Effect of 5-Hydroxytryptophan on Fatigue in Quiescent Inflammatory Bowel Disease: A Randomized Controlled Trial.

BACKGROUND & AIMS: Fatigue is highly prevalent among patients with inflammatory bowel disease (IBD), and only limited treatment options are available. Based on the hypothetical link between low serum tryptophan concentrations and fatigue, we determined the effect of 5-hydroxytryptophan supplementation on fatigue in patients with inactive IBD. METHODS: A multicenter randomized controlled trial was performed at 13 Belgian hospitals, including 166 patients with IBD in remission but experiencing fatigue, defined by a fatigue visual analog scale (fVAS) score of ≥5. Patients were treated in a crossover manner with 100 mg oral 5-hydroxytryptophan or placebo twice daily for 2 consecutive periods of 8 weeks. The primary end point was the proportion of patients reaching a ≥20% reduction in fVAS after 8 weeks of intervention. Secondary outcomes included changes in serum tryptophan metabolites, Functional Assessment of Chronic Illness Therapy Fatigue scale, and scores for depression, anxiety, and stress. The effect of the intervention on the outcomes was evaluated by linear mixed modeling. RESULTS: During 5-hydroxytryptophan treatment, a significant increase in serum 5-hydroxytryptophan (estimated mean difference, 52.66 ng/mL; 95% confidence interval [CI], 39.34-65.98 ng/mL; P < .001) and serotonin (3.0 ng/mL; 95 CI, 1.97-4.03 ng/mL; P < .001) levels was observed compared with placebo. The proportion of patients reaching ≥20% reduction in fVAS was similar in placebo- (37.6%) and 5-hydroxytryptophan (35.6%)-treated patients (P = .830). The fVAS reduction (-0.18; 95% CI, -0.81 to 0.46; P = .581) and Functional Assessment of Chronic Illness Therapy Fatigue scale increase (0.68; 95% CI, -2.37 to 3.73; P = .660) were both comparable between 5-hydroxytryptophan and placebo treatment as well as changes in depression, anxiety, and stress scores. CONCLUSIONS: Despite a significant increase in serum 5-hydroxytryptophan and serotonin levels, oral 5-hydroxytryptophan did not modulate IBD-related fatigue better than placebo. (Trial Registration: Belgian Federal Agency for Medication and Health Products, EudraCT number: 2017-005059-10 and ClinicalTrials.gov: NCT03574948, https://clinicaltrials.gov/ct2/show/NCT03574948.).

5-Hydroxytryptophan as adjuvant therapy in treatment of moderate to severe obsessive-compulsive disorder: a double-blind randomized trial with placebo control.

On the basis of numerous previous studies, the serotonergic system plays a role in the pathogenesis of obsessive-compulsive disorder (OCD) and effective agents in this pathway, such as 5-hydroxytryptophan, can potentially contribute to treatment of patients with this disorder. Evaluating the efficacy of 5-hydroxytryptophan in treating OCD was the aim of the present randomized, double-blind, placebo-controlled 12-week trial. In a 12-week, randomized double-blind study, 60 patients with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of moderate to severe OCD and a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score of >21 were randomly assigned to receive either fluoxetine plus placebo or fluoxetine plus 5-hydroxytryptophan (100 mg twice daily). All patients, regardless of their treatment group, received fluoxetine at 20 mg/day for the initial 4 weeks of the study followed by 60 mg/day of fluoxetine for the rest of the trial course. Symptoms were assessed using the Y-BOCS at baseline and weeks 4, 8 and 12. General linear model repeated measure showed significant effects for time × treatment interaction on total Y-BOCS (F = 12.07, df = 2.29, P-value <0.001), obsession (F = 8.25, df = 1.91, P-value = 0.001) and compulsion subscale scores (F = 6.64, df = 2.01, P-value = 0.002). 5-Hydroxytryptophan augmentation therapy demonstrated higher partial and complete treatment response rate (P = 0.032 and P = 0.001, respectively) according to the Y-BOCS total scores. The results of this study confirm that 5-hydroxytryptophan may be effective as an augmentative agent in treatment of moderate-to-severe OCD.

Physicochemical Properties of Zwitterionic Drugs in Therapy.

