A Review of the Evidence for the Efficacy and Safety of Trazodone in Insomnia

Introduction

Major depressive disorder (MDD) is a mutual psychiatric status characterized past depressed mood combined with psychological and vegetative changes, such as sleep and/or ambition disturbances, fatigue, loss of motivation, feelings of guilt and despair, difficulties in maintaining mental focus, and suicidal thinking and behavior (^{Kelliny et al., 2015}). The WHO estimates that major depression affects approximately 350 one thousand thousand people worldwide and is one of the leading causes of global disability (^{Marcus et al., 2012}). According to recent projections, MDD will ascent to be amongst the top 3 disabling conditions in the earth by 2030, together with HIV/AIDS and ischemic heart illness (^{Mathers and Loncar, 2006}).

Co-ordinate to the electric current guidelines, a successful treatment for MDD includes the achievement of symptomatic remission and functional recovery (^{Davidson, 2010}). Nevertheless, evidence from trials and clinical practice has shown that the efficacy of antidepressants is suboptimal. Indeed, approximately 30–40% of patients accomplish full remission afterward a unmarried course of treatment, and 30%, although achieving a clinically significant response, bear witness residue symptoms with increased take a chance of relapse and affecting the social functioning (Katona and ^{Katona, 2014}).

However, antidepressants still play a crucial role in the handling of MDD, provided that adherence to medications is guaranteed. Indeed, low adherence is widely recognized as one of the master reasons for treatment failure and is associated with an increased risk of relapse and recurrence (^{Ho et al., 2016}). Evidence from clinical studies show that adherence rates are generally depression in patients with MDD, in some cases every bit low every bit 50% (^{Melartin et al., 2005 ; Cantrell et al., 2006 ; Akincigil et al., 2007 ; Alekhya et al., 2015a ; Alekhya et al., 2015b}). This is mainly because mood disorders impairing cerebral focus, energy, and motivation might bear upon the willingness and ability of patients to maintain the handling (^{DiMatteo et al., 2000}). The occurrence of treatment-related side effects, such equally weight gain, sexual dysfunction, nausea, headache, and sleep disturbances, is also common and may influence treatment adherence.

In this context, a simplified daily regimen represents a clinical reward, and information technology may be practical to increment treatment success rates in depression (^{Yildiz et al., 2004}). In fact, information technology is a rule that the fewer the daily doses, the improve the compliance (^{Claxton et al., 2001}). The American Psychiatric Association practice guidelines for the treatment of patients with MDD report that well-nigh clinicians prefer products with one time-daily dosing, which may exist less oft associated with withdrawal symptoms (^{Gelenberg et al., 2010}). Premature discontinuation of medication is usually associated with a poorer outcome in the treatment of mood disorders. It has been observed in clinical practise that adherence, simplicity, and efficacy usually go together (^{De las Cuevas et al., 2014}).

Trazodone hydrochloride, a triazolopyridine derivative antidepressant drug interim through 5-HT receptors and inhibiting the 5-HT transporter, is the kickoff member of the serotonin antagonist and reuptake inhibitor (SARI) class (^{Stahl, 2009}). Trazodone is a multimodal antidepressant (^{Bortolotto et al., 2017}); information technology binds with loftier analogousness to serotonin 5-HT_2A receptors, where it acts as an adversary, and has moderate analogousness for the five-HT transporter (^{Stahl, 2009}). It also shows activity at 5-HT_1A and 5-HT_2C receptors, acting as a weak agonist and an adversary, respectively (^{Stahl, 2009 ; Ghanbari et al., 2010}). Due to its dose-dependent pharmacological deportment, trazodone has been besides defined equally 'multifunctional', exerting hypnotic actions by blocking 5HT_2A and α1 adrenergic receptors at low doses. Its antidepressant deportment are instead accomplished past acting at 5-HT receptors with high analogousness and by blocking serotonin transporter (SERT) at college doses (^{Stahl, 2009}).

Trazodone was compared to several other antidepressants, including tricyclics, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors. Overall, it was shown to be an constructive and well-tolerated antidepressant (^{Fagiolini et al., 2012}).

