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Antidepressants and the serotonin hypothesis of depression

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• Peer review
• Tony Kendrick , professor of primary care 1 ,
• Susan Collinson , specialist TB case worker 2
• 1 Primary Care, Population Sciences and Medical Education, University of Southampton, Aldermoor Health Centre, Southampton, UK
• 2 Homerton University Hospital NHS Foundation Trust, London, UK
• Correspondence to: T Kendrick A.R.Kendrick{at}Southampton.ac.uk

Antidepressants remain an effective treatment for depression, even without the “chemical imbalance” explanation

A recent umbrella review of evidence for the serotonin theory of depression 1 was widely reported in UK media as showing that depression is not caused by low levels of serotonin or a “chemical imbalance” and therefore casting doubt on the use of selective serotonin reuptake inhibitor (SSRI) antidepressants by millions of people. 2 3 4 5

The review brought together existing systematic reviews, meta-analyses, and large dataset analyses on associations between depression and concentrations of serotonin and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in body fluids; serotonin 5-HT1A receptor binding; serotonin transporter (SERT) levels measured by imaging or postmortem analysis; tryptophan depletion; SERT gene polymorphism; and SERT gene-environment interactions. It reported no consistent evidence to support the hypothesis that depression is caused by reduced serotonin activity, and called for acknowledgment that the theory is not empirically substantiated. 1

The polarising debate that ensued risks undermining the evidence based treatment of depression and causing harm to people who take or need SSRI antidepressants. Critics of the review and its coverage noted that study selection was incomplete, as an omitted 2021 meta-analysis had concluded that changes in blood biochemistry, notably of L-tryptophan, were …

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How your gut microbiome is linked to depression and anxiety

February 2, 2022

Gut microbiome as an extra organ in human body

The human body harbors a large collection of microorganisms—predominantly bacteria, but also viruses, protozoa, fungi, and archaea. They are collectively known as the microbiome. Gut microbiota, gut flora, or microbiome are the microorganisms that live in the digestive tracts of humans and other animals. While some bacteria are associated with disease, others are particularly important for many aspects of health. In fact, there are more bacterial cells in the human body than human cells–roughly 40 trillion bacterial cells vs. only 30 trillion human cells. These microbes may weigh roughly as much as the brain. Together, they function as an extra organ in the human body and play a huge role in human health. The collective genome of the gut microbiome exceeds over 100 times the amount of human DNA in the body. Considering this enormous genetic potential of the microbiota, it is anticipated that it plays a role in virtually all physiological processes in the human body. Gut bacteria have been linked to several mental illnesses, and patients with various psychiatric disorders such as depression, bipolar disorder, schizophrenia, and autism have been found to have significant alterations in the composition of their gut microorganisms.

The interest in gut microbiome as related to human health, and specifically to mental health, is exponentially increasing in the years after 2000, as demonstrated by a search in CAS Content Collection TM . Currently, there are over 7,000 publications on gut microbiome as related to mental health (Figure 1).

Babies acquire their first dose of microbes at birth. Development of the human gut microbiome

It is generally believed that the uterus is a sterile environment, and that bacterial colonization starts during birth. The microbiome of a newborn varies according to mode of delivery: the microbiome of vaginally delivered infants is like the maternal vaginal microbiome and that of infants delivered by cesarean section resembles the maternal skin microbiome. Various other factors affect the developing neonatal microbiome such as premature birth and mode of feeding. The major determinant of gut microbiome composition throughout adulthood seems to be diet. Fast changes in microbiome composition happen in response to changes in dietary intake. Characteristic patterns are noticeable in plant-based versus animal-based diets .   The development and alteration of the gut microbiome are affected by multiple other factors as well. Exposure to stress ranks as the second most important factor (after diet) affecting the gut microbiome composition, according to a search in the CAS Content Collection . Other factors include: mode of delivery and infant feeding method, environmental conditions, medications, stage and mode of lifecycle, comorbid diseases, and medical procedures (Figure 2). A disruption to the microbiota homeostasis caused by an imbalance in their functional composition and metabolic activities, or a shift in their local distribution is termed dysbiosis, indicating microbial imbalance or maladaptation.

Considering the now recognized significant role of diet on gut microbiome composition, and the vital impact of the gut microbiome on health, the million-dollar question remains: –which diet is beneficial and thus recommendable to keep our gut bacteria happy? Although there is not a definitive unambiguous answer pointing out certain food as a specific illness remedy, some major guidelines have been figured out. A high-fiber diet specifically affects the gut microbiota. Dietary fiber can only be digested and fermented by enzymes from microbiota living in the colon. Short chain fatty acids are released because of fermentation, which lowers the pH of the colon. The highly acidic environment determines the type of microbiota that would survive. The lower pH limits the growth of certain harmful bacteria such as Clostridium difficile. High-fiber foods such as inulin, starches, gums, pectins, and fructooligosaccharides have become known as prebiotics because they feed our beneficial microbiota. In general, high amounts of such prebiotic fibers are found in fruits, vegetables, beans, and whole grains like wheat, oats, and barley. Another highly beneficial class of foods contains probiotics, live bacteria that are good for the digestive system and may further amend our gut microbiome. These include fermented foods such as kefir, yogurt with live active cultures, pickled vegetables, kombucha tea, kimchi, miso, and sauerkraut.

Gut microbiota participants

The human gut microbiota is divided into many groups called phyla. The gut microbiota primarily comprises four main phyla including Firmicutes, Bacteriodetes, Actinobacteria, and Proteobacteria, with the Firmicutes and Bacteroidetes representing 90% of gut microbiota . The majority of bacteria reside within the gastrointestinal tract, with most predominantly anaerobic bacteria housed in the large intestine (Figure 3).  

The gut-brain axis – gut microbiome as the “second brain”

It is now well established that gut and brain are in constant bidirectional communication, of which the microbiota and its metabolic production are a major component. Michael Gershon called the digestive system “the second brain” in his 1999 book , at the time when scientists were beginning to realize that the gut and the brain in humans were engaged in constant dialogue and the gut microbes significantly modulate brain function. It is now a common belief that gut microbiota communicates with the central nervous system through neural, endocrine, and immune routes, and thereby controls brain function. Studies have demonstrated a substantial role for the gut microbiota in the regulation of anxiety, mood, cognition, and pain. Thus, the emerging concept of a microbiota–gut–brain axis suggests that modulation of the gut microbiota may be an effective strategy for developing novel therapeutics for central nervous system disorders.

Gut microbiota and COVID-19

Recently, correlation has been reported between gut microbiota composition and levels of cytokines and inflammatory markers in patients with COVID-19 .  It is suggested that the gut microbiome is involved in the magnitude of COVID-19 severity via modulating host immune responses. Moreover, the gut microbiota dysbiosis could contribute to persistent symptoms even after disease resolution, emphasizing a need to understand how gut microorganisms are involved in inflammation and COVID-19.

Gut microbial neuroactive metabolites

Abnormalities in the gut microbiota-brain axis have come out as a key factor in the pathophysiology of neural disease, therefore increasing amount of research is devoted to understanding the neuroactive potential of the products of gut microbial metabolism. Thus, major neuroactive gut microbial metabolites have appeared as follows.

Neurotransmitters

Gut microbiome produces neurotransmitters, which regulate brain activity. The majority of central nervous system neurotransmitters are also present in the gastrointestinal tract, where they exercise local effects such as modulating gut motility, secretion, and cell signaling. Members of the gut microbiota can synthesize neurotransmitters, e.g., Lactobacilli and Bifidobacteria produce GABA; Escherichia coli produce serotonin and dopamine; Lactobacilli produce acetylcholine .  (Figure 4) They signal the brain via the vagus nerve.

Short-chain fatty acids

Short-chain fatty acids are small organic compounds produced in the cecum and colon by anaerobic fermentation of dietary carbohydrates thatfeed other bacteria and are readily absorbed in the large bowel.  Short-chain fatty acids are involved in digestive, immune and central nervous system function, though different viewpoints regarding their impact on behavior exist.  The three most abundant short-chain fatty acids produced by gut microbiome are acetate, butyrate, and propionate (Figure 5).  Their administration was demonstrated to alleviate symptoms of depression in mice. Gram-positive, anaerobic bacteria that ferment dietary fibers to produce short-chain fatty acids are Faecalibacterium and Coprococcus bacteria.Faecalibacteria are abundant gut microbes, with significant immunological roles and clinical relevance for various diseases, including depression.

Tryptophan metabolites

Tryptophan is an essential amino acid participating in protein synthesis. Its metabolic breakdown by bacterial enzymes (tryptophanase) gives rise to neuroactive molecules with established mood-modulating properties, including serotonin, kynurenine, and indole (Figure 6). It has been found that dietary intake of tryptophan can modulate central nervous system concentrations of serotonin in humans, and that tryptophan depletion aggravates depression.

Lactic acid

Lactic acid (Figure 6) is an organic acid developing mainly from the fermentation of dietary fibers by lactic acid bacteria (e.g., L. lactis, L. gasseri, and L. reuteri), Bifidobacteria and Proteobacteria. Lactates can be converted by several bacterial species to short-chain fatty acids contributing to the total short-chain fatty acid pool. Lactic acid is absorbed into the bloodstream and can cross the blood-brain barrier. Lactic acid has a well-recognized role in central nervous system signaling in the brain. Due to its ability to be metabolized into glutamate, it is used as an energy substrate by neurons. It also contributes to synaptic plasticity and triggers memory development.

Most bacteria in the gut, such as Lactobacillus and Bifidobacterium, synthesize vitamins (particularly from the group of B-vitamins and vitamin K) as part of their metabolism in the large intestine. Humans rely on the gut microbiota for vitamin production. Vitamins are key micronutrients with ubiquitous roles in a multitude of physiological processes in the human body, including the brain. Active transporters bring them across the blood-brain barrier. In the central nervous system, their role spreads from energy homeostasis to neurotransmitter production. Vitamin deficiencies can have a significant negative effect on neurological function. Folic acid (vitamin B9) is a vitamin of microbial origin that has been extensively implicated in the pathology of depression.

A recent innovative investigational treatment, fecal microbiota transplantation, has been tested in clinical trials and found extremely therapeutically promising. In the last five years, ~1,000 documents related to fecal transplants have been included each year in the CAS Content Collection. For example, it has been reported that fecal microbiota transplantation is able to resolve 80-90% of infections caused by recurrent Clostridioides difficile that does not respond to antibiotics. The unique implications for clinical trials using fecal microbiota transplants, which are increasingly investigated as potential treatments for a range of diseases, need to be promptly explored. At present, research into the modulation of the gut-brain axis via the gastrointestinal microbiota is an emerging innovative, frontline science. A large portion of the data available is based on either basic science or animal models that may not be adaptable to effective human interventions. Therefore, individualized prescriptions of specific prebiotic compounds and probiotic strains that would represent the ideal of personalization for nutrition and lifestyle medicine remain hopeful. Ongoing efforts to further characterize the functions of the microbiome and the mechanisms underlying host-microbe interactions will provide a better understanding of the role of the microbiome in health and disease.

For more on how emerging trends and new approaches are helping the millions of people who suffer from depression, anxiety, and PTSD see our blog on psychedelics and their progress as a therapeutic approach .

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Dr Mark Horowitz, MBBS PhD

The serotonin theory of depression: is it supported by evidence.

The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is

associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of

research. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception

until December 2020. Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified:

serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT 1A receptor binding; serotonin transporter

(SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT geneenvironment

interactions. Studies of depression associated with physical conditions and specific subtypes of depression (e.g.

bipolar depression) were excluded. Two independent reviewers extracted the data and assessed the quality of included studies

using the AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study. The certainty of study results was assessed

using a modified version of the GRADE. We did not synthesise results of individual meta-analyses because they included

overlapping studies. The review was registered with PROSPERO (CRD42020207203). 17 studies were included: 12 systematic reviews

and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative

synthesis, 1 genetic association study and 1 umbrella review. Quality of reviews was variable with some genetic studies of high

quality. Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with

depression (largest n = 1002). One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression,

and evidence that lowered serotonin concentration was associated with antidepressant use (n = 1869). Two meta-analyses of

overlapping studies examining the 5-HT 1A receptor (largest n = 561), and three meta-analyses of overlapping studies examining

SERT binding (largest n = 1845) showed weak and inconsistent evidence of reduced binding in some areas, which would be

consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly.

However, effects of prior antidepressant use were not reliably excluded. One meta-analysis of tryptophan depletion studies found

no effect in most healthy volunteers (n = 566), but weak evidence of an effect in those with a family history of depression (n = 75).

Another systematic review (n = 342) and a sample of ten subsequent studies (n = 407) found no effect in volunteers. No systematic

review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT

gene, one genetic association study (n = 115,257) and one collaborative meta-analysis (n = 43,165), revealed no evidence of an

association with depression, or of an interaction between genotype, stress and depression. The main areas of serotonin research

provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis

that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that

long-term antidepressant use reduces serotonin concentration.

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Central Neuromodulators in Irritable Bowel Syndrome: Why, How, and When

Hanna-Jairala, Ignacio MD 1 ; Drossman, Douglas A. MD, MACG 2

1 Division of Gastroenterology, Department of Internal Medicine, Hospital Alcivar, Guayaquil, Ecuador;

2 Center for Education and Practice of Biopsychosocial Care, Drossman Gastroenterology, University of North Carolina, Chapel Hill, North Carolina, USA.

Correspondence: Ignacio Hanna-Jairala, MD. E-mail: [email protected] .

SUPPLEMENTARY MATERIAL accompanies this paper at https://links.lww.com/AJG/D247

This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Corresponding Article

Irritable bowel syndrome (IBS) is responsive to treatments using central neuromodulators. Central neuromodulators work by enhancing the synaptic transmission of 5-hydroxytryptamine, noradrenalin, and dopamine, achieving a slower regulation or desensitization of their postsynaptic receptors. Central neuromodulators act on receptors along the brain-gut axis, so they are useful in treating psychiatric comorbidities, modifying gut motility, improving central downregulation of visceral signals, and enhancing neurogenesis in patients with IBS. Choosing a central neuromodulator for treating IBS should be according to the pharmacological properties and predominant symptoms. The first-line treatment for pain management in IBS is using tricyclic antidepressants. An alternative for pain management is the serotonin and noradrenaline reuptake inhibitors. Selective serotonin reuptake inhibitors are useful when symptoms of anxiety and hypervigilance are dominant but are not helpful for treating abdominal pain. The predominant bowel habit is helpful when choosing a neuromodulator to treat IBS; selective serotonin reuptake inhibitors help constipation, not pain, but may cause diarrhea; tricyclic antidepressants help diarrhea but may cause constipation. A clinical response may occur in 6–8 weeks, but long-term treatment (usually 6–12 months) is required after the initial response to prevent relapse. Augmentation therapy may be beneficial when the therapeutic effect of the first agent is incomplete or associated with side effects. It is recommended to reduce the dose of the first agent and add a second complementary treatment. This may include an atypical antipsychotic or brain-gut behavioral treatment. When tapering central neuromodulators, the dose should be reduced slowly over 4 weeks but may take longer when discontinuation effects occur.

INTRODUCTION

Irritable bowel syndrome (IBS) is a disorder of gut-brain interaction (DGBI) characterized by abdominal pain related to defecation and changes in the frequency and form of stool ( 1,2 ). The predominant bowel habits are classified into subtypes, with a predominance of constipation (IBS-C), a predominance of diarrhea (IBS-D), mixed bowel habit (IBS-M), and unclassifiable (IBS-U) ( 2 ).