In solution, amphoteric compounds exist in anionic, uncharged, zwitterionic and cationic forms. The importance of zwitterionic drugs is currently under-represented in the literature. Herein, the acid-base parameters, lipophilicity and solubility of such compounds are discussed to deepen the molecular-level understanding of their pharmacokinetic and pharmacodynamic behaviour. Our recent studies show there are many drug molecules, including thyroid hormones and 5-hydroxytryptophan, the precursor of the neurotransmitter serotonin, for which the contribution of the zwitterionic microspecies to the overall lipophilicity exceeds that of the uncharged one, which is of higher individual lipophilicity, but occurs in much lower concentration. The second part of the minireview highlights the most important zwitterionic compounds in therapy, grouped into therapeutic classes. The importance of the charge of the molecules is emphasized in their binding to the target molecules.

Efficacy and safety of 5-Hydroxytryptophan on levodopa-induced motor complications in Parkinson's disease: A preliminary finding.

BACKGROUND AND PURPOSE: Several studies have indicated that altered serotonergic neurotransmission may contribute to the motor features commonly associated with Parkinson's disease (PD) drug treatment such as levodopa-induced dyskinesias (LIDs). 5-Hydroxytryptophan (5-HTP) is the immediate precursor of serotonin. We have recently demonstrated that 5-HTP produces significant antidyskinetic effects in a rat model of PD. To date, there has been inconsistent research on the use of 5-HTP in PD. The purpose of this study was to compare the effects of 5-HTP versus placebo on levodopa-induced motor complications in PD patients. MATERIAL AND METHODS: A single-center, randomized, double-blind placebo-controlled cross-over study was performed. A total of 12 PD patients were diagnosed with LIDs and motor fluctuactions and subsequently were randomized to intervention; 11 subjects completed the entire 16-week protocol. Patients received placebo or 50 mg of 5-HTP daily in a cross-over design over a period of 4 weeks. For the assessment of efficacy on the motor functions and motor complications, the UPDRS (parts III and IV), Unified Dyskinesia Rating Scale (UDysRS), Wearing-Off Questionnaire (WOQ-19) and the self-reported 24-h home dyskinesia diaries were obtained at baseline and weeks 4, 8, 12 and 16 (T-end). RESULTS: Repeated measures analysis revealed a significant improvement of LIDs during the 50 mg 5-HTP treatment as assessed by the UDysRS and UPDRS-IV scores. CONCLUSIONS: This study provides preliminary evidence of clinical benefit of 5-HTP against LIDs in PD. Larger studies with a longer treatment duration and a wider range of doses are warranted to corroborate these findings.

Efficacy and safety of 5-hydroxytryptophan on depression and apathy in Parkinson's disease: a preliminary finding.

BACKGROUND AND PURPOSE: Several studies have indicated that altered serotonergic neurotransmission may contribute to non-motor features commonly associated with Parkinson's disease (PD) such as apathy and depression. 5-hydroxytryptophan (5-HTP) is the intermediate metabolite of L-tryptophan in the production of serotonin. To date, there has been inconsistent research on the use of 5-HTP in PD. The purpose of this study was to compare the effects of 5-HTP with those of placebo on apathy and depressive symptoms in patients with PD. METHODS: A single-center, randomized, double-blind placebo-controlled cross-over trial was employed; 25 individuals were subsequently enrolled into the study. Patients received placebo and 50 mg of 5-HTP daily over a period of 4 weeks. For the assessment of efficacy on depressive and apathy symptoms the Beck Depression Inventory-II (BDI-II), Hamilton Depression Rating Scale (HDRS) and Apathy Scale (AS) were respectively administered at screening, baseline and weeks 4, 8, 12 and 16. Primary efficacy outcomes were the comparison of 5-HTP to placebo in mean change from baseline to weeks 4, 8, 12 and 16 in total score on the AS, BDI-II and HDRS. RESULTS: Repeated-measures analysis revealed a significant improvement of depressive symptoms during the 50-mg 5-HTP treatment compared with placebo as assessed by the HDRS. No effect of 5-HTP was seen on apathy symptoms assessed by the AS. CONCLUSIONS: This study provides preliminary evidence of clinical benefit of 5-HTP for treating depressive symptoms in PD. Larger studies with a longer treatment duration are needed to corroborate these early findings.

Effects of 5-hydroxytryptophan on distinct types of depression: a systematic review and meta-analysis.

