Depression is referred to as a ‘common mood disorder' characterised by long periods of sadness and lack of interest in otherwise normal hobbies (World Health Organisation, 2018). There are also many other symptoms which have been recorded as resulting from depression, however a definitive cause of the mental disorder has not yet been identified. There are many possible risk factors which have been studied such as biogenic amine deficiency, neurogenesis and genetic factors. The monoamine hypothesis model and the use of SSRIs are both used in the treatment of depression.
The mono-amine hypothesis has served as a development for drugs used in treating depression. It was thought that agents utilised to increase synaptic concentrations of monoamines via an array of mechanisms could be vital in improving the symptoms of depression (Hirschfeld, 2000). This led to the introduction of the monoamine hypothesis, also referred to as the biogenic amine hypothesis in many studies. The hypothesis proposes that the reduced availability of 5HT, NE and DA neurotransmitters results in ‘decreased neurotransmission and impaired cognitive performance' which may essentially lead to depression (Barchas and Altemus, 1999).
Selective serotonin reuptake inhibitors work to block the uptake of serotonin from the extracellular space to regulate serotonergic neurotransmission (James et al, 2017). This results in an antidepressant effect but the methodology behind this remains undetermined. Many articles make reference to using PET in an attempt to quantify SSRI's target; the serotonin transporter (SERT). Fluoxetine, referred to commonly as Prozac, was the first SSRI to be introduced into the US in 1987. Post marketing clinical trials of the drug have seen adverse side effects such as sexual dysfunction rates of 75% (Rosen, Lane and Menza,1999) . Due to the benefits of SSRI use at the sub- receptor level, it is most likely that the majority of side effects of the drugs such as nausea can be alleviated with a reduced dose. However, an overdose of the drug can cause the potentially life-threatening serotonin syndrome; a group symptoms such as hyperreflexia, incoordination and myoclonus.
In 2017, a study was carried out to investigate the serotonergic circuits of patients both at baseline and during treatment of major depressive disorder with SSRIs. James et al hypothesised that there would be a significant difference in the before and after treatment of the interregional relation of availability of the SERT protein; responsible for the transportation of serotonin to the presynaptic neuron from the synaptic cleft. This hypothesis was finalised with the idea that these regions would inadvertently differ between healthy patients and sufferers of MDD. PET scans were taken 3 times each for a total of 38 patients (19 healthy patients and 19 MDD patients). A baseline measurement was taken before administering citalopram or escitalopram, followed by a measurement within 6 hours and finally after at least 3 weeks of daily oral drug administration. Protein availability was measured by its binding potential. Main areas of interest during the investigation were the thalamus, pautamen and caudate nucleus, due to previously researched links between these brain regions and SSRIs (Anand et al, 2005) .
Correlations of the different regions of the brain were examined to have increased significantly following the three week treatment. Baseline results showed that patients suffering from MDD had low binding potential and low serotonin levels in comparison to healthy patients. The treatment of SSRIs used in the trial showed an increase in binding potential, after only 6 hours. It could also be inferred from the results that regions of the brain associated with emotion and sadness, appetite and other depression symptoms in suffering patients had a low density of SERT and therefore low serotonin levels. James and co-authors determined that using SSRIs to focus on protein function in brain regions associated with the symptoms of depression should be investigated further to develop treatment, because transport proteins play a vital role in monoaminergic transmission by facilitating the reuptake of neurotransmitters in the presynaptic cleft so that it can bind to the postsynaptic receptor. This is important to allow for continuous neurotransmission.
