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Introduction: In recent years, the consumption of antidepressants has arisen. However, deprescribing antidepressant therapy is very complicated. The aim of this study was to implement practical recommendations for the development of guidelines to be used for antidepressant deprescription in clinical practice. Materials and methods: The literature search has been conducted on March 13, 2023, using Scopus and PubMed databases. The following search string has been used: "antidepressants AND (deprescribing OR deprescription)". All studies reporting a deprescribing intervention for antidepressant medication, regardless of the study design, have been included. Studies that did not report antidepressant drug deprescription interventions and non-English-language papers have been excluded. Results: From the literature search, a total of 230 articles have been extracted. Applying the exclusion criteria, 26 articles have been considered eligible. Most of the analyzed studies (16, 61%) have been carried out in the real world, 3 (11%) were RCTs, 5 (19%) were qualitative studies, in particular expert opinions, 1 (4%) was a literature review, and 1 (4%) was a post-trial observational follow-up of an RCT. In 8 out of 26 studies (31%), the analyzed antidepressants have been specified: 2 (8%) focused on anticholinergics, 2 (8%) on SSRIs, 3 (11%) on tricyclic antidepressants, and 1 (4%) on esketamine. Nineteen out of 26 studies (73%) did not stratify antidepressants by therapeutic class. The sample sizes analyzed in the studies ranged from a minimum of 4 patients to a maximum of 113,909, and 12 studies included geriatric age as an inclusion criterion. A patient's therapy review has been the main deprescribing intervention, and it has been identified in 14 (54%) articles. Interventions have been carried out by clinicians in 4 (15%) studies, general practitioners in 5 (19%) studies, nurses in 2 (8%) studies, pharmacists in 4 (15%) studies, multidisciplinary teams in 10 (38%) studies, and patients in 1 (4%) study. Conclusions: From the literature review, it emerged that there is no clear evidence useful to support clinicians in antidepressant deprescribing interventions. [ABSTRACT FROM AUTHOR]

This paper presents a novel, high sensitive analytical method for electrochemical determination of viloxazine at boron-doped diamond electrode using differential pulse voltammetry (DPV). The verification of viloxazine electrochemical behavior proved that viloxazine undergoes diffusion controlled, one-electron irreversible oxidation process. Optimization stage allowed for selection of acetate buffer solution (pH 5; 0.1 mol dm−3) as the best suitable supporting electrolyte and determination of DPV parameters. The calibration curve was obtained in the concentration range 0.1–20.0 µmol dm−3 with the detection limit equal to 0.04 µmol dm−3, respectively. The optimized procedure was validated by studying the sensitivity, accuracy, and precision of obtained results. The proposed method was successfully employed for viloxazine determination in spiked tap and river water samples with recovery of 95.8–98.8%. [ABSTRACT FROM AUTHOR]

In this paper, we have reported the synthesis and biological evaluation of nineteen (S)-N-substituted-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide derivatives as novel candidate antidepressant and anticonvulsant agents. Compounds 2h, 2k, 2r, and 2s exhibited better potent antidepressant activity and displayed the antidepressant effects in a dose-dependent manner from 10 to 30 mg/kg in the FST and TST. And, we found that the best antidepressant effect of compounds 2r and 2s are likely mediated by an increase in central nervous system 5-HT and NE. In addition, compounds 2r and 2s also exhibited the anticonvulsant activity against MES-induced seizures. Thus, compounds 2r and 2s may be a useful antidepressant adjunct therapy for treating depression in patients with epilepsy. In addition, compounds 2r and 2s showed the anti-inflammatory activity and the excellent analgesic activity. Several scholars have postulated the anti-inflammatory and analgesic effects of antidepressant drugs, suggesting that they may be possess a similar mechanism of action. [ABSTRACT FROM AUTHOR]

In this paper, I offer one moral reason to eschew antidepressant medication in favor of cognitive therapy, all other things being equal: taking antidepressants can be a form of self-objectification. This means that, by taking antidepressants, one treats oneself, in some sense and some cases, like a mere object. I contend that, morally, this amounts to a specific form of devaluing oneself. I argue this as follows. First, I offer a detailed definition of 'objectification' and argue for the possibility of self-objectification on this definition. I then explain why this form of self-objectification is morally problematic. (Morally problematic does not mean morally impermissible. It means, instead, that there is a moral reason opposing the activity in question). After, I describe how taking antidepressants can count as self-objectifying. Finally, I defend my thesis against a key objection offered by Levy. Thus, assuming that antidepressants and cognitive therapy are equally efficacious, and that all other things are equal, the self-objectifying character of antidepressants is a compelling reason to regard cognitive therapy as a first-choice treatment for depression. [ABSTRACT FROM AUTHOR]

Purpose: Educational attainment has been shown to be positively associated with mental health and a potential buffer to stressful events. One stressful life event likely to affect everyone in their lifetime is bereavement. This paper assesses the effect of educational attainment on mental health post-bereavement.Methods: By utilising large administrative datasets, linking Census returns to death records and prescribed medication data, we analysed the bereavement exposure of 208,332 individuals aged 25-74 years. Two-level multi-level logistic regression models were constructed to determine the likelihood of antidepressant medication use (a proxy of mental ill health) post-bereavement given level of educational attainment.Results: Individuals who are bereaved have greater antidepressant use than those who are not bereaved, with over a quarter (26.5 %) of those bereaved by suicide in receipt of antidepressant medication compared to just 12.4 % of those not bereaved. Within individuals bereaved by a sudden death, those with a university degree or higher qualifications are 73 % less likely to be in receipt of antidepressant medication compared to those with no qualifications, after full adjustment for demographic, socio-economic and area factors (OR 0.27, 95 % CI 0.09,0.75). Higher educational attainment and no qualifications have an equivalent effect for those bereaved by suicide.Conclusions: Education may protect against poor mental health, as measured by the use of antidepressant medication, post-bereavement, except in those bereaved by suicide. This is likely due to the improved cognitive, personal and psychological skills gained from time spent in education. [ABSTRACT FROM AUTHOR]

Fluoxetine (FLX) is one of the most persistent pharmaceuticals found in wastewater due to increased use of antidepressant drugs in recent decades. In this study, a nanocomposite of ternary ZnCoAl layered double hydroxide supported on activated carbon (LAC) was used as an adsorbent for FLX in wastewater effluents. The nanocomposite was characterized using Fourier Transform Infrared Spectroscopy (FTIR), scanning electron microscope (SEM), transmission electron microscope (TEM), X-ray diffraction (XRD), and surface area analysis (BET). The adsorption investigations showed that the maximum removal capacity was achieved at pH 10, with a 0.1 g/L adsorbent dose, 50 mL volume of solution, and at a temperature of 25 °C. The FLX adsorption process followed the Langmuir–Freundlich model with a maximum adsorption capacity of 450.92 mg/g at FLX concentration of 50 µg/mL. Density functional theory (DFT) computations were used to study the adsorption mechanism of FLX and its protonated species. The safety and toxicity of the nanocomposite formed from the adsorption of FLX onto LAC (FLX-LAC) was investigated in male albino rats. Acute toxicity was evaluated using probit analysis after 2, 6, and 24 h to determine LD50 and LD100 values in a rat model. The FLX-LAC (20 mg/kg) significantly increased and lengthened the sleep time of the rats, which is important, especially with commonly used antidepressants, compared to the pure standard FLX (7 mg/kg), regular thiopental sodium medicine (30 mg/kg), and LAC alone (9 mg/kg). This study demonstrated the safety and longer sleeping duration in insomniac patients after single-dose therapy with FLX-LAC. Selective serotonin reuptake inhibitors (SSRIs) like FLX were found to have decreased side effects and were considered the first-line mood disorder therapies. [ABSTRACT FROM AUTHOR]

