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This perspective paper explores the choice of psychotherapy for psilocybin‐assisted psychotherapy for treatment‐resistant depression. There is evidence to support the use of some psychotherapies in treating 'treatment‐resistant' depression, and emerging evidence for the efficacy of psilocybin. The next step which is the focus of this paper is to identify psychotherapies that are both effective and congruent with the psilocybin experience. The evidence for the efficacy of the psychotherapies is drawn from a Cochrane review and the analysis of their congruence with the psilocybin experience is drawn from a qualitative meta‐synthesis of the experience of psilocybin. The paper will examine whether three one‐to‐one psychotherapies identified as effective in the treatment of treatment‐resistant depression are compatible with the psilocybin experience. Each psychotherapy will be examined in relation to its congruence with the qualitative evidence that suggests the choice of psychotherapy needs to give priority to the subjective experience, facilitate emotional processing, support connectedness with others, acceptance of the self as emotional and support change based on the person's insights into their relationships with others and the world in which they live. We conclude that interpersonal psychotherapy and intensive short‐term dynamic psychotherapy align with that experience, although others are currently being trialled. [ABSTRACT FROM AUTHOR]

Purpose: Adverse effects of selective serotonin reuptake inhibitors (SSRIs) on sexual function have been an important area of research for many years. However, the duration of SSRI‐associated sexual adverse effects, and their possible persistence after treatment discontinuation, is still uncertain. The aims of the current systematic review were first to identify existing evidence of sexual dysfunction following SSRI discontinuation, and to provide an account of reported symptoms and proposed treatment options; and second, to establish whether current literature allows accurate estimates of the prevalence of such sexual dysfunction. Methods: A systematic review was conducted on PubMed, Embase, and Google Scholar; papers with clinical data regarding patients with persistent sexual dysfunction after SSRI treatment suspension were included. Results: Overall, two retrospective interventional studies, six observational studies and 11 case reports were judged eligible for inclusion. It was not possible to determine reliable estimates of prevalence. Similarly, a cause‐effect relationship between SSRI exposure and persistent sexual impairment could not be ascertained. Nonetheless, the potential for continued sexual disturbances despite discontinuation could not be entirely ruled out. Conclusions: There is a need to investigate a possible dose–response relationship between SSRI exposure and persistent sexual adverse effects. Treatment options for persistent dysfunctions remain limited, but novel therapeutic approaches may be required in order to address an otherwise neglected need for sexual well‐being. [ABSTRACT FROM AUTHOR]

Aim: Research has shown that preventative intervention in individuals at ultra‐high risk of psychosis (UHR) improves symptomatic and functional outcomes. The staged treatment in early psychosis (STEP) trial aims to determine the most effective type, timing and sequence of interventions in the UHR population by sequentially studying the effectiveness of (1) support and problem solving, (2) cognitive‐behavioural case management and (3) antidepressant medication with an embedded fast‐fail option of (4) omega‐3 fatty acids or low‐dose antipsychotic medication. This paper presents the recruitment flow and baseline clinical characteristics of the sample. Methods: STEP is a sequential multiple assignment randomized trial. We present the baseline demographics, clinical characteristics and acceptability and feasibility of this treatment approach as indicated by the flow of participants from first contact up until enrolment into the trial. Recruitment took place between April 2016 and January 2019. Results: Of 1343, help‐seeking young people who were considered for participation, 402 participants were not eligible and 599 declined/disengaged, resulting in a total of 342 participants enrolled in the study. The most common reason for exclusion was an active prescription of antidepressant medication. Eighty‐five percent of the enrolled sample had a non‐psychotic DSM‐5 diagnosis and symptomatic/functional measures showed a moderate level of clinical severity and functional impairment. Discussion: The present study demonstrates the acceptability and participant's general positive appraisal of sequential treatment. It also shows, in line with other trials in UHR individuals, a significant level of psychiatric morbidity and impairment, demonstrating the clear need for care in this group and that treatment is appropriate. [ABSTRACT FROM AUTHOR]

Quinazoline‐2,4(1H,3H)‐dione is a significant class of N‐fused heterocyclic with a wide range of biological functions, including anti‐HIV, anticancer, antifungal, antibacterial, antimutagenic, anticoccidial, anticonvulsant, anti‐inflammatory, antidepressant, antimalarial, antioxidant, antileukemic, and antileishmanial activities, and other activities, and has attracted great attention in organic and medicinal chemistry. As a result, all chemists and pharmaceutical chemists must be aware of many methods to make quinazoline‐2,4(1H,3H)‐dione. This review paper focuses on various methods for producing quinazoline‐2,4(1H,3H)‐diones, such as green methods and homogeneous or heterogeneous catalysts from various precursors under varied conditions. [ABSTRACT FROM AUTHOR]

Aim: Selective serotonin reuptake inhibitors (SSRIs) are used to treat major depressive disorder (MDD) and other psychiatric disorders (e.g., obsessive compulsive disorder, social anxiety disorder, and panic disorder). In MDD treatment, SSRIs do not show remission in approximately 30% of patients, indicating a need for a better treatment option. Forced swimming test (FST) is a behavioral assay to evaluate depression‐like behavior and antidepressant efficacy in rodents. In the present study, we evaluated the combination effect of brexpiprazole with SSRIs on FST in mice, in order to investigate their synergistic effect. Methods: Brexpiprazole (0.003 mg/kg) was intraperitoneally injected to mice 15 min before testing. Escitalopram (10 mg/kg), fluoxetine (75 mg/kg), paroxetine (10 mg/kg), or sertraline (15 mg/kg) were orally administered to mice 60 min before testing. Then, the mice were placed in water and immobility time was measured. Data from animals treated with escitalopram, fluoxetine, paroxetine, and sertraline were pooled as SSRI‐treated group data. Results: Combination treatment of brexpiprazole with SSRIs reduced immobility time in FST more than vehicle or each single treatment. A significant interaction effect was confirmed in the combination of brexpiprazole and SSRIs (p = 0.0411). Conclusion: Efficacy of adjunctive brexpiprazole has already been demonstrated in clinical trials in MDD patients not adequately responding to antidepressants including escitalopram, fluoxetine, paroxetine, and sertraline. The synergistic antidepressant‐like effect of brexpiprazole with SSRIs found in this study supports the already known clinical findings. [ABSTRACT FROM AUTHOR]

A simple, eco‐friendly, accurate and inexpensive pencil graphite electrode (PGE) was utilized for the quantitative determination of Vilazodone hydrochloride (VLZ) by Square wave voltammetric (SWV) method. Optimum electrochemical performance of the electrode was achieved by optimizing the pH of the measuring solution, the rate of potential scan and the time of accumulation onto the electrode surface. The SWV showed linearity over the concentration range of 9.99×10−9 to 9.78×10−7 M, with LOD of 6.4×10−9 M. This method was applied to evaluate VLZ in pharmaceutical preparation and spiked plasma with %recovery± RSD of 99.99±0.41 and 99.40±1.36, respectively. [ABSTRACT FROM AUTHOR]

