Treatment resistant depression (TRD) is estimated to affect 10–30% of patients with major depressive disorder (Al‑Harbi et al. Patient Prefer Adherence 2012; 6 369–88). Esketamine nasal spray (NS), in combination with a selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI), increases remission and response rates in patients with TRD compared with placebo plus SSRI/SNRI (Popova et al. Am J Psychiatry 2019; 176 428–38). ESCAPE-TRD (NCT04338321) is the first randomised clinical trial to compare esketamine NS to quetiapine extended-release (XR), an antipsychotic augmentation therapy for patients with TRD.

To explore the efficacy and safety of esketamine NS compared with quetiapine XR in TRD over 32 weeks (wks).

In the ESCAPE-TRD phase IIIb open-label, rater-blinded trial, patients were randomised 1:1 to esketamine NS (56/84 mg; twice per wk, weekly or every 2 wks) or quetiapine XR (150–300 mg daily) both in combination with an ongoing SSRI/SNRI. Remission (Montgomery-Åsberg Depression Rating Scale [MADRS] total score of ≤10) and response (≥50% improvement in MADRS total score from baseline or MADRS≤10) rates were analysed over time using last observation carried forward. MADRS change from baseline was analysed using Mixed Models for Repeated Measures (MMRM). The most common adverse events (AEs) leading to discontinuation are reported for patients who received ≥1 dose of study medication.

At baseline, 336 patients were randomised to esketamine NS and 340 to quetiapine XR. A significantly higher percentage of patients in the esketamine NS group achieved remission (at each visit from Wk6 [p=0.008] onward) and response (at each visit from Day 15 [p<0.001] onward) versus patients treated with quetiapine XR. Esketamine NS significantly improved MADRS score compared to quetiapine XR at each visit from Day 8 onwards, with an average difference over time in the least squares means total MADRS score change from baseline of -2.4 (Figure). The most common AEs leading to treatment discontinuation for esketamine NS were dizziness (n=2, 0.6%), dissociation (n=2, 0.6%) and vomiting (n=2, 0.6%), and for quetiapine XR were sedation (n=7, 2.1%), weight increased (n=6, 1.8%) and somnolence (n=5, 1.5%).

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Esketamine NS increased the percentage of patients achieving response and remission and improved MADRS total score over time compared with quetiapine XR. Rates of discontinuation arising from the most common AEs were generally lower with esketamine NS than quetiapine XR.

We thank participating patients and all who assisted with the study. This study was funded by Janssen; medical writing support was provided by Carolyn Walsh, PhD, Costello Medical, UK.

A. Reif Grant / Research support from: Medice, Consultant of: National Care Guidelines (NVL, S3) on major depression, bipolar disorder, ADHD and suicidal behaviour (aided in developing guidelines); board member of DGBS, DGPPN, ECNP and German Depression Foundation, Speakers bureau of: (and participated in advisory boards over the last 3 years) for Cyclerion, Janssen, Medice, SAGE/Biogen and Shire/Takeda; received speaker’s honoraria from Das Fortbildungskolleg; , A. E. Anıl Yağcıoğlu Grant / Research support from: Participated as an investigator for Janssen, Speakers bureau of: (and participated in advisory boards over the last 3 years) for Janssen and Abdi İbrahim Otsuka, A. Luts Speakers bureau of: (or participated in advisory boards for or participated as an investigator) for Janssen-Cilag, Asarina Pharma, Bristol Meyer Squibb, Dr August Wolff GmbH & Co, Eli Lilly, Lundbeck, Pfizer, Allergan, Sunovion and Regeneron., T. Messer Consultant of: National Care Guidelines (NVL, S3) on major depression (aided in developing guidelines), Speakers bureau of: (and participated in advisory boards) for Janssen-Cilag and Otsuka/Lundbeck, R. Nielsen Consultant of: Board member of DSAL and IGSLi, Speakers bureau of: (or participated in advisory boards, received research funds or participated as investigator over the last 3 years) for Boehringer Ingelheim, Compass Pharmaceuticals, Janssen-Cilag, Lundbeck, Otsuka, Sage and Teva Pharmaceuticals, J. Buyze Employee of: Janssen, T. Ito Employee of: Janssen, Y. Kambarov Employee of: Janssen, S. Mulhern Haughey Employee of: Janssen, B. Rive Employee of: Janssen, I. Usankova Employee of: Janssen, C. von Holt Employee of: Janssen, Y. Godinov Employee of: Janssen

