“Depression is no longer seen as a disorder of monoamine neurotransmitters” – discuss this assertion in the light of the current neurobiological hypotheses of depression

The most common mental health disorder not only in United Kingdom but everywhere around the world is depression. Even more disturbing is the fact that depression disorder is estimated to affect around 10% of the people in England. Moreover, approximately 5 to 15 percent of men population and 10 to 20 percent of women population in the USA will suffer from depression during their life. Or to put it more simply, one in five adults worldwide will experience depression at some point of their lives (Kessler et al, 1997). World Health Organization described depression as state of sadness which is accompanied by loss of pleasure or interest in almost every activity. It also includes feelings of guilt, low self-worth, tiredness, poor concentration and disturbed sleep and appetite. According to the criteria of Diagnostic and Statistical Manual of Mental Disorders (DSM) for depression, a person suffers from depression if it experience at least five of the symptoms during the same 2 weeks period. These symptoms include depressed mood, loss of interest, weight loss or weight gain, lack of energy, feelings like worthlessness and thoughts of death or suicide etc. Apart from the mental suffering that depression brings, it is also considered as one of the most often reasons for deaths. In 1996 suicide was listed as one of the leading causes of death in the USA (Mireault & Deman, 1996). In other words, depression was the reason for more than 30,000 people to take their lives, which was even more than the one infected with the AIDS virus. Even more disturbing is the verifiable truth that most of the investigators believe that the number of deaths because of depression are more than the ones listed due to the fact that those who kill themselves sometimes do it in a way that looks not like a suicide because of depression (Nemeroff, 1998). The financial costs due to depression are also extremely high. Only in UK costs for the economy are estimated at around £8.6 billion a year. Recent research revealed that consultations with the GP for treating a depression are estimated at around £30 million a year and moreover, treating it in hospitals costs more than £200 million a year. Furthermore, anti-depressants are also one of the leading costs for NHS – £270 million for the last year only (Mentalhealth.org.uk, 2016). Results of recent studies also showed that the major depressive disorder increase the risk of future hearth attack or stroke (McManus, Meltzer, Brugha, Bebbington and Jenkins, 2009).

Having explained how important the problem of depression is to our society, it is now important to review the hypotheses and reasons of why people suffer from it. Firstly, this essay will aim to introduce and explain the genetic factors, how the monoamine theory of depression was developed and why in the recent years depression is no longer seen as a disorder of the monoamine transmitters. In addition, this essay aims to discuss how early life stress can increase the risk of depression later in life.

One of the oldest explaining of depression provided by researchers is the fact that it runs in families. In other words, geneticist determined that the ones that are blood related to the one suffering from severe depression are much more likely to suffer from this condition too than the general population. Furthermore, family, twin and adoption studies also supported the hypothesis that depression might be inherited (Sanders et al., 1999; Fava and Kendler, 2000). According to the results, around 40% – 50% of the risk of depression is on genetic base. Even though the researchers were able to confirm that the risk of depression is partly genetic, there are still many difficulties in finding the vulnerable genes. This is due to the fact that depression is a very complex disorder and it is believed that it involves many genes (Burmeister, 1999). (Nestler et al., 2002). Another reason for the complexity and difficulty in the identifying the faulty gene is that it is also possible that different variants in genes may cause depression in families.

Additionally, as the risk of depression is only partly genetic, another important point needs to be considered – the nongenetic factors such as individually specific or environmental. Results from a number of studies, including Akiskal (2000) and Fava and Kendler (2000), shed light on the importance of the stress and emotional trauma during the brain development and the importance they have in the etiology of depression. Even though there are a lot of evidences that depression is a stress related disorder, stress itself is not the leading cause of it. As a matter of fact, usually after a stressful event or situations most of the people are not becoming depressed. Indeed, experiencing a serious stress because of physical abuse or rape does not lead to depression but to post-traumatic stress disorder (PTSD). Another important point to consider is also that in general, there are gender differences in the way people respond to a stressor. To put it simply, Kendler, Thornton and Prescott (2001) found that even though men and women are more or less equally sensitive to stressful life events, depending on the type of stressor they tend to respond very differently. In their study they revealed that men are much more likely to become depressed after divorce or having troubles in the work place. On the contrary, it was found that women are more likely to have depressive episodes if they have difficulties in relationships, suffer from serious illnesses or death of someone close to them. Having said that, findings again shed the light into the fact that depression is very complex disorder and there are other important factors and mechanisms that need investigation.

