The Effects of Antidepressant Treatment on Oxidative Stress and
Anti-oxidants in Subjects with Depression
Depression is a common disorder characterized by persistent feelings of hopelessness and sadness. According to the DSM-IV criteria, the 2 core symptoms are a depressed mood and anhedonia (reduced pleasure and loss of interest in activities). Depression afflicts large populations. It was pointed out by the NEMESIS-2 research that the prevalence of mood disorders in the age range between 18 and 65 is about 4.9% and 7.4% per year among men and women, respectively (De Graaf, Ten Have & Dorsselaer, 2010). Major depressive disorder (MDD) is the most common mood disorder and has been accepted to be an independent risk factor for many illnesses, such as cardiovascular disease (Loomba, 2015). Cuijpers & Smit (2002) observed that depression is also accompanied by a higher mortality rate. Furthermore, depression has a profound negative influence on quality of life and functioning; it accounts for 8.2% of global years lived with disability (YLDs) and for 2.5% of global disability adjusted life years (DALYs). This makes depression a huge global health priority, which is worldwide the second leading cause of disability and sickness absence (Ferrari et al., 2013).
Oxidative stress has been implicated in the pathophysiology of depression (Pandya, Howell, & Pillai, 2012). Oxidative stress is a metabolic condition in which the amount of reactive oxygen species (ROS) is increased or the quantity of anti-oxidants is decreased. This disturbance in the balance between the oxidative and anti-oxidative markers – leading to oxidative stress – can cause irreversibly biological damage to all parts of the cells, including DNA, proteins and lipids (Behr, Moreira & Frey, 2012). Oxidative stress plays an important role in accelerating the ageing process (Valko et al., 2007) and is also a well-known mechanism in the pathophysiological pathway of cancer, neurodegenerative disorders (Halliwell, 2006), atherosclerosis (Harrison et al., 2003), several kinds of cardiovascular diseases, diabetes mellitus (Rosmond & Bjorntorp, 2000) and mortality (Semba et al., 2007). Tissues have the ability to protect themselves against oxidative stress with a defense mechanism by antioxidants, which captures the free radicals out of the cells. Anti-oxidative enzymes can defuse thousands of free radicals. This enzyme system is probably the primary defense system against oxidative stress. There is also a recovery mechanism which consists of a regular protein turnover and a system that frequently repairs the DNA (Imlay, 2008).
ROS are a normal waste product from the aerobic metabolism and include superoxide, single oxygen, hydrogen peroxide and lipid peroxide. Consequently, the human body itself is the main source of oxidative stress (Kalyanaraman, 2013). Other causes of oxidative stress are smoking, excessive alcohol abuse, radiation exposure and hypoglycemia (Al-Gubory, 2014). Several medications and different types of sport are able as well to elicit oxidative stress. Oxidative stress is also a common finding in patients with obesity (Boyer et al., 2015).
There are many ways to look at oxidative stress and anti-oxidant defenses, because of the existence of plenty oxidative- and anti-oxidative biomarkers, numerous effect measures and a wide range of available laboratory techniques (Dalle-Donne et al., 2006). Every manner has its own limitations and advantages. The levels of antioxidants, anti-oxidative enzymes- and vitamins could be informative, but they reflect only 1 side of the redox homeostasis. Due to this, it is still unclear whether increased levels are strongly associated with decreased oxidative damage or vice versa (Black et al., 2015).
Previous studies have reported increased levels of oxidative stress markers relating to patients who suffer from a psychiatric disorder, depression in particular. At the same time, their anti-oxidant defenses were significantly decreased (Palta et al., 2014). This association may be explained by lifestyle factors and genetics. Increased oxidative stress in depression may contribute to accelerated ageing, somatic disease, increased risk of co morbid chronic medical illnesses (Rawdin et al., 2013) and brain damage, because the brain is particularly vulnerable to oxidative stress (Moylan, 2013).
