Diseases and Disorders

A Modern Biological Theory of Depression

Kevin Bao


Purely biological theories of major depressive disorder (MDD) have waned in favor of a holistic approach in modern psychology, encompassing social, psychological, and other factors. The biological theories of depression still employed in medicine require revising. Recent evidence shows that depression is not just a chemical disorder localized in the brain that can be treated with antidepressants that target neurotransmitters alone. Depression is a body-wide disorder, and an effective biological approach to treatment must be holistic. The monoamine hypothesis is worth revisiting in light of new research that connects disruptions of biological mechanisms throughout the body to chemical changes in the brain. Even with the decline of a solely biological perspective, it’s been well established that the monoamine neurotransmitters serotonin, dopamine, and norepinephrine have a strong link with depressive symptoms. These chemicals are the main regulators of the limbic system —the emotional control center of the brain—and low levels strongly correlate with depressive symptoms.


Modern Theories of Antidepressant Mechanisms

The biggest shortcoming of the monoamine hypothesis is that monoamine levels rise within hours of consuming antidepressants, but depressive symptoms are only relieved after weeks of medication. If depression was indeed caused by low monoamine neurotransmitter levels, why don’t symptoms relieve when levels are raised? At best, this suggests that the relationship between monoamine neurotransmitters and depressive symptoms is not as straightforward as initially proposed; at worst, the monoamine hypothesis may need to be reexamined for its validity. 

Recent research has managed to salvage the monoamine hypothesis by proposing alternate, slower mechanisms of action that are consistent with the delay before relief. Serotonin receptors require two components to function properly: the receptor itself and a G protein that converts the receptor binding to the release of the primary messenger cAMP, which is responsible for bringing about an appropriate cellular response. It has been observed in depressives that an abnormally high number of G proteins clump in lipid rafts in the cell membrane, which impairs their function [1]. As a result, serotonin receptors do not detect serotonin properly. Accordingly lower levels of cAMP have been observed inside depressives, which lead to cell dysfunction and possible depressive symptoms regardless of the levels of serotonin. The study showed that SSRIs and MAOIs accumulated in the rafts when compared with non-antidepressant controls, displacing G proteins to other areas of the cell membrane where they can better function. Increased cAMP levels have been observed after antidepressant treatment. This is a slow process that better aligns with the symptom relief time frame observed in depressives that take anti-depressants. 

More empirical evidence shows that when serotonin reuptake transporters are inhibited, sometimes dopamine reuptake transporters (DATs) will absorb the serotonin. The serotonin could then be excreted simultaneously with dopamine from the same dopaminergic terminal. Dopamine receptors are slightly sensitive to serotonin, but they will trigger if enough serotonin builds up [2]. This process takes up an extended period of time, again much closer to the timeframe of observed symptom relief. This shows that serotonin levels alone are not responsible for MDD and opens up a field of potential research of novel dopamine approaches to depression. 

As part of a negative feedback loop to maintain controlled levels of serotonin in the synaptic gap, presynaptic 5-HT1A autoreceptors send a message that inhibits the secretion of more serotonin from the presynaptic neuron. Unlike postsynaptic receptors, autoreceptors are located on the presynaptic neuron but are also stimulated when binded to serotonin. When there is excess serotonin in the synaptic gap, 5-HT1A autoreceptors are stimulated more which results in less serotonin being secreted into the synaptic gap. This creates a contradiction with the theory that antidepressants work only by increasing serotonin levels in the synaptic gap: wouldn’t the decreased secretion of serotonin revert the increased levels brought about by SSRIs? This contradiction may be resolved by the fact that autoreceptors become desensitized and downregulated when chronically overstimulated. 5-HT1A autoreceptor overstimulation may be a primary mechanism of action for antidepressants that increase synaptic serotonin. However, more recent research proves this approach to be much more complex. SSRI treatment actually resulted in greater anxiety for mice that lacked the 5-HT1A gene [3]. However, increased metabolism of serotonin was also observed, which likely reverted the effects of increased secretion of serotonin due to the absence of 5-HT1A. Since 5-HT1A autoreceptor stimulation initially decreases synaptic serotonin before desensitization, this mechanism accounts for the delay before symptom relief. 5-HT1A autoreceptor agonists may hold potential as antidepressants. Full agonism of presynaptic 5-HT1A  (as well as partial agonism of postsynaptic 5-HT1A) likely explains the antidepressant effect of buspirone, an anti-anxiety drug.  