Background: Postpartum depression (PPD) is a condition that can affect any woman regardless of ethnicity, age, party, marital status, income, and type of delivery. This condition is highly prevalent worldwide. PPD, if not treated timely, can affect the maternal‐child bond and can have a detrimental impact on the future cognitive, emotional, and behavioral development of the child. Interpersonal psychotherapy (IPT) has been reported as an effective treatment of PPD in previous studies as this focuses on relationship and social support issues. Previous reviews conducted in developed nations have reported the superior efficacy of IPT in comparison to other treatment options. There is no systematic review conducted in low to middle‐income countries on the efficacy of IPT on PPD. Therefore it was necessary to undertake a systematic review to assess the effectiveness of IPT in reducing the depression among postpartum women in low and middle‐income countries (LMICs). Objectives: The main aim of this systematic review was to assess the effectiveness of IPT alone or in conjunction with pharmacological therapy and/or other psychological and psychosocial interventions, in reducing depressive symptoms among women diagnosed with PPD residing in LMICs. Search Methods: The systematic search encompassed several prominent databases and grey literature. Furthermore, experts specializing in the field of IPT were consulted to identify any relevant studies conducted in LMICs that fulfilled the predetermined eligibility criteria. The most recent search update was performed in July 2022. Selection Criteria: The PICOS criteria were meticulously defined for this review as described. Participants: Postpartum women diagnosed with PPD in LMICs were included. Intervention: IPT either as a standalone treatment or in conjunction with pharmacological therapy was included. Comparison: any form of psychological therapy or pharmacological therapy, whether administered individually or in combination, was considered for comparison. Study designs: experimental and quasi‐experimental, factorial designs, and quantitative components (experimental, quasi‐experimental, factorial designs) of mixed methods designs were eligible to be included. Studies with single‐group study designs and qualitative studies were excluded from the review. Data Collection and Analysis: Two reviewers from our team conducted a rigorous screening process to determine the eligibility of articles for inclusion. This involved an initial evaluation of titles and abstracts, followed by a comprehensive assessment of the full text of selected articles. In instances where discrepancies arose between the two reviewers, resolution was achieved through discussion or consultation with a third author to establish a consensus. Following the screening process, two team members independently extracted pertinent information and data from the studies that met the inclusion criteria. The treatment effect of the intervention, in comparison to the control group, was subsequently analyzed utilizing the fixed effects model taking into account the small number of studies. Main Results: A total of 17,588 studies were identified from various databases, and 6493 duplicate studies were removed. Subsequently, 9380 studies underwent independent title and abstract screening resulting in the exclusion of 9040 studies. 345 full texts were thoroughly assessed leading to the exclusion of 341 studies, finally including 4 studies for review. The four included trials were randomized trials and comprised a total sample size of 188 women diagnosed with PPD residing in LMICs. Among these studies, three compared IPT with usual treatment, while one study compared IPT with antidepressant medications (ADMs). In terms of the providers of IPT, in one study, IPT was administered by nurses, while psychologists delivered IPT in another study. In one study, community health workers were responsible for providing IPT. However, in one study, information regarding the specific providers of IPT was not available or reported. The primary outcome measure reported in all four studies was depression, assessed using the Edinburgh Postnatal Depression Scale (EPDS). The geographical distribution of the studies included; one conducted in Zambia, one in Kenya, one in Pakistan, and one in Iran. Out of the four studies, three were included in the meta‐analysis, as missing data from one study could not be obtained. Based on the overall treatment effect, it was found that depression scores decreased significantly more in the IPT group compared to other interventions (usual treatment or ADMs) (standardized mean difference [SMD] −0.62, 95% confidence interval [CI] (−1.01, −0.23), Z = 3.13 (p = 0.002), χ2 = 49.49; df = 2; p < 0.00001; I2 = 96%; 3 studies, n = 136). Out of the three studies, two studies compared the effectiveness of IPT in reducing depression scores specifically when compared to the usual treatment, and in both studies, depression scores were reduced significantly in the IPT group as compared to the usual treatment group. Only one study directly compared the effectiveness of IPT with ADM, reporting that IPT was more effective than ADM in reducing depression scores among postpartum women. Regarding adverse outcomes, only one study reported suicidal ideation with one participant in the IPT group and two in the ADM group (RR 0.50, 95% CI (0.05, 5.30), p = 0.56, n = 78). The same study reported seven participants in the ADM group had adverse drug reactions as compared to none in the IPT group (RR 15.0, 95% CI (0.89, 254), p = 0.06, n = 78). Authors' Conclusions: Our comprehensive search yielded a limited number of four studies conducted in such settings. Despite the scarcity of available evidence, the findings collectively suggest that IPT is indeed an effective treatment for reducing PPD when compared to usual treatment and pharmacological therapy. However given the low certainty of evidence, there is a need for further research in the form of well‐designed randomized controlled trials with larger sample sizes and a reduced risk of bias. Such studies would greatly contribute to enhancing the strength and reliability of the evidence base regarding the effectiveness of IPT in the context of PPD in LMICs. The knowledge generated from future research endeavors would be highly valuable in guiding the development of more affordable and cost‐effective treatment approaches for PPD in resource‐limited settings. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to verify the real‐world efficacy and safety of quetiapine fumarate extended‐release tablets (Bipresso® 50 mg and 150 mg; marketing authorization holder is KYOWA Pharmaceutical Industry Co., Ltd., Osaka, Japan) in patients with bipolar depression. Methods: We performed a post‐marketing surveillance with an observation period of 12 weeks. Results: In the safety analysis group (n = 345), adverse drug reactions (ADRs) occurred in 111 patients (32.17%). The most common ADRs (>1%) were somnolence in 55 patients (15.94%), akathisia in 11 (3.19%), dizziness in 10 (2.90%), weight increase in 6 (1.74%), thirst in 5 (1.45%), and hypersomnia, constipation, and nausea in 4 patients each (1.16%). The only severe ADR was one patient of suicidal ideation, and "longer time since the onset of the first episode" (p = 0.011) and "presence of complications" (p < 0.001) were identified as significant risk factors for the occurrence of ADRs. In the efficacy analysis group (n = 265), the average changes from baseline in the total Montgomery–Åsberg Depression Rating Scale (MADRS) score were −7.3 ± 8.8, −12.2 ± 10.7, −16.8 ± 12.7, and −13.2 ± 12.7 points after 4, 8, and 12 weeks, and at the last evaluation, respectively. The mean MADRS total score decrease had no significant association with maximum daily dose, diagnosis, and presence or absence of prior or concomitant treatment for bipolar disorder with mood stabilizers/antipsychotics/antidepressants. Conclusion: The efficacy of quetiapine fumarate extended‐release tablets was confirmed in clinical practice, and no new safety concerns or risks were identified. [ABSTRACT FROM AUTHOR]

Though the discontinuer group was a better comparison group than pregnancies occurring in individuals who did not use antidepressants prior to pregnancy, the observed results could still be due to confounding by severity of symptoms of the condition that indicated antidepressant use. Dear Editor, More than 13% of pregnant individuals experience depression making depression during pregnancy a highly prevalent condition.1 In addition, anxiety is rather common during pregnancy with rates of specific anxiety disorders varying from 3% to 6% among pregnant individuals.2 Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), are commonly prescribed to treat depression and anxiety.3 For example, a Canadian study found that 55% of antidepressants were prescribed for depression and 19% were prescribed for anxiety. We would expect individuals with more severe depression and anxiety symptoms to be more likely to continue antidepressant use during pregnancy than individuals who discontinue antidepressant use before pregnancy. [Extracted from the article]

Locus coeruleus (LC) dysfunction is involved in the pathophysiology of depression; however, the neural circuits and specific molecular mechanisms responsible for this dysfunction remain unclear. Here, it is shown that activation of tyrosine hydroxylase (TH) neurons in the LC alleviates depression‐like behaviors in susceptible mice. The dorsolateral septum (dLS) is the most physiologically relevant output from the LC under stress. Stimulation of the LCTH‐dLSSST innervation with optogenetic and chemogenetic tools bidirectionally can regulate depression‐like behaviors in both male and female mice. Mechanistically, it is found that brain‐derived neurotrophic factor (BDNF), but not norepinephrine, is required for the circuit to produce antidepressant‐like effects. Genetic overexpression of BDNF in the circuit or supplementation with BDNF protein in the dLS is sufficient to produce antidepressant‐like effects. Furthermore, viral knockdown of BDNF in this circuit abolishes the antidepressant‐like effect of ketamine, but not fluoxetine. Collectively, these findings underscore the notable antidepressant‐like role of the LCTH‐dLSSST pathway in depression via BDNF‐TrkB signaling. [ABSTRACT FROM AUTHOR]

Aims: In Japan, the daily dosage of hypnotic drugs for insomnia treatment is increasing year by year, and over‐dependence on treatment with hypnotic drugs is a major problem. This study aimed to examine the factors related to the elimination of prescriptions of three or more hypnotic drugs within 1 year in our clinic. Methods: We conducted two surveys. Survey ① assessed the frequency of prescriptions of three or more hypnotic drugs by retrospectively reviewing the medical records of all patients who visited general and psychiatric outpatient clinics from January 2013 to March 2019. Survey ② assessed changes in prescriptions of hypnotic and psychotropic drugs within the subsequent year by retrospectively reviewing the medical records of all patients prescribed three or more hypnotic drugs who visited neuropsychiatric outpatient clinics multiple times between April 2013 and March 2019. Results: The frequency of prescribing three or more hypnotic drugs was six to nine times higher in psychiatry than in other departments. Flunitrazepam and brotizolam were the most common drugs prescribed and had the second lowest discontinuation rate after zolpidem. Conversely, eszopiclone, zopiclone, and suvorexant had the highest discontinuation rates. The success factors for drug reduction were age (odds ratio [OR]: 0.97, p < 0.0037), trazodone addition (OR: 12.86, p < 0.0194) and number of years of psychiatric experience. Conclusions: The characteristics and success factors in relation to drug reduction in patients with multiple prescriptions of hypnotic drugs identified in this study may contribute to solving the problem of multiple prescriptions of hypnotic drugs. [ABSTRACT FROM AUTHOR]

