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.

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.

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.

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.

Systematic review of preclinical, clinical, and post-marketing evidence of bupropion misuse potential.

Background: Bupropion is a substituted cathinone compound widely used as a first line or add-on treatment for depression, smoking cessation, and more recently in combination with naltrexone for weight loss. As abuse of synthetic cathinone compounds has received more attention in recent years, concern about the misuse potential of bupropion has grown as well. Objectives: We review bupropion pharmacology and assessments of misuse potential including preclinical evidence, human studies, and post-marketing surveillance of bupropion misuse. Methods: This review reports the results of a systematic review of publications evaluating the potential for bupropion to be misused. Publications were identified using PubMed and Medline through Ovid® as well as iterative bibliographic searches. A summary of data from informal sources of information including substance-user experience from online forum entries is included. Results: Preclinical evidence demonstrates some potential for misuse based on psychomotor, discrimination, self-administration, and conditioned place preference tasks. However, this potential is less than that of commonly misused stimulants. Studies in human populations similarly indicate that bupropion shares interoceptive effects with other stimulants, but lacks some key reinforcing effects of other stimulants. In the real-world setting, misuse of bupropion occurs, but is uncommon. Adverse effects of bupropion misuse are frequently cited as significant barriers to obtaining any desired interoceptive effect. Conclusions: While bupropion demonstrates some potential for misuse, pharmacological differences from other structurally-related stimulants limit bupropion's reinforcing effects. Without additional data indicating susceptibility of specific populations to bupropion misuse, there is no empirical data suggesting a need to modify bupropion prescribing patterns.

Fluoxetine oral treatment discloses 5-HT1D receptor as vagoinhibitor of the cardiac cholinergic neurotransmission in rat.

Although depression and cardiovascular diseases are related, the role of antidepressants such as fluoxetine (increasing serotonin levels) within cardiac regulation remains unclear. We aimed to determine whether fluoxetine modifies the pharmacological profile of serotonergic influence on vagal cardiac outflow. Rats were treated with fluoxetine (10 mg/kg per day; p.o.) for 14 days or equivalent volumes of drinking water (control group); then, they were pithed and prepared for vagal stimulation. Bradycardic responses were obtained by electrical stimulation of the vagal fibers (3, 6, and 9 Hz) or i.v. acetylcholine (ACh; 1, 5, and 10 µg/kg). The i.v. administration of 5-hydroxytryptamine (5-HT; 10 and 50 µg/kg) inhibited the vagally induced bradycardia. 5-CT (5-HT1/7 agonist) and L-694,247 (5-HT1D agonist) mimicked the serotonin inhibitory effect while α-methyl-5-HT (5-HT2 agonist) was devoid of any action. SB269970 (5-HT7 antagonist) did not abolish 5-CT inhibitory action on the electrically induced bradycardia. Pretreatment with LY310762 (5-HT1D antagonist) blocked the effects induced by L-694,247 and 5-CT. 5-HT and 5-CT failed to modify the bradycardia induced by exogenous ACh. Our outcomes suggest that fluoxetine treatment modifies 5-HT modulation on heart parasympathetic neurotransmission in rats, evoking inhibition of the bradycardia via prejunctional 5-HT1D in pithed rats.

Nutraceuticals to promote neuronal plasticity in response to corticosterone-induced stress in human neuroblastoma cells.

