The mean baseline MADRS total score was 31.4±3.5, indicating moderate-to-severe depression, as also reflected in the mean CGI-S score of 4.8. All the patients had experienced a previous MDE, and the current episode had typically started about 6–7 months before enrolment (Table 1). Patients had a mean number of two previous MDEs and a median duration of 22 weeks (range 14–317 weeks) for the current MDE, and over half (51.2%) of the patients had one previous MDE, 24.5% had two and 24.3% had at least three previous MDEs. There was a substantial level of anxiety symptoms, indicated by a mean baseline HAM-A total score of 20.8.
Withdrawals from the study
The withdrawal rate due to all reasons during the entire study was 16.6% [15.8% (placebo), 22.5% (vortioxetine 15 mg), 17.2% (vortioxetine 20 mg) and 10.9% (duloxetine)] (Fig. 1). Overall, the most frequent primary reason for withdrawal was AEs (6.8%). There was no statistically significant difference to placebo in any of the active treatment groups in the proportion of patients who withdrew from the study. The percentage of patients who withdrew because of AEs was statistically significantly different only between vortioxetine 20 mg (11.3%) and placebo (4.4%). Analysis of time to withdrawal for any reason, or for lack of efficacy, showed no statistically significant differences in any of the treatment groups versus placebo. However, analysis of time to withdrawal due to AEs showed a statistically significantly shorter time to withdrawal in the vortioxetine 20 mg group than in the placebo group (Cox model; P=0.043). At least 83% of the patients in each treatment group received study medication for at least 43 days in the 8-week treatment period. The total exposure accrued in each treatment group was ∼21 patient years.
Primary efficacy endpoint
In the primary efficacy analysis, both doses of vortioxetine were statistically significantly superior to placebo in mean change from baseline in MADRS total score at week 8 (FAS, MMRM), with a mean treatment difference to placebo of −5.5 (vortioxetine 15 mg, SE=1.1, P<0.0001) and −7.1 points (vortioxetine 20 mg, SE=1.1, P<0.0001). The active reference duloxetine was also significantly superior to placebo (nominal P<0.0001), thus validating the study methodology and patient population.
There were no statistically significant main effects on the primary efficacy variable of any of the covariates (site, country, baseline MADRS and HAM-A total scores, sex, baseline weight, waist circumference, and age). Adjusting for these main effects did not change the estimates and conclusions on treatment differences. There was a statistically significant interaction between treatment and country (P=0.032). This was quantitative, with the size of effect varying per country as expected. None of the remaining covariates investigated interacted with treatment at the 5% level of significance.
Key secondary efficacy endpoints
Both doses of vortioxetine were statistically significantly superior to placebo in all the predefined key secondary efficacy analyses, including response and remission based on the MADRS (Table 2). Response rates (≥50% decrease from baseline in MADRS total score, FAS, LOCF, logistic regression) were 32.3% (placebo), 57.0% (vortioxetine 15 mg) and 61.6% (vortioxetine 20 mg). Remission rates (MADRS total score≤10, FAS, LOCF, logistic regression) were 19.0% (placebo), 34.9% (vortioxetine 15 mg) and 38.4% (vortioxetine 20 mg).
For patients with a baseline HAM-A score of at least 20 [55.6% (336/604)], statistically significant superiority to placebo in mean change from baseline in MADRS total score at week 8 (FAS, MMRM) was seen, with a mean treatment difference to placebo of −5.2 (vortioxetine 15 mg, n=87, P=0.0007) and −6.4 (vortioxetine 20 mg, n=80, P<0.0001). Separation from placebo (nominal P<0.05) in mean MADRS scores was seen from week 4 onwards in all active treatment groups (FAS, MMRM).
The mean CGI-I score decreased (improved) throughout the 8-week treatment period to 2.2 (vortioxetine 15 mg), and 1.9 (vortioxetine 20 mg) at week 8 (FAS, MMRM). Separation from placebo (nominal P<0.05) was seen from week 2 onwards in the vortioxetine 20 mg group and from week 4 onwards in the vortioxetine 15 mg group (FAS, MMRM).
