Potential Antidepressant Effects Research Articles

N-(3-((3-(trifluoromethyl)phenyl)selanyl)prop-2-yn-1-yl) benzamide induces antidepressant-like effect in mice: involvement of the serotonergic system.

Major Depressive Disorder (MDD) significantly impairs the quality of life for those affected. While the exact causes of MDD are not fully understood, the deficit of monoamines, especially serotonin and noradrenaline, is widely accepted. Resistance to long-term treatments and adverse effects are often observed, highlighting the need for new pharmacological therapies. Synthetic organic compounds containing selenium have exhibited pharmacological properties, including potential antidepressant effects. To evaluate the antidepressant-like effect of N-(3-((3-(trifluoromethyl)phenyl)selenyl)prop-2-yn-1-yl) benzamide (CF3SePB) in mice and the involvement of the serotonergic and noradrenergic systems. Male Swiss mice were treated with CF3SePB (1-50mg/kg, i.g.) and 30min later the forced swimming test (FST) or tail suspension test (TST) was performed. To investigate the involvement of the serotonergic and noradrenergic systems in the antidepressant-like effect of CF3SePB, mice were pre-treated with p-CPA (a 5-HT depletor, 100mg/kg, i.p.) or the receptor antagonists WAY100635 (0.1mg/kg, s.c., a 5-HT1A receptor antagonist), ketanserin (1mg/kg, i.p., a 5-HT2A/2C receptor antagonist), ondansetron (1mg/kg, i.p., a 5-HT3 receptor antagonist), GR110838 (0.1mg/kg, i.p., a 5-HT4 receptor antagonist), prazosin (1mg/kg, i.p., an α1-adrenergic receptor antagonist), yohimbine (1mg/kg, i.p., an α2-adrenergic receptor antagonist) and propranolol (2mg/kg, i.p., a non-selective beta-adrenergic receptor antagonist) at specific times before CF3SePB (50mg/kg, i.g.), and after 30min of CF3SePB administration the FST was performed. CF3SePB showed an antidepressant-like effect in both FST and TST and this effect was related to the modulation of the serotonergic system, specially the 5-HT1A and 5-HT3 receptors. None of the noradrenergic antagonists prevented the antidepressant-like effect of CF3SePB. The compound exhibited a low potential for inducing acute toxicity in adult female Swiss mice. This study pointed a new compound with antidepressant-like effect, and it could be considered for the development of new antidepressants.

Non-Volatile metabolome of different cultivars of Prunus mume blossoms and screening of the antidepressant molecules targeting monoamine oxidase A

Prunus mume is a traditional Chinese plant with high ornamental and medicinal values. Although there has been some research on the antidepressant effect of green calyx Mume Flos through animal tests, there is limited information on the potential antidepressant effects of different cultivars of P. mume and their relevance with intrinsic non-volatile metabolites. In this work, the non-volatile metabolites of P. mume blossom from seven cultivars were analyzed using UPLC-Q-TOF/MS, and their antidepressant activities were examined by targeting monoamine oxidase A (MAO-A). The cultivars included Gulihong (GLH), Yudie (YD), LvE (LE), Zhusha (ZS), Jiangmei (JM), Gongfen (GF) and Meirenmei (MRM). The untargeted analysis identified 148 compounds, including flavonoids, acylated sucroses, phenolic acids etc., out of 1120 compound ions. The Blireiana Prunus MRM displayed a significant difference in both metabolites and activity, compared to the other six true Prunus cultivars, with the lowest inhibitory effect on MAO-A. The correlation analysis between the spectrum and effect of the six true Prunus cultivars was conducted by partial least squares regression (PLSR) and grey correlation (GRA) and screened 45 common active compounds that are likely responsible for the antidepressant activity. A joint analysis with the 50 untargeted differential compounds resulted in 15 compounds finally, which are believed to contribute to the differences in activity between the six cultivars. All of them have a low binding energy with MAO-A in molecular docking. According to their regression coefficients, the plentiful polyacetyl coumaroylsucroses identified in blossom are believed to be the main effective substances for the inhibition activity of MAO-A instead of the flavonoids. The results also suggest that JM may be better than LE as a potential antidepressant herb. However, experiments are required for further validation.