In 2014, Purgato and colleagues investigated the effects of paroxetine against other anti-depressive agents in the treatment of depression. They used the Cochrane depression, anxiety and neurosis review group's specialised register (CCDANCTR) to review randomised controlled trials involving paroxetine use against other drug treatments such as TCAs and other SSRIs. Their aim with to compare drug efficacy in alleviating acute symptoms of depression along with any adverse effects and acceptability of treatment. The authors included 115 randomised controlled trials with numerous participants involved (26,134). Of those 115, 21 studies involved SSRIs in comparison to paroxetine, 54 with older Anti-depressants and 40 trials with newer anti-depressants not categorised as SSRIs. All the trials provided unclear information, but provided results supporting the idea that paroxetine was most effective in early responders to the treatment compared to reboxetine. It was less effective than mirtazapine and citalopram in overall improvement over longer periods of time (6-12 weeks). The authors therefore concluded that there is no definitive conclusion to be obtained from these findings regardless of the clinical differences between the SSRI paroxetine and other drug treatments. Most studies were at high risk of bias and so the results would be better used for further investigation into what SSRI, if SSRIs at all, are a better treatment option for mental depression disorder. (Purgato et al,2014)
Authors Jesulola, Micalos and Baguley reviewed the pathophysiology of depression and the related hypothesis models in 2017. Considering the research behind depression began in the 50s, this article serves to bring together all the conclusive research into what causes depression and possible treatments. The authors state that ‘the precise mechanism(s) by which depression develops is incomplete' due to the disorder being heterogenous with multiple aetiologies. Jesulola et al determine that the monoaminergic system comprised of NE,5HT and DA are extremely significant in the symptoms associated with depression. This article claims that the poor pathophysiology understanding of the disease explains the numerous investigative failures in MDD treatment. Evidence for this statement is the numerous clinical trials that show positive results as opposed to placebos, with a number of scientists also querying these findings. The authors suggest the reasoning behind failed therapies is the lack of post psychotherapy treatments which would explain the low efficacy in single treatments. Jesulola et al go on to discuss the recognised mechanisms including the biogenic amine hypothesis, genetic and environmental factors and dysregulation of the hypothalamic-pituitary- adrenal axis. Changes in cerebral 5HT levels are affiliated with behavioural and somatic function changes associated with depression, supported by evidence that post-mortem studies show depressed patients demonstrate low levels of serotonin in comparison to non-depressed patients. Neurotransmitters play a significant role in brain activity and the article specifies dopamine, serotonin and norepinephrine to be ones involved in the ‘development and clinical manifestation of depression' (Nemeroff, 2008). The authors provide an overview of experimental findings in relation to monoamine oxidase and it's degrading effect in the synaptic cleft. The decreased neurotransmission which results in depression is a result of continuous activity of the enzyme monoamine oxidase. The article goes on to list inhibitors for this enzyme as a possible treatment. (Jesulola et al, 2017)
PET studies support the hypothesis that 5HT, NE and DA play vital roles in depression. The altered binding potential of 5-HT1A in depressed patients differs from those who do not suffer from MDD. The PET studies provide a background of evidence towards SSRIs providing therapeutic effects for depressed patients by increasing the serotonergic neurotransmission. However, some authors hypothesise that the hindered dopamine function is the source of low 5HT levels in depressed individuals. Increasing the occupancy of NE transporter/receptors by administering certain drugs also relieves symptoms of depression, indicated by results of PET scans (Moriguchi et al, 2017).
Included in the article are other ways in which SSRIs can aid in the treatment of depression. The authors discuss the role of cerebrospinal fluid which has elevated levels of corticotrophin releasing factor (CSF) in depressed patients (Nemeroff et al , 1991). The article indicates the use of SSRI fluoxetine to stabilise the CSF levels. Another use of SSRIs according to Jesulola, Micalos and Baguley are in neurogenesis. It was suggested that pathophysiology of depression in adults could be due to a reduced neurogenesis capacity which could be resolved by SSRIs as the regeneration of the hippocampus could result in higher SERT density. However, this hypothesis would require further testing, as depressive behaviour was found in animals with normal neurogenesis (David et al, 2009).
