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Identifying new antifungals for cryptococcal meningitis is a priority given the inadequacy of current therapy. Sertraline has previously shown in vitro and in vivo activity against cryptococcus. We aimed to assess the efficacy and cost-effectiveness of adjunctive sertraline in adults with HIV-associated cryptococcal meningitis compared with placebo. In this double-blind, randomised, placebo-controlled trial, we recruited HIV-positive adults with cryptococcal meningitis from two hospitals in Uganda. Participants were randomly assigned (1:1) to receive standard therapy with 7–14 days of intravenous amphotericin B (0·7–1·0 mg/kg per day) and oral fluconazole (starting at 800 mg/day) with either adjunctive sertraline or placebo. Sertraline was administered orally or via nasogastric tube at a dose of 400 mg/day for 2 weeks, followed by 200 mg/day for 12 weeks, then tapered off over 3 weeks. The primary endpoint was 18-week survival, analysed by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT01802385. Between March 9, 2015, and May 29, 2017, we screened 842 patients with suspected meningitis and enrolled 460 of a planned 550 participants, at which point the trial was stopped for futility. Three patients in the sertraline group and three patients in the placebo group were lost to follow-up and therefore discontinued before study end. At 18 weeks, 120 (52%) of 229 patients in the sertraline group and 106 (46%) of 231 patients in the placebo group had died (hazard ratio 1·21, 95% CI 0·93–1·57; p=0·15). The fungal clearance rate from cerebrospinal fluid was similar between groups (0·43 –log10 CFU/mL per day [95% CI 0·37–0·50] in the sertraline group vs 0·47 –log10 CFU/mL per day [0·40–0·54] in the placebo group; p=0·59), as was occurrence of grade 4 or 5 adverse events (72 [31%] of 229 vs 75 [32%] of 231; p=0·98), most of which were associated with amphotericin B toxicity. Sertraline did not reduce mortality and should not be used to treat patients with HIV-associated cryptococcal meningitis. The reasons for sertraline inactivity appear to be multifactorial and might be associated with insufficient duration of therapeutic sertraline concentrations. National Institutes of Health and Medical Research Council, Wellcome Trust.

Cryptococcus is the most common cause of adult meningitis in Africa. We assessed the safety and microbiological efficacy of adjunctive sertraline, previously shown to have in-vitro and in-vivo activity against cryptococcus. In this open-label dose-finding study, we recruited HIV-infected individuals with cryptococcal meningitis who presented to Mulago Hospital in Kampala, Uganda between Aug 14, 2013, and Aug 30, 2014. To assess safety and tolerability, the first 60 participants were given sertraline at escalating doses of 100 mg/day, 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for an additional 8 weeks. From Nov 29, 2013, participants were randomly assigned (1:1) to receive open-label sertraline at predetermined doses of 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for 8 weeks. Dose assignment was made via computer-generated, permuted block randomisation stratified by antiretroviral therapy (ART) status for people with a first episode of meningitis. The primary outcome was 2-week cerebrospinal fluid (CSF) clearance rate of cryptococcus, termed early fungicidal activity, measured in patients with a first episode of culture-positive meningitis and two or more CSF cultures. This study is registered with ClinicalTrials.gov, number NCT01802385. Of the 330 individuals assessed, 172 HIV-infected adults with cryptococcal meningitis were enrolled. We gave 100 mg/day sertraline to 17 patients, 200 mg/day to 12 patients, 300 mg/day to 14 patients, and 400 mg/day to 17 patients. 112 participants were randomly assigned to receive sertraline at 200 mg (n=48), 300 mg (n=36), or 400 mg (n=28) daily for the first 2 weeks, and 200 mg/day thereafter. The final population consisted of 17 participants in the 100 mg group, 60 in the 200 mg group, 50 in the 300 mg group, and 45 in the 400 mg in group. Participants receiving any sertraline dose averaged a CSF clearance rate of −0·37 colony forming units per mL per day (95% CI −0·41 to −0·33). Incidence of paradoxical immune reconstitution inflammatory syndrome was 5% (two of 43 newly starting ART) and no cases of relapse occurred over the 12-week study period. 38 (22%) of 172 participants had died at 2 weeks, and 69 (40%) had died at 12 weeks. Six grade 4 adverse events occurred in 17 participants receiving 100 mg, 14 events in 60 participants receiving 200 mg, 19 events in 50 participants receiving 300 mg, and eight events in 45 participants receiving 400 mg. Grade 4 or 5 adverse event risk did not differ between current US Food and Drug Administration-approved dosing of 100–200 mg/day and higher doses of 300–400 mg/day (hazard ratio 1·27, 95% CI 0·69–2·32; p=0·45). Participants receiving sertraline had faster cryptococcal CSF clearance and a lower incidence of immune reconstitution inflammatory syndrome and relapse than that reported in the past. This inexpensive and off-patent oral medication is a promising adjunctive antifungal therapy. National Institutes of Health, Grand Challenges Canada.

Selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacological treatments for depression and anxiety. However, little is known about how pharmacological action is related to cognitive and affective processes. Here, we examine whether specific reinforcement learning processes mediate the treatment effects of SSRIs. The PANDA trial was a multicentre, double-blind, randomized clinical trial in UK primary care comparing the SSRI sertraline with placebo for depression and anxiety. Participants ( = 655) performed an affective Go/NoGo task three times during the trial and computational models were used to infer reinforcement learning processes. There was poor task performance: only 54% of the task runs were informative, with more informative task runs in the placebo than in the active group. There was no evidence for the preregistered hypothesis that Pavlovian inhibition was affected by sertraline. Exploratory analyses revealed that in the sertraline group, early increases in Pavlovian inhibition were associated with improvements in depression after 12 weeks. Furthermore, sertraline increased how fast participants learned from losses and faster learning from losses was associated with more severe generalized anxiety symptoms. The study findings indicate a relationship between aversive reinforcement learning mechanisms and aspects of depression, anxiety, and SSRI treatment, but these relationships did not align with the initial hypotheses. Poor task performance limits the interpretability and likely generalizability of the findings, and highlights the critical importance of developing acceptable and reliable tasks for use in clinical studies. This article presents research supported by NIHR Program Grants for Applied Research (RP-PG-0610-10048), the NIHR BRC, and UCL, with additional support from IMPRS COMP2PSYCH (JM, QH) and a Wellcome Trust grant (QH).

Major depressive disorder (MDD) is one of the most prevalent and disabling illnesses worldwide. Treatment of MDD typically relies on trial-and-error to find an effective approach. Identifying early response-related biomarkers that predict response to antidepressants would help clinicians to decide, as early as possible, whether a particular treatment might be suitable for a given patient. Data were from the two-stage Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) trial. A whole-brain, voxel-wise, mixed-effects model was applied to identify early-treatment cerebral blood flow (CBF) changes as biomarkers of treatment response. We examined changes in CBF measured with arterial spin labeling 1-week after initiating double-masked sertraline/placebo. We tested whether these early 1-week scans could be used to predict response observed after 8-weeks of treatment. Response to 8-week placebo treatment was associated with increased cerebral perfusion in temporal cortex and reduced cerebral perfusion in postcentral region captured at 1-week of treatment. Additionally, CBF response in these brain regions was significantly correlated with improvement in Hamilton Depression Rating Scale score in the placebo group. No significant associations were found for selective serotonin reuptake inhibitor treatment. We conclude that early CBF responses to placebo administration in multiple brain regions represent candidate neural biomarkers of longer-term antidepressant effects.

Little evidence exists on the treatment of traumatised refugees. To estimate treatment effects of flexible cognitive-behavioural therapy (CBT) and antidepressants (sertraline and mianserin) in traumatised refugees. Randomised controlled clinical trial with 2 × 2 factorial design (registered with Clinicaltrials.gov, NCT00917397, EUDRACT no. 2008-006714-15). Participants were refugees with war-related traumatic experiences, post-traumatic stress disorder (PTSD) and without psychotic disorder. Treatment was weekly sessions with a physician and/or psychologist over 6 months. A total of 217 of 280 patients completed treatment (78%). There was no effect on PTSD symptoms, no effect of psychotherapy and no interaction between psychotherapy and medicine. A small but significant effect of treatment with antidepressants was found on depression. In a pragmatic clinical setting, there was no effect of flexible CBT and antidepressants on PTSD, and there was a small-to-moderate effect of antidepressants and psychoeducation on depression in traumatised refugees.

