Encyclopedia
Please note this is a comparison between Version 1 by Bożena Muszyńska and Version 2 by Peter Tang.
Major depressive disorder (MDD) is still defined as a unitary entity characterized by decontextualized symptoms, which include either: (1) depressed mood or (2) loss of interest or pleasure (anhedonia); and at least five out of nine other symptoms (e.g., fatigue, insomnia, suicidal thoughts, diminished concentration, and psychomotor delay). To qualify as a major depressive episode, the symptoms have to persist for a minimum of 2 weeks and cause significant distress and disturbances in initiating and performing daily activities. Individuals with recurrent episodes are diagnosed with MDD. Edible medicinal mushrooms may be an adjunctive treatment for MDD.
- Cordyceps
- major depressive disorder
- diet
- Hericium erinaceus
- Reishi
- serotonin
1. Introduction
1.1. Definition
For at least 2500 years, depression has been recognized as a maladaptive, prolonged reaction to adverse circumstances that have detrimental psychosocial implications [1]. This approach—initiated by Hippocrates—was dimensional, since melancholy was viewed as an exaggeration of naturally occurring sadness. Therefore, for evaluating the severity of the condition, a physician had to contextualize the symptoms within personal history and take into account the seriousness of potential causes [1]. In the early 20th century, depression was classified into two categories: melancholic and neurotic depression [1]. The former was believed to be caused by unknown brain damage and considered a more serious condition, while the latter was thought to have a psychosocial origin and not require hospitalization; this assessment method is often referred to as “etiological”. The first editions of the Diagnostic and Statistical Manual (DSM) of the American Psychiatric Association published in the 1950s and 1960s described melancholic depression as a type of psychosis and neurotic depression as a defense mechanism against anxiety. Additionally, the existence of different forms of neurotic depression was well established in the clinic, but until the late 1970s, the exact number and characteristics remained a widely debated topic among scientists [1].
Although the above debate was far from conclusion, and necessary research was still lacking, the third edition of the DSM published in 1980 described a single category of major depressive disorder (MDD), which was defined solely based on symptoms [2]. In the fifth and most recent edition of the DSM, MDD is still defined as a unitary entity characterized by decontextualized symptoms, which include either: (1) depressed mood or (2) loss of interest or pleasure (anhedonia); and at least five out of nine other symptoms (e.g., fatigue, insomnia, suicidal thoughts, diminished concentration, and psychomotor delay) [3]. To qualify as a major depressive episode, the symptoms have to persist for a minimum of 2 weeks and cause significant distress and disturbances in initiating and performing daily activities [3]. Individuals with recurrent episodes are diagnosed with MDD.
1.2. Epidemiology
The World Health Organization estimated that, in 2015, 322 million people were living with MDD around the world, which constituted 4.4% of the global population [4]. The disease mainly affects women, with 5.1% of females worldwide suffering from it, compared to 3.6% of the male population [4]. Moreover, a higher incidence of MDD in females is observed across studied age groups and regions. Among psychiatric disorders, MDD is the leading cause of suicide, accounting for approximately 33% of 800,000 suicidal deaths each year [5]. Depression is also the leading cause of nonfatal health loss as measured by Years Lived with Disability (YLD). It has been estimated that MDD accounted for 7.5% of global YLD in 2015, with low- and middle-income countries bearing >80% of the burden of this disease [4].
Compared to other affective disorders, depression has a low heritability rate of ~37% [6]; for instance, the rate of heritability of bipolar disorder is estimated to be between 60% and 85% [7]. Furthermore, genome-wide association studies [8] and transcriptome-wide association studies [6] have, respectively, identified 44 and 94 genes associated with an increased risk of MDD, a majority of which are not specific to this condition, but rather predispose to global vulnerability [7]. One of the most important environmental factors that interact with MDD vulnerability throughout the lifespan is stress [9]. However, modulation of stress hormones is not necessary for achieving desired clinical outcomes in MDD patients [10]. This points to the complexity of the relation between the etiology and treatment of MDD, which—due to both the chronic nature of this disease and the proven impact of early life adversity on the disease risk—are separated by plastic changes in the brain [11][12][11,12].