A new controlled release conception of trazodone, allowing a once-a-day assistants due to the use of the Contramid engineering, was developed with the aim of enhancing handling compliance and of reducing both the plasma summit concentration and dosing frequency. The pharmacokinetic profile of trazodone OAD (once-a-twenty-four hour period) is characterized by a slow increment of plasma level with a single low and delayed pinnacle followed past a slow decline in plasma concentration. This is an advantage of the new formulation, since loftier trazodone peak plasma levels may be associated with the occurrence of adverse furnishings, such equally somnolence or hypotension, especially during the first weeks of treatment. These adverse effects might limit the treatment tolerability and compliance in patients with depression (^{Fagiolini et al., 2012}).

After a half dozen-week treatment period, a mean daily dose of trazodone OAD 310 mg was significantly more constructive than placebo in a randomized, double-blind study performed in 412 patients with MDD (^{Sheehan et al., 2009b}). Compared to placebo, the antidepressant consequence of trazodone OAD was significant every bit measured by the Hamilton Depression Rating Calibration (HAM-D-17) starting from the commencement week of treatment and was maintained throughout all study visits (^{Sheehan et al., 2009b}).

The aim of the nowadays study is to compare the efficacy and safety of trazodone OAD with that of venlafaxine XR (extended-release).

Materials and methods

Study design

This was a randomized, active-controlled, double-bullheaded, parallel-group study (ClinicalTrials.gov Identifier: NCT02086929) (Supplementary Fig. 1, Supplemental digital content 1, https://links.lww.com/ICP/A70).

The study was performed between December 2012 and Apr 2014. Patients were enrolled in 31 study centers beyond Europe (two in Austria, nine in the Czech republic, half-dozen in Italian republic, seven in Romania, half dozen in Slovakia, and one in Espana). The written report was conducted in compliance with the International Briefing on Harmonization Guidelines on General Considerations for Clinical Trials and the Declaration of Helsinki as adopted by the 18th Globe Medical Association (WMA) Full general Associates in 1964 and with subsequent revisions. All patients provided written informed consent. Written approval from all relevant Review Boards/Ethics Committees was obtained earlier the commencement of the study, and the study sponsor was compliant with the National Drug Agency requirements of each land involved in the report. The trial was performed in compliance with the Good Clinical Practice guidelines.

A total of x visits were scheduled: ane in the Pretreatment Stage and 9 in the double-blind Treatment Phase. Efficacy and rubber evaluations occurred at Visit ii (baseline), Visit 3 (seven days mail-randomization; D7), Visit four (D21), Visit 6 (D35), and Visit 9 (D56). Patients receiving increased dosages at the scheduled visits (Visit 4 and Visit six) were strictly monitored for condom with farther visits at Twenty-four hour period 28, 42, 49 (Visits v, vii, viii, respectively).

During the pretreatment phase, patients signed the informed consent form and underwent initial screening. Potential candidates were instructed to discontinue antidepressants or prohibited medications for a wash-out period specific to let a taper schedule based on 5 elimination half-lives of the medication used. On the final 24-hour interval of the pretreatment phase, patients were evaluated for the final eligibility, and those qualified were randomly allocated to trazodone OAD 300 mg/mean solar day (one calendar week of tapering with trazodone OAD 150 mg/mean solar day) or to venlafaxine XR 75 mg/twenty-four hour period once daily, and treated for 8 weeks.

After three and v weeks of treatment, the dose was increased (in increments of 75 mg/day) up to 225 mg/day for venlafaxine XR and 450 mg/day for trazodone OAD in nonresponding patients. If symptoms or adverse events (AEs) became intolerable for the patient, dose adjustments were attempted after one week of dose increase.

Patients divers every bit responders at the final visit could proceed treatment with the respective formulations currently available on the marketplace. Patients not responding to treatment at the final visit tapered the study medication over 1–three weeks according to the maximum dose reached during the report. These patients were monitored for safety throughout the tapering flow (Visit 10).

If a patient discontinued early, he/she was asked to return to the clinic for the treatment early termination visit (TETV) as shortly as possible, but no later than ane week after discontinuation. All efficacy and safety evaluations were performed at the TETV.

If the treatment was judged unsuccessful and/or the tolerability unsatisfactory later on dose adjustments, patients were discontinued from the study by the investigator and were started on an appropriate antidepressant therapy.

