mdd is one of the leading causes of disability in both the developed and the developing world . it has consistently been found to be associated with significant reductions in quality of life , impaired work productivity , reduced social functioning , poor physical health , and substantial direct and indirect economic costs . according to the world health organization s global burden of disease project,1 mdd antidepressants , together with evidence - based psychological therapies such as cognitive behavioral therapy , are important components of current treatment for major depression . their efficacy is , however , quite limited . only about 30%40% achieve a full remission after a single adequate course of antidepressants . a further third have a clinically significant response to antidepressant therapy but have residual symptoms which limit their social functioning and increase their risk of relapse.2 treatment adherence is a further problem.3 fewer than half of patients with mdd take their antidepressants consistently and for the full recommended duration . this reflects the delayed onset of action associated with antidepressant use and their considerable side effect burden . common side effects ( which are often prominent in the weeks before any clinical response becomes evident ) include weight gain , sexual dysfunction , nausea , headache , and sleep disturbances . there is therefore , a clear need for novel antidepressants with distinct mechanisms of action and improved side effect profiles . vortioxetine , an antidepressant produced and co - marketed by lundbeck and takeda , was approved by the us food and drug administration under the trade name brintellix . at the time of writing this paper reviews the mechanism of action of vortioxetine , the evidence regarding its safety and efficacy , and its potential place in the depression treatment armamentarium . vortioxetine was developed as one of a series of compounds developed from halogenated benzenes and was intended to have combined effects on multiple 5-ht receptors and on the serotonin transporter . it has been shown in recombinant cell lines to combine 5-ht3 and 5-ht7 receptor antagonism , 5-ht1b receptor partial agonism , 5-ht1a receptor agonism , and serotonin transporter inhibition.4 mrk et al5 assessed the effects of vortioxetine on brain neurotransmitter levels in vivo in freely - moving rat models predictive of antidepressant and anxiolytic - like activity . they confirmed that vortioxetine had multimodal serotonergic actions including partial 5-ht1b receptor agonism , 5-ht7 antagonism , 5-ht3 antagonism , and inhibition of the serotonin transporter . btry et al6 used electrophysiological and autoradiography studies in male sprague  dawley rats to examine the acute and chronic effects of vortioxetine on 5-ht neuronal firing activity and to compare them with the effects of the selective serotonin reuptake inhibitor fluoxetine . vortioxetine caused a rapid decrease in spontaneous firing of 5-ht neurons in the dorsal raphe nucleus , which ( in contrast with the effects of fluoxetine ) recovered within 1 day . subsequent autoradiographic studies indicated that 5-ht neuronal firing was inhibited by vortioxetine at doses that only partially blocked the serotonin transporter . vortioxetine administered for 3 days desensitized 5-ht1a autoreceptors to the effects of the 5-ht1a agonist flexinoxan . the authors concluded that vortioxetine inhibited 5-ht neuronal activity indirectly by inducing the release of extracellular 5-ht and suggested that 5-ht3 receptor antagonism was also an important aspect of its mechanism of action . pehrson et al7 examined the effects of acute and subchronic treatment with vortioxetine ( compared with escitalopram ) on extracellular 5-ht norepinephrine ( ne ) and dopamine ( da ) levels in a rat ventral hippocampus ( vhc ) , medial prefrontal cortex , and nucleus accumbens , as well as its effects on ne and da neuronal firing in the locus coeruleus and in the ventral tegmental area . 5-ht levels were increased by vortioxetine ( most markedly in the vhc ) despite quite low 5-ht receptor occupancy . ne and da levels were also somewhat increased in the vhc and medial prefrontal cortex but not in the nucleus accumbens . the authors concluded that vortioxetine had two main mechanisms of action ( 5-ht receptor modulation and serotonin transporter inhibition ) through which it induced region - dependent increases in the concentration of multiple neurotransmitters . single dose human studies show that vortioxetine is extensively metabolized in the liver , and is a substrate for a range of cytochrome p450 ( cyp450 ) isoforms.8 in vitro studies using human liver cells indicate that vortioxetine has no cyp450 inducing or inhibitory effects.9,10 areberg et al11 carried out an extensive human pharmacokinetic study . they administered vortioxetine by mouth and intravenously in a total of 97 healthy volunteers aged 1851 years ( median 24 ) . the volume of distribution was large , indicating that vortioxetine is lipophilic with high affinity for peripheral tissues . once