Switching From SSRI to Desvenlafaxine on Cognitive Functioning

• Conditions: Major Depressive Disorder
• Interventions: Drug: Desvenlafaxine

• Registration Number: NCT03432221
• Lead Sponsor: Corporacion Parc Tauli

Brief Summary

Given the importance of cognitive function on depressed patients' treatment outcome and return to premorbid functioning, the effect of antidepressant drugs on cognition has become of primary concern. The aim of the present study is to assess the clinical outcome of switching from a selective serotonin reuptake inhibitor (SSRI) to desvenlafaxine on cognitive function in a Spanish sample of adults with moderate to severe major depressive disorder (MDD).

This open-label clinical study will include a total of 36 MDD outpatients receiving treatment with desvenlafaxine according to treating psychiatrist clinical judgment.

The primary efficacy endpoint will be changes from baseline to week 12 in cognitive function measured by a composite z-score comprising the Digit Symbol Substitution Test (DSST) and Rey Auditory Verbal Learning Test (RAVLT) scores. The secondary efficacy endpoints will involve depression severity, additional measures of subjective and objective cognitive function (including cold and hot cognitive function tasks), and functional status.

A matched sample of 36 healthy controls will be assessed in order to obtain reference data for all cognitive function measurements. Patients with MDD and healthy controls will be compared regarding cognitive function both at baseline and after 12 weeks.

Detailed Description

BACKGROUND

Depression is a significant contributor to the global burden of disease and affects people in all communities across the world. Today, depression is estimated to affect 350 million people. The World Mental Health Survey conducted in 17 countries found that, on average, about 1 in 20 people reported having an episode of depression in the previous year. Depressive disorders often start at a young age; drastically reduce people's functioning and often are recurring. For all these reasons, depression is the leading cause of disability worldwide in terms of total years lost due to disability.

Commonly the diagnosis and treatment of major depressive disorder is based on mood symptoms. However, cognitive impairments are often present in this disorder. In this respect, the recent Diagnostic and Statistical Manual 5 (DSM-5) highlight impairment in cognitive function as a criterion in the diagnosis of a major depressive episode (MDE) (American Psychiatric Association. At clinical level, patients frequently present subjective complaints during and after resolution of an MDE. Moreover, objective deficits measured by neuropsychological tests are also reported in different cognitive domains in cold cognitive function - executive function, processing speed, attention, learning or memory- (Hammar \&Ardal, 2009) or also in hot cognitive function -negative biases in perception, attention and memory, and aberrant reward/punishment processing-.

Different meta-analyses have demonstrated that these deficits may emerge from the first depressive episode with relevant intensification during each acute MDE persisting in some depressive patients even during the resolution of the acute episode. These deficits, both in an acute episode and in remission, have a relevant impact on clinical and functional outcomes, in the first case by reducing the chance to fully recover and in the second by increasing the risk of relapse. Moreover, cognitive deficits have shown to have a negative influence in functional performance in academic, social and working life (Lee et al., 2013,). In this context, recent studies have shown that a larger number of MDD episodes, a longer duration of illness and a poor response to antidepressant treatments might explain the maintenance of cognitive dysfunction, even in patients with some clinical response.

Persistent cognitive deficits in depression play a crucial role in some patients׳ ability to achieve a functional recovery. With this respect, cognitive function in depression is significantly also related to employment status. A preliminary study suggests that deficits in executive functioning have a mediating effect on the relationship between depression and impaired activities of daily living. Moreover, mood disorder patients with neuropsychological deficits tend to be less compliant with antidepressant treatment (Martinez-Aran et al., 2009) and show an increased risk for suicide. In this context, the identification and treatment of specific cognitive deficits may be a cardinal aspect in the achievement of depression recovery and, even more important, in the functional normalization of patients to their pre-morbid levels.

At present there is a growing interest on the role of antidepressant treatment in the modulation of cognitive deficits associated with depression. Despite the wide array of effective antidepressant agents, the knowledge on the impact of available drugs on cognitive function constitutes a relevant unmet need. Indeed, the number of studies focusing on this issue is relatively scarce and the outcome of cognitive symptoms is widely variable. Potential pro-cognitive effect of a particular antidepressant mostly relay on its specific mechanisms of action, anf in the last years the evidence accumulated have support that drug involving more targets such as dual (duloxetine) or multimodal (vortioxetine) antidepressants show more pro-cognitive properties than those with one major mechanism (SSRI).

However, the clinical studies putting cognitive dysfunction as the primary outcome in depression trials are scarce and further support of these initial promising findings of the effects of dual/multimodal antidepressants on cognition are required.

OBJECTIVES

This open-label clinical study will evaluate the clinical outcome of switching to desvenlafaxine on cognitive function of patients with major depressive disorder with inadequate response to selective serotonin reuptake inhibitor (SSRI)

\* Primary Objective

To study differences in cognitive function in moderate to severe MDD patients with inadequate response to SSRI and healthy controls at baseline and after 12 weeks of treatment with desvenlafaxine.

\* Secondary Objective

To study differences in subjective cognitive function (cognitive complains), measured by PDQ-5 at baseline and after 12 weeks of treatment with Desvenlafaxine.

To study differences in cognitive function, measured by neuropsychological tests battery (including cold and hot cognitive function) at baseline and after 12 weeks of treatment with desvenlafaxine.

To study differences in depression severity, measured HDRS-17 and CGI at baseline and after 12 weeks of treatment with desvenlafaxine.

