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The Evaluation of The Serotonin Theory of MDD and the Effectiveness of SSRIs

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Major depressive disorder (MDD), one of the leading causes of disability worldwide (Thornicroft et al., 2018), is a common psychological condition categorized under mood disorders in the DSM-5. Mood disorders consist of conditions that involve predominant problems with either mood or affect (American Psychiatric Association, 2013). According to the World Health Organisation, the prevalence of MDD in all age categories has increased in recent years, with over 300 million cases reported worldwide (Pan et al., 2018). Affecting one in six adults at some point in their lifetime (Otte et al., 2016) and costing a predicted $147 billion to treat over the next 14 years in the US alone (Chisholm et al., 2016), MDD merits singular discourse regarding its theories and appropriate treatment. In order to achieve a definitive diagnosis of Major Depressive Disorder, the patient must have experienced several of the clinical characteristics of the disorder for a minimum period of 2 weeks. Depressed mood, loss of interest, and feelings of worthlessness are a few examples of the required symptoms (American Psychiatric Association, 2013). The common assumption is that MDD simply occurs as a result of a chemical imbalance within the brain (Deacon & Baird, 2009). Upon reviewing this theory, researchers discovered that MDD actually occurs due to a complex combination of biological, social, and psychological factors (Kupferberg et al., 2016; Beck & Bredemeier, 2016). Even though it is not the primary cause of MDD, a chemical imbalance within the brain as part of the biological approach for MDD does provide some explanation for the symptoms involved with Major Depressive Disorder (Patten, 2015).

In recent years, an accumulating number of studies have looked into and observed the effects of the “serotonin hypothesis”, a distinct dysfunction of serotonin neurotransmission (5-HT) in participants diagnosed with MDD (Domínguez-López et al., 2012). Serotonin, which acts as both a neurotransmitter and a hormone, is crucial to the functioning of several systems and the regulation of mood and anxiety (Carhart-Harris & Nutt, 2017). The hypothesis concerning serotonin neurotransmission states that reduced levels of 5-HT (5-hydroxytryptamine) can increase the likelihood of developing depression (Albert & Benkelfat, 2013). Since the formation of this hypothesis, various studies have confirmed this association between 5-HT and Major Depressive Disorder. Maurer-Spurej et al. (2007) found that patients who were diagnosed with depression displayed significantly low levels of 5-HT in their blood platelets. A more recent study by Ogawa et al. (2014) also found that depression can cause reduced plasma levels of L-tryptophan, which is a precursor for 5-HT.

A monoamine transporter protein known as SERT maintains the regulation of serotonergic neurotransmission by removing variable levels of 5-HT from the surrounding extracellular fluid (Sundaramurthy et al., 2017). The fluctuating levels of 5-HT associated with Major Depressive Disorder are based on the on changes in the promoter region of this gene (Fakhoury, M., 2016). Otherwise known as the serotonin transporter, solute carrier family 6 member 4, or sodium-dependent serotonin transporter, SERT proteins are encoded by the SLC6A4 gene (Manoharan et al., 2016). Neurons in the central nervous system communicate using chemical and electrical messengers. This form of communication is a result of neurotransmission, in this circumstance, serotonergic neurotransmission (Kavalali, 2015). When serotonin (5-HT) is released into the synaptic cleft that exists between a presynaptic and postsynaptic neuron, after generating an action potential in the postsynaptic neuron, SERT allows the re-uptake of 5-HT from this synaptic space in order to be re-used in the presynaptic neuron and thus terminating the serotonin’s effect (Vuorenpää et al., 2016). Due to polymorphisms in the promoter region of SERT, serotonin levels in the brain decrease, leading researchers to discover an association between low serotonin levels and Major Depressive Disorder (Kohen et al., 2013).

Despite the compelling evidence supporting the authenticity of serotonergic transmission in MDD, as well as it being a theory established over 50 years ago (Albert et al., 2012), not all studies in this field have obtained supportive results. Cowen & Browning (2015) proposed that theories linking low serotonin levels with major depressive disorder should no longer be considered tenable, as more recent studies into MDD have found promising results when observing the influence of serotonin on emotional processing. The basis of this explanatory theory for MDD is based on the function and mechanisms of the neurotransmitter, serotonin (5-HT) despite its actual role not yet confirmed after decades of research (Marazziti, 2017). Lacking a formal role for serotonin in cognition may partially be due to the difficulties associated with attempting to identify serotonergic neurons electrophysiologically; current advances in optogenetics may be able to resolve this in the near future (Miyazaki et al., 2014). Another inconsistency within this model for Major Depressive Disorder is the theory of polymorphism when regarding the SERT protein channels. Despite its recent popular use in determining the cause of depression or MDD, this form of polymorphism never received subsequent confirmation (Murthy et al., 2010). According to Booij et al. (2015), this resulted in the formation of inconclusive hypotheses or less conclusive hypotheses concerning how polymorphism actually contributed to this theory.