Like the other DGBI, IBS is frequently associated with neuropsychiatric disorders such as depression and anxiety, which are considered triggers for the onset of symptoms or occur in response to having them ( 3 ). In the Rome Foundation global study that included 54,127 participants, subjects with psychological distress or clinically relevant somatic symptoms were 4.45 times more likely to have 1 or more DGBI than those without psychological distress. The same study reported that those who met specific criteria for bowel disorders presented clinically relevant psychological distress or somatic symptoms in 55.5% of cases ( 4 ). In addition, in a meta-analysis that included 7,095 subjects with IBS exclusively, the global prevalence of depression was 36%: 38% in IBS-C, 37% in IBS-D, 34% in IBS-M, and 22% in IBS-U. Anxiety was present in 44% of patients with IBS, 47% in IBS-C, 37% in IBS-D, 37% in IBS-M, and 11% in IBS-U ( 5 ).

Based on this association, it would be logical to think that using neuromodulators could be of value in treating these psychological comorbidities. However, the value of neuromodulator treatment in IBS goes beyond its association with neuropsychiatric disorders ( 6 ). Neuromodulators act directly in regulating different pathophysiological mechanisms involved with visceral or central hypersensitivity, alterations of intestinal transit, or neurogenic effects, all of which are responsible for the clinical manifestations of IBS ( 6,7 ). This approach allows us to choose therapeutic alternatives based on symptom intensity and the nature of the symptoms (e.g., pain, diarrhea, constipation) treated ( 6 ). Neuromodulators are frequently prescribed after an unsatisfactory response to peripherally targeted treatments including diet, antispasmodics, microbiota modulation, laxatives or prokinetics, and antidiarrheals (depending on the subtype). We propose they can be prescribed initially based on the severity of the symptoms (e.g., predominant pain) or the coexistence of anxiety or depression. Because neuromodulator treatment is still considered off-label, many of the recommendations herein are based on expert consensus ( 6 ) and the experience of the senior author. Further studies are needed to confirm the empirically derived information.

In this article, we will review several relevant publications and provide our perspective on using neuromodulators in treating IBS to answer why, how they act, and when to use them. Although the focus is on treating IBS, this knowledge can also be applied to treating other DGBI. See Video 1 in the Supplementary Materials (Supplementary Digital Content 1, https://links.lww.com/AJG/D247 ) for a comprehensive review of the use of neuromodulators in IBS.

WHY USE NEUROMODULATORS IN IBS?

Neuromodulators (previously called antidepressants, antianxiety, or antipsychotic medications) act on receptors along the brain-gut axis (BGA) and affect brain-gut function relating to motility, secretion, and visceral and central neural signaling ( 6 ). Since IBS and other DGBI are caused by dysregulation of the BGA (see below), neuromodulators serve to normalize their action. Specifically, they have effects to (i) treat psychiatric comorbidity, (ii) modify gut motility, (iii) improve central downregulation of visceral signals, and (iv) enhance neurogenesis ( 6–8 ).

Some neuromodulators act peripherally in the enteric nervous system, including 5-hydroxytryptamine (5-HT) 4 receptor agonists, 5-HT3 receptor antagonists, guanylate cyclase C agonists, opioid receptor agonists/antagonists, delta ligand, and or muscarinic receptors antagonists. However, in this review, we will focus on centrally acting neuromodulators, particularly tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRI), tetracyclics (TNAS), and atypical antipsychotics agents (AAPs), which act on various specific receptors as shown in Table 1 ( 6 ). Their actions help improve symptoms of pain or discomfort, bloating, nausea, and vomiting. They can also have peripheral effects on motility and secretion ( 6,8 ). Table 1 reviews the central neuromodulator receptor activity that affects these symptoms ( 6 ).

Brain-gut axis

The BGA is a bidirectional complex connecting the central nervous and digestive systems. It comprises the brain, spinal cord, autonomic nervous system (which includes the sympathetic, parasympathetic, and enteric nervous systems), neuroendocrine, and neurohumoral systems ( 6,8,9 ).

The afferent nerve signals involved in the transmission of pain reach the brain through a chain of 3 orders of neurons from the primary spinal afferent arising from the gut to second-order neurons from the dorsal horn of the spinal cord to the thalamus and then to the midbrain ( 6,10 ).

The brain nuclei involved in regulating visceral pain include the nucleus of the solitary tract, parabrachial nucleus, locus coeruleus, rostral ventromedial medulla, anterior cingulate cortex, paraventricular nucleus, and the amygdala ( 11 ). Once these signals are registered centrally, the brain can modify incoming visceral signals through descending modulation via the gate control mechanism. This is related to the activity of descending brainstem fibers, which can affect the sensitivity of the dorsal horn neurons. This mechanism can alter visceral sensitivity and central control of pain perception through the involvement of 2 neurotransmitters, serotonin or 5-HT, and noradrenalin (NA), the main targets of drug treatment ( 6,10 ). See Video 2 in the Supplementary Materials (Supplementary Digital Content 1, https://links.lww.com/AJG/D247 ) for further information on how to explain the BGA to a patient.

The BGA also interacts with the intestinal microbiota's composition and the intestinal barrier's permeability, so much so that some authors use the term brain-gut-microbiota axis ( 9,12 ). The microbiome as part of the biopsychosocial conceptual model of the DGBI ( Figure 1 ) can influence central nervous system function. The metabolome of an eubiotic microbiota contributes to the functioning of the healthy brain since some of its components can cross the blood-brain barrier ( 9,13,14 ). Tryptophan produced in the gut by the enterochromaffin cells, crosses the intestinal barrier, and is transformed into 5-HT after crossing the blood-brain barrier; 5-HT is crucial in the development and functioning of the microglia. Short-chain fatty acids, which are metabolic products of the microbiota, are directly involved in strengthening the tight junctions of intestinal barrier cells ( 9,13 ).

Another aspect that supports the relationship between depression and the intestinal microbiota is the data showing that the microbiota composition differs significantly between healthy subjects and patients diagnosed with depression ( 15,16 ). In addition, a recent meta-analysis found changes in the composition of gut microbiota after the administration of antidepressants ( 17 ), and preliminary evidence suggests a possible effect of Bifidobacterium longum on improving psychological scores in patients with IBS ( 18 ); however, further research is needed.

A critical component of the BGA is the autonomic nervous system, which involves the enteric nervous system, acting as a mediator of the visceral response to central influences ( 19 ). There is evidence to suggest the presence of autonomic function disorders in patients with DGBI, which supports the presence of decreased or increased vagal outflow or sympathetic activity. Disturbance of autonomic balance can also alter visceral perception and be involved in pain perception; for these reasons, autonomic dysfunction could be a pathophysiological mechanism involved in many of the symptoms of IBS and contribute to associated factors such as sweating, cardiac arrhythmias, or alterations in the respiratory cycle ( 19,20 ), including their co-association with autonomically driven disorders like postural orthostatic tachycardia syndrome ( 21 ).

Figure 1 shows the biopsychosocial conceptual model demonstrating the influence of early-life factors on the BGA and its psychophysiological relationships leading to the clinical expression of IBS and other DGBI.

Neuromodulator effects on depression and pain: the monoamine hypothesis

The monoamine hypothesis proposes that depression results from a deficiency of 1 or more of 3 monoamines, which are 5-HT, NA, and dopamine. According to this hypothesis, antidepressants work by enhancing the synaptic transmission of these monoamines, achieving a slower regulation or desensitization of their postsynaptic receptors ( Figure 2 ) ( 6 ).

The same hypothesis can explain the activity of antidepressants on the perception of visceral pain through the BGA previously described since their monoaminergic actions interfere with the activity of brain circuits related to pain, emotions, anxiety, and cognitive ability ( 6,22 ). Antidepressants also interfere with nociceptive transmission mechanisms at the dorsal horn of the spinal cord, modulating the transmission of afferent pain. The increase of NA in the spinal cord by inhibiting reuptake directly inhibits pain through α₂-adrenergic receptors; in addition, NA acts on the locus coeruleus and improves the function of a descending noradrenergic inhibitory system ( 23 ). Brain regions, including the amygdala and anterior cingulate cortex, control the descending pathways from top to bottom. These projections are noradrenergic and serotonergic, so antidepressants can act by directly modulating these processes ( 6,22 ).

Neuroplasticity

Neuroplasticity refers to the brain's remarkable ability to reorganize itself by forming or losing new neural connections throughout life. It involves the brain's ability to adapt and change in response to experiences, learning, environmental influences, injury, and other factors. Neurodegeneration refers to the loss of cortical neurons with chronic pain, traumatic life events, and psychiatric disease, and neurogenesis of neurons refers to new growth and neural connections as may occur with clinical treatment. This new concept helps us understand how antidepressants can improve gastrointestinal (GI) symptoms ( 6 ). Central nervous system neurons are plastic and capable of new growth in regions such as the hippocampus and can die after severe psychological trauma, and this is associated with developing post-traumatic stress disorder or chronic pain as in IBS; reduced cortical density after trauma is seen in other brain regions involved in emotional and pain regulation and relevant here to pain control regions such as the cingulate cortex, in chronic and painful GI conditions like IBS ( 6,24 ).

Antidepressant treatments appear to increase precursor neuronal growth following reduced cortical density from traumatic experiences; brain-derived neurotrophic factor levels, a precursor of neuronal growth, increase with antidepressant treatment, which correlates with longer treatment periods and the degree of recovery from depression ( 6,25,26 ).

Furthermore, the longer patients are treated with antidepressants, the lower the frequency of relapse or recurrence of the depression. This may help explain why these treatments have more than immediate effects of symptom reduction; over time, they may help rewire the brain to approach a premorbid functioning state ( 6,27 ).

ACTION OF CENTRAL NEUROMODULATORS DETERMINED BY CLASS OF AGENT

Tricyclic antidepressants.

The TCAs are central neuromodulators whose mechanism of action is by presynaptic 5-HT and NA reuptake inhibition in combination with additional antagonistic properties on postsynaptic 5-HT2A, 5-HT2C, 5-HT3, muscarinic 1, histamine receptor (H) 1, α-noradrenalin receptor (α) 1, and presynaptic α2 NA receptors ( 6 ). The antimuscarinic effect of TCAs is associated with constipation due to decreased intestinal motility. This condition can also be related to the inhibitory action of these agents on transient receptor potential channel canonical type 4 in colonic myocytes that disrupt colonic motility ( 6,28 ).

While historically, TCAs have been used in psychiatry to treat depression, newer agents such as SSRIs and SNRIs have largely supplanted their use ( 22 ). However, TCAs are also prescribed in low dosages to treat painful conditions like IBS and other DGBI ( 6,22 ). The hallmark feature of TCAs, believed to be primarily responsible for their antidepressant and analgesic properties, is a variable combination of 5-HT and NA reuptake inhibition properties ( 6,29 ). Based on this dual action, TCAs have more potential for analgesic effects than other antidepressant classes targeting only 1 monoamine system, such as SSRIs. However, this may also be associated with an increased risk of side effects ( 6,8 ).

Most TCAs have additional receptor affinities, some of which may be primarily responsible for their side effect profile ( 6,22,29 ). Thus, muscarinic-1 receptor antagonism may cause classic anticholinergic side effects, including dry mouth, constipation, drowsiness, and blurred vision; a1 adrenergic receptor antagonism may lead to dizziness, drowsiness, and orthostatic hypotension; and H1 receptor antagonism may lead to weight gain, especially in combination with 5-HT2C antagonism, as well as drowsiness. Sedation, fatigue, headache, nausea, and sexual dysfunction are additional adverse effects ( 6,10,30 ).

In addition, some TCAs have weak sodium channel-blocking properties, which leads to a risk of arrhythmias and coma or seizures upon overdosing; these side effects seem to be less common with the secondary amine TCAs, desipramine, and nortriptyline ( 6 ). Therefore, TCAs should be avoided in patients with bundle branch block or prolonged QT intervals ( 6,29 ). Some of the side effects of TCAs may be beneficial in patients with DGBI. For example, slowing of GI transit due to their anticholinergic properties, which should be helpful in patients with IBS-D, and increased appetite and weight gain will be useful in patients with functional dyspepsia with early satiation and weight loss ( 6,22 ).

TCA agents are subtyped into secondary amines like desipramine and nortriptyline and tertiary amines like amitriptyline and imipramine, the latter having greater antimuscarinic and antihistaminic actions ( 6,22 ). While both types can work for the pain of IBS, the secondary amines are preferred if constipation is a dominant symptom. The initial dose and titration schedule of the various TCAs are similar. However, tertiary amines have more side effects because of their greater antagonism of cholinergic, adrenergic, and histamine receptors ( 6,22 ). Dosing can start at 25 mg, going up to 50 mg after a week if well tolerated by the patient and, if needed, increased to 75 mg. If there is an insufficient benefit at this low dose after a month, the TCA dose can be further increased if tolerated and side effects are minimal ( Table 2 ) ( 22 ).

Doses used in psychiatry (150–300 mg) for depression are higher than are needed to target pain and other GI symptoms. One recent 6-month placebo-controlled trial of amitriptyline 10–30 mg dose range in primary care showed benefit with GI but not psychological symptoms although adverse anticholinergic effects were common. Unfortunately, the study did not provide information on the differential benefit or frequency of side effects based on dose. One small study was published using a 10 mg dose of amitriptyline for IBS-D that showed modest benefit in treating pain and diarrhea, but it had methodological limitations ( 31 ). While very low doses may be insufficient for the control of digestive symptoms, it could be a starting point for future research ( 6,22,32 ).

Many providers choose to start with low doses, presumably to avoid side effects ( 33 ) or ease patient anticipatory anxiety. However, if 10 mg is started, it needs to be increased to a higher dose target ( Table 2 ). Suppose a patient reports side effects immediately and at low doses. In that case, it may be a nocebo effect rather than a medication effect, so rather than stop or switch the medication, we suggest the patient stay on the same dose for a week to adapt and then subsequently try to increase the dose further. Dose-related antimuscarinic side effects may be anticipated with higher doses up to 150 mg/d ( 34 ).

Selective serotonin reuptake inhibitors

SSRIs act by selective blockade of the presynaptic 5-HT transporter, boosting 5-HT neurotransmission and consequently stimulating intestinal transit; however, by not acting on NA receptors, SSRIs do not treat pain ( 6 ). Their primary serotonergic effect, without noradrenergic effect, leads to more significant expected benefits in treating anxiety, obsessive-compulsive disorder, and phobic-related behaviors. They can be added to a TCA or SNRI in low doses when anxiety is dominant ( 6,8 ). Similarly SSRIss may be used instead of a TCA to manage a patient with IBS-C when pain is not dominant. SSRI are more likely to cause diarrhea, while TCAs tend to be constipating due to their NA effect ( 29,30 ).

The SSRIs include fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, and escitalopram. Although all act on 5-HT reuptake inhibition, each of them has specific pharmacologic properties, like greater 5-HT2C antagonism of fluoxetine and greater anticholinergic action of paroxetine, so unlike the other SSRIs, paroxetine may produce constipation ( 22 ).

Sertraline, citalopram, and escitalopram tend to have the fewest pharmacokinetic drug interactions as they exhibit minimal effects on the cytochrome P450 enzyme system. Fluoxetine and paroxetine, however, have an increased risk of pharmacokinetic drug interactions through their strong inhibition of the P450 isoenzymes 1A2 and 2D6; therefore, they should be administered with caution when used in conjunction with TCAs and beta-blockers like metoprolol, opioids, lithium, tryptophan and monoamine oxidase inhibitors ( 22,35 ).

SSRIs are first-line pharmacologic agents for treating anxiety disorders, but they have the potential to induce restlessness and exacerbate anxiety when the drug is initiated. They are typically initiated at half of the usual starting dose to minimize these potential anxiogenic adverse effects. The dose may gradually increase to the regular starting dose after about 1 week ( Table 3 ) ( 22 ). The higher effect of the SSRI is usually delayed 3–4 weeks, which may represent a problem for those patients with significant anxiety that is complicating treatment and causing significant functional impairment. A useful strategy for this situation is to schedule a long-acting benzodiazepine to temporarily bridge this lag time and provide symptomatic relief for the patient's anxiety symptoms. The benzodiazepine should then be tapered after about 4 weeks of SSRI treatment ( 22 ).

Other side effects of SSRIs are agitation, sleep disturbance, nausea, diarrhea, night sweats, headache, weight loss, and sexual dysfunction ( 6,22,30 ).

