Tryptophan lessens reserpine induced anxiety, depression and memory impairment by modulating oxidative stress and serotonergic activity.

Reserpine (Res)-induced depletion of monoamines and altered neurotransmission and produces oxidative stress. Tryptophan (TRP) regulated the serotonin neurotransmission. Because systemically injected Res induced behavioral deficits and oxidative stress, while, dietary components prevented these adverse effects, we used TRP a pharmacological tool to prevent Res- induced changes in behavior, memory impairments, oxidative stress and regulation of serotonin neurotransmission in rats. Anxiolytic, antidepressant, cognitive functions, lipid peroxidation, antioxidant enzymes serotonin metabolism were studied in Res and vehicle treated animals following administration of 50 and 100 mg/ml/kg of tryptophan. Following administration of TRP [50 and 100mg/ml/kg], Res induced anxiety-and/or depression like behaviors normalized. Res-induced impaired cognitive function and increased acetylcholinesterase activity also improved following administration of TRP at both doses. Res induced increased brains' malondialdehyde (MDA) and decreased antioxidant enzymes activity also normalized by TRP. Res-induced decreased 5-HT metabolism also regulated by administration of TRP at both doses. In conclusion it can be recommended that administration/supplementation of TRP in daily life can aid in battling the anxiety, depression, modulating serotonergic activity and oxidative stress. Study also exhibits the anti-acetylcholinesterase role of TRP which may be possible reason for improved cognition following stress situation.

From forest to pharmacy: Should we be depressed about a sustainable Griffonia simplicifolia (Fabaceae) seed supply chain?

ETHNOPHARMACOLOGICAL RELEVANCE: Griffonia simplicifolia D.C (Baill.) (Fabaceae) seeds are unusually high (6-20% wet weight) in 5-HTP (5-Hydroxytryptophan), a serotonin precursor widely used to treat depression. Consequently, this species is regarded as a herbal "Prozac®". Contemporary use as an anti-depressant contrasts with traditional uses for insecticides, arachnicides, fodder, dyes, mordants and chewing-sticks. G. simplicifolia seeds are wild-harvested for the export trade. Over the past 15 years, use of 5-HTP extracted from G. simplicifolia in cosmetics has added to global demand. Wild populations in West Africa are the sole commercial source of G. simplicifolia seed. AIMS OF THE STUDY: Were to (i) assess the scale of the global trade in G. simplicifolia seeds and (ii) produce a synthesis of the challenges facing sustainable harvest of G. simplicifolia. MATERIALS AND APPROACH: Firstly, we analysed global trade data for G. simplicifolia, taking into account historical trends over the past 40 years. Secondly, we reviewed published studies on the distribution, population biology and harvest impacts of wild G. simplicifolia populations. RESULTS AND CONCLUSION: s: Wild G. simplicifolia populations have been the focus of commercial harvest of their pods (for seeds) for international trade from West Africa for almost 50 years. In the late 1980's, when Ghana exported 75-80 metric tonnes (MT) of G. simplicifolia seed to Europe, this species was already Ghana's main medicinal plant export. Currently, 5 West African countries export G. simplicifolia seeds (Cote d'Ivoire, Ghana, Liberia, Nigeria and Togo). Although in the 1980's, most seed exports were to Europe, today China is the main importer of G. simplicifolia seed. These seeds are value-added for production of 5-HTP extracts, and then re-exported, particularly to North America (c.48% of exports). The low habitat specificity and vigorous re-sprouting of G. simplicifolia after cutting, plus its occurrence in forest reserves and national parks confer some resilience on wild populations. Sustaining future supply chains faces six future challenges, however: (1) Rapid loss of forest habitats; (2) Declining populations of understorey birds and disruption of G. simplicifolia pollination in this bird pollinated species; (3) Negative effects of introduced invasive plant species (Broussonetia papyrifera, Chromolaena odorata) on G. simplicifolia regeneration; (4) Grazing by livestock and use of G. simplicifolia leaves as forage; (5) The long-term impact of industrial scale seed "predation": Over a 9-year period (2005-2013), G. simplicifolia exports from Ghana totalled at least 5550 metric tonnes (or between 9.1 billion to 13.5 billion seeds). This could affect the long-term population dynamics of this species, which produces a low number of seeds per pod (1-4 seeds) and has short distance (ballistic) seed dispersal; and (6) Destructive harvest methods, when plants are cut to harvest get the seed pods. Improved resource management, monitoring, quality control and careful pricing are important if supply chains from wild stocks are to be maintained. If wild populations decline, then 5-HTP biosynthesis may compete with low G. simplicifolia seed yields, leading to loss of income to West African harvesters and traders.

Acupuncture Can Play an Antidepressant Role by Regulating the Intestinal Microbes and Neurotransmitters in a Rat Model of Depression.

