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This was a double-blind, randomized, phase 2 study of adults (18–64 years) with DSM−5 diagnosis of major depressive disorder (MDD), with moderate-to-severe episode severity (Montgomery–Åsberg Depression Rating Scale [MADRS] ≥25) despite an adequate course with ongoing antidepressant for ≥6 weeks to ≤12 months. Following a double-blind placebo lead-in period (up to 3 weeks), participants were randomized to receive once daily aticaprant 10 mg or continue placebo, added to their ongoing treatment, for 6 weeks. Of 184 participants enrolled, 169 were included in safety analyses (aticaprant n  = 85, placebo n  = 84) and 166 in full intent-to-treat (fITT) efficacy analyses; 121 placebo lead-in non-responders (<30% reduction in MADRS total score) in fITT were included in enriched ITT (eITT) analyses. Improvement (least squares mean difference [upper limit 1-sided 80% CI] versus placebo) in MADRS total score at week 6 for aticaprant was significant versus placebo (eITT: −2.1 [−1.09], 1-sided p  = 0.044; effect size (ES) 0.23; fITT −3.1 [2.21], 1-sided p  = 0.002; ES 0.36). The between-group difference was larger among participants with Snaith–Hamilton Pleasure Scale (SHAPS) score greater/equal to versus less than baseline median SHAPS. The most common treatment-emergent adverse events reported for aticaprant (versus placebo) were headache (11.8% versus 7.1%), diarrhea (8.2% versus 2.4%), nasopharyngitis (5.9% versus 2.4%), and pruritus (5.9% versus 0%). One participant (1.2%) in each arm discontinued treatment due to an adverse event. In this study of participants with MDD and inadequate response to SSRI/SNRI, adjunctive treatment with aticaprant significantly reduced depressive symptoms versus placebo, without resulting in significant safety signals, supporting further investigation in larger trials.

Dravet syndrome is a rare, treatment-resistant developmental epileptic encephalopathy characterised by multiple types of frequent, disabling seizures. Fenfluramine has been reported to have antiseizure activity in observational studies of photosensitive epilepsy and Dravet syndrome. The aim of the present study was to assess the efficacy and safety of fenfluramine in patients with Dravet syndrome. In this randomised, double-blind, placebo-controlled clinical trial, we enrolled children and young adults with Dravet syndrome. After a 6-week observation period to establish baseline monthly convulsive seizure frequency (MCSF; convulsive seizures were defined as hemiclonic, tonic, clonic, tonic-atonic, generalised tonic-clonic, and focal with clearly observable motor signs), patients were randomly assigned through an interactive web response system in a 1:1:1 ratio to placebo, fenfluramine 0·2 mg/kg per day, or fenfluramine 0·7 mg/kg per day, added to existing antiepileptic agents for 14 weeks. The primary outcome was the change in mean monthly frequency of convulsive seizures during the treatment period compared with baseline in the 0·7 mg/kg per day group versus placebo; 0·2 mg/kg per day versus placebo was assessed as a key secondary outcome. Analysis was by modified intention to treat. Safety analyses included all participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov with two identical protocols NCT02682927 and NCT02826863. Between Jan 15, 2016, and Aug 14, 2017, we assessed 173 patients, of whom 119 patients (mean age 9·0 years, 64 [54%] male) were randomly assigned to receive either fenfluramine 0·2 mg/kg per day (39), fenfluramine 0·7 mg/kg per day (40) or placebo (40). During treatment, the median reduction in seizure frequency was 74·9% in the fenfluramine 0·7 mg/kg group (from median 20·7 seizures per 28 days to 4·7 seizures per 28 days), 42·3% in the fenfluramine 0·2 mg/kg group (from median 17·5 seizures per 28 days to 12·6 per 28 days), and 19·2% in the placebo group (from median 27·3 per 28 days to 22·0 per 28 days). The study met its primary efficacy endpoint, with fenfluramine 0·7 mg/kg per day showing a 62·3% greater reduction in mean MCSF compared with placebo (95% CI 47·7–72·8, p<0·0001); fenfluramine 0·2 mg/kg per day showed a 32·4% reduction in mean MCSF compared with placebo (95% CI 6·2–52·3, p=0·0209). The most common adverse events (occurring in at least 10% of patients and more frequently in the fenfluramine groups) were decreased appetite, diarrhoea, fatigue, lethargy, somnolence, and decreased weight. Echocardiographic examinations revealed valve function within the normal physiological range in all patients during the trial and no signs of pulmonary arterial hypertension. In Dravet syndrome, fenfluramine provided significantly greater reduction in convulsive seizure frequency compared with placebo and was generally well tolerated, with no observed valvular heart disease or pulmonary arterial hypertension. Fenfluramine could be an important new treatment option for patients with Dravet syndrome. Zogenix.