To study changes in subjective remission and functional status measured with Remission Depression Questionnaire (RDQ) and the Short Assessement Functioning Test (FAST), respectively.

Study Timeline

• Study First Submitted: 2018-01-08
• Study First Submitted QC: 2018-02-07
• Study First Posted: 2018-02-14
• Study Start: 2018-04-03
• Status Verified: 2019-04
• Last Update Submitted: 2019-04-17
• Last Update Posted: 2019-04-18
• Primary Completion: 2019-06-03
• Study Completion: 2019-06-03

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 36

Inclusion Criteria

1. MDD Patients in whom switching to desvenlafaxine is considered by treating psychiatrist as the next treatment option.
2. MDD diagnostic confirmation with the mini-international neuropsychiatric interview (MINI) (Sheehan et al., 1998),
3. Age range between 18 and 60
4. Non-response or incomplete response to a treatment with an SSRI in the current episode.
5. Score of 18 points or higher in the Hamilton depression rating scale (HAM-D-17) (Hamilton, 1967).

Exclusion Criteria

1. Subjects will be excluded if they met criteria or had past history for the following disorders: posttraumatic stress disorder, obsessive-compulsive disorder, schizophrenia, psychotic, delusional, bipolar or substance abuse disorders. MINI will be used to exclude these potentially comorbid disorders.
2. Subjects with any present or past disease involving the nervous central system
3. A clinically significant unstable illness or clinically significant abnormal vital signs as determined by the investigator
4. Women entering the study could not be pregnant, and had to be oral contraceptive-free.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
MDD	Desvenlafaxine	Patients who met DSM-5 criteria for MDD attending the outpatient psychiatric service of the Hospital Universitari Parc Taulí. Patients must have a lack of response to SSRI (Maximize dose for adequate time), being the next therapeutic option the introduction of desvenlafaxine.

Primary Outcome Measures

Name	Time	Method
Composite cognitive measure	Change from baseline to 12 weeks	Composite z-score (Digit Symbol Substitution Test (DSST) + Rey Auditory Verbal Learning Test (RAVLT))

Secondary Outcome Measures

Name	Time	Method
Executive Functions	Baseline and after 12 weeks	Composite score composed by: Trail Making Test-B + Phonetic fluency \& semantic fluency + Wisconsin Card Sorting Test
Anxiety symptoms	Baseline, 2nd week, 4th week, 6th week, 8th week, 10th week, 12th week	The Hamilton Anxiety Rating Scale (HAM-A), to measure the severity of anxiety symptoms.; 14-17 = Mild Anxiety 18-24 = Moderate Anxiety 25-30 = Severe Anxiety
Processing speed	Baseline and after 12 weeks	Psychomotor velocity (Digit Symbol Substitution Test, DSST)
Depressive symptoms	Baseline, 2nd week, 4th week, 6th week, 8th week, 10th week, 12th week	The Hamilton Depression Rating Scale, 17 items (HDRS), designed to rate the severity of depression in patients.; 0 - 7 = Normal 8 - 13 = Mild Depression 14-18 = Moderate Depression 19 - 22 = Severe Depression \>23 = Very Severe Depression
Functioning	Baseline and after 12 weeks	Functioning Assessment Short Test (FAST); FAST: brief instrument designed to assess the main functioning problems experienced by psychiatric patients, particularly those with mood disorders. Scores \> 11(out of 75)= Impairment.
Side effect rating scale for psychotropic drugs	Baseline, 2nd week, 4th week, 6th week, 8th week, 10th week, 12th week	The UKU side effect rating scale: A Comprehensive Rating Scale for Psychotropic Drugs and a Cross-sectional Study of Side Effects in Neuroleptic-treated Patients.
Subjective cognitive function	Baseline, 2nd week, 4th week, 6th week, 8th week, 10th week, 12th week	Perceived deficit Questionnaire short version (PDQ-5)
Self-perceived remission status	Baseline, 2nd week, 4th week, 6th week, 8th week, 10th week, 12th week	The Remission from Depression Questionnaire (RDQ)
Sexual dysfunction	Baseline and after 12 weeks	The Arizona Sexual Experience Scale (ASEX): a five-item rating scale that quantifies sex drive, arousal, vaginal lubrication/penile erection, ability to reach orgasm, and satisfaction from orgasm.
Attention	Baseline and after 12 weeks	Attention (Digits subtest forward -WAIS-IV- + Trail Making Test-A, TMT-A)
Verbal Memory	Baseline and after 12 weeks	Memory cognitive domain explored with: - Rey Auditory Verbal Learning Test (Verbal)
Hot cognition	Baseline and after 12 weeks	Emotion recognition ability explored with: - Pictures of Facial Affect (POFA)
Severity and improvement of depression	Baseline, 2nd week, 4th week, 6th week, 8th week, 10th week, 12th week	The Clinical Global Impression (CGI)
Disability	Baseline and after 12 weeks	Functional disability measured with the Sheehan Disability Scale (SDS) SDS: developed to assess functional impairment in three inter-related domains; work/school, social and family life. The 3 items can also be summed into a single dimensional measure of global functional impairment that rages from 0 (unimpaired) to 30 (highly impaired).
Intelligence quotient	Baseline	Measure of pre-morbid intelligence (Vocabulary (WAIS IV) + Block Design (WAIS-IV))

Trial Locations

Locations (1)

Corporació Sanitària Parc Taulí; 🇪🇸 Sabadell, Spain