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Tryptophan and 5-Hydroxytryptophan for depression
Abstract
Background:
5 Hydroxytryptophan (5-HTP) and tryptophan are so-called natural alternatives to traditional antidepressants, used to treat unipolar depression and dysthymia.
Objectives:
To determine whether 5-HTP and tryptophan are more effective than placebo, and whether they are safe to use to treat depressive disorders in adults.
Search strategy:
Trials were searched in computerized general (Medline, Psychlit, and Embase) and specialized databases (Cochrane Controlled Clinical Trials Register, Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trial Register); by checking reference lists of relevant articles; by handsearching relevant specialist journals; and by contacting relevant authors where appropriate. Publications in all languages were sought.
Selection criteria:
Trials were included if they were randomized, included patients with unipolar depression or dysthymia, compared preparations of 5-HTP or tryptophan with placebo, and included clinical outcomes assessed by scales assessing depressive symptoms.
Data collection and analysis:
Data was extracted independently by the three reviewers, onto data collection forms. Inclusion criteria were applied to all potential studies independently and a coefficient of agreement (Kappa) was calculated for them. Disagreement was resolved by reaching consensus. Trial quality was scored according to risk of bias. Analysis for 5-HTP and tryptophan were combined due to the small number of included trials.
Main results:
108 trials were located using the specified search strategy. Of these, only two trials, involving a total of 64 patients, were of sufficient quality to meet inclusion criteria. The available evidence suggests these substances were better than placebo at alleviating depression (Peto Odds Ratio 4.10; 95% confidence interval 1.28-13.15; RD 0.36; NNT 2.78). However, the evidence was of insufficient quality to be conclusive.
Reviewer's conclusions:
A large number of studies appear to address the research questions, but few are of sufficient quality to be reliable. Available evidence does suggest these substances are better than placebo at alleviating depression. Further studies are needed to evaluate the efficacy and safety of 5-HTP and tryptophan before their widespread use can be recommended. The possible association between these substances and the potentially fatal Eosinophilia-Myalgia Syndrome has not been elucidated. Because alternative antidepressants exist which have been proven to be effective and safe the clinical usefulness of 5-HTP and tryptophan is limited at present.
... Tryptophan cannot be generated by the body and is thus an essential amino acid. There is limited evidence of an antidepressive effect of tryptophan-containing food supplements [41], although excessive intake has been linked to potentially lethal toxicity (eosinophilia-myalgia syndrome). Whether this complication is attributable to tryptophan as such or to a contaminant metabolite remains a matter of debate [41,42]. ...
... There is limited evidence of an antidepressive effect of tryptophan-containing food supplements [41], although excessive intake has been linked to potentially lethal toxicity (eosinophilia-myalgia syndrome). Whether this complication is attributable to tryptophan as such or to a contaminant metabolite remains a matter of debate [41,42]. A diet rich in L-tryptophan preserved the secretion of insulin and delayed the progression of hereditary type 2 diabetes in rats [43]. ...
The topic of uremic toxicity has received broad attention from the nephrological community over the past few decades. An aspect that is much less often considered is the possibility that the metabolic pathways that generate uremic toxins also may produce molecules that benefit body functions. Here, we discuss this dualism based on the example of tryptophan-derived metabolites, which comprise elements that are mainly toxic, such as indoxyl sulfate, kynurenine and kynurenic acid, but also beneficial compounds, such as indole, melatonin and indole-3-propionic acid, and ambivalent (beneficial for some aspects and harmful for others) compounds such as serotonin. This dualism can also be perceived at the level of the main receptor of the tryptophan-derived metabolites, the aryl hydrocarbon receptor (AHR), which has also been linked to both harm and benefit. We hypothesize that these beneficial effects are the reason why uremic toxin generation remained preserved throughout evolution. This duality is also not unique for the tryptophan-derived metabolites, and in this broader context we discuss the remote sensing and signaling theory (RSST). The RSST proposes that transporters (e.g., organic anion transporter 1—OAT1; ATP-binding cassette transporter G—ABCG2) and drug metabolizing enzymes form a large network of proteins interacting to promote small molecule remote communication at the inter-organ (e.g., gut–liver–heart–brain–kidney) and inter-organismal (e.g., gut microbe–host) levels. These small molecules include gut microbe-derived uremic toxins as well as beneficial molecules such as those discussed here. We emphasize that this positive side of uremic metabolite production needs more attention, and that this dualism especially needs to be considered when assessing and conceiving of therapeutic interventions. These homeostatic considerations are central to the RSST and suggest that interventions be aimed at preserving or restoring the balance between positive and negative components rather than eliminating them all without distinction.
... g/mol Hydrophobic substance [56] One of the diseases frequently appearing in the population is depression; in this regard, a useful method could be the monitoring of the Phe, Tyr, and Trypt AAs, respectively [38]. This psychological affliction can manifest itself through various symptoms, such as concentration problems, insomnia, and sadness [57,58]. The causes of its emergence can reside in various sources: biological, genetic, environmental, and social-psychological factors [59]. ...
... Special attention should be paid to people who suffer from PKU, which is an inherited disorder caused by excessive accumulation of Phe in the human [56] One of the diseases frequently appearing in the population is depression; in this regard, a useful method could be the monitoring of the Phe, Tyr, and Trypt AAs, respectively [38]. This psychological affliction can manifest itself through various symptoms, such as concentration problems, insomnia, and sadness [57,58]. The causes of its emergence can reside in various sources: biological, genetic, environmental, and social-psychological factors [59]. ...
Recently, the studies on developing sensors and biosensors—with an obvious interdisciplinary character—have drawn the attention of many researchers specializing in various fundamental, but also complex domains such as chemistry, biochemistry, physics, biophysics, biology, bio-pharma-medicine, and bioengineering. Along these lines, the present paper is structured into three parts, and is aimed at synthesizing the most relevant studies on the construction and functioning of versatile devices, of electrochemical sensors and biosensors, respectively. The first part presents examples of the most representative scientific research focusing on the role and the importance of the phenylalanine, tyrosine, and tryptophan amino acids, selected depending on their chemical structure and their impact on the central nervous system. The second part is dedicated to presenting and exemplifying conductor polymers and molecularly imprinted polymers used as sensitive materials in achieving electrochemical sensors and biosensors. The last part of the review analyzes the sensors and biosensors developed so far to detect amino acids with the aid of conductor polymers and molecularly imprinted polymers from the point of view of the performances obtained, with emphasis on the detection methods, on the electrochemical reactions that take place upon detection, and on the electroanalytical performances. The present study was carried out with a view to highlighting, for the benefit of specialists in medicine and pharmacy, the possibility of achieving and purchasing efficient devices that might be used in the quality control of medicines, as well as in studying and monitoring diseases associated with these amino acids.
... For these reasons, L-TRP was selected to be products or nutraceuticals containing TRP can be administered in the case of depression caused by the new coronavirus (SARS-CoV-2) [11]. For these reasons, L-TRP was selected to be detected as fast as possible from pharmaceutics by a new device: a compound which contributes to preventing neuropsychiatric disorders led by the lack of AA, such as depression [12], anxiety [13], insomnia [14], attention deficit hyperactivity disorder (ADHD) [15], the premenstrual syndrome [16] and Parkinson's disease [17]. The physicochemical properties of TRP are very important, being important features for accurate detection. ...
... Inventions 2021, 6, × FOR PEER REVIEW 2 of 13 products or nutraceuticals containing TRP can be administered in the case of depression caused by the new coronavirus (SARS-CoV-2) [11]. For these reasons, L-TRP was selected to be detected as fast as possible from pharmaceutics by a new device: a compound which contributes to preventing neuropsychiatric disorders led by the lack of AA, such as depression [12], anxiety [13], insomnia [14], attention deficit hyperactivity disorder (ADHD) [15], the premenstrual syndrome [16] and Parkinson's disease [17]. The physicochemical properties of TRP are very important, being important features for accurate detection. ...
This study describes the development of a new sensor with applicability in the determination and quantification of yjr essential amino acid (AA) L-tryptophan (L-TRP) from pharmaceutical products. The proposed sensor is based on a carbon screen-printed electrode (SPCE) modified with the conductor polymer polypyrrole (PPy) doped with potassium hexacyanoferrate (II) (FeCN). For the modification of the SPCE with the PPy doped with FeCN, the chronoamperometry (CA) method was used. For the study of the electrochemical behavior and the sensitive properties of the sensor when detecting L-TRP, the cyclic voltammetry (CV) method was used. This developed electrode has shown a high sensibility, a low detection limit (LOD) of up to 1.05 × 10−7 M, a quantification limit (LOQ) equal to 3.51 × 10−7 M and a wide linearity range between 3.3 × 10−7 M and 1.06 × 10−5 M. The analytical performances of the device were studied for the detection of AA L-TRP from pharmaceutical products, obtaining excellent results. The validation of the electroanalytical method was performed by using the standard method with good results.
... Current studies, however, have shown that long-term use of 5-HTP may contribute to the washout of catecholamines, namely noradrenaline and dopamine, stored in neurons, and the imbalance in the monoamine system causes a predisposition to the development or exacerbation of existing diseases related to the catecholamine system, such as depression, anxiety, or affective disorders. [97,98] In a group of overweight women, the use of 5-HTP was found to reduce food consumption and promote weight loss. [99] In overweight patients with noninsulindependent diabetes, 5-HTP was found to contribute to a lower consumption of carbohydrates and fats and maintaining energy balance, leading to weight loss. ...
... A potential analogous adverse interaction may occur by the combined use of G. simplicifolia and H. perforatum. [98,103] Hillebrand et al. reported that G. simplicifolia and 5-HTP were sold online as ingredients of 'designer drugs' or 'party pills' as an alternative to the synthetic psychoactive substance ecstasy. [104] A previous study demonstrated the occurrence of hypomania in a man using 5-HTP and adenosylmethionine. ...
... Current studies, however, have shown that long-term use of 5-HTP may contribute to the washout of catecholamines, namely noradrenaline and dopamine, stored in neurons, and the imbalance in the monoamine system causes a predisposition to the development or exacerbation of existing diseases related to the catecholamine system, such as depression, anxiety, or affective disorders. [97,98] In a group of overweight women, the use of 5-HTP was found to reduce food consumption and promote weight loss. [99] In overweight patients with noninsulindependent diabetes, 5-HTP was found to contribute to a lower consumption of carbohydrates and fats and maintaining energy balance, leading to weight loss. ...
... A potential analogous adverse interaction may occur by the combined use of G. simplicifolia and H. perforatum. [98,103] Hillebrand et al. reported that G. simplicifolia and 5-HTP were sold online as ingredients of 'designer drugs' or 'party pills' as an alternative to the synthetic psychoactive substance ecstasy. [104] A previous study demonstrated the occurrence of hypomania in a man using 5-HTP and adenosylmethionine. ...
This review focuses on four new product categories of food supplements: pre‐workout, fat burner/thermogenic, brain/cognitive booster, and hormone/testosterone booster. Many food supplements have been shown to be contaminated with unauthorized substances. In some cases, the ingredients in the new categories of dietary supplements were medicinal products or new synthetic compounds added without performing clinical trials. Some of the new ingredients in dietary supplements are plant materials that are registered in the pharmacopoeia as herbal medicines. In other cases, dietary supplements may contain plant materials that have no history of human use and are often used as materials to “camouflage” stimulants. In the European Union, new ingredients of dietary supplements, according to European Food Safety Authority or unauthorized novel food. Furthermore, selected ingredients in dietary supplements may be prohibited in sports and are recognized as doping agents by World Anti‐Doping Agency.
... Six review summaries stated explicitly that available information on harms was missing or limited from the included studies, without presenting any information on numbers or types of events that was available from the studies [52,53,61,65,66,73]. Six review summaries discussed adverse events specifically [47-49, 51, 55, 62], and, of these, one review mentioned that the intervention was effective but potentially dangerous [47] while three summaries made a comparison between harms from the self-care intervention and some other active intervention, in one case based on one trial [53] and in the others on several trials [55,62]. ...
... Conversely, many types of self-care treatments mentioned in multiple surveys (aromatherapy, music, yoga) were not addressed in any Cochrane reviews. Some survey interventions were covered by Cochrane reviews but the review question was limited to specific populations (e.g., bibliotherapy for elderly Tryptophan and 5-Hydroxytryptophan for depression [47] 2002 Dietary supplement (Tryptophan and 5-Hydroxytryptophan) ...