Rationale: Current psychotropic medications have been shown to modulate immune activation. However, the effects of individual psychotropic agents on the immune system and how these might contribute to their efficacy remain largely unclear. Objective: This paper aims to review previous literature on the effects of antidepressants and antipsychotics on the immune system, with a systematic review of in vitro findings, and discuss the relevance of these effects for the response to treatment and future drug development. Results: Inflammatory markers have been associated with fluctuations in clinical status and with treatment response both in depression and psychosis. The in vitro literature on antidepressants shows that some antidepressants, such as clomipramine and fluoxetine, more consistently decrease pro-inflammatory cytokines (interleukin (IL)-6, interferon (IFN)-γ, tumour necrosis factor (TNF)-α), whilst others (mirtazapine and venlafaxine) tend to increase their levels. However, any overall conclusion is challenged by several inconsistent findings, which appear partly dependent on different methodological approaches used. The in vitro studies on antipsychotics are even less clear-cut showing pro- and anti-inflammatory activity for the same antipsychotic agent (haloperidol, clozapine, risperidone) across different studies. We also noted inconsistencies between in vivo and in vitro literature, which could partly be attributed to the interaction in vivo with various biological systems or lifestyle factors that can modulate the immune system. Conclusions: Inflammatory markers seem to hold potential for developing more individualised treatment strategies in the future. In this context, further research disentangling the differential immunomodulatory effects of different drugs could be used for tailoring treatment to specific individuals, according to their immune endophenotypes. [ABSTRACT FROM AUTHOR]

Selective serotonin reuptake inhibitors' (SSRIs') wide use, combined with the blurry limit between health and psychological illness, have led neuroscientists, clinicians and ethicists to envision the possibility of these medications' use in non-clinical populations. This prospect has evoked ethical debates, which have often ignored the findings of the empirical literature. In this context, an evaluation of the empirical evidence for SSRIs' personality enhancing effects is needed. The present paper examines SSRIs' effects on healthy personality, including the Five Factor Model traits Neuroticism and Extraversion, as well as some of their facets: Angry Hostility, Impulsiveness, Vulnerability, Warmth, Gregariousness and Assertiveness. The review encompasses investigations in healthy humans, human clinical populations, as well as relevant animal studies. Emerging data raise the possibility that SSRIs, when used by people without a currently diagnosable mental disorder, may reduce some facets of Neuroticism, especially Angry Hostility. On the other hand, very limited support exists for an SSRI-driven change in other Neuroticism facets, such as Impulsiveness, in healthy humans. An increase in Extraversion (potentially, Warmth, Gregariousness, and, in some contexts, Assertiveness) is possible, but currently available evidence is only indirect. Future research is needed, both to clarify methodological ambiguities in existing studies, and to answer unaddressed questions, such as ones of the stability, predictors, moderators, dose- and context-dependency of the effects. [ABSTRACT FROM AUTHOR]

Rationale: There is an urgent need to identify behaviours in animals that can provide insight into the aetiology and potential treatment of depression in humans. Objectives: This study aimed to validate a repeated measures cognitive affective bias (CAB) test in a rat model of chronic stress and compare CAB with forced swim test (FST) measures. Methods: Male and female Sprague Dawley rats were trained to associate large and small rewards with scent, spatial, and tactile cues, and their response to an ambiguous tactile stimulus tested. Rats underwent weekly CAB testing for 4 weeks with no intervention, or for 2 weeks of chronic restraint stress (CRS), followed by 2 weeks of fluoxetine, vehicle, or no treatment. CRS rats also underwent the FST at selected timepoints. Results: In control rats, CAB was positive and remained stable over the 4-week period. In CRS-fluoxetine and CRS-vehicle groups, CAB was initially positive, became negative during chronic restraint stress, and returned to positive by 2 weeks after treatment. However, in the CRS-no treatment group, CAB was variable at the outset and unstable over time. Behaviour in the FST was not affected by treatment, and there was no correlation between CAB and FST outcomes. Conclusions: Instability in the CRS-no treatment group precluded interpretation of the impact of fluoxetine on CAB post-CRS. Our results suggest that behaviour in the FST does not reflect or alter affective state and support the use of CAB tests as part of the behavioural testing repertoire for preclinical animal models of affective disorders. [ABSTRACT FROM AUTHOR]

Escitalopram, (S)-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile, is a highly selective and potent serotonin reuptake inhibitor that is used to treat depression. Herein, we report the synthesis of ester analogues of escitalopram having π-systems in their structures where the ester groups including allyl, propargyl, methoxyethyl, benzyl and ρ-tolyl replaced the cyano group in escitalopram. The analogues were designed to test the possibility of binding such groups to the phenyl in Phe341 amino acid that is in close proximity to the cyano group in human serotonin transporter (hSERT). In vivo antidepressant evaluation showed good activity for the analogues compared to escitalopram. [ABSTRACT FROM AUTHOR]

Amisulpride is approved for clinical use in treating schizophrenia in a number of European countries and also for treating dysthymia, a mild form of depression, in Italy. Amisulpride has also been demonstrated to be an antidepressant for patients with major depression in many clinical trials. In part because of the selective D2/D3 receptor antagonist properties of amisulpride, it has long been widely assumed that dopaminergic modulation is the proximal event responsible for mediating its antidepressant and antipsychotic properties. The purpose of these studies was to determine if amisulpride’s antidepressant actions are mediated by off-target interactions with other receptors. We performed experiments that: (1) examined the pharmacological profile of amisulpride at a large number of central nervous system (CNS) molecular targets and, (2) after finding high potency antagonist affinity for human 5-HT7a serotonin receptors, characterized the actions of amisulpride as an antidepressant in wild-type and 5-HT7 receptor knockout mice. We discovered that amisulpride was a potent competitive antagonist at 5-HT7a receptors and that interactions with no other molecular target investigated in this paper could explain its antidepressant actions in vivo . Significantly, and in contrast to their wild-type littermates, 5-HT7 receptor knockout mice did not respond to amisulpride in two widely used rodent models of depression, the tail suspension test and the forced swim test. These results indicate that 5-HT7a receptor antagonism, and not D2/D3 receptor antagonism, likely underlies the antidepressant actions of amisulpride. [ABSTRACT FROM AUTHOR]

As a reflection of an exponential increase in smoking rates throughout the world during the last century, the economic and human burden of mortality and morbidity related to smoking is now clearly defined. Smoking cessation is associated with health benefits for people of all ages. In this paper we provide a comprehensive review of current licensed pharmacological smoking cessation agents including efficacy and safety profiles, with comparisons of individual therapies available. Furthermore, we offer a prospective on the need for further testing of other agents including novel avenues of therapy. [ABSTRACT FROM AUTHOR]

It is widely known that new neurons are continuously generated in the dentate gyrus of the hippocampus in the adult mammalian brain. This neurogenesis has been implicated in depression and antidepressant treatments. Recent evidence also suggests that the dentate gyrus is involved in the neuropathology and pathophysiology of schizophrenia and other related psychiatric disorders. Especially, abnormal neuronal development in the dentate gyrus may be a plausible risk factor for the diseases. The synapse made by the mossy fiber, the output fiber of the dentate gyrus, plays a critical role in regulating neuronal activity in its target CA3 area. The mossy fiber synapse is characterized by remarkable activity-dependent short-term synaptic plasticity that is established during the postnatal development and is supposed to be central to the functional role of the mossy fiber. Any defects, including developmental abnormalities, in the dentate gyrus and drugs acting on the dentate gyrus can modulate the mossy fiber-CA3 synaptic transmission, which may eventually affect hippocampal functions. In this paper, I review recent evidence for involvement of the dentate gyrus and mossy fiber synapse in psychiatric disorders and discuss potential importance of drugs targeting the mossy fiber synapse either directly or indirectly in the therapeutic treatments of psychiatric disorders. [ABSTRACT FROM AUTHOR]