Although depression is associated with oxidative stress, the direction of this relationship is still unclear, just as the source of oxidative stress (endogenous either exogenous). Both factors and directions may play a role in the pathogenesis. It is known that depression is frequently associated with unhealthy exogenous lifestyle factors, like smoking, drinking and unhealthy eating habits (Bonnet et al., 2005). Earlier was mentioned that smoking, excessive drinking and obesity are able to cause oxidative stress. Thus, depression may indirectly cause oxidative damage, because of an underlying unhealthy lifestyle, which is possibly a second independent variable. In other words, smoking and alcohol abuse could be relevant confounders and partially explain the association between depression and increased oxidative stress. Secondly, an endogenously hereditary component may affect oxidative stress. Several investigators indicated that depression is associated with single nucleotide polymorphisms (SNPs) in genes. Those SNPs play a role in anti-oxidant defense mechanisms (Maes et al., 2011). In that way, depressed individuals may have a predisposition as well to develop oxidative damage.
As mentioned earlier, the relationship between oxidative stress and depression has been widely investigated and many reviews have been conducted on this research area. To date, however, little attention has been devoted to the effects of treatment with antidepressants; few reports either reviews have discussed this subject. Most literature studies have only focused on the association between depression and oxidative stress, but just a few papers have reviewed the research conducted on the relationship between the use of antidepressants and oxidative stress. Knowledge of this issue seems to be highly relevant for the treatment of depression to prevent this critical route of irreversible damage, due to oxidative stress. Lee and colleagues believe that this knowledge should be considered in the development of new antidepressant drugs, with the emphasis on these novel targets in the treatment of depression (Lee et al., 2013).
Antidepressants are widely employed for the treatment of different kinds of psychiatric disorders, such as many anxiety- and depressive disorders. Antidepressants could be classified based on their mechanism of action. Several groups could be distinguished. The most important ones are: SSRIs (selective serotonin re-uptake inhibitors), SNRIs (serotonin norepinephrine reuptake inhibitors), TCAs (tricyclic antidepressants) and MAOIs (monoamine oxidase inhibitors). Only little is known about the effects of treatment with antidepressants and the aim of this literature study is therefore to determine the effects on oxidative stress. The main research question addressed in this systematic review is as follows: what are the effects of antidepressants on oxidative stress and/or anti-oxidants in patients with depression? This question will be answered in this paper according to a literature search performed in the Pubmed database. It has been hypothesized that successful treatment of depression with antidepressant medicines can decrease or even normalize the levels of oxidative stress markers. It was also hypothesized that treatment of depressive symptoms can lead to increased anti-oxidant defense levels. This study aims to give an overview of the current evidence of the effects of antidepressant treatment on oxidative stress and anti-oxidants, including all types of antidepressant treatment on any markers of oxidative stress or anti-oxidants.
A literature search of recent studies (at least 2000) examining the relationship between the use of antidepressants and oxidative stress with regard to patients with a depression was conducted up to June 13th 2015 in Pubmed.
The terms were covering depression, anti-oxidants, oxidative stress, reactive oxygen species and antidepressants. The search involved the following combination of terms in the search builder, including ‘depressi*’ AND ‘antioxidant* OR oxidative stress OR reactive oxygen species’ AND ‘antidepressant*’.
Figure 1. Search builder with the terms filled in.
The database was searched without any limitations in the search strategy, except 2 filters; that is human studies and articles published from 2000 (custom date range 2000-2015).
In- and exclusion criteria for study selection
Studies were labeled as eligible if they satisfied the following requirements:
1. The study contains original data;
2. The study is composed of a clinical trial in human adults;
3. Participants were diagnosed with a major depressive disorder (MDD), major depressive episodes (MDE) (according to DSM- IV/ ICD-10 criteria) or depressive symptoms assessed by a validated instrument;
4. Oxidative stress and/or anti-oxidants were measured before and after treatment with antidepressants or compared with a non-treatment patient group;
5. Articles in English language only.
Studies were screened for inclusion on title and abstract.
The literature search in Pubmed brought 238 hits. After that, the records were screened based on title and summary. 220 articles were excluded as a result of this screening, due to multiple reasons, described in figure 2. This first part of the procedure ended up in 18 apparently eligible articles. Next, these 18 residual articles were judged based on a full text review. 9 articles were excluded. Eventually, 9 studies were left from the Pubmed search and included in this literature study. To simplify information, the flow diagram shown in figure 2 reproduces the study selection process of this literature search, including the varied reasons of rejection.