Background:
Self-care refers to a range of activities and approaches undertaken by an individual to maintain health and manage ill-health which may include various complementary or alternative approaches. The purpose of this study was to identify the self-care approaches used by the general public for depression and anxiety, assess the usefulness of Cochrane reviews for informing decisions on self-care and highlight any gaps in the evidence.
Methods:
Searches were carried out for surveys of self-care for anxiety and/or depression and for Cochrane reviews and protocols of interventions with potential for use in self-care. Data was extracted from each review and Plain Language Summaries assessed for content, consistency and readability. Interventions reported in surveys and in Cochrane reviews were compared and effectiveness of each assessed.
Results:
Surveys from 10 countries reported a variety of self-care interventions, 17 of which appeared in 2 or more surveys and which included dietary supplements, herbal medicines, mind-body therapies and various forms of exercise. Twenty-two reviews and 5 protocols on potential self-care interventions were identified, the majority in depression. Twelve interventions were judged effective or promising, most with small effect sizes. Readability of summaries was highly variable: half were written at college/university level. Several commonly used approaches were not covered by Cochrane reviews.
Conclusions:
This study has revealed the interventions currently used by the general public which are judged effective or promising based on Cochrane reviews. Some disparity is highlighted between interventions used in practice and the availability of reliable evidence, and in the presentation of effectiveness and safety. Being able to direct patients to reliable, accessible information is a positive step in ensuring effective patient-centered, evidence-informed care. Addressing gaps, ensuring consistency and increasing usability of evidence intended for the general public will support this goal.
... The relationship between tryptophan intake and mood status has been examined mainly in intervention studies using tryptophan supplementation, restriction, or dietary intervention (Lindseth et al., 2015;Shaw et al., 2001;Young, 2013). Few previous studies, however, have investigated the relationship between habitual dietary tryptophan intake and depression (Hakkarainen et al., 2003;Lieberman et al., 2016). ...
... A number of studies have examined the association between tryptophan intake and depressive symptoms (or mood status) using either tryptophan deprivation (Bell et al., 2001;Delgado et al., 1990), supplementation (Shaw et al., 2001), or administration of tryptophan-rich protein (Firk and Markus, 2009;Lindseth et al., 2015;Markus et al., 2010Markus et al., , 2008. These studies were conducted under experimental conditions, which is different from the habitual tryptophan intake of the study participants. ...
Background:
The intake of tryptophan, the precursor of serotonin, is assumed to affect serotonin availability and depression onset. Nevertheless, a definitive relationship between dietary tryptophan intake and depressive symptoms has not been established. We examined the association between tryptophan intake and depressive symptoms screened in a group of 4272 first-year female dietetic students and 3651 their mothers.
Methods:
Dietary tryptophan intake during the preceding month was assessed with a validated, self-administered diet history questionnaire. Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression Scale (CES-D) using two cutoff scores: CES-D score ≥ 16 and CES-D score ≥ 19 (the optimal cutoff score for Japanese people). The multivariate adjusted prevalence ratio (PR) and 95% confidence interval (CI) for depressive symptoms were calculated using Poisson regression analysis.
Results:
The prevalence of depressive symptoms (CES-D score ≥ 16) was 50.0% for young women and 26.5% for middle-aged women. The adjusted PR (95% CI) for depressive symptoms in the highest versus lowest quintile of tryptophan intake was 0.84 (0.75, 0.93) in young women (P for trend < 0.0001) and 0.83 (0.64, 1.01) in middle-aged women (P for trend < 0.0001). These associations were stable even when depressive symptoms were defined as a CES-D score ≥ 19.
Limitations:
This is a cross-sectional study. Depressive symptoms were assessed using a self-reported questionnaire.
Conclusions:
This cross-sectional study showed that a higher tryptophan intake was independently associated with a lower prevalence of depressive symptoms in young Japanese women.
... Also, in a mouse model of allergic asthma, serotonin derived from mast cells increases airway hyperresponsiveness (151). In contrast, 5HTP reduces airway hyperresponsiveness in several mouse models of allergic asthma (18), is not vasoconstricting (79-82, 152, 153), and still clinically effective for behavior disorders (154)(155)(156)(157)(158)(159)(160)(161)(162)(163)(164), but whether 5HTP can affect asthma is not known. Clinical studies with inhibitors of individual HTRs such as HTR1A or HTR2A have had only a small benefit for asthma (83), but this may reflect involvement of multiple HTRs during asthma. ...
Background
Previous research showed that 5-hydroxytryptophan (5HTP), a metabolic precursor of serotonin, reduces allergic lung inflammation by inhibiting eosinophil migration across endothelial monolayers.
Objective
It is unknown if serotonin receptors are involved in mediating this 5HTP function or if serotonin receptor (HTR) single nucleotide polymorphisms (SNPs) associate with lung function in humans.
Methods
Serotonin receptor subtypes were assessed by qPCR, western blot, confocal microscopy, pharmacological inhibitors and siRNA knockdown. HTR SNPs were assessed in two cohorts.
Results
Pharmacological inhibition or siRNA knockdown of the serotonin receptors HTR1A or HTR1B in endothelial cells abrogated the inhibitory effects of 5HTP on eosinophil transendothelial migration. In contrast, eosinophil transendothelial migration was not inhibited by siRNA knockdown of HTR1A or HTR1B in eosinophils. Surprisingly, these HTRs were intracellular in endothelial cells and an extracellular supplementation with serotonin did not inhibit eosinophil transendothelial migration. This is consistent with the inability of serotonin to cross membranes, the lack of selective serotonin reuptake receptors on endothelial cells, and the studies showing minimal impact of selective serotonin reuptake inhibitors on asthma. To extend our HTR studies to humans with asthma, we examined the CHIRAH and GALA cohorts for HTR SNPs that affect HTR function or are associated with behavior disorders. A polygenic index of SNPs in HTRs was associated with lower lung function in asthmatics.
Conclusions
Serotonin receptors mediate 5HTP inhibition of transendothelial migration and HTR SNPs associate with lower lung function. These results may serve to aid in design of novel interventions for allergic inflammation.
... In the positive ionization mode, the analysis of substances between UU and Uni showed that various metabolites were more abundant in Uni than in UU. Tryptophan is an essential amino acid for human nutrition that serves as a building block for protein synthesis, and it also exhibits antidepressant efects [67]. Daidzin, is a prevalent isofavone in soybean that has signifcant efects in preventing osteoporosis and regulating glucose homeostasis [68]. ...
Inflammation and the immune system are intricately linked, with the immune system serving as a vital defense mechanism in the human body. Consequently, there is great emphasis placed on the regulation of both the body’s inflammatory response and the immune system. This study investigated the anti-inflammatory properties and immunomodulatory effects of Unitein (fermented Glycine max, Panax ginseng, and chenpi mixture) in both RAW 264.7 macrophages and mice splenocytes while also comprehensively analyzing its components. To this end, the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay was employed to evaluate the cytotoxicity of the samples to RAW 264.7 cells. The Griess assay was utilized to determine nitrite concentrations, while the enzyme-linked immunosorbent assay (ELISA) was employed to assess the levels of inflammation-related cytokines in RAW 264.7 cells and isolated mouse splenocytes. Additionally, quantitative polymerase chain reaction was employed to quantify the mRNA expression of inflammation-related genes in the cells, while the lactate dehydrogenase assay was used to analyze natural killer (NK) cell activity. Our results revealed that Unitein exhibited no toxicity to RAW 264.7 cells at concentrations below 1.5 mg/mL. However, Unitein effectively suppressed the release of proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and interferon (IFN)-γ, as well as enzymes COX-2 and iNOS from RAW 264.7 cells, while concurrently promoting the release of anti-inflammatory cytokines IκB-α, IL-10, and IL-4. Furthermore, Unitein inhibited the increase in TNF-α, IL-1β, IFN-γ, IL-12, nuclear factor (NF)-κB p50, NF-κB p65, and iNOS induced by lipopolysaccharides (LPSs) in isolated mouse splenocytes. Notably, Unitein also exhibited the potential to stimulate NK cell activity. Metabolite analysis indicated that Unitein contained more active compounds with anti-inflammatory and immunity-enhancing properties than did unfermented Unitein. This study highlights the potential therapeutic role of Unitein in mitigating inflammation and enhancing immune responses, thereby deepening our understanding of its biological activities and underlying mechanisms. These findings underscore the significance of Unitein as a potential candidate for the development of novel anti-inflammatory and immunomodulatory interventions.
... The latter has also been used as a treatment for patients with depression. 51 There is also the presence of drugs from natural products, such as morphine, for severe and chronic pain management and a precursor of semisynthetic opioids. Ethyl and methyl salicylate are common predecessors of the widely used acetylsalicylic acid, such as the NSAID naproxen. ...
Food chemicals have a fundamental role in our lives, with an extended impact on nutrition, disease prevention, and marked economic implications in the food industry. The number of food chemical compounds in public databases has substantially increased in the past few years, which can be characterized using chemoinformatics approaches. We and other groups explored public food chemical libraries containing up to 26,500 compounds. This study aimed to analyze the chemical contents, diversity, and coverage in the chemical space of food chemicals and additives and, from here on, food components. The approach to food components addressed in this study is a public database with more than 70,000 compounds, including those predicted via omics techniques. It was concluded that food components have distinctive physicochemical properties and constitutional descriptors despite sharing many chemical structures with natural products. Food components, on average, have large molecular weights and several apolar structures with saturated hydrocarbons. Compared to reference databases, food component structures have low scaffold and fingerprint-based diversity and high structural complexity, as measured by the fraction of sp3 carbons. These structural features are associated with a large fraction of macronutrients as lipids. Lipids in food components were decompiled by an analysis of the maximum common substructures. The chemical multiverse representation of food chemicals showed a larger coverage of chemical space than natural products and FDA-approved drugs by using different sets of representations.
... As the sole precursor of 5-hydroxytryptamine (serotonin), tryptophan has been paid attention in mental disorders research. 8,9 The main catabolic route of tryptophan is the kynurenine pathway, which is responsible for approximately 95-99% of tryptophan metabolism in the body. Kynurenine final metabolic product, including neurotoxic quinolinic acid and neuroprotective kynurenic acid, have impacts on central nervous system partly by affecting N-methyl-D-aspartic acid receptor (NMDAR) function and inducing neural functional disturbance subsequently. ...
Purpose
Tryptophan metabolism is involved in the etiology and exacerbation of depressive disorders. Kai-Xin-San (KXS), a traditional Chinese medicine formula, has been widely used to treat depression and modulate serotonin simultaneously, but how it regulates depressive-like behavior by shifting the balance of the tryptophan-serotonin metabolism and kynurenine pathway remains vague.
Patients and Methods
Ten participants with mild to moderate depression treated with KXS (KXS preparation) were analyzed in this study. Depression rating scale score and the concentration of serum tryptophan, 5-hydroxytryptophan and kynurenine was measured at baseline and the endpoint of KXS treatment. To explore the specific regulatory mechanism of KXS in tryptophan metabolism, the chronic restraint stress (CRS) was used to induce depressive-like syndrome in rats and the hippocampus level of tryptophan, 5-hydroxytryptophan, kynurenine with downstream metabolites (kynurenic acid, quinolinic acid) and key enzymes (indoleamine 2,3-dioxygenase, kynurenine 3-monooxygenase, kynurenine aminotransferase) were analyzed by liquid chromatography–electros pray ionization tandem mass spectrometry, high performance liquid chromatography and enzyme-linked immunosorbent assay respectively.
Results
KXS significantly decreased depression rating scale scores and increased the serum tryptophan and kynurenine concentration in depressive patients compared to baseline. Also, it alleviated the depressive behavior in CRS rats obviously. Comparing with CRS group, KXS increased tryptophan, 5-hydroxytryptophan, kynurenine level in rat hippocampus. Furthermore, in kynurenine pathway, KXS decreased the expression of indoleamine 2,3-dioxygenase, increased kynurenic acid by upregulating the expression of kynurenine aminotransferase while decreased quinolinic acid level in hippocampus, which suggested that KXS more favored improving serotonin pathway, and neuroprotective kynurenic acid branch in the tryptophan metabolism.