Phytotherapeutic Effects of Ashanti Pepper and Horn of Plenty in Sleep Disorder Management Resulting from Stress-Induced Neurobehavioral Alterations

This investigation explores the potential antidepressant effects arising from the inherent bioactive compounds found in <i>Cnestis ferruguinea</i> and <i>Piper guineense</i>. Both botanical entities contain flavonoids, phenolics, saponins, and tannins, which are known for their anxiolytic, antidepressant, and antioxidant properties. It is worth noting that <i>Cnestis ferruguinea</i> also contains terpenoids, which are recognized for their anxiolytic effects. Given the growing interest in nutritional interventions for neuropsychiatric conditions, our study meticulously examines the antioxidant capacities and anxiolytic properties of these phytochemicals, positioning them as potential regulators of brain health, particularly in the realm of sleep disorders. In response to the increasing demand for therapeutic alternatives with reduced side effects, our inquiry thoroughly examines the antioxidant and anxiolytic profiles of these botanical extracts. Of particular importance, <i>Cnestis ferruguinea</i> exhibits superior antioxidant potential compared to <i>Piper guineense</i>, thus warranting further investigation into its pharmacological utility. Subsequent analysis of the effects of <i>Cnestis ferruguinea</i> on sleep architecture, especially in the context of chronic stress, reveals promising results. The botanical extract significantly prolongs sleep duration in rats exposed to stress, suggesting a potential dual role in mitigating stress-induced neurobehavioral changes and depressive symptoms. Additionally, a noticeable decrease in immobility duration in the forced swim test, along with improvements in acetylcholinesterase levels following <i>Cnestis ferruguinea</i> treatment, provides mechanistic insights into its antidepressant effects. Our findings provide substantial evidence to support the pharmacotherapeutic potential of <i>Cnestis ferruguinea</i>, highlighted by its antioxidant abilities and anxiolytic effects. Further investigations should delve into the intricate molecular pathways underlying these effects, potentially paving the way for innovative botanical-based interventions in neuropsychiatric disorders, particularly those associated with stress-induced neurobehavioral changes and sleep disorders.

Potential antidepressant effects of Traditional Chinese botanical drug formula Chaihu-Shugan-San and its active ingredients.

Background: Depression is a severe mental disorder that poses a significant threat to both the physical and mental wellbeing of individuals. Currently, there are various methods for treating depression, including traditional Chinese herbal formulations like Chaihu-Shugan-San (CSS), which have shown effective antidepressant effects in both clinical and animal research. Objective: This review aims to provide a comprehensive synthesis of evidence related to CSS, considering both preclinical and clinical studies, to uncover its potential multi-level, multi-pathway, and multi-target mechanisms for treating depression and identify its active ingredients. Methods: A thorough search was conducted in electronic databases, including PubMed, MEDLINE, Web of Science, Google Scholar, CNKI, and Wanfang, using keywords such as "Chaihu Shugan" and "depression" to retrieve relevant literature on CSS and its active ingredients. The review process adhered to the PRISMA guidelines. Results: This review consolidates the mechanisms underlying antidepressant effects of CSS and its active ingredients. It emphasizes its involvement in the regulation of monoaminergic neurotransmitter systems, synaptic plasticity, and the hypothalamic-pituitary-adrenal axis, among other aspects. Conclusion: CSS exerts a pivotal role in treating depression through various pathways, including the monoaminergic neurotransmitter system, the hypothalamic-pituitary-adrenal axis, synaptic plasticity, inflammation, brain-derived neurotrophic factor levels, and the brain-gut axis. This review facilitates a comprehensive understanding of the current state of CSS research, fostering an in-depth exploration of the etiological mechanisms of depression and the potential discovery of novel antidepressant drugs.

IV low dose ketamine infusions for treatment resistant depression: Results from a five-year study at a free public clinic in an academic hospital

Individuals with major depressive disorder and treatment resistant depression (MDD-TRD) have limited and sometimes poorly tolerated therapeutic options. Low dose ketamine has presented promising and potent antidepressant effects in this population. To support the existent literature, we conducted a longitudinal study examining five years of real-world clinical data on the use of IV low-dose ketamine alongside standard care for MDD-TRD outpatients. For this study we collected demographic information, clinical scale scores, side effects and dropout data. The data was analyzed using descriptive statistics, effect size using Cohen's D analysis, and multivariate ANOVA (MANOVA) to determine the impact of sociodemographic variables. 71 outpatients (50.28 years old, SD: 14.26; female 74.65%) were included in the analysis. The results showed a significant reduction in depressive symptoms and suicide ideation (SI) by treatment endpoint. 54.93% of patients responded to the treatment, 78.26% experienced transient and mild side effects, and 11.27% of dropped out of the treatment. Multivariate analysis showed that the demographic variables did not impact treatment effect or tolerability. The results of this study suggest that IV low dose ketamine treatment is effective, fast-acting, and well tolerated for the management of depressive symptoms and SI in patients with MDD-TRD in naturalistic clinical practice.

