Bupropion monotherapy alters neurotrophic and inflammatory markers in patients of major depressive disorder

Highlights

• Neurotropic factors and inflammation are involved in major depressive disorder (MDD).

• Major depressive disorder (MDD) was treated with bupropion sustained release (SR).

• Efficacy, safety, plasma serum BDNF levels and serum TNF-α were assessed at 12 weeks.

• Bupropion SR is effective and well tolerated in MDD patients.

• An increase in serum BDNF levels and a decrease in serum TNF-α levels was observed.

Abstract

Background

Emerging hypotheses in the pathophysiology of major depressive disorder (MDD) indicate the role of neurotrophic factors and inflammation. This study assessed the association between therapeutic response of bupropion and serum brain-derived neurotrophic factor (BDNF) and tumour necrosis factor-α (TNF-α) levels in patients with MDD.

Methods

Thirty patients (aged 18 to 60 years) with MDD diagnosed by DSM-5 criteria, with Hamilton Depression Rating scale (HAM-D) score ≥ 20 were included in the study. Patients were given bupropion sustained release (SR) in the doses of 150 mg once daily. All patients were followed up for 12 weeks.

Results

HAM-D score at the start of the treatment was 25.57 ± 1.85 which significantly reduced to 10.8 ± 4.24 at 12 weeks of treatment. The serum BDNF level increased significantly (p < 0.05) from 2.42 ± 0.19 ng/ml to 2.97 ± 0.10 ng/ml and the levels of serum TNF-α reduced significantly (p < 0.05) from 4.45 ± 0.95 pg/ml to 2.11 ± 0.84 pg/ml at 12 weeks of treatment, in responders to treatment.

Conclusion

The results of our study suggest that bupropion SR monotherapy is effective and well tolerated in MDD patients with moderate to severe depression, and its therapeutic efficacy is accompanied by an increase in serum BDNF levels and a decrease in serum TNF-α levels.

Introduction

Major Depressive Disorder (MDD) is a prevalent mental disorder with a complicated pattern of resistance and recurrence. MDD adversely affects the quality of life of patients and also leads to increased suicidal tendency among them. Around 6% of the population meets the MDD criteria at a specific point of time (Penninx et al., 2013). It is anticipated that by 2030, MDD will become the leading cause of ill health and premature death worldwide, accounting approximately for 4.4% of all disability adjusted life years lost (Mathers and Loncar, 2006).

Antidepressant drugs e.g. selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAO-Is) and atypical antidepressants have been used in the treatment of MDD, and found to be highly effective. The above drugs primarily act by increasing the levels of monoamines (serotonin, norepinephrine, dopamine) in the central nervous system (CNS) through various mechanisms. However, antidepressant drugs are associated with a variety of adverse effects such as anticholinergic, cardiac, orthostatic hypotension, gastrointestinal, genitourinary effects, sexual dysfunctions, weight gain and serotonin syndrome (Carvalho et al., 2016; Papakostas, 2008; von Wolff et al., 2013). These adverse effects are a major contributor to treatment discontinuation and lack of patient compliance – with rates as high as 43% in first 3 months and 27% in the second 3 months of treatment initiation (Bull et al., 2002). The clinical symptoms of MDD are non-specific; despite advances in the understanding of the pathogenesis of major depression and the introduction of newer antidepressants, 10–15% of the patients do not respond to pharmacotherapy and an additional 30–40% have only partial remission (Tundo et al., 2015).

To address the above-mentioned limitations, drugs having effects on more than one monoaminergic pathways have been explored in the management of depression (Nemeroff et al., 2002; Smith et al., 2002). Further, the true drug response to antidepressants cannot be measured. Therefore, search and identification for biomarkers for MDD is constantly going on. Increasing evidence suggests that the nerve growth factors (especially brain derived neurotrophic factor, BDNF) are critical for neurogenesis (Liu and Nusslock, 2018; Rossi et al., 2006). Clinical studies have reported that BDNF levels are low in MDD patients (Brunoni et al., 2008; Lee and Kim, 2010) and antidepressant drugs can increase BDNF level with improvement in the symptomatology of MDD (Ghosh et al., 2015; Gupta et al., 2017; Sen et al., 2008).