While genetic researchers continued to look to try to identify the faulty genes, neuroscientists concentrated themselves on the possible brain changes leading to depression. At the beginning most of the work was focused on the neurotransmitters of the monoamine class – serotonin, norepinephrine and dopamine in the central nervous system. The reason why researchers became interested in monoamines was because in the early 50s physicians found that depression symptoms appeared in around 20% of patients who were treated with drug reserpine which on the other hand was found to exhaust the supply of the monoamines. In other words, researchers found that these antidepressants were effective for depression as a side effect but they didn’t know yet exactly how they worked. Following these results, another research revealed that there is an underlying biological basis for depression and therefore the monoamine hypothesis of depression was proposed. However, it wasn’t cleared which of the monoamines was the most important in depression. At the beginning the theory was called the norepinephrine theory of depression because the scientist thought that the affected neurotransmitter is the norepinephrine. However, several years after the monoamine theory was proposed, there was a research on the hallucinogen lysergic acid diethylamide (LSD) and its action. During the investigation it was revealed that the serotonin receptors are being blocked by the LSD which brought the question whether serotonin might have an important role in the explaining of mood disorders and specifically depression. Therefore, these findings made serotonin the most studied neurotransmitter in the depression disorder. There are several indications that there is an aberrant decreased function of the serotonergic system. The most obvious evidence of reduced serotonin synthesis comes from the studies of Neumeister, Konstantinidis, Stastny et al. (2002) and Neumeister, Nurgent, Waldeck et al. (2004) in which was used tryptophan depletion. The results from these studies once again revealed and confirmed that the reduction of serotonin neurotransmitter leads to the development of depressive disorder. Despite the evidences that the studies on serotonin depletion provided, its mechanism in the depressed patients it still unclear. Meyer, Ginovart, Boovariwala et al. (2006) proposed that high amount of monoamine oxidase (MAO) in the brain is one of the reasons that causes the deficiency of the serotonin.

Since the hypothesis was proposed various of antidepressants were developed in order to increase the levels of serotonin in the nervous system. However, scientists realized that even though many of the produced antidepressants relieved the symptoms of depression they actually does not affect the serotonin levels. In fact, they were affecting the dopamine, norepinephrine and cholinergic systems but not the serotonin. Furthermore, there were also some drugs that acted only on the norepinephrine system but still they had shown to improve the symptoms of depression. Another important point to consider regarding the serotonin hypothesis is the fact that antidepressants don’t work immediately. In fact it can take more than a month to relieve the depression (Onder and Tural, 2002). Therefore, it raises the question if depression is caused because of the low serotonin levels in the brain then why the increasing levels did not change the symptoms right after. Another limitation of the theory is the fact that the antidepressants does not work on every depressed person. For example recently it was found that antidepressant drugs work in approximately 60 percent of the depressive patients (Gartlehner, Hansen, Thieda, DeVeaugh-Geiss, Gaynes, Krebs, Lux, Morgan, Shumate, Monroe and Lohr, 2007). This again raises the debates whether the low serotonin levels were really responsible for depression. Also, the final problem of the theory is that it is expected that the decreased levels of serotonin in human brain will low the mood. However, several studies were not able to conclude it. Actually, it was found that despite the fact the serotonin is increased by the antidepressants, the lack of serotonin in the brain does not cause the depression (it is like having a stomachache and taking a pill to reduce the pain, however not taking the pill does not mean it started to hurt you because of that), (van der Veen, Evers, Deutz and Schmitt, 2007).