The role of antidepressants in suicide prevention is a major public health question, given the high prevalence of both depression and depression-related suicidality. Therefore all means available should be utilised to clarify the influence of antidepressants on suicidality. This paper gives a comprehensive overview of the positive effects of antidepressants on suicidality. In the first section, principal methodological issues related to suicidology in general as well as to clinical and epidemiological studies that investigate the influence of antidepressants on suicidality are discussed. In the second section, the results of controlled clinical studies on the efficacy of antidepressants in suicidality are presented. The third section reports on the results of other types of studies, especially epidemiological studies. Altogether, there seems to be reasonable evidence from different research approaches that antidepressants are able to reduce suicidal ideation and also suicidal behaviour in depressive patients. While the evidence for the beneficial effect on suicidal ideation comes from randomised control group studies, some of which used a placebo arm, the evidence for the prophylactic effect on suicidal behaviour, especially suicide, was primarily obtained from well-designed epidemiological studies. [ABSTRACT FROM AUTHOR]

Pharmacogenetic studies in mood disorders are raising increasing interest, after the first findings of a significant association between antidepressant response and a functional polymorphism in the upstream regulatory region of the serotonin transporter gene (SERTPR). However, the results of published studies are not unequivocal. The reasons of these discordances could be various: the small samples, which could affect the power to detect a good effect size, the use of different and often not comparable scales and methodologies to assess the response rates. Notwithstanding all these limitations, the choice of candidate genes involved in antidepressant response is one of the crucial steps to target future research. In the present paper, we reviewed the literature concerning pharmacogenetic studies on antidepressant response. This analysis evidenced a number of studies consistently confirming the association of the SERTPR short variant with a poorer response to antidepressants, at least for the Caucasian samples. Further unreplicated positive findings included tryptophan hydroxylase (TPH), G-protein beta3-subunit (Gbeta3) and serotonin receptor 2A gene polymorphisms. Through the review, we also suggested possible candidate genes for future studies, which are involved in the main monoaminergic neurotransmitters pathways (norepinephrine, dopamine, serotonin), in substance P, neurokinines and glutamate systems, in the intracellular signal transduction pathway, in the phosphorylation process and in the control of the transcriptional activity system. [ABSTRACT FROM AUTHOR]

Metal oxide nanoparticles are prospective materials for wastewater treatment because of their natural abundance, low cost, and potent textural characteristics. Among metal oxide nanoparticles, manganese dioxide nanoparticles (MnO2NPs) are promising due to the associated structural flexibility, environmentally friendly nature, good stability, and high activity. However, there is a dearth of research on the use of MnO2NPs as adsorbents for water pollutants. In this work, MnO2NPs were synthesized by a green technique using the aqueous leaf extract of Populus nigra for the adsorption of nortriptyline antidepressant and celestine blue dye. The FTIR, XRD, SEM, EDX, TGA, BET, and pHpzc characterizations revealed the successful synthesis of MnO2NPs, possessing potent surface characteristics. The maximum adsorption capacity of 33.94 mg/g and 60.31 mg/g was obtained for the adsorption of nortriptyline and celestine blue, respectively. Optimum adsorption conditions of pH 7.0, concentration 50 mg/L, and sonication time of 60 min for nortriptyline and 180 min for celestine blue were maintained. The isotherm, kinetic, and thermodynamic evaluation revealed the participation of various processes in the adsorption of the pollutants on MnO2NPs. Moreover, MnO2NPs were successfully regenerated with ethanol and reused for adsorption over five cycles. The findings proved that MnO2NPs are promising materials for the efficient decontamination of nortriptyline and celestine blue from wastewater, especially for the dye pollutant. [ABSTRACT FROM AUTHOR]

The effects of the N-methyl-D-aspartate receptor activators D-serine, D-alanine, and sarcosine against schizophrenia and depression are promising. Nevertheless, high doses of D-serine and sarcosine are associated with undesirable nephrotoxicity or worsened prostatic cancer. Thus, alternatives are needed. DAAO inhibition can increase D-serine as well as D-alanine and protect against D-serine-induced nephrotoxicity. Although several DAAO inhibitors improve the symptoms of schizophrenia and depression, they can increase the plasma levels but not brain levels of D-serine. The mechanism of action of DAAO inhibitors remains unclear. We investigated the effects of the DAAO inhibitor sodium benzoate on the prefrontal cortex and hippocampal level of D-alanine as known another substrate with antipsychotic and antidepressant properties and other NMDAR-related amino acids, such as, L-alanine, D-serine, L-serine, D-glutamate, L-glutamate, and glycine levels. Our results indicate that sodium benzoate exerts antipsychotic and antidepressant-like effects without changing the D-serine levels in the brain prefrontal cortex (PFC) and hippocampus. Moreover, D-alanine levels in the PFC and hippocampus did not change. Despite these negative findings regarding the effects of D-amino acids in the PFC and hippocampus, sodium benzoate exhibited antipsychotic and antidepressant-like effects. Thus, the therapeutic effects of sodium benzoate are independent of D-serine or D-alanine levels. In conclusion, sodium benzoate may be effective among patients with schizophrenia or depression; however, the mechanisms of actions remain to be elucidated. [ABSTRACT FROM AUTHOR]

The effects of four serotonin (5-HT)-1A compounds (buspirone, gepirone, ipsapirone and zalospirone) were compared with 5-hydroxytryptophan (5-HTP) [a 5-HT precursor with antidepressant (AD) efficacy], and diazepam (a benzodiazepine anxiolytic), on a differential-reinforcement-of-low-rate 72-s (DRL 72-s) schedule. Past research has shown that AD and anxiolytic compounds each have distinct effects on the DRL 72-s interresponse time (IRT) distribution profile. In the present paper, the profile of the IRT distribution was quantitatively characterized by three metrics: burst ratio, peak location and peak area. 5-HTP shifted the IRT distribution peak toward longer IRT durations, increased reinforcement rate and decreased response rate. The profile of the IRT distribution was not disrupted by 5-HTP. Diazepam disrupted the IRT distribution and increased bursting. In general, the arylpiperazine, 5-HT compounds increased reinforcement rate, decreased response rate and disrupted the profile of the IRT distribution. The effects of the four arylpiperazine 5-HT compounds on the IRT distribution profile were different from the AD profile of 5-HTP and the benzodiazepine anxiolytic profile of diazepam. Disruption of the IRT distribution by buspirone, gepirone, ipsapirone and zalospirone may result from decreased 5-HT transmission mediated by the presynaptic, somatodendritic 5-HT receptor. [ABSTRACT FROM AUTHOR]

We comment on a recent paper of Wang et al. (J Mol Neurosci, ), who have shown that ketamine reduces neuregulin1-ErbB4 signaling in interneurons. [ABSTRACT FROM AUTHOR]