CONTEXT: Serotonergic dysfunction, including reduced central serotonin levels, is associated with different psychiatric syndromes, including depression. As a serotonin precursor, 5-hydroxytryptophan has long been used as a nonpharmacological treatment for depression. OBJECTIVE: A systematic review and meta-analysis was conducted to determine the antidepressant effects of 5-hydroxytryptophan in depressed patients. DATA SOURCES: MEDLINE (via PubMed) and Google Scholar were searched from inception to May 2018. DATA EXTRACTION: Thirteen investigations were included in the systematic review (using PRISMA guidelines), and 7 in the full meta-analysis (pre-registered on PROSPERO: CRD42018104415). DATA ANALYSIS: Analyses revealed a depression remission rate of 0.65 (95% confidence interval [CI], 0.55-0.78; remission rate [k] = 13), and this was confirmed by the questionnaire results, which revealed a large Hedges' g (1.11; 95%CI, 0.53-1.69). Methodological variability (in treatment duration, type of depression studied, experimental design, 5-hydroxytryptophan dosage) contributes to heterogeneity in the results (I2 = 76%, τ2 = 0.379). In addition, the OHAT (Office of Health Assessment and Translation risk of bias rating) tool suggested that, on the whole, current studies are relatively weak (few include placebo groups). CONCLUSION: Further trials should overcome these limitations by using placebo-controlled studies that include patients with well-defined depression diagnoses, along with strong characterization of psychological and physiological patient characteristics.

5-hydroxytryptophan attenuates imiquimod-induced psoriasiform dermatitis probably through inhibition of IL-17A production and keratinocyte activation.

Psoriasis is a chronic autoimmune disease with keratinocyte activation and lymphocyte infiltration in the skin. Our previous study found that 5-hydroxytryptophan (5(OH)Trp), a tryptophan metabolite, alleviated collagen-induced arthritis and suppressed cytokine production. In this study, we evaluated the effects of 5(OH)Trp in a mouse model for psoriasiform dermatitis, induced by imiquimod (IMQ). We showed that 5(OH)Trp significantly reduced the cumulative scores, epidermal thickness and ki-67 expression in the skin. In addition, 5(OH)Trp decreased local and systemic inflammation. Moreover, 5(OH)Trp significantly inhibited keratinocyte activation with decrease in IL-6 production and p-Erk1/2 and p-STAT3 expression. 5(OH)Trp also inhibited the differentiation of IFN-γ- and IL-17A-expressing CD4+ T cells and related cytokine production (TNF-α, IL-6, IL-17A and IFN-γ) in splenocytes. In conclusion, 5(OH)Trp can inhibit imiquimod-induced psoriasiform dermatitis in mice and inhibit activation in keratinocytes and splenocytes.

Combination pharmacotherapy for the treatment of fibromyalgia in adults.

BACKGROUND: Fibromyalgia is a chronic widespread pain condition affecting millions of people worldwide. Current pharmacotherapies are often ineffective and poorly tolerated. Combining different agents could provide superior pain relief and possibly also fewer side effects. OBJECTIVES: To assess the efficacy, safety, and tolerability of combination pharmacotherapy compared to monotherapy or placebo, or both, for the treatment of fibromyalgia pain in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase to September 2017. We also searched reference lists of other reviews and trials registries. SELECTION CRITERIA: Double-blind, randomised controlled trials comparing combinations of two or more drugs to placebo or other comparators, or both, for the treatment of fibromyalgia pain. DATA COLLECTION AND ANALYSIS: From all studies, we extracted data on: participant-reported pain relief of 30% or 50% or greater; patient global impression of clinical change (PGIC) much or very much improved or very much improved; any other pain-related outcome of improvement; withdrawals (lack of efficacy, adverse events), participants experiencing any adverse event, serious adverse events, and specific adverse events (e.g. somnolence and dizziness). The primary comparison was between combination and one or all single-agent comparators. We also assessed the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We identified 16 studies with 1474 participants. Three studies combined a non-steroidal anti-inflammatory drug (NSAID) with a benzodiazepine (306 participants); two combined amitriptyline with fluoxetine (89 participants); two combined amitriptyline with a different agent (92 participants); two combined melatonin with an antidepressant (164 participants); one combined carisoprodol, paracetamol (acetaminophen), and caffeine (58 participants); one combined tramadol and paracetamol (acetaminophen) (315 participants); one combined malic acid and magnesium (24 participants); one combined a monoamine oxidase inhibitor with 5-hydroxytryptophan (200 participants); and one combined pregabalin with duloxetine (41 participants). Six studies compared the combination of multiple agents with each component alone and with inactive placebo; three studies compared combination pharmacotherapy with each individual component but did not include an inactive placebo group; two studies compared the combination of two agents with only one of the agents alone; and three studies compared the combination of two or more agents only with inactive placebo.Heterogeneity among studies in terms of class of agents evaluated, specific combinations used, outcomes reported, and doses given prevented any meta-analysis. None of the combinations of drugs found provided sufficient data for analysis compared with placebo or other comparators for our preferred outcomes. We therefore provide a narrative description of results. There was no or inadequate evidence in any comparison for primary and secondary outcomes. Two studies only reported any primary outcomes of interest (patient-reported pain relief of 30%, or 50%, or greater). For each 'Risk of bias' item, only half or fewer of studies had unequivocal low risk of bias. Small size and selective reporting were common as high risk of bias.Our GRADE assessment was therefore very low for primary outcomes of pain relief of 30% or 50% or greater, PGIC much or very much improved or very much improved, any pain-related outcome, participants experiencing any adverse event, any serious adverse event, or withdrawing because of an adverse event.Three studies found some evidence that combination pharmacotherapy reduced pain compared to monotherapy; these trials tested three different combinations: melatonin and amitriptyline, fluoxetine and amitriptyline, and pregabalin and duloxetine. Adverse events experienced by participants were not serious, and where they were reported (in 12 out of 16 studies), all participants experienced them, regardless of treatment. Common adverse events were nausea, dizziness, somnolence, and headache. AUTHORS' CONCLUSIONS: There are few, large, high-quality trials comparing combination pharmacotherapy with monotherapy for fibromyalgia, consequently limiting evidence to support or refute the use of combination pharmacotherapy for fibromyalgia.