Mitochondrial Metabolism in Major Depressive Disorder: From Early Diagnosis to Emerging Treatment Options.

Major Depressive Disorder (MDD) is one of the most disabling diseases in the world. MDD is traditionally diagnosed based on a patient's symptoms, which can lead to misdiagnosis. Although the pathogenic mechanisms of MDD are unknown, several studies have identified mitochondrial dysfunction as a central factor in the onset and progression of MDD. In the context of MDD, alterations in mitochondrial metabolism can lead to imbalances in energy production and oxidative stress, contributing to the disorder´s underlying pathophysiological mechanisms. Consequently, the identification of mitochondrial dysfunction as a key biomarker for early and accurate diagnosis of MDD represents a significant challenge. Faced with the limits of traditional treatments with antidepressants, new pharmacological therapeutic targets are being investigated such as ketamine/esketamine, psychedelics, or anti-inflammatories. All of these drugs show potential antidepressant effects due to their speed of action and ability to modulate neuroplasticity and/or motor processing. In parallel, non-pharmacological therapeutic targets are studied, like Transcranial Magnetic Stimulation (TMS) and Deep Brain Stimulation (DBS), recognized for their ability to modulate neuronal activity and offer treatment alternatives. As cellular activity is directly related to mitochondrial respiration, the aim of this review is examining the link between mitochondrial dysfunction and MDD, assessing how mitochondrial biomarkers could provide a more objective and precise diagnostic tool, and exploring other treatments in addition to traditional antidepressants, with a specific focus on emerging therapeutic targets. Finally, a detailed analysis of the strengths, weaknesses, opportunities, and threats of these approaches was carried out, highlighting the key challenges that must be addressed.

Erucic acid treatment in lipopolysaccharide-induced anxiety and depression using ADMET properties / behaviour paradigms / interleukins pathways in rats

The neuroimmune system plays a vital role in the etiology of anxiety and depression. In the current research, the aim was to investigate erucic acid's ability to counteract depression and anxiety induced by lipopolysaccharide (LPS) in rats. Erucic acid is known to have anti-inflammatory properties, and it was hypothesized that it would be able to reduce the inflammation and stress associated with LPS-induced anxiety and depression. The rats were distributed into five groups (n = 6). The impact of erucic acid with the dose administration of 10 and 20 mg/kg on anxiety depression-like behaviour was studied using the elevated plus maze test, staircase test, marble-burying behaviour, open field test, hyper emotionality, force swimming, and tail suspension test. Also, the biochemical parameters including cytokines i.e., interleukin-6 (IL-6) and IL-10 were performed. Swiss ADME, pkCSM, and ProTox-II served as as an integrated online platform for precise and complete predictions to determine ADME/T properties of erucic acid. LPS significantly increased anxiety and depression-like behaviour in rats. Erucic acid reduced the lengthening in time of immobility on LPS administration in the tail suspension test and forced swim test indicating the antidepressant type of action. Anti-anxiety effects of erucic acid were increased time spent in the open arms in the elevated plus maze test, decreased repetitive behaviors in the staircase test, marble-burying, and hyper emotionality tests. The high LD50 value (1.382) indicates that erucic acid is relatively non-toxic in acute oral exposures in rats. Erucic acid also prevented LPS-induced elevation of IL-6 and restored the IL-10 levels. It was demonstrated that erucic acid significantly attenuates LPS-induced depression and anxiety in rats. These findings suggest that erucic acid has potential antidepressant and anxiolytic effects, possibly through modulation of the neuroimmune system and inflammatory response. Erucic acid may be beneficial for neuropharmacological effects like anxiety and depression. Additionally, erucic acid may have potential benefits in treating other neurological disorders, such as Alzheimer's disease and Parkinson's disease. Further research is needed to better understand the potential therapeutic applications of erucic acid in neurological disorders.