Rationale: Preclinical studies indicate that high-frequency oscillations, above 100 Hz (HFO:100–170 Hz), are a potential translatable biomarker for pharmacological studies, with the rapid acting antidepressant ketamine increasing both gamma (40–100 Hz) and HFO. Objectives: To assess the effect of the uncompetitive NMDA antagonist ketamine, and of D-cycloserine (DCS), which acts at the glycine site on NMDA receptors on HFO in humans. Methods: We carried out a partially double-blind, 4-way crossover study in 24 healthy male volunteers. Each participant received an oral tablet and an intravenous infusion on each of four study days. The oral treatment was either DCS (250 mg or 1000 mg) or placebo. The infusion contained 0.5 mg/kg ketamine or saline placebo. The four study conditions were therefore placebo-placebo, 250 mg DCS-placebo, 1000 mg DCS-placebo, or placebo-ketamine. Results: Compared with placebo, frontal midline HFO magnitude was increased by ketamine (p = 0.00014) and 1000 mg DCS (p = 0.013). Frontal gamma magnitude was also increased by both these treatments. However, at a midline parietal location, only HFO were increased by DCS, and not gamma, whilst ketamine increased both gamma and HFO at this location. Ketamine induced psychomimetic effects, as measured by the PSI scale, whereas DCS did not increase the total PSI score. The perceptual distortion subscale scores correlated with the posterior low gamma to frontal high beta ratio. Conclusions: Our results suggest that, at high doses, a partial NMDA agonist (DCS) has similar effects on fast neural oscillations as an NMDA antagonist (ketamine). As HFO were induced without psychomimetic effects, they may prove a useful drug development target. [ABSTRACT FROM AUTHOR]

The antidepressant activity of (+) and (−)-paeoveitol was first evaluated using the forced swimming test (FST), and (+)-paeoveitol showed potential antidepressant activity by decreasing immobility time of mice (by approximately 26.4%) in the FST at a dose of 20 mg/kg. To explore the structure-activity relationships (SARs) and obtain more potent compounds, twenty derivatives of (+)-paeoveitol were synthesized and evaluated for their agonistic activities on melatonin type I (MT1) and type II (MT2) receptors. As a results, compound 13 with an N-methylpiperazine fragment exhibited obvious effect on MT1 and MT2 receptors with EC50 values of 0.20 and 0.24 mM. Moreover, compound 13 dose-dependently decreased the immobility of mice in the FST and showed an inverted U-shaped dose-effect, and the most efficacious dose (at 40 mg/kg) was comparable to fluoxetine (20 mg/kg) with a reduced immobility time of 29.2% and 34.5%, respectively. In vivo neurochemical assays suggested that compound 13 obviously increased 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine (NE) levels in the mice brain, indicating that its antidepressant effects might be related to the monoaminergic system. In silico ADMET study revealed that 13 has favorable pharmacokinetic properties. These findings suggest that compound 13 could be a potential antidepressant agent. [ABSTRACT FROM AUTHOR]

Epigallocatechin 3-gallate (EGCG) is a natural polyphenolic antioxidant in green tea leaves with well-known health-promoting properties. However, the influence of EGCG on a chronic animal model of depression remains to be fully investigated, and the details of the molecular and cellular changes are still unclear. Therefore, the present study aimed to investigate the antidepressant effect of EGCG in mice subjected to chronic unpredictable mild stress (CUMS). After eight consecutive weeks of CUMS, the mice were treated with EGCG (200 mg/kg b.w.) by oral gavage for two weeks. A forced swimming test (FST) was used to assess depressive symptoms. EGCG administration significantly alleviated CUMS-induced depression-like behavior in mice. EGCG also effectively decreased serum interleukin-1β (IL-1β) and increased the mRNA expression levels of brain-derived neurotrophic factor (BDNF) in the hippocampal CA3 region of CUMS mice. Furthermore, electron microscopic examination of CA3 neurons in CUMS mice showed morphological features of apoptosis, loss or disruption of the myelin sheath, and degenerating synapses. These neuronal injuries were diminished with the administration of EGCG. The treatment effect of EGCG in CUMS-induced behavioral alterations was comparable with that of clomipramine hydrochloride (Anafranil), a tricyclic antidepressant drug. In conclusion, our study demonstrates that the antidepressive action of EGCG involves downregulation of serum IL-1β, upregulation of BDNF mRNA in the hippocampus, and reduction of CA3 neuronal lesions. [ABSTRACT FROM AUTHOR]

Background: Functional dyspepsia (FD) is a disorder that presents with chronic dyspepsia, which is not only very common but also highly affects quality of life of the patients. In Japan, FD became a disease name for national insurance in 2013, and has been gradually recognized, though still not satisfactory. Following the revision policy of Japanese Society of Gastroenterology (JSGE), the first version of FD guideline was revised this time. Method: Like previously, the guideline was created by the GRADE (grading of recommendations assessment, development and evaluation) system, but this time, the questions were classified to background questions (BQs, 24 already clarified issues), future research questions (FRQs, 9 issues cannot be addressed with insufficient evidence), and 7 clinical questions that are mainly associated with treatment. Results and Conclusion: These revised guidelines have two major features. The first is the new position of endoscopy in the flow of FD diagnosis. While endoscopy was required to all cases for diagnosis of FD, the revised guidelines specify the necessity of endoscopy only in cases where organic disease is suspected. The second feature is that the drug treatment options have been changed to reflect the latest evidence. The first-line treatment includes gastric acid-secretion inhibitors, acetylcholinesterase (AChE) inhibitors (acotiamide, a prokinetic agent), and Japanese herbal medicine (rikkunshito). The second-line treatment includes anxiolytics /antidepressant, prokinetics other than acotiamide (dopamine receptor antagonists, 5-HT4 receptor agonists), and Japanese herbal medicines other than rikkunshito. The patients not responding to these treatment regimens are regarded as refractory FD. [ABSTRACT FROM AUTHOR]

A new series of benzocycloheptene amino vinyl bromide derivatives ( 9a- 9m) were synthesized from isomeric mixture of himachalenes through two-step synthesis. The unusual structure of benzocycloheptene amino vinyl bromide derivative ( 9a) was confirmed by NMR and X-ray crystallography analyses. The newly synthesized amino vinyl bromide derivatives of benzocycloheptene were further evaluated for their antidepressant activities. The compound 9c had shown significant reduction in the immobility period. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Ten derivatives of N1 substituted/unsubstituted 5-(4-chlorophenyl)-3-(2-thienyl) pyrazoline were synthesised from chalcone-like intermediate and substituted phenyl hydrazines, hydrazine hydrate, and semi/thiosemicarbazide. The chemical structure of compounds was confirmed by means of IR, H NMR, mass spectroscopy, and elemental analysis. The antidepressant and anticonvulsant activities were investigated by Porsolt's behavioural despair test (forced swimming) and maximum electroshock seizure test, respectively. Rota-Rod test was performed to assess any probable changes in motor coordination induced by the test compounds. Four compounds ( IId, IIg, IIi, and IIj) exhibited good activity profile against depression and docking studies confirmed their consensual interaction with monoamine oxidase A. In addition, compounds IIc and IIe showed protection against MES-induced seizures. [ABSTRACT FROM AUTHOR]

More than a third of patients treated with antidepressants experience treatment resistance. Furthermore, molecular pathways involved in antidepressant effect have yet to be fully understood. Therefore, we performed a systematic review of clinical studies that examined changes in RNA expression levels produced by antidepressant treatment. Literature search was performed through April 2021 for peer-reviewed studies measuring changes in mRNA or non-coding RNA levels before and after antidepressant treatment in human participants following PRISMA guidelines. Thirty-one studies were included in qualitative synthesis. We identified a large amount of heterogeneity between the studies for genes/RNAs measured, antidepressants used, and treatment duration. Of the six RNAs examined by more than one study, expression of the brain-derived neurotrophic factor (BDNF) gene and genes in the inflammation pathway, particularly IL-1β, were consistently reported to be altered by antidepressant treatment. Limitations of this review include heterogeneity of the studies, possibility of positive publication bias, and risk of false-negative findings secondary to small sample sizes. In conclusion, our systematic review provides an updated synthesis of RNA expression changes produced by antidepressant treatment in human participants, where genes in the BDNF and inflammatory pathways were identified as potential targets of antidepressant effect. Importantly, these findings also highlight the need for replication of the included studies in multiple strong, placebo-controlled studies for the identification of evidence-based markers that can be targeted to improve treatment outcomes. [ABSTRACT FROM AUTHOR]