Inclusion and exclusion criteria

Male person and female outpatients (18–75 years) who met the Diagnostic and Statistical Transmission of Mental Disorders, 4th edition (DSM)-Four criteria for MDD on the basis of the Mini International Neuropsychiatric Interview and 17-particular HAM-D score ≥ 18 at both screening and baseline visits, together with a decrease not >twenty% between screening and baseline were eligible for inclusion. Patients had symptoms of low for ≥1 month before screening (Visit 1) and were legally capable of giving written informed consent to participate in the study. Women of childbearing potential had to agree not to beginning a pregnancy from the fourth dimension of signing the informed consent upwards to thirty days subsequently the last assistants of the investigational production.

Exclusion criteria included the following: whatever experimental psychotropic or primal nervous system (CNS) treatment within the past 60 days; known hypersensitivity to venlafaxine or trazodone or their excipients; use of venlafaxine or trazodone within the previous vi months; acute, or chronic, or recurrent medical conditions that might affect/jeopardize the study results; pregnant liver or renal disease; myocardial infarction within 6 months of the start of double-blind handling; history of risk factors for Torsade de Pointes; clinically relevant laboratory values of electrolytes outside of the normal range; concomitant treatment with drugs known for QT prolongation, or with drugs producing hypokalaemia, or diuretics; QTcF interval >450 ms at the screening ECG. Patients with a history of major depression resistant to medical treatments, at acute risk of suicide (HAM-D, benchmark 3 with a value ≥three), with a history of seizure events, alcohol or psychoactive substance abuse or addiction during the last year, or a positive urine drug screen for CNS-agile drugs at screening (Visit 1) were also excluded. The presence of whatsoever principal psychiatric disorder other than major depression, history or presence of bipolar disorder, whatever psychotic disorder, or a mental disorder due to full general medical conditions, utilise of antipsychotic drugs within 2 months before the baseline visit (Visit two), apply of whatever anxiolytic or sedative-hypnotic drug inside 7 days before the baseline visit and during the written report (except stable depression doses of benzodiazepines for insomnia), employ of any psychotropic drug or CNS-agile substance inside 7 days before the baseline visit, or the utilize of any nonpsychotropic drug with psychotropic furnishings within seven days before the baseline visit (unless a stable dose of the drug had been maintained for at least i month; iii months for thyroid or hormonal medications) were not immune. Pregnancy, lactation; electroconvulsive therapy within 30 days before the screening visit, concomitant treatment with cytochrome P450 3A4 (CYP3A4) inhibitors, hyperthyroidism, outset or discontinuation of psychotherapy within 6 weeks before screening; clinically pregnant abnormalities on physical examination, vital signs, ECG, laboratory tests at the screening visit, treated or untreated supine systolic claret pressure level > 160 mmHg or supine diastolic claret pressure level > 90 mmHg at screening or baseline, inability to comply with the treatment program, or a relevant relationship to the investigator or his/her deputies were additional exclusion criteria. (for full inclusion/exclusion criteria, see Supplementary Appendix 1, Supplemental digital content 2, https://links.lww.com/ICP/A71).

Randomization and blinding

Patients were automatically assigned an identification number by an Interactive Web Response System (IWRS) at the screening assessment (Visit 1). At the finish of the pretreatment stage, patients meeting the eligibility criteria were randomized to trazodone OAD or venlafaxine XR by the IWRS system. Neither the investigators nor the patients were aware of the handling assigned. To maintain the blinding weather of the study, trazodone OAD tablets and venlafaxine XR capsules were inserted into capsules having an identical advent.

Efficacy and rubber measures

The primary study endpoint for clinical efficacy was the mean change from baseline in HAM-D score at the last visit. Secondary study endpoints were every bit follows: (i) mean change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) score at the concluding visit; (2) Clinical Global Impression-Severity of Disease (CGI-South) and Clinical Global Impression-Global improvement (CGI-One thousand) at Visit 9 (D56); (iii) rate of responders (defined as patients with a fifty% decrease with respect to baseline on the HAM-D score at the concluding visit), (4) rate of remitters (defined every bit patients with HAM-D score ≤ vii at the concluding visit); (v) comparative safe and tolerability of trazodone OAD vs. venlafaxine XR.