For patients with depression, the likelihood of remission decreases with each subsequent treatment failure. Per European Medicines Agency guidance, treatment resistant depression (TRD) is defined as nonresponse to ≥2 consecutive treatments at adequate dosage and duration in the current depressive episode. In ESCAPE-TRD (NCT04338321), esketamine nasal spray (NS) increased the probability of achieving remission and remaining relapsefree, compared with quetiapine extended release (QXR) in patients with TRD. Here, we report the efficacy of esketamine NS vs QXR in patient subgroups with 2 or ≥3 consecutive prior treatment failures (PTFs).

ESCAPETRD was a phase IIIb trial comparing the efficacy of esketamine NS with QXR in patients with TRD. Patients (N = 676) were randomised 1:1 to esketamine NS (n = 336; 56/84 mg; twice weekly, weekly, or every 2 weeks [wks]) or QXR (n = 340; 150–300 mg daily, both in combination with an ongoing selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor. Randomisation was stratified by age (18-64 years; 65–74 years) and PTFs (2; ≥3).

The primary endpoint of remission (Montgomery-Åsberg Depression Rating Scale total score ≤10) at Wk8 and the secondary endpoint of remaining relapse-free through Wk32 after remission at Wk8, were analysed in PTF patient subgroups and compared between study arms, with treatment discontinuation considered as a negative outcome. The effect on time to remission was assessed using hazard ratios (HR) from a Cox regression model.

Of the randomised patients, 415 (61.4%; esketamine NS: 204, QXR: 211) had experienced 2 PTFs and 261 (38.6%; esketamine NS: 132, QXR: 129) had experienced ≥3.

Of patients with 2 PTFs, 54/204 (26.5%) esketamine NS-treated patients and 46/211 (21.8%) Q-XR-treated patients achieved remission at Wk8 (p = 0.267). Of patients with ≥3 PTFs, 37/132 (28.0%) and 14/129 (10.9%) patients achieved remission at Wk8 in esketamine NS and Q-XR arms, respectively (p < 0.001). Of patients with 2 and ≥3 PTFs, 49/204 (24.0%) and 24/132 (18.2%) of esketamine NS-treated patients and 38/211 (18.0%) and 10/129 (7.8%) of Q-XR-treated patients achieved remission at Wk8 without relapse to Wk32 (p = 0.133 and p = 0.013), respectively.

Esketamine NS significantly improved time to remission, with a greater effect in the ≥3 PTF subgroup (2 PTFs: HR = 1.547 [95% confidence interval (CI) 1.210–1.976]; p < 0.001 vs ≥3 PTFs: HR = 2.066 [95% CI 1.469–2.907]; p < 0.001).

Esketamine NS demonstrated a significantly superior remission rate versus QXR at Wk8 in patients with ≥3 PTFs, and significantly shorter time to remission versus Q-XR in both subgroups.

Current evidence on the risk of admission- or medication-requiring psychiatric sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is limited to selected populations, short durations, and loss to follow-up. This study examined if SARS-CoV-2 infection was associated with increased long-term risk of psychiatric admissions and de novo prescription of psychoactive medication in the general population of Denmark.

Adults (≥18 years) were assigned to either the control or SARS-CoV-2 group based on polymerase chain reaction (PCR) tests between 1 January 2020 and 27 November 2021. Infected subjects were matched 1:5 to control subjects by propensity score. Incidence rate ratios (IRRs) were calculated. Adjusted Cox regression was applied to the unmatched population with SARS-CoV-2 infection as a time-dependent covariate. Follow-up time was 12 months or until the end of the study.