The SDS total scores were based on patients who were employed (placebo, n=115; vortioxetine 15 mg, n=97; vortioxetine 20 mg, n=107). The mean SDS total score decreased (improved) from ∼20 at baseline to 12 (vortioxetine 15 and 20 mg) at week 8. Separation from placebo (nominal P<0.05) was seen at weeks 6 and 8 in each of the active treatment groups (FAS, MMRM) (Table 2).
Secondary efficacy endpoints
Separation from placebo was seen from week 2 onwards (vortioxetine 20 mg) and week 4 onwards (vortioxetine 15 mg) and was maintained throughout the remainder of the treatment period (Fig. 2). To analyse the robustness of the results of the primary efficacy analysis, sensitivity analyses were performed. For both doses of vortioxetine, using ANCOVA (OC and LOCF), the difference to placebo was associated with a nominal P-value less than 0.0001. Separation from placebo (nominal P<0.01) was seen for all 10 MADRS single items at week 8 (FAS, MMRM) for each of the active treatment groups. The mean CGI-S score decreased (improved) throughout the 8-week treatment period from 4.8±0.7 at baseline to 2.6±1.2 (vortioxetine 15 mg, nominal P<0.0001 vs. placebo) and 2.4±1.2 (vortioxetine 20 mg, nominal P<0.0001 vs. placebo) at week 8 (FAS, LOCF). Separation from placebo (nominal P<0.05) was seen from week 2 onwards in the vortioxetine 20 mg group, and from week 4 onwards in the vortioxetine 15 mg group (FAS, MMRM).
The mean HAM-A total score decreased (improved) from 20.8±6.7 at baseline in all the active treatment groups throughout the 8-week treatment period, with an adjusted mean change from baseline to week 8 of −9.6 (vortioxetine 15 mg, nominal P=0.0012 vs. placebo) and −11.1 (vortioxetine 20 mg, nominal P<0.0001 vs. placebo) (Fig. 3). The proportion of CGI-I responders (CGI-I ≤2) and CGI-S remitters (CGI-S ≤2) is shown in Table 2.
Separation from placebo (nominal P<0.05) was seen for the SDS single-item scores at week 8 in each of the active treatment groups (FAS, MMRM) (Table 2). The mean Q-LES-Q total score increased (improved) in all the active treatment groups from ∼34 at baseline to 43 (vortioxetine 15 mg), and 44 (vortioxetine) at week 8. Separation from placebo (nominal P<0.01) was seen at week 8 in all active treatment groups (FAS, LOCF, ANCOVA). Item 16 scores (overall life satisfaction and contentment) increased from ∼2 at baseline to 3.0 (vortioxetine 15 mg), and 3.1 (vortioxetine 20 mg) at week 8. Separation from placebo (nominal P<0.01) was seen at week 8 in all active treatment groups (FAS, LOCF, ANCOVA).
Tolerability and safety
During the 8-week treatment period, approximately two-thirds of patients in the active treatment groups had one or more AEs (Table 3). During this period, 41 patients withdrew because of AEs (Fig. 1). The only AE leading to withdrawal of more than two patients in any of the treatment groups was nausea (3.3% in the vortioxetine 15 mg group, 6.6% in the vortioxetine 20 mg group and 2.0% in the duloxetine group).
The most common AEs reported by at least 5% of patients in either of the vortioxetine groups and for which the incidence was numerically higher than that in the placebo group were nausea, headache, diarrhea (20 mg) and dry mouth (20 mg). In the duloxetine group, AEs with an incidence of greater than 5% and higher in the placebo group were nausea, headache, dizziness, dry mouth, hyperhidrosis, diarrhea and fatigue. The incidence of AEs related to insomnia was low in all the treatment groups, ranging from 0% in the vortioxetine 15 mg group to 3% in the placebo and duloxetine groups.