Tryptophan, a Precursor to Serotonin 

Serotonin is synthesized from the amino acid L-tryptophan (TRP), but their relationship is more complex than direct. TRP must first cross into the brain through the blood-brain barrier before it can potentially have any effects on depressive symptoms after being converted to serotonin. When crossing the barrier, it must compete with other amino acids in passing through; the more competing amino acids (CAA), the less likely TRP will enter the brain [4]. Thus, the ratio of TRP to CAA is a measure of the potential for TRP to enter the brain, and the higher the ratio the higher the potential for symptom relief. The obvious way to do this would be to increase serotonin levels, and indeed depressives are consistently observed to have lower TRP levels [5], and TRP supplements have been shown to reliably relieve depressive symptoms [6]. The second method of increasing TRP/CAA ratio is by decreasing CAA levels. One study has even suggested that a CAA abundance rather than a TRP deficiency is more responsible for depressive symptoms [7].  Injecting rabbits with insulin significantly decreases quantities of CAA, but also halved the amount of free TRP due to increased TRP binding to the carrier protein albumin in the presence of insulin [8]. Overall, the decreased CAA levels compensated for the decreased free TRP levels, and there was a net increase in the influx of TRP into the brain, which supports the findings of [7]. However, without further research into human subjects no firm conclusion can be made about insulin’s potential to treat MDD. There is little current research into CAA levels on depressive symptoms, but it holds great potential as a treatment approach.

Relief of symptoms after increasing the TRP/CAA ratio shows that there is still validity in a serotonin hypothesis. However, in order for this course of treatment to be efficacious, patients must already have an abnormally low TRP/CAA ratio; the higher the TRP/CAA ratio of a depressive, the less likely the increase of the ratio will result in symptom relief [9].

Early wakening and disruption of sleep/wake cycles is a common depressive symptom. Conveniently, one precursor of melatonin – the main hormone that regulates sleep/wake cycles – is serotonin. Also convenient is that melatonin levels fall when waking from sleep. It’s easy then to make the connection and theorize that since serotonin levels are lowered in depressives, melatonin levels may be lowered as well, possibly causing their levels in the brain to drop sooner when sleeping and cause early awakening. Low serotonin, possibly explains yet another depressive symptom, but chemical interactions are extremely complex and may not be this straightforward.  Moreover, sleep stages in depressives are disordered, which further suggests disrupted melatonin levels, possibly due to disrupted serotonin levels.


The Inflammation Hypothesis and Tryptophan Metabolism 

It has been observed that inflammation due to increased pro-inflammatory cytokine levels and increased release of glucocorticoids caused by a dysfunction of the immune system and hyperactive HPA axis accompanies MDD [10]. The inflammation hypothesis proposes that inflammation and MDD might be causally linked and that inhibiting the activity of cytokines may be able to combat depressive symptoms. The release of glucocorticoids from the adrenal glands is controlled by tropic hormones released by the pituitary gland and regulated by negative feedback. Glucocorticoids bind to glucocorticoid receptors (GRs) that inhibit the transcription of corticotropin-releasing hormone in the hippocampus, which mediates the release of ACTH, which stimulates the release of corticosteroids from the adrenal glands. In depressives, GRs have decreased function—possibly due to hippocampal damage due to excessive glucocorticoid release [11]—which results in failure of negative feedback regulation and further excessive release of glucocorticoids. This evidence provides a biological basis for the “downward spiral” of symptoms often reported by depressed individuals. Monoamine reuptake inhibitors have been observed to increase GR mRNA, possibly restoring functional negative feedback inhibition of glucocorticoid release of the HPA axis [12].

The inflammation theory also provides some insight into the possible external causes for depression, since stressors can trigger a stress response from the HPA axis and prompt the release of both pro-inflammatory cytokines and glucocorticoids. This is one of the bridges between the biological and psychological approaches to treatment: Modifying biology by eliminating stressors through therapy instead of medication may be more effective for some individuals.

Increased glucocorticoid indirectly leads to less serotonin through its interaction with the second major TRP metabolic pathway, the kynurenine pathway (KP). Unlike the serotonin pathway, the KP disposes of excess TRP to help maintain homeostasis by converting it into kynurenine, which is then further decomposed into many catabolites. The first enzyme in the pathway, tryptophan 2,3-dioxygenase, limits the rate of pathway completion and is induced by glucocorticoids. Therefore increased glucocorticoid levels would increase TRP depletion through the KP and reduce TRP availability for serotonin synthesis, potentially leading to depressive symptoms. Empirical evidence supports this: treating patients with the synthetic glucocorticoid dexamethasone significantly decreases plasma TRP levels and TRP/CAA ratios [13].  Inhibition of the KP to reduce inflammation may be a potential treatment, though little research has been done so far. 

The goal of the inflammation theory approach is to use anti-inflammatory medication to counter the effects of pro-inflammatory cytokines to alleviate depressive symptoms, and this form of treatment has been efficacious [14]. Nonsteroidal anti-inflammatory drugs have been the most successful at MDD treatment, likely because they do not lead to TRP depletion like glucocorticoids, which are steroid hormones that also act as anti-inflammatory agents. This suggests that glucocorticoids are naturally released to counter cytokine-caused inflation and that the use of anti-inflammatory drugs reduces the need for glucocorticoids, thus reducing TRP depletion. Though it is well-known that glucocorticoids act as the body’s anti-inflammatory agents, recent evidence suggests that chronic exposure to glucocorticoids may actually increase inflammation [15].

