The Role of Vortioxetine in the Treatment of Depressive Symptoms in General Hospital Psychiatry: A Case-Series and PRISMA-Compliant Systematic Review of the Literature

Depressive symptoms are a customary finding in hospitalized patients, particularly those who are undergoing long hospitalizations, underwent major surgical procedures or suffer from high levels of multimorbidity and frailty. The patients included in this case series shared high degrees of frailty-complexity and were evaluated within the ordinary consultation and liaison psychiatry service of the University Hospital in Pisa, Italy, from September 2021 to June 2023. Patients were administered at least one follow-up evaluation after a week and before discharge. To relate this case series to the extant literature, a comprehensive systematic review of vortioxetine safety and efficacy was performed. None of the six patients included developed serious safety issues, but one patient complained of mild-to-moderate nausea for some days after the vortioxetine introduction. Five out of six patients exhibited at least a slight clinical benefit as measured by the clinical global impression scale. Of the 858 entries screened via Scopus and Medline/PubMed, a total of 134 papers were included in our review. The present case series provides preliminary evidence for vortioxetine’s safety in this healthcare domain. The literature reviewed in this paper seems to endorse a promising safety profile and a very peculiar efficacy niche for vortioxetine in consultation and liaison psychiatry.


Introduction
Mood symptoms are highly prevalent in hospitalized patients and are often mutually associated with various medical comorbidities [1,2].The complex polypathology of some of these inpatients poses an arduous challenge for specialists in the context of consultation and liaison (CL) psychiatry.As a matter of fact, the greater part of the available psychotropic agents entails a certain amount of risk linked to specific organ functions (e.g., heart repolarization time or haematological toxicity).Clinicians have to face a daily, more or less implicit, multivariate analysis to choose the best drugs for each particular case in terms of risk-benefit ratios [3].Furthermore, the comorbid physical illnesses of these patients often determine pharmacokinetic and pharmacodynamic alterations that may increase the risk of side effects and/or interactions.Moreover, methods of therapeutic drug monitoring (TDM) are not available or not routinely performed for every single antidepressant [4].The subsequent impossibility of monitoring systemic concentrations of drugs daily and assessing the pharmacokinetic phenotype represents a further major setback in CL psychopharmacology.
Vortioxetine is a relatively novel antidepressant developed by Lundbeck in 2002, with the experimental name Lu-AA21004 [5].It was approved in September 2013 by the Food and Drug Administration (FDA) and in December 2013 by the European Medicines Agency (EMA).It is commonly classified as a serotonin modulator and stimulator (SMS) or a multimodal antidepressant.Its pharmacodynamic profile is unique, sharing a serotonin transporter (SERT) blocking activity with Selective Serotonin Reuptake Inhibitors (SSRI) and adding a host of modulatory activities on serotonin receptors (5-HT).Of primary importance among these effects is that the 5-HT1A agonist and the 5-HT3 antagonist activities are considered key in reducing the classical latency of action of most antidepressants and ameliorating cognitive symptoms [6,7].Vortioxetine is also a 5-HT1B partial agonist, 5-HT1D antagonist and 5-HT7 antagonist.It is fairly bioavailable when administered orally (about 75%), and its terminal half-life approximately amounts to 66 h [8].It is approved for prescription at 5 mg, 10 mg, and 20 mg daily doses, although caution should be applied in patients older than 65 for lack of data.
Vortioxetine seems a promising candidate for a favourable risk-benefit ratio in the treatment of depressive syndromes in hospitalized patients with a heavy burden of medical comorbidity [9].A 2016 meta-analysis including 12 randomized controlled trials (RCTs) and 1508 patients showed that vortioxetine was associated with a placebo-level incidence (1.2%) of serious treatment-emergent adverse events (TEAEs) in patients older than 55 [10].Accordingly, this meta-analysis found no rate difference between vortioxetine and placebo in crucial variables such as changes in blood pressure, heart rate, electrocardiographic (ECG) intervals, liver markers and body weight.The most common TEAE are nausea and vomiting, whose incidence resulted in more or less twice as high for all-dose vortioxetine compared to placebo.Consistently, more up-to-date review accounts report similar results as to the vortioxetine safety and tolerability [11].
Considering this favourable efficacy/tolerability profile, the apparent paucity of studies addressing the use of vortioxetine in general hospital psychiatry is quite surprising.With this work, we tried to provide an innovative contribution to the subject using a twofold strategy.First, we present a case-series sample of multimorbid inpatients hospitalized for non-psychiatric conditions whose indication for psychiatric evaluation was depressive symptoms and whom we treated with different doses of vortioxetine.Second, we have performed a systematic PRISMA-compliant review to take stock of the available information, relate our experience with the current literature and outline possible paths for future research.