Statistical analysis

Three study populations were defined for statistical assay: the intention-to-treat (ITT) population defined equally all randomized patients who took at to the lowest degree ane dose of report medication, and having a baseline and at least 1 post-baseline HAM-D-17 total score assessment; the per-protocol (PP) population defined as all randomized patients who had no major protocol violations, completed the study flow (from V1 to V9) and had a 17-items HAM-D rating at the cease of the report period (V9) and the Safety Population, defined every bit all patients who took at least 1 dose of the study medication.

The rubber population was used for the assay of safety parameters. The ITT and PP populations were used for the analysis of efficacy parameters equally, in a noninferiority trial, the ITT and PP sets have equal importance (^{Committee for Proprietary Medicinal Products, 1998, 2000}).

Significance tests (two-sided) were performed at an alpha level of v%. Secondary and other analyses were supportive in nature. Therefore, no adjustment for multiplicity was planned. Efficacy parameters were analyzed on the ITT population using the concluding observation carried forwards imputation scheme for missing data.

The primary efficacy cease-point of the written report, the demonstration of the noninferiority of trazodone OAD vs. venlafaxine XR evaluated equally change from baseline at Visit ix on the 17-items HAM-D full score, was analyzed by an assay of covariance (ANCOVA) model with baseline as covariate and treatment and pooled centers as sources of variation. The noninferiority was fulfilled if the upper limit of the ii-sided 95% conviction interval (CI) for the deviation between treatments did not exceed the threshold of 3, representing the maximum difference of no clinical relevance (^{Sauer et al., 2003}). The change from baseline at each postbaseline visit of the HAM-D full score, of the HAM-D factors (feet/somatization, cognitive disturbance, retardation, sleep disturbance) and of the MADRS full score were analyzed by the aforementioned ANCOVA model [or assay of variance (ANOVA) if the statistical assumptions underlying the ANCOVA were non satisfied]. CGI-S and CGI-Thou were compared between groups using the Cochran-Mantel-Haenszel test stratified by pooled sites. Treatment groups were too evaluated treating the responses every bit continuous, and applying the ANCOVA or ANOVA model. Responders and remitters were compared between treatment groups by a Cochran-Mantel-Haenszel test at each visit.

AEs were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) dictionary ver. xv.1. AEs were classified as AEs started on or later on the offset study medication administration date, and AEs started before the first study medication administration appointment. Summaries of AEs started on or after the first study medication administration were presented as counts and percentages based on the number of patients exposed and compared by a Chi-square test or Fisher's exact test. Listing of pretreatment and during treatment AEs were provided past treatment grouping displaying the description reported by the Investigator, the preferred term and the system organ class. Serious AEs (SAEs), other significant AEs, and deaths were listed and discussed with patient narratives. Separate listings were provided for pretreatment SAEs and SAEs that emerged during the administration of study medication.

Each laboratory examination was presented by descriptive statistics per handling group, available visits, and alter from screening. Shift tables were calculated on the basis of Investigators' cess (normal, altered simply not clinically pregnant, altered and clinically meaning). Pregnancy tests were listed. Descriptive statistics were presented past handling group for vital signs and body weight at each visit and on the alter from baseline; 95% CIs were besides provided. The number and percentage of patients with QTcF values higher than 450 ms or showing prolongation college than 60 ms at any visit were provided and compared by a Chi-Foursquare test or Fisher's exact test. The number and pct of patients with an abnormal ECG assessed every bit clinically pregnant past the investigator were provided for each handling group at each visit.

The number and per centum of patients showing changes in the ECG evaluations with respect to the screening (from normal to abnormal) were provided for each treatment group at each visit.

Descriptive statistics on Hour, RR, PR, QRS, QT, QTcB, and QTcF were provided past treatment group at each available visit and on the changes from screening. Treatment group comparisons were performed by an ANOVA model at each visit. Changes from screening in the physical examination were reported.

Results

Effigy 1 shows the disposition of patients throughout the course of the study.

Fig. 1:

Patient disposition throughout the study.

Baseline characteristics

Patients enrolled in this study were significantly ill (moderate-to-severe depression), as measured past validated clinical inventories. There were no clinically relevant or statistically meaning differences between the treatment groups in patient demographics or clinical characteristics at baseline in all populations analyzed. Among the patients of the Safety population, 99.i% were White, the majority of patients (67.5%) had not had previous episodes of depression necessitating hospitalization, and most patients (97.v%) had no other previous symptoms of other psychiatric illnesses. Baseline demographic and clinical characteristics of the Condom population are presented in Table 1.

