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By Amelia Wellings
~ 7 min read

During the second half of the twentieth century, advances in molecular biology and computational technology helped to expand the study of neuroscience. The developed ability to measure brain activity during this time allowed scientists to focus on determining the pathophysiology of cognitive disorders that negatively impact one’s well-being. They sought to treat unwanted disorders by understanding their causes.
More specifically, scientists could study the biological mechanisms involved in depression: chemical messengers that are essential for nervous system communication (Peroutka & Snyder, 1980). Serotonin, one of these neurotransmitters, has been implicated in depression throughout the history of neuroscience. The original serotonin hypothesis stated that diminished activity of serotonin pathways causes depression (Lacasse & Leo, 2005). A brief assessment of the development, conflicts and current state of the field suggests that serotonin may not be the sole biological factor influencing depression and happiness.

First Generation: The Original Serotonin Hypothesis

The original serotonin hypothesis was developed in a novel way: the drug testing of medications for prevalent ailments in the 1950s gave rise to the production of antidepressants with a known physiological link to serotonin. While determining the efficacy of a drug to treat tuberculosis, iproniazid, scientists discovered that a side effect of this drug could have implications in treating depression.
In 1957, Loomer, Saunders, and Kline (1958) were some of the first researchers to assess the efficacy of iproniazid on depression by carrying out procedures with humans without tuberculosis. They found that iproniazid had a stimulant effect on depressed patients. Since the biological mechanics of iproniazid were known, these preliminary findings allowed other researchers to progress their understanding of depression. By using known neurotransmitter-affecting drugs that were also monoamine oxidase (MAO) inhibitors to compare efficacy with iproniazid, researchers deduced that serotonin was the major monoamine neurotransmitter affecting depression symptoms (Peroutka & Snyder, 1980). Ultimately, this conclusion led to the original serotonin hypothesis.
The first neuroscientists who ventured to research serotonin’s role in depression established evidence for the original serotonin hypothesis. From the establishment of this hypothesis in the early 1960s through the 1990s, researchers discovered a direct relationship between diminished serotonin pathways and depression. In 1990, Phil Cohen (1990) found that certain 5-HT-mediated neuroendocrine responses were enhanced by tricyclic antidepressants and MAO inhibitors; thus, it seemed likely that tricyclic antidepressants may act as 5-HT2 receptor antagonists in the human brain.
Further, the finding that tricyclic antidepressants inhibited the reuptake of 5-HT implied enhanced brain 5-HT activity in depressed patients (Cohen, 1990). Before this finding, Peroutka and Snyder (1980) discovered that long-term treatment with tricyclic antidepressants and MAO inhibitors decreases the number of labeled serotonin receptors. This favored the role of receptor sensitivity in mediating antidepressant action. In other words, the development of selective serotonin reuptake inhibitors (SSRIs) suggested that increased 5-HT function could be sufficient to diminish depressive symptoms in patients.

Second Generation: Specific Alterations in the Serotonergic Pathway

The second generation of neuroscientists, from the 1990s through the early 2000s, further advanced serotonin research and succeeded in identifying neurochemical alterations in the nervous systems of patients diagnosed with depression. An overlap of generations is seen in 1990 where first generation scientists continued to confirm the direct relationship between serotonin and depression while second generation researchers developed techniques to specify the mechanical pathway through which serotonin affects depression.
Deakin, Pennell, Upadhyaya, and Lofthouse (1990) pioneered this transition by using their knowledge of hormone and serotonin synthesis to create a procedure that measured blood levels of two hormones sharing the same precursor as serotonin. They determined that an impairment in 5-HT systems may be one of two processes causing decreased GH and PRL responses to LTP, which present as abnormalities in depression (Deakin et al., 1990).
A different research group produced similar evidence in supporting the hypothesis of serotonergic diminished activity by studying presynaptic autoreceptors in suicide victims with major depression. Stockmeier et al. (1998) found, “enhanced radioligand binding of an agonist to inhibitory serotonin-1A autoreceptors” (p. 7394); this provided pharmacological evidence showing diminished activity of serotonin neurons.
Advances in molecular biology and computational technology in the 21st century enabled researchers to expand their scope from studying neuroendocrine function and presynaptic autoreceptors in depressed patients to consider the binding density of serotonin postsynaptic receptors as well as polymorphisms in the serotonin-encoding gene.
More specifically, the development of the modern positron emission tomography (PET) scanner in 2000 allowed Sargent et al. (2000) to measure 5-HT1A receptor binding in depressed patients before and during treatment with SSRIs. That same year, they concluded that the binding density of 5-H1A receptors showed a widespread decrease in depressed patients (Sargent et al., 2000).
Similarly, the recent development and completion of the Human Genome Project allowed Avshalom Caspi (2003) to study the effect on depression of single nucleotide polymorphisms (SNPs) in a serotonin gene. Three years after Sargent et al.’s conclusion, Caspi found that a polymorphism in the 5-HTT gene can moderate response to environmental stress, resulting in depression (Caspi, 2003).