Case Series
All of the patients included in this case series were assessed within the ordinary clinical activity of the consultation and liaison (CL) psychiatry service of the Pisa University Hospital (AOUP).Relevant first consultations were administered from September 2021 to June 2023.Patients were included considering the complexity of their general medical condition in comorbidity with depressive symptoms developed or recognized during the course of their hospitalization.Inclusion criteria were: (1) hospitalization for any medical condition; (2) two or more medical comorbidities; (3) a diagnosis of "Frailty Syndrome" according to the criteria operationalized by Fried et al. [12]; (4) a psychiatric consultation request for depressive symptoms; (5) eligibility for antidepressant treatment with vortioxetine (adult, non-pregnant patient); (6) at least one week of observation after vortioxetine introduction; (7) vortioxetine dose titrated to at least 5 mg per day; (8) no other antidepressant in combination (other classes of psychotropics were allowed).
Information about patients (personal data, diagnoses, treatments, course, and discharge) was collected from the ordinary clinical documentation (medical records and discharge letter) produced during their hospitalization, in line with the good clinical practice guidelines of the AOUP.All available data about medical diagnoses, surgical and pharmacological treatment, organ insufficiencies, blood testing, instrumental examinations and other specialistic consultations were collected upon the first psychiatric consultation.A complete psychiatric examination was performed, a clinical global impression (CGI) Field [13] severity scores were recorded, and psychotropic treatment was introduced.All patients received at least one further evaluation before discharge, during which CGI severity, CGI improvement and CGI efficacy index were filled out.Complications, possible TEAEs, and mental and physical conditions at discharge were documented in the clinical diary and discharge letter.The patient had expressed their consent to the use of anonymized clinical data for research purposes at the moment of their admission.

Systematic Review of the Literature
The systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [14][15][16].Search methods and results are highlighted in Figure 1.
practice guidelines of the AOUP.All available data about medical diagnoses, surgical and pharmacological treatment, organ insufficiencies, blood testing, instrumental examinations and other specialistic consultations were collected upon the first psychiatric consultation.A complete psychiatric examination was performed, a clinical global impression (CGI) Field [13] severity scores were recorded, and psychotropic treatment was introduced.All patients received at least one further evaluation before discharge, during which CGI severity, CGI improvement and CGI efficacy index were filled out.Complications, possible TEAEs, and mental and physical conditions at discharge were documented in the clinical diary and discharge letter.The patient had expressed their consent to the use of anonymized clinical data for research purposes at the moment of their admission.

Systematic Review of the Literature
The systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [14][15][16].Search methods and results are highlighted in Figure 1.First, a comprehensive literature search on PubMed and Scopus was performed from inception to 16 June 2023, cross-checking the obtained references.The systematic search was conducted using the following search string: "Vortioxetine AND (liver disease OR hepatic disease OR hepatopathy) or vortioxetine AND (kidney disease OR renal disease OR nephropathy) OR vortioxetine AND (heart disease OR cardiovascular disease OR cardiopathy) OR vortioxetine AND (brain disease OR encephalopathy OR stroke OR dementia OR neurodegeneration) OR vortioxetine AND (inpatients OR hospital OR medical condition) or vortioxetine AND (safety OR tolerability OR adverse)".
We included all studies exploring the efficacy, safety, and tolerability of vortioxetine that supply original data.Taking as a reference the classification of clinical research proposed by Grimes and Schulz [17], we set the following inclusion criteria: descriptive observational studies (case series and case reports), analytical observational studies (cross-sectional, case-control and cohort studies), experimental studies (including open, single-blind, double-blind randomized, non-randomized, controlled and non-controlled studies).We concurrently posited the following exclusion criteria: non-English articles; studies recruiting subjects under the age of 18 years; review articles (including narrative and systematic reviews, pooled analyses, and meta-analyses); preclinical studies; study protocols; books and book chapters; expert opinions or consensus articles; other documents not exhibiting original data.

