Vortioxetine in the Elderly vs. Selective Serotonin Reuptake Inhibitors (SSRIs): a Pragmatic Assessment (VESPA)

Assessing Tolerability and Efficacy of Vortioxetine Versus SSRIs in Elderly Patients With Depression: a Pragmatic, Multicenter, Open-label, Parallel-group, Superiority, Randomized Trial

Background. Depression is a highly frequent condition in the elderly, with a huge impact on quality of life, life expectancy, and medical outcomes. SSRIs are commonly prescribed in elderly depressed patients and, although generally safe, they may be associated with tolerability issues. Based on available studies, vortioxetine is likely to have a promising tolerability profile in the elderly, as it does not adversely affect psychomotor or cognitive performance, wakefulness, body weight, and electrocardiogram parameters.

Objectives. Assessing the comparative tolerability, safety and efficacy of vortioxetine compared with the SSRIs as a group (including sertraline, citalopram, escitalopram, paroxetine, fluoxetine, fluvoxamine) in elderly patients affected by major depression. The primary outcome will be the withdrawal rate due to adverse events.

Methods. This is a pragmatic, multicenter, open-label, parallel-group, superiority, randomized trial. Twelve Italian Community Psychiatric Services will consecutively enrol elderly patients suffering from an episode of major depression who get in contact over a period of 12 months. By employing the web-based application RedCap, doctors will be able to randomize patients to vortioxetine or one of the SSRIs, chosen on the basis of clinical judgment, and to collect basic socio-demographic and clinical data. Trained and blinded assessors will administer five validated rating scales: Montgomery-Åsberg Depression Rating Scale (MADRS), Antidepressant Side-Effect Checklist (ASEC), EuroQual 5 Dimensions (EQ-5D), Charlson Age-Comorbidity Index (CACI), and Short Blessed Test (SBT). Patients will be assessed after 1, 3 and 6 months.

Expected results. On the basis of current literature, the investigators hypothesize vortioxetine to be superior to SSRIs as a group in terms of tolerability. As vortioxetine is expected to reduce the withdrawal rates due to adverse events of about 12% compared to SSRIs, and assuming that about 23% of the participants could be lost within 6 months, the investigators aim to enrol 358 patients (179 in each group).

Study Overview

• Status: Completed
• Conditions: Major Depressive Disorder
• Intervention / Treatment: Drug: Vortioxetine; Drug: Sertraline; Drug: citalopram; Drug: Escitalopram; Drug: Paroxetine; Drug: Fluoxetine; Drug: Fluvoxamine

• Study Type: Interventional
• Enrollment (Actual): 362
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • Catanzaro, Italy
    • Azienda Ospedaliera Universitaria Mater Domini, Università Magna Grecia
  • Roma, Italy
    • Sapienza Università di Roma, Dipartimento di Neurologia e Psichiatria
  • Verona, Italy, 37134
    • Azienda Ospedaliera Universitaria Verona

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 63 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 65 years old or above;
2. willing to participate by signing an informed consent;
3. suffering from an episode of major depression, based on clinical judgment (guided by DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) criteria);
4. treatment with an antidepressant is clinically appropriate, based on clinical/medical judgment;
5. agreement between investigator and patient to discontinue any current antidepressant, second generation antipsychotic, or lithium. According to the pragmatic design of the study, the discontinuation will be performed according to common routine practice. No specific protocols for discontinuation will be applied. All other concomitant medications are allowed;
6. uncertainty about which trial treatment would be best for the participant.

Exclusion Criteria:

