Switching From SSRI to Desvenlafaxine on Cognitive Functioning

Major Depressive Disorder Clinical Trial

Official title:

Efficacy Of Switching From SSRI to Desvenlafaxine on Cognitive Function In Patients With an Acute Episode of Major Depression

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03432221
• Other study ID #: 2017.116
• Status: Recruiting
• Start date: April 3, 2018
• Est. completion date: June 3, 2019

Study information

• Verified date: April 2019
• Source: Corporacion Parc Tauli
• Contact: Narcís Cardoner, MD, PhD
• Phone: 0034 93 723 10 10
• Email: ncardoner[@]tauli.cat
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 36
• Est. completion date: June 3, 2019
• Est. primary completion date: June 3, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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.

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Major Depressive Disorder

Intervention

Drug:
• Desvenlafaxine
Patients included in the study will receive antidepressant treatment with desvenlafaxine. The switch from SSRI to desvenlafaxine will coincide with the baseline visit (Visit 0). The dose of desvenlafaxine will be established based on clinical judgment. As the approach will be naturalistic, the inclusion in this study will not influence the clinical choice, hence changes in the pharmacological strategy will be permitted.

Locations

Country	Name	City	State
Spain	Corporació Sanitària Parc Taulí	Sabadell

Sponsors (2)

Lead Sponsor	Collaborator
Corporacion Parc Tauli	Pfizer

Country where clinical trial is conducted

Spain, 

References & Publications (18)

Baune BT, Miller R, McAfoose J, Johnson M, Quirk F, Mitchell D. The role of cognitive impairment in general functioning in major depression. Psychiatry Res. 2010 Apr 30;176(2-3):183-9. doi: 10.1016/j.psychres.2008.12.001. — View Citation

Bora E, Harrison BJ, Yücel M, Pantelis C. Cognitive impairment in euthymic major depressive disorder: a meta-analysis. Psychol Med. 2013 Oct;43(10):2017-26. doi: 10.1017/S0033291712002085. Epub 2012 Oct 26. Review. — View Citation

Ferguson JM, Wesnes KA, Schwartz GE. Reboxetine versus paroxetine versus placebo: effects on cognitive functioning in depressed patients. Int Clin Psychopharmacol. 2003 Jan;18(1):9-14. — View Citation

Hammar A, Ardal G. Cognitive functioning in major depression--a summary. Front Hum Neurosci. 2009 Sep 25;3:26. doi: 10.3389/neuro.09.026.2009. eCollection 2009. — View Citation

Herrera-Guzmán I, Gudayol-Ferré E, Herrera-Abarca JE, Herrera-Guzmán D, Montelongo-Pedraza P, Padrós Blázquez F, Peró-Cebollero M, Guàrdia-Olmos J. Major Depressive Disorder in recovery and neuropsychological functioning: effects of selective serotonin reuptake inhibitor and dual inhibitor depression treatments on residual cognitive deficits in patients with Major Depressive Disorder in recovery. J Affect Disord. 2010 Jun;123(1-3):341-50. doi: 10.1016/j.jad.2009.10.009. Epub 2009 Nov 6. — View Citation

Herrera-Guzmán I, Gudayol-Ferré E, Herrera-Guzmán D, Guàrdia-Olmos J, Hinojosa-Calvo E, Herrera-Abarca JE. Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on memory and mental processing speed in patients with major depressive disorder. J Psychiatr Res. 2009 Jun;43(9):855-63. doi: 10.1016/j.jpsychires.2008.10.015. Epub 2009 Jan 6. — View Citation

Jaeger J, Berns S, Uzelac S, Davis-Conway S. Neurocognitive deficits and disability in major depressive disorder. Psychiatry Res. 2006 Nov 29;145(1):39-48. Epub 2006 Oct 11. — View Citation

Kiosses DN, Alexopoulos GS. IADL functions, cognitive deficits, and severity of depression: a preliminary study. Am J Geriatr Psychiatry. 2005 Mar;13(3):244-9. — View Citation

Lee RS, Hermens DF, Porter MA, Redoblado-Hodge MA. A meta-analysis of cognitive deficits in first-episode Major Depressive Disorder. J Affect Disord. 2012 Oct;140(2):113-24. doi: 10.1016/j.jad.2011.10.023. Epub 2011 Nov 15. Review. — View Citation

Levkovitz Y, Caftori R, Avital A, Richter-Levin G. The SSRIs drug Fluoxetine, but not the noradrenergic tricyclic drug Desipramine, improves memory performance during acute major depression. Brain Res Bull. 2002 Aug 15;58(4):345-50. — View Citation