Objectives: To search for novel compounds that will protect neuronal cells under stressed conditions that may help to restore neuronal plasticity. Methods: A model of corticosterone (CORT)-induced stress in human neuroblastoma cells (SH-SY5Y) was used to compare the efficacy of 6 crude extracts and 10 pure compounds (6 polyphenols, 2 carotenoids, 1 amino acid analogue, and 1 known antidepressant drug) to increase neuronal plasticity and to decrease cytotoxicity. Results: Astaxanthin (among pure compounds) and phlorotannin extract of Fucus vesiculosus (among crude extracts) showed a maximum increase in cell viability in the presence of excess CORT. BDNF-VI mRNA expression in SH-SY5Y cells was significantly improved by pretreatment with quercetine, astaxanthin, curcumin, fisetin, and resveratrol. Among crude extracts, xanthohumol, phlorotannin extract (Ecklonia cava), petroleum ether extract (Nannochloropsis oculata), and phlorotannin extract (F. vesiculosus) showed a significant increase in BDNF-VI mRNA expression. CREB1 mRNA expression was significantly improved by astaxanthin, ß-carotene, curcumin, and fluoxetine whereas none of the crude extracts caused significant improvement. As an adjunct of fluoxetine, phlorotannin extract (F. vesiculosus), ß-carotene, and xanthohumol have resulted in significant improvement in BDNF-VI mRNA expression and CREB1 mRNA expression was significantly improved by phlorotannin extract (F. vesiculosus). Significant improvement in mature BDNF protein expression by phlorotannin extract (F. vesiculosus) and ß-carotene as an adjunct of fluoxetine confirm their potential to promote neuronal plasticity against CORT-induced stress. Discussion: The carotenoids, flavonoids, namely quercetine, curcumin, and low molecular weight phlorotannin-enriched extract of F. vesiculosus may serve as potential neuroprotective agents promoting neuronal plasticity in vitro. Graphical abstract: Cascade of events associated with disturbed homeostatic balance of glucocorticoids and impact of phlorotannin extract (F. vesiculosus) and ß-carotene in restoring neuronal plasticity. Abbreviation: TrKB, tropomyosin receptor kinase B; P-ERK, phosphorylated extracellular signal-related kinase; PI3K, phosphatidylinositol 3-kinase; Akt, protein kinase B; Ca++/CaMK, calcium/calmodulin-dependent protein kinase; pCREB, phosphorylated cAMP response element-binding protein; CRE, cAMP response elements, CORT, corticosterone; and BDNF; brain-derived neurotrophic factor.

The effect of graded concentrations of dietary tryptophan on canine behavior in response to the approach of a familiar or unfamiliar individual.

Tryptophan (Trp) is an indispensable dietary amino acid that supports the modulation of mood and behavior in mammalian species through its role in the serotonergic pathway. This study assessed the behavior patterns of 36 healthy, female adult mixed-breed hound dogs fed a control diet (tryptophan = 0.18% as-fed) or 1 of several experimental diets with graded concentrations of tryptophan (0.05%, 0.1%, and 0.15% of the total diet) supplemented on top of the 0.18% basal level. At baseline, and every 8 weeks throughout the 24-week period, behavioral parameters were evaluated for each dog in response to the approach of an individual familiar to the dogs and another individual who was unfamiliar to the dogs. Differences in behavior scores (activity, P = 0.0197; distance, P = 0.0358; confidence, P < 0.0001; and ear position, P < 0.0001) between the unfamiliar and familiar individuals supported the efficacy of the behavioral ethogram used. No consistent and significant differences in behavior were observed, however, among dogs fed the control diet and those fed an experimental diet with any level of tryptophan supplementation. Future research should consider the tryptophan-to-large-neutral-amino-acid ratio and not just tryptophan concentrations, seek to understand the variation in tryptophan requirements among breeds, and look to utilize additional markers of serotonin status.

Le tryptophane (Trp) est un acide aminé alimentaire indispensable qui supporte la modulation de l'humeur et le comportement chez des espèces animales via son rôle dans le cycle sérotonergique. La présente étude a évalué les patrons de comportement de 36 chiennes adultes en santé de race mélangée de type chien de chasse nourries avec une diète contrôlée (tryptophane = 0,18 %, tel que nourri) ou 1 de plusieurs diètes expérimentales avec des concentrations graduées de tryptophane (0,05 %, 0,1 %, et 0,15 % de la diète totale) ajoutées en plus du niveau de base de 0,18 % de la diète. Au temps 0, et à toutes les 8 semaines pendant la période de 24 semaines de l'étude, les paramètres de comportement furent évalués pour chaque chien en réponse à l'approche d'un individu familier aux chiens et un autre individu qui n'était pas familier aux chiens. Les différences dans les pointages de comportement (activité, P = 0,0197; distance, P = 0,0358; confiance, P < 0,0001; et position des oreilles P < 0,0001) entre l'individu familier et le non-familier supporte l'efficacité de l'éthogramme de comportement utilisé. Aucune différence constante ou significative dans le comportement ne fut observée, toutefois, parmi les chiens nourris la diète témoin et ceux nourris avec une diète expérimentale quelque soit le niveau de Trp ajouté. Des recherches ultérieures devraient considérer le ratio tryptophan/gros acide aminé neutre et pas seulement les concentrations de tryptophane, essayer de comprendre la variation dans les besoins de tryptophane parmi les races, et voir à utiliser des marqueurs additionnels du statut de la sérotonine.(Traduit par Docteur Serge Messier).

