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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.
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