Antidepressant-like effects of geniposide in chronic unpredictable mild stress-induced mice by regulating the circ_0008405/miR-25-3p/Gata2 and Oip5os1/miR-25-3p/Gata2 networks.

Evidence exists suggesting the anti-depressive activities of geniposide (GP), a major compound in Gardenia jasminoides Ellis. Accordingly, the present study attempts to explore the anti-depressive mechanism of GP in chronic unpredictable mild stress (CUMS)-induced depression-like behaviors of mice. CUMS-induced mice were given GP daily and subjected to behavioral tests to observe the effect of GP on the depression-like behaviors. It was noted that GP administration reduced depression-like behaviors in CUMS mice. Transcriptome sequencing was conducted in three control and three CUMS mice. Differentially expressed circRNAs, lncRNAs and mRNAs were then screened by bioinformatics analyses. Intersection analysis of the transcriptome sequencing results with the bioinformatics analysis results was followed to identify the candidate targets. We found that Gata2 alleviated depression-like behaviors via the metabolism- and synapse-related pathways. Gata2 was a target of miR-25-3p, which had binding sites to circ_0008405 and Oip5os1. circ_0008405 and Oip5os1 competitively bound to miR-25-3p to release the expression of Gata2. GP administration ameliorated depression-like behaviors in CUMS mice through regulation of the circ_0008405/miR-25-3p/Gata2 and Oip5os1/miR-25-3p/Gata2 crosstalk networks. Taken together, GP may exert a potential antidepressant-like effect on CUMS mice, which is ascribed to regulation of the circ_0008405/miR-25-3p/Gata2 and Oip5os1/miR-25-3p/Gata2 crosstalk networks.

Neurobiological Correlates of Psilocybin Response in Depression.

Objective: To synthesize the neurobiological basis of brain-resetting effects of psilocybin and identify neuroimaging correlates of psilocybin response in depressed patients.Data Sources: MEDLINE(R), Embase, APA PsycINFO, Cochrane, and CINAHL were systematically searched on June 3, 2022, with no date restrictions using the following string: (psilocybin) AND (psychedelics) AND (MRI) OR (fMRI)) OR (PET)) OR (SPECT)) OR (imaging)) OR (neuroimaging)).Study Selection: After duplicates were removed from 946 studies, 391 studies remained, of which 8 qualified for full-text analysis, but only 5 fulfilled the eligibility criteria of randomized, double-blind, or open-label neuroimaging study with psilocybin treatment in depressed patients.Data Extraction: The Covidence platform was used for deduplication and bias assessment. The a priori data points included concomitant psychological intervention, modality of neuroimaging technique, changes in depression scores, brain functional changes, and association between functional and psilocybin response. Assessment bias was assessed with the standard risk of bias tool for randomized controlled trials and the tool for risk of bias in nonrandomized studies of interventions.Results: Four studies were open-label, and one was a combined open-label and randomized controlled trial using functional magnetic resonance imaging. Psilocybin-assisted psychotherapy was administered in 3 studies, 1 in refractory and 2 in nonrefractory patients. The remaining 2 studies were in refractory patients. The transient increase in psilocybin-induced global connectivity in major neural tracts and specific areas of brain activation was associated with antidepressant response.Conclusions: Transient functional brain changes with psilocybin therapy resemble the "brain reset" phenomenon and may serve as the putative predictors of psilocybin antidepressant response.