Case Series
Six patients were included in this case series, four males and two females, aged between 64 and 77 years (arithmetic mean: 71.67 years).The main comorbidities and surgical procedures for each single patient are listed in Table 1.Vortioxetine dose ranged from 5 to 10 mg per day, with four patients taking 10 mg/day and two patients taking 5 mg/day.Psychotropic (including opioids) and non-psychotropic co-prescribed medications for each patient are listed in Table 2.The severity of depressive symptoms at baseline assessed with CGI severity scale ranged from 3 ("mildly ill") to 5 ("markedly ill").The CGI-Severity scores at follow-up resulted in a sensitive reduction, ranging from 2 ("borderline mentally ill") to 4 ("moderately ill").At discharge, CGI improvement scores were as follows: four patients were scored 2 ("much improved"), one was scored 3 ("minimally improved"), and one was scored 4 ("unchanged").Considering the CGI efficacy index calculated at discharge, one patient scored 1 ("complete or nearly remission of symptoms with no side effects"), three patients scored 5 ("partial remission of symptoms with no side effects"), one patient scored 9 ("slight improvement with no side effects"), and one patient was scored 13 ("unchanged or worse with no side effects").One safety issue was recorded (nausea in patient 06).Four patients were discharged at home, one transferred to a palliative care facility, and one transferred to an intermediate care facility.Efficacy and safety data are synthesized in Table 3.

Systematic Review of the Literature
The literature research with the above-presented string yielded a total of 858 articles, of which 299 were listed on PubMed and 559 were found on Scopus.After accurate duplicate screening, 243 duplicates were found and excluded.Of the remaining 615 records, 326 were excluded according to a priori exclusion criteria after abstract screening.Primary screening was performed manually, as no automation tool was employed.Excluded items were listed and subdivided into Reviews (n = 180), Meta-analyses (n = 47), Books and book chapters (n = 13), Preclinical studies (n = 10), Children and adolescents (n = 7), Study protocols (n = 8) and Other documents (n = 61).We sought to retrieve 289 papers, and we did not manage to retrieve eight entries.The resulting 281 articles underwent eligibility assessment via full-text examination, following which 148 articles were further excluded, and 134 studies were finally included in this review.Excluded items from eligibility assessment were listed and subdivided in: Non relevant (n = 103), Review articles (n = 31), non-English articles (n = 7), Preclinical (n = 4), Retracted (n = 3).Among the included articles, 72 were experimental studies, 45 were analytical observational studies, and 16 were descriptive observational studies.Open-label extension studies articles (n = 4) were conventionally included within experimental studies.Following snowballing research, we finally added a further article in the experimental studies category (n = 73), and the total number of entries included in the review reached n = 134.Since the main purpose of this work was to assess safety and tolerability issues, efficacy-related data will only be briefly summarized in the text, while safety-related findings will be exhibited in Tables 4-8 in an orderly manner.

Experimental Studies
A total of 73 records were included in this macro-category.Among these, 48 studies dealt with the efficacy and tolerability of vortioxetine in the treatment of major depressive disorder.For analytical purposes, these studies were subdivided into (1) placebo-controlled studies without active reference and (2) controlled trials with active reference.Placebocontrolled studies without active reference (n = 25) were conducted starting in 2007.Among the studies (n = 12) that investigated the acute response to vortioxetine in major depression (6-, 8-and 12-week designs), four trials found a statistically significant advantage compared to placebo [18][19][20][21], two showed mixed results [22,23], and six provided no statistical difference between treatment and placebo [24][25][26][27][28], including one trial involving depressed patients with Alzheimer's disease [29].Three post hoc analyses (n = 3) based on one positive trial conducted in Japan found (a) that patients obtaining an early partial improvement with vortioxetine were more likely to be responders/remitters at 8 weeks [30]; (b) that vortioxetine was effective also on anxiety and anhedonic symptoms [31,32].
No food effect on the pharmacokinetics of vortioxetine.