Martinez-Aran A, Scott J, Colom F, Torrent C, Tabares-Seisdedos R, Daban C, Leboyer M, Henry C, Goodwin GM, Gonzalez-Pinto A, Cruz N, Sanchez-Moreno J, Vieta E. Treatment nonadherence and neurocognitive impairment in bipolar disorder. J Clin Psychiatry. 2009 Jul;70(7):1017-23. doi: 10.4088/JCP.08m04408. Epub 2009 Jun 2. — View Citation

McIntyre RS, Lophaven S, Olsen CK. A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol. 2014 Oct;17(10):1557-67. doi: 10.1017/S1461145714000546. Epub 2014 Apr 30. — View Citation

Miskowiak KW, Carvalho AF. 'Hot' cognition in major depressive disorder: a systematic review. CNS Neurol Disord Drug Targets. 2014;13(10):1787-803. — View Citation

Nierenberg AA, Husain MM, Trivedi MH, Fava M, Warden D, Wisniewski SR, Miyahara S, Rush AJ. Residual symptoms after remission of major depressive disorder with citalopram and risk of relapse: a STAR*D report. Psychol Med. 2010 Jan;40(1):41-50. doi: 10.1017/S0033291709006011. Epub 2009 May 22. — View Citation

Roiser JP, Sahakian BJ. Hot and cold cognition in depression. CNS Spectr. 2013 Jun;18(3):139-49. doi: 10.1017/S1092852913000072. Epub 2013 Mar 12. Review. — View Citation

Trivedi MH, Greer TL. Cognitive dysfunction in unipolar depression: implications for treatment. J Affect Disord. 2014 Jan;152-154:19-27. doi: 10.1016/j.jad.2013.09.012. Epub 2013 Sep 25. Review. — View Citation

Wagner S, Doering B, Helmreich I, Lieb K, Tadic A. A meta-analysis of executive dysfunctions in unipolar major depressive disorder without psychotic symptoms and their changes during antidepressant treatment. Acta Psychiatr Scand. 2012 Apr;125(4):281-92. doi: 10.1111/j.1600-0447.2011.01762.x. Epub 2011 Oct 18. — View Citation

Westheide J, Quednow BB, Kuhn KU, Hoppe C, Cooper-Mahkorn D, Hawellek B, Eichler P, Maier W, Wagner M. Executive performance of depressed suicide attempters: the role of suicidal ideation. Eur Arch Psychiatry Clin Neurosci. 2008 Oct;258(7):414-21. doi: 10.1007/s00406-008-0811-1. Epub 2008 Mar 11. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite cognitive measure	Composite z-score (Digit Symbol Substitution Test (DSST) + Rey Auditory Verbal Learning Test (RAVLT))	Change from baseline to 12 weeks
Secondary	Subjective cognitive function	Perceived deficit Questionnaire short version (PDQ-5)	Baseline, 2nd week, 4th week, 6th week, 8th week, 10th week, 12th week
Secondary	Attention	Attention (Digits subtest forward -WAIS-IV- + Trail Making Test-A, TMT-A)	Baseline and after 12 weeks
Secondary	Processing speed	Psychomotor velocity (Digit Symbol Substitution Test, DSST)	Baseline and after 12 weeks
Secondary	Verbal Memory	Memory cognitive domain explored with: - Rey Auditory Verbal Learning Test (Verbal)	Baseline and after 12 weeks
Secondary	Executive Functions	Composite score composed by: Trail Making Test-B + Phonetic fluency & semantic fluency + Wisconsin Card Sorting Test	Baseline and after 12 weeks
Secondary	Hot cognition	Emotion recognition ability explored with: - Pictures of Facial Affect (POFA)	Baseline and after 12 weeks
Secondary	Intelligence quotient	Measure of pre-morbid intelligence (Vocabulary (WAIS IV) + Block Design (WAIS-IV))	Baseline
Secondary	Depressive symptoms	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	Baseline, 2nd week, 4th week, 6th week, 8th week, 10th week, 12th week
Secondary	Anxiety symptoms	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	Baseline, 2nd week, 4th week, 6th week, 8th week, 10th week, 12th week
Secondary	Severity and improvement of depression	The Clinical Global Impression (CGI)	Baseline, 2nd week, 4th week, 6th week, 8th week, 10th week, 12th week
Secondary	Self-perceived remission status	The Remission from Depression Questionnaire (RDQ)	Baseline, 2nd week, 4th week, 6th week, 8th week, 10th week, 12th week
Secondary	Disability	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).	Baseline and after 12 weeks
Secondary	Functioning	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.	Baseline and after 12 weeks
Secondary	Sexual dysfunction	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.	Baseline and after 12 weeks
Secondary	Side effect rating scale for psychotropic drugs	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.	Baseline, 2nd week, 4th week, 6th week, 8th week, 10th week, 12th week