Additionally, depression has been associated with activation of the inflammatory system followed by higher levels of proinflammatory cytokines [tumour necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6] (Himmerich et al., 2008; Kim et al., 2007); and use of antidepressants has shown to decrease the activity of inflammatory and immune system (Kubera et al., 1995; Manikowska et al., 2014; Neis et al., 2014). Experimental models and clinical studies have demonstrated the role of TNF-α, and its elevated level in major depression (Neis et al., 2014; Yoshimura et al., 2009). However, results of clinical studies showing the effect of antidepressants on TNF-α levels are conflicting; some studies have shown that antidepressant treatment causes reduction in TNF-α levels (Lanquillon et al., 2000; Tuglu et al., 2003) whereas other studies found no change in TNF-α level (Brunoni et al., 2014; Yoshimura et al., 2009).

Among antidepressants, SSRIs has been the most studied group with regard to inflammatory markers, followed by tricyclic antidepressants (TCAs) and SNRIs. However, various classes of antidepressants influence TNF-α level differently. For example, amitriptyline (a TCA) was shown to decrease (Lanquillon et al., 2000), whereas venlafaxine (an SNRI) did not affect (Berthold-Losleben and Himmerich, 2008) and SSRIs have shown conflicting results regarding the level of TNF-α. The difference in TNF-α effects observed among the different classes of antidepressants could be explained by their different mechanisms of action, and in particular, their different effects on the inflammatory pathway and on the Th1/Th2 balance (Chen et al., 2018; Martino et al., 2012). In addition, differences in the study design, in the population, in inclusion and exclusion criteria, in baseline values of TNF-α and in TNF-α assay may explain this inconsistent finding among studies. Further, studies have demonstrated the possible effects of gender on cytokines (Carboni et al., 2019; Majd et al., 2018). Also, the differences could be attributed to the heterogeneous, complex nature of MDD and severity of symptoms (Köhler et al., 2017; Strawbridge et al., 2015) and TNF-α genetic polymorphism among MDD populations (Ma et al., 2016).

The use of SSRI was shown to decrease TNF-α (Tuglu et al., 2003); in this study the effect of SSRIs including sertraline (50–100 mg), citalopram (20–40 mg), fluoxetine (20–40 mg), fluvoxamine (100–200 mg), and paroxetine (20 mg) for 6 weeks was investigated. It had a limited number of MDD patients (26 MDD patients and 17 controls), which did not allow subgroup analysis based on - males-females, smokers-non-smokers to demonstrate the effect of confounding factors on inflammatory markers, depression characteristics and antidepressant drugs. Contrary to this, ‘The Netherlands Study of Depression and Anxiety (NESDA)’ found that SSRIs did not decrease TNF-α levels in depressed patients (Vogelzangs et al., 2012). NESDA had a large sample size (n = 2981) comprising MDD patients and healthy controls. In addition, their study did subgroup analysis with adequate adjustment for potential confounders, examined the role of depression characteristics and four antidepressant medication groups TCA, SSRI, SNRI and tetracyclic antidepressants. They found that older age of depression had higher levels of CRP and TNF-alpha than those with a younger age of depression onset. Women with more severe depressive symptoms had higher levels of TNF-α. Their study indicated the plausibility that immune dysregulation/alteration in inflammatory markers might not be generally present in depression, but may be restricted to a particular subgroup of depressed persons, in particular in men with a late-onset depression.

Bupropion, an atypical antidepressant drug, exhibits unique pharmacodynamics. It acts by blocking the norepinephrine transporter (NET) and the dopamine transporter (DAT), thus inhibiting the re-uptake of nor-adrenaline (NA) and dopamine neurotransmitters in the CNS (Stahl et al., 2004) and enhancing dopaminergic and noradrenergic neurotransmission (Foley et al., 2006). Bupropion has no effect on serotonin, histamine, acetylcholine or adrenaline receptors.