Diosmin ameliorates LPS-induced depression-like behaviors in mice: Inhibition of inflammation and oxidative stress in the prefrontal cortex

Diosmin is a flavone glycoside with a confirmed therapeutic effectiveness on the chronic venous disorders. In this paper, the classical mouse depression model induced by LPS was established to explore the effect of Diosmin on depression. Firstly, we found that Diosmin could inhibit the inflammation and neuronal damage in the prefrontal cortex (PFC) of mice, and thus alleviating the LPS-induced depressive-like behaviors. Specifically, Diosmin treatment significantly suppressed the secretion of pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β), reduced the activation of microglia, and inhibited the expression of NLRP3 inflammasome and its downstream effector caspase-1 in both PFC of mice and BV2 microglial cells exposed to LPS. Then, we demonstrated that pretreatment with Diosmin dramatically suppressed the LPS-induced oxidative stress in the PFC of mice, manifested in the decrease of reactive oxygen species and malondialdehyde while increase of catalase activity. Consistently, Diosmin also alleviated the oxidative stress in BV2 cells exposed to LPS. Finally, we confirmed that Diosmin effectively suppressed the activation of NF-κB signaling pathway in the PFC of LPS-treated mice. Further in vitro experiments also verified that Diosmin could prevent the p65 transposition to nucleus in LPS-treated BV2 cells, suggesting that the antidepressant effects of Diosmin are partially mediated by blocking of NF-κB signaling. Taken together, this study proposes the potential antidepressant effect of Diosmin, which provides useful support to the development of new therapies for depression.

Treatment outcomes and cognitive function following electroconvulsive therapy in patients with severe depression

BACKGROUND Traditional treatments for major depressive disorder (MDD), including medication and therapy, often fail and have undesirable side effects. Electroconvulsive therapy (ECT) uses electrical currents to induce brief seizures in the brain, resulting in rapid and potent antidepressant effects. However, owing to misconceptions and controversies, ECT is not as widely used as it could and often faces stigmatization. AIM To evaluate the efficacy and safety of ECT compared to those of medication and/or therapy in patients with severe MDD. METHODS This prospective cohort study included 220 individuals with severe MDD who were divided into the ECT and non-ECT groups. The patients in the ECT group underwent bilateral ECT three times a wk until they either achieved remission or reached a maximum of 12 sessions. The non-ECT group received medication and/or therapy according to clinical guidelines for MDD. The primary outcome was the variation in the hamilton depression rating scale (HDRS) score from treatment/ECT initiation to week 12. In addition, patients’ quality of life, cognitive abilities, and biomarkers were measured throughout the study. RESULTS Although both groups showed significant improvements in their HDRS scores over time, the improvement was more pronounced in the ECT group than in the non-ECT group. Additionally, the ECT group exhibited a more substantial improvement in the quality of life and cognitive function than those of the non-ECT group. Compared with the non-ECT group, the ECT group exhibited evi-dently lower variations in the brain-derived neurotrophic factor (BDNF) and cytokine interleukin-6 (IL-6) levels. The side effects were generally mild and comparable between the two groups. ECT is safer and more potent than medication and/or therapy in mitigating depressive symptoms, enhancing well-being, and bolstering cognitive capabilities in individuals with severe MDD. ECT may also affect the levels of BDNF and IL-6, which are indicators of neuroplasticity and inflammation, respectively. CONCLUSION ECT has emerged as a potentially advantageous therapeutic approach for patients with MDD who are unresponsive to alternative treatments.

Resistance Training in Depression.

More than 320 million people around the world suffer from depression. Physical activity and sports are effective treatment strategies. Endurance training has already been intensively studied, but any potential antidepressant effect of resistance training is unknown at present, nor is it clear whether this could yield any relevant benefit in clinical use. The PubMed database was selectively searched for recent studies and review articles concerning the use, efficacy, and safety of resistance training in persons with depressive symptoms and diagnosed depression. Two meta-analyses revealed that resistance training alleviated depressive symptoms with a low to moderate effect size (0.39-0.66). Resistance training in patients with diagnosed depression was studied in seven randomized controlled trials, in which the duration of the intervention ranged from eight weeks to eight months. In six of these trials, the depressive symptoms were reduced. In one trial, a persistent benefit was seen in the resistance-training group at 26 months of follow-up (adherence, 33%). Moreover, resistance training improved strength, quality of life, and quality of sleep. No serious adverse events occurred; this indicates that resistance training in depression is safe. Resistance training seems to have an antidepressant effect. Open questions remain concerning its effects in different age groups, as well as the optimal training parameters. Further high-quality trials will be needed to document the effect of resistance training more conclusively and to enable the formulation of treatment recommendations.