Is bupropion useful in the treatment of post-stroke thalamic apathy? A case report and considerations.

Post-stroke apathy is considered to be one of the clinical consequences of lesions affecting the structures of the prefrontal cortex, basal ganglia, thalamus and limbic system. However, there is no current consensus on the treatment of post-stroke apathy, which mainly depends on the underlying etiology and comorbidities. A 62-year-old man, affected by hemorrhagic stroke in the left thalamus, presented with mood depression, anhedonia, hyporexia and marked apathy. The patient underwent clinical evaluation before and after receiving two different pharmacological therapies: escitalopram and bupropion. Only after treatment with the latter drug did the patient show changes: high motivation and willingness to pursue activities, greater interest in the external environment and social life activities, and an overall reduction of apathy. On the basis of our observations in this case, we hypothesize that the thalamic lesion resulted in disconnection of the fronto-striatal-thalamic circuits, and that loss of the dopaminergic striatal innervation caused the patient's apathetic state. The resolution of the apathetic disorder may be attributable to the action of the dopaminergic drug bupropion on the mesocortical pathway.

Escitalopram and NHT normalized stress-induced anhedonia and molecular neuroadaptations in a mouse model of depression.

Anhedonia is defined as a diminished ability to obtain pleasure from otherwise positive stimuli. Anxiety and mood disorders have been previously associated with dysregulation of the reward system, with anhedonia as a core element of major depressive disorder (MDD). The aim of the present study was to investigate whether stress-induced anhedonia could be prevented by treatments with escitalopram or novel herbal treatment (NHT) in an animal model of depression. Unpredictable chronic mild stress (UCMS) was administered for 4 weeks on ICR outbred mice. Following stress exposure, animals were randomly assigned to pharmacological treatment groups (i.e., saline, escitalopram or NHT). Treatments were delivered for 3 weeks. Hedonic tone was examined via ethanol and sucrose preferences. Biological indices pertinent to MDD and anhedonia were assessed: namely, hippocampal brain-derived neurotrophic factor (BDNF) and striatal dopamine receptor D2 (Drd2) mRNA expression levels. The results indicate that the UCMS-induced reductions in ethanol or sucrose preferences were normalized by escitalopram or NHT. This implies a resemblance between sucrose and ethanol in their hedonic-eliciting property. On a neurobiological aspect, UCMS-induced reduction in hippocampal BDNF levels was normalized by escitalopram or NHT, while UCMS-induced reduction in striatal Drd2 mRNA levels was normalized solely by NHT. The results accentuate the association of stress and anhedonia, and pinpoint a distinct effect for NHT on striatal Drd2 expression.

Genome-wide transcriptome analysis of hippocampus in rats indicated that TLR/NLR signaling pathway was involved in the pathogenisis of depressive disorder induced by chronic restraint stress.

Data from clinical investigations and laboratory fundings have provided preliminary evidence for the effectiveness and safety of acupuncture therapy in depression. However, the mechanisms underlying the antidepressant response of acupuncture are not fully elucidated. To elucidate the potential effects of acupuncture for depression on the hippocampal genome-wide transcriptome at the molecular level, we evaluated the transcriptomic profile of depression rats under treatment of acupuncture, and fluoxetine. We identified a very significant effect of acupucture intervention, with 107 genes differentially expressed in acupuncture vs. model group; while 41 genes between fluoxetine vs. model group. Notably, the 54 differentially expressed genes between acupuncture and fluoxetine showed the significantly different effect between acupuncture and fluoxetine. Through GO (gene ontology) functional term and KEGG (kyoto encyclopedia of genes and genomes) pathway analysis, we identified that the upregulation of gene sets were related to inflammatory response, innate immunity and immune response. We found that toll-like receptor signalling pathway and NOD like receptor signalling pathway were associated with the function of inflammatory response, innate immunity and immune response. Importantly, acupuncture reversed the upregulation of gene sets that were related to inflammatory response, innate immunity and immune response (including toll-like receptor signalling pathway and NOD like receptor signalling pathway), which might be critical for the pathogenesis of depression and provide evidence for the antidepressive effects of acupuncture by regulating inflammatory response, innate immunity and immune response via toll-like receptor signalling pathway and NOD like receptor signalling pathway.

Escitalopram or novel herbal treatments differentially alter cytokine and behavioral responses to immune challenge.