BACKGROUND Acupuncture, which has many good effects and few adverse effects, is widely recognized as an alternative therapy for depression in clinical practice. This study aimed to explore the mechanism of acupuncture in antidepressant treatment. MATERIAL AND METHODS In this experiment, Sprague-Dawley rats were randomly divided into 4 groups: control, chronic unpredictable mild stress (CUMS), acupuncture, and fluoxetine groups. The CUMS, acupuncture, and fluoxetine groups were orphaned and subjected to chronic unpredictable stress for 6 weeks, and the acupuncture and fluoxetine groups were treated with their respective intervention in weeks 4-6. The body weight of rats was monitored weekly. After behavioral tests were completed, serum, feces, and hippocampal tissue of rats were collected. RESULTS The results showed that the acupuncture and fluoxetine treatments could alleviate the behavioral changes caused by CUMS. The treatments increased the total distance of rat crossing in the open-field test, prolonged the activity time of the open cross maze in the open arm, and improved the rate of sucrose consumption in the sucrose preference test. In addition, both the decreased level of dopamine (DA) and 5-hydroxytryptamine (5-HT) in serum and hippocampus caused by CUMS were improved after the treatments with acupuncture and fluoxetine, and the decreased expression of brain-derived neurotrophic factor signaling and the astrocytes in the hippocampus caused by CUMS were increased after the treatments with acupuncture and fluoxetine. Acupuncture and fluoxetine also decreased the ß isoform of calmodulin-dependent protein kinase II in the hippocampus, which was increased by CUMS. Furthermore, acupuncture regulated intestinal microbial disorders caused by CUMS, which reduced the relative abundance ratio of Bacteroidetes/Firmicutes in rats. CONCLUSIONS Our experimental results indicate that acupuncture can alleviate depression-like performance in CUMS rats by regulating intestinal microbes and neurotransmitters.

Treatments of Sexual Dysfunction in Opioid Substitution Therapy Patients: A Systematic Review and Meta-Analysis.

Sexual dysfunction is a common condition in the opioid substitution therapy (OST) population. We aimed to determine the efficacy and safety of treatment for sexual dysfunction in the OST population. We searched for interventional studies from Medline, PubMed, and Scopus. Three independent authors conducted a risk-of-bias assessment (RoB 2). A total of seven studies (five randomized-controlled trials, two quasi-experimental), including 473 patients with sexual dysfunction, were identified. Among these, three bupropion (n=207), one trazodone (n=75), two rosa Damascena (n=100), and one ginseng (n=91) studies had reported significantly improve various sexual functioning domains in both genders. In a meta-analysis, bupropion significantly increased male sexual function with standardized mean difference of 0.53; 95% confidence interval of 0.19-0.88; P < 0.01; I2=0. The adverse effects were minor for all agents, and no significant difference between treatment and placebo groups in randomized-controlled trials. These agents have a promising future as therapy for sexual dysfunction in the OST population. However, given the limited sample size and number of studies, further studies should be conducted to confirm the use of these agents.

Second-generation antidepressants for treatment of seasonal affective disorder.

BACKGROUND: Seasonal affective disorder (SAD) is a seasonal pattern of recurrent depressive episodes that is often treated with second-generation antidepressants (SGAs), light therapy, or psychotherapy. OBJECTIVES: To assess the efficacy and safety of second-generation antidepressants (SGAs) for the treatment of seasonal affective disorder (SAD) in adults in comparison with placebo, light therapy, other SGAs, or psychotherapy. SEARCH METHODS: This is an update of an earlier review first published in 2011. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 1) in the Cochrane Library (all years), Ovid MEDLINE, Embase, and PsycINFO (2011 to January 2020), together with the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (all available years), for reports of randomised controlled trials (RCTs). We hand searched the reference lists of all included studies and other systematic reviews. We searched ClinicalTrials.gov for unpublished/ongoing trials. We ran a separate update search for reports of adverse events in the Ovid databases.  SELECTION CRITERIA: For efficacy we included RCTs of SGAs compared with other SGAs, placebo, light therapy, or psychotherapy in adult participants with SAD. For adverse events we also included non-randomised studies. DATA COLLECTION AND ANALYSIS: Two review authors independently screened abstracts and full-text publications against the inclusion criteria. Data extraction and 'Risk of bias' assessment were conducted individually. We pooled data for meta-analysis where the participant groups were similar, and the studies assessed the same treatments with the same comparator and had similar definitions of outcome measures over a similar duration of treatment. MAIN RESULTS: In this update we identified no new RCT on the effectiveness of SGAs in SAD patients. We included 2 additional single-arm observational studies that reported on adverse events of SGAs.  For efficacy we included three RCTs of between five and eight weeks' duration with a total of 204 participants. For adverse events we included two RCTs and five observational (non-randomised) studies of five to eight weeks' duration with a total of 249 participants. All participants met the DSM (Diagnostic and Statistical Manual of Mental Disorders) criteria for SAD. The average age ranged from 34 to 42 years, and the majority of participants were female (66% to 100%). Results from one trial with 68 participants showed that fluoxetine (20/36) was numerically superior to placebo (11/32) in achieving clinical response; however, the confidence interval (CI) included both a potential benefit as well as no benefit of fluoxetine (risk ratio (RR) 1.62, 95% CI 0.92 to 2.83, very low-certainty evidence). The number of adverse events was similar in both groups (very low-certainty evidence). Two trials involving a total of 136 participants compared fluoxetine versus light therapy. Meta-analysis showed fluoxetine and light therapy to be approximately equal in treating seasonal depression: RR of response 0.98 (95% CI 0.77 to 1.24, low-certainty evidence), RR of remission 0.81 (95% CI 0.39 to 1.71, very low-certainty evidence). The number of adverse events was similar in both groups (low-certainty evidence). We did not identify any eligible study comparing SGA with another SGA or with psychotherapy. Two RCTs and five non-randomised studies reported adverse event data on a total of 249 participants who received bupropion, fluoxetine, escitalopram, duloxetine, nefazodone, reboxetine, light therapy, or placebo. We were only able to obtain crude rates of adverse events, therefore caution is advised regarding interpretation of this information. Between 0% and 100% of participants who received an SGA suffered an adverse event, and between 0% and 25% of participants withdrew from the study due to adverse events. AUTHORS' CONCLUSIONS: Evidence for the effectiveness of SGAs is limited to one small trial of fluoxetine compared with placebo showing a non-significant effect in favour of fluoxetine, and two small trials comparing fluoxetine against light therapy suggesting equivalence between the two interventions. The lack of available evidence precluded us from drawing any overall conclusions on the use of SGAs for SAD. Further, larger RCTs are required to expand and strengthen the evidence base on this topic, and should also include comparisons with psychotherapy and other SGAs. Data on adverse events were sparse, and a comparative analysis was not possible. The data we obtained on adverse events is therefore not robust, and our confidence in the data is limited. Overall, up to 25% of participants treated with SGAs for SAD withdrew from the study early due to adverse events.

Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is characterized by symptoms of inattention or impulsivity or both, and hyperactivity, which affect children, adolescents, and adults. In some countries, methylphenidate is the first option to treat adults with moderate or severe ADHD. However, evidence on the efficacy and adverse events of immediate-release (IR) methylphenidate in the treatment of ADHD in adults is limited and controversial. OBJECTIVES: To evaluate the efficacy and harms (adverse events) of IR methylphenidate for treating ADHD in adults. SEARCH METHODS: In January 2020, we searched CENTRAL, MEDLINE, Embase, eight additional databases and three trial registers. We also searched internal reports on the European Medicines Agency and the US Food and Drug Administration websites. We checked citations of included trials to identify additional trials not captured by the electronic searches. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing IR methylphenidate, at any dose, with placebo or other pharmacological interventions (including extended-release formulations of methylphenidate) for ADHD in adults. Primary outcomes comprised changes in the symptoms of ADHD (efficacy) and harms. Secondary outcomes included changes in the clinical impression of severity and improvement, level of functioning, depression, anxiety and quality of life. Outcomes could have been rated by investigators or participants. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently on the characteristics of the trials, participants, interventions; outcomes and financial conflict of interests. We resolved disagreements by discussion or consulting a third review author. We obtained additional, unpublished information from the authors of one included trial that had reported efficacy data in a graph. We calculated mean differences (MDs) or standardized MDs (SMDs) with 95% confidence intervals (CIs) for continuous data reported on the same or different scales, respectively. We summarized dichotomous variables as risk ratios (RRs) with 95% CI. MAIN RESULTS: We included 10 trials published between 2001 and 2016 involving 497 adults with ADHD. Three trials were conducted in Europe and one in Argentina; the remaining trials did not report their location. The RCTs compared IR methylphenidate with placebo, an osmotic-release oral system (OROS) of methylphenidate (an extended-release formulation), an extended-release formulation of bupropion, lithium, and Pycnogenol® (maritime pine bark extract). Participants comprised outpatients, inpatients in addiction treatment, and adults willing to attend an intensive outpatient program for cocaine dependence. The duration of the follow-up ranged from 6 to 18 weeks. IR methylphenidate versus placebo We found very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce symptoms of ADHD when measured with investigator-rated scales (MD -20.70, 95% CI -23.97 to -17.43; 1 trial, 146 participants; end scores; Adult ADHD Investigator Symptom Report Scale (AISRS), scored from 0 to 54), but the evidence is uncertain. The effect of IR methylphenidate on ADHD symptoms when measured with participant-rated scales was moderate, but the certainty of the evidence is very low (SMD -0.59, 95% CI -1.25 to 0.06; I2 = 69%; 2 trials, 138 participants; end scores). There is very low-certainty evidence that, compared with placebo, IR methylphenidate may reduce the clinical impression of the severity of ADHD symptoms (MD -0.57, 95% CI -0.85 to -0.28; 2 trials, 139 participants; I2 = 0%; change and end scores; Clinical Global Impression (CGI)-Severity scale (scored from 1 (very much improved) to 7 (very much worse))). There is low-certainty evidence that, compared with placebo, IR methylphenidate may slightly impact the clinical impression of an improvement in symptoms of ADHD (MD -0.94, 95% CI -1.37 to -0.51; 1 trial, 49 participants; end scores; CGI-Improvement scale (scored from 1 (very much improved) to 7 (very much worse))). There is no clear evidence of an effect on anxiety (MD -0.20, 95% CI -4.84 to 4.44; 1 trial, 19 participants; change scores; Hamilton Anxiety Scale (HAM-A; scored from 0 to 56); very low-certainty evidence) or depression (MD 2.80, 95% CI -0.09 to 5.69; 1 trial, 19 participants; change scores; Hamilton Depression Scale (HAM-D; scored from 0 to 52); very low-certainty evidence) in analyses comparing IR methylphenidate with placebo. IR methylphenidate versus lithium Compared with lithium, it is uncertain whether IR methylphenidate increases or decreases symptoms of ADHD (MD 0.60, 95% CI -3.11 to 4.31; 1 trial, 46 participants; end scores; Conners' Adult ADHD Rating Scale (scored from 0 to 198); very low-certainty evidence); anxiety (MD -0.80, 95% CI -4.49 to 2.89; 1 trial, 46 participants; end scores; HAM-A; very low-certainty evidence); or depression (MD -1.20, 95% CI -3.81 to 1.41, 1 trial, 46 participants; end scores; HAM-D scale; very low-certainty evidence). None of the included trials assessed participant-rated changes in symptoms of ADHD, or clinical impression of severity or improvement in participants treated with IR methylphenidate compared with lithium. Adverse events were poorly assessed and reported. We rated all trials at high risk of bias due to selective outcome reporting of harms and masking of outcome assessors (failure to blind outcome assessor to measure adverse events). Overall, four trials with 203 participants who received IR methylphenidate and 141 participants who received placebo described the occurrence of harms. The use of IR methylphenidate in these trials increased the risk of gastrointestinal complications (RR 1.96, 95% CI 1.13 to 2.95) and loss of appetite (RR 1.77, 95% CI 1.06 to 2.96). Cardiovascular adverse events were reported inconsistently, preventing a comprehensive analysis. One trial comparing IR methylphenidate to lithium reported five and nine adverse events, respectively. We considered four trials to have notable concerns of vested interests influencing the evidence, and authors from two trials omitted information related to the sources of funding and conflicts of interest. AUTHORS' CONCLUSIONS: We found no certain evidence that IR methylphenidate compared with placebo or lithium can reduce symptoms of ADHD in adults (low- and very low-certainty evidence). Adults treated with IR methylphenidate are at increased risk of gastrointestinal and metabolic-related harms compared with placebo. Clinicians should consider whether it is appropriate to prescribe IR methylphenidate, given its limited efficacy and increased risk of harms. Future RCTs should explore the long-term efficacy and risks of IR methylphenidate, and the influence of conflicts of interest on reported effects.