Serotonin and noradrenaline reuptake inhibitors

SNRIs block presynaptic 5-HT and NA reuptake, boosting 5-HT and NA neurotransmission and decreasing the perception of visceral pain but without antihistamine and anticholinergic effects, have less effect on intestinal motility than TCAs so that they can be used as first-line neuromodulator treatment in the presence of constipation, with lower risk of adverse effects ( 6 ). Their value has been demonstrated for somatic pain such as fibromyalgia, diabetic neuropathy, or migraine headaches. It has not been adequately studied for visceral pain. Still, they are commonly used for this purpose off-label, with empiric benefit, because of the lower side effect burden than the TCAs and similar pain reduction ( 22,36,37 ). It should be noted that in addition to showing benefits with depression and painful disorders, SNRIs have shown significant improvement in anxiety, so they could be considered for this purpose as monotherapy or as part of augmentation therapy ( 36 ).

SNRIs are prescribed as primary agents for treating IBS and other painful DGBI. They may be used in patients with pain who failed initial treatment with TCAs or experienced intolerable side effects from the TCAs that precluded them from reaching a potentially therapeutic dose ( 6,22 ).

Regarding adverse effects related to the use of SNRIs, nausea may occur using SNRIs, more frequently under duloxetine, but can be minimized when taken with meals ( 21,29 ). Other side effects related to SNRIs are hypertension, more frequently under venlafaxine, agitation, dizziness, sleep disturbance, fatigue, headache, especially when decreasing doses, and rarely liver dysfunction ( 6,22,30 ).

Inhibition of NA reuptake varies according to each neuromodulator, so dosage changes between agents ( Table 4 ) ( 22 ). Venlafaxine, dosed for depression at 75–225 mg, acts primarily as an SSRI at lower doses, but higher doses (>225 mg) are needed to achieve NA inhibition and be effective as a pain treatment ( 22 ). Duloxetine has a strong and similar affinity for the 5-HT transporter and NA, acting as a true SNRI even at lower doses; in a comparative study, duloxetine activity was evaluated in patients with IBS-D, and the results showed a clinical remission of pain and diarrhea, as well as an increase in the threshold of visceral sensitivity, using the balloon dilation test ( 7,22 ). Milnacipran is more potent in inhibiting the reuptake of NA compared with its ability to inhibit the reuptake of 5-HT. For this reason, it is used for the treatment of chronic somatic pain, and although as an SNRI, it is not marketed for depression in the United States. This may help to facilitate acceptance by patients who are concerned about being prescribed a psychiatric medication ( 6,22 ).

Tetracyclics or noradrenergic and specific serotonergic antidepressants

The NA and specific serotonergic antidepressants, known as TNAS, have indirect effects resulting in increased NA and serotonergic activity through antagonism on α2 NA, 5-HT2A, 5-HT2C 5-HT3, H1, and muscarinic 1 receptors. The most representative agent of this class is mirtazapine ( Table 5 ). However, their effects seem to be mainly on anxiety, early satiety, nausea, and other symptoms associated with esophageal and gastroduodenal disorders, so their use in IBS is limited ( 6,22,38,39 ). Because of its sedative effect, it is usually given at bedtime; however, it may be transient, and there is a paradoxical effect, with sedation decreasing at higher dosages of mirtazapine ( 40 ).

Mirtazapine boosts 5-HT and NA neurotransmission-blocking presynaptic α2 NA autoreceptors and heteroreceptors on NA and 5-HT neurons, which act as brakes on both NA and 5-HT release from these respective neurons ( 6,29 ). In addition, like some of the TCAs, it has 5-HT2A and 5-HT2C receptor antagonist properties, which may account for some additional antidepressant properties, as well as a more favorable side effect profile by blocking some of the unwanted receptor actions of boosting 5-HT transmission ( 6,29 ). The same applies to its 5-HT3 antagonist properties, which may explain its more favorable GI side effect profile, including reduced nausea, pain, and diarrhea, although this same mechanism could induce constipation ( 6,20,28 ). Likewise, through its H1 and 5-HT2C antagonist properties, mirtazapine may cause increased appetite, weight gain, sedation, fatigue, sweating, and dry mouth ( 6,30,39,41 ).

Atypical antipsychotic agents

AAP are a group of second-generation drugs, which differ from first-generation antipsychotics by presenting fewer adverse effects. This classification includes quetiapine, olanzapine, brexpiprazole, and aripiprazole ( Table 6 ). However, the most used for DGBI are quetiapine and olanzapine, so in this review, we focus on these 2 agents ( 22 ).

AAPs act through complex mechanisms, resulting in favorable clinical effects, like anxiety reduction and regulation of sleep patterns. AAPs also have effects as a norepinephrine transporter inhibitor, which is of theoretical advantage for analgesic effects; particularly, quetiapine has been used as an augmenting agent or second-line treatments in patients with abdominal pain related to IBS who do not respond to treatment with TCAs or SNRIs ( 6,22,42 ).

Dopamine receptor antagonist activity (D2) is the target of traditional antipsychotics, its modulation is responsible for the antipsychotic effect, and it is also the cause of unwanted side effects such as extrapyramidalism, dyskinesia, hyperprolactinemia, and affective or cognitive disorders ( 6 ). AAPs, on the other hand, have 5-HT2A receptor antagonist properties (olanzapine, quetiapine), rapid dissociation of the D2 receptor, partial D2 agonism, and/or partial 5-HT1A agonism (quetiapine); these additional mechanisms of action reduce the impact of its D2 receptor antagonist activity and thus reduce the incidence of side effects ( 6,8 ). However, related to their additional anticholinergic properties, different receptor antagonist effects (H1, 5-HT2C, α1-NA, and/or α2-NA), and other not-well-known mechanisms, AAPs can increase appetite and cause extrapyramidal syndrome, weight gain, fatigue, sweating, dizziness, cardiometabolic disease, and sedation; therefore, although in the treatment of IBS and DGBI low doses are prescribed, these agents should be used with sufficient care and monitored for side effects, especially when used chronically. However, most of these side effects are reported in the psychiatric literature with dosages 5–10 times greater than that prescribed for GI disorders. Thus, we would anticipate fewer side effects with lower dosages used for GI disorders ( 6,30,42–46 ).

The pharmacological properties by which quetiapine and olanzapine act to improve nausea, abdominal pain, and general symptoms of DGBI remain uncertain. It is known that olanzapine and quetiapine have combined D2/5-HT2A antagonist properties, characteristic of most atypical antipsychotics, with in addition H1, 5-HT2C, and α1-antagonist, as well as anticholinergic properties. Quetiapine has additional 5-HT1A partial agonist properties, as well as noradrenaline reuptake inhibitory effects, which may provide a rationale for its use in IBS and other DGBI ( 6,22 ).

CENTRAL NEUROMODULATOR SELECTION

Choosing a central neuromodulator for treating IBS should be taken according to the pharmacological properties of the different groups and the predominant symptoms of each patient ( Table 7 ), as well as considering the potential side effects ( Table 8 ).

HOW TO PRESCRIBE CENTRAL NEUROMODULATORS

General approach.

Prescribing a central neuromodulator involves providing the rationale for their use, clarifying their targeted benefits and side effects, and paying attention to patient concerns. It is not uncommon for patients to believe a central neuromodulator is being prescribed for a psychiatric condition rather than a brain-gut disorder. It is important to explain to the patients, clearly and concisely, the meaning of the BGA and link their symptoms to dysregulation between the brain and the gut. So, neuromodulators are not necessarily used for the treatment of depression but are a therapeutic alternative in the management of DGBI. It helps to use the term “neuromodulator” instead of “antidepressant” ( 6,8 ) It also helps to clarify that these medications can treat pain and other GI symptoms independent of treating depression, and the dosages are often lower than those used for treating major depression. This will preclude any patient concerns that their symptoms are being underestimated or considered to be in their head ( 6,8 ). See Video 3 in Supplementary Materials (Supplementary Digital Content 1, https://links.lww.com/AJG/D247 ) for details how to best communicate the use of central neuromodulators to a patient.

This approach strengthens the patient's understanding and reduces the possibility of nonadherence. It also helps to note that chronic pain can lead to anxiety and depression so these medications can help both components. In this way, the patient will be more open to accepting a component of anxiety and depression in their illness ( 4–6 ).

Pharmacogenomic testing

Pharmacogenomic testing has gained ground in the selection of a neuromodulator for the treatment of psychiatric diseases, and there are limited studies to address this strategy in patients with DGBI ( 47,48 ). Pharmacogenomics is the study of the variability of the expression of individual genes relevant to disease susceptibility, as well as drug response. It is used to identify genetically determined interactions and neuromodulator profiles to optimize benefits and reduce toxicity. Practically, it can determine if a patient is a rapid (causing low blood levels and reduced benefit) or a slow (leading to high blood levels and toxicity) metabolizer, which helps determine the selection of medication or its dosage and helps when augmenting treatment using several medications where interaction effects are to be avoided ( 47,48 ). However, its clinical value has not yet been determined for GI disorders, so it is only a guide.

We propose that testing is not needed initially. The choice of neuromodulator, the starting dose, and possible changes over time should be made based on predominant symptoms and tolerance to the drug (as described in later sections of this article). However, we believe that pharmacogenomic testing is an option under 2 conditions. First, when the patient reports no symptom benefit to high doses of neuromodulators, to determine if the patient is a rapid metabolizer of them. If present, one can switch to another medication with normal metabolism. Second, testing may be of value for the patient who reports multiple side effects to several medications. Testing may determine if the patient is a slow metabolizer, thereby accumulating high blood levels and the provider can then search for a better option. If the study shows normal metabolism, this may help patient adherence. Then one could try to encourage the patient to stay on the medication a bit longer until treatment benefit occurs and side effects diminish.

TARGETS FOR TREATMENT BASED ON SYMPTOMS

The selection of a neuromodulator in patients with IBS should be made carefully, considering its pharmacological properties and side effects. In this section, we detail the main arguments for choosing and combining neuromodulators according to the predominant symptoms.

When the main symptom is abdominal pain

The first-line neuromodulator treatment for pain management in IBS is using a TCA ( 6,8,10,22,29 ). In a meta-analysis that evaluated the effects of TCAs and SSRIs in treating IBS, conducted from 18 RCTs with 1,127 patients, while both groups showed significant global improvement of symptoms, only the TCAs differed significantly in abdominal pain ( 49 ). Another first-line neuromodulator alternative for pain management is the SNRIs ( 6,8,10,22 ). A meta-analysis that included 13 studies with amitriptyline and 3 with duloxetine confirmed the efficacy of amitriptyline in terms of pain improvement in patients with IBS-D; the same study also showed benefit for duloxetine in the management of IBS pain. However, the duloxetine studies included uncontrolled trials with lower quality of evidence than that of TCAs ( 50 ). Nevertheless, SNRIs are increasingly used based on supportive data from treating other painful conditions and personal experience. The anticholinergic effect of TCAs could be reduced by using secondary amines (desipramine and nortriptyline), as well as with the alternative of using SNRIs, whose use in IBS-C with pain as the predominant symptom appears to be safer ( 6,22,29 ).

When the patient has anxiety

While not effective in treating abdominal pain, SSRIs are useful when symptoms of anxiety and hypervigilance, obsessive behaviors, social phobia, or agoraphobia are dominant ( 6,22 ). When the main symptom is abdominal pain in conjunction with significant anxiety, TCAs may be combined with low-dose SSRIs ( 6,8,22 ). In these cases, low dose escitalopram may be used, based on its tolerability and low frequency of drug interactions ( 22,30 ). Alternatively, an SNRI can be used as monotherapy for anxiety and pain.

When the patient has constipation

The predominant bowel habit is important when choosing a neuromodulator to treat IBS, both for the opportunity to improve it and to be aware of when the treatment may worsen it ( 6,8,10,22 ). When constipation predominates, avoid neuromodulators with strong anticholinergic action, such as tertiary amine TCAs like amitriptyline and imipramine. SNRIs or secondary amine TCAs are more acceptable due to less effect on reducing intestinal transit ( 6,22 ). Although SSRIs generally stimulate intestinal transit, they do not improve the pain of IBS-C ( 6,22,29,51 ).

When the patient has diarrhea

When diarrhea predominates, tertiary amines like amitriptyline and imipramine are a good choice due to their strong anticholinergic action; if constipation occurs, the option of adding treatment for the constipation may be considered, especially if the neuromodulator therapy helps reduce abdominal pain and other symptoms ( 6,22,29 ). Alternatively, a secondary amine having less anticholinergic effect or duloxetine may be prescribed ( 6,22 ). In a randomized study conducted with 61 patients with IBS-D, SNRI-duloxetine therapy showed a significant clinical remission of pain and diarrhea ( 7 ). In patients with diarrhea where the anxiety component is predominant over pain, paroxetine could be chosen since it has greater anticholinergic effects than the other SSRIs ( 6,22,51 ).

When the patient has mixed bowel habits

When there is a mixed bowel pattern, secondary amine TCAs such as desipramine and nortriptyline, or SNRIs like duloxetine, could be preferred because they do not have as strong an effect on intestinal transit. Note that mirtazapine, tertiary amine TCAs such as amitriptyline and imipramine, and paroxetine may cause constipation. By contrast, SSRIs may cause diarrhea, so they should be prescribed when anxiety cannot be effectively managed with neuromodulators of another class ( 6,8,22,29 ).

AUGMENTATION: WHAT TO DO WHEN MONOTHERAPY IS NOT SUFFICIENT

When to implement augmentation therapy.

Central neuromodulators require between 4 and 8 weeks of use to reach their maximum level of effectiveness, although there is some evidence that a partial benefit may occur at 2–3 weeks and, when it occurs, predicts a favorable long-term response ( 49,50 ). It is also important to gradually increase the dose over several weeks to reach the targeted dose and minimize side effects. Therefore, allow proper time to determine when a treatment is not sufficient. In that case, consider augmentation treatment in several situations: (i) when a single treatment is ineffective in controlling symptoms, (ii) when increasing doses is considered risky or produces side effects, and (iii) when comorbidities also need additional treatment. Under these circumstances, a second central acting agent, a peripheral neuromodulator, or a brain-gut behavioral treatment should be added ( 6,8,10,22,29 ).

How to implement augmentation therapy

Adding another first-line neuromodulator agent may be beneficial when the therapeutic effect of the first agent is partial. Benefits can occur with medications that have complementary mechanisms of action; thus, one would add an SSRI if a patient with IBS shows pain relief using a TCA but has insufficient control of coexisting anxiety; it may also be that patients are using SSRIs prescribed by a psychiatrist; in these cases, we consider adding a TCA or SNRI agent to control the symptoms of IBS, starting with low doses, ideally in collaboration with the psychiatrist. It is important to remember that the usual dose of TCAs may not be enough to treat the psychiatric condition or to produce serotonin-related side effects ( 6 ).

Another option is adding a second-line neuromodulator agent like an AAP, which, as previously explained, has less risk for side effects than first-generation antipsychotics. There is some experience from using quetiapine in treating chronic pain; quetiapine can also improve pain when used to augment the effects of a TCA or SNRI. This combination has added clinical effects, like anxiety reduction and establishing a normal sleep pattern; its main metabolite also has effects as an NA transporter inhibitor, which is a theoretical advantage for analgesic effects ( 6,22,43 ).

Using quetiapine above 200 mg/d may lead to poor tolerability because of excessive sedation and dizziness and metabolic side effects such as weight gain, hyperlipidemia, and diabetes. For this reason, the recommended dose range would be 25–200 mg/d for patients with IBS or DGBI. Sometimes we use higher dosing when there are coexisting psychological comorbidities such as post-traumatic stress disorder or anxiety. Figure 3 demonstrates the selection of neuromodulators for monotherapy or augmentation when treating DGBI ( 6,22,42 ).

It should be noted that although we recommend the use of AAP as previously described, some gastroenterologists and primary care providers may feel uncomfortable because they are not familiar with using AAP ( 33 ). It should also be considered that the regulations for prescribing these drugs differ according to different countries. In this situation, we recommend prescribing AAP in conjunction with a psychiatrist.

