Switching From SSRI to Desvenlafaxine on Cognitive Functioning
Switching From SSRI to Desvenlafaxine on Cognitive Functioning
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.
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.
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.