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Critically discuss the usefulness or otherwise of the biochemical theory of major depressive disorders Depression is a widespread illness with an estimated 340 million people affected globally, making it the second largest cause of disease or injury worldwide (Tran, Bymaster, Mcnamara, & Potter, 2003). For a diagnosis of a major depressive disorder a person must be markedly depressed and/or lose interest in pleasurable activities for at least two weeks along with a range of other accompanying symptoms that, according to the DSM-V diagnosis criteria, may include weight loss, sleep disturbance, suicidal thoughts, social or occupational impairment and often anxiety, for which there is high comorbidity (Butcher, Hooley, & Mineka, 2015). This essay considers major depressive disorders that are unipolar and not bipolar or manic and shall use the general term depression for simplicity and consistency. Although there are various theories regarding the cause of depression including genetic, psychosocial and anatomical, this essay will consider the role of biochemistry in causing and alleviating depression. The biochemical theory considers that chemicals in the brain, namely neurotransmitters or hormones, may be responsible for causing depression and therefore may ultimately hold the key to curing it. It will be argued that although there is some evidence that biochemistry plays a role in depression, there is no clear evidence to fully support the biochemical theory of depression. This essay will review the evidence in the context of the two main arguments that are debated: that low levels of neurotransmitters or high levels of the hormone cortisol cause depression; and that drugs that increase certain brain chemicals are effective in curing depression. Depression is understood to be the result of life stresses interacting with the genetic and personality makeup of an individual, resulting in psychological and physiological dysfunction, with prolonged exposure leading to changes in brain neurotransmitters that cause what is often called a ‘chemical imbalance’ (Friedman & Anderson, 2011). Research as far back at the 1950s began looking at the relationship between depression and brain chemistry resulting in the theory that depression is caused by low levels of monoamine neurotransmitters in the synapse (Hindmarch, 2002). The monoamine theory posits that low levels of serotonin and/or norepinephrine neurotransmitters are the cause of depression, with more recent research suggesting this could also be due to lower concentrations of dopamine (Rampello, Nicoletti, & Nicoletti, 2000; Chaudhuri & Schapria, 2009). The synthesis of early antidepressant drugs such as monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) appeared to reduce depression in patients by increasing the levels of monoamines in the brain (Hindmarch, 2002). This became known as the monoamine hypothesis or theory of depression. Monoamine oxidase A (MAO-A) is an enzyme that metabolizes monoamines in the presynaptic cells. It has been proposed that high levels of MAO-A could cause too great a reduction of monoamines in the neurons and result in depression (Friedman & Anderson, 2011). Research by Meyer, et al. (2006) used PET scanning technology to compare the levels of MAOA in the brains of both depressed and healthy individuals. They found that MAO-A was on average 34% higher in depressed individuals than in non-depressed, in all areas of the brain that were tested. TCAs prevent serotonin and norepinephrine reuptake back into the presynaptic cells thus creating higher concentrations in the synaptic cleft (Pinel, 2011). In more recent years, researchers began to focus on serotonin as being the primary neurotransmitter of interest in depression and numerous drugs were developed, including Selective Serotonin Reuptake Inhibitors (SSRIs), that increase synaptic Serotonin levels by blocking the reuptake of serotonin into the synapse (Lacasse & Leo, 2005). Early support for the monoamine theory came in a meta-study by Schildkraut (1965) who found that monoamine drugs alleviated 60-80% of depression in patients tested. Further support came from the finding that the anti-hypertensive drug Reserpine, which reduces monoamine levels in patients, was also found to increase depression (Stein & Himwich, 1962). Researchers attributed this to be a result of depletion of norepinephrine (Keltner, 2014). Later research also appeared to find that both TCAs and SSRIs were more effective than both no treatment and placebo, for example a meta study by Hirschfeld (1999), looking at antidepressants in the treatment of depression in studies over 14 years, showed improvements of greater than 50% on the Hamilton Rating Scale for Depression (considered the benchmark for being significantly improved), with reductions in 53-64% of cases with SSRIs and 43-70% with TCAs. However, far from being an accepted hypothesis, the monoamine theory is hotly contested with many institutes and researchers finding no support or even conflicting results – for example it should be observed that the DSM does not mention serotonin in any causes of mental illnesses and explicitly states that the cause of depression is not known (Lacasse & Leo, 2005). As a way of looking at the efficacy of antidepressants in all drug trials and not