IMPORTANT SIDE EFFECTS AND SITUATIONS TO ADDRESS

Central neuromodulators are generally safe, and treating patients with DGBI are frequently prescribed in lower doses than used in psychiatry ( 6,22 ). However, all agents have well-recognized side effect profiles that providers must consider ( 30,52 ). This is especially true when combining medications for augmentation or when patients have underlying medical conditions, such as heart disease or pregnancy ( 30,52,53 ). The following section will review some of the frequent side effects or situations requiring medication adjustment.

Serotonin syndrome

Many of the central neuromodulators activate serotonin receptors. Therefore, a possible complication is serotonin syndrome, which in its more severe form is characterized by fever, hyperreflexia, spontaneous clonus, muscle stiffness, tremors, confusion, tachycardia, seizures, pupillary dilation, and increased risk of death if not treated immediately ( 6,22,30 ). However, providers should be more alert to milder episodes of increased anxiety and tachycardia.

Serotonin syndrome is more likely to occur when using high doses of neuromodulators that strongly inhibit serotonin reuptake such as SSRIs or when several agents with serotonergic effects are combined. Clinical manifestations usually appear shortly after implementing augmentation therapy when serum serotonin levels are highest ( 22 ).

All drugs with serotonergic properties should be temporarily discontinued when the syndrome occurs. Reimplementation occurs gradually, starting with low doses that are slowly increased over several days to a week. In addition, other classes of medications such as tramadol, ondansetron, or triptans may also increase serotonin levels and trigger the syndrome ( 22,30 ).

Cardiac side effects

Qt prolongation..

Although initial publications suggest that SSRIs and SNRIs have a lower risk of cardiovascular disease when compared with TCAs, many of the newer antidepressants are not exempt from the onset of heart disease ( 30,53,54 ). In a comprehensive review that analyzed the antidepressant-induced QT prolongation in people with psychiatric disorders, the authors found an increased mortality odds ratio of 2.11 with high doses of TCA and 2.78 in SSRI users compared with controls matching for age and sex ( 55,56 ).

The QT interval is the period between the onset of a Q wave and the end of a T wave on the electrocardiogram (EKG). By contrast, the corrected QT interval (QTc) refers to the QT after adjustment to baseline heart rate. An increased QT interval can be associated with a malignant ventricular tachyarrhythmia known as Torsade de Pointes ( 55 ). The risk of QT prolongation should be considered during the use of TCAs and in patients when using SSRIs ( 30,53,54 ). A meta-analysis found that among SSRIs, citalopram appears to be the agent most significantly associated with QTc prolongation ( 57 ).

A clinically consistent association with cardiac conduction defects or arrhythmias has not been identified with the SNRIs. However, venlafaxine (in doses over 200 mg daily) and duloxetine have been associated with increases in diastolic blood pressure ( 54,58,59 ).

Although the risk of cardiovascular disease is not high in central neuromodulator users, they should be prescribed in the lowest doses required to be effective. An EKG should be considered to evaluate for QT prolongation and cardiac arrhythmias and must be done in the elderly population and patients with heart disease or concomitant treatment with drugs known to cause prolongation of the QTc interval. Examples include antiarrhythmics such as amiodarone, sotalol, quinidine, procainamide, verapamil, and diltiazem. In addition, noncardiovascular drugs such as ondansetron, macrolide, fluoroquinolone antibiotics, and first-generation antipsychotic agents such as haloperidol, thioridazine, and sertindole should be considered. If the EKG confirms QT prolongation, stop the high-risk medication and restart treatment at a lower dose after a cardiac consult and then repeat the EKG ( 55,60 ).

Orthostatic hypotension.

The risk of orthostatic hypotension, secondary to using central neuromodulators, has been well-established with TCAs due to their well-known antagonistic α1-adrenergic receptor activity ( 30,53 ). Paroxetine seems to be the SSRI most frequently linked with orthostatic hypotension because of its anticholinergic effects, especially in the elderly population; however, the main mechanisms associated with other SSRI-induced orthostatic hypotension remain unknown ( 52,60,61 ). Mirtazapine may also cause orthostatic hypotension in up to 7% of patients. However, venlafaxine, due to its strong noradrenergic action, can cause this side effect in more than 50% of patients older than 60 years ( 53,61–63 ).

Weight gain

Weight gain related to the use of central neuromodulators may be beneficial for patients with DGBI with early satiation and low weight. Still, it may be inappropriate when there are overweight and metabolic disorders risks. This side effect may occur during the acute and maintenance phases of treatment with central neuromodulators ( 6,30,53 ).

Weight gain induced by central neuromodulators may occur due to the interaction of several mechanisms, including (i) action on specific neuroreceptors, (ii) decreased caloric expenditure due to sedative effects, (iii) change in food preference, and (iv) dry mouth/throat may induce increased intake of caloric beverages ( 53 ).

As mentioned in previous sections, the affinity of neuromodulators for the H1 receptor seems to be linked to weight gain. Based on this hypothesis, one study evaluated weight gain as part of metabolic syndrome during antidepressant treatment and showed that patients who used amitriptyline, trimipramine, mirtazapine, and nortriptyline showed high affinity for the H1 receptor and experienced significantly greater weight gain than those who used duloxetine, venlafaxine, citalopram, escitalopram, sertraline, paroxetine, and fluoxetine, which showed a low affinity for the H1 receptor ( 64 ).

In a meta-analysis that evaluated the adverse effects of antidepressants, amitriptyline (relative risk [RR] = 8.74), mirtazapine (RR = 6), and nortriptyline (RR = 2.9) were significantly associated with weight gain compared with placebo ( 54 ). The magnitude of the effect has been quantified in patients receiving low-modest doses of tricyclic antidepressants given for an average of 6 months. There was a mean weight increase of 0.59–1.32 kg/mo, which led to an average total weight gain of 1.36–7.26 kg, depending on drug, dose, and duration of the treatment ( 65,66 ). Another meta-analysis conducted from studies with antipsychotics found that the use of olanzapine and, to a lesser extent, quetiapine may be associated with significant weight gain compared with placebo ( 67 ). The magnitude of weight gain appears to be dose-related, being more likely at higher doses ( 68 ). It is also more common when combining an antidepressant with an AAP.

Although SSRIs are commonly associated with weight loss at least initially, evidence suggests that paroxetine may induce weight gain ( 69 ). Regarding SNRIs, weight gain appears to be an uncommon adverse effect in patients treated with venlafaxine and duloxetine ( 70 ).

If weight gain occurs during treatment with neuromodulators, reduce the dose of the neuromodulator. Additional options include recommending dietary changes and possibly concomitantly using interventions for treating obesity, such as metformin or glucagon-like peptide 1 agents ( 65,71 ).

Complications related to pregnancy

Central neuromodulators are considered safe during pregnancy, especially TCAs, SNRs, mirtazapine, and AAPs ( 72 ). Although SSRIs appear to be less safe, they are the most prescribed antidepressants during pregnancy; however, publications questioning the safety profile of SSRIs appear to have confounding factors that may produce questionable results, such as maternal age, smoking, and/or concomitant use of other medications like anticonvulsants ( 53,72,73 ).

While SSRIs are the most used neuromodulators during pregnancy ( 72,73 ), evidence shows that the use of SSRIs is associated with reduced fetal head growth and increased risk of preterm birth ( 72 ). Avoid paroxetine as it is related to congenital heart defects compared with other SSRIs. Other birth defects may be related to the use of SSRIs. Thus, sertraline seems to increase the risk of heart defects and craniosynostosis, citalopram with cardiac malformations, and escitalopram with musculoskeletal malformations ( 53 ).

SNRIs during pregnancy do not appear to be associated with an increased risk of birth defects; however, although the evidence is not extensive, SNRIs have been associated with an increased risk of postpartum hemorrhage and particularly venlafaxine with hypertension during pregnancy ( 53 ).

Treating with central neuromodulators during pregnancy should balance with its associated risks. If the patient is stabilized on a specific drug, it is preferable to maintain the same treatment, except for paroxetine. If it is a woman who has not received treatment with neuromodulators, the use of TCAs, mirtazapine, AAPs, and SNRIs are quite safe alternatives; if SSRIs are required, sertraline and citalopram appear to be the most appropriate alternatives ( 54,73 ).

PRESCRIBING AND DISCONTINUING CENTRAL NEUROMODULATORS

How to prescribe and taper.

The general practice is to prescribe central neuromodulators to reduce GI symptoms of pain, nausea, bloating, bowel dysmotility, and, at times, psychological symptoms of anxiety or depression and to titrate the dose up until an optimal dose achieves benefit. We recommend that the medication be prescribed at half dose for 1–2 weeks to assess side effects and if no side effects occur the full dose can be prescribed. If side effects occur and are tolerated, the patient should be encouraged to stay with the treatment for 1–2 weeks more because it is likely that the effects will diminish and can then be increased to the targeted dose. In general, if side effects do not occur with the initial dose, they are much less likely to occur when increasing the dose.

It should be kept in mind that nocebo effects may occur where the patient experiences symptoms related more to anticipatory anxiety or conditioning from earlier treatment experiences rather than to the pharmacological effect of the medication. This may occur when the side effects are not usual for the particular medication or occur after 1 pill is taken, before achieving adequate blood levels. In one National Institutes of Health study of patients taking desipramine, most of the side effects were reported as symptoms existing before beginning treatment or were not the anticipated side effects. Furthermore, the severity of the side effect symptoms correlated with anxiety scores and was not related to drug blood levels ( 74 ). When this occurs, it is important to help the patient understand the importance of staying on a course with a medication with a gradual increase in dose to achieve anticipated expectations instead of switching from 1 medication to another.

Using central neuromodulators for IBS requires long-term treatment. From our experience, 6–12 months of treatment or more are needed to increase the likelihood of remission. In some cases, a good clinical response may occur in a shorter period. The decision to discontinue is based on the clinical response. If the patient achieves meaningful improvement or best symptom resolution over this period, remission may have occurred, and a slow reduction in the dose can begin. If there is a partial response, the patient should be treated longer. Treatment may also continue when there are ongoing psychosocial stressors, a history of multiple previous episodes, or psychiatric comorbidities ( 6,8,10,22,29 ).

The provider can consider reducing or tapering off the central neuromodulators when the patient has achieved reasonable symptom control for at least 6 months. The dose should be tapered slowly over 4 weeks (25% per week) but may take longer when discontinuation effects occur. This commonly occurs with SNRIs. If the patient has been on the central neuromodulator for less than 4–6 weeks, it can usually be discontinued rapidly with minimal if any side effects occurring ( 6,8 ). However, in our experience, many, if not most, patients' symptoms tend to wax and wane over weeks or months. This often requires titrating the medications up and down to accommodate the fluctuations in the clinical conditions. It is essential to wait for 3–4 weeks after a dose adjustment to determine if the treatment was effective.

If the treatment is not effective after this period, one can then switch to another neuromodulator. When switching from 1 medication to another, for example, a TCA to an SNRI, because of overlapping receptor effects, it is possible to switch over a relatively short time when compared with tapering off monotherapy. For example, the TCA could be reduced to half dose while adding the SNRI at half dose, and then 2 weeks later, the TCA is stopped while raising the SNRI to full dose. Changes in dosage may take longer or shorter depending on the patient's therapeutic response and tolerance.

Antidepressant discontinuation syndrome

If the decision is to withdraw treatment, abrupt discontinuation of central serotonergic neuromodulators (mainly SSRIs and SNRIs) may be associated with antidepressant discontinuation syndrome (ADS), which consists of various symptoms, including nausea, headache, flulike symptoms, imbalance, insomnia, anxiety, agitation, and sensory disturbance like brain zaps and paresthesia ( 6,22,75 ).

The ADS is more common using agents with a shorter half-life. So, for the SSRIs, paroxetine, with a half-life of less than a day, is more likely to produce ADS when stopped abruptly. By contrast, fluoxetine has a half-life of 3–4 days, and ADS is less common. Citalopram, escitalopram, and sertraline are intermediate and exhibit half-lives of longer than a day but may still require a gradual taper to avoid the uncomfortable symptoms of ADS ( 22,75 ).

There is no clearly defined strategy for preventing and treating ADS symptoms, and patient attributions to the withdrawal must be considered. The patient who is hypervigilant to withdrawal effects is more likely to have difficulty withdrawing. In addition, when comorbidities such as major depression or anxiety disorders are present, cognitive behavioral therapy or other brain-gut behavior therapies should be used concurrently to supplement the loss of the use of the medication. In addition, self-care behavior interventions like mindfulness, relaxation, and supportive relationships explain up to 20%–30% of the variance in predicting successful discontinuation of the antidepressants ( 75 ).

Some strategies may be helpful. It is better to discontinue the morning dose for a week and then discontinue the evening dose. Another alternative is to switch to an agent with a longer half-life, like fluoxetine when planning to stop another antidepressant. However, in cases where symptoms are severe, sometimes it is necessary to reintroduce the neuromodulator and retry using a slower discontinuation process ( 22,76 ). Since the lowest dose of duloxetine is 20 mg, we sometimes advocate patients opening the capsule and taking half the dose (10 mg) when continuing the tapering protocol.

In this review article, we have discussed how to use central neuromodulators when treating IBS. Their action on the reuptake of neurotransmitters such as 5-HT, dopamine, or NA demonstrates that its mechanism of action goes beyond improving psychiatric comorbidity for some of these patients via its action on visceral sensitivity, intestinal transit, and neurogenesis as seen with IBS.

Central neuromodulators are an essential treatment in managing IBS when symptoms, particularly pain, are dominant or when there are psychological comorbidities. TCAs seem to have the best evidence as to their benefit in pain management, SNRIs are also a useful alternative to treat pain with fewer adverse effects, but further research is needed to confirm their value. SSRIs should be considered when a significant component of anxiety without pain is present.

Augmentation therapy is a strategy to improve therapeutic effects when the initial treatment is insufficient, and it is impossible to increase doses due to the risk of side effects. This should be done by adding to the initial neuromodulator chosen to treat pain a second centrally acting agent, one that acts peripherally or a behavioral treatment.

Gastroenterologists managing patients with IBS and other DGBI should be familiar with central neuromodulators and know their characteristics, mechanism of action, indications, and possible adverse effects because they are a beneficial alternative in the treatment of these disorders.

CONFLICTS OF INTEREST

Guarantor of the article: Douglas A. Drossman and Ignacio Hanna-Jairala.

Specific author contributions: Medical education.

Financial support: Nothing to declare.

Potential competing interests: Internal medicine—gastroenterology—clinical practice.

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Continuing Medical Education Questions: July 2024

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Depression, Serotonin and Tryptophan

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• 1 Dipartimento di Medicina Clinica e Sperimentale, Section of Psychiatry, University of Pisa, Via Roma 67, 56100 Pisa, Italy. [email protected].
• PMID: 26654774
• DOI: 10.2174/1381612822666151214104826

Depression is a major cause of worldwide disability. Although its etiology is unclear, for over sixty years the study of its pathophysiology has focused mainly on serotonin (5-HT) and serotonergic neurotransmission. Generally, the study of the pathophysiological processes underpinning depression have led to the appreciation of its complexity, although such study continues to support the role of 5-HT in this disorder. The aim of this review is to briefly summarize the available findings on 5-HT and depression, with a special focus on alterations in tryptophan (TRP) metabolism that can shift from 5-HT synthesis towards other, potentially neurotoxic, compounds, such as the tryptophan catabolite, quinolinic acid. The evidence that the TRP shunt may be promoted by stress hormones and proinflammatory cytokines strongly supports the notion that depression should now be considered a systemic disorder that can be triggered by different factors that ultimately target the 5-HT system in vulnerable individuals. In addition, such intriguing findings suggest biochemical targets for novel treatment options in depression.