Intranasal administration of white tea alleviates the olfactory function deficit induced by chronic unpredictable mild stress.

CONTEXT: White tea [Camellia sinensis (L) O.Ktze. (Theaceae)] is popular in Asia, but its benefits on olfactory injury are unknown. OBJECTIVE: The present study explores the effects of white tea on the olfactory injury caused by chronic unpredictable mild stress (CUMS). MATERIALS AND METHODS: C57BL/6J mice (WT) were exposed to CUMS. CUMS mice (CU) were intranasally treated with white tea extract [low tea (LT), 20 mg/kg; high tea (HT), 40 mg/kg] and fluoxetine (CF, 20 mg/kg) for 7 days. Several behavioural tests were conducted to assess depression and olfactory function. The transmission electron microscope (TEM) and semi-quantitative reverse transcription PCR were performed separately to observe the changes of related structures and genes transcription level. RESULTS: The depressive behaviours of the LT and HT mice were reversed. The latency time of the buried food pellet test decreased from 280 s (CU) to 130 s (HT), while the olfactory sensitivity and olfactory avoidance test showed that the olfactory behaviours disorder of LT and HT mice were alleviated. The white tea increased the A490 nm values of the cortisol treated cells from 0.15 to 1.4. Reduced mitochondrial and synaptic damage in the olfactory bulb (OB), enhanced expression of the brain-derived neurotrophic factor (BDNF) and olfactory marker protein (OMP) were observed in the LT and HT mice. CONCLUSIONS AND DISCUSSION: White tea has the potential in curing the olfactory deficiency related to chronic stress. It lays the foundation for the development of new and reliable drug to improve olfactory.

Effects of Jian-Pi-Zhi-Dong Decoction on the Expression of 5-HT and Its Receptor in a Rat Model of Tourette Syndrome and Comorbid Anxiety.