Pharmacological efforts to treat anorexia nervosa (AN) have predominantly repurposed medications that treat conditions with overlapping symptoms and yielded generally disappointing results. Despite limited empirical support, SSRIs are often prescribed to patients with AN. Whether SSRIs are effective in a subgroup of individuals with AN, such as those with depression, is not known. A secondary analysis of a randomized trial of fluoxetine versus placebo for relapse prevention in AN was conducted. Participants (  = 92) were weight-restored women with AN who completed the Beck Depression Inventory (BDI) at the time of randomization. BDI scores were dichotomized to reflect moderate/severe depression (BDI > 20,  = 26). A Cox Proportional Hazards model estimated the association of the level of depression, medication, and their interaction with time to relapse. Mixed effects models examined the effects of medication on symptom trajectories in high versus low depression groups and whether depression severity modified the effect of the drug on symptom trajectory. There was a significant interaction between medication and depression severity in time to relapse (hazard ratio = 0.46, 95% CI: [0.25, 0.85],  = .01). Depression severity modified the effect of fluoxetine on the time course of symptoms of depression (  = -0.27, 95% CI: [-0.42,-0.12],  = 0.001) and bulimia (  = -0.15, 95% CI: [-0.25,-0.05],  = 0.004) in the twelve month follow-up period. Fluoxetine was more effective than placebo in reducing relapse among more depressed, weight-restored individuals with AN. These results require replication but provide support for the use of antidepressant medication for patients with AN who remain depressed following weight restoration.

Abstract Background Ozanimod, approved for the treatment of moderately to severely active ulcerative colitis (UC) and relapsing multiple sclerosis (RMS), is a weak in vitro monoamine oxidase B (MAO-B) inhibitor. MAO-B inhibitors can cause serotonin accumulation with concomitant use of selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs). We evaluated the incidence of treatment-emergent adverse events (TEAEs) potentially associated with serotonin accumulation during ozanimod and concomitant SSRI/SNRI use in this post hoc analysis of pooled UC studies and the open-label extension RMS DAYBREAK. Methods Data for ozanimod 0.92 mg from pooled UC studies (n = 1158; cutoff: January 10, 2022) and RMS DAYBREAK (n = 2257; cutoff: February 1, 2022) were analyzed. Concomitant SSRI/SNRI use was allowed in the UC (n = 67) and RMS (n = 274) studies. A narrow Medical Dictionary for Regulatory Activities search (“serotonin syndrome,” “neuroleptic malignant syndrome,” and “malignant hyperthermia”) and a broad search including terms potentially associated with serotonin accumulation were conducted. The percentages of patients with TEAEs in both searches were analyzed by concomitant SSRI/SNRI use when the TEAE occurred. Results No patients had TEAEs matching the narrow search criteria. No differences were observed in the percentages of patients with ≥1 TEAE matching the broad search regardless of SSRI/SNRI use in UC (with: 25.4% [n = 17 of 67]; without: 15.0% [n = 164 of 1091]) and RMS (with: 12.4% [n = 34 of 274]; without: 15.6% [n = 310 of 1982]) studies. Conclusions No evidence of increased TEAEs potentially associated with serotonin accumulation was observed with concurrent use of ozanimod and SSRIs/SNRIs. Clinical trial registration NCT01647516, NCT02531126, NCT02435992, NCT02576717 Lay Summary No evidence of increased treatment-emergent adverse effects potentially associated with serotonin accumulation was observed with concurrent use of ozanimod and serotonergic antidepressants. Our findings support the absence of clinically meaningful ozanimod monoamine oxidase B inhibition in vivo. Graphical Abstract Graphical Abstract