a steady state was reached , plasma vortioxetine levels varied little throughout the day . mean elimination half - life following oral administration was 57 hours . in single - dose studies , women had higher exposure to vortioxetine ( as measured both by peak concentration and area under the curve ) , but the differences were small after correcting for weight . the authors also noted that previous studies had reported that food had no effect on the pharmacokinetics of vortioxetine . chen et al12 carried out multiple studies in healthy human volunteers to evaluate potential pharmacokinetic interactions between vortioxetine and coadministered agents with a range of activity as inhibitors , inducers , or substrates for cyp450 subtypes . they identified potentially significant interactions in the form of increased vortioxetine levels when it was coadministered with bupropion ( cyp2d6 inhibitor and cyp2b6 substrate ) , fluconazole ( inhibitor of cyp450 2c9 , 2c19 , and 3a ) , and ketoconazole ( cyp3a and p - glycoprotein inhibitor ) and decreased vortioxetine levels when it was coadministered with rifampicin ( cyp inducer ) . the authors considered that only the interactions with bupropion and rifampicin were likely to be sufficiently significant to warrant possible dosage adjustment . the us datasheet ( http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204447s000lbl.pdf ) recommends reducing the dose of vortioxetine when giving it in combination with powerful cyp2d6 inhibitors such as bupropion , fluoxetine , paroxetine , and quinidine , and increasing it when it is administered in combination with powerful cyp inducers such as carbamazepine and phenytoin . animal studies suggest that not only does vortioxetine have an antidepressant - like profile but also that  unlike many established antidepressants  it may have memory - enhancing effects . the putative antidepressant effects of vortioxetine were confirmed in a behavioral model of depression13 in which vortioxetine ( as well as amitriptyline ) significantly reduced immobility in rats in the forced swim test model of induced depression , whereas neither fluoxetine nor duloxetine did so . in keeping with this , guilloux et al14 assessed the effects of vortioxetine in three mouse models of anxiety and depression - like behavior  the forced swim test , the open field test , and the novelty - suppressed feeding paradigm . both acute and repeated dosing with vortioxetine produced antidepressant and anxiolytic effects greater than those produced by fluoxetine and comparable ( in the open field test ) with those produced by diazepam . vortioxetine also increased cell proliferation and cell survival of immature granule cells in the dentate gyrus of the hippocampus and stimulated their maturation . mrk et al15 examined the effect of vortioxetine on memory in rats using contextual fear conditioning and novel object recognition tests . they found that vortioxetine enhanced both contextual and episodic memory and that these effects were unrelated to pain sensitivity . they concluded that these effects were consistent with the multiple neurotransmitter effects induced by vortioxetine via 5-ht3 and 5-ht7 receptor antagonism and 5-ht1a receptor agonism . in keeping with this , du jardin et al16 found that vortioxetine dose - dependently reversed memory deficits in female long  evans rats ( as measured by object recognition and y - maze spontaneous alternation tests ) induced by 5-ht depletion . we have identified five placebo - controlled short - term ( 68 weeks ) studies of vortioxetine in younger adult patients with major depression . in addition there has been an acute placebo - controlled study in the elderly and two longer - term relapse prevention studies ( one of them randomized and placebo - controlled ) . baldwin et al17 compared vortioxetine ( 2.5 mg , 5 mg , or 10 mg ) with placebo ( with duloxetine 60 mg as an active comparator ) in 766 patients with major depression and a montgomery  sberg depression rating scale ( madrs ) score of at least 26 . on the predefined ( last observation carried forward ) primary analysis , in mixed model repeat measures analyses however , the two higher doses of vortioxetine were significantly superior to placebo , as was duloxetine . mahableshwarkar et al18 evaluated the safety and efficacy of vortioxetine ( 2.5 mg or 5 mg ) against placebo and against the active comparator duloxetine ( 60 mg ) in an 8-week study in a total of 611 participants . the primary outcome variable was the change from baseline in the 24-item hamilton depression scale ( hamd-24 ) . for vortioxetine , although there was substantial reduction in the hamd-24 scores , the difference against placebo was not statistically significant for either dose . in contrast , duloxetine showed superiority from placebo at 8 weeks ( and also at 6 weeks ) . jain et al19 randomized 600 people to 5 mg vortioxetine or placebo in a 6-week study . participants were required to have a madrs score of at least 30 and a diagnosis of a major depressive episode . the primary endpoints were change from baseline