Improvement of Self-Injury With Dopamine and Serotonin Replacement Therapy in a Patient With a Hemizygous PAK3 Mutation: A New Therapeutic Strategy for Neuropsychiatric Features of an Intellectual Disability Syndrome.

PAK3-related intellectual disability is caused by mutations in the gene encoding the p21-activated kinase (PAK) protein. It is characterized by mild to moderate cognitive impairment, micro/normocephaly, and a neurobehavioral phenotype characterized by short attention span, anxiety, restlessness, aggression, and self-abusive behaviors. The authors report a patient with a novel PAK3 mutation, who presented with intellectual disability, severe automutilation, and epilepsy. His magnetic resonance imaging changes were most likely secondary to lacerations from parenchymal contusions. His behavior was difficult to manage with behavior interventions or multiple medications. After finding low levels of dopamine and borderline low serotonin metabolites in the spinal fluid, treatment with low dose L-dopa/carbidopa and 5-hydroxytryptophan significantly improved his self-injurious behavior. This is the first case of PAK3-related intellectual disability presenting with severe self-injury with improvement following treatment. The patient's response to neurotransmitter replacement therapy raises the question if this treatment intervention might help other individuals suffering genetic syndromes and self-injurious behaviors.

An Open-Label Pilot Study of Combined Augmentation With Creatine Monohydrate and 5-Hydroxytryptophan for Selective Serotonin Reuptake Inhibitor- or Serotonin-Norepinephrine Reuptake Inhibitor-Resistant Depression in Adult Women.

PURPOSE: Many women with major depressive disorder (MDD) respond inadequately to standard treatments. Augmentation of conventional antidepressants with creatine monohydrate and 5-hydroxytryptophan (5-HTP) could correct deficits in serotonin production and brain bioenergetics associated with depression in women, yielding synergistic benefit. We describe an open-label study of 5-HTP and creatine augmentation in women with MDD who had failed selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) monotherapy. METHODS: Fifteen women who were adequately adherent to an SSRI or SNRI and currently experiencing MDD, with a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or higher, were treated with 5 g of creatine monohydrate daily and 100 mg of 5-HTP twice daily for 8 weeks, with 4 weeks of posttreatment follow-up. The primary outcome was change in mean HAM-D scores. RESULTS: Mean HAM-D scores declined from 18.9 (SD, 2.5) at pretreatment visits to 7.5 (SD, 4.4) (P < 0.00001), a decrease of 60%. Participants did not experience any serious treatment-related adverse events. CONCLUSIONS: Combination treatment with creatine and 5-HTP may represent an effective augmentation strategy for women with SSRI- or SNRI-resistant depression. Given the limitations of this small, open-label trial, future study in randomized, placebo-controlled trials is warranted.