Introduction: The question remains to be elucidated: "Is treatment with antidepressants at doses approved in Japan effective for Japanese patients with MDD?" It is crucial to confirm this in order to provide appropriate treatments for Japanese patients with major depressive disorder (MDD). Therefore, we conducted a systematic review and random‐effects pairwise meta‐analysis including these nine double‐blind, randomized, placebo‐controlled trials. Methods: We calculated the standardized mean difference (SMD) and risk ratio (RR) with a 95% confidence interval (95% CI). Results: Pooled newer antidepressants outperformed placebo regarding improvement of depressive symptom scale scores [SMD (95% CI) = −0.20 (−0.27, −0.12), p < 0.00001], response to treatment [RR (95% CI) = 1.23 (1.13, 1.32), p < 0.00001], and remission rate [RR (95% CI) = 1.30 (1.16, 1.45), p < 0.00001]. Although all‐cause discontinuation was not significantly different between the treatment groups, the pooled antidepressant group showed a higher discontinuation rate due to adverse event [RR (95% CI) = 1.60 (1.13, 2.26), p = 0.007] and a higher incidence of at least one adverse event than the placebo group [RR (95% CI) = 1.13 (1.08, 1.18), p < 0.00001]. Discussion: We concluded that newer antidepressants are effective for Japanese adults with MDD although the clinicians must monitor the health conditions of these individuals. [ABSTRACT FROM AUTHOR]

Background: Our knowledge of the broader impacts of antidepressant withdrawal, beyond physical side effects, is limited. Further research is needed to investigate the lived experiences of withdrawal, to aid clinicians on how to guide patients through the process. Aim: To explore antidepressant users' experiences and views on the withdrawal process and how it affected their quality of life across multiple life domains. Design and Setting: We conducted in‐depth qualitative interviews with 20 individuals from the community who had attempted to withdraw from Serotonin Reuptake Inhibitor antidepressants in the past year. Method: Semi‐structured interviews were conducted online. A topic guide was used to ensure consistency across interviews. The interviews were audio‐recorded and transcribed verbatim and analysed using inductive reflexive thematic analysis. Results: Five themes were generated. The first highlighted the challenges of managing the release from emotional blunting and cognitive suppression following antidepressant discontinuation. The second related to the negative impact of withdrawal on close relationships and social interactions. The third showed that concurrent with negative physical symptoms, there was a positive impact on health (exercise was reported by some as a coping mechanism). The fourth theme focused on support from GPs and families, emphasising the importance of mental health literacy in others. The final theme underscored the importance of gradual and flexible tapering in enabling a manageable withdrawal experience, and the consideration of timing. Conclusion: The lived experience of withdrawal significantly impacts individuals' well‐being. Participants emphasised that withdrawal is not just about physical side effects but also affects their emotional, cognitive, and social functioning. Patient and Public Involvement (PPI): Eight people attended individual online meetings to share their experiences of antidepressant withdrawal to help inform the study design and recruitment strategy. Insights from these meetings informed the development of the topic guide. Questions about GP involvement, family relationships, and mood and thinking changes were included based on this PPI work. This ensured the inclusion of topics important to antidepressant users and facilitated the researcher's questioning during the interviews. [ABSTRACT FROM AUTHOR]

Association between antidepressant use and reduced risk of intubation or death in hospitalized patients with COVID-19: results from an observational study. Hence, FIASMA initiation within the first 24 hours, and a median follow-up of 9.2 days, as reported in the study, may not be suitable to establish a link between FIASMAs and a reduced risk of intubation or death; furthermore, confounding variables may be present. We read with great interest the paper by Hoertel I et al i .1 suggesting that functional inhibitors of acid sphingomyelinase (FIASMA) medication use was significantly associated with reduced likelihood of intubation or death in patients hospitalized for severe coronavirus disease 2019 (COVID-19). [Extracted from the article]

Cenesthopathy is a rare syndrome characterized by strange bodily and oral sensations and is classified as a delusional disorder, somatic type, according to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders. Cenesthopathy has been considered difficult to treat. However, to improve cenesthopathy, many pharmacotherapeutic options are reported, including antidepressants and antipsychotics. In this case report, vortioxetine significantly alleviated the distress of oral cenesthopathy in a patient with cerebral ischemia and depression without any adverse effects. To the best of our knowledge, this is the first report on the efficacy of vortioxetine in treating cenesthopathy. Though it is unclear why vortioxetine was effective for cenesthopathy in our case, we stated two possibilities for improving his oral cenesthopathy. When treating oral cenesthopathy in elderly patients, clinicians consider to be one of the options to prescribe vortioxetine. In this case report, vortioxetine significantly alleviated the distress of oral cenesthopathy in a patient with cerebral ischemia and depression without any adverse effects. [ABSTRACT FROM AUTHOR]

I Sir, i We are grateful to Drs Braillon and Bewley for their interest in our recent paper in I BJOG i 1 and would like to elaborate on some of the important points they raise. GRAPH: Supplementary Material GRAPH: Supplementary Material GRAPH: Supplementary Material GRAPH: Supplementary Material GRAPH: Supplementary Material GRAPH: Supplementary Material GRAPH: Supplementary Material References 1 Kolding L, Ehrenstein V, Pedersen L, Sandager P, Petersen OB, Uldbjerg N, et al. [Extracted from the article]

Introduction: Treatment‐resistant depression (TRD) is depression unresponsive to antidepressants and affects 55% of British primary care users with depression. Current evidence is from secondary care, but long referral times mean general practitioners (GPs) manage TRD. Studies show that people with depression use Twitter to form community and document symptoms. However, Twitter remains a largely unexplored space of documented patient experience. Twitter data could provide valuable insights into learning about primary care experiences of TRD. In this study, we explored Twitter comments and conversations about TRD and produced patient‐driven recommendations. Methods: Tweets from UK‐based users were collected manually and using a browser extension in June 2021. Conventional content analysis was used to provide an overview of the Tweets, followed by interpretation to understand why Twitter may be important to people with TRD. Results: A total of 415 Tweets were organised into five clusters: self‐diagnosis, symptoms, support, small wins and condition experts. These Tweets were interpreted as showing Twitter as a community for people with TRD. People had a collective sense of illness identity and were united in their experiences of TRD. However, users in the community also highlighted the absence of effective GP care, leading users to position themselves as condition experts. Users shared advice from a place of lived experience with the community but also shared potentially harmful information, including recommendations about nonevidence‐based medications. Conclusions: Findings illuminate the benefits of the TRD Twitter community and also highlight that the perception of a lack of knowledge and support from GPs may lead community members to advise nonevidenced‐based medications. Patient and Public Contribution: This study was led by a person with lived experience of TRD and bipolar. Two public contributors with mental health conditions gave feedback on our study protocol and results. [ABSTRACT FROM AUTHOR]

Objective: The term "mood stabilizer" is controversial in the literature and criticized for being imprecise and overly inclusive, having its retirement suggested to avoid misuse. Nevertheless, it continues to be employed as it may still carry important meaning. Methods: We employed document analysis for reviewing relevant definitions of mood stabilizer employed in the literature. Then, we clarify the meanings associated with the term by employing evolutionary concept analysis. Based on its results, we present a theoretical model for a mood stabilizer and further match it with evidence gathered from published meta‐analyses and other sources for drugs used in the treatment of bipolar disorder. Results: Concept analysis unearthed four attributes of a mood stabilizer that were nested into the following ascending hierarchy: "not worsening," "acute effects," "prophylactic effects," and "advanced effects." "Prophylactic effects" were often considered the core aspect of a legitimate mood stabilizer. Conclusion: The proposed model uses a hierarchy of attributes that take into account the complexity of the term and help to determine whether a drug is a mood stabilizer. Prophylaxis is pivotal to the concept, whose utility lies in implying a drug able to truly treat bipolar disorder, as opposed to merely targeting symptoms. Consistent use of the term could encourage investigation of drugs that modify long‐term outcomes and illness trajectory, instead of simply approaching symptom clusters. [ABSTRACT FROM AUTHOR]

To evaluate the effectiveness, safety and tolerability of antidepressants in helping smokers quit tobacco dependence, five databases were searched for randomized controlled trials (RCTS) on different antidepressant interventions involving smoking cessation in populations (September 2022). The STATA 15.1 software was used to perform network meta‐analysis. The Cochrane bias risk tool was used to assess the risk of bias, and CINeMA was used to evaluate the evidence credibility for the effect of different interventions on smoking cessation. In all, 107 RCTs involving 42 744 patients were included. Seven studies were rated as having a low risk of bias. All trials reported 18 interventions and 153 pairwise comparisons were generated. The network meta‐analysis showed that compared with placebo, varenicline + bupropion (OR = 3.53, 95% CI [2.34, 5.34]), selegiline + nicotine replacement therapy (NRT) (OR = 3.78, 95% CI [1.20, 11.92]), nortriptyline + NRT (OR = 2.33, 95% CI [1.21, 4.47), nortriptyline (OR = 1.58, 95% CI [1.11,2.26]), naltrexone + bupropion (OR = 3.84, 95% CI [1.39, 10.61]), bupropion + NRT (OR = 2.29, 95% CI [1.87, 2.81]) and bupropion (OR = 1.70, 95% CI [1.53, 1.89]) showed benefits with respect to smoking cessation. In addition, bupropion + NRT showed better effects than bupropion (OR = 1.35, 95% CI [1.12, 1.64]) and NRT (OR = 1.38, 95% CI [1.13, 1.69]) alone. The final cumulative ranking curve showed that varenicline + bupropion was the most likely to be the best intervention. There was moderate‐ to very‐low‐certainty evidence that most interventions showed benefits for smoking cessation compared with placebo, including monotherapy and combination therapies. Varenicline + bupropion had a higher probability of being the best intervention for smoking cessation. [ABSTRACT FROM AUTHOR]