only those supporting the claims of drug manufacturers, Kirsch, Moore, Scoboria, & Nicholls (2002) conducted an analysis of all antidepressant drug clinical trials submitted to the FDA. They found that 80% of drugs’ efficacy could be duplicated by the placebo and that even 57% of pharmaceutical company-funded trials showed no improvement over placebo. Furthermore, if the monoamine hypothesis is correct then it needs to account for the number of people not responding successfully to antidepressant treatment, which should be more consistent and much higher. A review of pharmaceutical industry efficacy trials found remission rates for the newer SSRI antidepressants to be between 35% and 45% (Thase, Entsuah, & Rudolph, 2001), which means that more than half of people do not respond or improve under antidepressants. In stark contrast to the theory that increasing synaptic serotonin reduces depression, Nickel, et al. (2003) found that treatment of depressed inpatients using the drug Tianeptine - which actually reduces available serotonin by increasing reuptake into the presynaptic cells - had both a significant effect on improving depression symptoms and was equally as effective as Paroxetine - a commonly prescribed SSRI. This again appears to demonstrate that Serotonin is not directly or uniquely responsible for causing depression. To better understand whether a relationship exists between low neuronal monoamine levels and depression, researchers have looked at the levels of serotonin and norepinephrine in the brain, and other more available areas such as urine and spinal fluids of severely depressed patients, and found a relationship between impoverished monoamine levels, in particular serotonin, and increased occurrence of depression (Nemeroff, 1998). Post mortem studies also revealed an increased density of norepinephrine receptors in the brains of suicide victims who suffered from depression, further suggesting that depleted monoamines may cause depression - increased receptor cells are considered to be indicative of consistently lower levels of neurotransmitter (Bunny & Davis, 1965). Although research findings appeared to show a correlation between lowered monoamines and depression, recent reviews of the research have found “the primary literature is mixed and plagued with difficulties such as very small sample sizes and uncontrolled variables” (Lacasse & Leo, 2005). In addition, since no method is available to selectively deplete neuronal norepinephrine and no imaging technology available to analyse the brain’s norepinephrine system in living patients, clear evidence supporting the relationship between abnormalities in norepinephrine neurotransmitter and depression is not available (Pandey & Dwivedi, 2007). Low serotonin or norepinephrine being the direct cause of depression appears severely flawed and a key consideration is that of causation. How can one know whether low levels of monoamine neurotransmitters are the cause of depression or a result of it? Furthermore, if the monoamines were directly responsible for depression, it would be expected that increasing neural levels would reduce the symptoms of depression almost instantly, when in fact it can take many weeks before antidepressant drugs begin to work, if they ever do, despite neurotransmitter levels rising almost instantly (Kennett, 1999). Other research carried out to try and understand whether lowered monoamine neurotransmitter levels directly cause depression subjected depressed and normal participants to a specific diet that lowered tryptophan – a serotonin precursor– and found that lowered serotonin levels led to increased depressive symptoms which disappeared once a normal diet was restored (Delgado, et al., 1994; Smith, Fairburn, & Cowen, 1997). This should therefore mean that increasing serotonin levels in the brain would reverse depressive symptoms, however research by Mendels, Stinnett, Burns, & Frazer (1975) had patients with depression injected with large amounts of L-tryptophan or levodopa - serotonin and dopamine precursors – both of which raised neuronal monoamine levels but had no significant effect on improving depressive symptoms or mood, again confounding the view that neuronal monoamines directly caused or cured depression. There has also been research into dopamine’s role in depression with some evidence supporting that dopamine dysfunction may be a key contributor to some forms of depression (Thase, 2009). The theoretical basis appears valid in that the known functions of dopamine in pleasure and reward match well with the anhedonia expereienced in many cases of depression (Butcher, Hooley, & Mineka, 2015). However the veracity of the claims remain similar to those of the effectiveness of other monoamines. For example the findings that dopamine metabolites such as homovanillic acid (HVA) are reduced in patients with depression (Kapur & Mann, 1992) does not specify causation – depression could conversley lead to reduced HVA levels. Research that correlates the high levels of depression expereienced by patients with Parkinson’s disease and its associated low levels of dopamine (Mayeux, 1990; Chaudhuri & Schapria, 2009) also brings up the question of causation and difficulties in assessing patients with comorbidities, in this case understanding whether Parkinson’s disease itself and not dopamine dysfunction may