BACKGROUND Anxiety is one of the common comorbidities of Tourette syndrome (TS). The serotonin (5-HT) system is involved in both TS and anxiety. Jian-pi-zhi-dong decoction (JPZDD) is widely used. However, the mechanism remains unknown. In this study, a rat model of TS and comorbid anxiety was used to evaluate the effect of JPZDD on 5-HT and its receptor. MATERIAL AND METHODS 48 rats were divided into 4 groups randomly (n=12). The model was established by empty water bottle stimulation plus iminodipropionitrile injection for 3 weeks. Then the control and model groups were gavaged with saline, while the treatment groups were gavaged with fluoxetine hydrochloride (Flx) or JPZDD. Body weights were measured, and behavioral tests were evaluated with stereotypy and elevated plus maze. The morphologic characters were observed by hematoxylin and eosin staining. The content of 5-HT was detected by enzyme-linked immunosorbent assay and high-performance liquid chromatography. The expression of 5-HT2C receptor was detected by western blot and quantitative polymerase chain reaction. RESULTS The stereotypy score was lower and the time spent in the open arm was longer in the JPZDD group compared with the model group. After the treatment of Flx or JPZDD, the structure of neurons became gradually normal and the cells were arranged neatly. The contents of 5-HT in the treatment groups were higher compared with the model group in the striatum. The expression of 5-HT2C mRNA in the striatum of JPZDD and Flx groups decreased compared with the model group, and the JPZDD group was lower than the Flx group. CONCLUSIONS JPZDD alleviated both tic and anxiety symptoms and the mechanism may be via reducing the expression of 5-HT2C mRNA in the striatum, increasing the concentration of 5-HT, and enhancing the activity of the 5-HT system, which in turn exerts neuro-inhibition.

Maternal Tryptophan Supplementation Protects Adult Rat Offspring against Hypertension Programmed by Maternal Chronic Kidney Disease: Implication of Tryptophan-Metabolizing Microbiome and Aryl Hydrocarbon Receptor.

Hypertension and chronic kidney disease (CKD) can originate during early-life. Tryptophan metabolites generated by different pathways have both detrimental and beneficial effects. In CKD, uremic toxins from the tryptophan-generating metabolites are endogenous ligands of the aryl hydrocarbon receptor (AHR). The interplay between AHR, nitric oxide (NO), the renin-angiotensin system (RAS), and gut microbiota is involved in the development of hypertension. We examined whether tryptophan supplementation in pregnancy can prevent hypertension and kidney disease programmed by maternal CKD in adult offspring via the aforementioned mechanisms. Sprague-Dawley (SD) female rats received regular chow or chow supplemented with 0.5% adenine for 3 weeks to induce CKD before pregnancy. Pregnant controls or CKD rats received vehicle or tryptophan 200 mg/kg per day via oral gavage during pregnancy. Male offspring were divided into four groups (n = 8/group): control, CKD, tryptophan supplementation (Trp), and CKD plus tryptophan supplementation (CKDTrp). All rats were sacrificed at the age of 12 weeks. We found maternal CKD induced hypertension in adult offspring, which tryptophan supplementation prevented. Maternal CKD-induced hypertension is related to impaired NO bioavailability and non-classical RAS axis. Maternal CKD and tryptophan supplementation differentially shaped distinct gut microbiota profile in adult offspring. The protective effect of tryptophan supplementation against maternal CKD-induced programmed hypertension is relevant to alterations to several tryptophan-metabolizing microbes and AHR signaling pathway. Our findings support interplay among tryptophan-metabolizing microbiome, AHR, NO, and the RAS in hypertension of developmental origins. Furthermore, tryptophan supplementation in pregnancy could be a potential approach to prevent hypertension programmed by maternal CKD.

A double-blind, randomized pilot study for comparison of Melissa officinalis L. and Lavandula angustifolia Mill. with Fluoxetine for the treatment of depression.

BACKGROUND: Depression has rapidly progressed worldwide, and the need for an efficient treatment with low side effect has risen. Melissa officinalis L and Lavandula angustifolia Mill have been traditionally used in Asia for the treatment of depression. Many textbooks of traditional Persian medicine refer to these herbs for the treatment of depression while there are no adequate clinical trials to support this claim. The present study aimed to evaluate the efficacy of M. officinalis and L. angustifolia compared to fluoxetine for the treatment of mild to moderate depression in an 8-week randomized, double-blind clinical trial. METHODS: Forty-five adult outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) for major depression, were randomly assigned to 3 groups to daily receive either M. officinalis (2 g) or L. angustifolia (2 g) or fluoxetine (20 mg) and were assessed in weeks 0, 2, 4 and 8 by the Hamilton Rating Scale for Depression (HAM-D) including 17 items. RESULTS: Our study showed that M. officinalis and L. angustifolia effect similar to fluoxetine in mild to moderate depression. (F = 0.131, df = 2,42, p = 0.877). CONCLUSION: Due to some restrictions in this study including absence of placebo group, large-scale trials are needed to investigate the anti-depressant effect of these two herbs with more details. TRIAL REGISTRATION: IRCT2014061718126N1 . Registration date: 2015-06-04-"Retrospectively registered".

Influence of Zuojin Pill on the Metabolism of Venlafaxine in Vitro and in Rats and Associated Herb-Drug Interaction.