Impact of elexacaftor/tezacaftor/ivacaftor on depression and anxiety in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is associated with worsening of depression and anxiety symptoms. Elexacaftor/tezacaftor/ivacaftor (Trikafta®), a cystic fibrosis transmembrane regulator (CFTR) modulator approved in 2019, significantly improves lung function, decreases pulmonary exacerbations, and improves quality of life. Studies are needed to evaluate the effects of Trikafta on symptoms of anxiety and depression. RESEARCH QUESTION: Do adults with CF report a change in depression and anxiety symptoms after Trikafta initiation? STUDY DESIGN AND METHODS: A retrospective chart review was conducted of patients with CF (n = 127) receiving care from January 2015 through February 2022. Data collected included demographics, annual PHQ-9 and GAD-7 scores, FEV1 percent predicted at each visit, BMI, consistency and timeline of Trikafta use, mental health diagnoses, counseling/psychotherapy use, psychiatric medication use, prescriber of psychiatric medications, number of psychiatric emergency department visits and psychiatric hospital admissions, and sleep disturbances. RESULTS: Of the 127 patients screened for eligibility, 100 patients were included. Data collected yielded 563 PHQ-9, 563 GAD-7, and 560 ppFEV1 data points. No significant changes in average PHQ-9 or GAD-7 scores were found after Trikafta initiation or due to the COVID-19 pandemic. However, 22% of patients initiated or had a change in psychiatric medications, and patients with changes in psychiatric medications had significantly higher PHQ-9 and GAD-7 scores than patients not prescribed psychiatric medications. Trikafta use improved lung function by an average of 5.23% (p = 8.56e-08). Around a quarter (23%) of all patients reported sleep issues after initiating Trikafta. INTERPRETATION: No significant changes in average PHQ-9 and GAD-7 scores were found after Trikafta initiation. A quarter of patients required a change in psychiatric medications, and significant differences in depression and anxiety scores were found between patients with a change in psychiatric medications and those not prescribed medication. Twenty-three percent of patients reported a prevalence of sleep issues after Trikafta initiation.

The Role of Probiotics and Their Metabolites in the Treatment of Depression.

Depression is a common and complex mental and emotional disorder that causes disability, morbidity, and quite often mortality around the world. Depression is closely related to several physical and metabolic conditions causing metabolic depression. Studies have indicated that there is a relationship between the intestinal microbiota and the brain, known as the gut-brain axis. While this microbiota-gut-brain connection is disturbed, dysfunctions of the brain, immune system, endocrine system, and gastrointestinal tract occur. Numerous studies show that intestinal dysbiosis characterized by abnormal microbiota and dysfunction of the microbiota-gut-brain axis could be a direct cause of mental and emotional disorders. Traditional treatment of depression includes psychotherapy and pharmacotherapy, and it mainly targets the brain. However, restoration of the intestinal microbiota and functions of the gut-brain axis via using probiotics, their metabolites, prebiotics, and healthy diet may alleviate depressive symptoms. Administration of probiotics labeled as psychobiotics and their metabolites as metabiotics, especially as an adjuvant to antidepressants, improves mental disorders. It is a new approach to the prevention, management, and treatment of mental and emotional illnesses, particularly major depressive disorder and metabolic depression. For the effectiveness of antidepressant therapy, psychobiotics should be administered at a dose higher than 1 billion CFU/day for at least 8 weeks.

Adaptogens on Depression-Related Outcomes: A Systematic Integrative Review and Rationale of Synergism with Physical Activity.

Depression is considered the most important disorder affecting mental health. The aim of this systematic integrative review was: (i) to describe the effects of supplementation with adaptogens on variables related to depression in adults; and (ii) to discuss the potential combination with physical exercise to aid planning and commissioning future clinical research. An integrative review was developed complementing the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement (PROSPERO registration: CRD42021249682). A total of 41 articles met the inclusion criteria. With a Price index of 46.4%, we found that: (i) Hypericum perforatum (St. John's Wort) is the most studied and supported adaptogen (17/41 [41.46%], three systematic reviews with meta-analysis) followed by Crocus sativus L. or saffron (6/41 [14.63%], three systematic reviews with meta-analysis and two systematic reviews); (ii) it is possible that the significantly better performance of adaptogens over placebo is due to the reduction of allostatic load via the action of secondary metabolites on BDNF regulation; and, (iii) the number of studies reporting physical activity levels is limited or null for those that combine an exercise program with the consumption of adaptogens. Aware of the need for a multidisciplinary approach for depression treatment, this systematic integrative review provides an up-to-date view for supporting the use of St. John's Wort and saffron as non-pharmacological strategies while also help commissioning future research on the efficacy of other adaptogens. It also contributes to the design of future clinical research studies that evaluate the consumption of herbal extracts plus physical exercise, mainly resistance training, as a potentially safe and powerful strategy to treat depression.