Chen et al., [83] / /
Vortioxetine exposure tends to be about 25% higher in the elderly, blacks and females.Severe hepatic or renal impairment does not significantly alter vortioxetine disposition.
The most interesting findings were related to vortioxetine's safety and tolerability in comparison with other agents.Throughout all of the experimental studies reviewed here, the most commonly reported TEAE during vortioxetine treatment was nausea, whose frequency was often significantly higher than under placebo.Other very commonly reported TEAEs were diarrhoea, headache, dry mouth, drowsiness, fatigue, dizziness, and insomnia, but their frequencies were often not significantly higher than under placebo.Vortioxetine was generally well-tolerated, with a tolerability profile at least equal or superior compared to other antidepressants and only mild-to-moderate adverse events.Vortioxetine was very rarely associated with severe adverse events in all studies, and severe adverse events were unlikely to be related to medication.One of the most iterated findings was that vortioxetine does not impair sexual function compared to placebo, whereas other serotonergic or dual antidepressants consistently did so.Table 6 summarizes data extracted from randomized trials reporting adverse events-related inferential statistics.Finally, Table 7 gathers differences in withdrawal rates due to adverse events between vortioxetine and other antidepressant agents.
Table 7. Discontinuations due to adverse events in head-to-head trials.

Analytical Observational Studies
A total of 45 records were included in this macro-category.The greatest part (n = 18) were studies related to various clinical outcomes in patients suffering from major depres-sive disorder.All of these studies reported high levels of safety and tolerability, with no unexpected TEAEs.A number of experiences demonstrated that vortioxetine was associated with significant improvements in affective, cognitive and functional outcomes in patients diagnosed with depression [90][91][92][93][94]. RELIEVE was an international (United States, Canada, Italy, France and, independently, China) observational, prospective 24-week study protocol involving adult patients with a diagnosis of major depression initiating treatment with vortioxetine in the context of routine clinical practice.The articles derived from this design (n = 6) are reports of significantly favourable functional outcomes (Digit Symbol Substitution Test, EuroQoL 5 dimensions five levels utility index, 5-item Perceived Deficits Questionnaire-Depression, 9-item Patient Health Questionnaire, Sheehan Disability Scale) in patients after twelve (eight in the Chinese study) and twenty-four weeks of treatment with vortioxetine [95][96][97][98][99][100].
Two studies dealt with outcomes related to coronavirus disease 2019 (COVID-19): one showed that vortioxetine treatment in patients with post-COVID-19 major depression was associated with a significant reduction in depressive, cognitive and physical symptoms after three months [101]; the other reported data suggesting that vortioxetine is associated with a significantly greater reduction in depressive symptoms worsening after a COVID-19related trauma compared to sertraline and trazodone [102].An Italian study demonstrated that vortioxetine was associated with significantly higher therapeutic adherence relative to SSRIs and dual selective antidepressants (among the latter, the lowest risk of poor adherence was observed with sertraline and the highest with venlafaxine) [103].A South Korean study with 3263 patients showed that improvement with vortioxetine treatment was associated with significant reductions in mood and cognitive symptoms after eight and twenty-four weeks, without any detrimental influence of age and liver dysfunction on safety and efficacy [104].Vortioxetine was also associated with equal effectiveness in depression comorbid with GAD or alcohol use disorder [105,106].Finally, a study reported data suggesting that vortioxetine adjunct to SSRIs is associated with a significant amelioration of depressive symptoms in patients resistant to SSRIs alone [107].
VOR was associated with a higher frequency of itch, nausea, anxiety, agitation, crying, and headache compared to DUL and ESC.
VOR was associated with a lower frequency of insomnia, sexual complains, emotional numbing, and motor disorders compared to DUL and ESC.Greenblatt et al., 2018 [125] Comparison of VOR pharmacokinetics between obese subjects and control.
VOR accumulation and washout half-lives were significantly longer (about 50%) in obese individuals.
Possible pharmacodynamic interaction (serotonin toxicity) after VOR withdrawal might last longer than expected in obese individuals.FAERS database vigilance study on antidepressants risk of hyponatremia.
VOR was significantly associated with a higher risk of hyponatremia (although probably overestimated).
Relative to VOR, the risk of hyponatremia was higher for CLO, TRI, MIRT, SSRIs and SNRIs.
Miao et al., 2019 [132] Pharmacokinetics and safety of VOR in Chinese subjects compared to non-Chinese.
VOR exposure was higher in the Chinese than non-Chinese population, but difference did not reach significance.
VOR linked to a case of hyponatremia (+HCTZ) and a case of nose/urinary bleeding (+WARF).
The association between VOR and QT prolongation was non-significant.
VOR bears a lower risk of inducing QT prolongation than SSRIs.
VOR showed the lowest risk of somnolence (but no risk for levomilnacipran).
Amoxapine showed the greatest association with somnolence, probably due to highest 5HT2 A affinity.