Exploring the Role of Drug Repurposing in Bridging the Hypoxia-Depression Connection.

High levels of oxidative stress are implicated in hypoxia, a physiological response to low levels of oxygen. Evidence supports a connection between this response and depression. Previous studies indicate that tryptophan hydroxylase can be negatively affected in hypoxia, impairing serotonin synthesis and downstream pathways. Some studies also hypothesize that increasing hypoxia-inducible factor-1 (HIF-1) levels may be a new therapeutic modality for depression. Hence, this study delved into the influence of hypoxia on the cellular response to drugs designed to act in depression. By the induction of hypoxia in SH-SY5Y cells through a hypoxia incubator chamber or Cobalt Chloride treatment, the effect of Mirtazapine, an antidepressant, and other drugs that interact with serotonin receptors (TCB-2, Dextromethorphan, Ketamine, Quetiapine, Scopolamine, Celecoxib, and Lamotrigine) on SH-SY5Y cellular viability and morphology was explored. The selection of drugs was initially conducted by literature search, focusing on compounds with established potential for employment in depression therapy. Subsequently, we employed in silico approaches to forecast their ability to traverse the blood-brain barrier (BBB). This step was particularly pertinent as we aimed to assess their viability for inducing potential antidepressant effects. The effect of these drugs in hypoxia under the inhibition of HIF-1 by Echinomycin was also tested. Our results revealed that all the potential repurposed drugs promoted cell viability, especially when hypoxia was chemically induced. When combined with Echinomycin, all drugs decreased cellular viability, possibly by the inability to interact with HIF-1.

Evaluation of the Therapeutic Effect of Curcumin-Conjugated Zinc Oxide Nanoparticles on Reserpine-Induced Depression in Wistar Rats

Depression, a devastating brain illness, necessitates the exploration of novel antidepressant treatments. We evaluated the antidepressant effects of free curcumin, zinc oxide nanoparticles (ZnO NPs), and curcumin-conjugated zinc oxide nanoparticles (Zn(cur)O NPs). The nanoformulations were extensively characterized using advanced techniques. An acute toxicity study ensured the safety of Zn(cur)O NPs. Rats were assigned to one of five groups: control, reserpine-induced depression model, treatment with ZnO NPs, free curcumin, or Zn(cur)O NPs. Behavioral assessments (forced swimming test [FST] and open-field test [OFT]) and neurochemical analyses were conducted. Zn(cur)O NPs exhibited superior efficacy in ameliorating reserpine-induced behavioral and neurochemical effects compared to free curcumin and ZnO NPs. The reserpine-induced model displayed reduced motor activity, swimming time, and increased immobility time in the FST and OFT. Treatment with Zn(cur)O NPs 45 mg/kg significantly improved motor activity and reduced immobility time. Furthermore, Zn(cur)O NPs decreased malondialdehyde (MDA) levels while increasing reduced glutathione (GSH) and catalase (CAT) levels. Additionally, concentrations of serotonin (5-HT) and norepinephrine (NE) increased. In conclusion, curcumin-conjugated zinc oxide nanoparticles demonstrate potent antidepressant effects, alleviating depressive-like behavior in rats. These findings support Zn(cur)O NPs as a promising therapeutic strategy for depression management, warranting further investigation and clinical validation.