Women diagnosed with premenstrual dysphoric disorder (PMDD) report significant symptom relief when treated with selective serotonin reuptake inhibitors, but few studies have addressed the possibility of capturing this effect in behavioral, laboratory-based tests. This study examined the effects of intermittent treatment with escitalopram (vs. placebo) on a behavioral measure of impulsivity and inattentiveness in women reporting high levels of premenstrual irritability and anger. Participants (  = 27) rated cardinal PMDD mood symptoms over three menstrual cycles using Visual Analogue Scales. In Cycles 2 and 3, participants displaying cyclicity with respect to the irritability/anger item received escitalopram (20 mg) or placebo in a randomized, single-blind, crossover design. The participants completed the Conners Continuous Performance Test (CPT 3) in the luteal phase of the intervention cycles. Additionally, they filled out the UPPS Impulsive Behavior Scale, once in the luteal phase and once in the follicular phase of the placebo cycle. In line with previous reports, escitalopram caused a significant reduction in self-rated irritability and anger in the luteal phase. When on escitalopram, the participants demonstrated a lower frequency of anticipatory responses and greater consistency in response speed in the CPT 3. With respect to self-reported impulsivity, participants reported higher levels of urgency and lower levels of sensation seeking in the luteal placebo phase versus the follicular phase. The finding that escitalopram impacted the outcome of the CPT 3 test in women with premenstrual irritability highlights the possible role of impulsivity in this condition.

Serotonin is implicated in multiple executive functions including goal-directed learning, cognitive flexibility, response inhibition and emotional regulation. These functions are impaired in several psychiatric disorders, such as depression and obsessive–compulsive disorder. We tested the cognitive effects of the selective serotonin reuptake inhibitor escitalopram, using an acute and clinically relevant dose (20 mg), in 66 healthy male and female volunteers in a double-blind, placebo-controlled study. Participants performed a cognitive test battery including a probabilistic and reversal learning task, the CANTAB intra-dimensional/extra-dimensional shift test of cognitive flexibility, a response inhibition task with interleaved stop-signal and No-Go trials and tasks measuring emotional processing. We showed that acute escitalopram administration impaired learning and cognitive flexibility, but improved the ability to inhibit responses in stop-signal trials while leaving unaffected acute emotional processing. Our findings suggest a dissociation of effects of acute escitalopram on cognitive functions, possibly mediated by differential modulation of brain serotonin levels in distinct functional neural circuits.

Background In general, traditional antidepressants often have limited efficacy in patients with major depressive disorder (MDD). Agomelatine, as an antidepressant with a different mechanism of action, might have adjunctive effects on traditional antidepressants. This study aimed to investigate the augmentation effect of agomelatine versus placebo in treating MDD patients who failed to respond to selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs). Methods This is an 8-week, multi-centred, double-blinded, randomized, and placebo-controlled trial. Participants diagnosed with MDD and demonstrated inadequate response to SSRI or SNRI lasting at least 2 weeks were randomly allocated to receive either agomelatine or placebo in conjunction with SSRIs or SNRIs. The 17 items of the Hamilton Depression Scale (HAMD-17) were employed to assess depression severity. The primary outcome is the total score of HAMD-17 at week 8. Secondary outcomes included HAMD-17 scores at weeks 2 and 4 and clinical remission and response over 8 weeks. Adverse events (AEs) reported in both groups were recorded. A linear mixed model was established for both primary and secondary outcomes. Results A total of 123 eligible participants were included, among which 60 were randomized into the agomelatine group, and 63 were randomized into the placebo group. The between-group difference in HAMD-17 score reduction from baseline to week 8 was not significant (difference = − 0.12, 95% CI = − 3.94 to 3.70,  P  = 0.90; Cohen’s d  = 0.022). In addition, we did not observe significant differences between the two treatment groups for secondary outcomes, including response remission, and AEs. Conclusions This study did not obtain significant findings in favour of the augmentation effect of agomelation for MDD patients. However, agomelatine was generally well tolerated and demonstrated a favourable safety profile when used in combination with SSRIs and SNRIs. Trial registration. This trial is registered at ClinicalTrials.gov ( https://clinicaltrials.gov ), the registration number is NCT 04589143.