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• Integrated metagenomic and metabolomic analysis reveals distinctive stage-specific gut-microbiome-derived metabolites in intracranial aneurysms
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• http://orcid.org/0000-0001-7925-9506 Haitao Sun 1 , 2 , 3 ,
• Kaijian Sun 1 ,
• Hao Tian 1 ,
• Xiheng Chen 4 ,
• Shixing Su 1 ,
• Shilan Chen 1 , 2 ,
• Jiaxuan Wang 2 ,
• Meichang Peng 1 , 2 ,
• Meiqin Zeng 1 , 2 ,
• Yunhao Luo 2 ,
• Yugu Xie 2 ,
• Xin Feng 1 ,
• Zhuang Li 2 ,
• Xin Zhang 1 ,
• Xifeng Li 1 ,
• Yanchao Liu 1 ,
• Zhengrui Chen 5 ,
• Zhaohua Zhu 6 ,
• Youxiang Li 4 ,
• Fangbo Xia 2 ,
• Hongwei Zhou 2 ,
• Chuanzhi Duan 1
• 1 Neurosurgery Centre, Department of Cerebrovascular Surgery, Engineering Technology Research Centre of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, The National Key Clinical Specialty, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province , Zhujiang Hospital, Southern Medical University , Guangzhou , Guangdong , China
• 2 Microbiome Medicine Centre, Clinical Biobank Centre, Guangdong Provincial Clinical Research Centre for Laboratory Medicine, Department of Laboratory Medicine , Zhujiang Hospital, Southern Medical University , Guangzhou , Guangdong , China
• 3 Key Laboratory of Mental Health of the Ministry of Education, Guangdong–Hong Kong–Macao Greater Bay Area Centre for Brain Science and Brain-Inspired Intelligence , Southern Medical University , Guangzhou , Guangdong , China
• 4 Beijing Neurosurgical Institute, Beijing Engineering Research Center for Interventional Neuroradiology, Department of Neurosurgery , Beijing TianTan Hospital, Capital Medical University , Beijing , China
• 5 The Second School of Clinical Medicine , Southern Medical University , Guangzhou , Guangdong , China
• 6 Clinical Research Centre, Orthopedic Centre , Zhujiang Hospital, Southern Medical University , Guangzhou , Guangdong , China
• Correspondence to Professor Chuanzhi Duan; doctor_duan{at}126.com ; Professor Hongwei Zhou; hzhou{at}smu.edu.cn ; Dr Fangbo Xia; xiafb08{at}163.com ; Dr Haitao Sun; 2009sht{at}smu.edu.cn

Objective Our study aimed to explore the influence of gut microbiota and their metabolites on intracranial aneurysms (IA) progression and pinpoint-related metabolic biomarkers derived from the gut microbiome.

Design We recruited 358 patients with unruptured IA (UIA) and 161 with ruptured IA (RIA) from two distinct geographical regions for conducting an integrated analysis of plasma metabolomics and faecal metagenomics. Machine learning algorithms were employed to develop a classifier model, subsequently validated in an independent cohort. Mouse models of IA were established to verify the potential role of the specific metabolite identified.

Results Distinct shifts in taxonomic and functional profiles of gut microbiota and their related metabolites were observed in different IA stages. Notably, tryptophan metabolites, particularly indoxyl sulfate (IS), were significantly higher in plasma of RIA. Meanwhile, upregulated tryptophanase expression and indole-producing microbiota were observed in gut microbiome of RIA. A model harnessing gut-microbiome-derived tryptophan metabolites demonstrated remarkable efficacy in distinguishing RIA from UIA patients in the validation cohort (AUC=0.97). Gut microbiota depletion by antibiotics decreased plasma IS concentration, reduced IA formation and rupture in mice, and downregulated matrix metalloproteinase-9 expression in aneurysmal walls with elastin degradation reduction. Supplement of IS reversed the effect of gut microbiota depletion.

Conclusion Our investigation highlights the potential of gut-microbiome-derived tryptophan metabolites as biomarkers for distinguishing RIA from UIA patients. The findings suggest a novel pathogenic role for gut-microbiome-derived IS in elastin degradation in the IA wall leading to the rupture of IA.

• BRAIN/GUT INTERACTION
• INTESTINAL MICROBIOLOGY

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information. All data relevant to the study are available in the manuscript including its online supplementary files, or from the corresponding authors upon reasonable request.

https://doi.org/10.1136/gutjnl-2024-332245

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HS, KS and HT contributed equally.

Contributors HS is responsible for the overall content as guarantor. HS and CD jointly conceptualised and organised the study. HS, KS and HT designed experiments and prepared the manuscript. FX, HZ, ZL and ZZ provided expertise and participated in the design of the experiments. FX mainly completed targeted metabolomic analysis. HS, FX, KS, HT and JW interpreted the data; HT and MP mainly completed animal experiments. SC, HT, FX, MP and YT assisted in drafting the manuscript. XC, SS, MZ, XL, YLu, YX, XF, XZ, XL and YLiu collected the patient samples, and WY and ZC collected clinical information. HZ, CD and ZL revised the manuscript. All authors read and approved the final manuscript.

Funding This work was supported by the National Natural Science Foundation of China (81974178, 81974177), Guangdong Basic and Applied Basic Research Foundation (2023A1515030045) and the Presidential Foundation of Zhujiang Hospital of Southern Medical University (No. yzjj2022ms4), Guangzhou Key Research Programme on Brain Science (202206060001).

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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Tryptophan Metabolism in Depression: A Narrative Review with a Focus on Serotonin and Kynurenine Pathways

Ana salomé correia.

1 OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal; moc.liamg@70rrocnna

2 Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal

3 CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Hernâni Monteiro, 4200-319 Porto, Portugal

4 Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal

Associated Data

Not applicable.

Depression is a common and serious disorder, characterized by symptoms like anhedonia, lack of energy, sad mood, low appetite, and sleep disturbances. This disease is very complex and not totally elucidated, in which diverse molecular and biological mechanisms are involved, such as neuroinflammation. There is a high need for the development of new therapies and gaining new insights into this disease is urgent. One important player in depression is the amino acid tryptophan. This amino acid can be metabolized in two important pathways in the context of depression: the serotonin and kynurenine pathways. These metabolic pathways of tryptophan are crucial in several processes that are linked with depression. Indeed, the maintenance of the balance of serotonin and kynurenine pathways is critical for the human physiological homeostasis. Thus, this narrative review aims to explore tryptophan metabolism (particularly in the serotonin and kynurenine pathways) in depression, starting with a global overview about these topics and ending with the focus on these pathways in neuroinflammation, stress, microbiota, and brain-derived neurotrophic factor regulation in this disease. Taken together, this information aims to clarify the metabolism of tryptophan in depression, particularly the serotonin and kynurenine pathways.

1. Introduction

Depression is a disease that affects millions of people around the world. It is a very complicated disease, difficult to study and fully understand, being one of the biggest challenges in medicine and neurosciences. Currently, there are several therapeutic modalities for this disease, particularly antidepressant therapy and psychotherapy. However, despite being quite effective, there is still a lot of failure in this therapy, and, above all, relapse of depression is a common reality. Thus, the deepening of the molecular knowledge inherent to this disease to fill the existing gaps in the therapy is a major focus of neuroscience. In fact, several factors are associated with the development of depression, such as exposure to high levels of permanent stress; neuroinflammation; and general dysregulation of neurotransmitters, such as serotonin (5-HT), dopamine, and noradrenaline [ 1 , 2 ]. The metabolism of the amino acid tryptophan (Trp) has a high participation in all of these processes. This amino acid is obtained exclusively from the diet and plays a fundamental role in several physiological reactions. Its metabolism into 5-HT and kynurenine (Kyn) plays a key role in depression [ 3 ], as will be explained in detail throughout this manuscript. Thus, all of the processes associated with the metabolism of Trp into 5-HT/Kyn must be strictly regulated to not disturb its homeostatic balance. The Kyn pathway is important for several physiological processes including the generation of cell energy, inflammation, immune response, and neurotransmission. However, overactivation of this pathway is generally associated with a lower activation of the 5-HT pathway, promoting the development of mechanisms associated with depression. Furthermore, it is important to note that this pathway is divided into two major branches: neurotoxic and neuroprotective branches. In depression, there is much greater activation of the neurotoxic branch of this pathway [ 4 , 5 ]. Regarding the 5-HT pathway, it also assumes vital functions throughout the body, involving various physiological processes such as mood, motor control, regulation of circadian rhythm, and gastrointestinal regulation. In depression, this pathway is widely studied, and in general, it is known that increased levels of 5-HT and disruptions to its receptors and pathways are also widely associated with this disease [ 6 , 7 ]. Thus, the study of Trp metabolism in Kyn and 5-HT takes a central importance in the investigation of depression. Therefore, this narrative review will focus on these pathways in processes such as neuroinflammation, stress, microbiota, and brain-derived neurotrophic factor dysregulation in depression. The main goal is to clarify these processes, which may help in the development of new therapies or biomarkers and help to improve the quality of life of patients who suffer from this condition that is so disturbing and challenging to their daily lives. For the research, collection of papers was carried out through a search on the PubMed database, considering mainly literature published in the last 5 years and focusing on the most relevant papers for the topic. Figure 1 summarizes the information presented in this review.

Schematic abstract of the information presented in this review. Briefly, the Trp metabolism is important in several processes connected with depression, particularly neuroinflammation, stress response, gut microbiota dysregulation, and brain-derived neurotrophic factor activity. Illustration created with BioRender [ 8 ]. TPH2: tryptophan hydroxylase 2; 5-HT1A: serotonin 1A receptor; IDO: indoleamine 2-3-dioxygenase 1; TDO: tryptophan 2,3-dioxygenase; SERT: serotonin transporter.

2. Depression—A Brief Contextualization

Depression is a globally prevalent disease. About 280 million people in the world have depression [ 9 ]. This is a very debilitating illness, characterized by anhedonia, sad mood, disrupted circadian cycle, changes in appetite or weight, lack of energy, and cognitive abnormalities. In severe cases, this disease can even lead to death by suicide [ 9 , 10 ]. One of the major problems associated with depression is the high rate of recurrence, therapy failure, and lack of diagnosis/treatment, especially in low- and middle-income countries [ 1 , 2 , 9 ]. However, there are effective treatment modalities, particularly psychotherapy and/or antidepressant medication [ 2 ]. Despite all of the recent advances in neurosciences, there is still no explanation for all of the molecular aspects of depression. However, it is known that biogenic amine deficiency (particularly 5-HT, dopamine, and noradrenaline), neurotrophic factors such as brain-derived neurotrophic factor (BDNF), gut microbiota deregulation, genetic, immunologic, endocrine, environmental factors, and neurogenic problems are underlying the origin of depression [ 11 ]. The role of monoamines in depression is widely studied. Particularly, 5-HT is highly connected with depression. This monoamine is produced from the amino acid Trp, and the disrupted activity of 5-HT pathways is related to the pathophysiology of depression [ 6 ]. Indeed, nowadays, antidepressants based on 5-HT reuptake to the synaptic cleft (SSRIs—selective 5-HT reuptake inhibitors) and are effective and one of the most prescribed worldwide, highlighting the role of 5-HT in depression. Nevertheless, it is important to keep in mind that this disease is extraordinarily complex, and impaired 5-HT activity can cause depression, but is neither necessary nor sufficient, with the presence of other factors being important [ 6 ], as referred above ( Figure 2 ).

Depression is a complex disease. Hypothalamic–pituitary–adrenal (HPA) axis dysfunction, low levels of neurotransmitters (such as 5-HT, noradrenaline, and dopamine) and neurotrophic factors (such as BDNF), brain atrophy of regions such as the hippocampus, increased levels of inflammation and oxidative stress, and decreased levels of neurogenesis are some underlying features of depression. Illustration created with BioRender [ 8 ].

3. Trp Metabolism

Trp is an amino acid obtained exclusively through the diet. This amino acid is essential for several human processes, including gastrointestinal and nervous functions, being used for protein synthesis and metabolized essentially by two pathways: the Kyn and the 5-HT pathways. Additionally, in the gut, the microbiota metabolizes Trp by the indole pathway. Figure 3 summarizes the Trp metabolism by the Kyn and 5-HT pathway, which are the focus of this article.

Summary of the two major metabolic pathways of the amino acid Trp: 5-HT and Kyn pathways. All of the abbreviations are described in text. Illustration created with BioRender [ 8 ].

The Kyn is the major Trp metabolism pathway (about 95% of free Trp is a substrate for this pathway) [ 12 ]. This pathway is important for physiological processes including the generation of cell energy, inflammation, immune response, and neurotransmission. Indeed, this metabolic pathway influences physical exercise responses and mental health, being linked to diseases such as depression, schizophrenia, cancer, and diabetes [ 4 , 5 , 12 ]. This pathway exists in several cells/tissues, such as the liver, brain, and immune cells [ 4 ]. The rate-limiting and first step in the Kyn pathway is the conversion of Trp to Kyn by the enzymes indoleamine 2-3-dioxygenase 1 and 2 (IDO1 and IDO2) and tryptophan 2,3-dioxygenase (TDO). Then, Kyn is mainly converted to 3-hydroxykyn (3-HK) by the enzyme kynurenine 3-monooxygenase (KMO). 3-HK is then converted to xanthurenic acid (XA) by the enzyme kynurenine aminotransferase (KAT) and to 3-hydroxyanthranilic acid (3-HAA) by the enzyme kynureninase (Kynu). Then, 3-HAA is metabolized in picolinic acid (PA) by aminocarboxymuconate-semialdehyde decarboxylase (ACMSD) and in quinolinic acid (QA) by non-enzymatic conversion. After that, QA is metabolized to NAD+ by the action of quinolinate phosphoribosyl transferase (QPRT). Additionally, to a lesser extent, Kyn is metabolized into kynurenic acid (Kyna) by the enzymatic action of KAT and in anthranilic acid (AA) by Kynu’s action [ 4 , 13 ].

The 5-HT pathway is also extremely important to human physiology. Serotonergic networks are crucial in behavioral aspects (such as mood, sexuality, memory, appetite, stress response, and anger), as well as other central nervous system effects (like motor control, regulation of circadian rhythm, and body temperature) and effects outside of the central nervous system, such as gastrointestinal regulation, nociception, mammary gland development, vasoconstriction/dilation, regulation of heart rate, and platelet aggregation [ 7 ]. This pathway’s first and rate-limiting step is the conversion of Trp to 5-hydroxytryptophan (5-HTP) by the enzymes tryptophan hydroxylase 1 or 2 (TPH1 or 2, mostly expressed in peripheral and in the central nervous tissues, respectively). Then, 5-HTP is decarboxylated by the aromatic acid decarboxylase (AADC) to form 5-HT, which can be metabolized to form N-acetylserotonin (NAS) by arylalkylamine N-acetyltransferase (AANAT), and then by N-acetylserotonin O-methyltransferase (ASMT) to form melatonin. 5-HT can also be metabolized by the enzyme monoamine oxidase (MAO) to form 5-hydroxyindoleacetic acid (5-HIAA), the major 5-HT metabolite [ 3 , 13 , 14 ].

Lastly, the indole pathway is conducted by the gut microbiota. Briefly, this pathway generates several metabolites (like indole and tryptamine) that are important to the host physiology. Indeed, these metabolites participate in processes such as immune system regulation, gastrointestinal motility, inflammation, and anti-oxidative effects [ 13 , 15 ].

4. Trp Metabolism in Depression—An Overlook

The Trp metabolism is widely involved in depression and other neuropsychiatric disorders, mainly by being responsible for the synthesis of both 5-HT and Kyn, which are important neuroactive compounds [ 3 ]. Indeed, a study focused on the effect of dietary Trp on affective disorders highlighted that a diet enriched in Trp may result in less depressive symptoms and better mood states of individuals. Additionally, a diet with low levels of Trp resulted in irritability and anxiety in comparison with when the same individuals had a Trp-rich diet [ 16 ].