1.3. Treatment
A recent study investigating the effectiveness of over 140 available pharmacological and nonpharmacological MDD treatments identified two evidence-based treatment modalities, namely the use of second-generation antidepressants (ADs) and cognitive behavioral therapy (CBT) [13]. Although not conclusive, the report may provide clinicians and patients with valuable guidance, as there are at least 87 known psychological and 56 interventions derived from alternative medicine, aimed at treating MDD [13]. Second-generation ADs are a group of nearly 15 drugs introduced in the 1980s and 1990s, and most of them are either selective serotonin reuptake inhibitors (SSRIs) or serotonin and noradrenaline reuptake inhibitors (SNRIs). CBT—a combination of behavioral and cognitive therapies—emerged around the same time as SSRIs and SNRIs. In principle, this approach to psychotherapy focuses on modifying cognitive distortions and behavioral patterns, in order to regulate emotions and develop strategies that can help the patient to cope with potential triggers. The efficacy of second-generation ADs and CBT is comparable, and the treatment effects are small (for example, Hedge’s g for ADs is −0.35 [13]). Therefore, it is not uncommon to combine these two approaches, especially due to the fact that SSRI-only treatment leads to full remission in about one-third of MDD patients [14]. Evidence suggests that a combination of ADs with CBT is more effective than ADs alone, resulting in moderate-to-medium effect sizes (Hedge’s g for ADs and CBT is 0.49) [15]. However, this effect may be restricted to adults, since SSRI-only treatment is as effective as SSRI–CBT combination in the case of children and adolescents [16]. It also seems that a significant proportion of the one-third of MDD patients who are treatment-resistant to the abovementioned therapies [14] will benefit from esketamine administered alone [17][18][17,18] or as an adjunct to other treatments [19].
2. Monoaminergic Neuromodulation, HPA, Inflammation and MDD
MDD is characterized by a multitude of symptoms accompanied by structural changes in both cortical (orbitofrontal, cingulate, insular, and temporal cortex) [11] and subcortical (hippocampus, amygdala) [12] areas that regulate the interaction between affective and cognitive processing. The orbitofrontal cortex, cingulate cortex, hippocampus, and amygdala are considered parts of the limbic system, which plays a major role in regulating motivation and emotions. Through their connections with the hypothalamus, another limbic structure, these regions also control the endocrine and autonomic nervous system, while functioning under the neuromodulatory influence of the ascending monoaminergic systems from the brainstem. The main neurotransmitters of monoaminergic systems are serotonin, dopamine, and norepinephrine, which regulate several brain functions such as mood, attention, reward processing, sleep, appetite, and cognitive abilities [20]. The role of monoamines in MDD is thought to be related to the action of ADs, which inhibit their reuptake from the synaptic cleft and/or increase their accumulation.
The role of serotonin in MDD has been most widely studied. It has been shown that experimental reduction in the amount of tryptophan, a precursor of serotonin, leads to a recurrence of acute symptoms of MDD in patients who were cured to remission [21]. In addition, a decrease in the number of serotonin receptors was observed in various brain structures in patients [22]. However, the mechanism leading to a decrease in the amount of serotonin in patients with MDD remains unknown, because studies of its metabolites in the blood or urine are equivocal.
The course of MDD may also involve changes in the noradrenergic system, such as reduced metabolism of noradrenaline, a decrease in the density of its receptors, and increased activity of tyrosine hydroxylase decomposing it at locus coeruleus—the main source of noradrenaline in the brainstem [23]. Clinical data also indicate the efficacy of noradrenaline reuptake inhibitors in the treatment of MDD [24].
Increasingly, similar to bipolar disorder, evidence highlights the role of dopamine in MDD [25]. MDD patients have been found to have reduced dopamine transmission as well as decreased concentration and uptake of dopamine transporter [26]. In addition, more than half of people with Parkinson’s disease, who are characterized by degenerated dopamine projections to the striatum, show symptoms of MDD before the onset of symptoms related to the musculoskeletal system [27].