Although there have been several studies of people's information behaviors during the COVID‐19 epidemic, the information practices of a specific group of people—those with depression—have been neglected. This study reports on qualitative interviews with 24 participants to explore the information practices of people living with depression during the pandemic lockdown. We use the theory of information worlds and the concept of transition to understand the phases of chaos, expansion, and contraction that the information worlds of this group present during the lockdown, and examine the interrelationship between the information worlds and the individual's transition experiences during specific periods. Our results show that, first, emotion, body, and embodiment play key roles in the individual's information worlds, while individuals' information practices are regulated by the economic environment, group norms, and other social circumstances. Second, government‐level information, the volunteer community, social media, and nonhuman objects further impact participants' information practices. We suggest that health management strategies need to have different priorities at different stages of the transition, and attention should be paid to the provision of emotional information support systems during the pandemic lockdown. [ABSTRACT FROM AUTHOR]

Keywords: psychopharmacology EN psychopharmacology 1 2 2 01/04/23 20230101 NES 230101 Guy Edwards dedicated his life to the clinical care of patients and was a full-time NHS consultant psychiatrist in Southampton until his retirement in 1993. Guy's summary of the ethical principles supporting placebo-controlled trials of antidepressants and the way in which such studies can be carried out practically and safely in depressed patients still makes compelling reading ( I Human i I Psychopharmacology, i 1989, 4, 235-236). Guy was also an early advocate of placebo-controlled trials of new antidepressant agents at a time when this approach was unfashionable and often rejected by ethics committees. [Extracted from the article]

Background and aims: Cocaine use disorder (CUD) is a significant public health issue for which there is no Food and Drug Administration (FDA) approved medication. Drug repurposing looks for new cost‐effective uses of approved drugs. This study presents an integrated strategy to identify repurposed FDA‐approved drugs for CUD treatment. Design: Our drug repurposing strategy combines artificial intelligence (AI)‐based drug prediction, expert panel review, clinical corroboration and mechanisms of action analysis being implemented in the National Drug Abuse Treatment Clinical Trials Network (CTN). Based on AI‐based prediction and expert knowledge, ketamine was ranked as the top candidate for clinical corroboration via electronic health record (EHR) evaluation of CUD patient cohorts prescribed ketamine for anesthesia or depression compared with matched controls who received non‐ketamine anesthesia or antidepressants/midazolam. Genetic and pathway enrichment analyses were performed to understand ketamine's potential mechanisms of action in the context of CUD. Setting The study utilized TriNetX to access EHRs from more than 90 million patients world‐wide. Genetic‐ and functional‐level analyses used DisGeNet, Search Tool for Interactions of Chemicals and Kyoto Encyclopedia of Genes and Genomes databases. Participants: A total of 7742 CUD patients who received anesthesia (3871 ketamine‐exposed and 3871 anesthetic‐controlled) and 7910 CUD patients with depression (3955 ketamine‐exposed and 3955 antidepressant‐controlled) were identified after propensity score‐matching. Measurements EHR analysis outcome was a CUD remission diagnosis within 1 year of drug prescription. Findings Patients with CUD prescribed ketamine for anesthesia displayed a significantly higher rate of CUD remission compared with matched individuals prescribed other anesthetics [hazard ratio (HR) = 1.98, 95% confidence interval (CI) = 1.42–2.78]. Similarly, CUD patients prescribed ketamine for depression evidenced a significantly higher CUD remission ratio compared with matched patients prescribed antidepressants or midazolam (HR = 4.39, 95% CI = 2.89–6.68). The mechanism of action analysis revealed that ketamine directly targets multiple CUD‐associated genes (BDNF, CNR1, DRD2, GABRA2, GABRB3, GAD1, OPRK1, OPRM1, SLC6A3, SLC6A4) and pathways implicated in neuroactive ligand‐receptor interaction, cAMP signaling and cocaine abuse/dependence. Conclusions: Ketamine appears to be a potential repurposed drug for treatment of cocaine use disorder. [ABSTRACT FROM AUTHOR]

Introduction: Despite frequent recognition of emotional blunting in the published literature, either as a primary symptom of depression or as an adverse effect of antidepressants, there is no systematic synthesis on this topic to our knowledge. We undertook this scoping review to assess the prevalence, clinical features, implicated causes and management of emotional blunting, outlining the phenomenological and clinical gaps in research. Method: A systematic search was done until March 15, 2022, to include all original studies (i.e., interventional trials, cohort & cross‐sectional studies, case reports, and case series). All reviewed data were delineated to answer pertinent clinical, phenomenological, and management questions related to the phenomenon of emotional blunting. Results: A total of 25 original studies were included in our scoping review. Emotional blunting was described as a persistent diminution in both positive and negative feelings in depressed patients, who could subjectively differentiate it from their acute symptoms. However, the literature lacked the distinction between emotional blunting as a primary symptom of depression or an adverse effect of antidepressants. Common clinical strategies to manage antidepressant‐induced emotional blunting included dose reduction or switching to a different antidepressant. Conclusion: Emotional blunting was a significant patient‐reported concern with antidepressants. Future research should clarify phenomenological and neurobiological constructs underlying emotional blunting to improve diagnostic and management skills. [ABSTRACT FROM AUTHOR]

Background: Quality of Life (QoL) is an important outcome in mental disorders. We investigated whether antidepressant pharmacotherapy improved QoL vs. placebo among patients with MDD. Methods: Systematic literature search in CENTRAL, Medline, PubMed Central, and PsycINFO of double‐blind, placebo‐controlled RCTs. Screening, inclusion, extraction, and risk of bias assessment were conducted independently by two reviewers. We calculated summary standardized mean differences (SMD) with 95%‐CIs. We followed Cochrane Collaboration's Handbook of Systematic Reviews and Meta‐Analyses and PRISMA guidelines (protocol registration at OSF). Results: We selected 46 RCTs out of 1807 titles and abstracts screened, including 16.171 patients, 9131 on antidepressants and 7040 on placebo, a mean age of 50.9 years, with 64.8% women. Antidepressant drug treatment resulted in a SMD in QoL of 0.22 ([95%‐CI: 0.18; 0.26] I2 39%) vs. placebo. SMDs differed by indication: 0.38 ([0.29; 0.46] I2 0%) in maintenance studies, 0.21 ([0.17; 0.25] I2 11%) in acute treatment studies, and 0.11 ([−0.05; 0.26], I2 51%) in studies focussing on patients with a physical condition and major depression. There was no indication of subtstantial small study effects, but 36 RCTs had a high or uncertain risk of bias, particularly maintenance trials. QoL and antidepressive effect sizes were associated (Spearman's rho 0.73, p < 0.001). Conclusions: Antidepressants' effects on QoL are small in primary MDD, and doubtful in secondary major depression and maintenance trials. The strong correlation of QoL and antidepressive effects indicates that the current practice of measuring QoL may not provide sufficient additional insights into the well‐being of patients. [ABSTRACT FROM AUTHOR]

While antidepressants may be effective in treating depression for some people, a third of people do not have an improvement in mood after a trial of two different antidepressants for an adequate duration. These people are diagnosed as having 'treatment‐resistant' depression which situates the problem as part of their biological or psychological makeup. We conducted a search of studies that examined this problem from the perspective of people whose depression did not improve on antidepressants. Nine studies were included in a qualitative meta‐synthesis that identified four themes across these studies: feeling trapped, disconnection, loss of self, and questioning. The participants experienced considerable distress associated with the constant presence of depression in their lives. While antidepressants may help some people, there is a need for more innovative approaches to the treatment of depression. There is a strong argument for trialling appropriate evidence‐based psychotherapy before a person is categorized as having treatment‐resistant depression. It is perhaps better to describe the issue as inadequate efficacy of antidepressants to situate the problem with the treatment provided rather than with the person. [ABSTRACT FROM AUTHOR]