Conclusion
This is the first tryptophan metabolomic study of patients with depression undergoing KXS treatment. Combining these clinical results with CRS induced rat model studies, it verified that KXS achieves an excellent antidepressant effect and balances tryptophan-kynurenine metabolic pathways by regulating some key metabolic products and enzymes.
... There are also studies exploring tryptophan supplementation as a treatment to alleviate depression, solely or in combination with other antidepressants, as a method to increase serotonin concentration in the brain. The outcomes of these studies were conflicting, but some clinical data support the usefulness of tryptophan supplementation, at least in a subgroup of patients (Shaw et al., 2002). ...
Clinical depression is a multifactorial disorder and one of the leading causes of disability worldwide. The alterations in tryptophan metabolism such as changes in the levels of serotonin, kynurenine, and kynurenine acid have been implicated in the etiology of depression for more than 50 years. In recent years, accumulated evidence has revealed that gut microbial communities, besides being essential players in various aspects of host physiology and brain functioning are also implicated in the etiology of depression, particularly through modulation of tryptophan metabolism. Therefore, the aim of this review is to summarize the evidence of the role of gut bacteria in disturbed tryptophan metabolism in depression. We summed up the effects of microbiota on serotonin, kynurenine, and indole pathway of tryptophan conversion relevant for understanding the pathogenesis of depressive behavior. Moreover, we reviewed data regarding the therapeutic effects of probiotics, particularly through the regulation of tryptophan metabolites. Taken together, these findings can open new possibilities for further improvement of treatments for depression based on the microbiota-mediated modulation of the tryptophan pathway.
... The urge need for more e cient antidepressant strategies is calling for further exploration in monoamine transmitter mechanism. As the sole precursor of 5hydroxytryptamine (serotonin), tryptophan has been paid attention in mental disorders research (Shaw, Turner et al. 2001, Wigner, Czarny et al. 2018). The main catabolic route of tryptophan is the kynurenine pathway, which is responsible for approximately 95-99% of tryptophan metabolism in the body. ...
Objective: Tryptophan metabolism is involved in the etiology and exacerbation of depressive disorders. Kai-Xin-San (KXS) has been widely used to treat depression, but how it regulates depressive-like behavior by shifting the balance of the tryptophan-serotonin metabolism and kynurenine pathway remains vague.
Methods: Ten participants with mild to moderate depression treated with KXS (KXS preparation) were analyzed in this study. Depression rating scale score, the concentration of serum tryptophan, 5-hydroxytryptophan and kynurenine was measured at baseline and the endpoint of KXS treatment. To explore the specific regulatory mechanism of KXS in tryptophan metabolism, chronic restraint stress (CRS) induced depressive rats were conducted and the hippocampus level of tryptophan metabolites and key enzymes were analyzed respectively.
Results: KXS significantly decreased depression rating scale scores and increased the serum tryptophan and kynurenine concentration in depressive patients. Also, it alleviated the depressive behavior in CRS rats obviously. Comparing with CRS group, KXS increased tryptophan, 5-hydroxytryptophan, kynurenine level in hippocampus. Furthermore, KXS decreased the expression of indoleamine 2,3-dioxygenase, increased kynurenic acid by upregulating the expression of kynurenine aminotransferase while decreased quinolinic acid level in hippocampus, which suggested that KXS more favored improving serotonin pathway and neuroprotective kynurenic acid branch in tryptophan metabolism.
Conclusion: This is the first tryptophan metabolomic study of patients with depression undergoing KXS treatment. Combining these clinical results with CRS induced rat model studies, it verified that KXS achieves an excellent antidepressant effect and balances tryptophan-kynurenine metabolic pathways by regulating some key metabolic products and enzymes.
... Here, 5-HT, an important neurotransmitter in the central nervous system, may lead to abnormal 5-HT receptor function and neurotransmission disorders if abnormalities occur in the central nervous system, and changes in its level are often associated with mood disorders and depression [43]. Studies have shown that the dysregulation of tryptophan metabolism is a possible mechanism for depression-related behaviors [44]. Booij and Van der Does found that acute depletion of tryptophan results in depressive symptoms, which may be caused by a dramatic decrease in 5-HT production [45]. ...
This study aimed to investigate the association between complex brain functional networks and the metabolites in urine in subclinical depression. Electroencephalography (EEG) signals were recorded from 78 female college students, including 40 with subclinical depression (ScD) and 38 healthy controls (HC). The phase delay index was utilized to construct functional connectivity networks and quantify the topological properties of brain networks using graph theory. Meanwhile, the urine of all participants was collected for non-targeted LC-MS metabolic analysis to screen differential metabolites. The global efficiency was significantly increased in the α-2, β-1, and β-2 bands, while the characteristic path length of β-1 and β-2 and the clustering coefficient of β-2 were decreased in the ScD group. The severity of depression was negatively correlated with the level of cortisone (p = 0.016, r = −0.40). The metabolic pathways, including phenylalanine metabolism, phenylalanine tyrosine tryptophan biosynthesis, and nitrogen metabolism, were disturbed in the ScD group. The three metabolic pathways were negatively correlated (p = 0.014, r = −0.493) with the global efficiency of the brain network of the β-2 band, whereas they were positively correlated (p = 0.014, r = 0.493) with the characteristic path length of the β-2 band. They were mainly associated with low levels of L-phenylalanine, and the highest correlation sparsity was 0.11. The disturbance of phenylalanine metabolism and the phenylalanine, tryptophan, tyrosine biosynthesis pathways cause depressive symptoms and changes in functional brain networks. The decrease in the L-phenylalanine level may be related to the randomization trend of the β-1 frequency brain functional network.
... 65 Only 1%-3% of consumed tryptophan produces central serotonin through the pathway. 66,67 5-HTP, which can cross the blood-brain barrier like tryptophan, is converted to serotonin within serotonergic neurons, and to neurotransmitters within dopaminergic and noradrenergic neurons. Because of this, and also because tryptophan's entry into the brain depends on its ratio to other abundant neutral amino acids, tryptophan is not used to increase serotonin, and the use of 5-HTP to provide serotonin production is theoretically more rational. ...
Depression is a chronic and debilitating psychiatric disorder that affects 300 million people worldwide. Pharmacotherapy is one of the treatments. Due to delay in initiating treatment efficacy and the incomplete response to mono-drug therapy in one-third of patients, new approaches need to be considered. One of the ways to overcome this resistance to treatment and to enhance standard medical practice is to add complementary medicines. We aimed to document research progress from studies on integrative medicine for the treatment of depression. Review of PubMed and Scopus databases on the topic and a personal collection of the relevant publications are the sources for this study. Some of the nutraceuticals and complementary medicines in the treatment of depression will be reviewed. Supplements discussed in this review include S-adenosyl-methionine (SAMe), Crocus sativus (Saffron), carnosine, theanine, palmitoylethanolamide (PEA), tryptophan and 5-hydroxytryptophan (5-HTP), gemfibrozil, curcumin (the main active ingredient in turmeric), Hypericum perforatum (St John's wort), Lavandula angustifolia (Lavender), and Cinnamomum tamala. Despite evidence in favor of the antidepressant effect of several supplements, their efficacy and tolerability should be evaluated and validated by further high-quality studies.
... Amino acid that is used in the biosynthesis of proteins, which is converted into 5-hydroxytryptophan (5-HTP), which is then converted into serotonin and melatonin; dietary supplement used as an antidepressant, anxiolytic, and sleep aid with limited evidence for depression [76] "Melatonin" ...
Nutritional interventions have beneficial effects on certain psychiatric disorder symptomatology and common physical health comorbidities. However, studies evaluating nutritional literacy in mental health professionals (MHP) are scarce. This study aimed to assess the across 52 countries. Surveys were distributed via colleagues and professional societies. Data were collected regarding self-reported general nutrition knowledge, nutrition education, learning opportunities, and the tendency to recommend food supplements or prescribe specific diets in clinical practice. In total, 1056 subjects participated in the study: 354 psychiatrists, 511 psychologists, 44 psychotherapists, and 147 MHPs in-training. All participants believed the diet quality of individuals with mental disorders was poorer compared to the general population (p < 0.001). The majority of the psychiatrists (74.2%) and psychologists (66.3%) reported having no training in nutrition. Nevertheless, many of them used nutrition approaches, with 58.6% recommending supplements and 43.8% recommending specific diet strategies to their patients. Only 0.8% of participants rated their education regarding nutrition as ‘very good.’ Almost all (92.9%) stated they would like to expand their knowledge regarding ‘Nutritional Psychiatry.’ There is an urgent need to integrate nutrition education into MHP training, ideally in collaboration with nutrition experts to achieve best practice care.
... It's used to treat many diseases including depression and mood disorders , of used in some obesity drugs as a treatment , case of irritable bowel syndrome and colitis , chronic insomnia and sleep problems . To stimulate the mind and noise the efficiency of concentration and treatment of hepatitis psychotic [11][12][13][14][15][16][17][18][19][20] . Tryptophan in turn is necessary for the production of serotonin which called happiness hormone ( a brain chemical necessary for the mood regulation and sleep ) . ...
... Nonetheless, the pharmacological use and benefit of both 5-HTP and 5-HT (serotonin) have been matters of controversy [30,37,38], in part because many clinical studies of either metabolite lacked proper controls and were considered inconclusive in meta-analyses. Both exhibit a plethora of adverse effects, particularly in higher doses, including cardiovascular problems, upset stomach, headache, agitation, panic attacks, fatigue, sexual dysfunction, and suicidality. ...
Tryptophan (Trp) holds a unique place in biology for a multitude of reasons. It is the largest of all twenty amino acids in the translational toolbox. Its side chain is indole, which is aromatic with a binuclear ring structure, whereas those of Phe, Tyr, and His are single-ring aromatics. In part due to these elaborate structural features, the biosynthetic pathway of Trp is the most complex and the most energy-consuming among all amino acids. Essential in the animal diet, Trp is also the least abundant amino acid in the cell, and one of the rarest in the proteome. In most eukaryotes, Trp is the only amino acid besides Met, which is coded for by a single codon, namely UGG. Due to the large and hydrophobic π-electron surface area, its aromatic side chain interacts with multiple other side chains in the protein, befitting its strategic locations in the protein structure. Finally, several Trp derivatives, namely tryptophylquinone, oxitriptan, serotonin, melatonin, and tryptophol, have specialized functions. Overall, Trp is a scarce and precious amino acid in the cell, such that nature uses it parsimoniously, for multiple but selective functions. Here, the various aspects of the uniqueness of Trp are presented in molecular terms.
... Bibliografía: [211][212][213][214][215][216] L-TIROSINA La L-tirosina actúa como precursor en la síntesis de las catecolaminas, un grupo de neurotransmisores formados por la adrenalina, noradrenalina y la dopamina, favoreciendo sus concentraciones en plasma. Este grupo de neurotransmisores actúa en el sistema nervioso central y ayudan a aumentar el rendimiento físico y mental. ...
This book is intended for anyone passionate about nutrition and
sports supplementation. It aims to introduce readers to what
regards the subject, combining areas such as nutrition, biological chemistry, the physiology of the exercise, food science and pharmacology. It is by no means intended to replace a good
book on each of these areas, just try to give a general snapshot of each of the substances that are currently being used in the world of supplementation sports, its functions, applications, benefits and doses that are usually used.
Heber E. Andrada
October 5, 2020
... The neurotransmitter serotonin (5-HT) plays a major role in neuropsychiatric disorders and is a key player in brain development [1,2]. In adulthood, 5-HT cannot cross the blood-brain barrier, while its precursors tryptophan and 5-hydroxytryptophan (5-HTP) can (see review [3]). However, roughly during the first half of pregnancy, 5-HT can be transferred from the mother's placenta, via the fetal periphery, to the fetal brain [4][5][6]. ...
Serotonin (5-HT) is a critical player in brain development and neuropsychiatric disorders. Fetal 5-HT levels can be influenced by several gestational factors, such as maternal genotype, diet, stress, medication, and immune activation. In this review, addressing both human and animal studies, we discuss how these gestational factors affect placental and fetal brain 5-HT levels, leading to changes in brain structure and function and behavior. We conclude that gestational factors are able to interact and thereby amplify or counteract each other’s impact on the fetal 5-HT-ergic system. We, therefore, argue that beyond the understanding of how single gestational factors affect 5-HT-ergic brain development and behavior in offspring, it is critical to elucidate the consequences of interacting factors. Moreover, we describe how each gestational factor is able to alter the 5-HT-ergic influence on the thalamocortical- and prefrontal-limbic circuitry and the hypothalamo-pituitary-adrenocortical-axis. These alterations have been associated with risks to develop attention deficit hyperactivity disorder, autism spectrum disorders, depression, and/or anxiety. Consequently, the manipulation of gestational factors may be used to combat pregnancy-related risks for neuropsychiatric disorders.