The Role of Genetics in the Development and Pharmacotherapy of Depression and Its Impact on Drug Discovery.

Complex disorders, such as depression, remain a mystery for scientists. Although genetic factors are considered important for the prediction of one's vulnerability, it is hard to estimate the exact risk for a patient to develop depression, based only on one category of vulnerability criteria. Genetic factors also regulate drug metabolism, and when they are identified in a specific combination, may result in increased drug resistance. A proper understanding of the genetic basis of depression assists in the development of novel promising medications and effective disorder management schemes. This review aims to analyze the recent literature focusing on the correlation between specific genes and the occurrence of depression. Moreover, certain aspects targeting a high drug resistance identified among patients suffering from major depressive disorder were highlighted in this manuscript. An expected direction of future drug discovery campaigns was also discussed.

THERAPY OF POST-COVID DEPRESSION: A PROACTIVE PSYCHOSOMATIC APPROACH.

OBJECTIVE: Aim: Evaluation of the effectiveness of the early 8-week monotherapy with escitalopram as a form of proactive psychosomatic intervention for patients with post-COVID depression. PATIENTS AND METHODS: Materials and methods: 44 patients with post-COVID depression were involved in a proactive psychosomatic intervention in the form of an 8-week intake of escitalopram (Medogram, Medochemiе Ltd) for 2-8 weeks in the case of a diagnosis of severe depression. Hamilton Depression Scale (HAM-D), Somatic Symptom Scale (SSS-8), Quality of Life Scale (CQLS) were used to assess symptoms and status dynamics. RESULTS: Results: Patients with post-COVID depression after an 8-week course of escitalopram therapy showed a significant reduction in mental and somatic symptoms of depression and an improvement in quality of life. At the time of enrollment in the study, 12 (28.58%) individuals had mild depression, 15 (35.71%) had moderate depression, and 15 (35.71%) had severe depression. At the end of the 8th weeks of taking the drug in 24 (57.14%) there were no signs of depression on the HAM-D scale, in 18 people there were subclinical manifestations of depression. The effectiveness of escitalopram in reducing the symptoms of depression in this study was 66%. CONCLUSION: Conclusions: With the introduction of pharmacotherapy with escitalopram there was a significant reduction in mental and so¬matic symptoms of depression and an improvement in quality of life. Escitalopram (Medochemie Ltd) may be an effective drug for psychopharmacotherapy of depressive symptoms in patients who have had COVID-19. Further studies are promising its effective¬ness in the treatment of post-COVID depression.

Trends in incident diagnoses and drug prescriptions for anxiety and depression during the COVID-19 pandemic: an 18-month follow-up study based on the UK Biobank.

Serious concerns have been raised about the negative effects of the COVID-19 pandemic on population psychological well-being. However, limited data exist on the long-term effects of the pandemic on incident psychiatric morbidities among individuals with varying exposure to the pandemic. Leveraging prospective data from the community-based UK Biobank cohort, we included 308,400 participants free of diagnosis of anxiety or depression, as well as 213,757 participants free of anxiolytics or antidepressants prescriptions, to explore the trends in incident diagnoses and drug prescriptions for anxiety and depression from 16 March 2020 to 31 August 2021, compared to the pre-pandemic period (i.e., 1 January 2017 to 31 December 2019) and across populations with different exposure statuses (i.e., not tested for COVID-19, tested negative and tested positive). The age- and sex-standardized incidence ratios (SIRs) were calculated by month which indicated an increase in incident diagnoses of anxiety or depression among individuals who were tested for COVID-19 (tested negative: SIR 3.05 [95% confidence interval 2.88-3.22]; tested positive: 2.03 [1.76-2.34]), especially during the first six months of the pandemic (i.e., March-September 2020). Similar increases were also observed for incident prescriptions of anxiolytics or antidepressants (tested negative: 1.56 [1.47-1.67]; tested positive: 1.41 [1.22-1.62]). In contrast, individuals not tested for COVID-19 had consistently lower incidence rates of both diagnoses of anxiety or depression (0.70 [0.67-0.72]) and prescriptions of respective psychotropic medications (0.70 [0.68-0.72]) during the pandemic period. These data suggest a distinct rise in health care needs for anxiety and depression among individuals tested for COVID-19, regardless of the test result, in contrast to a reduction in health care consumption for these disorders among individuals not tested for and, presumably, not directly exposed to the disease.