Depression is common in pregnant women. However, the rate of antidepressant treatment in pregnancy is significantly lower than in nonpregnant women. Although some antidepressants may cause potential risks to the fetus, not treating or withdrawing the treatment is associated with relapsing and adverse pregnancy outcomes such as preterm birth. Pregnancy‐associated physiologic changes can alter pharmacokinetics (PK) and may impact dosing requirements during pregnancy. However, pregnant women are largely excluded from PK studies. Dose extrapolation from the nonpregnant population could lead to ineffective doses or increased risk of adverse events. To better understand PK changes during pregnancy and guide dosing decisions, we conducted a literature review to catalog PK studies of antidepressants in pregnancy, with a focus on maternal PK differences from the nonpregnant population and fetal exposure. We identified 40 studies on 15 drugs, with most data from patients taking selective serotonin reuptake inhibitors and venlafaxine. Most of the studies have relatively poor quality, with small sample sizes, reporting concentrations at delivery only, a large amount of missing data, and not including times and adequate dose information. Only four studies collected multiple samples following a dose and reported PK parameters. In general, there are limited data available regarding PK of antidepressants in pregnancy and deficiencies in data reporting. Future studies should provide accurate information on drug dosing and timing of dose, PK sample collection, and individual‐level PK data. [ABSTRACT FROM AUTHOR]

Objectives: A third of people suffering from major depressive disorder do not experience a significant improvement in their symptoms even after adequate treatment with two different antidepressant medications. This common condition, termed treatment‐resistant depression (TRD), severely affects the quality of life of millions of people worldwide, causing long‐lasting interpersonal problems and social costs. Given its epidemiological and clinical relevance and the little consensus on whether the neurobiological underpinnings of TRD differ from treatment‐sensitive depression (TSD), we sought to highlight the convergent morphometric and functional neuroimaging correlates of TRD. Methods: We systematically reviewed the published literature on structural and resting‐state functional neuroimaging of TRD compared to TSD and healthy controls (HC) and performed exploratory coordinate‐based meta‐analyses (CBMA) of significant results separately for each modality and multimodally ("all‐effects"). CBMAs were also performed for each direction and combining both directions of group contrasts. Results: Out of the initial 1929 studies, only eight involving 555 participants (189 patients with TRD, 156 with TSD, and 210 HC) were included. In all‐effects CBMA, precentral/superior frontal gyrus showed a significant difference between TRD and HC. Functional and structural imaging meta‐analyses did not yield statistically significant results. A marginally significant cluster of altered intrinsic activity was found between TRD and HC in the cerebellum/pons. Conclusions: Frontal, cerebellar, and brainstem functions can be involved in the pathophysiology of TRD. However, the design and heterogeneity of the (scarce) published literature hinder the generalizability of the findings. [ABSTRACT FROM AUTHOR]

Depressive symptoms are common among patients with glioblastoma, but patients are often not treated with antidepressants. There is only limited evidence on the association of antidepressant drug use with survival in glioblastoma. We performed a pooled analysis of patients treated within the CENTRIC, CORE, AVAglio and ACT‐IV trials to explore the relation of antidepressant drug use with progression‐free (PFS) and overall survival (OS) at baseline, at the start of maintenance therapy and at the start of maintenance cycle 4. We further assessed the association of antidepressant drugs with seizure, cognition, fatigue and a diagnosis of depression. Among more than 1700 patients, we found no significant association between the use of antidepressants at baseline or at the start of maintenance therapy and PFS or OS. However, we found OS, but not PFS, to be significantly worse in patients using antidepressants at the start of maintenance cycle 4. After adjustment for antiepileptic drug use and despite showing a trend for increased risk, seizures were not significantly associated with antidepressant drug use, nor was there a change in mini mental state examination (MMSE) scores or fatigue by antidepressant drug use at baseline. However, there was a significant positive association between antidepressant use at the start of maintenance treatment and fatigue during maintenance treatment. The association of antidepressant use at the start of maintenance cycle 4 with inferior OS of glioblastoma patients requires independent confirmation and further study. Further prospective trials should evaluate efficacy, side effects and associations with outcome of antidepressants in glioblastoma. [ABSTRACT FROM AUTHOR]

Introduction: The management of pediatric bipolar disorder (PBD) requires pharmacotherapy to control acute symptoms, reduce relapse, prevent suicide, and improve psychosocial functioning. The purpose of this study was to investigate prescribing patterns among PBD patients discharged from two public mental hospitals in Taiwan, from 2006 to 2019. Methods: PBD patients discharged from the two study hospitals, from 1 January 2006 to 31 December 2019 (n = 420), were included in the analysis. Prescribed drugs at discharge, including mood stabilizers (i.e., lithium, valproate, carbamazepine, and lamotrigine), antipsychotics (i.e., second‐ and first‐generation antipsychotics, SGAs and FGAs), and antidepressants, were explored. Complex polypharmacy was defined as the use of 3 or more agents among the prescribed drugs. Time trends of each prescribing pattern were analyzed using the Cochran‐Armitage Trend test. Results: The most commonly prescribed psychotropic agents were SGAs (76.0%), followed by valproate (65.7%) and FGAs (24.8%). The prescription rates of SGAs, antidepressants, antidepressant plus antipsychotic, and antidepressant without mood stabilizer significantly increased over time, whereas the prescription rates of mood stabilizers, lithium, and FGAs significantly decreased. Discussions: Prescribing patterns changed greatly for PBD patients over time. However, much more evidence supporting the effectiveness of psychotropic agents in PBD patients is required. [ABSTRACT FROM AUTHOR]

There is still limited knowledge about alterations of blood concentrations of psychotropic drugs during pregnancy, the transfer of psychotropic drugs into breastmilk and the effects on exposed children. We investigated changes in concentrations of psychopharmacological medication during pregnancy and lactation in serum and breastmilk at different time points in a naturalistic sample of 60 mothers and observed the development of the exposed children in the first 12 months. We found a decrease in serum concentrations from the first to the second trimester of amitriptyline, duloxetine, escitalopram, quetiapine and sertraline. Citalopram stayed rather stable during pregnancy, sertraline levels interestingly increased again from the second to the third trimester. High concentration‐by‐dose ratios in breastmilk were found for venlafaxine as well as lamotrigine, low for quetiapine and clomipramine. Similarly, clomipramine and quetiapine showed low milk/serum–penetration ratios. Regarding the birth outcome measures in children, we found no significant differences between in utero exposed compared to nonexposed newborns. There were no significant differences in the development in the first 12 months. Psychotropic medication in the peripartum needs a balancing of risks and benefits and a continuous therapeutic drug monitoring can be a guidance for clinicians to monitor drug alteration patterns, which are likely to occur due to physiological pregnancy‐associated changes in pharmacokinetics. Accordingly, therapeutic drug monitoring can optimize a medication in pregnancy and lactation with the lowest effective dose. [ABSTRACT FROM AUTHOR]

Background: Compliance with psychotropic dosage guidelines has been shown to improve mental health status, reduce severity of symptoms, and decrease adverse effects. However, guideline recommendations are not always implemented. While deviation from dosage recommendations may be clinically appropriate in some patients, variation can cause a lack of efficacy or patient harm. Aim: To evaluate the incidence of antidepressant and antipsychotic prescribing at doses outside the recommended range provided by local guidelines, TherapeuticGuidelines:Psychotropic. Method: This study is a retrospective clinical audit of 793 patients admitted to hospital between August 2018 and July 2019. Data were collected through extensive file and chart reviews of patients treated with any of the antidepressant and antipsychotic medications listed in the Psychotropic Dosage Guidelines. Descriptive statistical analyses were performed to determine frequencies and proportions. Results: The audit identified that 38.0% of patients received doses of antidepressants or antipsychotics outside the recommended range. Most antidepressants were prescribed within recommended doses (83.0%), with 10.5% above the recommended dose, and 6.2% below. Fewer antipsychotics were prescribed within the recommended range (56.8%), 2.8% were prescribed at doses above the recommended range, and 40.3% were prescribed at doses below the recommendation range. Quetiapine was frequently prescribed at doses lower than recommended. Conclusion: The audit revealed a substantial amount of prescribing outside the recommended dosage ranges. It also highlighted the necessity of reviewing policies to limit the use of off‐label, low‐dose quetiapine. Audit and feedback could target psychiatrists who seem to have the highest propensity to prescribe outside the recommended dosage ranges. [ABSTRACT FROM AUTHOR]