The hypothalamus regulates the endocrine and autonomous system through the hypothalamic–pituitary–adrenal (HPA) axis. This neuroendocrine system is responsible for the stress response, which is one of the factors contributing to MDD [9]. The HPA axis acts as a negative feedback loop, where: stressors elicit the production of corticotropin-releasing hormone (CRH) from the hypothalamus; CRH causes secretion of adrenocorticotropic hormone (ACTH) from the pituitary; ACTH stimulates the secretion of cortisol from the adrenal cortex; and cortisol reversibly inhibits the secretion of ACTH. In some MDD patients, cortisol was found to be significantly increased, and this level decreases to normal as the disease subsides [10]. The administration of synthetic cortisol causes inhibition of cortisol secretion in healthy people. However, in a significant number of MDD patients, this negative feedback is disrupted, and cortisol remains at a consistently high level [10], suggesting impaired HPA regulation, resulting in abnormal and prolonged stress response. Symptoms similar to those of MDD were also observed in animals that were experimentally administered CRH to the nervous system. These animals exhibited autonomic system responses in the form of increased heart rate, increased blood pressure, or reduced digestion, accompanied by a change in behaviors such as sleep and wakefulness, rhythm disorders, decreased sex drive, or increased anxiety [28]. In MDD patients, increased content of CRH in the cerebrospinal fluid and reduced mRNA expression of the CRH receptor in the frontal cortex have been observed [29][30][29,30].
The activity of HPA can be disturbed by an inflammatory response of the immune system. Pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α activate the HPA and cause the so-called “sickness behavior” syndrome, which is characterized by similar symptoms as MDD, such as fatigue, psychomotor slowdown, anhedonia, or cognitive impairment [31]. In animals, blockade of pro-inflammatory processes leads to effects similar to those observed with the administration of ADs [32]. In addition, pro-inflammatory cytokines influence the metabolism of monoamine neurotransmitters, mainly serotonin, through indoleamine 2,3-dioxygenase, which is responsible for the breakdown of tryptophan and the formation of neurotoxic kynurenine [33].
3. Diet and MDD
Numerous studies have investigated the possible relationship between dietary patterns and MDD [34][35][34,35]. Although the first meta-analyses of observational studies on this subject suggested an inverse relation between a healthy diet and depression symptoms [36][37][36,37], the results were inconclusive as most of the analyzed studies were cross-sectional. Since data obtained in a single time-point cannot allow for determination of whether dietary patterns are a risk factor, concomitant, or an effect of MDD, Molendijk et al. (2018) reviewed only longitudinal observational studies [38]. The authors mainly found an association of high-quality or low pro-inflammatory diet with lower levels of depression symptoms, but not with clinical diagnosis of MDD [38]. Moreover, the lack of association between low-quality diet and incidence of MDD suggested that consumption of low-quality foods is concurrent to MDD, and not a risk factor of this condition [38]. These results were replicated in a recent meta-analysis, which differentiated cross-sectional and longitudinal studies, as well as dietary measures [34]. Overall, a traditional Mediterranean diet, as well as a lower Dietary Inflammatory Index, was associated with a lower risk of incident depression (i.e., a major depressive episode with no prior MDD history) in longitudinal studies [34]. Since the associations of dietary patterns with depression symptoms have been shown to be explained by confounding factors, such as socioeconomic status and physical activity [39], it is important to note that studies controlling these factors suggest diet as being independently associated with the risk of incident depression (see Table 1 in [34] for detailed list of studies and controlled factors). An outstanding question is whether these associations hold true in low- and middle-income countries, as these were underrepresented in the meta-analysis [34].
Due to its low risk and potential beneficial effect in reducing the severity of MDD symptoms, a high-quality diet may seem a valuable preventive strategy. Indeed, in the PREDIMED trial, a subsample of 620 patients with type 2 diabetes who were at a high risk of cardiovascular disease had a 40% lower risk of incident depression after at least 3 years of following the Mediterranean diet supplemented with nuts [40]. On the contrary, in the more recent randomized clinical trial (MooDFOOD) conducted among overweight adults, no effect of diet on the risk of a depressive episode was observed after 21 behavioral therapy sessions aimed at the improvement of dietary patterns (or multinutrient supplementation) over the course of 1 year [41]. Thus, it is still unclear which groups of patients and/or healthy individuals could benefit from preventive dietary interventions. It is therefore intriguing that data from 15 studies in patients suffering from comorbid, subclinical depression, or depressive symptoms secondary to other disease revealed that dietary treatment had slightly (Hedge’s g = 0.162) positive effects on depression symptoms [42]. Of note, these effects were mainly observed among female participants [42].