Third Generation: Questioning Serotonin’s Sole Role

The third group of neuroscientists to take on the endeavor of understanding serotonin’s function in depression approached its research differently while inspecting previous research in the field. In the mid-2000s, these scientists questioned serotonin’s sole role in mediating depression as well as the reliability and altruism of previous experiments.
A study by Nelson et al. (2004) was the first of its kind to compare autonomous serotonin with a combined serotonin and norepinephrine concoction to decrease depressive symptoms. This group of researchers became intrigued by the limited efficacy and delayed onset of 5-HT antidepressants. Despite the high percentage of participants experiencing remission with only the serotonin, the number of participants experiencing remission on the combination serum was greater; thus, serotonin may be aided in mediating depression (Nelson et al., 2004).
Some researchers went so far as to accuse previously published papers of having false evidence to support the pharmaceutical industry. In a paper by Lacasse and Leo (2005), it is argued that the success of pharmaceutical advertising by SSRI manufacturers relied on a claim that had nonexistent convincing evidence: that SSRI treatment corrected a 5-HT chemical imbalance in depression. By nonexistent convincing evidence, the two researchers refer to the results of multiple published papers that other researchers have not been able to replicate using the same methods and operational definitions (Lacasse & Leo, 2005).
These serotonin-function counterarguments have motivated the field to reach a resolution in recent years: serotonin has some effects, but is not the sole neurotransmitter effector, in depression. A review published by Sprangers et al. (2014) explored the genetic basis to patient-reported quality of life (QOL) by collecting data that explain the role of multiple neurobiological pathways in depression.
More specifically, a review of new developments in literature on the biological pathways, candidate genes and molecular markers involved in fatigue, pain, negative and positive emotional functioning, social functioning and overall quality of life revealed serotonin and dopamine function as common factors (Sprangers et al., 2014).
While researchers like Sprangers et al. are interested in determining the other factors that may regulate depression, some neuroscientists still have focused on determining the singular, molecular mechanism that causes serotonin to have some effect on depression. A recent article by J. de Neve (2011) concluded that variation in the promotor region of the serotonin transporter gene is a promising candidate for better understanding individual heterogeneity in subjective well-being or happiness, as measured by life satisfaction.
Relating to the research conducted by Caspi in 2003, de Neve’s work studied a serotonergic mechanism in a broader, more behavioral way. While Caspi concentrated on mood and suppressed activity to determine depression, Sprangers et al. took the research a step further and implicated depression in one’s well-being.

Implications and Future Research

Conceptual and technological advances combined with conflicts presented by scientists in the neuroscience field have caused the specific serotonin research implicated in depression to change through many decades. Even though research in this field has come a long way, there are a couple of major implications in studying any neurotransmitter and involving it in a cognitive disorder.
First, researchers have developed a way to measure blood levels of neurotransmitter in the brain. However, researchers do not know if blood levels reflect the brain’s actual level of serotonin. This uncertainty is because of the fact that neurotransmitter action occurs at the level of neurons instead of in the blood. Therefore, scientists assume that an increased neurotransmitter blood level is synonymous to an increased neurotransmitter use in the brain through metabolic factors even though there is lack of empirical evidence.
Additionally, many researchers have not yet determined whether the decrease in serotonin causes depression or whether the depression causes serotonin levels to decrease. The machinery and concepts have unfortunately not yet been developed to determine or resolve these implications.
Lastly, depression and overall well-being is subjective and dependent on one’s perception. Therefore, it is difficult to map a biological mechanism such as serotonin transmission onto a disorder that is variable in its presented symptoms. More research and improved technology is needed to determine other neurochemical pathways or psychological mechanisms mediating depression.
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