Sociotropy and autonomy are cognitive-personality styles that have been hypothesized to confer vulnerability to different presentations of major depressive disorder (MDD), which may respond differentially to treatment. Specifically, the profile of low sociotropy and high autonomy is hypothesized to indicate a positive response to antidepressant medication. The current study examines sociotropy and autonomy in relation to sertraline treatment response in individuals with MDD. As part of an ancillary study to the larger Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) project, individuals with MDD participated in an 8-week trial of sertraline and completed a self-report questionnaire of sociotropy and autonomy. Discriminant function analyses were used to examine whether sociotropy and autonomy scores could distinguish antidepressant treatment responders (determined by a 50% or greater reduction in depressive symptoms) from non-responders. The sociotropy scale successfully discriminated sertraline treatment responders from non-responders. Further, lower sociotropy was associated with greater improvements in depressive symptomology following sertraline treatment. The current findings suggest individuals with MDD characterized by low sociotropy are more likely to benefit from sertraline. Given the promising results of the Sociotropy-Autonomy Scale in discriminating treatment responders from non-responders, the low resources necessary for administration, and the ease of translation into routine clinical care, the scale warrants further research attention. [ABSTRACT FROM AUTHOR]

Preclinical studies on the effects of abrupt cessation of selective serotonin reuptake inhibitors (SSRIs), a medication often prescribed in alcohol use disorder (AUD) patients with depression, results in alcohol consumption escalation after resuming drinking. However, a potential neuroinflammatory component on this escalation remains unexplored despite the immunomodulatory role of serotonin. Here, we utilized a rat model of 14-daily administration of the SSRI fluoxetine (10 mg/kg/day) along alcohol self-administration deprivation to study the effects of fluoxetine cessation on neuroinflammation after resuming alcohol drinking. Microglial morphology and inflammatory gene expression were analyzed in prelimbic cortex, striatum, basolateral amygdala and dorsal hippocampus. Results indicated that alcohol drinking reinstatement increased microglial IBA1 immunoreactivity and altered morphometric features of activated microglia (fractal dimension, lacunarity, density, roughness, and cell area, perimeter and circularity). Despite alcohol reinstatement, fluoxetine cessation modified microglial morphology in a brain region-specific manner, resulting in hyper-ramified (spatial complexity of branching), reactive (lower heterogeneity and circularity)-like microglia. We also found that microglial cell area correlated with changes in mRNA expression of chemokines (Cx3cl1/fractalkine, Cxcl12/SDF1α, Ccl2/MCP1), cytokines (IL1β, IL6, IL10) and the innate immune toll-like receptor 4 (TLR4) in dorsal hippocampus. Specifically, TLR4 correlated with microglial spatial complexity assessed by fractal dimension in striatum, suggesting a role in process branching. These findings suggest that alcohol drinking reinstatement after fluoxetine treatment cessation disturbs microglial morphology and reactive phenotype associated with a TLR4/inflammatory response to alcohol in a brain region-specific manner, facts that might contribute to alcohol-induced damage through the promotion of escalation of alcohol drinking behavior. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this study was to compare the initiation and type of antidepressant use between refugees and matched Swedish-born youth after a diagnosis of a common mental disorder (CMD) and assess sociodemographic and clinical factors associated with the initiation. Methods: The study cohort included youth aged 16–25 years, with an incident diagnosis of CMD based on specialized health care registers in Sweden 2006–2016, without prior antidepressant use during 1 year. One Swedish-born person was matched for each identified refugee youth (N = 3936 in both groups). Initiation of antidepressant use and factors associated with the initiation, were investigated with logistic regression yielding Odds ratios, OR, and 95% Confidence Intervals, CI. Results: Refugees were less likely to initiate antidepressant use compared with Swedish-born (40.5% vs. 59.6%, adjusted OR 0.43, 95% CI 0.39–0.48). Selective serotonin reuptake inhibitors (SSRIs) were less frequently initiated for refugees than Swedish-born (71.2% vs. 81.3% of initiations, p < 0.0001). Sertraline was the most commonly initiated antidepressant both for refugees (34.3%) and Swedish-born individuals (40.3%). Among refugees, factors associated with increased odds of antidepressant initiation were previous use of anxiolytics or hypnotics, previous sickness absence of < 90 days, cancer and older age (OR range 1.07–2.72), and less than 5 years duration of residency in Sweden was associated with decreased odds (OR 0.76, 95% CI 0.63–0.92). Conclusion: Young refugees with a CMD seem to initiate antidepressants in general and those most effective considerably less often than their Swedish-born counterparts. [ABSTRACT FROM AUTHOR]

The repositioning of drugs has been shown to be an advantageous alternative for treating diseases caused by multidrug-resistant (MDR) microorganisms. The study aimed to investigate the in vitro antibacterial activity of the antidepressants fluoxetine and paroxetine alone and in combination with the antibacterial ciprofloxacin against standard strains and clinical isolates to explore the repositioning of these drugs in severe bacterial infections. Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), tolerance level, fractional inhibitory concentration index (FICI) and interaction of antidepressants with the ciprofloxacin antibiotic were determined using the Checkerboard method against six American Type Culture Collection (ATCC) standard strains and seventy MDR clinical isolates. Both antidepressants showed better antibacterial activity than ciprofloxacin, in addition to being separately bactericidal against all tested Gram-negative and Gram-positive strains. When associated with ciprofloxacin, fluoxetine and paroxetine exhibited significant synergism compared to seventy ciprofloxacin-resistant clinical isolates, demonstrating that these antidepressants were able to increase the antibacterial activity of the antibiotic by eight times. The combination of antidepressants with ciprofloxacin showed relatively better activity against Acinetobacter baumannii, Enterococcus faecium and Klebsiella pneumoniae, strains in which the FICI value obtained was 0.008. The MDR isolates tested in this study ratify the antibacterial properties of the non-antibiotic fluoxetine and paroxetine. In addition, synergism when associated with ciprofloxacin is an alternative for treating serious infections in hospitalized patients. However, additional in vivo studies must be conducted to elucidate the mechanisms of action of these drugs. [ABSTRACT FROM AUTHOR]

Managing irritable bowel syndrome (IBS) has attracted international attention because single-agent therapy rarely relieves bothersome symptoms for all patients. The Japanese Society of Gastroenterology (JSGE) published the first edition of evidence-based clinical practice guidelines for IBS in 2015. Much more evidence has accumulated since then, and new pharmacological agents and non-pharmacological methods have been developed. Here, we report the second edition of the JSGE-IBS guidelines comprising 41 questions including 12 background questions on epidemiology, pathophysiology, and diagnostic criteria, 26 clinical questions on diagnosis and treatment, and 3 questions on future research. For each question, statements with or without recommendations and/or evidence level are given and updated diagnostic and therapeutic algorithms are provided based on new evidence. Algorithms for diagnosis are requisite for patients with chronic abdominal pain or associated symptoms and/or abnormal bowel movement. Colonoscopy is indicated for patients with one or more alarm symptoms/signs, risk factors, and/or abnormal routine examination results. The diagnosis is based on the Rome IV criteria. Step 1 therapy consists of diet therapy, behavioral modification, and gut-targeted pharmacotherapy for 4 weeks. For non-responders, management proceeds to step 2 therapy, which includes a combination of different mechanistic gut-targeted agents and/or psychopharmacological agents and basic psychotherapy for 4 weeks. Step 3 therapy is for non-responders to step 2 and comprises a combination of gut-targeted pharmacotherapy, psychopharmacological treatments, and/or specific psychotherapy. These updated JSGE-IBS guidelines present best practice strategies for IBS patients in Japan and we believe these core strategies can be useful for IBS diagnosis and treatment globally. [ABSTRACT FROM AUTHOR]

