Clinical Efficacy and Tolerability Studies: Effectiveness in short term therapy
Thase M et al. performed meta-analysis on 10 short term placebo-controlled clinical trials [studies analyzed were with Clinical trial registry no:NCT00839423, NCT00635219, NCT00735709, NCT01140906, NCT01153009, NCT01163266, NCT00672958, NCT00672620, NCT01179516, NCT00811252]outcome submitted to USFDA for vortioxetine approval purpose and demonstrate the efficacy of the compound in treatment of MDD. They observed existence of dose response correlation across the dosage strength (5-20mg/day) of vortioxetine on the basis of MADRS as efficacy measurement scale. The analysis reported clinically meaningful efficacy of vortioxetine through mean difference in change from baseline MADRS total score (32.4±4.1 for vortioxetine(n=2416) and 32.1±4.0 for placebo(n=1439)) observed for 5mg strength(difference of change in score: -2.6; p=0.008), 10 mg strength (-3.5; p<0.001), 15mg strength (-2.6; p=0.105) and 20 mg strength (-4.5; p<0.001) compared to placebo.
The very first study to identify efficacy, safety and tolerability of vortioxetine 5mg and 10 mg/day dosage vs. placebo was carried out for 6 weeks with participation of 429 patients with baseline Montgomery–Asberg Depression Rating Scale (MADRS) total score 30. Venlafaxine XR 225mg/day was used as an active reference in this multi-site study. The study exhibited superior treatment by vortioxetine in comparison of placebo as evident by significant difference (p<0.0001) in change of baseline MADRS total score. Vortioxetine treated subjects (For 5mg/day: n=108; For 10 mg/day: n=100) in comparison of placebo treated group (n=105). Comparatively low patient drop out ratio and absence of any severe adverse effect were also the key findings of this study.
Impairment in health-related quality of life (HRQoL) is a chronic illness directly related to depression. Improvement in HRQoL in patient suffering of MDD reflects therapeutic effectiveness and enhance patient adherence to the drug. Florea I et al. performed random effect meta-analysis on 9 placebo controlled short term studies [Studies included are Clinical trial registry no.: NCT 00839423; NCT00635219; NCT01323478; NCT00672958; NCT00672620; NCT00735709; NCT01153009; NCT01163266] of patients with MDD receiving vortioxetine using a variety of quality-of-life assessment tools. The meta-analysis (FAS, MMRM) showed a statistically significant difference from placebo in favor of vortioxetine (p<0.05) in terms of meaningful improvement in HRQoL on the basis of applied tools including short form-36, Quality of Life Enjoyment and Satisfaction scale-Short Form(Q-LES-Q-SF), the EuroQoL Five-Dimension(EQ-5D), the Health Status Questionnaire(HSQ-12) and the Sheehan Disability Scale(SDS). The study outcome represented efficacy of vortioxetine in case of both adult and elder populations.
Effectiveness on Cognitive function:
Efficacy of vortioxetine on cognitive function in depressed adults
Memory impairment as a Neurocognitive mutilation is prominent in patients with MDD and the same is considered s a marker of brain dysfunctinality (Burt D). Antidepresant drugs with positive effect on reversal of cognitive dysfunction are differenciated from the antidepressants with no cognitive effect to facilitate good prescription in general. In a preclinical study, Vortioxetine enhanced memory in rat as evident by novel object recognition test and alleviated extracellular level of acetylcholine and histamine when 1-10 mg/kg drug is administered subcutaneously to experimental animals (Mork A, 2013). The chronic dietary administration of drug also found to be effective in alleviation of stress-induced impairment in reversal learning when adult male rats were exposed to chronic intermittent cold (CIC) stress and 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), a 5-HT depleting agent (Wallace A, 2014). Restoration of 5-HT depletion impaired memory by Vortioxetine was also demonstrated by Jardin KG and Jansen JB through PCPA induced 5-HT depletion model and behavioural tests including object recognition (OR) and Y-maze spontaneous alternation (SA) tests respectively. SERT (Serotonin transporters) occupancy (>90%) by vortioxetine was established in their preclinical work, with reports of dose-dependently reversed recognition memory and spatial working memory in rats.