Bupropion has largely been used as add-on therapy and co-prescribed with other antidepressant drugs in clinical practice in previous years. This might be on account of lack of licensing or absence of adequate amount of evidence for its use as monotherapy or lack of clear recommendations of its prescribing in MDD (Patel et al., 2016). Also, data from open label clinical trials has been suggestive of enhanced therapeutic effect of other antidepressants, especially SSRIs/serotonergic drugs after adding bupropion (Leuchter et al., 2008; Maron et al., 2009), as bupropion had different pharmacodynamics (no effect on serotonergic system). In addition, many studies have reported that bupropion is as effective as other SSRIs (Clayton et al., 2006; Dhillon et al., 2008; Thase et al., 2005) and has an important role in the treatment of MDD (Fava et al., 2005).

Safety studies have demonstrated that bupropion treatment is associated with adverse effects including headache, dry mouth, nausea, insomnia, which are relatively common (Hewett et al., 2009). Rare adverse effects with bupropion are restlessness, anxiety, constipation, dizziness, nasopharyngitis and fatigue (Patel et al., 2016); whereas the most common and frequently occurred side effects with SSRIs are drowsiness, sexual dysfunction, dry mouth, headache, dizziness, insomnia, anxiety, agitation, nausea, vomiting, diarrhea, weight gain, tachycardia and fatigue (Beasley et al., 2000; Hu et al., 2004; Mackay et al., 1997). SSRIs increase the concentration of serotonin at the synapse, which affects sleep, arousal, appetite, sexual functions, gut motility and smooth muscle tone accountable for adverse effects. SSRIs have risk of some serious side effects such as serotonin syndrome and hyponatremia (Warden et al., 2010) The rate of insomnia for bupropion (11%–20%), has been reported to be similar to the rate associated with SSRIs (10%–19%) (Coleman et al., 2001; Croft et al., 1999; Feighner et al., 1991; Kavoussi et al., 1997). However, the somnolence rate was higher with SSRIs relative to bupropion (Croft et al., 1999; Weihs et al., 2000). In addition, bupropion treatment has not been found to be associated with weight gain as it has no effect on serotonergic receptors and, in fact, results in weight loss (e.g., approximately equal to 1.5 kg with initial treatment). In the long term relapse prevention study, a greater weight loss was observed in patients with a greater body mass index at baseline (Croft et al., 2002).

It is important to mention that weight gain as well as sexual dysfunctions caused by other antidepressants is a major reason for discontinuation of antidepressant therapy (Patel et al., 2016). According to one hypothesis, the serotonergic action of SSRIs and SNRIs reduce dopaminergic transmission in the mesolimbic area, which in turn is known to regulate orgasm and sexual desire (Bella and Shamloul, 2014). Hypodopaminergic activity may be associated with diminished drive, amotivation, reduced cognitive function and lack of positive mood (Schlaepfer et al., 2012). In addition, an analysis suggests that patients with symptoms related to loss of interest or reduced activity experience diminished response to antidepressant drugs (Uher et al., 2012).

Therefore, bupropion might be an effective drug to mitigate specific symptoms associated with hypodopaminergic activity as mentioned above and to minimize adverse effects e.g. sexual dysfunctions and weight gain and hence could be an option for overweight/obese MDD patients with sexual dysfunctions.

Nevertheless, studies on bupropion use as monotherapy to treat MDD are limited. Also, data regarding the effect of bupropion on serum BDNF and TNF-α level is not available. Therefore, the present study was designed to evaluate the therapeutic efficacy and tolerability of bupropion monotherapy; and the association between clinical response of bupropion and its effect on serum BDNF and TNF-α level in patients of MDD with moderate to severe depression after 12 weeks of treatment.