Descriptive Observational Studies
A total of 16 records were included in this macro-category.Some of these (n = 7) include a case of hyperprolactinemia/galactorrhea [135], three cases of moderate-to-severe allergic skin reactions with petechial and pruritic features [136,137], a case of ingravescent acneiform eruption [138], a case of tinnitus [139], a case of acutely arising hemoptysis [140], and a case of restless leg syndrome [141].There was also a report relating to a case of Call-Fleming syndrome or Reversible Cerebral Vasoconstriction Syndrome (RCVS), which arose in a twenty-year-old woman seven weeks after vortioxetine introduction.The presentation was somewhat aspecific, with features of meningism (headache, photophobia), strokelike motor deficits (hemiparesis and dysarthria) and intracranial hypertension (projectile vomiting) and completely resolved in three weeks with vortioxetine discontinuation and introduction of nimodipine 120 mg/day [142].One report refers to two cases of Meige syndrome (bilateral orofacial dystonia with perioral dyskinesia and blepharospasm), which occurred in two sisters, both ten days after vortioxetine introduction and resolved a few days after vortioxetine discontinuation [143].Vortioxetine was also associated with two cases of manic switch that occurred after vortioxetine introduction (10 mg/day) in two female patients previously diagnosed with unipolar depression [144,145].One of the two patients had a history of multiple antidepressant treatments (escitalopram, fluoxetine, paroxetine, and duloxetine) without evidence of former manic reactions.
Interestingly, for our purposes, vortioxetine was found safe in the case of a suicidal attempt by overdosage (250 mg), with no changes in blood pressure, electrocardiogram, creatinine and only modest changes in g-glutamyl-transferase levels (71 U/L twenty-four hours after ingestion) [146].A case series showed that vortioxetine (10-20 mg/day) was safe and effective in a sample of nine patients suffering from epilepsy (seven cases were structural, and two were cryptogenetic) without any apparent destabilization of epileptic thresholds [147].A report found a favourable outcome after three months 10 mg/day vortioxetine treatment in a patient with rapid eye movement (REM) sleep behaviour disorder previously treated with paroxetine and melatonin without benefit [148].Another paper described a case of severe vortioxetine-induced nausea successfully treated with mirtazapine in a patient with a history of multiple SSRI trials interrupted for sexual dysfunction.The combination of vortioxetine-mirtazapine was well-tolerated, and the patient achieved significant remission of mood, anxiety and sleep symptoms without any sexual complain [149].Finally, a paper presented a case of fatally complicated hyponatremia in a 72 years old woman who had had previous episodes of severe hyponatremia with other psychotropics (fluoxetine, amitriptyline, mirtazapine and asenapine) [150].