Improved strength on 5-hydroxytryptophan and carbidopa in spinal cord atrophy.

There is ample evidence of an important role of descending serotonergic projections in modulating spinal motor neuron activation and firing, and experimental studies suggest that 5-HT receptor stimulation can improve motor function after spinal cord injury; however, relevant clinical data is sorely lacking. We describe two sisters with hemiplegic migraine, low CSF and platelet serotonin levels, and progressive spastic paraparesis associated with profound spinal cord atrophy whose lower extremity strength and ambulation responded to a precursor replacement strategy (5-hydroxytryptophan and carbidopa administration), an approach that may have broader applicability in myelopathies of diverse etiology where descending serotonergic projections are compromised.

5-Hydroxytryptophan, a precursor for serotonin synthesis, reduces seizure-induced respiratory arrest.

OBJECTIVE: The DBA/1 mouse is a relevant animal model of sudden unexpected death in epilepsy (SUDEP), as it exhibits seizure-induced respiratory arrest (S-IRA) evoked by acoustic stimulation, followed by cardiac arrhythmia and death. Defects in serotonergic neurotransmission may contribute to S-IRA. The tryptophan hydroxylase-2 (TPH2) enzyme converts L-tryptophan to 5-hydroxytryptophan (5-HTP), a precursor for central nervous system (CNS) serotonin (5-HT) synthesis; and DBA/1 mice have a polymorphism that decreases TPH2 activity. We, therefore, hypothesized that supplementation with 5-HTP may bypass TPH2 and suppress S-IRA in DBA/1 mice. METHODS: TPH2 expression was examined by Western blot in the brainstem of DBA/1 and C57BL/6J mice both with and without acoustic stimulation. Changes in breathing and cardiac electrical activity in DBA/1 and C57BL/6J mice that incurred sudden death during generalized seizures evoked by pentylenetetrazole (PTZ) were studied by plethysmography and electrocardiography. The effect of 5-HTP administration on seizure-induced mortality evoked by acoustic stimulation or by PTZ was investigated in DBA/1 mice. RESULTS: Repetitive acoustic stimulation resulted in reduced TPH2 protein in the brainstem of DBA/1 mice as compared with C57BL/6J mice. S-IRA evoked by acoustic stimulation in DBA/1 mice was significantly reduced by 5-HTP. Following S-IRA, cardiac electrical activity could be detected for minutes before terminal asystole and death in both DBA/1 and C57BL/6J mice after PTZ treatment. The incidence of S-IRA by PTZ administration was greater in DBA/1 than in C57BL/6J mice, and administration of 5-HTP also significantly reduced S-IRA by PTZ in DBA/1 mice. SIGNIFICANCE: Our data suggest that S-IRA is the primary event leading to death incurred in most DBA/1 and some C57BL/6J mice during PTZ-evoked seizures. Suppression of S-IRA by 5-HTP suggests that 5-HT transmission contributes to the pathophysiology of S-IRA, and that 5-HTP, an over-the-counter supplement available for human consumption, may be clinically useful in preventing SUDEP.

What Is Not in the Name? Dopa-Responsive Dystonia May Respond to More Than L-Dopa.

BACKGROUND: Classic L-dopa-responsive dystonia is characterized by the triad of dystonia, diurnal fluctuation of signs, and dramatic response of signs to low-dose L-dopa therapy. Dopa-responsive dystonia succinctly summarizes the relevant clinical features. However, literal application of this label or consideration of dopa-responsive dystonia as a diagnostic end without molecular and/or biochemical definition may contribute to misdiagnosis and incomplete treatment in dopa-responsive conditions that impair synthesis of monoamine neurotransmitters besides dopamine. PATIENT DESCRIPTION: We describe and provide video for twin patients with a rare form of dopa-responsive dystonia due to sepiapterin reductase deficiency. As is typical in dopa-responsive dystonia, these patients displayed dramatic improvement with L-dopa/carbidopa therapy. However, treatment was suboptimal until 5-hydroxytryptophan was added to address their serotonergic deficit. DISCUSSION: Our report highlights the limitations of the dopa-responsive dystonia label and increases awareness of sepiapterin reductase deficiency and other conditions that may present as dopa-responsive dystonia. We provide a diagnostic and therapeutic approach to guide the clinician in evaluating and treating individuals with dopa-responsive dystonia.