in hamd-24 total score at 6 weeks and sequential change week by week in hamd-24 score . withdrawal rates ( both for adverse events and for lack of efficacy ) were similar for vortioxetine and for placebo . there were no significant differences between vortioxetine and placebo in either of the primary outcome variables , though post hoc analyses revealed greater improvement on vortioxetine in the subgroup with high baseline anxiety scores . alvarez et al20 evaluated vortioxetine ( 5 mg or 10 mg fixed dose ) in a 6-week comparison against placebo , with venlafaxine ( 225 mg slow release ) as an active comparator . the primary outcome variable was mean change in madrs total score . both doses of vortioxetine were significantly superior to placebo at the 6-week endpoint , with mean madrs differences from placebo of 5.9 for 5 mg and 5.7 for 10 mg . venlafaxine was also superior to placebo ( mean difference in 6-week madrs score of 6.4 ) . secondary outcome measures ( response rates as measured by hamd-24 and madrs ) also showed superiority for both doses of vortioxetine ( and for venlafaxine ) against placebo . the efficacy of vortioxetine ( at doses of 1 mg , 5 mg , and 10 mg a day ) against placebo was evaluated by henigsberg et al21 in an 8-week trial involving a total of 560 participants . participants fulfilled diagnostic and statistical manual of mental disorders fourth edition text revision criteria for major depressive episode and had a minimum madrs score of 26 . the highest dose of vortioxetine ( 10 mg ) was significantly superior to placebo on the primary endpoint measure , reduction from baseline in the hamd-24 total score at week 8 ( p<0.001 ) . there were also greater improvements with all doses of vortioxetine than with placebo for most depression - related variables . in a 12-week flexible dose study22 in 493 patients with mdd who had failed to respond adequately to a selective serotonin reuptake inhibitor or a serotonin - norepinephrine reuptake inhibitor ( snri ) , vortioxetine ( 1020 mg ) vortioxetine also showed superiority in several secondary outcome measures . in a three - arm comparison with duloxetine ( 60 mg ) and placebo over 8 weeks in patients aged 65 and over , vortioxetine ( 5 mg fixed dose ) showed significantly greater improvement than placebo on the predefined primary efficacy endpoint ( ie , analysis of covariance , last observation carried forward ) of hamd-24 score at week 8.23 duloxetine was also superior to placebo at week 8 . vortioxetine also showed superiority to placebo in a range of cognitive tests ( processing speed , verbal learning , and memory ) , in keeping with the findings from animal studies . it is perhaps noteworthy that in three of the above studies,18,20,23 although formal statistical comparison between active drugs was not reported , there was a trend for the snri active comparator to be associated with numerically superior outcomes to vortioxetine . in common with other antidepressants baldwin et al24 reported on a 52-week , open - label extension study which followed an 8-week lead - in . the madrs total score was used as the primary outcome variable . in total , 328/535 patients ( 61.3% ) completed the study , representing a total of 393 patient years of exposure to vortioxetine . at the point of entry to the extension study , participants had a mean madrs total score of 13.58.7 . during the subsequent year , the mean madrs total score in completers decreased by approximately 8 points to 5.56.0 at week 52 ( oc ) and the proportion of responders rose from 63% to 94% . remission rate in completers ( 42% at the start of the study ) had increased to 83% ( oc ) . relapse rate in those in remission at the start of the study ( n=226 ) was 9.7% . boulenger et al25 confirmed that vortioxetine was effective in preventing depressive relapse in a study of 396 patients who , after achieving remission during 12-weeks of open - label treatment with 510 mg vortioxetine , were randomized to either placebo or vortioxetine ( fixed dose of 5 mg or 10 mg as determined during the open - label phase ) . the primary efficacy variable was time to relapse ( defined on the basis of a madrs score of > 21 or clinically judged lack of efficacy ) . overall , fewer patients ( 13% versus 26% ) relapsed on vortioxetine than on placebo ( p=0.013 ) . nausea was the only side effect that occurred significantly more often with vortioxetine than with placebo during the double - blind phase of the study . animal studies suggest that not only does vortioxetine have an antidepressant - like profile but also that  unlike many established antidepressants  it may have memory - enhancing effects . the putative antidepressant effects of vortioxetine were confirmed in a behavioral model of depression13 in which vortioxetine ( as well as amitriptyline ) significantly reduced immobility in rats in the forced swim test model of induced depression , whereas neither fluoxetine nor duloxetine did so . in keeping with this , guilloux et al14 assessed the effects of vortioxetine in three mouse models of anxiety and depression - like