Effectiveness in MDD relapse prevention (Long term therapy)
Major depressive disorder (MDD) patients have to maintain therapy even after remission by acute treatment to prevent relapse especially when residual symptom and comorbid illnesses (E.g: MDD with generalized anxiety disorder) are present at the remission point (Keller M, 2007). The long term efficacy of antidepressants is also be established by study of its role in maintenance treatment in preventing depression recurrence in patients who responded to acute therapy (Kornstein 2006)(Steinert C 2014).
Alam M et al (NCT 00707980) carried out an open-label, 52-weeks, long term study to identify efficacy of vortioxetine along with monitoring of adverse effects. This was the extension of two double blind, placebo controlled short term (8weeks) lead in studies involving participants suffering of MDD. Total 834 patients were treated with 5 mg/day dose of vortioxetine for first week followed by dose titration from 2.5 mg/day to 10 mg/day depending on intensity of response till 52 weeks. The study concluded with absence of potential adverse effect reports and proved efficacy of vortioxetine by maintenance of remission observed by Change From Baseline score of MADRS Total Score (Observation: -7.4 ±9.81 units Change from baseline score as end point result) and 24-item Hamilton Depression total score (Observation: -7.9 ±9.66 units change from baseline score as end point result). Furthermore, Baldwin DS et al reported safety and efficacy of vortioxetine in prevention of relapse of MDD on the basis of 52 weeks of remission maintenance therapy in patients who previously completed acute therapy of vortioxetine for 8 weeks with evidence of remission. Patients reported approximately 8 points reduction from 13.5±8.7 base line MADRS score after 52 weeks of treatment indicated favorable profile of vortioxetine (2.5, 5 and 10 mg/day) in relapse prevention during long term remission maintenance therapy of MDD. At the end of 52 week treatment, approximately 2% patients have shown sign of relapse (MDRS score ? 22) as per Montgomery-Asberg Depression Rating Scale.
For vortioxetine, a MDD relapse prevention study was carried out with participation of 639 MDD patients aged between 18-75 years and diagnosed with a current major depressive episode (MDE) within four weeks duration. In this investigation, against baseline score in MADRS scale ?26, a remission point was considered as MADRS total score ?10 for vortioxetine (5 or 10 mg/day) treated patients to enter in double-blind, 24 weeks phase of treatment with either placebo (n=192) or vortioxetine (n=204) for relapse time analysis. At the end of the study, relapse rate was 13% and 26% for vortioxetine and placebo treated groups respectively as an evidence of efficacy of vortioxetine in prevention of relapse in 396 patients participated in 24 week phase (Boulenger JP 2012).
Treatment with vortioxetine (2.5 mg, 5 mg, 10 mg) failed to make differentiation from placebo when Change From Baseline in MADRS Total Score was considered as a primary efficacy analysis tool in a 8 Week randomized, double blind clinical study. In the same investigation, Duloxetine (60 mg), a reference drug used to find efficacy of vortioxetine, also failed to make differentiation against placebo in primary efficacy analysis. Secondary efficacy outcome analysis and tolerability analysis suggested efficacy of vortioxetine with 5mg and 10 mg strength through MMRM (Mixed-Effect Model Repeated Measure) model (Badwin DS, 2012).
In a randomized, double blind study involving comparison of vortioxetine (n= 252) and agomelatine (n=241), superiority of treatment with vortioxetine (p<0.05) was confirmed in MDD patients with Inadequate Response to Previous therapies. Patient adherence rate (5.9% drop out rate for vorteoxetine in comparison of 9.5% dropout rate for agomelatine), positive results in Predefined primary measure, MADRS and secondary efficacy analysis including HAM-A, CGI-S, CGI-I and SDS confirmed efficacy of 10-20 mg/day vorteoxetine dosage for treatment of MDD (Haggstrom L).