Particularly, the role of 5-HT in this disease is deeply studied. Focusing on the metabolism of Trp to 5-HT/melatonin/5-HIAA, several aspects are intimately connected with depression’s etiology and pathophysiology. The enzyme TPH has an essential role in many mental disorders, including depression. Studies demonstrate that stress inhibits the expression of this enzyme, reducing the levels of 5-HT [ 17 ]. Indeed, studies also correlate the expression of TPH1 enzyme with depression and responses to antidepressant medication. A solid hypothesis is that the periphery cells that produce 5-HT have a TPH1 dysfunction, leading to deficient brain 5-HT levels. This leads to a homeostatic response to low 5-HT levels by the TPH2 enzyme, which was overexpressed in individuals that have committed suicide [ 18 , 19 ]. Additionally, both 5-HTP and 5-HT play important roles in depression. 5-HTP may help increase 5-HT levels, reducing the symptoms of depression. Evidence points out that the transport of 5-HTP across to the brain is deficient in depression [ 20 , 21 ]. Another study showed that the combination of 5-HTP with nialamide (an antidepressant, MAO inhibitor) was beneficial when compared with the administration of nialamide alone [ 20 , 22 ]. The same happened with the combination of L-deprenil (another MAO inhibitor) with 5-HTP [ 20 , 23 ]. Decreased levels of 5-HT and disruptions in its receptors and pathways are also widely associated with this pathology. Indeed, deficits in serotonergic transmission, including reductions in 5-HT neurons and their projections, are associated with this disease and failure of antidepressant responses. Additionally, the most commonly prescribed antidepressants are based on the blockade of 5-HT transporter (5-HTT or SERT), increasing the levels of 5-HT on the synaptic cleft, promoting antidepressant responses [ 6 , 24 ]. MAO enzyme imbalances are also associated with the pathology of depression. Indeed, monoamine oxidase inhibitors (MAOIs) have proven efficacy in treating depression [ 25 ]. MAO-A is more involved in the pathophysiology of depression, as elevated MAO-A activity and expression are observed in depressed individuals and in animal models of depression [ 26 ]. Nevertheless, MAO-B activity is also altered in depression. Indeed, a study revealed that elevated MAO-B levels were found in the prefrontal cortex of patients with major depressive episodes [ 27 ]. Other important metabolites in the 5-HT pathway are 5-HIAA and melatonin. Starting with 5-HIAA, a study reported that low levels of this metabolite in cerebrospinal fluid were associated with suicidal attempts in depressed individuals [ 28 ], being linked with low levels of 5-HT. Lastly, low levels of melatonin were also observed in depressed patients [ 29 ], despite some literature inconsistencies. For example, there are studies that correlate lower nocturnal serum/saliva levels of melatonin to depression, whereas others found no differences or even elevated levels (versus non depressed individuals) [ 30 , 31 ]. Nevertheless, studies in animals demonstrated that melatonin reduced neuroinflammation induced by lipopolysaccharide (LPS), as well as NF-κB expression in the cortex and the hippocampus of these animals, leading to the attenuation of autophagy impairment and improvement of depressive symptoms [ 32 ].

The Kyn pathway is also implicated in depression. Indeed, this pathway is strongly activated in depression, and may contribute to the progression of the disease [ 33 ]. Both IDO and TDO enzymes are overactivated during depression, highlighting the use of IDO and TDO inhibitors as potential drugs to treat depressive disorder [ 33 ]. Additionally, it is important to remember that the metabolite Kyna is considered a neuroprotective compound, whereas 3HK is neurotoxic. In depression, there is an imbalance between these compounds. Indeed, astrocytes mainly produce Kyna because they lack the enzyme KMO, whereas microglia and macrophages produce essentially the neurotoxin QA from the 3HK pathway [ 19 , 34 , 35 ]. In depression, it is stated that there is a loss of astrocytes, contributing to the overactivation of 3HK pathway. In turn, the overactivation of this pathway induces even more astrocyte and neuronal apoptosis, lowering the levels of important neuroprotective factors produced by these cells, such as glial-derived neurotrophic factor (GDNF) [ 19 ]. Thus, KMO activation relates to depression. Additionally, it was observed that increases in the levels of QA contribute to reduced levels of dopamine, choline, and γ-aminobutyric acid (GABA) [ 36 ], as well as disturbances in glutamatergic pathways, also known to be dysfunctional in depression [ 19 , 37 ]. Furthermore, in depression, hippocampal atrophy is described. This hippocampal atrophy may also be linked with imbalances in neurotoxic/neuroprotective compounds such as QA/Kyna [ 38 ]. Evidence also suggests that the overproduced proinflammatory cytokines in depression induce the IDO enzyme, promoting the Kyn pathway, and thus decreasing the activation of the 5-HT pathway and reducing 5-HT production [ 38 ]. In mice exposed to chronic unpredictable mild stress, a Trp-rich diet shifted the Trp metabolism more toward the 5-HT pathway than to the Kyn pathway, which was enhanced in these mice previously to Trp supplementation [ 39 ]. Thus, several pieces of evidence indicate that the Kyn pathway is an important player in depression, being a potential therapeutic target. In this review, we will focus on processes such as inflammation and neurotrophic factor expression in depression, associated with Trp metabolism in the Kyn and 5-HT pathways.

4.1. Trp Metabolism and Depression’s Associated Neuroinflammation

Neuroinflammation is a hallmark widely associated with several neurological and neuropsychiatric diseases, such as depression and Alzheimer’s disease. By regulating the production of immune factors and immune cell activation, neuroinflammation assumes an important role in depression [ 40 ]. There is a positive relationship between antidepressant therapy/psychotherapy and the reduction of inflammatory signs, highlighting the connection between depression and inflammatory processes [ 41 ]. Proinflammatory cytokines are substances produced essentially by activated macrophages, involved in the overactivation of inflammatory reactions. Some examples are IL-1β, IL-6, and TNF-α [ 42 ]. These cytokines are involved in HPA–axis overactivation, leading to an increase in cortisol concentration and glucocorticoid receptor resistance, mechanisms linked to the pathogenesis of depression [ 41 , 43 ].

Alteration of Trp metabolism by proinflammatory cytokines is also an important process that links inflammation to depression. Indeed, these cytokines induce the IDO enzyme, promoting the activation of the Kyn pathway and consequently reducing the activation of 5-HT pathway of Trp, leading to an overall decrease in 5-HT synthesis [ 38 ]. Additionally, as referred above, the overactivation of Kyn pathway leads to an imbalance in neurotoxic/neuroprotective compounds, particularly 3-HK/QA/Kyna. Studies revealed that patients treated with IFN-α have reduced levels of Trp, increased levels of Kyn and Kyn/Trp ratio activity, and increases in depressive symptoms [ 44 ]. Other evidence that highlights the importance of Kyn pathway in inflammatory processes associated with depression is the efficacy of ketamine as an antidepressant agent. Indeed, this drug appears to induce anti-inflammatory effects. Animal studies and clinical evidence revealed that this drug decreased pro-inflammatory cytokines levels (such as IL-6 and TNF-α), decreased levels of IDO enzyme, and reduced the activation of the neurotoxic pathway of the Kyn pathway [ 45 , 46 , 47 , 48 , 49 ]. Furthermore, COVID-19-associated depression is widely reported [ 50 ]. A recent study also indicated that, in COVID-19 patients, there was a major urinary increase in Kyn, which was associated with disease severity and systemic inflammation [ 51 ] and may be associated with the high levels of depressive symptoms in COVID-19 patients. Indeed, inflammatory cytokines released in the process of COVID-19 inflammation activate both the HPA–axis and the IDO enzyme, increasing the levels of toxic metabolites of the Kyn pathway, which increases overall neuroinflammation and neuronal death, promoting depressive conditions [ 52 ]. Additionally, antidepressants with anti-inflammatory properties inhibit IDO induction by decreasing the levels of proinflammatory cytokines in immune-activated individuals, contributing to attenuation of depressive symptoms [ 53 ]. The role of the immune system in depression is also supported by the homeostasis of glutamatergic neurotransmission, which can be regulated by the QA/Kyna ratio, synthetized by microglia and astrocytes, respectively [ 54 ]. Overactivation of the neurotoxic arm of Kyn pathway was also observed in suicide attempters, coupled to increased inflammatory responses. By raising the levels of QA (agonist of NMDA-receptor—N-methyl-D-aspartate receptor, a glutamate receptor), NMDA-receptor was overactivated, supporting the use of NMDA-receptor antagonists such as ketamine and dextromethorphan in the treatment of this disease [ 55 ]. Another recent study also supported the role of Kyn in depression’s associated neuroinflammation. Saffron administration in mice attenuated inflammation-related metabolic pathways and modulated the expression of Kyn-related neurotoxicity, attenuating depressive-like behaviors in these animals [ 56 ]. Furthermore, the administration of the anti-inflammatory herb Radix Polygalae to mice exposed to chronic restraint stress led to modulation of inflammation, microbiota, and Trp/Kyn metabolism. Indeed, Radix Polygalae reversed the 5-HIAA decrease and the Trp, Kyna, and 3-HK increase induced by the stress exposure. This herb increased the 5-HT/Kyn ratio, which was decreased under the stress exposure, revealing an interaction between the anti-inflammatory mechanism of action and Trp metabolism [ 57 ]. Another study that evaluated the link between Trp metabolism and depressive symptoms in obesity reported that elevated levels of C-reactive protein (that reflects inflammation) correlated with low levels of Trp and Trp indole pathway metabolites such as indole-3-carboxaldehyde, observed in the more severe cases of depressive behavior [ 58 ]. In post-partum women with severe depression, dysregulation of the immune response and Kyn pathway, as well as a reduction in 5-HT levels, was also observed. Indeed, Trp was directed more towards the Kyn pathway than to the 5-HT pathway, and had high levels of inflammatory markers, such as IL-6 and IL-8 [ 59 ].

Inflammation is also connected to disturbances in the 5-HT pathway of Trp metabolism, not only by the overactivation of Kyn pathway (explained above), but also by other mechanisms. There is a large amount of evidence showing that, in patients with depression, proinflammatory cytokines originated by the microglia (TNF-α for example) reduce the presence of 5-HT [ 60 ]. Indeed, modulation of 5-HT levels by the administration of SSRIs reduced the Th17/Treg ratio, supporting an anti-inflammatory action of these drugs [ 61 ]. Other studies also demonstrated this connection between 5-HT and inflammatory processes. Mice treated with rapamycin (blocks activation of immune T and B cells) showed increased levels of 5-HT (compared with healthy controls) [ 62 ]. Another depressogenic action of cytokines is the increased expression of the 5-HT transporter, SERT [ 63 ]. This transporter was reported to be upregulated in neurons by the cytokines IL-1β and TNFα. Indeed, it was found that p38 mitogen-activated protein kinase induced activation of SERT by inflammatory cytokines [ 64 ]. Additionally, SERT expression in immune cells was also observed in response to IFNα [ 65 ]. Other studies also support this evidence of SERT overexpression by the action of cytokines. After cytokine-induced LPS administration in mice, SERT activity was stimulated, triggering depressive-like behavior in these animals. In cultured serotonergic cells and nerve terminal preparations in vitro, SERT activity was also upregulated by inflammatory cytokines [ 66 ]. Cytokines are also reported to affect the synthesis of monoamines such as 5-HT through disruption of tetrahydrobiopterin, an important enzyme co-factor to Trp hydroxylase [ 67 , 68 ]. Additionally, high stress levels can also lead to increased levels of pro-inflammatory cytokine production, leading to changes in serotonergic pathways, involved in the development of depression [ 67 ]. Paroxetine, an SSRI, has also been demonstrated to be an effective treatment for minimizing depression induced by IFNα, in patients with melanoma and hepatitis C [ 69 , 70 ]. These studies support the interplay between neuroinflammation and Kyn/5-HT pathways in depressive disorder.

4.2. Trp Metabolism and Depression’s Associated Chronic Stress

Uncontrolled stress induces changes in the central nervous system, promoting the development of neuropsychiatric disorders such as depression [ 41 ]. The human stress response is strictly regulated by the HPA–axis, which, when activated, is responsible for the increase in glucocorticoid levels, particularly cortisol, an important player in depression and other neurological disorders [ 71 ].

As discussed above, proinflammatory cytokines promote an imbalance in neurotoxic/neuroprotective metabolites by the overactivation of the neurotoxic arm of the Kyn pathway. Besides that, these proinflammatory cytokines also activate the HPA–axis, leading to stress responses that underlie depressive states, such as the observed hippocampal atrophy [ 38 ]. Particularly, by activating NMDA receptors, QA stimulates the production of interleukins such as IL-6, promoting the overactivity of this axis [ 72 ]. Elevated levels of cortisol correlate with lower levels of Trp in the plasma and a higher Kyn/Trp ratio, observed in patients who tried to commit suicide [ 73 ]. Indeed, cortisol is known to activate TDO, increasing Kyn production and shifting Trp metabolism from 5-HT to Kyn production [ 74 ]. Thus, the conversion of Trp in Kyn is promoted by chronic stress levels, mainly by elevations in cortisol and pro-inflammatory cytokines, which in turn activate IDO/TDO enzymes [ 75 ]. Indeed, treatment with allopurinol (TDO inhibitor) prevented stress-related reduction in brain 5-HT concentrations by blocking TDO activity. This treatment led to a reduction in the Kyn pathway activation ratio [ 76 , 77 ]. Additionally, the administration of 1-methyl-Trp (an inhibitor of IDO enzyme) alleviated depressive-like behavior in rodents exposed to LPS-induced stress [ 78 ]. Indeed, LPS exposure increased brains’ IDO mRNA expression in rodents, resulting in overactivation of the Kyn pathway [ 79 ]. Physical exercise also supports the effects of Kyn pathway in depression’s associated stress. The skeletal muscle PGC-1α1 enzyme’s activity is induced by physical exercise, inducing kat expression and the conversion of Kyn into Kyna, a neuroprotective metabolite of the Kyn pathway. This conversion of Kyn into Kyna controls the Kyn/Kyna balance, reducing the levels of free Kyn and protecting the brain against stress-induced depressive behaviors [ 80 ]. PGC-1α1 activity is known to reduce with age and with pathologies such as diabetes. Thus, this lack of activity may contribute to the depression associated with other pathologies/age [ 76 ].

Serotonergic networks are deeply influenced by stress responses. Indeed, some experiments demonstrate this connection. For example, a study carried out in cynomolgus monkeys revealed that the animals that were more sensitive to stress underexpressed genes such as TPH2 and 5-HT 1A receptor, important genes in the normal functioning of 5-HT pathways [ 81 ]. Additionally, as referred above, it was revealed that rats exposed to stress presented lower levels of 5-HT compared with healthy or treated rats. TPH1 and TPH2 were also less expressed in the rats exposed to high stress levels [ 17 ]. Other studies support the connection of cortisol to serotonergic pathways. For example, the administration of crocin decreased cortisol levels and increased the levels of 5-HT, ameliorating depressive-like behavior in mice [ 82 ]. The same profile of response was also obtained with the administration of gossypetin [ 83 ], aqueous extracts of miswak, and date palm [ 84 ]. Lower levels of HPA–axis hormones and increased levels of 5-HT and brain-derived neurotrophic factor were also obtained with Trp oligopeptide diets, promoting positive effects on anxious depression in mice [ 85 ]. Taken together, all of this information highlights the relationship between Trp metabolism and the stress response present in depression.

4.3. Trp Metabolism and Microbiota in Depression

A lot of studies support the role of gut microbiota in the pathogenesis of disorders such as depression. Indeed, the changes in the gut microbiota observed in depression affect the HPA–axis, neurotransmitter levels, and inflammatory processes [ 86 ]. The use of germ-free models to study the relationship between depression and the microbiome has revealed the crucial role of these microorganisms in normal brain functioning. For example, exaggerated levels of corticosterone and adrenocorticotropin (HPA–axis hormones) were observed in germ-free mice exposed to elevated levels of stress [ 87 ]. Furthermore, the administration of Lactobacillus sp. normalized the elevated corticosterone levels present in rats after maternal separation [ 88 ].