bring on depression (Rampello, Nicoletti, & Nicoletti, 2000). Some drugs that increase dopamine in patients have also been shown to be effective in reducing depression. For instance trials of the drug Pramipexole, a dopamine D2 agaonist, on patients with major depression were found to significantly reduce depression compared to no treatment and placebo (Corrigan, Danahan, Wright, Ragual, & Evans, 2000). However most studies into dopamine and depression have been small open-label or non-randomised (Chaudhuri & Schapira, 2009) and have often been carried out on patients with other comorbidies such as Parkinson’s, meaning that causastion is difficult to clearly ascertain. More recent research has considered the effect that hormones may have on depression, with a strong focus being on the steroidal hormone cortisol. Research by Sachar, et al. (1973) found that approximately half of patients with depression showed disturbed cortisol diurnal rhythms. Furthermore blood cortisol levels in depressed patients was measured to be elevated in 20 to 40% of cases, and in patients hospitalised for severe depression between 60 and 80% (Thase, Jindal, & Howland, 2002). Other research has found that a significant minority of people suffering or predisposed to depression have elevated levels of cortisol found in nearly all bodily fluids at various times of day compared to non-depressed participants (Thase, 2009; Portella, Harmer, Flint, Cowen, & Goodwin, 2005; Goodyear, Herbert, Tamplin, & Altham, 2000). Cortisol helps to organise the circadian system of the body (Herbert, 2012) and Hasler, et al. (2010) found that sleep patterns, melatonin cycles and body temperature – all of which are believed to be effected by cortisol levels – were different in depressed patients than in non-depressed. Corticoid receptors are widely distributed in the limbic system of the brain, in particular the areas of the hippocampus, amygdala and hypothalamus, which are widely recognised as playing a role in pleasure and emotions, which also form some of the key symptoms of depression i.e. anhedonia and mood/affective disorders (Rosenfeld, van Eekelen, Levine, & de Kloet, 1993). As it is known that excessive exposure of corticoids to receptors endangers the brain by making it more susceptible to noxious agents, it may be the case that higher cortisol levels also potentiate psychopathological actions of these agents (Herbert, 2012), leading to depression in those effected. Further evidence to support the cortisol theory of depression comes from experiments using dexamethasone – a chemical that suppresses cortisol. While dexamethasone successfully suppresses cortisol in normal individuals, it fails to lower cortisol in around 45% of patients with severe depression (Thase, Jindal, & Howland, 2002). However it should be noted that later research has also found that dexamethasone fails to suppress cortisol levels in patients with other illnesses such as panic disorders and is therefore unlikely to be a direct indicator of depression. Another challenge to the cortisol theory is again that of causality - does cortisol cause depression or is it a result of it? Measuring cortisol levels over a sustained period of time and/or following specific life events is incredibly difficult and makes predicting depression based upon cortisol fluctuations almost impossible (Herbert, 2012). This essay has considered the usefulness of the biochemical theory of major depression by looking at the evidence that levels of neurotransmitters and hormones, in this case cortisol, may cause depression and that medications designed to alter brain chemical levels directly succeed in reducing depression. It is clear from the preceding review that there is no clear evidence that depression is directly or uniquely caused by biochemistry alone. While much research has found that altering neurotransmitter or cortisol levels can effect depression, the findings are inconsistent and often opposing. It does however appear that brain chemicals play a role in depression and could ultimately likely contribute to a cure. As research into brain chemistry increases and a better understanding of how chemicals interact with each other is learned, researchers will undoubtedly have a clearer insight into what causes depression and how best to approach curing it. It is however unlikely that depression is an entirely biological problem and that the environment of individuals plays a role in determining who becomes depressed. It is also likely that psychotherapy will continue to be a beneficial form of treatment, alongside any biochemical solutions such as antidepressants. Depression is ubiquitous and commonplace and remains a debilitating disease for millions of people worldwide. While there appears to be no unanimously evidenced cause, research into a biochemical basis for depression is a step in the right direction, with the data ascertained so far being an important basis for finding better cures in the future. References Bunny, W. E., & Davis, J. M. (1965). Norepinephrine in depressive reactions. Archives of General Psychiatry, 13, 483-494. Butcher, J. N., Hooley, J. M., & Mineka, S. (2015). Abnormal Psychology. Harlow: Pearson Education Limited. Chaudhuri, R. K., & Schapira, A. H. (2009). Chaudhuri, K. Ray, and Anthony HV Schapira. 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