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Even though there is much scepticism regarding this “serotonin hypothesis” model for Major Depressive Disorder, the successful studies that go towards supporting this theory promoted the introduction of selective 5-HT re-uptake inhibitors (SSRIs) as a form of treatment for MDD (Healy, 2015). The introduction of SSRIs into clinical practice represents one of the most significant and successful advances in psychopharmacology as it is still a widely used drug for treating depression and MDD (Stahl, 2017). During normal communication between two nerve cells in the nervous system, after serotonin neurotransmission has occurred, SERT proteins recycle the neurotransmitters back into the presynaptic neuron for future use (Vuorenpää et al., 2016). However, according to the “serotonin hypothesis”, individuals diagnosed with depression or MDD have lower levels of serotonin in their brains (Albert & Benkelfat, 2013). Therefore, any treatment attempting to reverse this would need to have an effect on the regulating mechanisms of 5-HT levels. Such treatments, including SSRIs, are known as reuptake inhibitors (Hicks et al., 2015). SSRIs act as a barricade or a blockage for the SERT protein channels, thus stopping serotonin from reabsorbing back into the presynaptic neurone, therefore forcing the neurotransmitters to remain in the synaptic cleft of the synapse (Holck et al., 2018).

As with the “serotonin hypothesis” for MDD, there is both scrutiny and support for SSRIs as an effective form of treatment. Arroll et al. (2016) reported a significant effect of SSRIs on MDD in primary care when compared to use of a placebo. Cipriani et al. (2018) who conducted a systematic review on several different antidepressants (SSRIs), discovered that all the SSRIs analysed during their research had a significantly larger effect on adults diagnosed with MDD than those who were given a placebo can see similar results in the study. Additionally, during an analysis of several SSRIs based on cost-effectiveness, Sussman et al. (2017) found that brexpiprazole and other specific SSRIs were not only more cost-effective, but also increased response levels and chances of remission after a 6-week period. Based on the success of using SSRIs when treating MDD, this lead to a development of a second generation of SSRIs designed to target specific subtypes of the 5-HT receptors (Stahl, 2008). Unfortunately, not all types of 5-HT dysfunction are detected in patients, which resulted in 50% of cases showing no-response to the drug, and only 30% of patients ever reaching effective remission (Trivedi et al., 2008). Despite some studies finding insignificant results relating to SSRI treatment, Gibbons et al. (2012) observed a significant difference in treatment when comparing fluoxetine and venlafaxine with a placebo drug. In contrast, Fournier et al. (2012) found that SSRIs either had little or no effect on mild or moderate MDD when compared with a placebo, suggesting the SRRIs may only be useful on more severe cases of depression or MDD. However, researchers questioned this study on its statistical basis suggesting that the researchers involved may have underestimated the effect size of various antidepressants (Horder, 2010; Fountoulakis & Möller, 2010).

Biochemical theories, such as the “serotonin hypothesis” have been around for many decades, suggesting that they are probably outdated approaches by now and replacement is necessary. However, supportive studies as recent as the last 12 months found the hypothesis to be fairly accurate.

Research into the effectiveness of SSRIs on treating MDD show both successful and unsuccessful results suggesting that it is an effective form of treatment, but perhaps not for everyone, possibly due to another contributing external or internal factor. With regards for the future of diagnosing and treating MDD, perhaps more advanced research into discovering the link between serotonergic neurotransmitters and MDD will fill in the missing details researchers are currently lacking. Until then, as the “serotonin hypothesis” and SSRI treatments are still producing significant clinical results, it is very likely that they will remain as essential parts of the clinical practice revolved around Major Depressive Disorder.

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The Evaluation of The Serotonin Theory of MDD and the Effectiveness of SSRIs. (2022, September 01). Edubirdie. Retrieved May 29, 2023, from
“The Evaluation of The Serotonin Theory of MDD and the Effectiveness of SSRIs.” Edubirdie, 01 Sept. 2022,
The Evaluation of The Serotonin Theory of MDD and the Effectiveness of SSRIs. [online]. Available at: <> [Accessed 29 May 2023].
The Evaluation of The Serotonin Theory of MDD and the Effectiveness of SSRIs [Internet]. Edubirdie. 2022 Sept 01 [cited 2023 May 29]. Available from:
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