Table ane:

Baseline characteristics of patients

The mean baseline severity of disease measured with HAM-D-17 total score was at least moderate for both ITT and PP populations (ITT: trazodone OAD 23.7 ± 3.42, venlafaxine XR 23.eight ± 3.93; PP: trazodone OAD 23.9 ± 3.41, venlafaxine XR 24.ane ± 4.02). The baseline mean MADRS score was consequent with the HAM-D-17 total score. Approximately, half (52.2%) of patients were assessed by CGI-S as at least moderately mentally ill.

Written report medication

A full of 324 patients (166 in the trazodone OAD group and 158 in the venlafaxine XR group) were randomized, and 321 received at least one dose of the allocated handling (165 trazodone and 156 venlafaxine). At the end of the treatment menstruum, 77.6% of patients in the trazodone OAD grouping received a dosage of 300 mg, while in the venlafaxine XR grouping xc.four% of the patients received a dosage of 75 mg. The mean ± SD daily dose administered during the written report was 311.4 (48.72) mg for trazodone and 84.one (29.93) mg for venlafaxine XR.

The ITT population consisted of 314 patients (162 trazodone and 152 venlafaxine) who took at to the lowest degree one dose of the report medication and had a baseline and at least one post-baseline 17-items HAM-D full score assessment. The PP population consisted of 249 patients (122 trazodone and 127 venlafaxine) who completed the study catamenia and had the 17-items HAM-D rating at the terminal visit without major protocol violations.

Efficacy

Primary efficacy endpoint

Both treatments showed adept efficacy in terms of reduction of mean ± SD HAM-D-17 total score at the final visit compared to baseline (Fig. 2) (ITT: trazodone –12.9 ± half dozen.82, venlafaxine –xiv.7 ± half dozen.56; PP: trazodone –15.4 ± 5.32, venlafaxine –16.iv ± 5.39). The difference between treatments was on average 1.half-dozen with the 95% CI ranging from 0.4 to 2.nine in the ITT population (P = 0.010) and i.1 with the 95% CI ranging from –0.0 to two.2 in the PP population (P = 0.056). A statistically significant difference in favor of venlafaxine XR was detected in the ITT population subsequently eight weeks, whereas no difference was detected in the PP population, which represents the study population with a college level of compliance with the study procedure.

Fig. ii:

Mean full score over time in the ITT/LOCF population (a) and the PP population (b). HAM-D-17, 17-particular Hamilton Depression Rating Scale; ITT, intention-to-treat; LOCF, last ascertainment carried forrad; PP, per-protocol; *P < 0.05.

The severity of depression in both groups decreased from moderate to mild, based on the mean HAM-D-17 total score at the final visit (ITT: trazodone x.viii ± half-dozen.49, venlafaxine 9.i ± 6.00; PP: trazodone 8.five ± 4.97, venlafaxine vii.7 ± 5.07). Once once again, the PP population showed, in both groups, the best performance in terms of efficacy outcomes.

Secondary efficacy endpoints

Trazodone OAD showed an early onset of activity compared to venlafaxine XR. Indeed, a significantly college reduction in the mean HAM-D-17 score was observed in the trazodone OAD group subsequently merely 7 days of handling. This deviation was statistically significant in both the ITT and PP population (P < 0.05) (Supplementary Fig. 2, Supplemental digital content three, https://links.lww.com/ICP/A72). A summary of chief and secondary efficacy outcomes in the ITT and PP populations is presented in Table ii.

Table two:

Primary and secondary efficacy outcomes

The severity of disease decreased in both arms from moderate to mild, based on the hateful MADRS total score at the final visit (ITT: trazodone 12.7 ± 8.58, venlafaxine x.two ± 7.02; P = 0.003; PP: trazodone 9.7 ± half-dozen.37, venlafaxine 8.6 ± 5.40). A statistically significant departure in favor of venlafaxine XR was detected in both the ITT and PP population (P < 0.05). As already observed with the HAM-D-17, the PP population showed the best performance in terms of efficacy outcomes in both groups.