A recent review of preclinical animal studies identified at least nine possible biological factors contributing to the effects of diet on the symptoms of MDD. These factors include inflammation, oxidative stress, gut microbiota, HPA axis, adult neurogenesis and brain-derived neurotropic factor (BDNF), tryptophan-kynurenine metabolism, mitochondrial dysfunction, epigenetics, and obesity [43]. Other notable factors identified based on clinical observations as possibly mediating the abovementioned effects are chronic diseases comorbid with MDD, such as metabolic syndrome, type 2 diabetes, or cardiovascular disease [43]. Although there are no experimental studies in humans in this regard, it has been shown that no differences in the adaptation of brain metabolism to metabolic stress (fasting) were observed between healthy controls and MDD patients [44] and that women with MDD history displayed higher post meal blood pressure than those without MDD history [45]. Some studies have examined supplementation with isolated nutraceuticals as an adjunct to pharmacotherapy. A meta-analysis of these studies showed that S-adenosylmethionine (SAMe), methylfolate, omega-3, and vitamin D produced positive results [46].
4. 5-Hydroxy-L-tryptophan and MDD
l-tryptophan is an exogenous amino acid that acts as a precursor for the synthesis of serotonin in a metabolic pathway involving two enzymes: tryptophan hydroxylase (TPH) and aromatic amino acid decarboxylase (DDC). 5-Hydroxy-L-tryptophan (5-HTP), a product of TPH and an immediate precursor of serotonin, is broken down by DDC. Contrary to its precursors, serotonin does not cross the blood–brain barrier, and therefore its total pool in the brain is determined by the amount of substrates and the activity of TPH, which is the rate-limiting step for serotonin synthesis. The main source of serotonin in the brain is neurons of nine raphe nuclei located in the medial brainstem [47]. The axons of these neurons project to the majority of the brain, with rostral raphe nuclei mainly sending their serotonergic projections to the forebrain and caudal group to the lower brainstem and spinal cord [47].
Experimental studies in rats have clearly shown that different forms of stressors (e.g., tail shock, forced swimming, loud sound stress) activate TPH specifically in one of the nuclei of the rostral group—the median raphe nucleus [48]. Serotonergic projections of this nucleus directly target basal ganglia and hippocampi, and indirectly target septum and cingulate cortex [47], which are structures involved in the processing of and response to affective stimuli. Following stress, the activity of TPH is upregulated, refilling the intracellular stores of serotonin, which are depleted due to the increased firing of serotonergic neurons, mediated by glucocorticoids [48]. Moreover, daily changes in the expression of TPH2 (one of the two TPH-encoding genes expressed predominantly in the brain) are also dependent on daily rhythms of glucocorticoids, which are regulated by the suprachiasmatic nucleus [48]—the main pacemaker of the brain located in the hypothalamus. Although initial reports indicated that chronic stress does not influence TPH2 expression in the rodent brain [48], a recent study suggested that this is dependent on sex in the case of humans. Specifically, a higher transcription of TPH2 in the dorsolateral prefrontal cortex was observed in female, but not in male MDD patients, when compared to healthy controls of the same sex [49]. This may indicate that in women with MDD the neuronal response to stress is abnormal, which would lead to a higher demand on TPH2 activity due to stress-induced depletion of serotonin stores. Interestingly, a previous meta-analysis of studies addressing the deleterious effects of tryptophan depletion on verbal episodic memory, which is a function contingent on dorsolateral prefrontal cortex activity [50], showed that women are generally more prone to acute lowering of tryptophan levels [51].
Recent meta-analyses of studies comparing plasma tryptophan concentrations between MDD patients and healthy controls yielded ambiguous results. A study of 24 published datasets combined with authors’ own data showed a significantly higher decrease in tryptophan levels in unmedicated MDD patients, and a weak correlation between the severity of MDD symptoms and tryptophan concentrations [52]. On the other hand, a more recent meta-analysis with more stringent inclusion criteria, which included nine studies, did not find any significant effect of MDD on peripheral tryptophan levels [33]. Similarly, the results of meta-analyses of studies examining the therapeutic potential of tryptophan [46] or 5-HTP [53] in MDD are inconclusive, with 5-HTP found to be a more promising treatment option for the disease.