Venlafaxine (VEN), a first-line antidepressant, and Zuojin Pill (ZJP), a common Chinese herbal medicine consisting of Rhizoma Coptidis and Fructus Evodiae, have a high likelihood of combination usage in patients with depression with gastrointestinal complications. ZJP exhibits inhibitory effects on recombinant human cytochrome P450 isoenzymes (rhP450s), especially on CYP2D6, whereas VEN undergoes extensive metabolism by CYP2D6. From this perspective, we investigated the influence of ZJP on the metabolism of VEN in vitro and in rats for the first time. In this study, ZJP significantly inhibited the metabolism of VEN in both rat liver microsomes (RLM) and human liver microsomes (HLM); meanwhile, it inhibited the O-demethylation catalytic activity of RLM, HLM, rhCYP2D6*1/*1, and rhCYP2D6*10/*10, primarily through CYP2D6, with IC50 values of 129.9, 30.5, 15.4, and 2.3 µg/ml, respectively. Furthermore, the inhibitory effects of ZJP on hepatic metabolism and pharmacokinetics of VEN could also be observed in the pharmacokinetic study of rats. The area under drug concentration-time curve0-24 hour of VEN and its major metabolite O-desmethylvenlafaxine (ODV) increased by 39.6% and 22.8%, respectively. The hepatic exposure of ODV decreased by 57.2% 2 hours after administration (P = 0.014). In conclusion, ZJP displayed inhibitory effects on hepatic metabolism and pharmacokinetics of VEN in vitro and in rats mainly through inhibition of CYP2D6 activity. The human pharmacokinetic interaction between ZJP and VEN and its associated clinical significance needed to be seriously considered. SIGNIFICANCE STATEMENT: Zuojin Pill, a commonly used Chinese herbal medicine, demonstrates significant inhibitory effects on hepatic metabolism and pharmacokinetics of venlafaxine in vitro and in rats mainly through suppression of CYP2D6 activity. The human pharmacokinetic interaction between Zuojin Pill and venlafaxine and its associated clinical significance needs to be seriously considered.

Therapeutic Interventions for Adjustment Disorder: A Systematic Review.

BACKGROUND: Adjustment disorder requires therapeutic intervention because of its complications, which include a significant risk of suicide, but evidence-based therapeutic guidelines are not available. AREAS OF UNCERTAINTY: The main problem is related to answer to the following question: What is the optimal therapeutic approach to adjustment disorder? In this respect we review all randomized controlled trials that aimed to investigate therapeutic interventions for adjustment disorder in adult populations. DATA SOURCES: Comprehensive search of the electronic database PubMed (January 1980-June 2019). The review included clinical trials that aimed to investigate a psychological or pharmacological treatment for adjustment disorder in adult population and reported outcome data for therapeutic interventions. RESULTS: The search identified 23 studies that fulfilled the inclusion criteria for this review. Pharmacotherapy interventions were the focus of 11 studies that used various medications and dosages including viloxazine, lormetazepam, S-adenosylmethionine, pivagabine, trazodone, clorazepate, etifoxine, lorazepam, diazepam, afobazole, and plant extracts (Kava-kava, Euphytose, and Ginkgo biloba) on a total number of 1020 patients. Psychotherapy interventions were identified in 12 studies that used mirror therapy, short-term dynamic psychotherapy, yoga meditation, body-mind-spirit technique, mindfulness, bibliotherapy (self-help manual), humor training, and cognitive behavioral therapy. CONCLUSIONS: Psychotherapy seems indicated for mildly symptomatic adjustment disorder. Given the fact that adjustment disorder with severe symptoms is associated with a high risk of suicidal ideation and suicide attempts, clinicians must consider the potential benefit of using psychotropic agents such as benzodiazepines, antidepressants, or etifoxine.

Effect of the warming and tonifying kidney- yang recipe on monoamine neurotransmitters and pathological morphology of hippocampus tissue in depression model rats.

OBJECTIVE: To study the molecular mechanism of warming and tonifying kidney-yang recipe (WTKYR) in the treatment of depression. METHODS: SD rats were divided into a control group, model group, WTKYR group, and fluoxetine group. Each group consisted of 21 rats. The chronic unpredictable mild stress model was used. Body weighing and SPT were performed regularly. After treatment, histopathology of the brain tissue was performed, and concentrations of 5-HT (5-hydroxytryptamine), NE (norepinephrine), and DA (dopamine) in the hippocampus were determined. RESULTS: The WTKYR group showed higher body weight and sucrose consumption than the control groups. Moreover, the concentrations of 5-HT, NE, and DA in the hippocampus were significantly different in the WTKYR group in comparison to those in the other groups. The hippocampus histomorphology of the WTKYR group exhibited less dematous pyramidal cells and mild inflammatory cell infiltration. CONCLUSION: The treatment effect of WTKYR in depression may be based on improvement in the content of 5-HT, NE, and DA in the hippocampus, extenuating edema of the cortical surface and pyramidal cells and decreasing the infiltration of inflammatory cells into hippocampus tissue.

Use of nutritional supplements based on melatonin, tryptophan and vitamin B6 (Melamil Tripto®) in children with primary chronic headache, with or without sleep disorders: a pilot study.