Rationale: Posttraumatic stress disorder (PTSD) is highly prevalent among veterans. Many veterans with PTSD respond well to serotonin reuptake inhibitors (SRIs). Nonresponders may be prescribed augmenting medications, which are not as well‐studied in PTSD. Aims and Objectives: We used Veterans Health Administration electronic records to compare mental health outcomes (PTSD symptoms and rates of mental health hospitalizations and psychiatric emergency room visits) in patients with PTSD who were prescribed four different groups of augmenting medications (atypical antipsychotics, mirtazapine, prazosin or tricyclic antidepressants) in addition to SRIs—from the year before to the year after the start of the augmenting medication. Method: We included data from 169,982 patients with a diagnosis of PTSD (excluding patients with comorbid bipolar or psychotic disorders) seen in Veterans Affairs care from 2007 to 2015 who were taking an SRI and filled a new prescription for one of the four augmenting medications for at least 60 days. Results: Patients evidenced minimal (<2%) reduction in PTSD symptoms and a larger reduction in psychiatric hospitalizations and psychiatric emergency room visits after receiving augmenting medications; this effect was largely similar across the four medication groups. Initiating augmenting medications was preceded by increases in PTSD symptoms, psychiatric hospitalizations and psychiatric emergency room visits. After initiating an augmenting medication, PTSD symptoms/hospitalizations/emergency room visits returned to baseline levels (before the start of the augmenting medication), but generally did not improve beyond baseline. Conclusion: Importantly, these effects could be explained by regression to the mean, additional interventions or confounding. These findings should be further explored with placebo controlled randomized clinical trials. [ABSTRACT FROM AUTHOR]

Relatedly, traditional RCTs report the between-treatment I P i -value, which is the 'probability of obtaining the observed or more extreme data assuming that the treatment is no better than placebo'. Moreover, placebo-controlled RCTs raise ethical concerns when an ineffective treatment as in the placebo arm could have severe consequences, for example, suicide in depression or status epilepticus in epilepsy. Percentage of heavy drinking days following psilocybin-assisted psychotherapy vs placebo in the treatment of adult patients with alcohol use disorder: a randomized clinical trial. Keywords: Bayesian analysis; depression; medical cannabis; psilocybin; RCTs; Sir Michal Rawlins EN Bayesian analysis depression medical cannabis psilocybin RCTs Sir Michal Rawlins 2646 2648 3 08/17/23 20230901 NES 230901 The two pillars of modern medical research are where in most randomized controlled trials (RCTs), the active treatment is compared with placebo. [Extracted from the article]

Aim: This systematic review is aimed to update and reintegrate the pharmacotherapy of social anxiety disorder (SAD), including the Japanese medical database. Methods: We conducted a systematic review and meta‐analysis of pharmacotherapy of SAD according to the Medical Information Distribution Service. We used data from a most recent systematic review, and updated search were conducted using MEDLINE, PubMed, CENTRAL, ICTRP, and ICHUSHI from August 1st, 2017 to January 31st, 2022. The outcome were response rates assessed by Clinical Global Impressions Improvement, efficacy assessed by the Liebowitz Social Anxiety Scale (LSAS), and dropout rates. We performed a random effect of meta‐analysis to obtain the differences in each outcome between active medication and placebo. We used RevMan version 5.3 for analyses. Results: We identified 5 studies through update search and performed meta‐analysis for 33 studies on selective serotonin reuptake inhibitor (SSRI) and 6 studies on serotonin noradrenalin reuptake inhibitor (SNRI). The response rate (RR = 1.62) and the LSAS score reduction (mean difference = −9.65) of SSRI, and the response rate (RR = 1.57) and the LSAS score reduction (mean difference = −11.72) of SNRI were significantly different from placebo. The dropout rates of SSRI or SNRI were not significant. The response rates of SSRIs in both Japanese studies (RR = 1.44) and countries other than Japan (RR = 1.67) were significant. Most findings were based on low quality of evidence. Conclusion: SSRIs are valid option for pharmacotherapy of SAD including Japanese patients. SNRIs are another effective option. However, the results should be interpreted cautiously due to several risk of bias. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the evidence on cost‐effectiveness of pharmacogenetic (PGx)–guided treatment for drugs with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. A systematic review was conducted using multiple biomedical literature databases from inception to June 2021. Full articles comparing PGx‐guided with nonguided treatment were included for data extraction. Quality of Health Economic Studies (QHES) was used to assess robustness of each study (0–100). Data are reported using descriptive statistics. Of 108 studies evaluating 39 drugs, 77 (71%) showed PGx testing was cost‐effective (CE) (N = 48) or cost‐saving (CS) (N = 29); 21 (20%) were not CE; 10 (9%) were uncertain. Clopidogrel had the most articles (N = 23), of which 22 demonstrated CE or CS, followed by warfarin (N = 16), of which 7 demonstrated CE or CS. Of 26 studies evaluating human leukocyte antigen (HLA) testing for abacavir (N = 8), allopurinol (N = 10), or carbamazepine/phenytoin (N = 8), 15 demonstrated CE or CS. Nine of 11 antidepressant articles demonstrated CE or CS. The median QHES score reflected high‐quality studies (91; range 48–100). Most studies evaluating cost‐effectiveness favored PGx testing. Limited data exist on cost‐effectiveness of preemptive and multigene testing across disease states. [ABSTRACT FROM AUTHOR]

Background: In Spain, the perceived professional quality of life among veterinarians has not been explored. Methods: Veterinarians were invited to complete an online questionnaire in which they answered the ProfessionalQuality of Life scale, theMedical Outcomes Study Social Support Survey and the Warwick-Edinburgh Mental Well-Being Scale. Participants were asked whether they were receiving psychological therapy or were taking anxiolytics, hypnotics or antidepressant medication. Alcohol consumption was measured using the Alcohol Use Disorders Identification Test and nicotine dependence was assessed using the Fagerström test; participants were asked whether they took illegal drugs. Results: The study sample comprised a total of 602 veterinarians, most of whom reported average levels of compassion satisfaction, secondary stress trauma and burnout. Emotional support andmental wellbeing influenced participants' professional quality of life. The percentage of veterinarians in psychological therapy and/or taking anxiolytics was higher than in the general population. Conclusions: A considerable number of clinical veterinarians in Spain may be suffering from work-related stress. Our study identifies salary, emotional support and mental wellbeing as important factors that affect the professional quality of life. Interventions to improve veterinary clinicians' professional quality of life should therefore focus on these factors. [ABSTRACT FROM AUTHOR]

Background: Clinical trials are an important source of adverse effects data, including analyses in systematic reviews and recommendations in therapy guidelines. Trial publication bias may have profound effects on safety perceptions. This MiniReview presents and discusses biases in reporting of safety data in clinical trials and the implications for systematic reviews and guidelines. Objectives: The objectives of this work are to analyse risk of gastrointestinal bleeding in systemic corticosteroid trials and to assess adverse effects reporting in a fluoxetine trial in depression (Treatment for Adolescents With Depression Study [TADS]) and descriptions of adverse effects in adolescent depression therapy guidelines. Methods: We performed literature reviews and descriptive analyse of clinical trials with corticosteroids, and publications from the TADS trial. Risk of gastrointestinal bleeding from corticosteroids was analysed by meta‐analysis. Findings: Gastrointestinal bleeding definitions varied considerably between trials. The incidence was significantly increased in hospitalized, but not in ambulant, patients compared to placebo. We identified several biases concerning TADS safety reporting, including severity thresholds and nonpublication of most adverse effects data beyond the initial 12 weeks. Therapy guidelines on adolescent depression mentioned suicidality risk, but many failed to mention other adverse effects. Conclusions: We identified several pitfalls in adverse effects reporting in clinical trials. These include heterogeneous disease definitions, reporting thresholds, and incomplete reporting. Trial bias may have great impact on risk assessments in systematic reviews and meta‐analyses. [ABSTRACT FROM AUTHOR]

Antibiotic resistance is a global concern threatening public health. Horizontal gene transfer (HGT) between bacterial species contributes greatly to the dissemination of antibiotic resistance. Conjugation is one of the major HGT pathways responsible for the spread of antibiotic resistance genes (ARGs). Antidepressant drugs are commonly prescribed antipsychotics for major depressive disorders and are frequently detected in aquatic environments. However, little is known about how antidepressants stress bacteria and whether such effect can promote conjugation. Here, we report that commonly prescribed antidepressants, sertraline, duloxetine, fluoxetine, and bupropion, can promote the conjugative transfer of plasmid‐borne multidrug resistance genes carried by environmentally and clinically relevant plasmids. Noteworthy, the transfer of plasmids across bacterial genera is significantly enhanced by antidepressants at clinically relevant concentrations. We also reveal the underlying mechanisms of enhanced conjugative transfer by employing flow cytometric analysis, genome‐wide RNA sequencing and proteomic analysis. Antidepressants induce the production of reactive oxygen species and the SOS response, increase cell membrane permeability, and upregulate the expression of conjugation relevant genes. Given the contribution of HGT in the dissemination of ARGs, our findings highlight the importance of prudent prescription of antidepressants and to the potential connection between antidepressants and increasing antibiotic resistance. [ABSTRACT FROM AUTHOR]