Post-COVID depression and its multiple factors, does Favipiravir have a protective effect? A longitudinal study of indonesia COVID-19 patients.

BACKGROUND: Coronavirus disease (COVID-19) not only has a long-term effect on its survivors, it also affects their quality of life, including inducing depression as a possible manifestation of central nervous system disruption. Favipiravir shows promising efficacy as an antiviral drug for the treatment of COVID-19. However, its effect on the sequelae of COVID-19 has not been explored. Therefore, this study aims to assess the impact of Favipiravir and address the factors associated with post-COVID depression in Indonesia. METHOD: This cohort study conducted a post-COVID-19 survey on Indonesian patients who were diagnosed by using real-time polymerase chain reaction (RT-PCR) and antigen tests until January 2022. An online questionnaire was distributed to obtain information on demographics, comorbidities, health behavior, symptoms, and treatment. The propensity technique was used to allocate the participants into the favipiravir and nonrecipient groups (1:1). The Patient Health Questionnaire-9 (PHQ-9) was used for outcome measurement. The cohort was followed up biweekly for 60 days after onset/diagnosis to determine the occurrence of depression. Cox regression analysis with an adjusted odds ratio and 95% confidence interval was used to estimate the effect of favipiravir on post-COVID-19 depression. RESULTS: The data included the information of 712 participants, of whom 18.54% had depression within 60 days after onset/diagnosis. Depression was higher in the nonrecipient group (21.06%) than in the favipiravir group (16.01%). After adjustment by other factors, favipiravir prescription was found to be associated with depression (aOR 0.488, 95% CI 0.339-0.701 p < 0.001). In accordance with the PHQ-9 subset, favipiravir exerted a significant protective effect against depressive mood and loss of interest. However, patients living alone were prone to experiencing loss of interest (aOR 2.253, 95% CI 1.329-3.818, p = 0.003). CONCLUSION: The data obtained in this preliminary survey suggested that favipiravir may be useful for preventing post-COVID depression. However, further study is needed. Moreover, the provision of mental health support, particularly to those who live alone, must be ensured. TRIAL REGISTRATION: Registry NCT05060562.

Antidepressant Effect of Ketamine on Inflammation-Mediated Cytokine Dysregulation in Adults with Treatment-Resistant Depression: Rapid Systematic Review.

Background: Major depressive disorder (MDD) and treatment-resistant depression (TRD) represent a global source of societal and health burden. To advise proper management of inflammation-related depression among TRD patients, it is important to identify therapeutic clinical treatments. A key factor is related to proinflammatory cytokines such as interleukin- (IL-) 1ß, IL-6, and tumor necrosis factor- (TNF-) α which have been implicated in the pathogenesis of depressive symptoms in MDD patients. Ketamine may provide an anti-inflammatory therapeutic strategy by targeting proinflammatory pathways associated with depressive disorders, which may be exacerbated in the ageing population with TRD. Objective: Despite a burgeoning body of literature demonstrating that inflammation is linked to TRD, there is still a lack of comprehensive research on the relationship between proinflammatory biomarkers and ketamine's antidepressant effect on TRD patients. Method: The Cochrane Library and PubMed/MEDLINE databases were systematically searched from inception up to February 1, 2022, adopting broad inclusion criteria to assess clinical topics related to the impact of ketamine on inflammatory cytokines in TRD patients. The present work is in compliance with the World Health Organization Rapid Review Guide. Results: Five out of the seven studies examined in this review show that ketamine infusion may reduce depressive symptoms with a quick start of effect on TRD patients. Based on the Montgomery-Åsberg Depression Rating Scale (MADRS) and Hamilton Depression Rating Scale (HAM-D) scores, the overall response rate for ketamine was 56%; that is, 56% of those treated with ketamine had MADRS/HAM-D scores decreased by at least 50%. Conclusions: While the anti-inflammatory effects of ketamine modulate specific proinflammatory cytokines, its rapid antidepressant effect on TRD patients remains inconsistent. However, our study findings can provide a reliable basis for future research on how to improve systemic inflammatory immune disorders and mental health. We suggest that ketamine infusion may be part of a comprehensive treatment approach in TRD patients with elevated levels of depression-specific inflammatory biomarkers.