Background Combined treatment with a selective serotonin reuptake inhibitor (SSRI) plus mirtazapine has shown superior efficacy in some studies of depression, but has not been studied in posttraumatic stress disorder (PTSD). This study aimed to assess acceptability of combined sertraline plus mirtazapine treatment for PTSD and to estimate its effect size relative to sertraline plus placebo. Methods Thirty‐six adults with PTSD were randomized to 24 weeks of double‐blind treatment with sertraline plus mirtazapine or sertraline plus placebo. Outcomes were analyzed with mixed effects models. Results The combined treatment group showed a significantly greater remission rate (P = .042) and improvement in depressive symptoms (P = .023) than the sertraline plus placebo group. There were no significant group differences in the two primary outcomes of treatment retention and PTSD severity, or in other secondary outcomes (sleep impairment, sexual functioning, quality of life, and physical and mental functioning), but the combined treatment group showed numerical advantages on all of these outcomes, and effect sizes relative to sertraline plus placebo ranged from small to moderate (d = .26–.63). Both treatments were well‐tolerated, with significantly increased appetite but not weight gain in the combined treatment group. Conclusion Findings suggest that combined treatment of PTSD with sertraline plus mirtazapine may have clinically meaningful advantages in symptomatic improvement, relative to SSRI treatment alone, and acceptable tolerability. Combined treatment with an SSRI plus mirtazapine in PTSD deserves additional study as initial treatment or as an augmentation strategy for nonresponders to an SSRI.

Understanding the mechanisms of major depressive disorder (MDD) improvement is a key challenge to determining effective personalized treatments. To identify a data-driven pattern of clinical improvement in MDD and to quantify neural-to-symptom relationships according to antidepressant treatment, we performed a secondary analysis of the publicly available dataset EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care). In EMBARC, participants with MDD were treated either by sertraline or placebo for 8 weeks (Stage 1), and then switched to bupropion according to clinical response (Stage 2). We computed a univariate measure of clinical improvement through a principal component (PC) analysis on the variations of individual items of four clinical scales measuring depression, anxiety, suicidal ideas, and manic-like symptoms. We then investigated how initial clinical and neural factors predicted this measure during Stage 1 by running a linear model for each brain parcel's resting-state global brain connectivity (GBC) with individual improvement scores during Stage 1. The first PC (PC1) was similar across treatment groups at stages 1 and 2, suggesting a shared pattern of symptom improvement. PC1 patients' scores significantly differed according to treatment, whereas no difference in response was evidenced between groups with the Clinical Global Impressions Scale. Baseline GBC correlated with Stage 1 PC1 scores in the sertraline but not in the placebo group.Using data-driven reduction of symptom scales, we identified a common profile of symptom improvement with distinct intensity between sertraline and placebo. Mapping from data-driven symptom improvement onto neural circuits revealed treatment-responsive neural profiles that may aid in optimal patient selection for future trials.

This study examined the relationship between caregivers’ and youths’ treatment expectations and characteristics of exposure tasks (quantity, mastery, compliance) in cognitive-behavioral therapy (CBT) for childhood anxiety. Additionally, compliance with exposure tasks was tested as a mediator of the relationship between treatment expectations and symptom improvement. Data were from youth (N = 279; 7–17 years old) enrolled in the Child/Adolescent Anxiety Multimodal Study (CAMS) and randomized to cognitive-behavioral therapy (CBT) or the combination of CBT and sertraline for the treatment of separation anxiety disorder, generalized anxiety disorder, and social phobia. Caregivers and youth independently reported treatment expectations prior to randomization, anxiety was assessed pre- and post-treatment by independent evaluators blind to treatment condition, and exposure characteristics were recorded by the cognitive-behavioral therapists following each session. For both caregivers and youths, more positive expectations that anxiety would improve with treatment were associated with greater compliance with exposure tasks, and compliance mediated the relationship between treatment expectations and change in anxiety symptoms following treatment. Additionally, more positive parent treatment expectations were related to a greater number and percentage of sessions with exposure. More positive youth treatment expectations were associated with greater mastery during sessions focused on exposure. Findings underscore the importance of addressing parents’ and youths’ treatment expectations at the outset of therapy to facilitate engagement in exposure and maximize therapeutic gains.