... A moderate-quality Cochrane review found two RCTs investigating the effectiveness and safety of tryptophan supplementation on depression severity. 158 Pooling the effects led to significant greater short-term response rates (figure 4) as well as significant more AEs in the tryptophan group than in the placebo group. The evidence was assessed as very low quality because of an unclear risk of detection, attrition and other bias, imprecision and a possible risk for publication bias. ...
Objectives
As clinical practice guidelines vary widely in their search strategies and recommendations of complementary and alternative medicine (CAM) for depression, this overview aimed at systematically summarising the level 1 evidence on CAM for patients with a clinical diagnosis of depression.
Methods
PubMed, PsycInfo and Central were searched for meta-analyses of randomised controlled clinical trials (RCTs) until 30 June 2018. Outcomes included depression severity, response, remission, relapse and adverse events. The quality of evidence was assessed according to Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) considering the methodological quality of the RCTs and meta-analyses, inconsistency, indirectness, imprecision of the evidence and the potential risk of publication bias.
Results
The literature search revealed 26 meta-analyses conducted between 2002 and 2018 on 1–49 RCTs in major, minor and seasonal depression. In patients with mild to moderate major depression, moderate quality evidence suggested the efficacy of St. John’s wort towards placebo and its comparative effectiveness towards standard antidepressants for the treatment for depression severity and response rates, while St. John’s wort caused significant less adverse events. In patients with recurrent major depression, moderate quality evidence showed that mindfulness-based cognitive therapy was superior to standard antidepressant drug treatment for the prevention of depression relapse. Other CAM evidence was considered as having low or very low quality.
Conclusions
The effects of all but two CAM treatments found in studies on clinical depressed patients based on low to very low quality of evidence. The evidence has to be downgraded mostly due to avoidable methodological flaws of both the original RCTs and meta-analyses not following the Consolidated Standards of Reporting Trials and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Further research is needed.
... Moreover, tryptophan, which is an indispensable amino acid, and a precursor of serotonin and melatonin, which are thought to regulate mood, is taken from food (Zhang, 2006). Intake of tryptophan has an influence on the regulation of emotional state by influencing serotonin synthesis, and this could be considered as an effective therapy for treating depression (Hartmann, 1982;Shaw et al., 2002;Lieberman, 2003). If there is a lack of food intake that is related to deficiency in tryptophan and eventually serotonin, emotional changes such as depression could happen, which parallels the findings from previous studies (Sainio et al., 1996;Birdsall, 1998;Lieberman, 2003;Le Floc'h et al., 2011;Yao et al., 2011). ...
Depression, an emotion regulation disorder, is a prevalent mental illness in the world. Meanwhile, traditional Chinese medicine (TCM) has been increasingly regarded as a promising and effective alternative therapy approach for patients with depression. Despite many years of research on depression, the current understanding of the pathological mechanism of depression based on TCM theories is still in its infancy. Due to the lack of scientific evidence in the past, TCM is not fully recognized by researchers around the world. This review firstly summarizes the pathogenesis and etiology of depression in terms of both Eastern and Western medical systems. Secondly, it adopts an integrated Eastern and Western approach to propose some plausible neurophysiological pathways linking the liver, spleen, and heart functions explicated in TCM theory. The aim of this theoretical review is to bridge the knowledge gap between Eastern and Western medicine, which may better explain the pathology of depression.
... While 5-HTP outperformed placebo in most trials, often with rapid improvement, the results are limited by small samples, with only six studies showing a statistically significant advantage for 5-HTP. A Cochrane review suggested most of these studies, except for one or two, did not meet criteria for a meta-analysis (Shaw et al. 2002), which does not represent a strong endorsement of the body of work thus far. ...
Depression remains difficult to manage, despite the many registered treatments available. For many depressed individuals, particularly those who have not responded to and/or had adverse effects from standard therapies, herbal and natural medications represent a potentially valuable alternative. This chapter will review several natural remedies used in the treatment of depression. Specific remedies covered include St. John’s wort (SJW), S-adenosyl-L-methionine (SAMe), omega-3 fatty acids, rhodiola, and others. We will begin by providing some historical and social context about these remedies. Then we will review efficacy and safety data, as well as biological mechanisms of action of these therapies. Finally, we will discuss the limitations of the current state of knowledge and provide suggestions for a productive research agenda focused on natural remedies. While many questions about these treatments remain unanswered and much work needs to be done before we determine their place in the psychiatric armamentarium, we believe that this chapter will give psychiatrists a good perspective on the pros and cons of herbal and natural antidepressants as part of the pharmacological armamentarium and sensible guidelines on how and when they should be used.
... These were: a) be randomized, b) include patients with unipolar depression or dysthymia, c) compare preparations of tryptophan or 5-HTP versus the placebo and d) that the clinical results were evaluated by scales. 43 In both studies, the preparations of tryptophan or 5-HTP showed superiority to the placebo in the relief of depressive symptoms, although the level of evidence is low. ...
There is increasing evidence about the role of nutrients in mental health. An adequate intake of nutrients contributes to better overall health and mental health in particular. Major depression is a severe mental illness with a high prevalence for which effective treatments exist but not in all cases the patient’s remission is achieved. Therefore, it is increasingly aimed at optimizing the supply of nutrients necessary for adequate brain functioning as adjunctive therapy to antidepressant treatment in depressive disorders. In this article we review those nutrients that have been related to depression: Omega-3 fatty acids, B vitamins, s-adenosylmethionine, tryptophan, magnesium, zinc and probiotics.
... It has been proposed that because the affinity of tryptophan hydroxylase for oxygen is dependent on tryptophan concentration, tryptophan supple- mentation could correct hypoxia-related deficits in serotonin synthesis. 11 Tryptophan has demonstrated antidepressant efficacy both as an adjunctive agent 111 and as monother- apy, 112 though its short half-life of roughly two hours 113 and its historical association with eosinophilia myalgia syn- drome 114 both present some barriers to clinical use. Simi- larly, supplementation with 5-HTP, which bypasses the oxygen-dependent step in serotonin production, could cor- rect alterations in serotonin metabolism associated with alti- tude. ...
Learning objectives:
After participating in this activity, learners should be better able to:• Assess epidemiologic evidence that increased altitude of residence is linked to increased risk of depression and suicide• Evaluate strategies to address hypoxia-related depression and suicidal ideation ABSTRACT: Suicide and major depressive disorder (MDD) are complex conditions that almost certainly arise from the influences of many interrelated factors. There are significant regional variations in the rates of MDD and suicide in the United States, suggesting that sociodemographic and environmental conditions contribute. Here, we review epidemiological evidence that increases in the altitude of residence are linked to the increased risk of depression and suicide. We consider the possibility that chronic hypobaric hypoxia (low blood oxygen related to low atmospheric pressure) contributes to suicide and depression, which is suggested by animal models, short-term studies in humans, and the effects of hypoxic medical conditions on suicide and depression. We argue that hypobaric hypoxia could promote suicide and depression by altering serotonin metabolism and brain bioenergetics; both of these pathways are implicated in depression, and both are affected by hypoxia. Finally, we briefly examine treatment strategies to address hypoxia-related depression and suicidal ideation that are suggested by these findings, including creatine monohydrate and the serotonin precursors tryptophan and 5-hydroxytryptophan.
... Thus, even in complex whole diets, TRP intake appears to provide psychological benefits. TRP supplementation has been employed as a potential treatment for depression and sleep disturbance since the early 1960s (24,79) , although a Cochrane Review of 108 trials (including for 5-hydroxytryptophan) for antidepressant effects in 2002 found that only two trials were of sufficient quality to be included (80) . Nevertheless, on that limited evidence, TRP was considered to be better than placebo in alleviating depression, at least in mild to moderately depressed people. ...
The neurotransmitter serotonin has a role in affective disorders such as depression and anxiety, as well as sleep, cognitive function and appetite. This review examines the evidence that serotonin-related genotypes may moderate the behavioural effects of supplementation with the serotonin precursor amino acid l -tryptophan (TRP), on which synthesis of serotonin (or 5-hydroxytryptamine; 5-HT) depends. However, 95 % of serotonin is synthesised and used in the periphery, and TRP is also metabolised via non-5-HT routes such as the kynurenine pathway. Moreover, understanding of genotypes involved in regulation of serotonin raises questions over the generalisability of TRP effects on behaviour across individuals with varied serotonergic genotypes. To date, only differences between variants of the 5-HT transporter-linked promoter region (5-HTTLPR) have been investigated in relation to behavioural effects of TRP supplementation. Effects of 5-HTTLPR genotypes are usually compared between the alleles that are either high (L/L′) or low (S/S′) expressing of mRNA for the 5-HT transporter receptor. Yet, another key genetic variable is sex: in women, the S/S′ genotype predicts sensitivity to improved mood and reduced cortisol by TRP supplementation, during stressful challenges, whereas the L/L′ genotype protects against stress-induced mood deterioration. In men, the L/L′ genotype may confer risk of stress-induced increases in negative affect; there are insufficient data to assess effects on male S/S′ genotypes. However, better-powered studies to detect sex by genotype by stress by TRP interactions, as well as consideration of more genotypes, are needed before strong conclusions and recommendations for behavioural effects of TRP treatment can be reached.
... Tryptophan and daonil treatment showed no remarkable change in glucose level, which could be due to interactions. However, in clinical setting tryptophan has not been thoroughly studied, therefore its possible side effects and interactions with other drugs are not well known [32]. The transport system which brings tryptophan across the blood-brain barrier is selective compared to other amino acids which are contained in protein food sources thus consumption of dietary tryptophan supplement could increase brain serotonin thereby causing serotonin syndrome whereas eating foods containing tryptophan may not [33]. ...
... Tryptophan and some of its metabolic products, such as serotonin and melatonin, are believed to participate in the regulation of mood, sleep, and circadian rhythms and are used to treat insomnia, sleep apnea, and depression (6)(7)(8). However, a Cochrane Review concluded that there was insufficient evidence that tryptophan or 5-hydroxytryptophan are effective therapies for treating clinical depression (9). Dietary tryptophanÕs availability as a precursor of serotonin may, however, be reduced because of its breakdown in the liver due to glucocorticoid induction of tryptophan dioxygenase enzyme (10). ...
Background:
Tryptophan is an indispensable amino acid and is a precursor of the neurotransmitter serotonin. Tryptophan metabolites, such as serotonin and melatonin, are thought to participate in the regulation of mood and sleep and tryptophan is used to treat insomnia, sleep apnea, and depression.
Objective:
This study examined the intake of tryptophan and its associations with biochemical, behavioral, sleep, and health and safety outcomes in adults in a secondary analysis of a large, publicly available database of the US population.
Methods:
Data from the NHANES 2001-2012 (n = 29,687) were used to determine daily intakes of tryptophan and its associations with biochemical markers of health- and safety-related outcomes, self-reported depression, and sleep-related variables. Data were adjusted for demographic factors and protein intake. Linear trends were computed across deciles of intake for each outcome variable, and P-trends were determined.
Results:
The usual tryptophan intake by US adults was 826 mg/d, severalfold higher than the Estimated Average Requirement for adults of 4 mg/(kg ⋅ d) (∼280 mg/d for a 70-kg adult). Most health- and safety-related biochemical markers of liver function, kidney function, and carbohydrate metabolism were not significantly (P-trend > 0.05) associated with deciles of tryptophan intake and were well within normal ranges, even for individuals in the 99th percentile of intake. Usual intake deciles of tryptophan were inversely associated with self-reported depression measured by the Patient Health Questionnaire raw score (0-27; P-trend < 0.01) and calculated level (1 = no depression, 5 = severe depression; P-trend < 0.01) and were positively associated with self-reported sleep duration (P-trend = 0.02).