Background: The treatment of depression in children and adolescents is a substantial public health challenge. This study examined artificial intelligence tools for the prediction of early outcomes in depressed children and adolescents treated with fluoxetine, duloxetine, or placebo. Methods: The study samples included training datasets (N = 271) from patients with major depressive disorder (MDD) treated with fluoxetine and testing datasets from patients with MDD treated with duloxetine (N = 255) or placebo (N = 265). Treatment trajectories were generated using probabilistic graphical models (PGMs). Unsupervised machine learning identified specific depressive symptom profiles and related thresholds of improvement during acute treatment. Results: Variation in six depressive symptoms (difficulty having fun, social withdrawal, excessive fatigue, irritability, low self‐esteem, and depressed feelings) assessed with the Children's Depression Rating Scale‐Revised at 4–6 weeks predicted treatment outcomes with fluoxetine at 10–12 weeks with an average accuracy of 73% in the training dataset. The same six symptoms predicted 10–12 week outcomes at 4–6 weeks in (a) duloxetine testing datasets with an average accuracy of 76% and (b) placebo‐treated patients with accuracies of 67%. In placebo‐treated patients, the accuracies of predicting response and remission were similar to antidepressants. Accuracies for predicting nonresponse to placebo treatment were significantly lower than antidepressants. Conclusions: PGMs provided clinically meaningful predictions in samples of depressed children and adolescents treated with fluoxetine or duloxetine. Future work should augment PGMs with biological data for refined predictions to guide the selection of pharmacological and psychotherapeutic treatment in children and adolescents with depression. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a highly prevalent and disabling disorder. Despite the many hypotheses proposed to understand the molecular pathophysiology of depression, it is still unclear. Current treatments for depression are inadequate for many individuals, because of limited effectiveness, delayed efficacy (usually two weeks), and side effects. Consequently, novel drugs with increased speed of action and effectiveness are required. Ketamine has shown to have rapid, reliable, and long‐lasting antidepressant effects in treatment‐resistant MDD patients and represent a breakthrough therapy for patients with MDD; however, concerns regarding its efficacy, potential misuse, and side effects remain. In this review, we aimed to summarize molecular mechanisms and pharmacological treatments for depression. We focused on the fast antidepressant treatment and clarified the safety, tolerability, and efficacy of ketamine and its metabolites for the MDD treatment, along with a review of the potential pharmacological mechanisms, research challenges, and future clinical prospects. [ABSTRACT FROM AUTHOR]

The use of areca nuts (areca) in the form of betel quids constitutes the fourth most common addiction in the world, associated with high risk for oral disease and cancer. Areca is a complex natural product, making it difficult to identify specific components associated with the addictive and carcinogenic properties. It is commonly believed that the muscarinic agonist arecoline is at the core of the addiction. However, muscarinic receptor activation is not generally believed to support drug-taking behaviour. Subjective accounts of areca use include descriptions of both sedative and stimulatory effects, consistent with the presence of multiple psychoactive agents. We have previously reported partial agonism of α4-containing nicotinic acetylcholine receptors by arecoline and subsequent inhibition of those receptors by whole areca broth. In the present study, we report the inhibition of nicotinic acetylcholine receptors and other types of neurotransmitter receptors with compounds of high molecular weight in areca and the ability of low molecular weight areca extract to activate GABA and glutamate receptors. We confirm the presence of a high concentration of GABA and glutamate in areca. Additionally, data also indicate the presence of a dopamine and serotonin transporter blocking activity in areca that could account for the reported stimulant and antidepressant activity. Our data suggest that toxic elements of high molecular weight may contribute to the oral health liability of betel quid use, while two distinct low molecular weight components may provide elements of reward, and the nicotinic activity of arecoline contributes to the physical dependence of addiction. [ABSTRACT FROM AUTHOR]

Objective: Drugs can be divided into two major categories, symptomatic and disease modifying. This review explores whether and how psychiatric drugs fall into one or the other of those categories, and the implications of those results for clinical practice and research in psychopharmacology. Method: Narrative review. Results: Most psychiatric drugs have only short‐term effects of improving active symptoms. They do not show long‐term benefits for the underlying disease, such as improving the course of illness and improving mortality. Evidence is provided for this claim in the treatment literature of antidepressants for depressive illness and antipsychotics for schizophrenia. Developing truly beneficial drugs for disease modification also is limited by the poor clinical and biological validity of Diagnostic and Statistical Manual diagnoses as well as the use of invalid falsely positive maintenance efficacy randomized discontinuation trial designs. Conclusions: Current psychopharmacology is limited mostly to symptomatic effects, not transformative treatments for the diseases underlying those symptoms. A change in approach is needed in psychopharmacology practice and research, focusing on long‐term disease modification rather than short‐term symptom improvement. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a life‐threatening disease that presents several characteristics. The pathogenesis of depression still remains poorly understood. Moreover, the mechanistic interactions of natural components in treating depression to target autophagy and neuroinflammation are yet to be evaluated. This study overviewed the effects of plant‐derived natural components in regulating critical pathways, particularly neuroinflammation and autophagy, associated with depression. A list of natural components, including luteolin, apigenin, hyperforin, resveratrol, salvianolic acid b, isoliquiritin, nobiletin, andrographolide, and oridonin, have been investigated. All peer‐reviewed journal articles were searched by Scopus, MEDLINE, PubMed, Web of Science, and Google Scholar using the appropriated keywords, including depression, neuroinflammation, autophagy, plant, natural components, etc. The neuroinflammation and autophagy dysfunction are critically associated with the pathophysiology of depression. Natural components with higher efficiency and lower complications can be used for targeting neuroinflammation and autophagy. These components with different doses showed the beneficial antidepressant properties in rodents. These can modulate autophagy markers, mainly AMPK, LC3II/LC3I ratio, Beclin‐1. Moreover, they can regulate the NLRP3 inflammasome, resulting in the suppression of proinflammatory cytokines (e.g., IL‐1β and IL‐18). Future in vitro and in vivo studies are required to develop novel therapeutic approaches based on plant‐derived active components to treat MDD. [ABSTRACT FROM AUTHOR]

Background and Purpose: Current mainstream antidepressants have limited efficacy with a delayed onset of action. Yueju, a herbal medicine, has a rapid antidepressant action. Identification of the active ingredients in Yueju and the mechanism/s involved was carried out. Experimental Approach: Key molecule/s and compounds involved in this antidepressant action was identified by transcriptomic and HPLC analysis, respectively. Antidepressant effects were evaluated using various behavioural experiments. The signalling involved was assessed using site‐directed pharmacological intervention or optogenetic manipulation. Key Results: Transcriptomic analysis showed that Yueju up‐regulated pituitary adenylate cyclase activating polypeptide (PACAP) expression in the hippocampus. Two iridoids, geniposide and shanzhiside methyl ester, were identified and quantified from Yueju. Only co‐treatment with both, at an equivalent concentrations found in Yueju, increased PACAP expression and elicited a rapid antidepressant action, which were blocked by intra‐dentate gyrus infusion of a PACAP antagonist or optogenetic inactivation of PACAP expressing neurons. Geniposide and shanzhiside methyl ester co‐treatment rapidly inhibited CaMKII phosphorylation and enhanced mTOR/4EBP1/P70S6k/BDNF ignalling, while intra‐dentate gyrus infusions of a CaMKII activator blunted the rapid antidepressant action and BDNF expression up‐regulation induced by the co‐treatment. A single co‐treatment of them rapidly improved depression‐like behaviours and up‐regulated hippocampal PACAP signalling in the repeated corticosterone‐induced depression model, further confirming the involvement of PACAP. Conclusion and Implications: Geniposide and shanzhiside methyl ester co‐treatment had a synergistic rapid onset antidepressant action by triggering hippocampal PACAP activity and associated CaMKII–BDNF signalling. This mechanism could be targeted for development of fast onset antidepressants. [ABSTRACT FROM AUTHOR]

Purpose: Despite the notable increase on the prescription of antidepressants and anxiolytics during pregnancy, recommendation on maintaining the treatment during prenatal period is still controversial. We aimed to separately assess the role of effects of the antidepressants and anxiolytic and the underlying illness, controlled by potential confounding associated with miscarriage onset. Methods: We used data from a validated pregnant cohort aged 15–49 years from 2002 to 2016 using BIFAP database. All confirmed miscarriages were used to perform a nested control analysis using conditional logistic regression. Women were classified according to use of each drug of interest into four mutually exclusive groups: nonusers, users only during prepregnancy, continuers, and initiators during first trimester. Adjusted odds ratios (aORs) for major confounders during pregnancy such as number of visits to primary care practitioners visits, obesity, smoking, HTA, diabetes with 95% confidence intervals were calculated. Results: Compared with nonusers, antidepressants continuers had the highest increased risk of miscarriage aOR (95%) of 1.29 (1.13–1.46), being continuers of paroxetine and fluoxetine the antidepressants with the strongest association. Likewise, continuers of anxiolytics and initiators showed an increased risk of 1.19 (1.04–1.37) and 1.30 (1.13–1.50). When separating the effect between the condition itself or the treatment, women exposed during first trimester, regardless treatment duration and/or the underlying illness, had the highest risk 1.27 (1.08–1.51) for antidepressants and 1.25 (1.13–1.39) for anxiolytics. Conclusions: Our analysis showed an association between prenatal exposure to antidepressants and anxiolytics and miscarriage onset after controlling by potential confounding adjusting for confounders and the underlying illness. This association was not supported for hypnotic medications. Further studies are warranted to evaluate the risk of miscarriage among subpopulation of pregnant women requiring these medications. [ABSTRACT FROM AUTHOR]