The above discrepancies in results might be related to the substantial heterogeneity of such studies, most of which lack placebo-controlled designs—an issue that has been raised for the last 20 years by authors analyzing the subject [53][54][53,54]. In the case of tryptophan, another confounding factor might be its second—and primary—kynurenine metabolic pathway, which has been proposed to play a role in inflammation-induced MDD [55]. Specifically, two metabolites resulting from kynurenine transformation in microglia have been shown to either exhibit neurotoxicity (3-hydroxykynurenine) or activate N-methyl-d-aspartate receptors (quinolinic acid) [33], the antagonists of which (e.g., esketamine) are effective against treatment-resistant MDD [56]. It still remains unclear whether tryptophan metabolism shifts away from serotonin to kynurenine in MDD, and the available results are conflicting [57][58][57,58]. Perhaps, the different subtypes of MDD (melancholic, anxious, energy-related) are associated with different profiles of tryptophan metabolites [59].
As a direct precursor of serotonin, 5-HTP is devoid of or has a low potential to cause undesirable effects in humans. There are no reports indicating serotonin syndrome, and only moderate gastrointestinal symptoms have been observed at a wide dose range [60]. Moreover, pilot experiments examining the effect of administration of 5-HTP at doses of 200–300 mg/day as an adjunct to pharmacological treatment with different classes of ADs have shown promising results in treatment-resistant MDD patients [60]. Such effects are explained by a synergistic effect of 5-HTP and serotonin transporter (SERT) inhibitors on extracellular serotonin levels measured directly in preclinical studies [61] or indirectly (via effects on cortisol levels) in humans, where the addition of 5-HTP can cause a 4-fold increase in the physiological effects of an SSRI [62].
To allow SERT inhibitors to achieve their therapeutic effects in MDD patients, it is necessary to not only elevate the extracellular levels of serotonin but also sustain the increase over the course of the day; it has been shown that tryptophan depletion causes a relapse in ~50% of remitted MDD patients within hours—an effect that may be exacerbated in females and chronically ill patients treated with SSRIs [21]. For this reason, most of the ADs have a half-life of >20 h, and a single missed dose of an SSRI may lead to a discontinuation syndrome [60]. Due to its half-life of 2 h, the dosing regimen of 5-HTP in humans can be challenging, and it is estimated that even three doses a day would cause 5-fold fluctuations in daily levels of 5-HTP (compared to 0.3-fold fluctuations of SSRIs) [60]. Therefore, for adjunctive 5-HTP therapy to work, either a slow-release formulation or dietary sources of the compound are needed.
Several edible mushroom species have so far been identified, with relatively high content of 5-HTP (Table 1). Of note, the highest content was found in all species of Pleurotus, which is popular in vegetarian cuisine. Moreover, high yields of mushroom mycelia can be easily achieved in standardized in vitro conditions by using bioreactors, and this mode of production can possibly boost levels of 5-HTP compared to fruiting bodies (Table 1).
Table 1.
Bioactive indole compounds found in selected 15 genera of edible mushrooms. NA—not available.