Conclusions:
Tryptophan intake was not related to most markers of liver function, kidney function or carbohydrate metabolism. Levels of tryptophan intake in the US population appear to be safe as shown by the absence of abnormal laboratory findings. Tryptophan intake was inversely associated with self-reported level of depression and positively associated with sleep duration.
... Its synthesis in the human system is catalyzed by the enzyme, 'tryptophan hydroxylase', present in the serotonergic neurons. 5-HTP is an intermediate precursor in the biosynthesis of an important neurotransmitter, Serotonin (5-HT) [1][2][3]. It is also considered as over the counter medicine in several developed countries as a dietary supplement. ...
Nano palladium decorated multi walled carbon nanotubes (PdNP:MWCNT) have been synthesized in a simple single step, followed by their characterization using field emission scanning electron microscopy, energy dispersion X-ray spectroscopy, X-ray diffraction, electrochemical impedance spectroscopy and voltammetry. The PdNP:MWCNT was then used for the surface modification of glassy carbon electrode (GCE) and applied for the electrochemical analysis of 5-hydroxytryptophan (5-HTP), a serotonin precursor. A significant increment in peak current response was observed and peak potential also shifted towards less positive potentials indicating the facilitated oxidation process at PdNP:MWCNT/GCE. The quantitative determination of 5-HTP was carried out by using square wave voltammetry and the anodic peak current was found to increase with increasing 5-HTP concentration in the linear range of 2–400 μM with a sensitivity and limit of detection of 0.2122 μA/μM and 77 nM respectively. The fabricated sensor further displayed excellent selectivity for 5-HTP in presence of major interfering biomolecules in the urine with excellent recovery.
... Its synthesis in the human system is catalyzed by the enzyme, 'tryptophan hydroxylase', present in the serotonergic neurons. 5-HTP is an intermediate precursor in the biosynthesis of an important neurotransmitter , Serotonin (5-HT) [1][2][3]. It is also considered as over the counter medicine in several developed countries as a dietary supplement. ...
... A systematic review of the literature from 1996 to 2000 revealed that tryptophan and 5-hydroxytryptophan or their combination is better than placebo in the treatment of depression although possible publication bias hampered further conclusions on the clinical efficacy of this serotonin precursor (Shaw et al., 2002;Parker and Brotchie, 2011). Long-term studies are needed to evaluate the efficiency of tryptophan supplementation because of its induction of TDO, which is not an issue for 5-hydroxytryptophan. ...
Lowered plasma tryptophan (TRP) and TRP/competing amino acid (CAA) ratio may be involved in the pathophysiology of major depression (MDD). Increased cortisol and immune-inflammatory mediators in MDD may affect the availability of TRP to the brain. We investigated whether baseline or post-treatment TRP, CAAs and TRP/CAA ratio are associated with a treatment response in MDD and whether these effects may be mediated by cortisol or immune biomarkers. We included 50 medication-free MDD patients with a depressive episode (DSM diagnosis) and assessed symptom severity with the Inventory of Depressive Symptomatology (IDS) before and after treatment as usual for 12 weeks (endpoint). Plasma levels of TRP, CAAs, the ratio, cortisol, CRP and 6 selected cytokines were assayed. The primary outcome was a 50% reduction in the IDS, while the secondary was a remission of the depressive episode. In IDS non-responders, CAAs increased and the TRP/CAA ratio decreased, while in IDS responders CAAs decreased and the TRP/CAA ratio increased from baseline to endpoint. In patients who were still depressed at endpoint TRP and CAAs levels had increased from baseline, while in remitted patients no such effects were found. Increases in CAAs were inversely correlated with changes in interleukin-1 receptor antagonist levels. The results show that increased CAA levels from baseline to endpoint are associated with a non-response to treatment in MDD patients. This suggests that the mechanism underpinning the CAA-related treatment resistance may be related to changes in immune pathways. CAA levels and amino acid metabolism may be new drug targets in depression.
Indole derivatives have become an important class of compounds in medicinal chemistry, recognized for their wide-ranging biological activities and therapeutic potential. This review provides a comprehensive overview of recent advances in the evaluation of indole-based compounds in the last five years, highlighting their roles in cancer treatment, infectious disease management, anti-inflammatory therapies, metabolic disorder interventions, and neurodegenerative disease management. Indole derivatives have shown significant efficacy in targeting diverse biological pathways, making them valuable scaffolds in designing new drugs. Notably, these compounds have demonstrated the ability to combat drug-resistant cancer cells and pathogens, a significant breakthrough in the field, and offer promising therapeutic options for chronic diseases such as diabetes and hypertension. By summarizing recent key findings and exploring the underlying biological mechanisms, this review underscores the potential of indole derivatives in addressing major healthcare challenges, thereby instilling hope and optimism in the field of modern medicine.
Classification of drug treatments for depression is described noting the ambiguities of current terminology and the move towards standardised nomenclature based on pharmacology and mode of action, such as that proposed by the Neuroscience-based Nomenclature group. Antidepressant drugs are described in terms of background, mechanism of action, pharmacokinetics, side effects, interactions, contraindications and toxicity in overdose. Groups include selective serotonin re-uptake inhibitors (SSRI), serotonin and noradrenaline re-uptake inhibitors (SNRI), tricyclics, noradrenergic and specific serotoninergic antidepressants (NaSSA), monoamine oxidase inhibitors (MAOI) and others such as buproprion, agomelatine, reboxetine, trazadone and vortioxetine. Augmentary medications are also described, including antipsychotics, antiepileptics and lithium. Developments with the use of ketamine and other compounds are discussed.
The classification of physical treatments for depression is into neuromodulatory (e.g. electroconvulsive therapy, transcranial magnetic stimulation, deep brain stimulation and phototherapy) and neuroablative techniques (e.g. stereotactic psychosurgery).
Kinetoplastids are the causative agents for a spectrum of vector-borne diseases including Leishmaniasis, Chagas disease and Trypanosomiasis that affect millions of people worldwide. In the absence of safe and effective vaccines, chemotherapy, in conjunction with vector control, remain the most significant control approach for kinetoplastid diseases. However, commercially available treatment for these neglected tropical diseases frequently ends up with toxic side effects and increasing resistance. To meet the rising need for innovative medications, alternative chemotherapeutic agents are required. Moreover, insights into target-based mode of action of chemotherapeutic agents are required if novel drugs that may outwit resistance to commercially available drugs are to be developed. Tryptophan has been implicated in a variety of diseases and disorders due to its fundamental role as a precursor to several bioactive metabolites, as well as its importance in the improvement of health and nutrition, diagnostics, and therapeutics. The regulation of tryptophan metabolism plays a fundamental role in the growth of kinetoplastids. Moreover, the levels of tryptophan may serve as a biomarker to distinguish between the stages of kinetoplastids making it an important amino acid to explore for drug targets. The main aim of this review is thus to provide a comprehensive literature synthesis of tryptophan derivatives to explore as potential anti-kinetoplastids. Here we highlight the role of tryptophan derivatives as chemotherapeutic agents against kinetoplastids. The reviewed compounds provide insights into potential new drug interventions that may combat the increasing problem of anti-kinetoplastid resistance.
Adaptogens are a group of substances capable to increase the nonspecific resistance of the organism to a wide range of harmful effects and stress. However, only limited data exist on their use in the composition of foods for special dietary uses.
The aim of the study was to evaluate the effect of a diet that included vegetable-fat spread enriched with 5-hydroxytryptophan, L-theanine and r-aminobutyric acid on memory, general well-being and emotional status of healthy volunteers.
Material and methods. The single-center, single-blind randomized prospective trial that enrolled persons without signs of significant organic pathology have been performed. Participants were randomly allocated to receive either 45 g/day standard spread enriched with 5-hydroxytryptophan (0.67%), I-theanine (0.56%) and v-aminobutyric acid (0.45%) (main group, MG) or 45 g/day standard spread (control group, CG) for 10 days. Beside this, all participants followed a standard diet. Initially, as well as on the 10th day after the start of using the diet, the emotional state was assessed using the HADS anxiety and depression scale and Beck's depression inventory (BDI), general well-being by SAN questionnaire, memory according to the Lure method; reaction time and attention concentration were assessed using the Krepelin counting test and the Burdon correction test. A 5-point Likert visual-analogue scale was used to assess the palatability (pasting) of the product, the severity of feelings of hunger and satiety at the baseline and on the 10th day of the study. All tests were performed under the supervision of staff. During the study, daily monitoring of the presence of adverse events was performed.
Results. There were 70 subjects in MG and 70 in CG. Lurie memory score significantly increased in the MG (59.9‡6.7 vs 58.1‡7.4 points at the baseline; p=0.001), but not in the CG (58.0‡6.9 os 57.3‡7.3 points, p>0.05). According to the SAN questionnaire, significant increase of well-being values (46.9‡13.4 vs 44.2=13.5 points; p=0.01) and mood (49.9‡12.6 os 47.4‡12.9 points; p=0.01) was found in MG, while in CG there was an increase of the mood category only (54.4‡10.8 vs 52.2‡12.1, p=0.04). At the end of the study an increase of «Satiety» (60.3‡22.8 us 51.5‡24.8, p=0.022) and decrease of «Hunger» score (24.1‡19.8 vs 29.1‡19.4, p=0.02) were revealed in CG but not in the CG. No significant change was found by the results of other tests, stool form and its frequency in both groups.
Conclusion. Newly developed spread enriched with 5-hydroxytryptophan, I-theanine, y-aminobutyric acid was well-tolerated, did not affect the feeling of hunger and satiety, and improved memory and well-being parameters. / Адаптогены-группа веществ, способных повышать неспецифическую сопротивляемость организма к различным неблагоприятным воздействиям и к стрессу. Однако данные об использовании этих веществ в составе специали-зированных пищевых продуктов ограничены. Цель исследования-оценить влияние включения в рацион растительно-жирового спреда, обогащенного 5-гидрокситриптофаном, L-теанином и γ-аминомасляной кислотой, на память, общее самочувствие и эмоциональный статус практически здоровых добровольцев. Материал и методы. Проведено одноцентровое рандомизированное слепое исследование, участниками которого были лица без признаков значимой орга-нической патологии. Всем участникам на 10 дней предоставляли стандарт-ный рацион, в состав которого был введен или растительно-жировой спред (45 г/сут), обогащенный 5-гидрокситриптофаном (0,67%), L-теанином (0,56%) и γ-аминомасляной кислотой (0,45%),-основная группа (ОГ), или то же количество обычного растительно-жирового спреда-группа сравнения (ГС).
The incidence of mental illness continues to increase since the start of the COVID-19 pandemic (Mental Health America, 2022). Demand for mental health services has grown, and providers report being “unable to meet the demand” or having an increase in wait times for access to care (American Psychological Association, 2022, para. 1). Due to this increase in demand, more patients are seeking mental health care from their primary care providers. Over the past decade, integrative models of care have been expanding into mental health care (Lake, 2017). Integrative Nursing is a strategy for improving the quality of care provided to patients seeking care for mental health diagnoses, as well as those with a goal of increasing mental health and wellbeing. This article proposes that Integrative Nursing can serve as a framework for providing whole-person mental health care.
Tryptophan is the essential amino acid precursor to the monoamine neurotransmitter serotonin, which is associated with several brain functions such as modulating mood, cognition, vomiting, impulsivity as well as sleep and circadian rhythm. The latter is due to serotonin's role as a precursor for melatonin—a light-sensitive hormone underlying the complex sleep–wake cycles in vertebrates. Melatonin and tryptophan supplementation have proven useful treatments in certain contexts, including depression, traumatic brain injury, delayed sleep phase syndrome, delirium, childhood parasomnias and insomnia. Background information and physiology of these two biomolecules are provided followed by investigation of the evidence for their clinical significance.
An evidence-based guide for laypeople on psychological, medical, complementary and lifestyle interventions for depression.
A novel and efficient reductive N-alkenylation of iminoquinones with electron-deficient olefins has been successfully developed by Pd(II)-catalyzed redox-neutral reactions, which provides a synthesis of tertiary (E)-enamines. We further demonstrate that the tertiary enamines can be converted to multifarious N-heterocyclic compounds, indoles, and quinolones in good yields.
Context:
Depression is one of the most commonly diagnosed psychiatric disorders, but antidepressant pharmacotherapy often fails to achieve remission, leading health care professionals and researchers to consider various augmentation strategies to improve clinical outcomes.