Studies suggest that inflammation is involved in the pathophysiology of depression. The present study examined the effects of the commonly used antidepressant escitalopram, in comparison with a novel herbal treatment (NHT) consisted of Crataegus pinnatifida, Triticum aestivum, Lilium brownii and Fructus Ziziphus jujuba, on cytokine and behavioral responses to an immune challenge. Escitalopram augmented lipopolysaccharide-induced tumor necrosis factor (TNF)-α peripheral secretion and induced a faster kinetics of interleukin-1ß secretion, while marginally reducing sickness behavior. NHT, on the other hand, completely abolished lipopolysaccharide-induced interleukin-1ß and TNFα peripheral secretion and diminished sickness behavior. These findings may have implications for the treatment of depressive symptoms associated with immune activation.

Acupuncture ameliorates inflammatory response in a chronic unpredictable stress rat model of depression.

Depression is one of the most common psychiatric disorders. Chronic inflammatory response has been viewed as a key factor in depression. Acupuncture in Chinese medicine has been shown to be an effective treatment for depression. In the present study, we investigated the mechanism underlying antidepressant effect of acupuncture. The rats were subjected to chronic unpredictable mild stress (CUMS) for 28days to induce depressive-like behaviors. Acupuncture treatment was applied once every other day during the 28-day stress period. The behavioral tests (body weight, sucrose consumption and locomotor activity) were performed. The expressions of nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and nuclear factor kappa B (NF-κB) were determined in the rat hippocampus and prefrontal cortex. CUMS induced depressive-like behavior in rats, which was alleviated by acupuncture treatment. The increased levels of NO, PGE2, iNOS and COX-2 induced by CUMS, were all significantly decreased in the hippocampus and prefrontal cortex by acupuncture. Moreover, acupuncture markedly inhibited the activation of NF-κB in rats. These findings showed that the antidepressant-like effect of acupuncture might be mediated by inhibition of inflammatory mediators via modulation of NF-κB in the brain regions.

Effects of Single Administration of Bupropion on Carboxypeptidase E Activity in Structures of Rat Brain.

Depression is associated with changes in the levels of some neurotransmitters in various brain structures. Being the key enzyme of peptide processing, carboxypeptidase E regulates their levels in various structures of the nervous system. Single injection of bupropion induced long-lasting changes in carboxypeptidase E activity in all brain structures. The decrease in enzyme activity observed in 12 and 24 h after bupropion injection confirmed the inhibiting effect of the drug on the hypothalamic-pituitary-adrenal axis. Activation of the enzyme in the medulla oblongata, hypothalamus, and hippocampus observed in 72 h after bupropion administration probably leads to enhanced synthesis and secretion of regulatory peptides (reduced during stress and depression) and stimulation of neurogenesis. Changes in enzyme activity can be a mechanism regulating the level of bioactive peptides involved in the pathogenesis of depression.

The influence of caffeine on the activity of moclobemide, venlafaxine, bupropion and milnacipran in the forced swim test in mice.

AIMS: Worrying data indicate that excessive caffeine intake applies to patients suffering from mental disorders, including depression. It is thus possible to demonstrate the usefulness of caffeine and its derivatives in the treatment of depression. The main goal of the present studywas to evaluate the influence of caffeine (5mg/kg) on the activity of moclobemide (1.5 mg/kg), venlafaxine (1 mg/kg), bupropion (10 mg/kg), and milnacipran (1.25 mg/kg). Moreover, we assessed the influence of caffeine on their serum and brain levels using highperformance liquid chromatography. MAIN METHODS: The experiment was carried out on naïve adult male Albino Swiss mice. Caffeine and tested drugs were administered intraperitoneally. The influence of caffeine on the activity of selected antidepressant drugs was evaluated in forced swim test (FST). Locomotor activity was estimated to verify and exclude false positive/negative results. To assess the influence of caffeine on the levels of studied antidepressant drugs, their concentrations were determined in murine serum and brains using high-performance liquid chromatography. KEY FINDINGS: Caffeine potentiated activity of all antidepressants examined in FST and the observed effects were not due to the increase in locomotor activity in the animals. Only in the case of co-administration of caffeine and milnacipran an increased milnacipran concentration in serum was observed without affecting its concentration in the brain. SIGNIFICANCE: Caffeine potentiates the activity of antidepressant drugs from different chemical groups. The interactions of caffeine with venlafaxine, bupropion and moclobemide occur in pharmacodynamic phase, whereas the interaction of caffeine­milnacipran occurs, at least partially, in pharmacokinetic phase.

