Vortioxetine for Major Depressive Disorder
Vortioxetine for Major Depressive Disorder
Vortioxetine 5–20 mg/day represents a new therapeutic option for the treatment of MDD, both acutely and for relapse prevention. Data for elderly patients are also supportive, with effect sizes for response and remission similar to that observed for the younger adults. Vortioxetine is not associated with excessive somnolence or with clinically meaningful changes in weight. The mechanism of action may be different enough from other available antidepressants to make it a reasonable option to try in the face of inadequate efficacy or tolerability issues with other agents, despite the apparent differences in effect size for response/remission observed with venlafaxine in one study, and the pooled data for duloxetine. Although certainly not unique to vortioxetine, nausea can be an obstacle to adherence, especially at the highest recommended dose. In addition, although spontaneously reported AEs related to sexual dysfunction were infrequent, prospectively collected ASEX data indicate potential issues with sexual side effects, again at the highest recommended dose. Further analyses of the ASEX data, including that for the active controls, would be helpful in better understanding this, and a study evaluating the effect of vortioxetine vs. escitalopram on sexual functioning is underway (NCT01364649). Despite these potential issues, the NNH vs. placebo for discontinuation because of an AE was numerically relatively favourable (NNH 36, 95% CI 24–70), compared with that observed with venlafaxine (NNH 10, 95% CI 6–26) or duloxetine (NNH 20, 95% CI 14–39) in the vortioxetine clinical trial programme.
Several limitations to this systematic review need to be made explicit. Available so far are the results of carefully conducted registration trials that enrolled subjects who fulfilled restrictive inclusion/exclusion criteria. Such patients may differ from persons encountered in routine clinical practice. For example, registration trials ordinarily exclude patients with current comorbid substance use disorders, untreated medical conditions, current suicidality, or who require concomitant use of other psychotropic agents. Known non-responders to antidepressants are also usually excluded from participating in these types of registration trials. Moreover, adherence to treatment in a clinical trial is enhanced compared with less structured settings. Thus, pragmatic clinical trials that are more generalisable will help place vortioxetine in clinical perspective for its use in the 'real world'.
Relying on spontaneously reported AEs to determine their incidence may underestimate what can actually be observed in clinical practice where patients are usually specifically asked about commonly occurring side effects. This is particularly the case with sexual side effects where patients may be reluctant to bring them up. The use of the ASEX in many of the studies described in this review helps in more accurately ascertaining true rates of treatment-emergent sexual dysfunction.
The time course for achieving response/remission and for encountering AEs is also of importance to the clinical utility of a medication. AEs that are short-lived and perhaps easily manageable, such as nausea, will be less likely to be an obstacle than AEs such as weight gain which can be persistent and more difficult to ameliorate. Plotting the time course of the NNT for response/remission and the NNH for a specific AE or for discontinuation because of an AE, may help further characterise what can be expected when using a medication. An example of analysing NNT over time can be found in an analysis of duloxetine where the estimated NNT decreased steadily from a value of 79 after 1 week of treatment to a value of 6 after 9 weeks of acute treatment.
An additional limitation of this review is that a substantial amount of the data was obtained from posters presented at professional meetings. Posters are not subject to the peer-review process of a medical journal, and the results presented at professional meetings prior to formal publication may be subject to further quality review and subsequent revision. At present, the product label is the most authoritative source of information regarding vortioxetine. It is anticipated that the publication of additional peer-reviewed study reports will soon occur, as well as the public availability of the FDA's Drug Approval Package, providing additional data and explanations.
In addition to any recently completed and ongoing trials listed in Table 2, such as studies examining cognition (NCT01422213, NCT01564862, NCT01607125), several clinical trials are pending as enumerated in the FDA's approval letter for vortioxetine. These include paediatric studies for the treatment of MDD in patients aged 7–17 years, a pharmacokinetic trial in subjects with severe hepatic impairment compared with healthy subjects using the 5 mg dose, a study of vortioxetine and its major metabolites as potential inhibitors of major transporters as recommended by the drug–drug interaction guidance, and a controlled trial to evaluate the longer term (i.e., maintenance) efficacy of multiple fixed doses of vortioxetine in the treatment of adults with MDD in the US.