The incidence of AEs related to sexual dysfunction (orgasm abnormal, anorgasmia, ejaculation delayed, ejaculation disorder, libido decreased, erectile dysfunction, orgasmic sensation decreased, sexual dysfunction) was 2.5% (placebo), 2.0% (vortioxetine 15 mg), 4.0% (vortioxetine 20 mg) and 3.5% (duloxetine) of patients. The mean ASEX total score remained at baseline level in all treatment groups throughout the 8-week treatment period (FAS, LOCF and OC). There were no statistically significant differences to placebo in any of the vortioxetine groups in ASEX total score at week 8 or any other week. There were no statistically significant differences to placebo in any of the active treatment groups in the proportion of patients without sexual dysfunction at baseline who developed sexual dysfunction any time during the 8-week treatment period. When the analysis was repeated for women and men separately, no statistically significant difference to placebo was seen in any of the active treatment groups. There were no significant changes from baseline in mean ASEX total scores in any of the treatment groups at week 8.
The incidence of AEs related to suicide and self-harm was low. Two patients took an intentional overdose of zolpidem (vortioxetine group) or zolpidem and lormetazepam (duloxetine group). Suicidal ideation was reported by 11.4% (placebo), 9.9% (vortioxetine 15 mg), 9.3% (vortioxetine 20 mg) and 6.1% (duloxetine) of patients. The C-SSRS data showed no clinically relevant differences between treatment groups at screening or during the study. An improvement in the scores for MADRS item 10 (suicidal thoughts) from baseline was seen in all treatment groups.
Serious AEs were reported by five patients: two patients in the vortioxetine 20 mg group and three patients in the duloxetine group. No serious AE was reported by more than one patient. No deaths occurred during this study. Two patients (one in each of the vortioxetine 20 mg and duloxetine groups) had serious AEs related to suicidal behaviour and self-harm.
For patients who completed 8 weeks of treatment, the DESS was assessed at week 8 (baseline value) and at weeks 9 and 10. In the placebo group, the DESS total score increased from the baseline value of 0.4 to 0.5 points in the first week and 0.6 points in the second week of the discontinuation period (Fig. 4). Patients in the vortioxetine groups were abruptly switched to placebo at completion. In the vortioxetine 15 mg group, the DESS total score increased from the baseline value of 0.8 to 1.3 points in the first week and decreased to 0.8 points in the second week. In the vortioxetine 20 mg group, the DESS total score increased from the baseline value of 0.7 to 1.4 points in the first week (week 9) (P=0.0297) and to 1.3 points in the second week (week 10) (P=0.1690). Patients in the duloxetine group were down-tapered to 30 mg/day in the first week of the discontinuation period and switched to placebo in the second week. In the duloxetine group, the DESS total score increased from the baseline value of 0.5 to 1.1 points in the first week and to 2.8 points (P<0.0001) after the switch to placebo during the second week. In the second week of the discontinuation period, the DESS single items for which at least 10% of the patients in the treatment groups had reported either new symptoms or a worsening of pre-existing symptoms compared with week 8 comprised increased dreaming or nightmares (vortioxetine 15 mg) and dizziness/lightheadedness (vertigo), trouble sleeping, insomnia, irritability, fatigue/tiredness, nervousness or anxiety, bouts of crying/tearfulness, headache, agitation, mood swings and sudden worsening of mood (duloxetine).
No clinically relevant changes over time or differences between treatment groups were seen in clinical laboratory test results, vital signs, weight or ECG parameters.