Comparison of venlafaxine alone versus venlafaxine plus bright light therapy combination for severe major depressive disorder.

OBJECTIVE: Phototherapy, ie, bright light therapy, is an effective and safe treatment of major depressive disorder (MDD). It exerts rapid mood-elevating activity, similar to antidepressant medications, most likely mediated through both monoaminergic and circadian system melatonergic mechanisms. We assessed the efficiency of bright light therapy as an adjuvant treatment to antidepressant pharmacotherapy in patients with severe MDD randomized by Hamilton Depression Rating Scale (HDRS) score to either (1) 150 mg venlafaxine hydrochloride daily at 7:00 AM or (2) 150 mg venlafaxine plus 60-minute light of 7000 lux the initial week of clinical management (venlafaxine + bright light therapy) daily at 7:00 AM. METHOD: 50 inpatients with severe MDD at the Psychiatry Clinic of Yüzüncü Yil University Training and Education Hospital participated. The study, which was conducted from January 2013 through June 2014, entailed patients diagnosed with severe MDD based on DSM-IV-TR for the first time. Mood states were assessed by the HDRS, Profile of Mood States (POMS), and Beck Depression Inventory (BDI) before treatment and at 1, 2, 4, and 8 weeks of treatment. RESULTS: On the basis of the HDRS score as the primary outcome variable, both strategies significantly improved depression and negative mood states already at the first treatment week (P < .001). Differences in therapeutic effects by treatment strategy were remarkable at the second and fourth weeks of clinical management (P = .018 and P = .011, respectively), with beneficial effects continuing until trial conclusion. Those treated with venlafaxine + bright light therapy evidenced significantly lower HDRS depression scores (P < .05) as well as BDI scores (P < .05) and POMS negative mood states scores (depression-dejection, tension-anxiety, anger-hostility, fatigue-inertia, and confusion-bewilderment subscales; all P < .05) after the second week. At week 4 of the trial, 19 (76%) of the 25 venlafaxine + bright light therapy patients versus just 11 (44%) of the 25 venlafaxine patients (P < .05) attained the target goal of treatment, a HDRS score ≤ 13, indicative of mild depression, and, although not statistically significant in our small sample study (P = .36), at week 8, 76% of venlafaxine + bright light therapy patients (n = 19) versus just 64% of the venlafaxine patients (n = 16) experienced complete remission of depression (HDRS score ≤ 7). CONCLUSIONS: Both venlafaxine and venlafaxine + bright light therapy treatment strategies significantly reversed the depressive mood of patients with severe MDD; however, the latter induced significantly stronger and more rapid beneficial effects. Future longer-term studies with large sample sizes, nonetheless, are required to confirm and generalize these results to patients of diverse ethnicities and cultures with both severe and mild MDD. TRIAL REGISTRATION: ANZCTR.org.au registration number: ACTRN12614001061628.

Mianserin, an antidepressant kills Leishmania donovani by depleting ergosterol levels.

In the present study, we have investigated the antileishmanial potential of mianserin, an antidepressant. Mianserin was found to inhibit both the promastigote and amastigote forms of the parasite in a dose dependant manner. The IC50 values for promastigotes and amastigotes were 21 µM and 46 µM respectively. Interestingly, mianserin failed to inhibit THP-1 differentiated macrophages up to 100 µM concentration thus, exhibiting parasite selectivity. When mianserin was incubated with recombinant Leishmania donovani 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) enzyme, it exhibited an IC50 value of 19.8 µM. Inhibition kinetics revealed competitive mode of enzyme inhibition as the Km increased with no change in Vmax. Further structural investigation of enzyme-inhibitor interaction revealed quenching of HMGR tryptophan intrinsic fluorescence with a K(sv) value of 3.025±0.37 M(-1) and an apparent binding constant of 0.0954 mM. We further estimated ergosterol levels which is a major component of Leishmania cell membrane. It is synthesized by HMGR enzyme, the first rate limiting enzyme of the sterol biosynthetic pathway. Analysis of ergosterol levels by HPLC revealed ∼2.5-fold depletion in mianserin treated promastigotes with respect to untreated parasites. This data was further validated by exogenous supplementation of mianserin treated cells with ergosterol and cholesterol. Reversal of growth inhibition was observed only upon ergosterol addition though it was refractory to cholesterol supplementation. Overall, our results demonstrate the possibility of repositioning of an antidepressant for the treatment of Visceral Leishmaniasis.