Background and Purpose: Many psychotherapeutic drugs, including clozapine, display polypharmacology and act on GABAA receptors. Patients with schizophrenia show alterations in function, structure and molecular composition of the hippocampus, and a recent study demonstrated aberrant levels of hippocampal α5 subunit‐containing GABAA receptors. The purpose of this study is to investigate the effects of tricyclic compounds on α5 subunit‐containing receptor subtypes. Experimental Approach Functional studies of effects by seven antipsychotic and antidepressant medications were performed in several GABAA receptor subtypes by two‐electrode voltage‐clamp electrophysiology using Xenopus laevis oocytes. Computational structural analysis was employed to design mutated constructs of the α5 subunit, probing a novel binding site. Radioligand displacement data complemented the functional and mutational findings. Key Results: The antipsychotic drugs clozapine and chlorpromazine exerted functional inhibition on multiple GABAA receptor subtypes, including those containing α5‐subunits. Based on a chlorpromazine binding site observed in a GABA‐gated bacterial homologue, we identified a novel site in α5 GABAA receptor subunits and demonstrate differential usage of this and the orthosteric sites by these ligands. Conclusion and Implications: Despite high molecular and functional similarities among the tested ligands, they reduce GABA currents by differential usage of allosteric and orthosteric sites. The chlorpromazine site we describe here is a new potential target for optimizing antipsychotic medications with beneficial polypharmacology. Further studies in defined subtypes are needed to substantiate mechanistic links between the therapeutic effects of clozapine and its action on certain GABAA receptor subtypes. [ABSTRACT FROM AUTHOR]

Conflicting results have been reported regarding the association between antidepressant use and out‐of‐hospital cardiac arrest (OHCA) risk. We investigated whether the use of antidepressants is associated with OHCA. Methods: We conducted a nationwide nested case–control study to assess the association of individual antidepressant drugs within drug classes with the hazard of OHCA. Cases were defined as OHCA from presumed cardiac causes. Cox regression with time‐dependent exposure and time‐dependent covariates was conducted to calculate hazard ratios (HR) and 95% confidence intervals (95% CIs) overall and in subgroups defined by established cardiac disease and cardiovascular risk factors. Also, we studied antidepressants with and without sodium channel blocking or potassium channel blocking properties separately. Results: During the study period from 2001 to 2015 we observed 10 987 OHCA cases, and found increased OHCA rate for high‐dose citalopram (>20 mg) and high‐dose escitalopram (>10 mg; HR:1.46 [95% CI:1.27–1.69], HR:1.43 [95% CI:1.16–1.75], respectively) among selective serotonin reuptake inhibitors (reference drug sertraline), and for high‐dose mirtazapine (>30; HR:1.59 [95% CI:1.18–2.14]) among the serotonin–norepinephrine reuptake inhibitors or noradrenergic and specific serotonergic antidepressants (reference drug duloxetine). Among tricyclic antidepressants (reference drug amitriptyline), no drug was associated with significantly increased OHCA rate. Increased OHCA rate was found for antidepressants with known potassium channel blocking properties (HR:1.14 [95% CI:1.05–1.23]), but for not those with sodium channel blocking properties. Citalopram, although not statistically significant, and mirtazapine were associated with increased OHCA rate in patients without cardiac disease and cardiovascular risk factors. Conclusion: Our findings indicate that careful titration of citalopram, escitalopram and mirtazapine dose may have to be considered due to drug safety issues. [ABSTRACT FROM AUTHOR]

Introduction: Postpartum depression (PPD) is a prevalent and debilitating disease that may affect medication adherence and thus maternal health and vertical transmission among women with HIV. We assessed the feasibility of a trial of interpersonal psychotherapy (IPT) versus antidepressant medication (ADM) to treat PPD and/or anxiety among postpartum women with HIV in Lusaka, Zambia. Methods: Between 29 October 2019 and 8 September 2020, we pre‐screened women 6–8 weeks after delivery with the Edinburgh Postnatal Depression Scale (EPDS) and diagnosed PPD or anxiety with the Mini International Neuropsychiatric Interview. Consenting participants were randomized 1:1 to up to 11 sessions of IPT or daily self‐administered sertraline and followed for 24 weeks. We assessed EPDS score, Clinical Global Impression‐Severity of Illness (CGI‐S) and medication side effects at each visit and measured maternal HIV viral load at baseline and final study visit. Retention, visit adherence, change in EPDS, CGI‐S and log viral load were compared between groups with t‐tests and Wilcoxon signed rank tests; we report mean differences, relative risks and 95% confidence intervals. A participant satisfaction survey assessed trial acceptability. Results: 78/80 (98%) participants were retained at the final study visit. In the context of the COVID‐19 pandemic, visit adherence was greater among women allocated to ADM (9.9 visits, SD 2.2) versus IPT (8.9 visits, SD 2.4; p = 0.06). EPDS scores decreased from baseline to final visit overall, though mean change was greater in the IPT group (−13.8 points, SD 4.7) compared to the ADM group (−11.4 points, SD 5.5; p = 0.04). Both groups showed similar changes in mean log viral load from baseline to final study visit (mean difference −0.43, 95% CI −0.32, 1.18; p = 0.48). In the IPT group, viral load decreased significantly from baseline (0.9 log copies/ml, SD 1.7) to final visit (0.2 log copies/ml, SD 0.9; p = 0.01). Conclusions: This pilot study demonstrates that a trial of two forms of PPD treatment is feasible and acceptable among women with HIV in Zambia. IPT and ADM both improved measures of depression severity; however, a full‐scale trial is required to determine whether treatment of PPD and anxiety improves maternal–infant HIV outcomes. [ABSTRACT FROM AUTHOR]

For the first time, an acidic deep eutectic solvent (DES) comprised of malonic acid and ChCl was used to complete dissolution of Co‐Al, Ni‐Al, and Cu‐Al layered double hydroxides (LDHs) as sorbents in the vortex‐assisted in‐situ solid‐phase extraction of doxepin and amitriptyline followed by high‐performance liquid chromatography‐ultraviolet (HPLC‐UV). Moreover, the ability of urea:ChCl and ethylene glycol:ChCl was investigated to dissolve the LDH sorbents. The extraction conditions were optimized in terms of vortex time, molar ratio of Co2+:Al3+, NaOH concentration, and volume of DES based on the Box‐Behnen design. The linearity, limit of detection, and coefficient of determination R2 for both analytes were assessed as well. Recoveries of more than 93.1 % with relative standard deviations of less than 5.3 % were achieved for spiking urine and pharmaceutical formulation samples. [ABSTRACT FROM AUTHOR]

Objective: Prenatal antidepressant use is widespread. Observational studies have investigated the neonatal effects of prenatal antidepressant exposure with inconclusive results. We aimed to comprehensively investigate the associations between prenatal antidepressant exposure and the most commonly studied adverse neonatal outcomes: preterm birth, birthweight, poor neonatal adaptation, persistent pulmonary hypertension of the neonate (PPHN), neonatal admission and congenital malformations. Methods: We included 45,590 singletons (born 1997‐2015) whose mothers used antidepressants within one year before pregnancy. Children were categorised into two groups: continuation (antidepressant use before and during pregnancy) or discontinuation (antidepressant use before but not during pregnancy). We applied random‐effects logistic and linear regressions, adjusting for covariates. Results: After adjusting for confounders, prenatal antidepressant exposure was associated with a 2.3 day (95% CI −2.9; −2.0) decrease in gestational age and a 51 g (95% CI −62g; −41 g) decrease in birthweight. The continuation group was at increased risk for moderate‐to‐late preterm birth (32–37 weeks) (aOR = 1.43; 95%CI 1.33; 1.55), moderately low birthweight (1500–2499 g) (aOR = 1.28; 95%CI 1.17; 1.41), postnatal adaptation syndrome (aOR = 2.59; 95%CI 1.87; 3.59) and neonatal admission (aOR = 1.52; 95%CI 1.44; 1.60) compared to the discontinuation group. Conclusion: Prenatal antidepressant exposure was associated with small decreases in gestational age and birthweight, as well as higher risk for moderate‐to‐late preterm birth, moderately low birthweight, neonatal admission and postnatal adaptation syndrome. No differences in risk were found for PPHN, or congenital malformations. The causality of the observed associations cannot be established due to the potential for unmeasured residual confounding linked to the underlying disease. [ABSTRACT FROM AUTHOR]