This study evaluated the efficacy, safety and tolerability of two fixed doses of vortioxetine compared with placebo after 8 weeks of treatment in patients with MDD. In this study, duloxetine, an SNRI antidepressant, was included as an active reference. Preclinical data have shown that vortioxetine’s mode of action has two main components: a direct modulation of several 5-HT receptor subtypes (5-HT3, 5-HT7 and 5-HT1D receptor antagonism, 5-HT1B receptor partial agonism and 5-HT1A receptor agonism) and 5-HT reuptake inhibition (Pehrson et al., 2012; Westrich et al., 2012). Vortioxetine increases brain levels of 5-HT, dopamine and noradrenaline in brain areas implicated in the regulation of emotions, that is medial prefrontal cortex, ventral hippocampus and nucleus accumbens, at doses active in behavioural models predictive of antidepressant and anxiolytic activity (Mørk et al., 2012). The results of five randomized clinical trials of vortioxetine in the acute treatment of MDD have been published to date; they used doses ranging from 1 to 10 mg/day. Apart from one failed and one negative placebo-controlled study, both conducted in the USA using vortioxetine 5 mg/day (Jain et al., 2013; Mahableshwarkar et al., 2013), three studies demonstrated a significant antidepressant activity of daily doses of 5 and 10 mg in adults and the elderly (Alvarez et al., 2012; Henigsberg et al., 2012; Katona et al., 2012) and one failed study was supportive of these doses (Baldwin et al., 2012). In all of these clinical trials, the withdrawal rate because of AEs was between 3 and 11% for vortioxetine compared with 1 and 8% for placebo. Vortioxetine was judged to be well tolerated, with nausea being the only AE with an incidence of more than 10%. Two long-term studies – an open-label extension study demonstrating the effectiveness of vortioxetine as maintenance therapy (Baldwin et al., 2012) and a relapse prevention study (Boulenger et al., 2012) – have supported the favourable safety and tolerability profile as well as the antidepressant activity of 5 and 10 mg vortioxetine. Thus, vortioxetine has been shown to be safe and well tolerated in both the short-term and long-term treatment of MDD.
The in-vitro pharmacological profile and in-vivo receptor and 5-HT transporter occupancies of vortioxetine coupled with neuronal firing and microdialysis studies suggest that the targets of vortioxetine interact in a complex fashion, leading to dose-dependent modulation of neurotransmission in several systems, including the 5-HT, norepinephrine, dopamine, histamine and acetylcholine systems within the rat forebrain. In addition, a relationship between dose and 5-HT transporter occupancy has been shown by human PET studies (Areberg et al., 2012b), predicting a greater involvement of the 5-HT receptors and of the 5-HT transporter with increasing doses of vortioxetine.
In the present placebo-controlled study, doses of 15 and 20 mg were used for 8 weeks for the treatment of patients with MDEs fulfilling DSM-IV criteria for more than 3 months and presenting an initial MADRS total score of at least 26. On the prespecified primary efficacy endpoint, the superiority of both doses of vortioxetine to placebo was highly statistically significant, with a significant mean treatment difference in MADRS total scores at 8 weeks of 5.5 points with 15 mg and 7.1 points with 20 mg. Such a difference, much greater than the two-point average for approved antidepressants (Montgomery and Möller, 2009) and the 3 points recognized by NICE as clinically significant (National Institute for Health and Clinical Excellence (NICE), 2004), is quite unusual in randomized controlled trials of antidepressants. These differences to placebo correspond to standardized effect sizes of 0.65 (15 mg) and 0.82 (20 mg). Clinical relevance is further shown by the proportions of responders and remitters and by the improvement in CGI-I score. As the difference to placebo of antidepressant medication increases with increasing baseline depression severity (Fournier et al., 2010), it cannot be ruled out that the high effect size is in part due to the inclusion of only patients with a baseline MADRS of at least 26. Differences in response rates compared with placebo (29.3 percentage points with 20 mg and 24.7 percentage points with 15 mg) were superior to the average 16 percentage points observed for antidepressants approved by the competent European authorities (Melander et al., 2008). The robustness of these results was confirmed by the statistically significantly better outcome than placebo observed in all the prespecified, multiplicity-corrected key secondary efficacy analyses. Previous studies evaluating vortioxetine in the treatment of MDD at 10 mg/day demonstrated statistically significant efficacy versus placebo (Alvarez et al., 2012; Henigsberg et al., 2012), with some indication of a dose–response effect, with numerically greater reductions at the higher dose levels. A similar trend was observed in the current study, with numerically greater improvement at the higher dose.