BACKGROUND: Headache is one of the main complaints in pediatric neurology. Exogenous melatonin has been shown to be useful and safe in improving sleep-wake cycles and sleep quality in children. Tryptophan as well plays a key role in sleep regulation. So far, no studies tried to analyze the effects of a combination of both melatonin and tryptophan in treating chronic headache in children affected also by night-time awakenings. METHODS: Thirty-four children with a diagnosis of chronic headache (with or without sleep disorders) have been enrolled. The study was articulated in two steps: 1) each child was observed for one month without any intervention; 2) children have been then randomized into two groups: the "ME-group", which received the nutritional supplement melatonin for two months and the "MET-group", which received the nutritional supplements melatonin, tryptophan, and vitamin B6 for two months. RESULTS: In terms of changes in number of headache events, responders in the ME-group were 91.7% and those in the MET-group were 66.7% (P=0.113). In terms of changes in number of night awakenings, in the ME group, mean number at baseline, after 30 days, and after 60 days were 3.6±3.2, 3.2±3.5, and 2.7±3.4 (P=0.495). In the MET group, mean number of night awakenings was 7.4±8.1, 4.0±4.4, and 3.3±2.9 (P=0.041). CONCLUSIONS: Using either nutritional supplement for two months can help in decreasing the monthly number of headache episodes and night awakenings. The addition of tryptophan and vitamin B6 appears to have stronger influence on night awakenings reduction than melatonin only.

Implementation research for public sector mental health care scale-up (SMART-DAPPER): a sequential multiple, assignment randomized trial (SMART) of non-specialist-delivered psychotherapy and/or medication for major depressive disorder and posttraumatic stress disorder (DAPPER) integrated with outpatient care clinics at a county hospital in Kenya.

BACKGROUND: Mental disorders are a leading cause of global disability, driven primarily by depression and anxiety. Most of the disease burden is in Low and Middle Income Countries (LMICs), where 75% of adults with mental disorders have no service access. Our research team has worked in western Kenya for nearly ten years. Primary care populations in Kenya have high prevalence of Major Depressive Disorder (MDD) and Posttraumatic Stress Disorder (PTSD). To address these treatment needs with a sustainable, scalable mental health care strategy, we are partnering with local and national mental health stakeholders in Kenya and Uganda to identify 1) evidence-based strategies for first-line and second-line treatment delivered by non-specialists integrated with primary care, 2) investigate presumed mediators of treatment outcome and 3) determine patient-level moderators of treatment effect to inform personalized, resource-efficient, non-specialist treatments and sequencing, with costing analyses. Our implementation approach is guided by the Exploration, Preparation, Implementation, Sustainment (EPIS) framework. METHODS/DESIGN: We will use a Sequential, Multiple Assignment Randomized Trial (SMART) to randomize 2710 patients from the outpatient clinics at Kisumu County Hospital (KCH) who have MDD, PTSD or both to either 12 weekly sessions of non-specialist-delivered Interpersonal Psychotherapy (IPT) or to 6 months of fluoxetine prescribed by a nurse or clinical officer. Participants who are not in remission at the conclusion of treatment will be re-randomized to receive the other treatment (IPT receives fluoxetine and vice versa) or to combination treatment (IPT and fluoxetine). The SMART-DAPPER Implementation Resource Team, (IRT) will drive the application of the EPIS model and adaptations during the course of the study to optimize the relevance of the data for generalizability and scale -up. DISCUSSION: The results of this research will be significant in three ways: 1) they will determine the effectiveness of non-specialist delivered first- and second-line treatment for MDD and/or PTSD, 2) they will investigate key mechanisms of action for each treatment and 3) they will produce tailored adaptive treatment strategies essential for optimal sequencing of treatment for MDD and/or PTSD in low resource settings with associated cost information - a critical gap for addressing a leading global cause of disability. TRIAL REGISTRATION: ClinicalTrials.gov NCT03466346, registered March 15, 2018.

The Management of Stroke Rehabilitation: A Synopsis of the 2019 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline.

Description: In June 2019, the U.S. Department of Veterans Affairs (VA) and U.S. Department of Defense (DoD) approved an update of the joint clinical practice guideline for rehabilitation after stroke. This synopsis summarizes the key recommendations from this guideline. Methods: In February 2018, the VA/DoD Evidence-Based Practice Work Group convened a joint VA/DoD guideline development effort that included clinical stakeholders and stroke survivors and conformed to the National Academy of Medicine (formerly the Institute of Medicine) tenets for trustworthy clinical practice guidelines. The guideline panel identified key questions, systematically searched and evaluated the literature, and developed 2 algorithms and 42 key recommendations using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. Stroke survivors and their family members were invited to share their perspectives to further inform guideline development. Recommendations: The guideline recommendations provide evidence-based guidance for the rehabilitation care of patients after stroke. The recommendations are applicable to health care providers in both primary care and rehabilitation. Key features of the guideline are recommendations in 6 areas: timing and approach; motor therapy; dysphagia; cognitive, speech, and sensory therapy; mental health therapy; and other functions, such as returning to work and driving.

Pharmacological and non-pharmacological treatments for major depressive disorder in adults: A systematic review and network meta-analysis.

