-term studies were vortioxetine 5 mg 4.5% vs. placebo 3.7%, vortioxetine 10 mg 4.8% vs. placebo 3.8%, vortioxetine 15 mg 7.8% vs. placebo 3.8% and vortioxetine 20 mg 7.1% vs. placebo 3.3%. Based on these rates, the NNHs (95% CI) for vortioxetine were 126 (not significant) (5 mg), 94 (not significant) (10 mg), 24 (14–99) (15 mg), and 26 (16–69 ) (20 mg). For vortioxetine, the most common EAST was nausea.
> Adverse events arising from treatment . For vortioxetine, EASTs with an incidence more than double that of placebo were nausea and vomiting. EASTs with vortioxetine were mild to moderate in intensity. Most patients reported nausea during the first two weeks of dosing. During the third week of treatment, the proportion of patients reporting nausea as new EAST was ~2% in all vortioxetine dose groups and 1% in the placebo group and remained low thereafter. Nausea from vortioxetine was transient, with a mean duration of 9 to 16 days. EASTs reported by ~5% of vortioxetine patients were: nausea, headache, dizziness, constipation, diarrhea, dry mouth, and fatigue.
> Serious adverse events. Its incidence was 0.5% for placebo and 0.6% for vortioxetine (5-20 mg) with no relation to the dose or pattern in the nature of the events.
> Suicidal thoughts and behaviors. Suicide-related events (including suicidal ideation, intentional overdose, intentional self-harm, self-injurious behavior, and suicide attempt) were reported by 11 vortioxetine-treated patients (0.4%) and six placebo-treated patients (0.3%), without clinically relevant differences between groups.
> Akathisia, mania, hostility and aggression. In short-term studies of MDD, the incidence of akathisia, restlessness, and psychomotor hyperactivity was 0.6% (placebo), 0.7% (vortioxetine 5-20 mg), 1.8% (venlafaxine 9% (duloxetine). The incidence of dyskinesia (including muscle spasms and tics) was 0.3% (placebo), 0.3% (vortioxetine 5-20 mg), 0% (venlafaxine XR), and 0.3% (duloxetine).
The incidence of events possibly associated with hostility/aggression (including irritability, agitation, aggression, anger, psychomotor hyperactivity, affective lability, attention seeking, hypomania, impulsive behavior, injuries, lacerations, mania, paranoia) was 2.5% ( placebo), 1.6% (vortioxetine), 0% (venlafaxine XR) and 2.1% (duloxetine). For vortioxetine, none of these individual terms had a higher incidence than for placebo.
> Insomnia. The incidence of EASTs associated with insomnia (baseline insomnia, middle insomnia, hyposomnia, sleep disorder, dyssomnia, poor sleep quality, and terminal insomnia) was 4% for placebo, 2-5.1% for vortioxetine, 15.9 % for venlafaxine XR and 8.1% for duloxetine.
> Sexual dysfunction. The incidence of EAST associated with sexual dysfunction (decreased or loss of libido, delay or disorder of ejaculation, abnormal orgasm, anorgasmia, impaired sexual arousal, insufficient ejaculation, erectile dysfunction, decreased orgasmic sensation, sexual dysfunction and dryness vulvovaginal) was 1.6 to 1.8% for vortioxetine and 1% for placebo. For women, the incidence was 0.6 to 1.1%. for vortioxetine vs. 0.7% for placebo and for men, the incidence was 2.8% to 3.6% for vortioxetine versus 1.6% for placebo.
> Discontinuation symptoms. Three studies used the DESS to assess possible discontinuation symptoms in patients who completed short-term treatment with vortioxetine. The results are consistent with the incidence of EAST reported during the discontinuation period.
> Weight . During short-term treatment, the mean change in weight from baseline to week 6/8 was similar for placebo (change +0.1 kg) and vortioxetine (change –0.1 to 0.1 kg) . The incidence of clinically significant weight gain (CBS) (7% increase from baseline) ranged from 0% (15 mg) to 1.2% (10 mg) for vortioxetine vs. 0.6% for placebo. Significant weight loss (7% decrease from baseline) ranged from 0.2% (5 mg) to 1.3% (20 mg) for vortioxetine vs. 0.6% for placebo.
> Clinical safety laboratory values. Mean changes from baseline in hematological and clinical biochemical values were small, of no clinical relevance, and similar in the placebo and vortioxetine groups.
> Cardiovascular parameters. There were no clinically relevant changes over time in blood pressure in patients treated with vortioxetine. All mean values of vital signs were within the reference ranges. The results indicate that vortioxetine is unlikely to affect cardiac repolarization.
| Long-term open studies |
In the five extension studies, 1313 patients were treated with 5 to 10 mg of vortioxetine and 1144 patients with 15 to 20 mg, representing 1015 and 775 patient-years of exposure, respectively, with a mean exposure of 52 weeks and 51 weeks. The most common EASTs that led to discontinuation were nausea (0.8% and 2.7%), depression (0.7% and 0.4%), vomiting (0.2% and 1.0%), headache ( 0.2% and 0.7%), weight gain (0.2% and 0.5%) and insomnia (0.2% and 0.5%) for vortioxetine 5–10 mg and 15-20 mg, respectively.