Following this discussion it is important to conclude that the depressive disorder is not entirely caused by the serotonin levels in the brain. The monoamine theory of depression does not sufficiently explain the pathology and treatment of depression. It is a fact that human brain is a very complex place and there is a high probability that depression is caused by a combination of factors. Nowadays, it is generally accepted that mood disorders such as depression are definitely occurring as a result of combinations of factors such as genetic, biological and environmental.

The discussion above made it clear that the low serotonin levels are not the cause of the depression. Even though antidepressants do not work on everyone, it is essential to examine the other things that these drugs are doing in the brain. Interestingly, recent study has found that the antidepressant drugs not only increase the levels of neurotransmitters in the brain but in fact they can also stimulate the birth of new neuron cells in the brain which is also called neurogenesis (Lucassen, Meerlo, Naylor, van Dam, Dayer, Fuchs, Oomen and Czeh, 2010).

Over the past decade, researchers are arising their interest on the fundamental process called neuronal plasticity (or neuroplasticity) which allows the brain to receive information and also to respond in an appropriate way to the same stimuli. The most studied examples of the neural plasticity are learning and memory or in other words the hippocampus of the brain. However, the structures of the brain and the neural plasticity in it can be also activated by various of other stimuli. An example of these include the environmental, pharmacological, social and behavioural. In other words, brain can be stimulated to produce new cells by positive emotions, actions, thoughts etc. These include healthy diet, active lifestyle (sport), good and healthy relationships, sex or in generally being happy stimulate the brain to produce new cells. Pharmacological stimuli such as antidepressant drugs have also been found to increase the formation of new cells and then neurons. On the contrary, bad lifestyle like binge drinking, smoking, having a stressful relationship, poor diet and chronically experience stress is associated with loss and death of brain cells, which on the other hands is believed to play an important role in the pathology of depression. Furthermore, according to the neurogenic hypothesis of depression, the reduced neurogenesis in the adult hippocampus lead to depression symptoms. Controversially, it has been suggested that the increased formation of new neurons in the adult hippocampus is associated with successful treatment of depression disorder. As a matter of fact it rapidly became clear that neural plasticity is one of the most important process that the human brain is able to perform and moreover it is closely associated with most of the functions of the nervous system (Duman, 2004).

Having introduced the topic of neurogenesis or neuroplasticity, it is now necessary to look at the factors that suppress the formation of new cells and what influence the formation of the new one. Over the past 25 years a certain amount of excellent reviews have been written on the topic of depression and stress (Kessler, 1997; Paykel, 2003; Monroe & Hadjiyannakis, 2002; Tenant, 2002). Many studies revealed that the experience of stress during the development of the brain is highly associated with impact on emotional and cognitive functions (Ammerman, Van Hasselt & Hersen, 1991; Fernald & Gunnar, 2009). Examples of stress events associated with vulnerability to stress related disorders later in life include poverty, loss of parent, divorce of parents, substance abuse of any of the parents, physical abuse etc. (Repetti, Taylor & Seeman, 2002; Halligan, Herbert, Goodyer & Murray, 2007; Lupien, McEwen, Gunnar & Heim, 2009; Schore, 2000). Post-traumatic stress disorder, depression and anxiety are all stress related disorders which are considered as important part of chronic early life stress (CES) (Heim, Newport, Mletzko, Miller & Nemeroff, 2008; Bremner, Southwick, Johnson, Yehuda & Charney, 1993; MacMillarn et al., 2001). Interestingly, recent studies proposed that the loss of the neurons in the hippocampus may contribute to the developing of the depressive disorder. As a matter of fact, the hippocampus is one of the parts of the brain where the formation of neurons is a very essential process that takes place during the life of the humans and animals (Eriksson et al., 1998). Many researchers also reported that the neurogenesis in the hippocampus is able to be influenced by several factors one of which is stress (Kempermann et al., 1997; van Praag et al., 1999). In a number of studies was demonstrated that hippocampus plays a significant role in the pathophysiology of the major depressive disorder (Ho and Wang, 2010; MacMillarn et al., 2001). Moreover, in one recent study (Ho and Wang, 2010) confirmed the theory using animal models that stress and shock reduce the cells in the hippocampus and also that the long term use of antidepressant treatment can significantly reverse the effect. Another important evidence supporting the neurogenesis theory are the posmortem studies of the hippocampal tissue. By investigating the hippocampal tissue from depressed patients, researchers found reductions in the neuropil network as well as decline in the neurogenesis of the hippocampus (Sheline, Wand, Gado, Csernansky and Vannier, 1996; Sheline, Gado and Kraemer, 2003).