behavior  the forced swim test , the open field test , and the novelty - suppressed feeding paradigm . both acute and repeated dosing with vortioxetine produced antidepressant and anxiolytic effects greater than those produced by fluoxetine and comparable ( in the open field test ) with those produced by diazepam . vortioxetine also increased cell proliferation and cell survival of immature granule cells in the dentate gyrus of the hippocampus and stimulated their maturation . mrk et al15 examined the effect of vortioxetine on memory in rats using contextual fear conditioning and novel object recognition tests . they found that vortioxetine enhanced both contextual and episodic memory and that these effects were unrelated to pain sensitivity . they concluded that these effects were consistent with the multiple neurotransmitter effects induced by vortioxetine via 5-ht3 and 5-ht7 receptor antagonism and 5-ht1a receptor agonism . in keeping with this , du jardin et al16 found that vortioxetine dose - dependently reversed memory deficits in female long  evans rats ( as measured by object recognition and y - maze spontaneous alternation tests ) induced by 5-ht depletion . we have identified five placebo - controlled short - term ( 68 weeks ) studies of vortioxetine in younger adult patients with major depression . of these in addition there has been an acute placebo - controlled study in the elderly and two longer - term relapse prevention studies ( one of them randomized and placebo - controlled ) . baldwin et al17 compared vortioxetine ( 2.5 mg , 5 mg , or 10 mg ) with placebo ( with duloxetine 60 mg as an active comparator ) in 766 patients with major depression and a montgomery  sberg depression rating scale ( madrs ) score of at least 26 . on the predefined ( last observation carried forward ) primary analysis , in mixed model repeat measures analyses however , the two higher doses of vortioxetine were significantly superior to placebo , as was duloxetine . mahableshwarkar et al18 evaluated the safety and efficacy of vortioxetine ( 2.5 mg or 5 mg ) against placebo and against the active comparator duloxetine ( 60 mg ) in an 8-week study in a total of 611 participants . the primary outcome variable was the change from baseline in the 24-item hamilton depression scale ( hamd-24 ) . for vortioxetine , although there was substantial reduction in the hamd-24 scores , the difference against placebo was not statistically significant for either dose . in contrast , duloxetine showed superiority from placebo at 8 weeks ( and also at 6 weeks ) . jain et al19 randomized 600 people to 5 mg vortioxetine or placebo in a 6-week study . participants were required to have a madrs score of at least 30 and a diagnosis of a major depressive episode . the primary endpoints were change from baseline in hamd-24 total score at 6 weeks and sequential change week by week in hamd-24 score . withdrawal rates ( both for adverse events and for lack of efficacy ) were similar for vortioxetine and for placebo . there were no significant differences between vortioxetine and placebo in either of the primary outcome variables , though post hoc analyses revealed greater improvement on vortioxetine in the subgroup with high baseline anxiety scores . alvarez et al20 evaluated vortioxetine ( 5 mg or 10 mg fixed dose ) in a 6-week comparison against placebo , with venlafaxine ( 225 mg slow release ) as an active comparator . the primary outcome variable was mean change in madrs total score . both doses of vortioxetine were significantly superior to placebo at the 6-week endpoint , with mean madrs differences from placebo of 5.9 for 5 mg and 5.7 for 10 mg . venlafaxine was also superior to placebo ( mean difference in 6-week madrs score of 6.4 ) . secondary outcome measures ( response rates as measured by hamd-24 and madrs ) also showed superiority for both doses of vortioxetine ( and for venlafaxine ) against placebo . the efficacy of vortioxetine ( at doses of 1 mg , 5 mg , and 10 mg a day ) against placebo was evaluated by henigsberg et al21 in an 8-week trial involving a total of 560 participants . participants fulfilled diagnostic and statistical manual of mental disorders fourth edition text revision criteria for major depressive episode and had a minimum madrs score of 26 . the highest dose of vortioxetine ( 10 mg ) was significantly superior to placebo on the primary endpoint measure , reduction from baseline in the hamd-24 total score at week 8 ( p<0.001 ) . there were also greater improvements with all doses of vortioxetine than with placebo for most depression - related variables . in a 12-week flexible dose study22 in 493 patients with mdd who had failed to respond adequately to a selective serotonin reuptake inhibitor or a serotonin - norepinephrine reuptake inhibitor ( snri ) , vortioxetine ( 1020 mg ) vortioxetine also showed superiority in several secondary outcome measures . in a three - arm comparison with duloxetine ( 60 mg ) and placebo over 8 weeks in patients aged 65 and over , vortioxetine ( 5 mg fixed dose ) showed significantly greater improvement than