Akkermansia muciniphila Improves Depressive-Like Symptoms by Modulating the Level of 5-HT Neurotransmitters in the Gut and Brain of Mice

Accumulating evidence has suggested that the gut microbiome plays an important role in depression. Akkermansia muciniphila (AKK), a next-generation probiotic, shows a beneficial effect on immune and metabolic homeostasis. The relative abundance of AKK was found negatively correlated with depressive symptoms in both clinical and pre-clinical studies. To evaluate the potential antidepressant effect of AKK and explore the possible mechanism, we used chronic alcohol exposure and chronic unpredictable mild stress (CUMS) to induce depressive-like behaviors in mice. We found that oral AKK administration significantly reduced the immobility time in the force swimming test (FST) and tail suspension test (TST) in the mice with chronic alcohol exposure and the CUMS mice. The sucrose preference in the mice receiving AKK was significantly increased in the sucrose preference test (SPT). More importantly, AKK implantation significantly increased the level of 5-HT in the gut and PFC of both the alcohol exposure mice and the CUMS mice. Furthermore, AKK had inhibited the expression of SERT in the gut but not in the brain for both NIAAA and the CUMS model mice. Interestingly, the expression of cFos in enteric nerves in the gut significantly decreased after AKK administration. In conclusion, our study demonstrated the antidepressant effect of AKK in mice exposed to alcohol exposure and CUMS, with the potential mechanism that AKK implantation might lead to an increased level of 5-HT and inhibited SERT expression in the gut, and might alter the gut-to-brain signal through suppression of enteric nerves activation.

Right posterior insular epidural stimulation in rats with neuropathic pain induces a frequency-dependent and opioid system-mediated reduction of pain and its comorbid anxiety and depression

Neuropathic pain (NP) is a sensory, emotional, and persistent disturbing experience caused by a lesion or disease of the somatosensory system which can lead when chronic to comorbidities such as anxiety and depression. Available treatments (pharmacotherapy, neurostimulation) have partial and unpredictable response; therefore, it seems necessary to find a new therapeutical approach that could alleviate most related symptoms and improve patients ‘emotional state’. Posterior Insula seems to be a potential target of neurostimulation for pain relief. However, its effects on pain-related anxiety and depression remain unknown. Using rats with spared nerve injury (SNI), this study aims to elucidate the correlation between NP and anxio-depressive disorders, evaluate potential analgesic, anxiolytic, and antidepressant effects of right posterior insula stimulation (IS) using low (LF-IS, 50 Hz) or high (HF-IS, 150 Hz) frequency and assess endogenous opioid involvement in these effects. Results showed positive correlation between NP, anxiety, and depression. LF-IS reversed anhedonia and despair-like behavior through pain alleviation, whereas HF-IS only reduced anhedonia, all effects involving endogenous opioids. These findings support the link between NP and anxio-depressive disorders. Moreover, IS appears to have analgesic, anxiolytic and antidepressant effects mediated by the endogenous opioid system, making it a promising target for neurostimulation.

Potential antidepressant effects of a dietary supplement from Huáng qí and its complex in aged senescence-accelerated mouse prone-8 mice.

Healthcare is an emerging industry with significant market potential in the 21st century. Therefore, this study aimed to evaluate the benefits of tube feeding Huáng qí and its complexes for 8 weeks on 3-month-old senescence-accelerated mouse prone-8 (SAMP8) mice, 48 in total, randomly divided into 3 groups including control, Huáng qí extract [820 mg/kg Body weight (BW)/day], and Huáng qí complexes (6.2 mL /kg BW/day), where each group consisted of males (n = 8) and females (n = 8). Behavioral tests (locomotion test and aging score assessment on week 6, the single-trial passive avoidance test on week 7, and the active shuttle avoidance test on week 8) were conducted to evaluate the ability of the mice to learn and remember. In addition, after sacrificing the animals, the blood and organs were measured for antioxidant and aging bioactivities, including malondialdehyde (MDA) content and superoxide dismutase (SOD) activity and catalase activities (CAT), and the effects on promoting aging in SAMP8 mice were investigated. The findings showed that Huáng qí enhanced locomotor performance and had anti-aging effects, with positive effects on health, learning, and memory in SAMP-8 mice (p < 0.05), whether applied as a single agent (820 mg/kg BW/day) or as a complex (6.2 mL/kg BW/day) (p < 0.05). Based on existing strengths, a more compelling platform for clinical validation of human clinical evidence will be established to enhance the development and value-added of astragalus-related products while meeting the diversified needs of the functional food market.

Central nervous system-related safety and tolerability of add-on ketamine to standard of care treatment in treatment-resistant psychotic depression in patients with major depressive disorder and bipolar disorder.