A meta-analysis shows that depressives have lower levels of kynurenic acid compared to non-depressives and antidepressant-free depressives have higher levels of quinolinic acid [17]. This makes sense considering that quinolinic acid is a glutamate agonist, and excessive stimulation of glutamate receptors causes excitotoxicity, or damage of neurons due to neurotransmitter excess in the synaptic gap. Ketamine, a channel blocker of the major glutamate receptor NMDA, is a major subject of current research and holds massive promise as an antidepressant. Alongside stimulating mTORC1 protein signaling with NV-5138, ketamine treatment acts extremely rapidly compared to current antidepressants, providing symptom relief within hours that lasts for about a week [18].  Neural damage caused by quinolinic acid likely correlates with depression and is worth investigating in future studies. 

Treatment with antidepressants—including serotonin reuptake inhibitors—results in an increase in kynurenic acid levels. This suggests that depressives have a dysfunctional KP that’s shifted towards the end of the pathway and the production of quinolinic acid. Antidepressants have yet another potential mechanism of action: restoring normal function of the pathway by shifting it towards the beginning of the pathway by increasing production of kynurenic acid.


Epigenetic Influence of Glucocorticoids on the Onset of MDD

The serotonin transporter (5-HTT) is a protein that facilitates reuptake of serotonin, and it has been discovered that polymorphisms exist for the protein’s gene, SLC6A4: a short (s) and long (l) allele. The gene itself does not directly cause depression, but rather it influences the likelihood of the development of depression following stressful life events. This further provides evidence for a relationship between stress-related glucocorticoids & inflammation and depression. Individuals with the (s) allele are more likely to develop depressive symptoms than individuals with the (l) allele. Homozygous (s) genotypes are the most likely to develop symptoms, followed by the heterozygous and homozygous (l) genotype [19]. 

The theory behind that is (s) allele leads to less production of functional transport proteins, leading to dysregulation of serotonin reuptake and less control over serotonin levels in the synaptic gap. Accordingly, individuals with the (s) allele have lower levels of 5-HTT mRNA.

Also,  it has been observed that increasing dexamethasone doses results in increased serotonin reuptake across all genotypes [20].

A systematic review of 67 studies reveals that increased DNA methylation of SLC6A4 and BDNF in general is heavily associated with MDD [21]. BDNF is involved in neurogenesis and neuron maintenance, and decreased BDNF levels along with excitotoxicity may explain the decreased neuron branching observed in depressives, which further demonstrate the massive potential of ketamine—which leads to the creation of new branches — as an antidepressant. Studies inside the review were also able to pinpoint specific CpG sites that were heavily associated with MDD, and there were also contradictory findings for the association of MDD with methylation of other genes, including NR3C1 and OXTR. The SLC6A4 (s) allele is associated with lower levels of mRNA, which is associated with methylation. Also, females also have higher CpG methylation and lower mRNA levels of the 5-HTT gene, providing a molecular explanation for the higher likelihood of females to develop depression than males [22].

Treatment with serotonin and norepinephrine reuptake inhibitors tended to decrease 5-HTT mRNA, and tricyclic antidepressants increase GR mRNA [23]. Also, Caucasians homozygous for the (l) SLC6A4 allele tended to respond better to SSRIs [24]. Both of these suggest that interactions with genetic material may be another antidepressant mechanism.



The monoamine hypothesis is not as outdated as some may argue it to be. Although notions about the pharmacological mechanisms of antidepressants may need to be reevaluated, modern research has paved the way for promising new theories. However, the idea that monoamine reuptake inhibitors solely affect neurotransmitter levels in the synaptic gap must be discarded in light of overwhelming new evidence that suggests mechanisms independent of reuptake inhibition. 

The strong link between biological disorder and MDD shows that there is value in focusing more on the biological approach to depression when it comes to research and diagnosis. It may even suggest that depression is ultimately a biological disorder and that psychological disorder may merely be a symptom, especially considering the biochemical changes caused by stressors. 

Research into the biology of depression is still in its infancy, and many more studies must be conducted before firm conclusions can be drawn. Medications that specifically target newly discovered depression mechanisms—instead of their targeting with conventional antidepressants only being a side effect—might bring about new classes of next-generation antidepressants.  By understanding the underlying pathological causes of depression, the efficacy of newer medication can be increased by targeting a broader range of biological mechanisms. 

Alongside the development of new treatments, a deep understanding of the biology of depression should help bring about a new, more accurate diagnosis criterion based on objective medical testing rather than just the psychological criterion currently outlined in the DSM-5, which is arguably arbitrary, subjective, and inaccurate.


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Kevin Bao

Kevin Bao

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