Background: Stress increases DNA methylation, primarily a suppressive epigenetic mechanism catalyzed by DNA methyltransferases (DNMT), and decreases the expression of genes involved in neuronal plasticity and mood regulation. Despite chronic antidepressant treatment decreases stress-induced DNA methylation, it is not known whether inhibition of DNMT would convey rapid antidepressant-like effects. Aim: This work tested such a hypothesis and evaluated whether a behavioral effect induced by DNMT inhibitors (DNMTi) corresponds with changes in DNA methylation and transcript levels in genes consistently associated with the neurobiology of depression and synaptic plasticity (BDNF, TrkB, 5-HT1A, NMDA, and AMPA). Methods: Male Wistar rats received intraperitoneal (i.p.) injection of two pharmacologically different DNMTi (5-AzaD 0.2 and 0.6 mg/kg or RG108 0.6 mg/kg) or vehicle (1 ml/kg), 1 h or 7 days before the learned helplessness test (LH). DNA methylation in target genes and the correspondent transcript levels were measured in the hippocampus (HPC) and prefrontal cortex (PFC) using meDIP-qPCR. In parallel separate groups, the antidepressant-like effect of 5-AzaD and RG108 was investigated in the forced swimming test (FST). The involvement of cortical BDNF-TrkB-mTOR pathways was assessed by intra-ventral medial PFC (vmPFC) injections of rapamycin (mTOR inhibitor), K252a (TrkB receptor antagonist), or vehicle (0.2 μl/side). Results: We found that both 5-AzaD and RG108 acutely and 7 days before the test decreased escape failures in the LH. LH stress increased DNA methylation and decreased transcript levels of BDNF IV and TrkB in the PFC, effects that were not significantly attenuated by RG108 treatment. The systemic administration of 5-AzaD (0.2 mg/kg) and RG108 (0.2 mg/kg) induced an antidepressant-like effect in FST, which was, however, attenuated by TrkB and mTOR inhibition into the vmPFC. Conclusion: These findings suggest that acute inhibition of stress-induced DNA methylation promotes rapid and sustained antidepressant effects associated with increased BDNF-TrkB-mTOR signaling in the PFC. [ABSTRACT FROM AUTHOR]

Neural stem cells can generate new neurons in the mouse adult brain in a complex multistep process called neurogenesis. Several factors regulate this process, including neurotransmitters, hormones, neurotrophic factors, pharmacological agents, and environmental factors. Purinergic signaling, mainly the adenosinergic system, takes part in neurogenesis, being involved in cell proliferation, migration, and differentiation. However, the role of the purine nucleoside guanosine in neurogenesis remains unclear. Here, we examined the effect of guanosine by using the neurosphere assay derived from neural stem cells of adult mice. We found that continuous treatment with guanosine increased the number of neurospheres, neural stem cell proliferation, and neuronal differentiation. The effect of guanosine to increase the number of neurospheres was reduced by removing adenosine from the culture medium. We next traced the neurogenic effect of guanosine in vivo. The intraperitoneal treatment of adult C57BL/6 mice with guanosine (8 mg/kg) for 26 days increased the number of dividing bromodeoxyuridine (BrdU)-positive cells and also increased neurogenesis, as identified by measuring doublecortin (DCX)-positive cells in the dentate gyrus (DG) of the hippocampus. Antidepressant-like behavior in adult mice accompanied the guanosine-induced neurogenesis in the DG. These results provide new evidence of a pro-neurogenic effect of guanosine on neural stem/progenitor cells, and it was associated in vivo with antidepressant-like effects. [ABSTRACT FROM AUTHOR]

Purpose: Some reports have described arterial hypertension (AH) in patients treated by serotonin reuptake inhibitor (SRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants. The mechanism remains discussed, some authors suggesting a role of SERT (SERotonin Transporter) inhibition whereas others discussing NET (NorEpinephrine Transporter) involvement. The present study used the pharmacoepidemiological-pharmacodynamic (PE-PD) method to investigate the role of these transporters in SRI- and SNRI-induced AH. Methods: The study involved two successive approaches: first, a PE study (disproportionality analysis) investigating in VigiBase®, the World Health Organization Individual Case safety Report (ICSR) database, the relationships between exposure to SRI AND SNRI, and reports of AH. The primary analysis compared patients receiving one SRI (or one SNRI) with non-users. Secondary analyses were performed according to the pharmacological classes. Results are expressed as reporting odds ratios (ROR) with 95% CI and information component (IC), an indicator for disproportionate Bayesian reporting. Second, we performed a PD study using linear regression analyses to explore the association between the AH signal and binding affinities for NET and SERT (expressed as their pKi ratio) of SRIs and SNRIs. Results: A significant ROR value was found for each individual SRI (except fluvoxamine) and each individual SNRI. ROR values were also significant for SRIs and SNRIs in general with higher values for SNRIs than for SRIs. Similar trends were found using IC. A significant correlation was found between the signal of AH and the NET/SERT pKi ratio (y = 6.57x – 2.55, R2 = 0.68, Pearson coefficient correlation = 0.82). Conclusion: The present study found a positive association between the NET/SERT pKi ratio and the occurrence of arterial hypertension with SRI and SNRI antidepressants. These results are important for the selection of antidepressants in hypertensive and/or at risk depressive patients as well as for future development of antidepressants devoid of hypertensive effect. [ABSTRACT FROM AUTHOR]

Rationale: Reward-related impairments are common in major depressive disorder (MDD) and may contribute to the loss of interest in pleasurable activities. A novel approach to studying reward-related decision-making are effort-based tasks; however, direct comparisons between delayed-onset and rapid-acting antidepressants (ADs) have not yet been carried out. Objectives: To investigate the effects of conventional delayed-onset ADs versus rapid-acting ADs, ketamine and scopolamine, on effort-related choice behaviour. Methods: Female Lister hooded rats were trained in an operant effort for reward task (EfRT) where animals choose between working for a high value-high effort reward and consuming low value-low effort chow. Using a within-subject study design, animals were then tested following acute treatment with different monoaminergic ADs, and the rapid-acting ADs ketamine or scopolamine. Results: Consistent with previous findings, we found choice behaviour was sensitive to dopaminergic manipulations. We observed that pre-feeding altered choice behaviour and that the use of high or low value reward differentially affected behaviour. Monoamine re-uptake inhibitors and rapid-acting ADs resulted in similar, general patterns of reduced motivation without any evidence for specific effects, and we did not observe any clear differences between these classes of antidepressant. Conclusions: Motivational changes induced by dopaminergic manipulations and pre-feeding differentially affect effort choice behaviour. However, both conventional delayed-onset ADs and ketamine and scopolamine appear to have detrimental effects on motivation in this task at the higher doses tested without any evidence of specificity for effort-related choice behaviour, in contrast to their specificity in tasks which look at more cognitive aspects of reward processing. [ABSTRACT FROM AUTHOR]