Katona C et al reported significantly (P = 0.0011) higher efficacy of vortioxetine (5 mg/day) in comparison of placebo by 24-item Hamilton Depression Scale (HAM-D (24)) total score () as the primary measure. 29.2 vs. 19.3% remission rate were observed at the endpoint for vortioxetine and placebo controlled population respectively during the study which also involved duloxetine as active reference. The patient adherence rate was 94.2% in case of vortioxetine and 90.1% in case of duloxetine demonstrated tolerability of vortioxetine in their study.
Comparative Safety of vortioxetine (10mg per day) in MDD treatment was established on the basis of 15 days study demonstrating its effect on psychomotor performance in 24 healthy subjects. The drug didn’t show alteration in psychomotor functioning withing and at the end point of te study. The investigation also involved use of Mirtazapine as an active reference which was found to be inferior through strandardized driving test due to cognitive impairment obsrved by it. (Theunissen).
EFFECTIVENESS ON ETHNIC POPULATION
Majority of the clinical investigations listed in table 3 were carried out at multi sites involving global population and diverse demographic distribution. The drug was found to be equally effective on participants from different countries.
Recently H.Lundbeck announced head-to-head study results comparing efficacy and tolerability of vortioxetine 10mg/day and venlafaxine XR 150mg/day in treatment of MDD in 437 adult participants (Inclusion criteria: MADRS total score ?26) from four Asian countries, Thailand, South Korea, Taiwan and China. The end point outcome established slightly more effectiveness of vortioxetine compared to venlafaxine with mean difference of -1.20 points in change observed in baseline MADRS total score(with 95% CI: -3.03 to -0.63). The superiority of vortioxetine was strongly supported by its tolerability data observed as lesser incidences of adverse events (6.6% vs. 13.7%) and lesser drop out ratio of participants (18% vs. 27.4%) in case of vortioxetine treatment compared to active reference. Efficacy of vortioxetine in Asian population was established by substantial improvement in MDD as evident by change in baseline score i.e.: -19.4 points on MADRS total score.
SAFETY AND TOLERABILITY
Efficacy and safety for Sexual function maintenance
Sexual dysfunction is one of the major risks of antidepressant therapy particularly with selective serotonin reuptake inhibitors (SSRIs)(Strohmaier J 2011). Therapy discontinuation is reported frequently in clinical studies involving various antidepressants due to adverse effects associated with sexual problems which includes including anorgasmia, problems in ejaculation, absence of libido and impotence but still sexual dysfunction is one of the most under-rated AEs (Serretti A). at the same time symptoms and illness of depression is also known to be associated with sexual dysfunctions(Baldwin D, 2013 AND Foong T; Reichenpfader U,). In this dilemma, the data generated through efficacy and safety studies of vortioxetine are supporting the selection of vortioxetine as an antidepressant with the minimum side effects as far as sexual health impairment is concerned.
A study involving MDD patients suffering of SSRI monotherapy (Treatment with citalopram, paroxetine or sertraline) induced sexual dysfunction indicated effectiveness of vortioxetine in clinically meaningful improvement in sexual functioning compared to escitalopram. This multicentre, randomized, double-blind, active controlled clinical trial was carried out on SSRI treated 447 participants who were already in partial or full remission state from MDD as measured by the MADRS and CGI-S/I(Clinical global impression severity and improvement scales). The participants were switched 10 mg/day fixed dose of vortioxetine or escitalopram for the first week of study. Further, the dose was increased to 20 mg/day in second week followed by flexible dose (10-20 mg/day) till the end of 8th week. The dose was taped down to 10 mg/day for escitalopram control group whereas vortioxetine treated group was switched to placebo control for another 1 week. Treatment with vortioxetine(n=169) concluded in a statistically significant treatment effect by change from baseline CSFQ-14(Changes in sexual functioning Questionnaire) total score at the end of 8th week of study in comparison of escitalopram(n=179). A mean treatment difference of 2.2 points for vortioxetine vs escitalopram groups(95% CI: 0.48—4.02; p=0.013, MMRM) proved efficacy of vortioxetine in sexual function restoration and MDD remission mintenance in patients treated with other antidepressant previously.