Discussion
In this case, report, five out of six patients displayed some improvement in depressive symptoms and only one patient resulted to be unchanged.Among them, none of the subjects suffered from clinically significant TEAE after vortioxetine introduction.Vortioxetine treatment was associated with no safety issues and nausea was the only tolerability issue recorded (in patient 06).The severity of this TEAE was mild and did not entail antidepressant switch or discontinuation.All of the patients included had different and significant physical conditions that required hospitalization, but none of these conditions worsened during antidepressant treatment nor impairment of any organ system function was evidenced at follow up.This datum is even more captivating if considered in light of the significant level of frailty shared by the patients of our sample.Intriguingly, we observed a relatively short latency of therapeutic effects, consistently with preclinical evidence [151][152][153].To the best of our knowledge there are no previous studies concerning vortioxetine use in patients hospitalized for general medical conditions.Our clinical experience seems to be in line with the available evidence regarding vortioxetine tolerability and provides preliminary support for a safe employment of vortioxetine in hospitalized patients with a significant level of clinical complexity and frailty.
Our literature review suggests that vortioxetine shows an efficacy profile different from other antidepressants.It is probably less effective than many other agents in reducing mood symptoms, but it seems to have unique properties on cognitive symptoms and negative symptoms, including emotional blunting [11].Since a large part of hospitalized patients do not meet the criteria for severe depressive states (melancholia) and exhibit somewhat milder demoralization experiences close to adjustment disorders [154][155][156][157][158][159][160][161][162], wherein somatic symptoms, cognitive distortions and a weakening of attentive functions play a key role, vortioxetine could be much more tailored to these forms.On the other hand, melancholic patients are less likely to respond to vortioxetine and might need a more incisive kind of antidepressant, ideally, tricyclic antidepressants [163,164], provided that clinical conditions and access to TDM can safely allow for their employment.Thanks to its long half-life and strong serotonergic activity, vortioxetine also seems to be an option to cover the withdrawal symptoms of SSRIs.Eventually, as inferable from its very diversified pharmacodynamic profile, it seems to be of promising usefulness in patients that require a therapeutic switch for unacceptable behavioural toxicity, eminently SSRI-induced affective and motivational issues (including SSRI-induced sexual dysfunction).
All of the features above can give vortioxetine great momentum in CL psychiatry.Safety and tolerability are probably the main strengths of this drug [165][166][167].The availability of pharmacokinetics and safety data relative to subjects with severe liver and kidney dysfunction provides the clinician with sound scientific evidence for its manageability in nephropathic and hepatopathic patients, for whom many psychotropics are often precluded or heavily restricted.The probable lack of significant effects on myocardium repolarization is also a considerable strength of this drug [168].The frequency of electrolyte imbalances (namely hyponatremia) appears to be lower with vortioxetine than with SSRIs, although vortioxetine is still associated with a non-negligible amount of risk, especially when combined with sodium-wasting diuretics.Nonetheless, to implement the employment of vortioxetine as safely as possible, its most common side effects are to be carefully evaluated [169,170].These appear to occur in two main clusters: gastrointestinal TEAEs (nausea, vomiting, Diarrhoea), which are type A dose-dependent reactions and can be severe in a minority of subjects, or hypersensitivity TEAE, which are mostly type B dose-independent reactions, oftentimes involving the integumentary system (pruritic symptoms, petechial rashes) and can also be severe.The former type of TEAE is predictable, tends to subside with time, is often treatable and does not always demand drug interruption, while the latter is unpredictable, could catch the clinician unawares and requires immediate drug discontinuation.
Vortioxetine seems to be linked to both favourable and unfavourable neurobehavioural side effects: on the one hand, it seems to promote cognitive and psychomotor performance, allegedly being one of the antidepressants with the mildest risk of diurnal sleepiness; on the other, vortioxetine seems to raise a non-negligible risk of mood lability, anxiety and agitation in a minority of patients.The effects on sleep structure seem to be similar to those of SSRIs, and the risk of a decline in sleep quality should always be sought.
A great advantage of vortioxetine compared to most SSRIs is its limited potential for pharmacokinetic interactions [8].In the literature here reviewed, there was no evidence of significant inhibitory activity on any cytochrome p-450 isoenzyme, and the only remarkable interactions implicated pharmacodynamic mechanisms shared by all SSRIs, together with venlafaxine and duloxetine (increased risk of bleeding with antiplatelets or anticoagulants).Conversely, SSRIs (especially paroxetine, fluoxetine and fluvoxamine) are perpetrators of a host of interactions due to enzyme inhibition and subsequent victim drug-related overdosage toxicity.
The present work has several limitations.The largest part of these limitations is implied by the nature of the case series design (small sample, no inferential statistics allowed).Another important limitation is the lack of extant comparable data about vortioxetine use in hospitalized patients with high degrees of complexity and fragility.Furthermore, the adoption of strict inclusion criteria had a twofold consequence: on the one hand, it allowed the selection of particularly "high-risk" patients in which to assess safety and tolerability, but on the other, it might have led to a sample that does not mirror the largest part of clinical pictures encountered in daily medical practice.Another significant limitation was the relatively short observation time after vortioxetine introduction in some of our cases.

Figure 1 .
Figure 1.Identification of studies via databases and registers.Figure 1. Identification of studies via databases and registers.

Figure 1 .
Figure 1.Identification of studies via databases and registers.Figure 1. Identification of studies via databases and registers.

12 *
Difference from placebo reached statistical significance.

Table 1 .
Personal data, medical comorbidities and surgery in included patients.

Table 2 .
Vortioxetine dose and co-prescribed psychotropic and non-psychotropic medications.

Table 3 .
Efficacy and safety data.

Table 4 .
Studies evaluating functional outcomes.

Table 6 .
Randomized studies (including both active-referenced and placebo-control studies) report inferential statistics relative to safety data.

Table 8 .
Summary of observational studies concerning safety and tolerability.