The alter in the mean CGI-S score from baseline showed a statistically pregnant difference in favor of venlafaxine at the concluding visit in the ITT but not in the PP population. The mean CGI-One thousand score at the final visit showed a statistically significant difference in favor of venlafaxine both in the ITT and PP population.

The rates of responders with trazodone and venlafaxine were 65.iv% and 76.three%, respectively, in the ITT population (P = 0.0396), and 82.8% and 87.4%, respectively, in the PP population (P = 0.2097). The divergence in favor of venlafaxine was statistically significant in the ITT (P = 0.0396) but not in the PP population (P = 0.2097).

In the ITT population, clinical remission occurred in 37.7% and 52.0% of trazodone- and venlafaxine-treated patients, respectively (P = 0.0068), while in the PP population remission occurred in 48.4% and 60.6% of patients, respectively (P = 0.0130). The difference in favor of venlafaxine was statistically significant in both the ITT (P = 0.0068) and the PP population (P = 0.0130).

Trazodone demonstrated a statistically significant difference in HAM-D-17 sleep disturbance scores from baseline in all visits in the PP population (meet Supplementary Table 1, Supplemental digital content 4, https://links.lww.com/ICP/A73).

Safe and tolerability

3 hundred and xx-one patients (165 in the trazodone OAD grouping and 156 in the venlafaxine XR group) who took at to the lowest degree one dose of the study medication were included in the safety population.

Three hundred and twenty-two AEs occurred in 159 patients: 161 AEs in 86 patients receiving trazodone OAD and 161 in 73 patients receiving venlafaxine XR. An overall summary of AEs is presented in Table 3. The well-nigh frequent AEs were dizziness (11.18%) and somnolence (eight.lxx%) in the trazodone group, and nausea (14.29%) and headache (11.eighty%) in the venlafaxine group. Overall, the severity of AEs experienced with both treatments was balmy-to-moderate in the majority of the cases. Two severe AEs occurred in 2 trazodone-treated patients, and seven astringent AEs occurred in four patients of the venlafaxine group.

Table 3:

Summary of agin events in the safety population

Two hundred and fifty-4 AEs were judged by the investigators as related to the investigational medications (i.e. certain, probable/likely, possible): 121 AEs in 67 patients treated with trazodone and 133 AEs in 63 patients treated with venlafaxine. Five SAEs, including ane death in the venlafaxine group, occurred during the written report. They occurred in iii patients of the trazodone grouping and one patient of the venlafaxine grouping (Table iii).

Statistically significant differences betwixt the two treatment groups were found in the changes of ECG parameters from the screening at postrandomization visits. At the terminal visit, both groups were significantly different in the changes from screening in the following parameters: QTcF, QT, RR, and QRS. 11 patients in the trazodone OAD grouping and six patients in the venlafaxine XR group showed QTcF values higher than 450 ms during the study or prolongation higher than lx ms at any visit with respect to the screening value. This difference between the two treatment groups was not statistically significant.

Discussion

The aim of the written report was to confirm that trazodone OAD is a valid therapeutic option in patients suffering from MDD. The efficacy and prophylactic of trazodone were previously tested vs. venlafaxine in two double-bullheaded studies, showing comparable efficacy and safety outcomes in patients with depressive disorders (^{Cunningham et al., 1994 ; Florkowski et al., 2005}).

Patients enrolled, who had moderate-to-astringent depression, showed a pregnant reduction of depressive symptoms in the HAM-D-17 and MADRS total scores at the final visit, in both treatment groups.

As required past the EMA guidelines on depression (EMA/CHMP/185423/2010 Rev. 2, 2013), besides statistically significant results, the incorporation of responder/remitter analyses permits the acceptable assessment of the clinical relevance of results. In this study, both treatments showed high response and remission rates, allowing the study results to be defined as robust and clinically meaningful, in accordance with the European guidance.

The venlafaxine group showed greater efficacy in terms of the primary and secondary endpoints after 8 weeks, in particular considering the responders and remitters' rates.

As expected, for both drugs, ameliorate efficacy outcomes were observed in the PP population, which represents the study population with the higher level of compliance with the study procedure and medication.