Previously, during the proof-of-concept, short term efficacy study for vortioxetine (5mg/day and 10 mg/day) with placebo control and active reference control has demonstrated statistically higher safety of vortioxetine in comparison of active reference (12.4% incidences for venlafaxine vs. 1.9% incidences for 5 mg/day vortioxetine and placebo, p=0.0033, Fisher’s exact test) and equivalent safety in comparison to placebo group for the incidences of sexual dysfunction related adverse effects. In contrast, Mahbaleshwarkar 2013 (NCT00672620) reported high incidences (51% for and 37.5% for vortioxetine 2.5 mg and 5 mg versus 26.9% duloxetine and 33.3% placebo group) of treatment-emergent sexual function impairment by treatment with vortioxetine. They monitored sexual dysfunction as a adverse effect using the ASEX (Arizona sexual experience) scale. The study involving a total 9f 611 participants also concluded with observation of non-significant difference in changes from baseline of HAM-D24 total score between 5mg, 10 mg vortioxetine and placebo.
The above studies indicate that sexual function related AEs is not a concern for long term use of vortioxetine as a remission maintenance therapy unlike other antidepressants whereas patients may suffer by adverse effects related with sexual dysfunction when the therapy for remission with 5mg or 10 mg dose is started in patients suffering of MDD.
Frequency and severity of adverse effect and change in selected vital body parameters, ECG, weight change due to vortioxetine (2.5, 5.0 and 10.0mg/day) administration were observed during a 52 week open labeled study by during a open label long term study by Baldwin DS. They also considered physical examination and clinical safety laboratory tests to make thorough investigation. Out of 535 participants, only 2% of individuals have shown sign of severe adverse effects but none of the adverse effect was prevalent in more than 0.56% individuals among total participants. Apart from this, majority of the patients reported the non-serious adverse effects have shown sign of nausea (19.81%) and headache (15.33%). Sexual dysfunction related adverse effects were reported in six patients at the end of the study. This study was also concluded with effectiveness of vortioxetine in long term treatment as mentioned previously in this article. The study was concluded with positive outcome in terms of tolerability of vortioxetine for long term maintenance therapy in patients with MDD remission.
Vortioxetine dose adjustment is not required based on age, race, gender, ethnicity, renal or hepatic impairment but due to serotonin syndrome and neuroleptic malignant syndrome, the drug is contraindicated in concomitant administration with irreversible non selective MAOIs(Monoamino oxidase inhibitors).
Chen G et al reported drug interaction cases affecting pharmacokinetic profile of vortioxetine in healthy subjects. They observed need of dosage adjustment of vortioxetin when it is concomminately administered with bupropion, rifampicin as steady state AUC and Cmax of of vorteoxetine enhanced by 128 and 114% in case of bupropion co-administration and suppressed by 72% and 51% in case of rifampicin co-administration. At the same time, tolerability of simultaneous therapy was evident by absence of any severe adverse effects. They also reported safety of vorteoxetine in concomminent administration of popular contraceptive, Estradiol.
Vortioxetine is mainly metabolized in liver by CYP2D6 and up to some extent by CYP2C9 and CYP34/5. This makes vortioxetine sensitive to other drugs which are CYP2D6 inhibitors, CYP3A4 and CYP2C9 inhibitors and Cytochrome P450 inducers. Other than these, reversible and non-selective MAOI and serotonergic medicinal products are also potential drug substances affecting efficacy and safety of vortioxetine.