Discussion
Vortioxetine 5–20 mg/day represents a new therapeutic option for the treatment of MDD, both acutely and for relapse prevention. Data for elderly patients are also supportive, with effect sizes for response and remission similar to that observed for the younger adults. Vortioxetine is not associated with excessive somnolence or with clinically meaningful changes in weight. The mechanism of action may be different enough from other available antidepressants to make it a reasonable option to try in the face of inadequate efficacy or tolerability issues with other agents, despite the apparent differences in effect size for response/remission observed with venlafaxine in one study, and the pooled data for duloxetine. Although certainly not unique to vortioxetine, nausea can be an obstacle to adherence, especially at the highest recommended dose. In addition, although spontaneously reported AEs related to sexual dysfunction were infrequent, prospectively collected ASEX data indicate potential issues with sexual side effects, again at the highest recommended dose. Further analyses of the ASEX data, including that for the active controls, would be helpful in better understanding this, and a study evaluating the effect of vortioxetine vs. escitalopram on sexual functioning is underway (NCT01364649). Despite these potential issues, the NNH vs. placebo for discontinuation because of an AE was numerically relatively favourable (NNH 36, 95% CI 24–70), compared with that observed with venlafaxine (NNH 10, 95% CI 6–26) or duloxetine (NNH 20, 95% CI 14–39) in the vortioxetine clinical trial programme.
Several limitations to this systematic review need to be made explicit. Available so far are the results of carefully conducted registration trials that enrolled subjects who fulfilled restrictive inclusion/exclusion criteria. Such patients may differ from persons encountered in routine clinical practice. For example, registration trials ordinarily exclude patients with current comorbid substance use disorders, untreated medical conditions, current suicidality, or who require concomitant use of other psychotropic agents. Known non-responders to antidepressants are also usually excluded from participating in these types of registration trials. Moreover, adherence to treatment in a clinical trial is enhanced compared with less structured settings. Thus, pragmatic clinical trials that are more generalisable will help place vortioxetine in clinical perspective for its use in the 'real world'.
Relying on spontaneously reported AEs to determine their incidence may underestimate what can actually be observed in clinical practice where patients are usually specifically asked about commonly occurring side effects. This is particularly the case with sexual side effects where patients may be reluctant to bring them up. The use of the ASEX in many of the studies described in this review helps in more accurately ascertaining true rates of treatment-emergent sexual dysfunction.
The time course for achieving response/remission and for encountering AEs is also of importance to the clinical utility of a medication. AEs that are short-lived and perhaps easily manageable, such as nausea, will be less likely to be an obstacle than AEs such as weight gain which can be persistent and more difficult to ameliorate. Plotting the time course of the NNT for response/remission and the NNH for a specific AE or for discontinuation because of an AE, may help further characterise what can be expected when using a medication. An example of analysing NNT over time can be found in an analysis of duloxetine where the estimated NNT decreased steadily from a value of 79 after 1 week of treatment to a value of 6 after 9 weeks of acute treatment.
An additional limitation of this review is that a substantial amount of the data was obtained from posters presented at professional meetings. Posters are not subject to the peer-review process of a medical journal, and the results presented at professional meetings prior to formal publication may be subject to further quality review and subsequent revision. At present, the product label is the most authoritative source of information regarding vortioxetine. It is anticipated that the publication of additional peer-reviewed study reports will soon occur, as well as the public availability of the FDA's Drug Approval Package, providing additional data and explanations.
In addition to any recently completed and ongoing trials listed in Table 2, such as studies examining cognition (NCT01422213, NCT01564862, NCT01607125), several clinical trials are pending as enumerated in the FDA's approval letter for vortioxetine. These include paediatric studies for the treatment of MDD in patients aged 7–17 years, a pharmacokinetic trial in subjects with severe hepatic impairment compared with healthy subjects using the 5 mg dose, a study of vortioxetine and its major metabolites as potential inhibitors of major transporters as recommended by the drug–drug interaction guidance, and a controlled trial to evaluate the longer term (i.e., maintenance) efficacy of multiple fixed doses of vortioxetine in the treatment of adults with MDD in the US.