Both antidepressants showed proficient performance compared to the literature information, since the response rate in the trazodone and venlafaxine arms were higher than that observed with citalopram (47%) after 14 weeks of treatment in the largest 'existent-earth' study on the handling of nonpsychotic depression, the STAR*D trial (^{Trivedi et al., 2006}).

From a clinical perspective, both trazodone and venlafaxine showed a HAM-D-17 total score at the final visit comprising between 7 and 17, indicating a reduction of the symptoms of depression to within the mild depression range (^{Cusin et al., 2010}).

The results of this trial confirmed the early onset of action of trazodone that was effective later on only 7 days of treatment. The early onset of action is a specific feature of trazodone, previously observed in a placebo-controlled written report (^{Sheehan et al., 2009b}) and in an observational report (^{Češková et al., 2018}). It can be assumed that the fast response to trazodone is achieved thanks to the combination of SERT inhibition with v-HT_1A receptor fractional agonism (^{Montalbano et al., 2019}). In a post-hoc analysis of the placebo-controlled report that analyzed whether the antidepressant response to trazodone OAD was associated with an early improvement in indisposition, it was confirmed that the antidepressant event of trazodone was robust and largely contained of the known effects of trazodone on insomnia (^{Sheehan et al., 2009a}).

Since compliance and treatment adherence are crucial aspects of the outcome of MDD treatment, an early onset of antidepressant activity is clinically important. Indeed, antidepressants that lead to a rapid comeback of depressive symptoms inside a few days, and whose furnishings are sustained in fourth dimension, would have an important impact on public health and on the life of MDD patients (^{Machado-Vieira et al., 2008}). A delayed onset of action could mean prolonged disability and could atomic number 82 to an increased risk of suicide (^{Tylee and Walters, 2007}). In a recent study, it was found that the issue of medication compliance straight afflicted the recurrence charge per unit of depression (^{Cheng et al., 2016}).

Compared to venlafaxine, trazodone demonstrated a statistically significant departure in HAM-D-17 sleep disturbance scores in almost all visits in both the ITT and PP populations, suggesting its greater efficacy in the treatment of MDD patients experiencing secondary indisposition. This is another specific characteristic of trazodone, previously reported in double-blind placebo-controlled and active-controlled studies (^{Kasper et al., 2005 ; Munizza et al., 2006}). It has been observed that sleep-related disturbances, such as difficulty in initiating or maintaining sleep, are often not resolved or even worsened past antidepressant treatments. An antidepressant able to reduce sleep disturbance in depression may improve the quality of life of patients, targeting a symptom that can strongly affect depression relapse and recurrence (^{Nutt et al., 2008}).

In general, reported AEs were as expected and mild-to-moderate in severity, and more than 90% of the AEs were recovered/resolved at the last visit. The virtually frequent AEs were dizziness and somnolence in the trazodone group, and nausea and headache in the venlafaxine group. This finding reflects the different pharmacological characteristics of trazodone and venlafaxine. As expected, both treatments influenced ECG parameters. Nonetheless, no patients experienced ECG alteration judged as 'abnormal and clinically meaning' across the study.

The chief limitation of this report is the lack of a placebo arm and the wide margin set for defining the noninferiority analysis. Withal, the results observed in this trial confirmed the evidence from comprehensive review of the literature that venlafaxine tin can be considered amidst the most effective antidepressants (^{Cipriani et al., 2018}) and reproduced the well-known efficacy and safety profile of trazodone, in particular the early onset of action and the positive consequence on sleep disturbances, which are specific characteristics of the drug.

In conclusion, both trazodone OAD and venlafaxine XR proved to exist effective antidepressants in patients with moderate to severe MDD. Trazodone OAD was shown to achieve an early response and good efficacy on sleep parameters, although venlafaxine XR was more than effective than trazodone OAD in terms of per responder and remitter rates, confirming data from the literature showing that it may be superior to conventional antidepressants in astringent depression.

Acknowledgements

The authors thank Ray Hill, an contained medical writer, for English language language editing and medical writing support before submission. This assistance was funded past Aziende Chimiche Riunite Angelini Francesco S.p.A., Italy.