Vortioxetine showed an effect on anxiety symptoms over placebo, as demonstrated by a decrease of HAM-A total scores of 9.6 (15 mg) and 11.1 (20 mg) throughout the 8-week treatment period. The subgroup of patients with anxious depression, as defined with a baseline HAM-A score of at least 20, demonstrated a statistically significant improvement in mean change from MADRS baseline scores with vortioxetine compared with placebo at week 8 (15 mg: 5.2; 20 mg: 6.4). Improving depressive symptoms in patients with higher baseline anxiety may be particularly clinically meaningful, as these patients may be slower to respond to treatment and have lower rates of response to antidepressants (Fava et al., 2008). The anxiolytic efficacy of vortioxetine in these patients is consistent with the results of recent studies suggesting its efficacy in both short-term (Bidzan et al., 2012) and long-term treatment (Baldwin et al., 2012) of generalized anxiety disorder.
Treatment of depression still remains a challenge, with one of the issues being the diversity of the individual patient symptom profiles, and often residual symptoms persist at the end of antidepressant treatment (Nierenberg et al., 1999). In the present study vortioxetine had a favourable effect on a broad range of depressive symptoms, as demonstrated by a statistically significant decrease in all 10 MADRS single items throughout the 8-week treatment period, suggesting that vortioxetine may offer therapeutic benefit in reducing overall residual symptomatology.
Depression is associated with impairment of HRQoL and overall functioning, and therefore assessment of these during treatment is clinically relevant to both clinicians and patients (Wells et al., 1989; Trivedi et al., 2006). Unmet medical needs include antidepressant treatments that allow patients to recover to an extent that restores their ability to work and function in daily life, so that the burden on patient, the patient’s family and society as a whole can be reduced (Lam et al., 2011). Vortioxetine had a favourable effect on patient-reported overall functioning, as assessed using the SDS. Statistically significant efficacy was found for both vortioxetine doses in improving patients’ functioning, on the basis of the SDS total score, with standardized effect sizes of 0.47 (15 mg) and 0.55 (20 mg), and the social, family and work single-item scores. Moreover, both vortioxetine doses demonstrated a significant improvement in patient-reported HRQoL, based on the Q-LES-Q(SF) total score and the score for the item addressing overall life satisfaction and contentment. The standardized effect sizes were 0.38 (15 mg) and 0.52 (20 mg) for the Q-LES-Q(SF) total score and 0.36 (15 mg) and 0.42 (20 mg) for the item addressing overall life satisfaction and contentment. The clinical relevance of the results is supported by the magnitude of the standardized effect sizes, which exceed the minimal clinically important difference of 0.2 (Brozek et al., 2006).
As this study assesses the higher dose range of vortioxetine in the treatment of MDD, safety and tolerability data are summarized in some detail below. During this study, the withdrawal rate due to all reasons was 16.6% and there was no statistically significant difference compared with placebo in any of the active treatment groups; however, a statistically significant difference in the rate of withdrawal for AEs was found between vortioxetine 20 mg (11.3%) and placebo (4.4%). The rate of withdrawal because of AEs with vortioxetine 15 mg (6.8%) was similar to the rates reported in previous studies using vortioxetine doses up to 10 mg, that is 3–9%. The most common AE reported for vortioxetine was nausea; headache, diarrhea and dry mouth were also reported more frequently than with placebo, but not significantly so. The emergence of suicidal ideation during the study was lower in the active treatment groups than in the placebo group and the C-SSRS data showed no clinically relevant differences in suicidal ideation and behaviour between groups during this period. The incidence of AEs related to insomnia and sexual dysfunction was low and the ASEX total score remained at baseline levels in all treatment groups. Although sexual side effects are frequently reported during antidepressant treatment with SSRIs and SNRIs (Baldwin, 2004), their incidence with vortioxetine did not differ significantly from that observed with placebo in all the randomized clinical trials published so far, including one where vortioxetine was administered for up to 64 weeks (Boulenger et al., 2012). No consistent trend was observed for vital signs, weight, clinical values or ECG parameters in the active treatment groups and there were no marked differences to the patients receiving placebo. The DESS total score after abrupt discontinuation of vortioxetine treatment was low and similar to that of placebo. In the duloxetine group, in which patients were down-tapered during the first week, the DESS total score increased in the second week to twice that in the first week. Overall, abrupt discontinuation of vortioxetine was well tolerated and the low DESS total score and the nature of the discontinuation symptoms suggest that down-tapering of vortioxetine is not needed. This might be because of its relatively long apparent half-life of 66 h (Areberg et al., 2012a).