Following the evidences that there is a possible link between the stress, depression and neurogenesis in the hippocampus, a study of Malberg, Eisch, Nestler and Duman (2000) aimed to examine whether the treatment with antidepressant drug will influence the neurogenesis in the hippocampus of an adult rat. It is challenging and difficult to create an animal model that can completely represent the symptoms of depression. This is due to the fact that most of the animals do not have self-consciousness, thinking abilities and most importantly they are not able to indicate the symptoms of the depressive disorders such as the depressed mood, the low self-esteem, the suicidal desires etc. However, many mental disorders including depression, consists endophenotypes which allows to be evaluated in animals. Examples of these endophenotypes that can be observed in the animal model of depression are anhedonia, changes in appetite, behavioural hopelessness, weight gain, changes in sleep etc. (Hasler et al., 2004). Moreover, brain responses to stress is similar in rodents (Lupien, McEwen, Gunnar and Heim, 2009).  So, in order to examine the effect that antidepressants have on the neurogenesis Malberg, Eisch, Nestler and Duman, (2000) examined adult rats. During the experiments, different kinds of antidepressant drugs were used for a period of 28 days. In order to find out the effects of the drugs on the cells there were two group of rats. In short, to one of the group was given antidepressant and to the other – vehicle. To label the dividing cells, four days after the last antidepressant drug treatment rats were given a thymidine analog bromodeoxyuridine (BrdU) and one of them were killed after 24 hours (to measure the cell proliferation) and the other one were killed after another 28 days (to determine the phenotype). The results of the study revealed that continuously treatment with antidepressants increases the formation of new neurons in the hippocampus part of the brain of an adult rats. Another very important finding that this study demonstrated is the fact that antidepressants are increasing the neurogenesis after a chronic treatment (28 days) and not a straight after the intake of the drug (short term).  These results are also consistent with the results of several similar studies (Santarelli, Saxe, Gross, Surget, Battaglia, Duman et al., 2003;). Furthermore, few recent studies also examined the effects that antidepressant drug therapies have on the cognitive functions of healthy humans. Results in one of the studies (Mowla et al., 2007) demonstrated that antidepressants positively influence the memory and other cognitive functions in the old patients that have cognitive problems. Several other researchers also demonstrated that antidepressant drug treatment of depression is associated with improvements in memory and also the cognitive functions (Allain et al, 1992).

To summarize, the neurogenesis theory has been supported by many researchers that also include animal studies. As stated earlier, antidepressant drugs were found to increase not only the levels of the neurotransmitters in the brain (serotonin, norepinephrine and dopamine) but also to increase the formation of the new cells in the brain on in other words the neurogenesis. It is generally widely known that during the life of a person new neurons are growing in the hippocampus. On the other hand, it was also found that stress is able to reduce the neurons in the hippocampus of the brain. However, nowadays there are a lot of evidences that taking antidepressant drugs for at least month will significantly increase the neurogenesis in the brain which at the same time will reduce the depression symptoms. In contrasts with the monoamine theory, neurogenesis theory takes the right amount of time to have an effect on the brain. Furthermore, many researchers are now trying to investigate the part that neurogenesis plays in depression disorder. This at the same time will help to increase the production of new cells directly, rather than focusing the antidepressants on the neurotransmitters. However, there are still many debates whether there are real changes in the neurogenesis in the brain of the people suffering from depression (Werry, Enjetu, Halliday, Sachdev and Double, 2010). Further investigation of the neuroplasticity and the antidepressant treatments will lead to better understanding of the disorder and the development of new treatments.

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