A study that involved a murine model of chronic restraint stress revealed that these animals had depressive-like behavior, as well as strong activation of the Kyn pathway. Indeed, IDO was overactivated in the brain and the gut. In these animals, the microbiome profile was altered, and the treatment with Parabacteroides elevated the 5-HT concentration, supporting the connection between 5-HT/Kyn pathways and the microbiome [ 89 ]. Another study revealed that, in stressed mice, there were reduced levels of Lactobacillus and high levels of Kyn, reflected in behavioral alterations. In these mice, when the Lactobacillus population was restored, Kyn metabolism was suppressed by IDO1 inhibition in the intestine, particularly by the reactive oxygen species produced by these microorganisms [ 90 ]. The evaluation of the antidepressant activity of probiotics such as Bifidobacteria infantis in rats also revealed that, compared with controls, these rats had a marked increase in plasma concentrations of Trp and Kyna, as well as reduced 5-HIAA levels, especially in the frontal cortex [ 91 ]. In depressive mice, a Trp-rich diet restructured the gut microbiome, increasing the number of Lachnospiracea , Lactobacillus , and Bifidobacterium [ 39 ].

The direct influence of gut microbiota in serotonergic networks is known. A study showed that oral administration of S. boulardii attenuated the LPS-induced depressive behaviors, increasing the levels of brain-derived neurotrophic factor and 5-HT in the serum [ 92 ]. Another study involved rats also exposed to stress, particularly chronic unpredictable mild stress. These rats developed depressive-like behavior and their fecal microbiota were evaluated by 16S rRNA sequence analysis. The results revealed that the microbiota of these rats differed significantly from healthy controls, which may contribute to depressive-like behavior by interfering with Trp metabolism. Indeed, the levels of 5-HT and TPH2 were low in the brain, contrasting with high levels of IDO expression [ 93 ]. The comparison of germ-free and conventional animals also indicated that the plasma levels of 5-HT in conventional animals were 2.8-fold higher than in germ-free animals, supporting the role of microorganisms in 5-HT production [ 94 ]. In another study, L. lactis strain WHH2078 increased 5-HTP levels and the expression of TPH1 in cells. In mice exposed to chronic unpredictable mild stress, these bacteria also alleviated the depressive-like behaviors, restoring central 5-HT and 5-HTP levels [ 95 ]. Another study evaluated the effect of a mung bean protein diet in undernourished rats. This diet led to the reproduction of probiotics, particularly Bifidobacteria and Lactobacillus , as well as increased levels of Trp and 5-HTP in the serum, compared with rats treated with low levels of mung bean protein, revealing low levels of cognitive dysfunction [ 96 ]. The administration of the probiotic strain L. rhamnosus IMC 501 to zebrafish also led to increased expression levels of bdnf and genes involved in the brain’s 5-HT signaling metabolism, particularly h1a, tph1b, tph2, htr1aa, slc6a4a, and mao. Indeed, this was correlated with the behavior of the fishes, particularly the shoaling behavior. Additionally, a significant increase in Firmicutes was also observed [ 97 ]. These studies support the role of the gut microbiota in Trp metabolism associated with depressive disorder.

4.4. Trp Metabolism and Brain-Derived Neurotrophic Factor Expression in Depression

Different neurotrophic factors are highly connected to depression, notably BDNF. These factors are important to neuronal plasticity, a process defined by the adaptation of the nervous system in response to different stimuli. Depressed individuals have decreased levels of BDNF in the blood and brain structures connected with depression, such as the hippocampus. Additionally, antidepressants such as SSRIs increase BDNF expression [ 98 , 99 ]. Trp metabolism is implicated in BDNF function. Indeed, a study reported that the depletion of Trp in healthy patients led to a compensatory increase in serum BDNF levels. This response was not observed in depressed individuals, in which BDNF levels, as well as plasma Trp levels, remained low [ 100 ]. In another study in depressive mice exposed to chronic unpredictable chronic stress, Trp supplementation also improved the expression of BDNF [ 39 ].

Kyn pathway and BDNF expression are also connected in the context of depression. By interacting with the NMDA receptor, QA induces signaling pathways that reduce BDNF expression [ 45 ]. Other Kyn neurotoxic metabolites besides QA also weaken glial-neuronal networks important to neurotrophic factor synthesis, particularly BDNF [ 19 ]. Indeed, studies demonstrate that BDNF may modulate the Kyn pathway. After exposure to stress conditions, heterozygous mice (BDNF+/−, about 50% reduction of BDNF expression) showed increased activation in the neurotoxic arm of the Kyn pathway, increasing the level of neurotoxic metabolites such as 3-HK, in contrast with the wild-type animals [ 101 ]. In another study, the Kyn pathway was altered in mice displaying BDNF Val66Met polymorphism. This polymorphism relates to increased predisposition to develop psychiatric disorders. In this study, these mice showed overactivation of the Kyn pathway [ 102 ]. Another study evaluated the effect of the acute examination stress in healthy students, revealing that the elevation of BDNF levels present in these students limited the neuroinflammatory arm of the Kyn pathway, supporting an interplay between BDNF and the Kyn pathway [ 103 ]. This interplay was also supported by a study that revealed that blockade of IDO1 attenuated depressive-like behavior in mice exposed to chronic unpredictable mild stress, with a concomitant increase in hippocampal BDNF expression and neurogenesis in the hippocampus [ 104 ].

Impaired expression of BDNF alters 5-HT pathways. For example, it is known that BDNF stimulates the plasticity of 5-HTergic neurons [ 105 ]. This neurotrophic factor reduces SERT and 5-HT1A receptor function mainly in the hippocampus, and reduces 5-HT2A receptor function in other brain areas such as the prefrontal cortex [ 106 ]. Indeed, studies in a rat model of acute psychological stress revealed that agonists of 5-HT1A and 5-HT2A receptors increased BDNF protein expression in diverse brain regions, opposing the effects of 5-HT1A and 5-HT2A receptor antagonists, supporting the connection between BDNF and the 5-HT system [ 107 ]. In raphe neurons, BDNF promoted the expression of TPH and upregulated the uptake of 5-HT. This neurotrophic factor also promoted the development and function of serotonergic neurons [ 108 ]. Indeed, the connection of BDNF to serotonergic pathways is supported by the interaction of this factor with serotonergic receptors such as 5-HT1A and 5-HT2A, which were impaired in conditions when the BDNF gene was deleted [ 108 , 109 , 110 ]. Another piece of evidence that supports this connection is that the increased levels of 5-HT may increase BDNF levels, as observed upon administration of SSRI antidepressants. Indeed, the block of SERT enhances 5-HT pathways through the interaction with different 5-HT receptors that, in turn, increase CREB phosphorylation, which leads to increased levels of BDNF transcription [ 108 ]. Another interesting study evaluated the effects of gardening in elderly people. In the gardening group, Trp metabolism was increased, correlated with increased levels of BDNF [ 111 ]. Another recent study highlights the relationship between TPH2 expression and BDNF levels. The administration of a pargyline (MAO inhibitor) in zebrafish treated with an irreversible inhibitor of TPH2 (p-chlorophenylalanine) led to reduced BDNF levels, revealing an interdependence between 5-HT and BDNF systems in the antidepressant response [ 112 ]. The interaction between 5-HT neurotransmission and the BDNF-related pathways was also supported by another study. In this study, enhanced Trp intake led to increased activation of 5-HT pathways that, in turn, modulated the BDNF system, protecting against cognitive decline in aged rats [ 113 ]. Physical exercise is also known to upregulate the BDNF–5-HT system. Indeed, 5-HT participates in BDNF-mediated neuroplasticity, stimulated by aerobic physical exercise in rats [ 114 ]. Altogether, these studies support the interplay between BDNF and Trp metabolism in the 5-HT and Kyn pathways.

4.5. Pharmacological Modulation of Trp Metabolism in Depression—An Overlook

As described throughout this manuscript, Trp metabolism is crucial in the pathophysiology of depression, with great emphasis on the 5-HT pathway. Thus, the pharmacological modulation of the effects of this pathway plays a major role in the therapy of this disease. Nevertheless, it is important to refer that, in the management of depression, psychotherapy also assumes a heavy role. Table 1 summarizes the main drug classes related to 5-HT in the treatment of depression. These drugs act mainly downstream the production of 5-HT.

Principal drug classes related to 5-HT in the treatment of depression.

Therapies regarding the direct manipulation of Kyn pathways are still not available in the common medical practice for depression. However, future and intensive research may generate novel insight into this pathway and the way to manipulate it. Nevertheless, administration of 4-chlorokynurenine (an investigational antidepressant drug) enhanced the neuroprotective arm of the Kyn pathway, decreasing the neurotoxic arm [ 121 ]. Additionally, the administration of escitalopram revealed a 50% decrease in plasma QA, suggesting that these drugs reduce the neurotoxic arm of the Kyn pathway [ 122 ]. Chronic administration of antidepressants (amitriptyline, imipramine, fluoxetine, and citalopram) in rats also revealed an increase in Kyna production in the hippocampus and cortex, increasing the neuroprotective arm of the Kyn pathway [ 123 ]. Ketamine also led to increased levels of Kyna in the serum, associated with a reduction in depression severity [ 49 ]. IDO1, TDO, KMO, and KAT inhibitors are also under investigation, mainly for cancer and not depression purposes [ 124 ]. Indeed, investigations focusing on Trp metabolism may generate a next step on the treatment of depression.

5. Conclusions

It is extremely important to deeply study depression’s molecular mechanisms, aiming to understand this extremely complex disease that is very prevalent worldwide. New therapies urgently need to be developed, and are only possible when research efforts are present. The study of Trp metabolism in the context of depression may provide new knowledge and therapeutic possibilities. This amino acid, by being metabolized into the 5-HT or Kyn pathway, assumes a crucial role in several aspects profoundly connected to depression’s physiopathology, such as neuroinflammation, chronic stress, dysregulation in the gut microbiota, and BDNF expression levels. The maintenance of the Trp-Kyn/Trp-5-HT balance is critical for physiological homeostasis, being important to prevent the development of neuropsychiatric diseases such as depression.

Acknowledgments

Ana Salomé Correia also acknowledges FCT for funding her PhD grant (SFRH/BD/146093/2019).

Funding Statement

This work was financed by FEDER—Fundo Europeu de Desenvolvimento Regional through the COMPETE 2020—Operational Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through FCT—Fundação para a Ciência e a Tecnologia, in a framework of the projects in CINTESIS, R&D Unit (reference UIDB/4255/2020) and within the scope of the project “RISE—LA/P/0053/2020. Nuno Vale also thanks support from FCT and FEDER (European Union), award number IF/00092/2014/CP1255/CT0004 and CHAIR in Onco-Innovation at FMUP.

Author Contributions

Conceptualization, N.V.; formal analysis, A.S.C. and N.V.; writing—original draft preparation, A.S.C.; writing—review and editing, A.S.C. and N.V.; supervision, N.V.; project administration, N.V.; funding acquisition, N.V. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Informed consent statement, data availability statement, conflicts of interest.

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

1. Introduction

3. results and discussion, 4. conclusions, 5. related literature, supporting information.

research papers \(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

A structural role for tryptophan in proteins, and the ubiquitous Trp C δ 1 —H⋯O=C (backbone) hydrogen bond

a Department of Molecular Physiology and Biological Physics, University of Virginia, 1340 Jefferson Park Avenue, Charlottesville, VA 22908-0736, USA, and b Department of Chemistry and Biochemistry, Utah State University, Logan, Utah, USA * Correspondence e-mail: [email protected]

Tryptophan is the most prominent amino acid found in proteins, with multiple functional roles. Its side chain is made up of the hydrophobic indole moiety, with two groups that act as donors in hydrogen bonds: the N ɛ —H group, which is a potent donor in canonical hydrogen bonds, and a polarized C δ 1 —H group, which is capable of forming weaker, noncanonical hydrogen bonds. Due to adjacent electron-withdrawing moieties, C—H⋯O hydrogen bonds are ubiquitous in macromolecules, albeit contingent on the polarization of the donor C—H group. Consequently, C α —H groups (adjacent to the carbonyl and amino groups of flanking peptide bonds), as well as the C ɛ 1 —H and C δ 2 —H groups of histidines (adjacent to imidazole N atoms), are known to serve as donors in hydrogen bonds, for example stabilizing parallel and antiparallel β -sheets. However, the nature and the functional role of interactions involving the C δ 1 —H group of the indole ring of tryptophan are not well characterized. Here, data mining of high-resolution ( r ≤ 1.5 Å) crystal structures from the Protein Data Bank was performed and ubiquitous close contacts between the C δ 1 —H groups of tryptophan and a range of electronegative acceptors were identified, specifically main-chain carbonyl O atoms immediately upstream and downstream in the polypeptide chain. The stereochemical analysis shows that most of the interactions bear all of the hallmarks of proper hydrogen bonds. At the same time, their cohesive nature is confirmed by quantum-chemical calculations, which reveal interaction energies of 1.5–3.0 kcal mol −1 , depending on the specific stereochemistry.

Keywords: tryptophan ; hydrogen bonds ; C—H⋯O bonds ; protein structure .

2.1. Data mining in the Protein Data Bank and stereochemical analysis

The resulting database of close contacts had another layer of redundancy due to the presence of noncrystallographic symmetry, which includes biologically relevant oligomers. To eliminate multiple observations of the same contact, we arbitrarily selected the median interaction from oligomeric structures. We assumed that at 1.5 Å resolution or higher, differences between monomers may be due to genuine differences in crystal packing, and so averaging would not be appropriate. However, as the shortest distances might be encumbered by errors, the median contact might be more representative. This final nonredundant data set was used for further calculations of stereochemistry.

2.2. Quantum-chemical calculations of interaction energies

3.1. identification of interactions involving trp c δ 1 —h as the donor group.

We obtained 17 012 close contacts, 5983 of which were with water O atoms. Another 1046 contacts involved Glu and Asp carboxylate groups and 1010 contacts were with side-chain hydroxyl groups of Ser, Thr and Tyr. A further 542 contacts involved side-chain carbonyl groups of Asn and Gln. Interestingly, nearly half of all contacts, i.e. 8431 (49.6%), were with backbone carbonyl O atoms, which are particularly strong acceptors owing to their partial negative charge. Given the preponderance of these interactions, we focused on this group of contacts and analysed the respective stereochemistry in order to assess their character and potential function.

3.2. The stereochemistry of the Trp C δ 1 —H⋯O=C backbone contacts

All calculations up to this point were carried out using raw coordinates from the Protein Data Bank (except for the riding hydrogen positions, which were added independently). As we embarked on the detailed analysis of specific structures, we were concerned about inconsistencies inherent in the data sets in the PDB introduced by different protocols or refinement and different software. Specifically, we were concerned about the lack of inclusion of H atoms during refinement, the lack of coordinates in the file etc . To avoid bias, all structures described below were subjected to additional standardized refinement and addition of riding H atoms at correct, uniform positions using the PyMOL script. Details are described in the supporting information and Supplementary Table S1 .

3.2.1. The C δ 1 —H → O=C (+1) class

3.2.2. The C δ 1 —H → O=C (−1) class

A small minority of contacts in this class, i.e. 30 examples, are of the m 105 type and almost all involve Trp residues in the α L region of the Ramachandran plot, with long d HO distances. Such stereochemistry suggests weak interactions. There are only three structures in the p -90 cluster.

3.2.3. The C δ 1 —H → O=C (−2) class

The m 0 cluster is represented by 190 structures. It is very close in conformational space to m 105 because the m 105 structures are shifted to lower χ 2 , with an average value of 82°, while the m 0 cluster is also shifted to higher values of χ 2 , with an average of 23°. In both groups Trp is primarily found in extended, β -secondary conformations, although right-handed and left-handed helical structures are also observed.