As in most clinical trials, the generalizability of this study is limited by the exclusion of patients with psychiatric or medical comorbidity and of those with marked suicidal ideation. To mitigate the risk of including ineligible patients in this study, first-episode patients were excluded and the duration of the depressive episode required for inclusion was 3 months or longer.
The present study reports the use of 15 or 20 mg doses of vortioxetine in the treatment of MDD. Both vortioxetine doses, as well as duloxetine 60 mg (used as the active reference), demonstrated a statistically significant effect on the primary and all key secondary efficacy criteria in prespecified testing sequence. Both doses of vortioxetine were well tolerated, with nausea and headaches being the AEs with the highest incidence.
The authors thank all patients for their participation in the study. The authors gratefully acknowledge the participation of the following investigators in the psychiatric sites in the trial: Belgium: Joseph Lejeune, Leo Ruelens; Estonia: Kairi Mägi, Ellen Grüntal-Oja; Finland: Riitta Jokinen, Antti Ahokas, Ulla Lepola, Anna Savela, Markku Timonen, Hannu Koponen, Marko Sorvaniemi; France: Francis Gheysen, Joël Pon, Thierry Loiseau, Charles-Siegfried Peretti, Marcel Zins-Ritter, Jöel Gailledreau, Paule Khalifa, Mocrane Abbar, Eric Neuman; Germany: Klaus-Ulrich Oehler, Klaus Sallach, Alexander Schulze, Cornelia Drubig, Hans Martin Kolbinger, Peter Franz, Jana Thomsen; Latvia: Linda Keruze, Aisma Bredovska, Ilona Paegle, Andris Arajs, Strolis Imants; Lithuania: Daiva Deltuviene, Dalia Peciukaitiene, Sonata Rudzianskiene; Norway: Torbjørn Tvedten, Sverre Tønseth; Russia: Vladimir A Tochilov, Anna V Vasilieva, Alexander P Kotsubinskyi, Natalia V Dobrovolskaya, Isaak Y Gurovich, Julia B Barylnik, Alexander F Parashchenko, Andrey V Gribanov, Vitaliy A Tadtaev, Anatoliy B Bogdanov; Slovakia: Jana Grešková, Monika Biačková, Eva Janíková, Viera Kořínková, Peter Molčan, Abdul Mohammad Shinwari; South Africa: Greta Brink, Hilda Russouw; Sweden: Maj-Liz Persson, Kurt Wahlstedt, Per Ekdahl, Frank Hoyles; Ukraine: Volodymyr Abramov, Yuliya Blazhevych, Viktoriya Verbenko, Nataliya Maruta, Vladyslav Demchenko, Oksana Serebrennikova, Pavlo Palamarchuk, Gennadiy Zilberblat, Viktor Kovalenko, Andrey Skripnikov, Olena Venger, Iryna Spirina. The authors also thank D. J. Simpson (H. Lundbeck A/S) for providing support in the preparation, revision and editing of the manuscript.
H. Lundbeck A/S sponsored the study as part of a joint clinical development programme with the Takeda Pharmaceutical Company. Lundbeck was involved in the study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper for publication.
Conflicts of interest
J.-P.B. has received grant funding from Lundbeck as well as honoraria and consultancy fees from Lundbeck, Sanofi, Astra-Zeneca and Servier. H.L. and C.K.O. are employees of Lundbeck.
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duloxetine; Montgomery–Åsberg Depression Rating Scale; placebo controlled; recurrent major depressive disorder; Sheehan Disability Scale; vortioxetine