Objective:
To assess the safety, tolerability, and efficacy of nutraceutical augmentation for depression.
Methods:
Nutraceutical-focused systematic reviews and clinical practice guidelines identified the more commonly studied augmentation strategies for depression.
Results:
S-adenosylmethionine, l-methylfolate, omega-3 fatty acids, and hydroxyvitamin D have sufficient scientific evidence to support their clinical consideration in the stepped care approach to the management of depression.
Conclusions:
Clinical remission is the goal in the management of depression, and nutraceuticals may be part of an overall treatment approach to achieve that outcome.
Fruits come in a wide variety of colors, shapes, and flavors. This chapter will cover selected fruits that are known to be healthy and highly nutritious. These fruits were chosen due to their common usage and availability. Since it is not possible to cover all health benefits or essential nutrients and important phytochemicals of the fruit composition, this chapter will focus on the key valuable constituents and their potential health effects.
A wide variety of plant species provide edible seeds. Seeds are the dominant source of human calories and protein. The most important and popular seed food sources are cereals, followed by legumes and nuts. Their nutritional content of fiber, protein, and monounsaturated/polyunsaturated fats make them extremely nutritious. They are important additions to our daily food consumption. When consumed as part of a healthy diet, seeds can help reduce blood sugar, cholesterol, and blood pressure.
A few drugs prescribed in internal medicine, ie, non-psychotropic drugs, can be used to treat certain neuropsychiatric disorders. For most of these situations, the level of evidence remains low. But when sufficient data becomes available, these molecules are then included in official guidelines for the treatment of neuropsychiatric disorders. In this article we review interesting drugs which may be relevant from an evidence-based medicine point of view, and could become part of psychiatric practice in the future.
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Over the past two decades, natural remedies have been growing in popularity in the USA and worldwide. Given the limitations of current treatments for depression, natural medications as well as other complementary therapies represent for many a beneficial alternative to registered medications, particularly in cases of limited efficacy and/or side effects. This chapter will review several popular natural remedies often used in the treatment of depression. Specific remedies covered include St. John’s wort (SJW), S-adenosyl-L-methionine (SAMe), omega-3 fatty acids, rhodiola, and some less-known ones. We will provide some historical and socioeconomic perspectives on treatment with natural products, including present-day limitations to the systematic study of these remedies. We will examine the published research data from efficacy studies and discuss potential mechanisms of antidepressant action and specific safety considerations for each. Evidence for these remedies is varied in quantity and quality, and many questions remain unanswered with regard to their place in the psychopharmacological armamentarium. Clinicians who read this chapter will develop a good sense of how to apply these remedies in clinical practice safely.
Complementary and alternative medicine (CAM) refers to a range of treatments, therapies and practices that are not considered part of conventional medicine. CAM approaches are widely used, and depression has been identified as one of the most frequent indications for CAM use. Prevalence and patterns of use are highly variable across different countries but frequently involve self-diagnosis and self-treatment. A critical review of the evidence on efficacy of CAM treatments in depression indicates that the approaches that have generated the most research interest include acupuncture, Chinese herbs, hypericum (St John’s wort), mindfulness and omega-3 fatty acids. Based on a critical review of the evidence, it appears that the most promising evidence is for hypericum (but with concerns with adverse effects and interactions), mindfulness, relaxation and yoga. Many trials are small, comparison interventions are varied, and there is a lack of systematically collated data on adverse events or long-term effects. Even where there is a strong evidence base, there may be factors preventing wider adoption for clinical use, such as concerns related to interactions or lack of standardisation or regulation of the practice and practitioners. Challenges in developing a rigorous evidence base in this area are also briefly discussed.
An integrative approach to individuals with mood, emotional or mental health concerns involves a comprehensive model of care that is person-centered. Integrative medicine builds on a patient's personal meaning and goals (spiritual aspects) and includes herbal therapies, nutritional support, movement and physical manipulative therapies, mindfulness, relaxation strategies, and psychotherapies.
English version: A review of modern psychopharmacological methods of therapy of depression is represented. The efficiency of antidepressants with a monoaminergetic mechanism of action is discussed. A possibility of usage of combined therapy by depressants and preparations of other pharmacological groups is considered. Special attention is paid to some medical drugs, which realize its antidepressive effect through influence upon Gamma-amino-butyric system.
Русскоязычная версия: Представлен обзор современных психофармакологических методов терапии депрессий. Обсуждается эффективность антидепрессантов с моноаминергическим механизмом действия. Рассматривается возможность применения комбинированной терапии антидепрессантами и препаратами других фармакологических групп. Отдельное внимание уделяется некоторым средствам, антидепрессивный эффект которыхреализуется через воздействие на ГАМКергическую систему.
• Preclinical and clinical evidence supports a theory of serotonin (5-hydroxytryptamine [5-HT]) dysregulation in bulimia. We therefore studied the prolactin (PRL) and cortisol responses following challenges with the postsynaptic 5-HT receptor agonist m-chlorophenylpiperazine (m-CPP), 0.5 mg/kg orally, the 5-HT precursor L-tryptophan, 100 mg/kg intravenously, and placebo in a group of 28 normal weight bulimic patients and 16 healthy controls. Patients with bulimia, regardless of the presence of major depression, had significantly blunted PRL responses following m-CPP administration compared with those in controls. In contrast, only bulimic patients with concurrent major depression had significantly blunted PRL responses following L-tryptophan administration compared with those in nondepressed bulimic patients and controls. Cortisol responses following m-CPP were not significantly different for bulimic patients vs controls, although there was a trend toward blunted cortisol responses following L-tryptophan administration in the depressed bulimic patients. These differences in neuroendocrine responses were not related to differences in age, percent of average body weight, medications, time of day, peak plasma drug levels, or baseline estradiol levels. Seasonal variations in PRL responses to both agents were identified, although covariation for season did not alter the group differences. The PRL responses following m-CPP administration were inversely correlated to baseline cortisol levels in the bulimic patients, but not in the controls, suggesting a dampening effect by hypothalamic-pituitaryadrenal axis dysfunction on postsynaptic 5-HT receptor sensitivity. The reasons for the differing hormonal responses to these two serotonergic agents may relate to differential involvement of presynaptic and postsynaptic mechanisms, 5-HT receptor subtypes, and anatomical loci of action. The blunted PRL responses to m-CPP administration suggest that postsynaptic 5-HT receptor sensitivity is altered in bulimia nervosa, and that similar alterations in 5-HT receptors at or above the level of the hypothalamus may contribute to binge eating and other behavioral symptoms.
In the last few years several open studies supported the hypothesis that L-5-HTP may be an effective antidepressant. Because of the lack of a controlled double-blind trial we started our own investigations to confirm this hypothesis in L-5-HTP. In 1972 we performed two open dose finding trials with L-5-HTP in combination with Benzerazide. These open studies were followed by a double-blind trial comparing L-5-HTP in combination with Benzerazide to Imipramine in 30 patients. Assessments were carried out on day 0, 5, 10, 15 and 20. For data collection we used the Hamilton Rating Scale for Depression, the AMP-system, a Global Rating Scale of Severity of Depression and a Brief Rating Scale for the Behaviour on the ward. In this article we report only a part of the results, mainly on the findings with the AMP-system and the Hamilton Rating Scale for Depression. During our double-blind trial we could not find any significant difference in efficacy of L-5-HTP and Imipramine. The same was found in an open trial. Furthermore the L-5-HTP results showed no difference compared with the results of an Imipramine treatment in 40 patients in earlier double-blind studies. L-5-HTP and Imipramine caused different patterns of side effects. L-5-HTP caused mainly gastrointestinal side effects and Imipramine caused mainly dryness of the mouth and tremor. The gastrointestinal side effects caused by L-5-HTP seemed to be dose dependent.
Preclinical and clinical evidence supports a theory of serotonin (5-hydroxytryptamine [5-HT]) dysregulation in bulimia. We therefore studied the prolactin (PRL) and cortisol responses following challenges with the postsynaptic 5-HT receptor agonist m-chlorophenylpiperazine (m-CPP), 0.5 mg/kg orally, the 5-HT precursor L-tryptophan, 100 mg/kg intravenously, and placebo in a group of 28 normal weight bulimic patients and 16 healthy controls. Patients with bulimia, regardless of the presence of major depression, had significantly blunted PRL responses following m-CPP administration compared with those in controls. In contrast, only bulimic patients with concurrent major depression had significantly blunted PRL responses following L-tryptophan administration compared with those in nondepressed bulimic patients and controls. Cortisol responses following m-CPP were not significantly different for bulimic patients vs controls, although there was a trend toward blunted cortisol responses following L-tryptophan administration in the depressed bulimic patients. These differences in neuroendocrine responses were not related to differences in age, percent of average body weight, medications, time of day, peak plasma drug levels, or baseline estradiol levels. Seasonal variations in PRL responses to both agents were identified, although covariation for season did not alter the group differences. The PRL responses following m-CPP administration were inversely correlated to baseline cortisol levels in the bulimic patients, but not in the controls, suggesting a dampening effect by hypothalamic-pituitary-adrenal axis dysfunction on postsynaptic 5-HT receptor sensitivity. The reasons for the differing hormonal responses to these two serotonergic agents may relate to differential involvement of presynaptic and postsynaptic mechanisms, 5-HT receptor subtypes, and anatomical loci of action. The blunted PRL responses to m-CPP administration suggest that postsynaptic 5-HT receptor sensitivity is altered in bulimia nervosa, and that similar alterations in 5-HT receptors at or above the level of the hypothalamus may contribute to binge eating and other behavioral symptoms.
• In a double-blind study of 24 patients with endogenous depression, a group treated with clomipramine hydrochloride (chlorimipramine) plus tryptophan was compared with a group treated with clomipramine plus placebo. The sum of the ratings for depressed mood, suicidal intent, depressive thought content, and anxiety showed a more rapid improvement in the former group, the difference being already significant after 12 days of treatment. On the other hand, the ratings for retardation decreased about equally in both groups during the three-week treatment period. Side-effect ratings showed no significant increase but seemed to be partly influenced by the improvement of depressive symptoms. Plasma levels of clomipramine appeared to reach a plateau within a few days, whereas the monodesmethylated metabolite continued to rise for a longer period of time, and reached considerably higher values than the parent compound. In the tryptophan group the degree of improvement seemed to be positively correlated to these levels, suggesting that further improvement might have been reached in some patients by increasing the dose of clomipramine. The levels of 5-hydroxyindoleacetic acid in the cerebrospinal fluid appeared to be reduced by clomipramine administration. This effect was prevented by the additional treatment with tryptophan.
The term eosinophilia myalgia syndrome (EMS) was coined in 1989 after a cluster of cases with symptoms of incapacitating myalgias and eosinophilia were reported. This syndrome has been only defined as varying degrees of myalgias and peripheral eosinophilia. Case reports of EMS are protean and do not show a consistent clinical picture, raising the question of whether this reflects a single disorder or is a conflation of various disorders. There have been only two studies evaluating the association of EMS with 1-tryptophan. These two included only 23 patients with EMS. Apart from the obvious statistical fragility inherent in such small studies, each is further weakened by differences in the mechanisms by which patients and controls were selected. Furthermore, the continued reports of EMS after 1-tryptophan was removed from the market raise additional questions about the association. Nonetheless, there has been an inordinate reliance on a history of 1-tryptophan ingestion in making the diagnosis of EMS. When presented case studies, clinicians were much more likely to make the diagnosis of EMS when a history of 1-tryptophan ingestion was included. These observations underscore the need for careful application of well-considered diagnostic criteria to the study of new syndromes and their potential associations.
• The therapeutic efficacy, plasma levels, and psychomotor effects of tryptophan (L-tryptophan), clomipramine hydrochloride, and doxepin were investigated in "neurotically" depressed outpatients. The tricyclic antidepressants were significantly more efficacious than tryptophan in inducing remission. The alleviation of depression was preceded by an improvement of the initially slow information-processing rates in the depressed patients. The plasma levels of the tricyclics that were associated with a therapeutic response were significantly lower than those reported in "endogenously" depressed inpatients.