Pharmacogenetic Aspects of COVID-19 Management and Post-COVID-19 Depression Treatment with Fluvoxamine.

BACKGROUND: Quarantine measures with self-isolation of varying duration have been significant psychosocial stressors in the context of the COVID-19 pandemic. The serotonin selective reuptake inhibitor fluvoxamine has been considered as a prophylaxis against depression in early COVID-19 patients, with additional benefits apparently arising from its antiviral activity. In this narrative review, we draw attention to the body of evidence showing efficacy of fluvoxamine in protecting against depressive disorders in COVID-19 patients, while also attenuating the severity of COVID-19 disease, with a notable reduction in the need for intubation and lower mortality. We consider this potential two-fold action of fluvoxamine in the light of its pharmacogenetic and pharmacological profiles. SUBJECTS AND METHODS: Full-text publications in English and Russian in Google Scholar, PubMed, NCBI, Web of Science, and E-Library databases were selected by keywords, solitary and in combination (fluvoxamine, COVID-19, depression, anxiety, antidepressants, adverse reactions) for the period from March 01, 2020 to June 06, 2022. We also analyzed the full-text publications in English and Russian language reporting adverse reactions caused by fluvoxamine use for the period from 2012 to 2022. RESULTS: The literature search yielded 10 papers reporting on the efficacy fluvoxamine in relieving depressive symptoms in COVID-19 patients, and 3 papers on its effect on medical outcome. The preponderance of data indicated a dual therapeutic action of fluvoxamine, and our further literature investigation was informative about drug-drug interactions and genetic factors moderating the antidepressant efficacy of fluvoxamine. CONCLUSIONS: Patients with COVID-19 seeking psychopharmacological treatment for depressive symptoms must be informed of the benefits and risks of fluvoxamine use. Several lines of findings indicate this agent to possess an additional antiviral action. However, optimal dosage regimens and the trade-off with drug-drug interactions remain unclear. Pharmacogenetic testing may assist in evidence-based optimization of fluvoxamine dosages in the context of COVID-19 infection with comorbid depression.

Biologicals decrease psychological distress, anxiety and depression in severe asthma, despite Covid-19 pandemic.

Patients with respiratory diseases suffer more from problems of severe psychiatric comorbidity than the general population. Asthma might cause psychiatric disorders and affect patients' quality of life negatively. Previous studies reported that mental disorders prevail in asthmatic patients, causing anxiety, depression, and suicidal risk. The aim of this study is to evaluate in real life the prevalence of psychological comorbidities in asthmatics with severe asthma treated by biologicals (Benralizumab, Mepolizumab, Omalizumab). This study starts with the hypothesis that psychological distress, anxiety, depression and suicidal risk in severe asthma patients decreases if treated by biologicals. This study involves a sample of 90 patients (32 males, 58 females and aged 53.92 ± 15.92) suffering from severe asthma and treated with the biological drugs of Benralizumab, Mepolizumab, Omalizumab during Covid-19 pandemic. At the beginning of the treatment (T0) and after 16 weeks (T1), there have been reported results from both clinical disease control, assessed using the ACT, and psychological disorders, assessed with the PSS, HADS and C-SSRS. In the sample of these patients treated with biologicals for severe asthma, the study reported a significant change in all observed parameters, including asthma control (ACT), stress (PSS), anxiety (HADS-A) and depressive symptoms (HADS-D, despite Covid-19 pandemic. In addition, there was a significant improvement in disease management, perceived stress, anxiety and depressive symptoms after a 16 week treatment for severe asthma, independent from the type of biologic drugs used during the pandemic.