Natural products of relevance in the prevention and supportive treatment of depression.

The use of herbs or their parts: leaves, roots, rhizomes, flowers, seeds, natural strains, as well as extracts or isolated metabolites is becoming more and more popular. Natural remedies not only act prophylactically, but also help to alleviate symptoms of many diseases and enhance the overall functioning of the internal organs. Many raw materials of natural origin plays a role in treatment of health problems, and also in case of serious diseases such as depression. Depression (affective disorder) now affects about 10% of the population, but in next few years due to the development of civilization and increasing pace of life, the probable number of people suffering from this disease can grow rapidly. Natural raw materials such as Bacopa monnieri, Crocus sativus, Eleutherococcus senticosus, Griffonia simplicifolia, Hypericum perforatum, Sceletium tortuosum, Piper methysticum, Rhodiola rosea, Aspalathus linearis, Camellia sinensis, Ficus carica, Lycium chinense, Cuminum cyminum, Panax Ginseng can effectively assist the prevention and treatment of depression. Daily diet may also have positive effect in prevention of this disease. It was found that 5-hydroxy-L-tryptophan, L-tryptophan (which are precursors of serotonin in the CNS), omega-3 fatty acids and anthranilic acid (vitamin L1) are able to improve mood. L-Tryptophan, 5-hydroxy-L-tryptophan are present in the largest quantities in the fruiting bodies of edible mushrooms. Omega-3 fatty acids are found in the flesh of fish, walnuts, soybeans, beans and chicken egg protein, while the anthranilic acid is commonly found in plants.

The Successful Treatment of Opioid Withdrawal-Induced Refractory Muscle Spasms with 5-HTP in a Patient Intolerant to Clonidine.

Instituting drug holidays for chronic opioid using patients is becoming commonplace for pain practitioners initiating procedures such as intrathecal pump or spinal cord stimulator trials. As such, pain practitioners need to be adept in their management of acute opioid withdrawal. Successfully weaning an opioid dependent patient off of chronic opioids requires a thorough knowledge of the available adjuvants to assist in this process. However, that selection can become exhausted by adjuvant side effects or by ineffective attenuation of opioid withdrawal symptoms. In that case, novel drugs, or novel application of currently available medications must be sought after to assist in the drug holiday. We present a case in which refractory muscle spasms secondary to opioid withdrawal were successfully treated with an over-the-counter supplement that is not typically used for the attenuation of opioid withdrawal symptoms. In a patient intolerant to the side effects of clonidine, we were able to successfully wean chronic opiates by treating refractory muscle spasms with the serotonin precursor, 5-hydroxytryptophan (5-HTP). We hypothesize that our success with this medication gives further credence to the role of serotonin in opioid withdrawal somatic symptomatology, and supports the need for future research to clarify the role of serotonin precursors or serotonin modulating drugs as potential alternatives in those unable to follow standard treatment protocols.

Diagnosis, treatment and follow-up of patients with tetrahydrobiopterin deficiency in Shandong province, China.

OBJECTIVES: To summarize the clinical and biochemical data, mutation analysis, treatment, outcome and the follow-up data of patients with BH4 deficiency from 2004 to 2012 in Shandong province, China. METHODS: We analyzed the clinical, biochemical and treatment data of 40 patients with BH4 deficiency. Urinary neopterin and biopterin were analyzed. Further BH4 loading tests were performed in suspected patients with abnormal urinary pterin profiles. The patients with BH4 deficiency were treated with BH4 and neurotransmitter after diagnosis. Blood phenylalanine level, clinical symptoms and mental development were followed up. RESULTS: 40 cases with BH4 deficiency were identified and all classified as PTPS deficiency between 2004 and 2012 in Shandong province, China. They were diagnosed at the age of 20d - 41m and most patients received treatment with BH4, l-dopa and 5-HTP after diagnosis. Seven different mutations (P87S, K91R, T106M, D96N, N52S, S21R, and L127F) were detected in 11 patients. But outcome assessments were not always available. We obtained 19 records of DQ/IQ assessment. In 9 patients (7 early and 2 late diagnosed) no development delay is observed, while in 10 patients (8 early and 2 late diagnosed) development was delayed. CONCLUSIONS: Our study emphasized that screening for BH4 deficiency should be carried out in all patients with HPA in order to minimize misdiagnosis. Although the outcomes of BH4 deficiency are highly variable, early diagnosis and treatment is essential for good outcomes.

