Major depressive disorder (MDD) is a common condition in society, characterized by episodes and remissions, and leads to significant functional and occupational impairment. Among the most frequent symptoms of depression—also included in diagnostic criteria—are difficulties in thinking, focusing, decision-making, and sustaining activities, all of which are linked to cognitive dysfunction (A.P.A., 2013). During the acute phase of MDD, individuals experience deficits in various cognitive domains, including memory, attention, psychomotor speed, visual learning, verbal fluency, cognitive flexibility, and executive functions such as problem-solving, decision-making, and judgment. Even after depressive symptoms improve, cognitive impairments often persist (Clark et al., 2016; Lee et al., 2012). Meta-analyses have shown that euthymic patients with depression exhibit significant cognitive impairment compared to healthy controls (Bora et al., 2013). Recent evidence indicates that cognitive deficits continue even when patients are in symptomatic remission. Individuals with ongoing cognitive deficits during remission frequently fail to achieve expected improvements in social or occupational functioning, regardless of mood symptoms (Knight et al., 2018; Pan et al., 2017). Persistent cognitive dysfunction has important clinical implications, as it can impair coping abilities, increase relapse risk, and affect treatment adherence (Bora et al., 2013; Clark et al., 2016). Therefore, treatment strategies should address cognitive symptoms as well as mood improvement (Knight et al., 2018).

Depression treatment approaches generally do not prioritize the identification, monitoring, or management of cognitive deficits. Research has yet to determine whether most conventional antidepressants directly and independently affect cognitive function in adults with MDD. Currently, there is no gold standard medication specifically targeting cognitive impairment in MDD (Pan et al., 2017).

In a randomized, double-blind, placebo-controlled study assessing the effects of vortioxetine on cognitive functions in depressed adults (n = 602), vortioxetine improved all cognitive domains—including executive functions, attention, processing speed, learning, and memory—independent of therapeutic dose and clinical improvement (McIntyre et al., 2014). A meta-analysis examining vortioxetine’s effects found that it produced small to moderate improvements in cognitive functions, independent of depressive symptom changes. Vortioxetine’s unique pharmacological profile—including 5-HT (serotonin) transporter inhibition, 5-HT1A agonism, 5-HT1B partial agonism, and antagonism at 5-HT3, 5-HT7, and 5-HT1D receptors—may contribute to its beneficial effects on cognitive impairment (McIntyre et al., 2016).

In a placebo-controlled study evaluating the use of 60 mg of duloxetine daily for 8 weeks in depressed individuals over 65, duloxetine improved verbal learning and memory; however, there was no difference in attention or executive functions compared to placebo (Raskin et al., 2007). In a 12-week follow-up study involving 21 depressed participants, duloxetine treatment led to improvements in processing speed, visual and verbal learning, memory, decision-making, and response control (Greer et al., 2014). Duloxetine binds to and inhibits serotonin and norepinephrine transporters with high affinity, thereby increasing the levels of serotonin and norepinephrine in the synaptic cleft. Inhibition of the norepinephrine transporter also increases dopamine, particularly in the prefrontal cortex. Consequently, noradrenergic projections to the frontal cortex play a regulatory role in cognitive functions (Stahl, 2015).

Limitations such as the lack of standardized measurement methods for assessing cognitive functions, small sample sizes, short follow-up periods, and the absence of comparisons with healthy control groups have hindered a clear understanding of the relationship between antidepressant treatment and cognitive functions. The lack of consensus in the literature regarding the effects of antidepressant treatments on cognitive functions prompted us to conduct research in this area. This study aimed to examine the effects of duloxetine and vortioxetine—two antidepressants with different mechanisms of action that are effective in MDD—on cognitive functions.