Longitudinal studies of thyroid function during a four-week comparative trial of imipramine hydrochloride and L-tryptophan in 30 depressed patients showed a significant fall in the free thyroxine index during the first week of the trial, but otherwise measures of thyroid activity were within normal limits and showed no change during clinical recovery. Administration of 25µg of L-triiodothyronine (T3, liothyronine sodium) for 14 days was sufficient to cause some suppression of endogenous thyroid function and demonstrated that the pituitary-thyroid axis remains responsive during depressive illness. Ankle reflex time estimated prior to treatment was very significantly correlated with response to imipramine therapy, ie, the patients with faster ankle reflex times showed a greater improvement than those with a slower ankle reflex time. A similar correlation was found between a low serum cholesterol level and a good clinical response to imipramine treatment.
In a trial lasting four weeks patients responded equally well to imipramine (150 mg daily) or to L-tryptophan (9 gm daily). Patients who received a small dose of L-triiodothyronine (T3, liothyronine sodium (25μg daily for the first two weeks of treatment) in addition to imipramine showed a significantly better therapeutic response than patients who received either imipramine or tryptophan alone. Liothyronine did not enhance the therapeutic response to L-tryptophan. None of the treatments tested seemed to benefit any particular symptom of depression differenntially. In particular, L-tryptophan had no specific effect on the sleep deficit of the syndrome. Liothyronine appeared to diminish the side effects of both imipramine and L-tryptophan in both men and women.
The amino acid precursors, levodopa and L-tryptophan, were given to a group of hospitalized depressed patients in a double-blind placebo controlled study. Relatively large doses were not associated with sufficient clinical improvement to allow the patients to leave the hospital.
Previous studies using the precursor-load strategy have produced conflicting findings on the use of these compounds for depressed patients.
• Serum cortisol levels were significantly increased following administration of 5-hydroxytryptophan (5-HTP), 200 mg orally, to patients with affective disorders. A three-to five-week period of treatment with lithium carbonate or monoamine oxidase (MAO) inhibitor augmented the mean 5-HTP-induced increase in serum cortisol concentration in manic or depressed patients, respectively: tricyclic antidepressant (TCA) and second-generation antidepressant treatment diminished the mean serum cortisol response in patients with major depression. These results are consistent with the hypothesis that lithium carbonate may enhance serotonin (5-HT) receptor sensitivity, whereas TCA and second-generation antidepressants diminish 5-HT receptor sensitivity. The enhancement of the cortisol response to 5-HTP by MAO inhibitors may be due to decreased metabolism of 5-HT. It is important to assess the effect of thymoleptic drug treatment on various responses to biogenic amine precursors or agonists in patients rather than laboratory animals.
A double-blind evaluation of the antidepressant efficacy of treatment with a combination of orally administered L-tryptophan (L-TP) and electroconvulsive therapy (ECT) was made in patients suffering from endogenous depression. The patients were randomly assigned to two groups, one treated with L-TP (6 g daily) and unilateral ECT, the other with placebo and unilateral ECT. L-TP treatment was initiated at least 1 day before the first ECT and terminated 4 days after the last ECT.
There was a good agreement between the two groups in several measures of antidepressant efficacy: doctors' and patients' ratings of depressive symptoms, and doctors' global rating of therapeutic effect 4 days and 1 month after the last ECT. In the L-TP group, however, there was a significantly better effect on retardation symptoms in the nurses' rating scale. This difference, which is not consistent with other measures of amelioration, contributes, at most, to a marginal therapeutic addition to the antidepressant effect of ECT. It is concluded that oral administration of L-TP, in the dose of 6 g daily, is not of practical value for potentiating the antidepressant efficacy of ECT.
In a double-blind controlled study lasting 4 weeks 25 newly admitted severely depressed patients were randomly assigned to tryptophan-nicotinamide or imipramine or tryptophan-nicotinamideimipramine combination. Nicotinamide was given to reduce peripheral breakdown of tryptophan. Although there were no substantial differences between the three treatments, the efficacy of tryptophannicotinamide tended to diminish after 2 weeks when the dose of tryptophan was increased from 4 g/day to 6 g/day and that of nicotinamide from 1.0 g/day to 1.5 g/day. The therapeutic response of patients treated with tryptophan-nicotinamide was significantly correlated with the rise in plasma tryptophan. For the tryptophannicotinamide-imipramine group, however, therapeutic response and rise in plasma tryptophan were negatively correlated, implying that tryptophan levels were too high in some patients. The data suggest that tryptophan-nicotinamide may be as effective as imipramine in unipolar patients providing the dose is kept within the therapeutic window, and that at low doses it could also potentiate the action of tricyclic antidepressants. Bipolar patients seem to require higher doses of tryptophan than unipolar patients.
In the last few years several open studies supported the hypothesis that L-5-HTP may be an effective antidepressant. Because of the lack of a controlled double-blind trial we started our own investigations to confirm this hypothesis in L-5-HTP. In 1972 we performed two open dose finding trials with L-5-HTP in combination with Benzerazide. These open studies were followed by a double-blind trial comparing L-5-HTP in combination with Benzerazide to Imipramine in 30 patients. Assessments were carried out on day 0, 5, 10, 15 and 20.For data collection we used the Hamilton Rating Scale for Depression, the AMP-system, a Global Rating Scale of Severity of Depression and a Brief Rating Scale for the Behaviour on the ward. In this article we report only a part of the results, mainly on the findings with the AMP-system and the Hamilton Rating Scale for Depression.During our double-blind trial we could not find any significant difference in efficacy of L-5-HTP and Imipramine. The same was found in an open trial. Furthermore the L-5-HTP results showed no difference compared with the results of an Imipramine treatment in 40 patients in earlier double-blind studies.L-5-HTP and Imipramine caused different patterns of side effects. L-5-HTP caused mainly gastrointestinal side effects and Imipramine caused mainly dryness of the mouth and tremor. The gastrointestinal side effects caused by L-5-HTP seemed to be dose dependent.In den letzten Jahren ergaben verschiedene offene Prfungen Hinweise fr die Hypothesen, da L-5-HTP ein wirksames Antidepressivum sei. Weil kontrollierte doppelblinde Prfungen fehlten, begannen wir eigene Untersuchungen, um diese Hypothese zu berprfen. Im Jahre 1972 fhrten wir 2 offene Studien mit L-5-HTP, in Kombination mit Benzerazid durch. Diesen beiden offenen Prfungen folgte eine Doppelblindstudie in der wir L-5-HTP in Kombination mit Benzerazid gegen Imipramin an 30 Patienten prften. Die Untersuchungen der Patienten wurden an den Tagen 0, 5, 10, 15 und 20 durchgefhrt.Fr die Datensammlung bentzten wir die Hamilton-Skala fr Depressionen, das AMP-System, eine globale Rating-Skala des Schweregrades der Depression und eine Rating-Skala des Verhaltens auf den Abteilungen. In diesem Artikel fhren wir nur einen Teil der Resultate auf, vor allem solche, die mit dem AMP-System und der Hamilton-Skala fr Depressionen gewonnen wurden.Die Doppelblindprfung ergibt keine signifikanten Wirkungsunterschiede zwischen L-5-HTP und Imipramin; das gleiche gilt fr eine offene Prfung. Die L-5-HTP Resultate zeigten ferner keinen Unterschied zu den Ergebnissen von Imipraminbehandlungen an 40 Patienten aus frheren doppelblinden Prfungen.L-5-HTP und Imipramin verursachten verschiedene Arten von Nebenwirkungen, L-5-HTP vor allem gastrointestinale Nebenwirkungen und Imipramin vor allem Mundtrockenheit und Tremor. Die gastrointestinalen Nebenwirkungen bei L-5-HTP scheinen dosisabhngig zu sein.
Previous work has suggested that acute depletion of the serotonin (5-HT) precursor tryptophan (TRP) causes transient compensatory changes in the 5-HT system that might be exploited for their antidepressant effects. In this study, neuroendocrine and mood responses to intravenous (i.v.) infusion of TRP were examined in order to evaluate central 5-HT function in depressed patients undergoing acute TRP depletion.
Thirty-eight drug-free patients with DSM-III-R major depression participated. Each patient underwent two randomized, double-blind TRP depletion tests, one sham and one active. At the estimated time of maximum TRP depletion, each patient received an i.v. infusion of TRP 100 mg/kg. Blood was obtained for serum cortisol, prolactin, and growth hormone. Mood was assessed using standardized rating scales.
The cortisol response to i.v. TRP was significantly greater during TRP depletion than during sham depletion. Depressive symptoms showed a tendency to decrease after i.v. TRP following active, but not sham, TRP depletion.
These findings are consistent with the present hypothesis and previous evidence that acute TRP depletion in drug-free depressed patients induces compensatory upregulation of postsynaptic 5-HT receptors. These changes are insufficient to serve as a means of effecting clinical improvement, but suggest that the antidepressant properties of rapid, marked manipulations of 5-HT function warrant further study.
In a double-blind study of 24 patients with endogenous depressiona group treated with clomipramine hydrochloride (chlorimipramine) plus tryptophan was compared with a group treated with clomipramine plus placebo. The sum of the ratings for depressed mood, suicidal intent, depressive thought content, and anxiety showed a more rapid improvement in the former group, the difference being already significant after 12 days of treatment. On the other hand, the ratings for retardation decreased about equally in both groups during the three-week treatment period. Side-effect ratings showed no significant increase but seemed to be partly influenced by the improvement of depressive symptoms. Plasma levels of clomipramine appeared to reach a plateau within a few days, whereas the monodesmethylated metabolite continued to rise for a longer period of time, and reached considerably higher values than the parent compound. In the tryptophan group the degree of improvement seemed to be positively correlated to these levels, suggesting that further improvement might have been reached in some patients by increasing the dose of clomipramine. The levels of 5-hydroxyindoleacetic acid in the cerebrospinal fluid appeared to be reduced by clomipramine administration. This effect was prevented by the additional treatment with tryptophan.
This paper reviews the evidence for a specific indoleamine deficiency in depression and the attempts to correct this suspected deficiency with serotonin precursors. It also presents the clinical and biochemical data on six patients with depression treated with L-5-HTP in a nonrandom, double-blind protocol. The oral administration of L5-HTP was associated with a rise in CSF5-HIAA, but only two of six patients studied had any decrease in depression ratings. 5-HTP was also shown to decrease urinary excretion of 17 hydroxycorticosteroids in twodepressed patients and three normal controls suggesting an interrelationship between serotonin metabolism and the pituitary adrenal system. This leads to the suggestion that in a postulated subgroup of depressed patients with pituitary adrenal hyperactivity and evidence of serotonin deficiency, L5-HTP deserves a further trial as an experimental treatment.
Serum levels of total L‐tryptophan (L‐TP) were determined in patients suffering from endogenous depression, randomly assigned to two groups, one treated with L‐TP (6 g daily) and unilateral ECT, the other with placebo and unilateral ECT. L‐TP treatment was initiated at least 1 day before the first ECT and terminated 4 days after the last ECT. The degree of amelioration in depressive symptomatology was measured by doctors', nurses' and patients' rating scales.
There was a close similarity in the levels of L‐TP concentration in the two groups before treatment (mean values 1.27 mg% and 1.28 mg%).
ECT seems not to alter the serum L‐TP levels, judging from the values before and during treatment in the placebo group.
During treatment, there was, as expected, a considerably higher L‐TP concentration in the L‐TP group (mean value 4.01 mg%).
The L‐TP concentrations were bimodally distributed in the L‐TP group. This bimodality was not correlated to clinical variables.
No relationship could be found between pretreatment L‐TP levels and depressive symptomatology. No evidence is therefore obtained that L‐TP levels are a pathogenic factor.
There was no correlation between initial L‐TP levels and residual symptomatology 4 days and 1 month after the last ECT. Thus the L‐TP levels before treatment seem not to be of value in predicting “responders” to L‐TP treatment combined with ECT or to ECT alone.
The levels of L‐TP during the treatment with L‐TP and ECT showed no relationship to residual symptomatology after the treatment. Thus the L‐TP levels do not seem to have a therapeutic significance when treating depressed patients with ECT.
With the aim of examining a possible influence on memory from L-tryptophan (L-TP), a double-blind comparison of the anterograde dysmnesic effect after a unilateral electroconvulsive therapy (ECT) series was carried out in depressive patients randomly assigned to two treatment groups, one receiving orally administered CTP (6 g daily) and ECT, the other placebo and ECT.