Of note is the fact that many of the motifs in all three clusters resemble the classic type II β -turn. The conformation of Trp is such that the C δ 1 —H group mimics the peptide amide which would serve as a donor in a classical β -turn, adding just one atom to the turn (11 atoms instead of 10). Therefore, the direction of the hydrogen bond is preserved, with residue i donating the hydrogen bond to residue i − 2. Unlike the canonical β -turn, this structural feature does not reverse the direction of the polypeptide chain but creates kinks and turns of ∼110°.

3.2.4. The C δ 1 —H → O=C (−3) class

The m 105 cluster contains motifs with Trp found in both α and β secondary structures. The average α H is 137.9°, but α O is again unfavourable (average 113.8°). Except for a few outliers, the p -90 cluster is stereochemically tight, with a mean χ 1 of 66° and χ 2 of −89°. The vast majority of the motifs contain Trp in an α -helical form, and the putative hydrogen bond has a more favourable geometry, with an α H of 138.5° and an α O of 135.4°, with an average elevation of 0.6 Å on the si face. The small m 0 cluster contains several motifs with Trp in α , β and left-handed helical secondary conformations. The d HO distances are longer in this cluster, with an average α H of 140.7° and α O of 136.4°

3.2.5. The C δ 1 —H → O=C (−4) class

The rare m 0 motifs also contain Trp in both α and β secondary conformations. They tend to have an unfavourable angular stereochemistry, with an average α H of 128° and α O of 141°, and longer d HO distances.

3.3. The interaction energies of C—H⋯O=C bonds

Interaction energies ( ) calculated for 3-methylindole and -methylacetamide pairs based on the coordinates of specific interactions in protein structures values are the changes in the C⋯O distance ( ) resulting from additional refinement; the final values ( hydrogen⋯acceptor distances) were obtained after the riding H atoms were replaced with those calculated by . Other parameters are α (the C—H⋯O angle), α (the C=O⋯H angle) and τ (the elevation of H from the plane). PDB entry Class Conformer (Å) Δ (Å) α (°) α (°) τ (Å) (Å) Trp Acceptor (kcal mol ) 1 0 3.026 0.027 153 120 1.36 2.029 612 Ser613 −2.12 1 -105 3.143 0.052 172 128 0.61 2.109 468B Pro469 −2.84 −2 -90 3.098 0.005 171 162 0.28 2.023 26B Gln24B −2.81 −2 0 2.862 0.069 140 153 −0.76 2.107 419A Val417 −1.57 −2 105 3.245 0.025 160 94 −2.15 2.230 304A Gly302 −1.53 −3 0 3.167 0.018 135 165 −0.42 2.343 470A Glu467 −2.94 −3 105 3.245 −0.023 166 152 0.80 2.183 347A Leu344 −2.74 −4 0 3.405 0.017 163 137 −0.52 2.375 913A Ala909 −2.41 The stereochemistry of the C 1—H⋯O=C interactions for which energies of interaction have been calculated (Table 1 ) superposed on the Trp side chain. The PDB codes are shown for each carbonyl O atom. All interactions show cohesive E int values irrespective of stereochemistry. As expected, the weakest E int values were obtained for those interactions in which the H atom is located significantly out of the sp 2 plane of the acceptor O atom. It appears that the α H and α O angles are less of a factor: both can be as low as ∼130° without a significant reduction in E int , as long as the hydrogen is within ∼0.8 Å of the sp 2 plane. We also noted that many of the structural motifs that we investigated show d HO distances as short as ∼2.0 Å, significantly shorter than the predicted optimal distance of ∼2.3 Å. We wondered whether such short interactions, resulting from intramolecular constraints, might be less favourable. The dependence of the energy of interaction ( ) on the distance for an -methylacetamide and 3-methylindole pair derived from PDB entry . The arrow shows the position on the energy curve corresponding to the actual distance in the crystal structure, 2.02 Å. The black arrow indicates the line along which the 3-methylindole moiety was translated to obtain the curve of versus distance. We also present evidence based on quantum-chemical calculations that the short C δ 1 —H⋯O=C contacts revealed by structural data mining are in fact invariably cohesive interactions of the order of approximately half a canonical hydrogen bond, and less sensitive to specific stereochemistry, such as C—H⋯O and H⋯O=C angles, than previously thought. The critical factor is the position of the H atom close to the sp 2 plane of the acceptor O atom. Note on the precision of the crystallographic coordinates and Supplementary Methods. DOI: https://doi.org/10.1107/S2059798324005515/chr5002sup1.pdf Supplementary Table S1. Crystallographic re-refinement of structural models analysed in the paper. DOI: https://doi.org/10.1107/S2059798324005515/chr5002sup2.xlsx ‡ Current address: Department of Biochemistry, Biophysics and Biotechnology, Doctoral School of Exact and Natural Sciences, Jagiellonian University, Krakow, Poland. Acknowledgements The authors declare no competing financial interests. Funding information ZSD and WM are supported by Harrison Family Funds; WM and ZSD acknowledge National Institutes of Health grants GM132595 and GM086457, respectively. This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence , which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited. Follow Acta Cryst. D Food & Drink Things To Do Tips to keep dogs calm during July 4th fireworks Often lost in all of our oohing and aweing over Fourth of July fireworks displays is the impact the corresponding explosions have on our pets. Dogs can be particularly sensitive to the loud bangs of fireworks or claps of thunder from passing storms, said Dr. Janelle Scott, a primary care veterinarian at Colorado State University’s James L. Voss Veterinary Teaching Hospital. So, dog owners should take extra precautions to ensure their animals are safe and as comfortable as possible as we celebrate our nation’s 248th birthday. Simple solutions, she said, include keeping dogs in their favorite spaces in your home, whether that be a certain room or kennel or crate for those that are crate-trained. She recommends dark spaces or closing window blinds because “sometimes the flash can be disturbing to them, too. You might even want to turn on a TV, radio, podcast or a YouTube video to provide white noise to sort of mask the fireworks noise. “If you can keep them in a quiet, safe place, for some dogs that might be enough.” More: Fort Collins City Council wants to consider banning sales of cats and dogs from puppy mills For dogs that need a little more help, a variety of safe, over-the-counter supplements are available, she said. Ideally, you’ve discussed these previously with your veterinarian and have a favorite or two, she said. If not, she recommends those containing tryptophan, the chemical we often blame for making us drowsy after eating turkey for Thanksgiving or other holidays. Tryptophan helps the body produce serotonin, a neurotransmitter that regulates behavior, mood, memory and digestion, according to the National Institutes of Health online library of medicine. “It’s similar to us eating lots of turkey at Thanksgiving that can give you that relaxed feeling,” Scott said. Dogs with more severe sensitivity to loud noises might need an actual pharmaceutical drug, prescribed by a veterinarian. Owners should speak to their veterinarians to determine which would be best for their pet, she said. If it’s too late to have that discussion before this year’s holiday fireworks, remember to plan ahead and have it before next summer, she said. Some cats exhibit noise sensitivity, too, and could benefit from some of the suggestions she shared for dogs. Those with new dogs, puppies or animals they’ve recently adopted need to be particularly careful about the environment those pets will be in for the holiday, Scott said. She recommended keeping them away from large crowds and loud noises as much as possible until they get to know them better. “Don’t be afraid to have a conversation with your vet about what you can do to keep your pet safe and not causing damage to themselves or your home when they hear fireworks or those 4 p.m. thunderstorms roll through,” she said. “Summer flies by but trying to plan this stuff ahead of time can help the patient, client and veterinarian.” Reporter Kelly Lyell covers education, breaking news, some sports and other topics of interest for the Coloradoan. Contact him at  [email protected] , x.com/KellyLyell and   facebook.com/KellyLyell.news .  376 IMAGES Use Tryptophan to Boost Serotonin for Better Mental Health Mechanisms of serotonin syndrome: (1) Increased levels of L-tryptophan Clearing Up the Serotonin Hypothesis/Depression Confusion Rethinking Serotonin's Role in Depression Tryptophan, Serotonin, Melatonin, and Kynurenine: Genetic Pathway IJMS VIDEO Antipsychotics 4 ~ Serotonin Hypothesis of Schizophrenia SEROTONIN PATHWAY of TRYPTOPHAN metabolism part 2 Rethinking the Treatment of Depression: Have We Been Misinformed About Antidepressants? What Does Serotonin Do? #serotonin The Serotonin Hypothesis in Depression Confusion and Enlightenment 5 HTP VS Tryptophan COMMENTS The serotonin theory of depression: a systematic umbrella ... The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a ... The serotonin theory of depression: a systematic umbrella review of the The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. ... and methods to reduce serotonin availability using tryptophan depletion do ... What has serotonin to do with depression? The "serotonin hypothesis" of clinical depression is almost 50 years old. At its simplest, the hypothesis proposes that diminished activity of serotonin pathways plays a causal role in the pathophysiology of depression. ... In healthy participants with no risk factors for depression, tryptophan depletion does not produce clinically ... Fifty years on: Serotonin and depression Nonetheless, tryptophan depletion offers a straightforward way to test the serotonin hypothesis of depression. It is well established that tryptophan depletion in healthy participants, who lack obvious risk factors for depression, does not cause significant lowering of mood ( Ruhé et al., 2007 ). The serotonin theory of depression: a systematic umbrella ... The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. ... (SERT) levels measured by imaging or at post-mortem; tryptophan depletion ... Fifty years on: Serotonin and depression Nonetheless, tryptophan depletion offers a straightforward way to test the serotonin hypothesis of depression. It is well established that tryptophan depletion in healthy participants, who lack obvious risk factors for depression, does not cause significant lowering of mood ( Ruhé et al., 2007 ). PDF The serotonin hypothesis of depression: both long discarded ... The main areas of research do not provide support for the most well-known neurochemical hypothesis, the serotonin theory of depression—the idea that depression is caused by low levels or low ... Fifty years on: Serotonin and depression Keywords. Serotonin, depression, psychopharmacology, learning, positron emission tomography. The notion that clinical depression might be caused by deficient activity of the brain neurotransmitter, serotonin (5-hydroxy-tryptamine (5-HT)) is over 50 years old. This theory seems to have been first proposed in 1967 by the British psychiatrist ... The serotonin theory of depression: A systematic umbrella review of the The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December ... Antidepressants and the serotonin hypothesis of depression Antidepressants remain an effective treatment for depression, even without the "chemical imbalance" explanation. A recent umbrella review of evidence for the serotonin theory of depression 1 was widely reported in UK media as showing that depression is not caused by low levels of serotonin or a "chemical imbalance" and therefore casting ... Tryptophan Metabolism in Depression: A Narrative Review with a ... One important player in depression is the amino acid tryptophan. This amino acid can be metabolized in two important pathways in the context of depression: the serotonin and kynurenine pathways. These metabolic pathways of tryptophan are crucial in several processes that are linked with depression. Indeed, the maintenance of the balance of ... Tryptophan depletion, serotonin, and depression: where do we stand? Tryptophan depletion is a widely used paradigm to study serotonin system-related mechanisms in the pathophysiology and treatment of depression. There is convincing evidence that tryptophan depletion primarily and selectively affects serotonergic transmission. The behavioral data in healthy controls with and without genetic risk for depression ... PDF Imaging Genetics of Depression Due in part to the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in the ... whereas perturbation of the serotonin system using tryptophan depletion influenced . 8 resting-state activity in the amygdala, ... Given the neurotrophin hypothesis of depression, as well as data implicating ELS as a vulnerability marker for MDD (Gatt ... How your gut microbiome is linked to depression and anxiety It has been found that dietary intake of tryptophan can modulate central nervous system concentrations of serotonin in humans, and that tryptophan depletion aggravates depression. Figure 6. Tryptophan, its metabolites, and lactic acid produced by the gut microbiome ... For more on how emerging trends and new approaches are helping the millions ... The neurobiology of depression—revisiting the serotonin hypothesis. I The serotonin (5-HT) hypothesis of depression dates from the 1960s. It originally postulated that a deficit in brain serotonin, corrected by antidepressant drugs, was the origin of the illness. ... Animal models as described earlier have shown that modifying any of the components of the 5-HT system, including tryptophan hydroxylase, ... Neural circuits expressing the serotonin 2C receptor regulate ... Restriction of dietary l-tryptophan (which is required for 5-HT synthesis) impairs short-term and long-term memory in rodents and humans (1, 2). In addition, depletion of 5-HT during synaptogenesis (using a tryptophan hydroxylase inhibitor) decreases synaptic density in the adult rat hippocampus . Gut-Brain Axis: A Cutting-Edge Approach to Target Neurological Tryptophan is the precursor of serotonin, and its secretion might be constrained by the stomach microbiota [86] and this action can control microglial enactment and hinder irritation in the CNS [87]. It was found that T cells get functionalized in the stomach [88] and gastrointestinal CD4+ T cells play a significant part in CNS autoimmunity. The serotonin theory of depression: is it supported by evidence? The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is. ... review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT. gene, one genetic association study (n = 115,257) and one collaborative meta ... What Is 5-HTP? The body generates 5-HTP from the essential amino acid L-tryptophan during the production of serotonin and a hormone called melatonin. 5-HTP can also be derived from plants, such as the African ... Loss of transient receptor potential channel 5 causes obesity and Disruption of TRPC5, a brain-expressed cation channel, causes obesity, maladaptive behavior, and postpartum depression in humans and mice. Acting on hypothalamic Pomc and oxytocin neurons, TRPC5 regulates instinctive behaviors such as feeding, arousal, social interaction, and maternal care, which are fundamental for survival. Official journal of the American College of Gastroenterology Tryptophan produced in the gut by the enterochromaffin cells, crosses the intestinal barrier, and is transformed into 5-HT after crossing the blood-brain barrier; 5-HT is crucial in the development and functioning of the microglia. ... Neuromodulator effects on depression and pain: the monoamine hypothesis. ... Serotonin syndrome is more likely ... Depression, Serotonin and Tryptophan Substances. Serotonin. Tryptophan. Depression is a major cause of worldwide disability. Although its etiology is unclear, for over sixty years the study of its pathophysiology has focused mainly on serotonin (5-HT) and serotonergic neurotransmission. Generally, the study of the pathophysiological processes underpinning depression hav …. Integrated metagenomic and metabolomic analysis reveals distinctive Results Distinct shifts in taxonomic and functional profiles of gut microbiota and their related metabolites were observed in different IA stages. Notably, tryptophan metabolites, particularly indoxyl sulfate (IS), were significantly higher in plasma of RIA. Meanwhile, upregulated tryptophanase expression and indole-producing microbiota were observed in gut microbiome of RIA. The serotonin hypothesis of depression: both long discarded and still The main areas of research do not provide support for the most well-known neurochemical hypothesis, the serotonin theory of depression—the idea that depression is caused by low levels or low ... Although serotonin is not a major player in depression, its ... The new '5-HT' hypothesis of depression: cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental ... Brain fog, depression, anxiety, irritability, and other ... Brain fog, depression, anxiety, irritability, and other mood changes become CRAZY common as we start our journey to menopause and beyond. And it sucks You just don't feel like you! #Serotonin... Tryptophan Metabolism in Depression: A Narrative Review with a Focus on There is a high need for the development of new therapies and gaining new insights into this disease is urgent. One important player in depression is the amino acid tryptophan. This amino acid can be metabolized in two important pathways in the context of depression: the serotonin and kynurenine pathways. A structural role for tryptophan in proteins, and the ubiquitous Trp Tryptophan is the most prominent amino acid found in proteins, with multiple functional roles. Its side chain is made up of the hydrophobic indole moiety, with two groups that act as donors in hydrogen bonds: the N ɛ —H group, which is a potent donor in canonical hydrogen bonds, and a polarized C δ 1 —H group, which is capable of forming weaker, noncanonical hydrogen bonds. Expert offers tips for calming dogs during Fourth of July fireworks Tryptophan helps the body produce serotonin, a neurotransmitter that regulates behavior, mood, memory and digestion, according to the National Institutes of Health online library of medicine. PDF The serotonin theory of depression: a systematic umbrella ... The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is ... tryptophan depletion (which lowers available serotonin) can ... assignment essay homework paper phd report resume review speech thesis