Figure 2. Flow diagram according to Prima guidelines 2009, which describes the study selection process.
Summary of the 9 remaining articles
The table below shows an overall picture of the chosen articles collected from the literature search, including their main findings.
Miscellaneous types of antidepressants were used in these clinical trials, including different sorts of SSRIs, 1 SNRI (venlafaxine), 1 NRI (bupropion) and 1 TCA (amitriptyline). Moreover, the number of patients (from 18 to 96) and the duration of treatment between the studies (6 weeks up to more than 10 months) differed as well. In addition, some articles were more recent than other ones. The eldest article and the latest article were published in 2001 and 2013, respectively. Finally, both different and common parameters were measured in these studies.
The results of those 9 studies are inconsistent. Some of them (n = 2) indicated increased levels of oxidative stress, contrary to the studies revealing decreased levels (n = 5). 1 study observed partly improved oxidative stress after antidepressant treatment. Both oxidative and antioxidant markers were decreased (Kotan et al., 2011). 1 study reported no effects at all (Sarandol et al. 2007). As mentioned before, the rest of the studies (n = 7) were inconsequent in their outcomes; they found contradictory results.
Author and year of publication Number of participants Antidepressants tested Treatment duration Most important results
Chung et al. 2013 patients (n = 18)
healthy controls (n = 36) sertraline either bupropion
(n = 9)
no treatment (n = 9) 8 weeks ‘F2-IsoP
Rawdin et al. 2013 patients (n = 20)
healthy controls (n = 20) sertraline (n = 20) 8 weeks F2-IsoP no longer correlated with IL-10, IL-6 or IL-6/IL-10 ratio
Moreno-Fern??ndez et al. 2012 patients (n = 40)
healthy controls (n = 20) amitriptyline (n = 20)
no treatment (n = 20) ‘ 10 months ‘CoQ10, ‘ATP, ‘mitochondrial mass, ‘LP
Michalakeas et al. 2011 patients (n = 52)
healthy controls (n = 40) sertraline (n = 28)
no treatment (n = 24) 3 months ‘MDA
Kotan et al. 2011 patients (n = 73)
drop-outs (n = 23)
healthy controls (n = 44) venlafaxine (n = 21) paroxetine (n = 8)
escitalopram (n = 8)
sertraline (n = 5)
citalopram (n = 3)
milnacipran (n = 2)
fluoxetine (n = 1)
tianeptin (n = 1)
moclobemid (n = 1) 24 weeks ‘SOD, ‘MDA, ‘TAC
Cumurcu et al. 2009 patients (n = 57)
healthy controls (n = 40) sertraline (n = 27)
paroxetine (n = 20)
escitalopram (n =10) 3 months ‘TOS, ‘OSI, ‘TAC
Sarandol et al. 2007 patients (n = 96)
drop-outs (n = 9)
healthy controls (n = 54) venlafaxine (n = 87) 6 weeks No significant effects
Herken et al. 2007 patients (n = 36)
healthy controls (n = 20) fluoxetine (n = 11)
citalopram (n = 10)
sertraline (n = 8)
fluvoxamine (n = 7) 8 weeks ‘ADA, ‘SOD, ‘NO, ‘XO
Bilici et al. 2001 patients (n = 30)
healthy controls (n = 32) sertraline (n = 13)
fluoxetine (n = 7)
citalopram (n = 5)
fluvoxamine (n = 5) 3 months ‘AEA, ‘LP
F2-IsoP, F2 isoprostane; IL, interleukine; CoQ10, coenzyme Q-10; ATP, Adenosine triphosphate; LP, lipid peroxidation; MDA, malondialdehyde; SOD, superoxide dismutase; TAC, Total antioxidant capacity; TOS, total oxidant status; OSI, oxidative stress index; ADA, adenosine deaminase; NO, nitric oxide; XO, xanthine oxidase; AEA, antioxidative enzyme activities.
Table 1. Overview of the 9 selected studies.
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