It is reported that dopamine D1 receptors in the medial prefrontal cortex play a role in the antidepressant actions of (R,S)-ketamine. However, its role in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, is unknown. In the locomotion test, tail suspension test, forced swimming test and 1% sucrose preference test, pretreatment with dopamine D1 receptor antagonist SCH-23390 did not block the antidepressant effects of (R)-ketamine in the susceptible mice after chronic social defeat stress. These findings suggest that dopamine D1 receptors may not play a major role in the antidepressant actions of (R)-ketamine. [ABSTRACT FROM AUTHOR]

Rationale: Dysregulation of the one carbon cycle is documented in depression. Thereby, S-adenosylmethionine (SAMe), a one–carbon cycle nutraceutical compound with a favourable side effect profile, has a theoretical rationale for efficacy. However, further controlled studies are required to confirm SAMe's efficacy. Objectives: To test the efficacy of SAMe versus placebo in unmedicated DSM-5 diagnosed (major depressive disorder) (MDD) patients with mild-to-moderate levels of depressive symptoms. Methods: We conducted an 8-week, double-blind, randomised controlled trial testing 800 mg/day of SAMe monotherapy versus placebo in 49 patients with MDD (Montgomery-Åsberg Depression Rating Scale [MADRS] score 14–25) who were not currently taking antidepressants. One–carbon cycle biomarkers, brain-derived neurotropic factor (BDNF), and relevant single nucleotide polymorphisms (SNPs) were analysed as potential treatment moderators. Results: A clinically relevant differential reduction from baseline to week 8 of 3.76 points occurred on the primary outcome (MADRS) in favour of SAMe. This however was not significant (p = 0.13) on an adjusted linear mixed model, notwithstanding a medium to large effect size of 0.72. A high placebo response rate of 53% occurred (> 50% reduction on MADRS). Exploratory analyses showed that SAMe was however effective in reducing depression amongst participants with milder depression severity (MADRS ≤ 22, p = 0.045). Response was not moderated by BDNF, SNPs, or one–carbon cycle biomarkers, although increased folate concentrations were correlated with improved symptoms in the SAMe group (r = − 0.57, p = 0.026). The treatment was safe and well tolerated. Conclusions: Although a differential reduction in depression symptoms between groups was observed in favour of SAMe, the results of this pilot study were not statistically significant. Trial registration: ANZCTR—Australian New Zealand Clinical Trials Registry; No.: ACTRN12613001299796; URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=364900 [ABSTRACT FROM AUTHOR]

Rationale: Androgen deprivation therapy (ADT) is an effective treatment for prostate cancer, but induces profound cognitive impairment. Little research has addressed mechanisms underlying these deficits or potential treatments. This is an unmet need to improve quality of life for prostate cancer survivors. Objectives: We investigated mechanisms of cognitive impairment after ADT in rats and potential utility of the multimodal serotonin-targeting drug, vortioxetine, to improve the impairment, as vortioxetine has specific efficacy against cognitive impairment in depression. Methods: Male Sprague-Dawley rats were surgically castrated. Vortioxetine (28 mg/kg/day) was administered in the diet. The attentional set-shifting test was used to assess medial prefrontal cortex (mPFC) executive function. Afferent-evoked field potentials were recorded in the mPFC of anesthetized rats after stimulating the ventral hippocampus (vHipp) or medial dorsal thalamus (MDT). Gene expression changes were assessed by microarray. Effects of vortioxetine on growth of prostate cancer cells were assessed in vitro. Results: ADT impaired cognitive set shifting and attenuated responses evoked in the mPFC by the vHipp afferent, but not the MDT. Both the cognitive impairment and attenuated vHipp-evoked responses were reversed by chronic vortioxetine treatment. Preliminary investigation of gene expression in the mPFC indicates that factors involved in neuronal plasticity and synaptic transmission were down-regulated by castration and up-regulated by vortioxetine in castrated animals. Vortioxetine neither altered the growth of prostate cancer cells in vitro nor interfered with the antiproliferative effects of the androgen antagonist, enzalutamide. Conclusions: These results suggest that vortioxetine may be useful in mitigating cognitive impairment associated with ADT for prostate cancer. [ABSTRACT FROM AUTHOR]

Rapid eye movement (REM) sleep without atonia (RWA), which is a hallmark of REM sleep behavior disorder (RBD) on polysomnography (PSG), may represent specific characteristics of prodromal Parkinson's disease (PD)/dementia with Lewy bodies (DLB), even when dream-enactment behavior is absent. We investigated the clinical profiles associated with PD/DLB in late-onset psychiatric patients exhibiting incidental RWA. Among patients who underwent PSG in our psychiatric ward, eight with incidental RWA, nine with idiopathic RBD, and seven with PD or DLB who had preceding RBD were included. Clinical variables, including the percentage of RWA in the total REM sleep (%RWA), were compared among the three groups. The frequency of depressive disorders as a primary psychiatric diagnosis and antidepressant usage were significantly higher in the incidental RWA group than in the other groups. There were no differences in the prevalence of supportive features of DLB among the three groups. The median %RWA was significantly lower in the incidental RWA group than in the other groups. Although the cardiac 123I-metaiodobenzylguanidine uptake was significantly higher in the incidental RWA group compared with the other groups, the groups showed overlap in the specific binding ratios on dopamine transporter imaging. All patients in the three groups exhibited cingulate island sign ratios on brain perfusion single-photon emission computed tomography within a threshold of 0.281, which is the optimal cut-off value for a diagnosis of DLB. In this series, late-onset psychiatric patients with incidental RWA partially shared common clinical profiles with idiopathic RBD and PD/DLB. [ABSTRACT FROM AUTHOR]

The human gut contains trillions of symbiotic bacteria that play a key role in programming different aspects of host physiology in health and disease. Psychotropic medications act on the central nervous system (CNS) and are used in the treatment of various psychiatric disorders. There is increasing emphasis on the bidirectional interaction between drugs and the gut microbiome. An expanding body of evidence supports the notion that microbes can metabolise drugs and vice versa drugs can modify the gut microbiota composition. In this review, we will first give a comprehensive introduction about this bidirectional interaction, then we will take into consideration different classes of psychotropics including antipsychotics, antidepressants, antianxiety drugs, anticonvulsants/mood stabilisers, opioid analgesics, drugs of abuse, alcohol, nicotine and xanthines. The varying effects of these widely used medications on microorganisms are becoming apparent from in vivo and in vitro studies. This has important implications for the future of psychopharmacology pipelines that will routinely need to consider the host microbiome during drug discovery and development. [ABSTRACT FROM AUTHOR]

Despite decades of clinical use and research, the mechanism of action (MOA) of antidepressant medications remains poorly understood. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the most commonly prescribed antidepressants—atypical antidepressants such as bupropion have also proven effective, while exhibiting a divergent clinical phenotype. The difference in phenotypic profiles presumably lies in the differences among the MOAs of SSRIs/SNRIs and bupropion. We integrated the ensemble of bupropion’s affinities for all its receptors with the expression levels of those targets in nervous system tissues. This “combined target tissue” profile of bupropion was compared to those of duloxetine, fluoxetine, and venlafaxine to isolate the unique target tissue effects of bupropion. Our results suggest that the three monoamines—serotonin, norepinephrine, and dopamine—all contribute to the common antidepressant effects of SSRIs, SNRIs, and bupropion. At the same time, bupropion is unique in its action on 5-HT3AR in the dorsal root ganglion and nicotinic acetylcholine receptors in the pineal gland. These unique tissue-specific activities may explain unique therapeutic effects of bupropion, such as pain management and smoking cessation, and, given melatonin’s association with nicotinic acetylcholine receptors and depression, highlight the underappreciated role of the melatonergic system in bupropion’s MOA. [ABSTRACT FROM AUTHOR]