The groups were similar in a number of background variables and in degree of depression. Scores for three operationally defined memory variables, immediate memory (IMS), delayed memory (DMS) and forgetting (FS), were obtained before the ECT series and 4 days after, the patients being on L-TP treatment or placebo on both occasions. The results were as follows:
1. Before treatment there was a higher FS in one test (30 Word-Pair Test) and after treatment a higher FS in another test (30 Face Test) in the L-TP group than in the placebo group, both findings indicating an adverse influence of L-TP.
2. There were a number of correlations between serum L-TP concentration levels and memory variables, all implying a more adverse influence on memory with higher levels of L-TP.
The findings suggest that L-TP has a dysmnesic effect on memory in depressive patients treated with ECT, but they need to be confirmed before a negative influence of L-TP on memory can be considered definite.
Trial performed do not provide evidence for an antidepressant effect of 5‐HTP.
L‐TP, without interacting pharmaca, does not appear to be a well‐documented antidepressant. The only convincing evidence for L‐TP as an antidepressant is that L‐TP enhances the effect of MAOI.
The combination of electroconvulsive treatment (ECT) and i.v. L-tryptophan (T) was compared with ECT and saline in double-blind study comprising 20 patients with endogenous depression. No significant difference was found with regard to the number of ECT given nor in the rate of reduction of depressive symptoms. Except for a slight decrease of plasma total tryptophan in the palcepo group, no difference were found in plasma total and free tryptophan nor in the concentration of total tryptophan in the cerebrospinal fluid.
In two randomized double-blind controlled trials on 63 depressed female in-patients subject to recurrent affective disorder (bipolar and unipolar manic-depressive psychosis) lithium was shown to have major acute antidepressant effects. At the end of three weeks lithium produced more uniform improvement than did imipramine; lithium in combination with tryptophan (in the form of Optimax) was superior to tryptophan alone—the latter drug having no discernible antidepressant activity in this group of patients.
Lithium did not produce an antidepressant effect until the second and third week of both trials.
Thirty-eight in-patients with endogenous- and 20 in-patients with non-endogenous depression, took part in a multi-Centre 3-week double-blind trial where patients were randomly allocated to treatment with either 6 g L-tryptophan or 150 mg imipramine daily. Item analysis of Hamilton ratings, before the investigation and weekly during the trial period demonstrated few statistically different mean scores on individual items between the two treatment groups. After 3 weeks' treatment a statistically significant item mean reduction on the 0.1 % level was found in the item Agitation in favour of imipramine-treated, and in the item Work and Activities in favour of L-tryptophan-treated endogenously depressed patients. After 3 weeks' treatment a statistically significant item mean reduction on the 5 % level was found in the item Suicide in favour of imipramine-treated non-endogenously depressed patients.
The present study has shown that, after 3 weeks' treatment, imi-pramine and L-tryptophan has decreased the mean score on individual items of HRS in about the same degree.
In an intra-individual crossover trial depressed patients were treated with the 5-hydroxytryptamine (5-HT) precursor Gtryptophan (GTP) and unilateral ECT, or with unilateral ECT alone. The oral dose of L-TP was 6 g the day before ECT and 3 g on the day of ECT, 4 hours before the treatment. The seizure duration was measured on EEG records.
The time of the electrical stimulation needed to induce generalized seizures was similar for both treatment alternatives. Thus L-TP seems not to elevate the threshold to ECT-induced convulsions.
The mean duration of a seizure was significantly shorter when the patients were treated with L-TP + ECT than when treated with ECT alone. It is suggested that L-TP exerts an inhibitory influence on the ability to sustain epileptic activity.
Psychomotor skills were measured in depressed out-patients during three-week double-blind treatment with 1-tryptophan (16 patients; 0.5--1.0 g t.i.d.), doxepin (13 patients; 25--50 mg t.i.d.), or chlorimipramine (13 patients; 25--50 mg t.i.d). The effect of depression on psychomotor skills was evaluated by comparing the results from the pre-drug scores (29 patients) with the respective performances of a matched reference group (20 healthy volunteers). Coordination, reactive skills and attention were impaired in depressed patients. The reaction times roughly correlated with the severity of depression, assessed both subjectively and objectively. During treatment with doxepin or chlorimipramine, but not with 1-tryptophan, the choice reaction times were shortened. The change in reaction times correlated with the amelioration of depression. When compared with the other treatment groups, doxepin impaired coordination, attention and flicker fusion discrimination. It is suggested that depressed out-patients with marked symptoms should be warned about driving. Treatment with doxepin is a contraindication to driving during the first two weeks or up to the time when amelioration of symptoms is recorded.
Through a controlled double-blind study in 30 hospitalized patients affected with endogenous depression, the antidepressant action of the combination of nialamide+l-5-HTP has been evaluated and compared with a control group which only received nialamide (+ placebo). The patients treated with nialamide + l-5-HTP achieved a fuller recovery than those who were treated with nialamide alone. The treatment with nialamide + l-5-HTP proved to have a shorter delay of onset. Side effects showed no marked differences except for the orthostatic hypotension which was less apparent in those patients treated with nialamide + l-5-HTP.
L-tryptophan, the amino acid precursor of serotonin, was administered to 16 depressive patients in a double-blind study of its potential antidepressant efficacy. Antidepressant responses were observed in one of ten unipolar patients and in three of six bipolar patients. These results are discussed in the context of possible interactions of amines with electrolyte systems in the etiology of affective illness.
Synopsis
Depressed patients who were suitable for drug treatment were allocated randomly to treatment for four weeks with either amitriptyline in doses reaching 150 mg daily or with l-tryptophan in a maximal dose of 8 G daily. Both in-patients and out-patients were included. The trial was double-blind and ratings were made at the start of treatment and weekly for the subsequent four weeks: the patients were then followed for a further six months. Both groups of patients improved steadily over the course of four weeks and there were no marked differences between the treatment groups though there was some tendency for the improvement of the tryptophan-treated patients to fade between the third and fourth weeks. Within the tryptophan group anxious patients improved least. It is concluded that L-tryptophan probably has some antidepressive action in patients with depressive illness of moderate severity.
The amino acid precursors, levodopa and L-tryptophan, were given to a group of hospitalized depressed patients in a double-blind placebo controlled study. Relatively large doses were not associated with sufficient clinical improvement to allow the patients to leave the hospital. Previous studies using the precursor-load strategy have produced conflicting findings on the use of these compounds for depressed patients.
The authors assessed the clinical antidepressant effects of L-tryptophan given alone and in combination with L-dopa in 12 patients with a diagnosis of primary affective disorder; Preliminary results did not demonstrate an antidepressant response when L-dopa was combined with L-tryptophan. Also, the results did not support the catecholamine or biogenic amine hypotheses of affective disorder.
Synopsis
Depressed patients (unipolar) were given one of the following combinations in an attempt to test aspects of the ‘amine hypothesis’ and to find a preferential therapy: (1) clomipramine; (2) clomipramine and tryptophan; (3) desipramine and clomipramine, and (4) desipramine and tryptophan. Treatment (2) should have given optimal potentiation of 5-HT neurones and (3) and (4) should have acted similarly on both serotoninergic and adrenergic pathways. In no group was there any evidence of accelerated recovery, indicating that the process of conversion to normal mood may be more complex than suggested by most versions of the amine hypothesis.
Serotonergic mechanisms have been implicated in the pathophysiology of depression and in the neuropharmacology of antidepressant treatment. One measure of central serotonergic function is the prolactin (PRL) response to IV L-tryptophan (L-TRP). We used the L-TRP test to assess the role of serotonin in the mechanism of action of lithium augmentation in refractory major depression. Twenty-six patients with antidepressant-refractory major depression each received three L-TRP tests (after 2 weeks of placebo, after 4 weeks of active primary antidepressant, and after 1 week of lithium augmentation). Primary antidepressant treatment did not increase the PRL response, but lithium augmentation resulted in a statistically significant increase in PRL response as compared to both placebo pretreatment (P less than 0.04) and antidepressant treatment alone (P less than 0.025). This study supports a role for serotonergic mechanisms in the action of lithium augmentation.
H.M. van Praag has been suggesting a reappraisal of syndromes in psychiatry for over 20 years. He has tried to define syndromes originating from the same biochemical disorder. He has denoted this concept as 'functional psychopathology'. As an example of such a functional syndrome, he has cited the serotonin-shortage syndrome which unifies various psychiatric symptoms under a new point of view. The treatment of the serotonin-shortage syndrome is best served by psychopharmaca which raise the metabolism of serotonin in the synaptic cleft, e.g. the selective serotonin re-uptake inhibitors. Borrowing F. Freyhan's concept of 'target symptoms', one can now speak of 'functional target syndromes', within the frame of functional psychopathology.
To identify chemical contaminant(s) associated with eosinophilia-myalgia syndrome (EMS), case and control lots of tryptophan were analyzed by HPLC with both UV and FL detection. Numerous contaminant peaks appeared on the chromatograms and some of them were identified as 5-hydroxytryptophan, indol aldehyde, indol, etc; from the retention time of authentic compounds. Among these, three peaks were significantly associated with case lots. One corresponds to di-tryptophan aminal of aldehyde (peak E). Others are unknown contaminants, UV-5 (FL-7) and UV-28 (FL-36). The structural elucidation and toxicological implication of UV-5 (FL-7) are currently in progress.
The ratios of total and free plasma tryptophan to the sum of five large neutral amino acids (LNAAs) were found to be significantly lower in a group of 16 depressed inpatients compared to nine normal subjects after oral loading with L-tryptophan. The group differences in these ratios were significant before, and 2 weeks after starting treatment with a tricyclic antidepressant. Plasma tryptophan ratios and severity of depression were not significantly correlated.
Serotonin has been implicated in the etiology of seasonal affective disorder (SAD). The authors compared the effect of the serotonergic precursor L-tryptophan, placebo, and artificial evening light on 13 SAD sufferers. L-Tryptophan and light were associated with greater improvement than was placebo, but the antidepressant effects of L-tryptophan and light were not significantly different.
1. Non-responders to cyclic antidepressants were treated with the MAO-inhibitor tranylcypromine in two studies: the first study in an open comparison with L-5-hydroxytryptophan (L-5HTP), the second study in a double blind comparison with nomifensine. 2. While both L-5HTP and nomifensine appeared to be ineffective, tranylcypromine was effective in 26 out of 45 patients. 3. It is concluded that besides ECT also MAO-inhibitors such as tranylcypromine are an effective alternative for depressed patients not responding to cyclic antidepressants.
Alcoholic male inpatients (N = 76) served as subjects in this study which examined the effect of L-tryptophan on depressive state and sleep disturbance. All subjects were residents of a 6-week alcohol treatment program at a Veterans Administration Medical Center. Subjects' degree of depression (Zung's Depression Scale) and sleep satisfaction (Webb's Post-Sleep Inventory) were measured four times during the study, just prior to and following ingestion of a substance that was either 3 gms L-tryptophan or 3 gms of an identical-appearing placebo. Subjects in the L-tryptophan/placebo condition received the active substance for 4 days followed by the placebo with a 4-day washout period in between. A second group of subjects received the same regimen of reverse order and a third received placebos on both occasions. There were two additional control groups that received no substances. All subjects in the study reported decreased levels of depression due to nonspecific treatment effects. The subjects who took L-tryptophan in either sequence reported even lower levels of depression. Sleep disturbance was not affected by L-tryptophan since it was barely present when the study began. A phenomenon referred to as the interval effect is discussed and an alternative explanation for this effect is offered.
Fifty elderly patients (mean age, 68 years) affected by depression were treated with a combination (P3007) containing 3 mg of dihydroergocristine and 100 mg of levo-5-hydroxytryptophan or placebo for 60 days in a double-blind trial. Efficacy of treatment was evaluated by means of neuropsychic tests and rating scales for depression before treatment and after 30 and 60 days. Patients treated with the drug combination showed significant improvements in their depressive state and psychic performance, whereas no change was observed in patients receiving placebo. The treatment was well tolerated.
A trial is described of new therapeutic approaches in treatment-resistant chronic depression. Phenelzine, L-tryptophan and lithium ("5HT-cocktail") was used as the major pharmacological strategy, and a regime aimed at reducing vanadium concentrations was added in the second part of the trial. Patients were randomly assigned to cognitive behaviour therapy in addition. All but 1 of the patients who ultimately entered the trial were unipolar depressives; 2 bipolar