5-Hydroxy-tryptophan for the treatment of L-DOPA-induced dyskinesia in the rat Parkinson's disease model.

The serotonin system has recently emerged as an important player in the appearance of L-DOPA-induced dyskinesia (LID) in experimental models of Parkinson's disease, as it provides an unregulated source of L-DOPA-derived dopamine release in the dopamine-depleted striatum. Accordingly, toxin lesion or pharmacological silencing of serotonin neurons suppressed LID in the rat and monkey models of Parkinson's disease. However, 5-HT1 receptor agonists were also found to partially reduce the therapeutic effect of L-DOPA. In this study, we evaluated whether enhancement of the serotonin tone induced by the administration of the serotonin precursor 5-hydroxy-tryptophan (5-HTP) could affect induction and expression of LID, as well as the therapeutic effect of L-DOPA, in 6-OHDA-lesioned rats. Drug naïve and L-DOPA-primed 6-OHDA-lesioned rats were chronically treated with a daily injection of L-DOPA (6 mg/kg plus benserazide, s.c.) alone, or in combination with 5-HTP (24-48 mg/kg, i.p.). The abnormal involuntary movements (AIMs) test, as well as the stepping and the motor activity tests, were performed during the chronic treatments. Results showed that 5-HTP reduced the appearance of LID of about 50% at both tested doses. A partial reduction of the therapeutic effect of L-DOPA was seen with the higher but not with the lower dose of 5-HTP. 5-HTP 24 mg/kg was also able to reduce the expression of dyskinesia in L-DOPA-primed dyskinetic rats, to a similar extent than in L-DOPA-primed rats. Importantly, the antidyskinetic effect of 5-HTP 24 mg/kg does not appear to be due to a competition with L-DOPA for crossing the blood-brain barrier; in fact, similar L-DOPA striatal levels were found in L-DOPA only and L-DOPA plus 5-HTP 24 mg/kg treated animals. These data further confirm the involvement of the serotonin system in the appearance of LID, and suggest that 5-HTP may be useful to counteract the appearance of dyskinesia in Parkinson's disease patients.

Mood disorders in youth: exercise, light therapy, and pharmacologic complementary and integrative approaches.

The therapeutic value of physical exercise, bright light therapy and dawn simulation, and several pharmacologic treatments, including hypericum (St. John's wort), S-adenosylmethionine, and 5-hydroxytryptophan, are reviewed, with a focus on their use for treating major depressive disorder in children and adolescents and also for alleviating depressed mood in the general (nonclinical) population of youth. For each treatment discussed, all published randomized, double-blind, placebo-controlled trials are summarized, along with some additional selected studies. Nutritional psychopharmacology and several other approaches to treating depression will be presented in an upcoming volume in the Child and Adolescent Psychiatric Clinics of North America.

Comparative study of efficacy of l-5-hydroxytryptophan and fluoxetine in patients presenting with first depressive episode.

INTRODUCTION: Role of l-5-hydroxytryptophan (l-5-HTP) in depression is relatively less studied but the literature has shown its robust role in depression. The present randomized double blind study was undertaken to assess the role of l-5-HTP as an antidepressant and to compare its antidepressant efficacy with fluoxetine in first depressive episode patients of Indian population. METHODS: A total of 70 patients of first depressive episode, all of whom were diagnosed with ICD-10 criteria, were recruited but only 60 patients completed the study and were randomly divided into two groups, receiving l-5-HTP and fluoxetine, respectively, for a period of 8weeks. All patients were administered Hamilton Rating Scale for Depression (HAM-D) to assess severity of depression at baseline, 2weeks, 4weeks and 8weeks. The efficacy of treatment was assessed by comparing HAM-D scores obtained at these examinations with the baseline examination; final evaluation of both efficacy and tolerance was assessed using the Clinical Global Impression (CGI) scale at the end of study. RESULTS: Both treatment groups showed significant and nearly equal reduction in HAM-D scores beginning at week two and continuing through week eight. Twenty-two patients (73.33%) in the l-5-HTP group and 24 patients (80%) in the fluoxetine group showed positive response at the end of the study. CONCLUSION: l-5-HTP has definitely got antidepressant effect in patients of depression. Antidepressant effect was seen within 2weeks of treatment and was apparent in all degrees of depression. The therapeutic efficacy of l-5-HTP was considered as equal to that of fluoxetine.