Common EASTs (reported by ~5 of the patients in any vortioxetine dose group) in these studies were nausea, headache, diarrhea, nasopharyngitis, weight gain, dizziness, insomnia-related events, vomiting, constipation, and respiratory tract infection superior.
The proportion of patients with sexual dysfunction during 52 weeks was 1.7% (vortioxetine 5-10mg) and 2.3% (vortioxetine 15-20mg). No new types of EAST were observed in long-term treatment compared to acute treatment with vortioxetine. The incidence of serious adverse events was 2.9% for vortioxetine 5 to 10 mg and 2.2% for vortioxetine 15 to 20 mg.
The mean weight change from the baseline studies to the last assessment in the extension studies was +0.8 kg (5–10 mg) and +0.7 kg (15–20 mg). The incidence of EAST related to cardiovascular diseases was 1.8% for hypertension and 0.9% for increased blood pressure. All mean vital sign values were within the reference ranges.
| Short-term placebo-controlled generalized anxiety disorder (GAD) studies |
In the four short-term GAT studies, 609 patients were treated with placebo, 453 with vortioxetine 5 mg/day (62.5 patient-years of exposure), 308 with vortioxetine 10 mg/day (40.7 patient-years of exposure). exposure) and 154 with duloxetine 60 mg/day.
Discontinuation rates due to EAST were vortioxetine 5.0% versus placebo 2.8%. EASTs leading to discontinuation were nausea, headache, irritability, dizziness, diarrhea, and vomiting versus none in the placebo group. The incidence of serious adverse events was 0.5% for placebo and 0.1% for vortioxetine (5 to 10 mg) with no dose effect or pattern in the nature of the events.
During short-term treatment, mean weight change from baseline to week 8 were similar for placebo and vortioxetine.
| Pregnancy |
39 women became pregnant during or shortly after stopping treatment in clinical pharmacology or TDM studies. In the vortioxetine group, 13 women had an elective abortion, 10 had a spontaneous abortion, and 13 had a healthy baby with no birth or developmental defects. For three women, the outcome was unknown.
| Discussion |
This data analysis compares the tolerability and safety profile of vortioxetine with placebo in acute randomized controlled clinical trials of 6/8 weeks duration, and its tolerability and safety in long-term open-label treatments of up to 52 weeks.
The most common EAST (incidence ≥5%) and occurring at least twice as frequently as observed with placebo during 6/8 weeks of vortioxetine treatment were nausea and vomiting. The effects of the vortioxetine dose were mainly observed in nausea and vomiting, the incidence of which stabilized at vortioxetine 15 mg/day.
EASTs commonly found with most antidepressants, such as headache, dry mouth, dizziness, constipation, insomnia, drowsiness, fatigue, sexual dysfunction, and hyperhidrosis, were observed at "placebo levels" and did not show any dose effects. Furthermore, the proportion of patients with suicidal ideation was similar in the placebo and vortioxetine groups, as measured by the C-SSRS and spontaneous patient reports.
The NNH for vortioxetine, based on the number of patients who discontinued treatment due to EAST, was markedly higher (i.e. better) for vortioxetine 5 mg and 10 mg than for the active references duloxetine and venlafaxine XR. Vortioxetine has a cardiovascular safety profile comparable to placebo.
Long-term treatment with vortioxetine in MDD did not result in the development of EASTs that had not been seen during acute treatment. The low incidence of sleep disturbances with vortioxetine may possibly be attributed to modulatory effects on several receptors. The incidence of treatment-emergent sexual dysfunction (TED) in patients treated with vortioxetine was not different from that of placebo, and there was no effect of dose.
The biotransformation of vortioxetine occurs mainly in the liver. Coadministration of vortioxetine had no clinically relevant effect on the pharmacokinetics of fluconazole, ketoconazole, lithium, diazepam, aspirin, or warfarin. The same is true for coadministration of ethinyl estradiol/levonorgestrel or omeprazole/5′-hydroxyomeprazole, although dose adjustment may be necessary when vortioxetine is coadministered with bupropion or rifampicin.
There is no clinically significant effect with a single dose of vortioxetine in patients with mild or moderate hepatic impairment or renal impairment (mild, moderate, severe or end-stage renal disease).
Limitations of this analysis include exclusion of patients with significant psychiatric or physical comorbidity, or at risk for suicidal behavior, and a variety of concomitant medications. This may reduce the generalizability of the findings.
EASTs during double-blind treatment were spontaneously reported and may underestimate the proportion of patients with adverse events. Long-term treatment was not placebo controlled. Fetal exposure to vortioxetine was limited. Vortioxetine is not recommended for the treatment of children or adolescents.
| Final summary |
This analysis indicates that vortioxetine is safe and generally well tolerated in short- and long-term treatment.
Some of the tolerability problems seen with other antidepressants, including sexual dysfunction, insomnia-related events, weight gain, and discontinuation symptoms, occur at a low incidence, which may represent an advantage for vortioxetine during treatment. long-term.