Post-COVID-19 Depressive Symptoms: Epidemiology, Pathophysiology, and Pharmacological Treatment.

The Coronavirus Disease 2019 (COVID-19) pandemic is still spreading worldwide over 2 years since its outbreak. The psychopathological implications in COVID-19 survivors such as depression, anxiety, and cognitive impairments are now recognized as primary symptoms of the "post-acute COVID-19 syndrome." Depressive psychopathology was reported in around 35% of patients at short, medium, and long-term follow-up after the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection. Post-COVID-19 depressive symptoms are known to increase fatigue and affect neurocognitive functioning, sleep, quality of life, and global functioning in COVID-19 survivors. The psychopathological mechanisms underlying post-COVID-19 depressive symptoms are mainly related to the inflammation triggered by the peripheral immune-inflammatory response to the viral infection and to the persistent psychological burden during and after infection. The large number of SARS-CoV-2-infected patients and the high prevalence of post-COVID-19 depressive symptoms may significantly increase the pool of people suffering from depressive disorders. Therefore, it is essential to screen, diagnose, treat, and monitor COVID-19 survivors' psychopathology to counteract the depression disease burden and related years of life lived with disability. This paper reviews the current literature in order to synthesize the available evidence regarding epidemiology, clinical features, neurobiological underpinning, and pharmacological treatment of post-COVID-19 depressive symptoms.

Pedicularis resupinata Extract Prevents Depressive-like Behavior in Repeated Corticosterone-Induced Depression in Mice: A Preliminary Study.

Excessive corticosterone (CORT), resulting from a dysregulated hypothalamic-pituitary-adrenal (HPA) axis, is associated with cognitive impairment and behavioral changes, including depression. In Korean oriental medicine, Pedicularis resupinata is used for the treatment of inflammatory diseases such as rheumatoid arthritis. However, the antidepressant properties of P. resupinata have not been well characterized. Here, the antidepressant-like effects of P. resupinata extract (PRE) were evaluated in terms of CORT-induced depression using in vivo models. HPLC confirmed that acteoside, a phenylethanoid glycoside, was the main compound from PRE. Male ICR mice (8 weeks old) were injected with CORT (40 mg/kg, i.p.) and orally administered PRE daily (30, 100, and 300 mg/kg) for 21 consecutive days. Depressive-like behaviors were evaluated using the open-field test, sucrose preference test, passive avoidance test, tail suspension test, and forced swim test. Treatment with a high dose of PRE significantly alleviated CORT-induced, depressive-like behaviors in mice. Additionally, repeated CORT injection markedly reduced brain-derived neurotrophic factor levels, whereas total glucocorticoid receptor (GR) and GR phosphorylation at serine 211 were significantly increased in the mice hippocampus but improved by PRE treatment. Thus, our findings suggest that PRE has potential antidepressant-like effects in CORT-induced, depressive-like behavior in mice.

[Correction of psychoemotional disorders and short-term prognosis in patients with COVID-19]. / Korrektsiya psikhoemotsional'nykh narushenii i kratkosrochnyi prognoz u patsientov s COVID-19.

This review discusses the importance of the main psychosocial risk factors in the development of chronic non-communicable diseases. The current data on the prevalence of anxiety and depressive disorders in patients with cardiovascular diseases (CVD) are presented. The article summarizes information about the relationship between the development of psychoemotional disorders and CVD, discusses the prospects for the management of such patients in the framework of interdisciplinary cooperation. The main pathogenetic mechanisms of the development of complications, including damage to the central nervous system during infection with a new coronavirus infection, are considered. The significance of the choice of pathogenetic therapy for patients with comorbid somatic and mental diseases in the conditions of a pandemic of a new coronavirus infection is assessed. The results of multicenter placebo-controlled studies on the use of fluvoxamine in patients with a new coronavirus infection of varying severity are discussed.

A randomised controlled trial investigating the clinical and cost-effectiveness of Alpha-Stim AID cranial electrotherapy stimulation (CES) in patients seeking treatment for moderate severity depression in primary care (Alpha-Stim-D Trial).