We admit the study investigators: Prof. Siegfried Kasper, Dr. Konstantinos Papageorgiou, Dr. Christoph Kraus, Dr. Sergio Rosales-Rodriguez, Dr. Marie Spies, Dr. Elena Akimova, Dr. Margot Schmitz, Dr. Nicole Stadler-Goldmann, Dr. Elisabeth Freydl, Mrs. Verena Riegler, Mrs. Jana Goldmann, Dr. Martin Anders, Dr. Hana Vanova, Dr. Jaroslav Lestina, Dr. Judita Strasrybkova, Dr. Jiri Pisvejc, Dr. Jan Drahozal, Dr. Klara Semeradova, Dr. Eva Soukupova, Dr. Nada Soukupova, Dr. Ales Urban, Dr. Jiri Masopust, Dr. Jaroslav Hronek, Dr. Miroslava Synkova, Dr. Slavomir Pietrucha, Dr. Kamila Marholdova, Dr. Erik Herman, Dr. Gabriela Novotna, Dr. Jiri Syrovatka, Dr. Michaela Klabusayova, Dr. Hana Lemanova, Dr. Radovan Prikryl, Dr. Maria Benitez Alonso, Prof. Filippo Bogetto, Dr. Sylvia Rigardetto, Dr. Andrea Aguglia, Dr. Nicolò Bertetto, Dr. Daniela Francesca Chiodelli, Prof. Eugenio Aguglia, Dr. Carmen Concerto, Dr. Francesca Magnano San Lio, Dr. Maria Cinconze, Prof. Massimo Casacchia, Dr. Chaira Di Venanzio, Prof. Rocco Pollice, dr. Lorenzo Annecchini, Prof. Paolo Girardi, Dr. Roberto Brugnoli, Dr. Daniele Serata, Dr. Juliana Fortes Lindau, Dr. Matteo Caloro, Prof. Roberto Quartesan, Dr. Patrizia Moretti, Dr. Norma Verdolini, Dr. Luca Pauselli, Prof. Andrea Fagiolini, Dr. Arianna Goracci, Dr. Silvia Di Volo, Dr. Claudia Martorelli, Dr. Simone Bolognesi, Dr Camelia Petcu, Dr. Ioana Silion, Dr. Juliana Alexandra Cozac, Dr. Vasile Chirita, Dr. Alexandra Bolos, Dr. Irina Stanciu-Sucio, Dr Alexandru Tiugan, Dr. Claudia Tiugan, Dr Malina Simu, Dr. Mihaela Rosca, Dr. Mihai Ardelean, Dr. Gabriela Buicu, Dr. Octavian Cosmin Popa, Dr. Theodor Moica, Dr Cosmina Muntean, Dr. Adela Bunea, Dr. Abdul Mohammad Shinwari, Dr. Zita Shinwariova, Dr. Monika Biackova, Dr. Pavol Balasic, Dr. Peter Molcan, Dr. Dagmar Dziakova, Dr. Jana Greskova, Dr. Stanislava Harcarova, Dr. Zuzana Vodova, Dr. Eva Janikova, Dr. Nada Lovichova, Dr. Eva Pálová, Dr. Erika Pálová.

Conflicts of interest

Umberto Albert is/has been a consultant and/or a speaker from Angelini, FB-Health, Janssen, Lundbeck, Otsuka, Recordati. Andrea Fagiolini is/has been a consultant and/or a speaker and/or has received research grants from Allergan, Angelini, Aspen, Boehringer Ingelheim, Doc Generici, FB-Health, Italfarmaco, Janssen, Lundbeck, Mylan, Otsuka, Pfizer, Recordati, Sanofi Aventis, Sunovion, Vifor. Siegfried Kasper received grants/research back up, consulting fees and/or honoraria within the last three years from Angelini, AOP Orphan Pharmaceuticals AG, Celgene GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH, KRKA-Pharma, Lundbeck A/Due south, Mundipharma, Neuraxpharm, Pfizer, Sage, Sanofi, Schwabe, Servier, Shire, Sumitomo Dainippon Pharma Co. Ltd., Sun Pharmaceutical Industries Ltd. and Takeda.

Laura Ferrando has received honoraria from Angelini. Erik Herman has received honoraria from Angelini, Janssen Research and Development.

The study was sponsored by Aziende Chimiche Riunite Angelini Francesco S.p.A., Italy.

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Keywords:

antidepressant; depression; major depressive disorder; trazodone; venlafaxine

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