Psychotic treatment-resistant depression represents a complex and challenging form of mood disorder in clinical practice. Despite its severity, psychotic depression is frequently underdiagnosed and inadequately treated. Ketamine has demonstrated rapid and potent antidepressant effects in clinical studies, while exhibiting a favorable safety and tolerability profile. Although there is limited literature available on the use of ketamine in psychotic TRD, reports on its efficacy, safety, and tolerability profile are of great interest to clinicians. The aim of this study is to investigate the relationship between dissociative symptomatology and psychomimetic effects in inpatients with treatment-resistant major psychotic depression and treatment-resistant bipolar psychotic depression, who receive intravenous ketamine treatment alongside psychotropic medication, both during and after treatment. A total of 36 patients diagnosed with treatment-resistant unipolar (17 patients) or bipolar (18 patients) depression with psychotic features were treated with eight intravenous infusions of 0.5 mg/kg ketamine twice a week over 4 weeks. Ketamine was given in addition to their standard of care treatment. The severity of depressive symptoms was evaluated using the MADRS, while dissociative and psychomimetic symptoms were assessed using the CADSS and BPRS, respectively. There were no statistically significant changes observed in MADRS, CADSS, and BPRS scores within the study group during ketamine infusions. However, significant improvements in MADRS, CADSS, and BPRS scores were observed during ketamine infusions in both the unipolar and bipolar depression groups. This study provides support for the lack of exacerbation of psychotic symptoms in both unipolar and bipolar depression.

A phase 1/2 trial to assess safety and efficacy of a vaporized 5-methoxy-N,N-dimethyltryptamine formulation (GH001) in patients with treatment-resistant depression.

Treatment-resistant depression (TRD) is a substantial public health burden, but current treatments have limited effectiveness. The aim was to investigate the safety and potential antidepressant effects of the serotonergic psychedelic drug 5-MeO-DMT in a vaporized formulation (GH001) in adult patients with TRD. The Phase 1 part (n = 8) of the trial investigated two single dose levels of GH001 (12 mg, 18 mg) with a primary endpoint of safety, and the Phase 2 part (n = 8) investigated an individualized dosing regimen (IDR) with up to three increasing doses of GH001 (6 mg, 12 mg, and 18 mg) within a single day, with a primary endpoint of efficacy, as assessed by the proportion of patients in remission (MADRS ≤ 10) on day 7. Administration of GH001 via inhalation was well tolerated. The proportion of patients in remission (MADRS ≤ 10) at day 7 was 2/4 (50%) and 1/4 (25%) in the 12 mg and 18 mg groups of Phase 1, respectively, and 7/8 (87.5%) in the IDR group of Phase 2, meeting its primary endpoint (p < 0.0001). All remissions were observed from day 1, with 6/10 remissions observed from 2 h. The mean MADRS change from baseline to day 7 was -21.0 (-65%) and - 12.5 (-40%) for the 12 and 18 mg groups, respectively, and - 24.4 (-76%) for the IDR. Administration of GH001 to a cohort of 16 patients with TRD was well tolerated and provided potent and ultra-rapid antidepressant effects. Individualized dosing with up to three doses of GH001 on a single day was superior to single dose administration.Clinical Trial registration: Clinicaltrials.gov Identifier NCT04698603.

Vitamins C and D Exhibit Similar Antidepressant Effects to Escitalopram Mediated by NOx and FKBPL in a Stress-Induced Mice Model.

The aim of this study was to investigate the potential antidepressant and anxiolytic effects of vitamin C and vitamin D in a stress-induced mouse model of depression, while also exploring the association between these effects and the levels of circulating NOx, periostin, and FKBPL. Our findings revealed that both vitamin C and vitamin D exhibited comparable antidepressant effects to escitalopram, a commonly used antidepressant, without demonstrating any anxiolytic effects. The antidepressant properties of vitamin C and vitamin D were linked to the normalization of Nox and FKBPL levels, while the levels of periostin showed no significant correlation. These results are consistent with previous research, indicating that the antidepressant effects of vitamin C and vitamin D may be attributed to their antioxidant and anti-inflammatory properties, as well as their modulation of neurotransmission and norepinephrine release. Additionally, our study uncovered elevated levels of periostin in stress-induced depression, which were only restored to normal levels by escitalopram, suggesting a potential role for periostin in mood disorders. Furthermore, FKBPL and NOx levels were increased in stress-induced depression and normalized by treatment with vitamin C, vitamin D, and escitalopram, indicating their involvement in the stress response and gene expression regulation. However, it is important to acknowledge certain limitations of our research, such as the use of a single depression induction model and limited dosing regimens. Future investigations should focus on examining these markers in specific brain regions, such as the hippocampus and prefrontal cortex, to gain a more comprehensive understanding of their potential implications for depression. Overall, our findings suggest that vitamin C, vitamin D, and escitalopram may possess antidepressant properties mediated by NOx and FKBPL levels, while emphasizing the potential significance of periostin in the context of depression.