BACKGROUND: Major depression is the second leading cause of years lost to disability worldwide and is a leading contributor to suicide. However, first-line antidepressants are only fully effective for 33%, and only 40% of those offered psychological treatment attend for two sessions or more. Views gained from patients and primary care professionals are that greater treatment uptake might be achieved if people with depression could be offered alternative and more accessible treatment options. Although there is evidence that the Alpha-Stim Anxiety Insomnia and Depression (AID) device is safe and effective for anxiety and depression symptoms in people with anxiety disorders, there is much less evidence of efficacy in major depression without anxiety. This study investigates the effectiveness of the Alpha-Stim AID device, a cranial electrotherapy stimulation (CES) treatment that people can safely use independently at home. The device provides CES which has been shown to increase alpha oscillatory brain activity, associated with relaxation. METHODS: The aim of this study is to investigate the clinical and cost-effectiveness of Alpha-Stim AID in treatment-seeking patients (aged 16 years upwards) with moderate to moderately severe depressive symptoms in primary care. The study is a multi-centre parallel-group, double-blind, non-commercial, randomised controlled superiority trial. The primary objective of the study is to examine the clinical efficacy of active daily use of 8 weeks of Alpha-Stim AID versus sham Alpha-Stim AID on depression symptoms at 16 weeks (8 weeks after the end of treatment) in people with moderate severity depression. The primary outcome is the 17-item Hamilton Depression Rating Scale at 16 weeks. All trial and treatment procedures are carried out remotely using videoconferencing, telephone and postal delivery considering the COVID-19 pandemic restrictions. DISCUSSION: This study is investigating whether participants using the Alpha-Stim AID device display a reduction in depressive symptoms that can be maintained over 8 weeks post-treatment. The findings will help to determine whether Alpha-Stim AID should be recommended, including being made available in the NHS for patients with depressive symptoms. TRIAL REGISTRATION: ISRTCN ISRCTN11853110 . Registered on 14 August 2020.

Quality of clinical practice guidelines for inadequate response to first-line treatment for depression according to AGREE II checklist and comparison of recommendations: a systematic review.

OBJECTIVE: To assess similarities and differences in the recommended sequence of strategies among the most relevant clinical practice guidelines (CPGs) for the treatment of depression in adults with inadequate response to first-line treatment. DATA SOURCES: We performed a systematic review of the literature spanning January 2011 to August 2020 in Medline, Embase, Cochrane Library and 12 databases recognised as CPGs repositories. CPGs quality was assessed using the Appraisal of Guidelines for Research and Evaluation II (AGREE II). STUDY SELECTION: The eligibility criteria were CPGs that described pharmacological recommendations for treating depression for individuals aged 18 years or older in outpatient care setting. We included CPGs considered of high-quality (≥80% in domain 3 of AGREE II) or recognised as clinically relevant. DATA EXTRACTION: Two independent researchers extracted recommendations for patients who did not respond to first-line pharmacological treatment from the selected CPGs. RESULTS: We included 46 CPGs and selected 8, of which 5 were considered high quality (≥80% in domain 3 of AGREE II) and 3 were recognised as clinically relevant. Three CPGs did not define inadequate response to treatment and 3 did not establish a clear sequence of strategies. The duration of treatment needed to determine that a patient had not responded was not explicit in 3 CPGs and was discordant in 5 CPGs. Most CPGs agree in reassessing the diagnosis, assessing the presence of comorbidities, adherence to treatment, and increase dosage as first steps. All CPGs recommend psychotherapy, switching antidepressants, and considering augmentation/combining antidepressants. CONCLUSION: Relevant CPGs present shortcomings in recommendations for non-responders to first-line antidepressant treatment including absence and divergencies in definition of inadequate response and sequence of recommended strategies. Overall, most relevant CPGs recommend reassessing the diagnosis, evaluate comorbidities, adherence to treatment, increase dosage of antidepressants, and psychotherapy as first steps. PROSPERO REGISTRATION NUMBER: CRD42016043364.