Depression is a major health problem with a high prevalence and a heavy socioeconomic burden in western societies. It is associated with atrophy and impaired functioning of cortico-limbic regions involved in mood and emotion regulation. It has been suggested that alterations in neurotrophins underlie impaired neuroplasticity, which may be causally related to the development and course of depression. Accordingly, mounting evidence suggests that antidepressant treatment may exert its beneficial effects by enhancing trophic signaling on neuronal and synaptic plasticity. However, current antidepressants still show a delayed onset of action, as well as lack of efficacy. Hence, a deeper understanding of the molecular and cellular mechanisms involved in the pathophysiology of depression, as well as in the action of antidepressants, might provide further insight to drive the development of novel fast-acting and more effective therapies. Here, we summarize the current literature on the involvement of neurotrophic factors in the pathophysiology and treatment of depression. Further, we advocate that future development of antidepressants should be based on the neurotrophin theory. [ABSTRACT FROM AUTHOR]

Synedrella nodiflora (SNE) has been used traditionally for many neurological conditions and some of these neuroactive effects have been scientifically substantiated. The usefulness of SNE in depression has however not been investigated despite the availability of data in other disease models indicating it may be useful. The present study therefore examined the effect of SNE in acute murine models of depression and the possible mechanisms mediating its activities in these models. Preliminary qualitative phytochemical and high performance liquid chromatography (HPLC) screening were conducted on SNE. The behavioural effects of SNE (100, 300 and 1000 mg/kg) pre-treated mice were examined in the forced swimming (FST) and tail suspension (TST) tests. Behavioural events such as mobility (swimming, climbing, curling and climbing), and immobility, were scored. The possible involvement of monoamines in the effects of SNE was assessed in the TST by pre-treating mice with α-methyldopa, reserpine and para-chlorophenylalanine (pCPA) in separate experiments. Flavonoids, tannins, saponins, alkaloids, cardiac glycosides, coumarins, triterpenes, sterols, anthraquinones and phenolic compounds were present in SNE. HPLC analysis revealed the presence of two major constituents observed at retention times 42.56 and 46.51 min, with percentage composition of 45.72% and 36.88% respectively. SNE significantly reduced immobility scores in both FST and TST, suggesting antidepressant effects. The antidepressant properties of SNE were reversed by the pre-treatment of α-methyldopa, reserpine and pCPA, suggesting a possible involvement of monoamines (noradrenaline and serotonin) in its mechanism(s) of actions. SNE exhibits antidepressant effects, possibly mediated through an interplay of enhancement of noradrenergic and serotoninergic mechanisms. [ABSTRACT FROM AUTHOR]

Our work is the first systematic meta-analysis to investigate the effect of selective serotonin reuptake inhibitor (SSRI) medication on bone mineral density. Through meta-analyzed 11 studies, our findings suggested that compared with nonusers, use of SSRIs was significantly associated with lumbar spine BMD reduction, particularly for old people. The use of selective serotonin reuptake inhibitors (SSRIs) has already been associated with bone mass loss. Their effects on bone mineral density (BMD) for the different bone sections have, however, thus been inconsistent. Here, we aim to assess the effects of SSRIs on BMD using a meta-analysis. We searched PubMed, Scopus, ISI Web of Knowledge, the Cochrane Library, and PsycINFO for all English-written studies investigating the effects of SSRIs on BMD and published before November 2017. BMD was compared between non-SSRI users and SSRI users using a random-effect model with standardized mean differences (SMD) and 95% confidence intervals (CIs). Furthermore, subgroup analyses were performed based on study design, age, and sex in order to find the origins of high heterogeneity. Eleven studies met the inclusion criteria and were used for the meta-analysis. Our study demonstrated that the use of SSRIs was significantly associated with lower BMD values (SMD − 0.40; 95% CI − 0.79 to 0.00; p = 0.05) and BMD Z-scores (SMD − 0.28; 95% CI − 0.50 to − 0.05; p = 0.02) of the lumbar spine, but not of the total hip and femoral neck. In addition, SSRI use was associated with a greater bone loss in older people. SSRI use is a risk factor of lower BMD of the lumbar spine, especially for older people. Future studies into the relationship between SSRI use and bone metabolism and bone mass need to be conducted with larger sample sizes for both men and women at different bone sites. [ABSTRACT FROM AUTHOR]

Imipramine (IMP), a tricyclic antidepressant drug, is commonly prescribed for treatment of psychiatric patients suffering from different forms of depression. The appropriate amount of drug intake is crucial to ensure the optimum therapeutic effects minimizing severe collateral effects and toxicity. Therefore, the monitoring of imipramine is essential for its clinical applications. Herein, we report an electrochemical sensor based on a composite of ferrocenecarboxylic acid (FCA), β-cyclodextrin (CD), and oxidized multi-walled carbon nanotubes (f-CNT) modified glassy carbon electrode for detection of IMP at low potential. The electrochemical behavior of the proposed sensor was characterized by scanning electron microscopy, Raman spectroscopy, and cyclic voltammetry. The results show that imipramine determination using the proposed sensor occurs around 0 V vs Ag/AgCl in phosphate buffer pH 7.0. The calibration curves were obtained by cyclic voltammetry and differential pulse voltammetry, with linear ranges of 10 to 350 μmol L−1 and 0.1 to 10 μmol L−1, respectively. A detection limit of 0.03 μmol L−1 was obtained for the detection of IMP. The sensor was applied for IMP determination in psychotropic drugs and urine samples and the results show a recovery percentage between 99 and 101% for the analyte. [ABSTRACT FROM AUTHOR]

Peripheral immune activation can have profound physiologic and behavioral effects. One mechanism through which immune activation may affect physiology and behavior is through actions on brainstem neuromodulatory systems, such as serotonergic systems. To test this hypothesis, in Experiment 1, adult male BALB/c mice were implanted with telemetric recording devices and then immunized with Mycobacterium vaccae NCTC 11659 (0.1 mg, s.c.; Days − 28, − 14; N = 36). On Day 1, mice received an acute challenge with M. vaccae (0.1 mg, s.c.) or borate-buffered saline vehicle. Core body temperature and locomotor activity recordings were conducted during a 36 h period beginning 24 h prior to challenge; 12 h following acute challenge, mice were either tested in a 6-min forced swim test, or served as home cage controls ( n = 9 per group). In Experiment 2, the protocol was repeated, but with the aim of assessing c-Fos expression in brainstem serotonergic neurons, assessed 90 min following exposure to forced swim ( N = 32; n = 8 per group). In Experiment 1, acute M. vaccae challenge in M. vaccae-immunized mice, relative to vehicle-challenged controls, decreased locomotor activity and core body temperature measured 3 h following challenge, as measured by continuous telemetric recordings, and decreased immobility in the forced swim test measured 12 h following challenge. In Experiment 2, acute M. vaccae challenge in M. vaccae-immunized mice decreased home cage locomotion, in alignment with findings in Experiment 1, as measured by video-based behavioral analysis, and, among mice exposed to the forced swim test, increased c-Fos expression in subsets of serotonergic neurons within the dorsal raphe nucleus (DR) measured 13.5 h following challenge. Together, these data are consistent with the hypothesis that acute peripheral immune activation with a heat-killed preparation of M. vaccae transiently induces mild hypothermia in association with suppression of locomotor activity, activates subsets of serotonergic neurons in the DR, and induces antidepressant-like behavioral responses. [ABSTRACT FROM AUTHOR]