Anxiolytic-like effects of an mGluR 5 antagonist and a mGluR 2/3 agonist, and antidepressant-like effects of an mGluR 7 agonist in the chick social separation stress test, a dual-drug screening model of treatment-resistant depression

Modulation of glutamate receptors has demonstrated anxiolytic and/or antidepressant effects in rodent stress models. The chick social-separation stress paradigm exposes socially raised aves to an isolation stressor which elicits distress vocalizations (DVocs) in an attempt to re-establish contact. The model presents a state of panic during the first 5 min followed by a state of behavioral despair during the last 60 to 90 min. Making it useful as a dual anxiolytic/antidepressant screening assay. Further research has identified the Black Australorp strain as a stress-vulnerable, treatment-resistant, and ketamine-sensitive genetic line. Utilizing this genetic line, we sought to evaluate modulation of glutamatergic receptors for potential anxiolytic and/or antidepressant effects. Separate dose-response studies were conducted for the following drugs: the AMPA PAM LY392098, the mGluR 5 antagonist MPEP, the mGluR 2/3 agonist LY404039, the mGluR 2/3 antagonist LY341495, and the mGluR 7 agonist AMN082. The norepinephrine α2 agonist clonidine and the NMDA antagonist ketamine were included as comparison for anxiolytic (anti-panic) and antidepressant effects, respectively. As in previous studies, clonidine reduced DVoc rates during the first 5 min (attenuation of panic) and ketamine elevated DVoc rates (attenuation of behavioral despair) during the last 60 min of isolation. The mGluR 2/3 agonist LY404039 and the mGluR 5 antagonist MPEP decreased DVoc rates during the first 5 min of isolation indicative of anxiolytic effects like that of clonidine while the mGluR 7 agonist AMN082 elevated DVoc rates in the later hour of isolation, representative of antidepressant effects like that of ketamine. Collectively, these findings suggest that certain glutamate targets may be clinically useful in treating panic disorder and/or treatment-resistant depression.

Sub-effective doses of a bendroflumethiazide-imipramine combination offer greater synergistic antidepressant effect compared to a bendroflumethiazide-fluoxetine combination: an isobolographic analysis

Background: Bendroflumethiazide is often prescribed with fluoxetine or imipramine for patients with both depression and hypertension. However, there is little data on the potential interactions between these drugs. Objective: The objective of this study was to investigate the potential antidepressant effects of bendroflumethiazide, as well as sub-effective dose combinations of bendroflumethiazide with fluoxetine or imipramine. Methods: Forced swimming and tail suspension tests were used to investigate the behavioural effects of bendroflumethiazide [5-20 mg/kg; per os (p.o],imipramine (3-30 mg/kg; p.o) and fluoxetine (3-30 mg/kg; p.o). Mean immobility, swimming, climbing, curling,and swinging scores were measured. Median effective dose (ED50) values were calculated from the immobility scores. The antidepressant effect of the combination of bendroflumethiazide with imipramine or fluoxetine at sub-effective doses was then investigated. Isobolographic analyses were performed on these combinations to investigate possible synergism, additivity or antagonism. Results: Bendroflumethiazide produced a significant diminution in mean immobility scores, suggestive of an antidepressant-like effect, while increasing swimming, climbing and swinging scores. Imipramine and fluoxetine also exhibited antidepressant-like effects. A combination of bendroflumethiazide and imipramine at sub-effective doses showed a synergistic antidepressant-like effect with an interaction index of 0.31 as did the bendroflumethiazide-fluoxetine combination (interaction index:0.41). Conclusion: This study demonstrated the acute antidepressant-like effect of bendroflumethiazide. Moreover, bendroflumethiazide-imipramine combinations offer greater synergy when compared to bendroflumethiazide-fluoxetine combinations.