COGNITIVE FUNCTIONS AND ITS CORRELATION WITH INTERFERON - GAMMA AND SEMAPHORIN 4D LEVELS IN DEPRESSED PATIENTS TREATED WITHPAROXETINE CR / BUPROPION SR: A PILOT STUDY

INTRODUCTION

Major depressive disorder (MDD) is a severe and disabling condition and the World Health Organization estimates that by the year 2030 it will become one of the leading causes of disability worldwide [1]. Various studies indicate that MDD is often coupled with disturbance in cognitive functions. In addition, cognitive dysfunction during remission may also play an important role as it may increase the individual’s vulnerability for the first onset, maintenance and future recurrence of depressive episodes. Moreover, it has been found that impairment in affective and cognitive processing may contribute to an increased risk for the alarming rates of suicide among people with depression. [2,3,4] Although, the relationship between depression and cognitive dysfunctions is not completely understood however, both may share a closely related inflammatory aetiology. [5,6]

Depression is considered as a multidimensional disorder and various underlying mechanisms have been recognized in the patho-physiology of depression. Recently, role of inflammation has been identified as an important contributory factor in depression as elevated levels of peripheral and central pro-inflammatory markers have been found among individuals with depression. [7]

Depression is often associated with neuroinflammation, stress, impaired neurogenesis, defects in synaptic plasticity and abnormal activation of microglia. Activated microglia, which are usually involved in regulation of neuroinflammation and tissue repair are also associated with release of various pro-inflammatory cytokines and may induce and propagate inflammatory reactions throughout the brain.[8,9]

Accumulating evidence also indicate causal relationship between inflammation and cognitive decline and dementia [10]. Semaphorins belong to a family of membrane-bound and secreted molecules that also exists in a functional soluble form following proteolytic cleavage after cellular activation. Sema4D has been reported regulate the functional activity of axons in the nervous system as it had been shown to induce microglia-mediated neuroinflammation or neurodegenration in central nervous system.[11]

Serotonin (5-HT) is the most important neurotransmitter implicated in the patho-physiology of depression and it has been suggested that treatment with antidepressant drugs can modulate both mood and cognition by increasing the activity of monoamine systems. [12] Selective serotonin reuptake inhibitors (SSRIs) are used as first line drug treatment of depression. Paroxetine is the most potent selective inhibitor of serotonin reuptake into the presynaptic among the available SSRIs. It has approved indications for the treatment of major depression, obsessive–compulsive disorder, panic disorder, generalized anxiety disorder, post-traumatic stress disorder and social phobia in adults. [13]Bupropion is a norepinephrine- dopamine reuptake inhibitor (NDRI) with minimal or no direct effects on serotonin. It has been reported that drugs such as bupropion that particularly cause increase in the available levels of norepinephrine and dopamine may be also helpful to produce neurocognitive change in depressed patients. [14]

Some studies have been done to assess the efficacy of antidepressant drugs like selective serotonin reuptake inhibitors and serotonin–norepinephrine reuptake inhibitors on cognitive dysfunction in depression but the results are conflicting. [15,16]

Even on extensive search of literature we could not find out any study to be done on RUDAS score in MDD patients in India and as per our best knowledge so far no study has been done in India to assess cognitive function in MDD patients using RUDAS as cognitive tool pre and post treatment of antidepressant drugs. Furthermore, there is no study available to show association between depression and cognitive dysfunctions by measuring levels of markers IFN-γ and SEMA4D following paroxetine CR and bupropion SR treatment. Therefore, the present pilot study will be done to examine the effect of paroxetine CR (SSRI) and bupropion SR (atypical antipsychotic) on cognitive function in MDD and on the levels of IFN-γ and SEMA4D.

LACUNAE IN EXISTING LITERATURE

  

• To the best of our knowledge the literature lacks the comparative study showing the effect of antidepressant drugs i.e.  paroxetine CR (SSRI) and bupropion SR (atypical antidepressants) on cognitive functions in major depressive disorder

 

• Though studies have reported association of deranged cognitive functions and depression but there is no study determining the cognitive functions in depressed patients using RUDAS cognitive screening tool.

 

• Literature suggests the role of inflammation in depression and cognitive impairment however; there is no study that establishes a clear relationship of cognitive dysfunctions and depression with respect to inflammatory markers.

AIM

To study cognitive functions and its correlation with interferon-gamma and semaphorin4D levels inpatients of major depressive disorders treated with anti-depressant drugs paroxetine CR / bupropion SR.

 Objectives:

 Primary Objectives:

 

• To study and compare the effect of paroxetine CR / bupropion SR on cognitive functions in patients of MDD before and after treatment using Rowland Universal Dementia Assessment Scale (RUDAS).

 Secondary Objectives:

1. To investigate the association between levels of IFNγ and SEMA4D with risk of cognitive dysfunctions in MDD patients receiving paroxetine CR and bupropion SR respectively.

2. To correlate the RUDAS score with age, gender and level of education of subjects.

3. To determine the response and adverse outcome of paroxetine CR and bupropion SR.

Study Methodology:Written informed consent in their own vernacular language will be taken from all the patient/guardian to participate in the study

Method of Randomization:  A computer generated randomized table will be used.

INTERVENTION/PROCEDURE:

Patients diagnosed with MDD by DSM-5 criteria, single or recurrent episode, aged between 18-60 years and complying scoring of Patient Health Questionnaire (PHQ-9) for depression will be enrolledfor the study.

80 such patients will be randomly divided in 2 groups of 40 each and will be followed up for 12 weeks:

Group A: 40 patients will be given paroxetine CR (25mg/day -37.5mg/day)

Group B: 40 patients will be given bupropion SR (150mg/day -300mg/day)

Baseline investigations: Complete hemogram, liver function test, renal function test, lipid levels and random blood sugar would be done on the 1st day and after 12th week of study.

Patient Health Questionnaire (PHQ-9) [35] will be used to clinically evaluate the patients before and after treatment with antidepressants. Scoring will be done on the 1st day and after that on the 12thweek.

 ASSESSMENT OF COGNITIVE FUNCTIONS

Rowland Universal Dementia Assessment Scale (RUDAS) [36] cognitive screening test (Annexure 3) will be performed to assess the cognitive functions once during recruitment (1st day) of the patients and once after 12 weeks of follow up for both the groups.

COLLECTION OF BLOOD SAMPLES

Blood sample from the patients will be taken with aseptic precautions on day 1 and on last day of 12thweek of treatment. The samples will be centrifuged at 4000 rpm for 10 minutes to remove serum and will be stored at -20°C until analysis.

   ESTIMATION OF IFNγ and SEMA4D LEVELS

Serum IFNγ and SEMA4D levels will be evaluated using human IFNγ and SEMA4D ELISA kits, respectively twice in the study, on the first day and after completing 12 weeks of treatment.

STATISTICAL ANALYSIS:

Results will be presented as Mean ± standard deviation. Repeated measure Analysis of variance (ANOVA) followed by Tukey’ test will be used to compare the groups between and within effects for different variables. Correlations of scores with level of markers and age will be analyzed using Pearson correlation test. Correlations of scores with sex and level of education will be analyzed by Kruskal-Wallis test. Results with a p value of < 0.05 will be considered as significant. The analysis will be carried out using SPSS 20.0 software package.