|
Mushroom |
Form |
Bioactive Indole Derivatives Compound Concentration [mg/100 g] |
References |
||||
|---|---|---|---|---|---|---|---|
|
Serotonin |
L-Tryptophane |
5-HTP |
Tryptamine |
Melatonin |
|||
|
Agaricus bisporus (White bottom mushroom) |
Fruiting bodies |
5.21 |
0.39 |
<0.001 |
0.06 |
0.11 |
[63] |
|
Armillaria mellea (Honey mushroom) |
Fruiting bodies |
2.21 |
4.47 |
<0.001 |
2.74 |
<0.001 |
[64] |
|
Boletus badius (Bay bolete) |
Fruiting bodies |
0.52 |
0.68 |
<0.001 |
0.47 |
<0.001 |
[64] |
|
Boletus edulis (King bolete) |
Fruiting bodies |
10.14 |
0.39 |
0.18 |
1.17 |
0.68 |
[64] |
|
Cantharellus cibarius (Chanterelle) |
Fruiting bodies |
29.61 |
0.01 |
0.02 |
0.01 |
0.14 |
[63] |
|
Ganoderma applanatum (Bracket fungus) |
Mycelium |
NA |
1.76 |
<0.001 |
1.12 |
0.02 |
[65] |
|
Ganoderma lucidum (Reishi) |
Mycelium |
10.58 |
NA |
NA |
NA |
0.98 |
[65] |
|
Hericium erinaceus (Lion’s mane) |
Mycelium |
NA |
NA |
152.72 |
11.88 |
1.04 |
[66] |
|
Fruiting bodies |
NA |
NA |
92.19 |
1.19 |
<0.001 |
[66] |
|
|
Lactarius deliciosus (Saffron milk cap) |
Fruiting bodies |
18.42 |
<0.001 |
0.25 |
<0.001 |
1.29 |
[63] |
|
Laetiporus sulphureus (Chicken of the wood) |
Mycelium |
NA |
14.08 |
1.5 |
1.16 |
<0.001 |
[65] |
|
Leccinum rufum (Birch bolete) |
Fruiting bodies |
31.71 |
<0.001 |
0.02 |
1.05 |
0.08 |
[63] |
|
Leccinum scabrum (Rough-stemmed bolet) |
Fruiting bodies |
13.99 |
9.56 |
<0.001 |
<0.001 |
<0.001 |
[67] |
|
Lentinula edodes (Shitake) |
Fruiting bodies |
1.03 |
0.58 |
24.83 |
0.04 |
0.13 |
[67] |
|
Macrolepiota procera (Parasol mushroom) |
Fruiting bodies |
<0.001 |
3.47 |
22.94 |
0.92 |
0.07 |
[67] |
|
Pleurotus citrinopileatus (Golden oyster mushroom) |
Mycelium |
<0.001 |
7.82 |
368.67 |
3.71 |
<0.001 |
[68] |
|
Fruiting bodies |
<0.001 |
13.84 |
128.89 |
1.29 |
<0.001 |
[68] |
|
|
Pleurotus djamor (Pink oyster mushroom) |
Mycelium |
<0.001 |
24.34 |
703.56 |
<0.001 |
<0.001 |
[68] |
|
Fruiting bodies |
7.68 |
24.84 |
193.95 |
3.54 |
<0.001 |
[68] |
|
|
Pleurotus eryngii (King trumpet mushroom) |
Mycelium |
8.54 |
7.60 |
221.51 |
2.67 |
0.08 |
[68] |
|
Fruiting bodies |
13.18 |
35.28 |
149.73 |
17.84 |
0.13 |
[68] |
|
|
Pleurotus florida (Pearl oyster mushroom) |
Mycelium |
<0.001 |
<0.001 |
215.53 |
<0.001 |
0.09 |
[68] |
|
Fruiting bodies |
3.31 |
10.84 |
95.21 |
1.52 |
<0.001 |
[68] |
|
|
Pleurotus ostreatus (Oyster mushroom) |
Mycelium |
<0.001 |
1.89 |
120.11 |
1.03 |
4.45 |
[68] |
|
Fruiting bodies |
6.52 NA |
<0.001 5.79 |
2.08 67.45 |
0.91 1.04 |
<0.001 0.33 |
[68] |
|
|
Pleurotus pulmonarius (Indian oyster) |
Mycelium |
<0.001 |
17.29 |
553.87 |
<0.001 |
<0.001 |
[68] |
|
Fruiting bodies |
<0.001 |
11.85 |
117.02 |
<0.001 |
<0.001 |
[68] |
|
|
Suillus bovinus (Jersey cow mushroom) |
Fruiting bodies |
<0.001 |
25.90 |
15.83 |
3.15 |
<0.001 |
[67] |
|
Suillus luteus (Slippery Jack) |
Fruiting bodies |
34.11 |
2.61 |
1.63 |
<0.001 |
0.71 |
[69] |
|
Trametes versicolor (Turkey tail) |
Mycelium |
NA |
3.91 |
0.9 |
1.69 |
0.01 |
[65] |
|
Tricholoma equestre (Man on horseback) |
Mycelium |
0.59 |
1.03 |
0.34 |
0.59 |
0.32 |
[70] |
|
Fruiting bodies |
0.18 |
2.85 |
0.58 |
2.01 |
<0.001 |
[70] |
|