placebo on the predefined primary efficacy endpoint ( ie , analysis of covariance , last observation carried forward ) of hamd-24 score at week 8.23 duloxetine was also superior to placebo at week 8 . vortioxetine also showed superiority to placebo in a range of cognitive tests ( processing speed , verbal learning , and memory ) , in keeping with the findings from animal studies . it is perhaps noteworthy that in three of the above studies,18,20,23 although formal statistical comparison between active drugs was not reported , there was a trend for the snri active comparator to be associated with numerically superior outcomes to vortioxetine . in common with other antidepressants baldwin et al24 reported on a 52-week , open - label extension study which followed an 8-week lead - in . the madrs total score was used as the primary outcome variable . in total , 328/535 patients ( 61.3% ) completed the study , representing a total of 393 patient years of exposure to vortioxetine . at the point of entry to the extension study , participants had a mean madrs total score of 13.58.7 . during the subsequent year , the mean madrs total score in completers decreased by approximately 8 points to 5.56.0 at week 52 ( oc ) and the proportion of responders rose from 63% to 94% . remission rate in completers ( 42% at the start of the study ) had increased to 83% ( oc ) . relapse rate in those in remission at the start of the study ( n=226 ) was 9.7% . boulenger et al25 confirmed that vortioxetine was effective in preventing depressive relapse in a study of 396 patients who , after achieving remission during 12-weeks of open - label treatment with 510 mg vortioxetine , were randomized to either placebo or vortioxetine ( fixed dose of 5 mg or 10 mg as determined during the open - label phase ) . the primary efficacy variable was time to relapse ( defined on the basis of a madrs score of > 21 or clinically judged lack of efficacy ) . overall , fewer patients ( 13% versus 26% ) relapsed on vortioxetine than on placebo ( p=0.013 ) . nausea was the only side effect that occurred significantly more often with vortioxetine than with placebo during the double - blind phase of the study . henigsberg et al21 reported that vortioxetine was generally well - tolerated ; the most common adverse events associated with it were nausea , headache , and dizziness . alvarez et al20 noted higher adverse - event - related withdrawal rates on venlafaxine ( 14% ) than for either dose of vortioxetine ( 3% on 5 mg and 7% on 10 mg ) or for placebo ( 4% ) . sexual dysfunction on vortioxetine was at a similar rate to that found on placebo . in keeping with this , baldwin et al17 reported sexual dysfunction was present in very few participants ( 2%4% ) at all three vortioxetine doses they studied , compared with 14% of those on duloxetine . in their comparison with agomelatine , hggstrm et al22 found that vortioxetine was better tolerated overall ( adverse - event - related withdrawal dates of 5.9% versus 9.5% ) . katona et al23 found that the adverse - event - related withdrawal rates were 5.8% for vortioxetine compared with 2.8% ( placebo ) and 9.9% ( duloxetine ) . nausea was the only adverse event with a significantly higher incidence on vortioxetine ( 21.8% ) than placebo ( 8.3% ) . in contrast , the incidence of nausea , constipation , dry mouth , hyperhidrosis , and somnolence were all higher for duloxetine than placebo . theunissen et al26 examined its effects ( at a dose of 10 mg / day ) on driving , cognitive , and psychomotor performance ( in a randomized controlled comparison with mirtazapine 30 mg / day and placebo ) in 24 healthy subjects over a 15-day period . vortioxetine did not cause any impairment in any of the measures at either of the time points ( day 2 and day 16  ie , the morning after the last dose ) . in contrast , mirtazapine ( which is of course relatively sedating ) was associated with cognitive and psychomotor impairment on day 2 , but this was no longer apparent on day 16 . this appears to have  knock - on  effects on other neurotransmitters implicated in the causation and maintenance of depressive disorders . vortioxetine is well - tolerated and appears to have relatively little potential for adverse drug interactions . though there is no suggestion of superiority over active comparators ( and some suggestion that snris may show greater efficacy ) , most studies suggest that there is a clinically meaningful advantage in terms of tolerability older people tolerate vortioxetine well , and there is some evidence that it may have cognitive benefits .
vortioxetine is a novel antidepressant with effects on multiple 5-ht receptors and on the serotonin transporter 
 . this paper reviews preclinical and clinical evidence regarding its mechanism of action , its tolerability , and its efficacy in treating major depression . 
 clinical studies indicate that vortioxetine is effective in the treatment of major depression , though there is no suggestion of superiority over active comparators . there may be a clinically meaningful advantage in terms of tolerability .