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).

Background Traumatic brain injury (TBI) is a common presentation in emergency departments worldwide. Approximately 1.4 million adults present with TBI in England and Wales annually. Post-TBI depression (PTD) is a common neuropsychiatric consequence, affecting up to 50% of patients within two years, and is associated with adverse functional outcomes. PTD remains underdiagnosed and undertreated. Sertraline, a selective serotonin reuptake inhibitor (SSRI), has shown potential in reducing PTD incidence, yet evidence of its effectiveness in preventing depression from adequately powered trials is lacking. This randomised controlled trial aims to compare the clinical and cost-effectiveness of sertraline in reducing the risk of PTD in adults compared to usual care. Methods The design is a multi-centre, double-blind, placebo-controlled, randomised controlled trial (RCT) aiming to recruit 514 participants. Eligible adults (aged ≥ 18 years) with possible, mild or moderate-severe TBI within eight weeks of injury and without current major depressive disorder (MDD) are randomly assigned to receive sertraline (100 mg daily) or placebo for 12 months. The primary outcome is depressive symptom severity at 12 months, measured using the Patient Health Questionnaire-9. Secondary outcomes include incidence rates of major depressive disorder, psychiatric comorbidities, cognitive impairment, substance use, carer burden, productivity and cost-effectiveness at 6, 12 and 18 months. Discussion This is the first adequately powered RCT to investigate sertraline as a preventive intervention for PTD. Findings will help inform whether prescribing an SSRI soon after a TBI may reduce the risk of depression and improve functional outcomes. Trial registration This study is registered in the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT no. 2022–000072-18, date: 7 January 2022) and the ISRCTN – The UK’s Clinical Study Registry (ISRCTN no. 17518945, date: 23 December 2022, https://www.isrctn.com/ISRCTN17518945 ).

Although clinicians frequently add a second medication to an ineffective antidepressant, randomized trials comparing augmentation medications are lacking. In this study, adult outpatients with nonpsychotic major depressive disorder who had not had a remission during citalopram therapy were assigned to sustained-release bupropion or buspirone and had similar remission rates on the basis of clinician and self-reports. Several important secondary measures favored citalopram plus bupropion over citalopram plus buspirone. Adult outpatients with nonpsychotic major depressive disorder who had not had a remission during citalopram therapy were assigned to bupropion or buspirone and had similar remission rates. Several important secondary measures favored citalopram plus bupropion over citalopram plus buspirone. Numerous studies, 1 – 7 including one by Rush et al. 8 reported elsewhere in this issue of the Journal, have shown that major depressive disorder often requires more than one step of treatment to elicit a remission of symptoms. Frequently, a second medication is added to augment the first. 4 , 6 Augmentations of an initial selective serotonin-reuptake inhibitor (SSRI) with sustained-release bupropion, buspirone, mirtazapine, or dopamine agonists (e.g., pramipexole, dextroamphetamine, and methylphenidate) have been evaluated largely in open case series conducted in symptomatic volunteers with few psychiatric or general medical coexisting illnesses. 9 No randomized, controlled, prospective trials have directly compared two or more . . .