Depression has brought huge disease burden to the world. This systematic review aimed to compare the efficacy and safety of pharmacological and non-pharmacological treatments for major depressive disorder (MDD). We searched electronic databases with time range from 1990.1.1 to 2018.9.5. Randomized controlled trials (RCTs) including adult patients with MDD were eligible for inclusion. We conducted network meta-analyses using multivariate meta-analyses models under the frequency framework. Primary outcomes were efficacy (response rate) and safety (overall risk of adverse events). We estimated summary odds ratios (ORs) based on group-level data. 20,937 citations were identified, 91 trials comprising 10,991 participants were included in efficacy study, and 32 trials comprising 5245 participants were included in safety study. In terms of efficacy, all treatments studied (acupuncture, mirtazapine, herbal medicine, venlafaxine, physical exercise, cognitive-behavioral therapy (CBT), bupropion, fluoxetine, and vortioxetine) except for probiotics were significantly more effective than placebo. In terms of safety, bupropion, fluoxetine, venlafaxine, and vortioxetine were significantly less safe than placebo. Herbal medicine and mirtazapine had no significant difference in overall risk of adverse events compared with placebo. Acupuncture, CBT, physical exercise and probiotics were lack of eligible safety data.

Combined Supplementation with Glycine and Tryptophan Reduces Purine-Induced Serum Uric Acid Elevation by Accelerating Urinary Uric Acid Excretion: A Randomized, Single-Blind, Placebo-Controlled, Crossover Study.

The authors previously confirmed the serum uric acid-lowering effects of the combination of glycine and tryptophan in subjects with mild hyperuricemia. This study examined whether combined supplementation with glycine and tryptophan suppressed the elevation in serum uric acid levels caused by purine ingestion and accelerated urinary uric acid excretion in subjects with lower urate excretion using a randomized, single-blind, placebo-controlled, crossover clinical trial design. Healthy Japanese adult males with lower urate excretion ingested water containing purines in addition to dextrin (placebo), tryptophan, glycine, or a glycine and tryptophan mixture. The combined supplementation with glycine and tryptophan significantly reduced the elevated serum uric acid levels after purine ingestion. Glycine alone and in combination with tryptophan significantly increased urinary uric acid excretion and urate clearance compared with the effects of the placebo. Urinary pH increased by the ingestion of the mixture. These results suggested that the improved water solubility of uric acid due to increased urinary pH contributed to the increase of urinary uric acid excretion.

Management of Depression in Adolescents in Japan.

Objectives: In Japan, there are currently no approved antidepressant treatments for pediatric patients with depression. This study aimed to estimate the prevalence of depression among adolescents under medical care in Japan, the pharmacological treatments used, and the perceived unmet needs among the medical specialties treating depression in the pediatric population. Methods: The study was conducted in November 2014 as an internet survey among physicians in clinical practice. It included a sample of 731 physicians with the potential to treat adolescent patients with depression and 161 physicians who had treated at least one adolescent with depression with pharmacotherapy in the previous 12 months. Of the sample of 161 treating physicians, 60 were internal medicine specialists, 73 were psychiatrists, and 28 were certified specialists from the Japanese Society of Child and Adolescent Psychiatry, Japanese Society of Psychosomatic Medicine Pediatrics, or Japanese Society of Pediatric Psychiatry and Neurology. The participants completed questionnaires concerning their patient population with depression, drug-treated population, and drugs prescribed. Results: Estimates of prevalence data indicated that there were ∼550,000 adolescent patients with depression in Japan (10% of the patient population with depression) under medical care of different medical specialties; ∼64% of these patients were receiving pharmacotherapy. Pharmacotherapy for adolescents with depression was prescribed mainly by psychiatrists (62% of prescriptions for these patients). The most common first-choice agent was sertraline (23% of respondents) followed by anxiolytics (17%) and fluvoxamine (13%), while antipsychotics were the preferred choice for 7%. Conclusion: The study indicates a high prevalence of depression among adolescents in Japan. These patients are seen by different medical specialties; the use of pharmacotherapy is relatively common and comprises various drug classes, including antidepressants, anxiolytics, and antipsychotics. This study shows that there is a medical need for approved treatments for adolescents with depression in Japan.

Orange peels modulate antioxidant markers and key enzymes relevant to erection in the penile tissue of paroxetine-treated rats.

In comparison to other antidepressant drugs, erectile dysfunction (ED) is more pronounced in paroxetine use. On the other hand, orange (Citrus sinensis) peels commonly consumed in various forms are used in folkloric medicine for ED management. Thus, this study evaluated the effect of orange peels infusion on sexual behaviour, nitric oxide (NO) level and some enzymes (arginase, phosphodiesterase-5 [PDE-5], acetylcholinesterase [AChE] and adenosine deaminase [ADA]) in paroxetine-treated rats. Erectile dysfunction was induced with paroxetine (10 mg/kg body weight). The animals were grouped into five (n = 6): normal rats; paroxetine-induced rats; paroxetine-induced rats treated with sildenafil citrate (5 mg/kg); paroxetine-induced rats treated with orange peels infusion (50 mg/kg); Paroxetine induced rats treated with orange peel infusions (100 mg/kg). The results revealed a significant decrease in sexual behaviour, NO level and the activities of antioxidant enzymes, while there was a significant increase in arginase, PDE-5, AChE and ADA activities in paroxetine-induced rats. However, orange peel infusions ameliorated erectile dysfunction in paroxetine-treated rats. This study showed some possible biochemical basis underlying the use of orange peels infusion in erectile dysfunction management.