Background Generalized anxiety disorder (GAD) (Chittodvega) is one among many types of mental disorders explained in Ayurveda. It can be defined as a Chitta (mind) + Udvega (anxiety)= Chittodvega- Anxious status of a mind. Celastrus paniculatus also known as Jyotishmati stimulates and improves the digestive fire and metabolism at a cellular level ( Jatharagni and Majja dhatwagni). It can be correlated to GAD. GAD is characterized by feelings of threat, restlessness, irritability, sleep disturbance, and tension, and symptoms such as palpitations, dry mouth, and sweating. It affects women more frequently than men and prevalence rates are high in midlife (prevalence in females over age 35: 10%) and older subjects. In modern medicine the first-line psychological and pharmaceutical treatments are selective serotonin reuptake inhibitors (SSRIs) like sertraline (SNRIs). Aim and objectives To evaluate the comparative efficacy of Jyotishmati versus sertraline in the management of Chittodvega. Methods In this randomized active controlled double blind equivalence trial a total of 70 patients will be enrolled and divided into two equal groups. Patients between 20-50 years age of either gender having symptoms of Chittodvega and a Hamilton anxiety rating (HAM-A) scale score less than 24 (i.e., mild to moderate) will be selected for the study. In Group A, sertraline capsules 25 mg for first 7 days and then dose increased to 50 mg at bedtime for next 53 days and in Group B Jyotishmati Capsules 500 mg will be given twice a day after food with water for 60 days. Result and observation The patients will be assessed on the HAM-A scale, serum cortisol and WHO Quality of Life on day 0, 30, 60 and 90 and data will be analyzed using paired and unpaired t-tests for continuous variables and chi-square tests for categorical variables to evaluate whether treatments are equivalent. Trial registration CTRI No. REF/2023/07/069880 Date - 15/09/2023

Objective: The aim of this study was to evaluate the safety and efficacy of sertraline in children and adolescents who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria for posttraumatic stress disorder (PTSD). Method: Children and adolescents (6–17 years old) meeting DSM-IV criteria for PTSD were randomized to 10 weeks of double-blind treatment with sertraline (50–200 mg/day) or placebo. The primary efficacy measure was the University of California, Los Angeles Post-Traumatic Stress Disorder Index for DSM-IV (UCLA PTSD-I). Results: A total of 131 patients met entry criteria and were randomized to sertraline (n = 67; female, 59.7%; mean age, 10.8; mean UCLA PTSD-I score, 43.8 ± 8.5) or placebo (n = 62; female, 61.3%; mean age, 11.2; mean UCLA PTSD-I score, 42.1 ± 8.8). There was no difference between sertraline and placebo in least squares (LS) mean change in the UCLA PTSD-I score, either on a completer analysis (−20.4 ± 2.1 vs. −22.8 ± 2.1; p = 0.373) or on an last observation carried forward (LOCF) end point analysis (−17.7 ± 1.9 vs. −20.8 ± 2.1; p = 0.201). Attrition was higher on sertraline (29.9%) compared to placebo (17.7%). Discontinuation due to adverse events occurred in a 7.5% treated with sertraline and 3.2% treated with placebo. Conclusions: Sertraline was a generally safe treatment in children and adolescents with PTSD, but did not demonstrate efficacy when compared to placebo during 10 weeks of treatment. ClinicalTrials.gov Identifier: NCT00150306.