1. dementia, of any type and stage, as formally diagnosed by a specialist (geriatrician, neurologist, or others);
2. diagnosis of schizophrenia or bipolar disorder;
3. clinical conditions or treatments which contraindicate the use of oral vortioxetine or SSRIs, according to clinical/medical judgment (for example conditions or treatments at high risk of bleeding, convulsions, serotoninergic syndrome, hyponatraemia, etc.). All concomitant medications will be prescribed according to routine clinical practice, in compliance with the synthesis of the product characteristics (Riassunto delle Caratteristiche del Prodotto - RCP) registered in the databank of the AIFA (Agenzia Italiana del Farmaco) (available at https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/cerca-farmaco).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: vortioxetine	Drug: Vortioxetine; Antidepressant classified under the category "other antidepressants" according to the ATC/DDD index [ATC=Anatomical Therapeutic Chemical Classification System; DDD=Defined Daily Dose]. The dose will be flexible according to the clinical evaluation and in accordance with doses reported for elderly in the Summaries of Product Characteristics (available: https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/home) (namely: 5-20 mg/day).; Other Names: Brintellix; Trintellix
Active Comparator: SSRIs	Drug: Sertraline; Antidepressant classified under the category "Selective serotonin reuptake inhibitors" according to the ATC/DDD index. The dose will be flexible according to the clinical evaluation and in accordance with doses reported for elderly in the Summaries of Product Characteristics (available: https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/home) (namely: 50-200 mg/day).; Other Names: Zoloft; Drug: citalopram; Antidepressant classified under the category "Selective serotonin reuptake inhibitors" according to the ATC/DDD index. The dose will be flexible according to the clinical evaluation and in accordance with doses reported for elderly in the Summaries of Product Characteristics (available: https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/home) (namely: 10-20 mg/day).; Other Names: Elopram; Drug: Escitalopram; Antidepressant classified under the category "Selective serotonin reuptake inhibitors" according to the ATC/DDD index. The dose will be flexible according to the clinical evaluation and in accordance with doses reported for elderly in the Summaries of Product Characteristics (available: https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/home) (namely: 5-10 mg/day).; Other Names: Entact; Drug: Paroxetine; Antidepressant classified under the category "Selective serotonin reuptake inhibitors" according to the ATC/DDD index. The dose will be flexible according to the clinical evaluation and in accordance with doses reported for elderly in the Summaries of Product Characteristics (available: https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/home) (namely: 20-40 mg/day).; Other Names: Daparox; Drug: Fluoxetine; Antidepressant classified under the category "Selective serotonin reuptake inhibitors" according to the ATC/DDD index. The dose will be flexible according to the clinical evaluation and in accordance with doses reported for elderly in the Summaries of Product Characteristics (available: https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/home) (namely: 20-60 mg/day).; Other Names: Prozac; Drug: Fluvoxamine; Antidepressant classified under the category "Selective serotonin reuptake inhibitors" according to the ATC/DDD index. The dose will be flexible according to the clinical evaluation and in accordance with doses reported for elderly in the Summaries of Product Characteristics (available: https://farmaci.agenziafarmaco.gov.it/bancadatifarmaci/home) (namely: 100-300 mg/day).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants withdrawing from treatment due to adverse events (tolerability)	Participants withdrawing from allocated treatment due to adverse events on the number of randomized patients.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants withdrawing from treatment due to any cause (acceptability)	Participants withdrawing from allocated treatment due to any cause on the number of randomized patients	6 months
Overall mortality	The number of deaths on the number of randomized patients	6 months
Number of participants with at least one episode of self-harm	Number of participants with at least one episode of self-harm on the number of randomized patients	6 months
Number of participants died by suicide	Number of participants died by suicide on the number of randomized patients	6 months
Treatment-related adverse events as assessed by the ASEC	The mean change score at the Antidepressant Side-Effect Checklist (ASEC). ASEC is a validated rating scale, administered by the clinician, measuring the occurrence and severity of 21 adverse events of antidepressants drugs. For each side effect, a score between 0 (absent) to 3 (severe) is reported. Also, the likelihood of its association with antidepressants is assessed with a yes/no question. Single side-effects scores are summed to obtain a total score (ranging from 0 to 63).	6 months
Number of participants with a reduction of at least 50% of the baseline score of the MADRS (responders)	The number of participants with a reduction of at least 50% of the baseline score of the Montgomery-Åsberg Depression Rating Scale (MADRS). The MADRS is a validated rating scale, administered by the clinician, measuring the occurrence and severity of 10 symptomatic dimensions of depression. For each dimension, a score between 0 (normal, no symptoms) to 6 (severely impaired) is reported. Single scores for each dimension are summed to obtain a total score (ranging from 0 to 60).	6 months
Efficacy on depressive symptoms as assessed by the MADRS	Mean change scores at MADRS. The MADRS is a validated rating scale, administered by the clinician, measuring the occurrence and severity of 10 symptomatic dimensions of depression. For each dimension, a score between 0 (normal, no symptoms) to 6 (severely impaired) is reported. Single scores for each dimension are summed to obtain a total score (ranging from 0 to 60).	6 months
Quality of life as assessed by the EQ-5D	Mean change scores at the EQ-5D. The EQ-5D is a validated rating scale, self-administered, measuring the quality of life according to 5 dimensions. In addition, the overall health status on the day of the interview is measured on a visual analogue scale ranging from 0 (worst possible health status) to 100 (best possible health status). When interpreting the scale, dimensions are to be considered separately and not summed in a total score.	6 months
Cognitive performance as assessed by the SBT	Mean change scores at the Short Blessed Scale (SBT). The SBT is a validated rating scale, administered by the clinician, measuring the cognitive performance. The SBT is a screening tool that aids in detecting early cognitive changes associated with dementia disorders. Further testing is warranted if dementia is suspected, the SBT should not be used to diagnose dementia. This is a weighted six-item instrument that evaluates orientation, registration, and attention.	6 months

Collaborators and Investigators

• Sponsor: Azienda Ospedaliera Universitaria Integrata Verona
• Collaborators: University of Catania

Publications and helpful links

General Publications

• Ostuzzi G, Gastaldon C, Barbato A, D'Avanzo B, Tettamanti M, Monti I, Aguglia A, Aguglia E, Alessi MC, Amore M, Bartoli F, Biondi M, Bortolaso P, Callegari C, Carra G, Caruso R, Cavallotti S, Crocamo C, D'Agostino A, De Fazio P, Di Natale C, Giusti L, Grassi L, Martinotti G, Nose M, Papola D, Purgato M, Rodolico A, Roncone R, Tarsitani L, Turrini G, Zanini E, Amaddeo F, Ruggeri M, Barbui C. Tolerability and efficacy of vortioxetine versus SSRIs in elderly with major depression. Study protocol of the VESPA study: a pragmatic, multicentre, open-label, parallel-group, superiority, randomized trial. Trials. 2020 Aug 3;21(1):695. doi: 10.1186/s13063-020-04460-6.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2019
• Primary Completion (Actual): February 28, 2023
• Study Completion (Actual): February 28, 2023

Study Registration Dates

• First Submitted: December 12, 2018
• First Submitted That Met QC Criteria: December 17, 2018
• First Posted (Actual): December 19, 2018

Study Record Updates

• Last Update Posted (Actual): May 19, 2023
• Last Update Submitted That Met QC Criteria: May 18, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: depression; elderly; SSRI; vortioxetine
• Additional Relevant MeSH Terms: Mental Disorders; Mood Disorders; Depressive Disorder; Depressive Disorder, Major; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists; Serotonin Antagonists; Anti-Anxiety Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Serotonin 5-HT3 Receptor Antagonists; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Selective Serotonin Reuptake Inhibitors; Sertraline; Citalopram; Paroxetine; Vortioxetine; Fluoxetine; Fluvoxamine; Escitalopram
• Other Study ID Numbers: 2016-0234923; 2018-001444-66 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No