A paper published in 2018 by Durgam et al outlines a double blinded, placebo controlled study of the effects of SSRI Vilazodone, an FDA approved drug in adults, in adolescents suffering from MDD. The study was fixed dose and randomised. Patients were given either a placebo, 15mg of vilazodone per day or 30mg per day. The most common adverse effects as a result of drug administration were upper abdominal pain, vomiting / nausea, dizziness and diarrhoea. Statistically there was no difference between any of the treatments and the efficacy of the SSRI was undetermined from the trial. Although there were signs of improved symptoms and the mean Children's Depression Rating Scale–Revised values decreased from the baseline readings to week 8, the mean difference was not statistically significant between placebo or either vilazodone treatment. Adverse effects occurred more in vilazodone patients than placebo treated patients including suicide-related effects which lead to some discontinuation of treatment. It was determined that the SSRI alone would not be effective due to serious adverse effects and inability to significantly differentiate itself from placebo drugs. The investigation determined a lack of clear efficacy evidence which maintains the question of harm Vs benefits. Fluoxetine seems to be the only SSRI investigated in clinical trials where the efficacy of the drug outweighs the adverse effects (Zhoue et al, 2018).
None of the above authors definitively state a significant difference between the efficacy of SSRIs and the placebo drugs. A popular statement made amongst the articles is the need for psychotherapy treatments alongside SSRIs. Purgato et al concluded that although not statistically different, paroxetine showed the most progression in treatment over a longer period of time. Durgam at el contradict this with the statement that fluoxetine appears to be the sole SSRI investigated in clinical trials where the efficacy of the drug outweighs any adverse effects.
James et al and Jesulola, Micalos and Baguley both reviewed the use of PET scans in evaluating the use of drugs in depression. They focused on processes involving monoamine oxidase and serotonergic receptors. James et al provided evidence on the relation of SERT proteins between depressed and non-depressed patients, suggesting further research should be conducted on the relation between SERT protein density in the brain and the levels of serotonin reaching the post synaptic receptors. Jesulola et al provided evidence to suggest that norepinephrine should be the focus of PET scans in relation to depression by increasing occupancy of its transporters/receptors.
Jesulola, Micalos and Baguley provided an overview of multiple trials and tests which have been published over the years. However, they proceed to explain depression to be a heterogenous disorder that has a complex phenomenon which is the reason the mechanism involved in the development of depression is unknown. This statement leaves room for considerable evaluation. All the drugs tested and used in the treatment and depression were developed and in the 1980s, and although many clinical trials have been carried out they only slightly outperform placebos. Research over the decades fails to provide a precise mechanism for these drugs and there has been little improvement to the clinical care of patients suffering from depression. Hamilton's rating scale for depression is almost 60 years old (Rausch, 1989) and still the gold standard for clinical trials but is profusely different to the MDD criteria stated in Diagnostic and Statistical Manual of Mental Disorders. A recent paper highlighted 1030 unique symptom profiles in 3703 patients suffering from depression (Fried and Nesse, 2015). Depression requires personal medicine, which questions why biological markers and risk factors are still being investigated, when there has been no significant findings in almost 30 years and each patient has a different set of symptoms.
Furthermore, SSRIs are potent inhibitors or serotonin reuptake; having very little effect on norepinephrine or dopamine reuptake. These drugs do not antagonise or -adrenergic receptors, nor dopamine D2 receptors. The majority of literature outlining depression, especially Jesulola et al, suggests dopamine and norepinephrine also play vital roles in depression, yet there is limited research on potential shock therapy or drugs to explore treatments of depression in this way.
Clinical trials have been submitted to the FDA for approval to license SSRIs; mainly paroxetine, fluoxetine, vilazodone, venlafaxine and nefazodone. The articles overviewed above outline trials that have investigated the effects of these drugs, efficacy and the resulting evidence gathered. Durgam et al and Purgato et al both state in their findings that although results show relief of depressive symptoms after the administration of an SSRI, the difference is so minute in comparison to that of placebos, and so the question arises as to whether the efficacy of selective serotonin reuptake inhibitors outweigh the adverse effects.
...(download the rest of the essay above)