A total of 4,585,083 adults were included in the study. Approximately 342,084 had a PCR-confirmed SARS-CoV-2 infection and were matched 1:5 with 1,697,680 controls. The IRR for psychiatric admission was 0.79 in the matched population (95% confidence interval [CI]: 0.73–0.85, p < 0.001). In the unmatched population, the adjusted hazard ratios (aHR) for psychiatric admission were either below 1.00 or with a 95% CI lower limit of 1.01. SARS-CoV-2 infection was associated with an increased risk of de novo prescription of psychoactive medication in both the matched (IRR 1.06, 95% CI: 1.02–1.11, p < 0.01) and unmatched population (HR 1.31, 95% CI: 1.28–1.34, p < 0.001).

We found a signal of increased use of psychoactive medication, specifically benzodiazepines, among SARS-CoV-2-positive persons, but the risk of psychiatric admissions did not increase.

To establish an antimicrobial stewardship program in the outpatient setting.

Prescribers of antimicrobials were asked to complete a survey regarding antimicrobial stewardship. We also monitored their compliance with appropriate prescribing practices, which were shared in monthly quality improvement reports.

The study was performed at Loyola University Health System, an academic teaching healthcare system in a metropolitan suburban environment.

Prescribers of antimicrobials across 19 primary care and 3 immediate- and urgent-care clinics.

The voluntary survey was developed using SurveyMonkeyand was distributed via e-mail. Data were collected anonymously. Rates of compliance with appropriate prescribing practices were abstracted from electronic health records and assessed by 3 metrics: (1) avoidance of antibiotics in adult acute bronchitis and appropriate antibiotic treatment in (2) patients tested for pharyngitis and (3) children with upper respiratory tract infections.

Prescribers were highly knowledgeable about what constitutes appropriate prescribing; verified compliance rates were highly concordant with self-reported rates. Nearly all prescribers were concerned about resistance, but fewer than half believed antibiotics were overprescribed in their office. Among respondents, 74% reported intense pressure from patients to prescribe antimicrobials inappropriately. Immediate- and urgent-care prescribers had higher rates of compliance than primary-care prescribers, and the latter group responded well to monthly reports and online educational resources.

Intense pressure from patients to prescribe antimicrobials when they are not indicated leads to overprescribing, an effect compounded by the importance of patient satisfaction scores. Compliance reporting improved the number of appropriate antibiotics prescribed in the primary care setting.

Aberrant anticipation of motivational salient events and processing of outcome evaluation in striatal and prefrontal regions have been suggested to underlie psychosis. Altered glutamate levels have likewise been linked to schizophrenia. Glutamatergic abnormalities may affect the processing of motivational salience and outcome evaluation. It remains unresolved, whether glutamatergic dysfunction is associated with the coding of motivational salience and outcome evaluation in antipsychotic-naïve patients with first-episode psychosis.

Fifty-one antipsychotic-naïve patients with first-episode psychosis (22 ± 5.2 years, female/male: 31/20) and 52 healthy controls (HC) matched on age, sex, and parental education underwent functional magnetic resonance imaging and magnetic resonance spectroscopy (3T) in one session. Brain responses to motivational salience and negative outcome evaluation (NOE) were examined using a monetary incentive delay task. Glutamate levels were estimated in the left thalamus and anterior cingulate cortex using LCModel.

Patients displayed a positive signal change to NOE in the caudate (p = 0.001) and dorsolateral prefrontal cortex (DLPFC; p = 0.003) compared to HC. No group difference was observed in motivational salience or in levels of glutamate. There was a different association between NOE signal in the caudate and DLPFC and thalamic glutamate levels in patients and HC due to a negative correlation in patients (caudate: p = 0.004, DLPFC: p = 0.005) that was not seen in HC.

Our findings confirm prior findings of abnormal outcome evaluation as a part of the pathophysiology of schizophrenia. The results also suggest a possible link between thalamic glutamate and NOE signaling in patients with first-episode psychosis.

Improved survival has led to a growing population of adults with congenital heart disease (CHD), followed by numerous reports of late complications. Liver disease is a known complication in some patients, with most studies focusing on Fontan associated liver disease. Whether liver disease also exists in other patients with CHD is not fully investigated. Elevated central venous pressure is considered pivotal in the development of liver disease in Fontan associated liver disease, and other patients with alterations in central venous pressure may also be at risk for developing liver fibrosis. We wanted to see if liver fibrosis is present in patients with tetralogy of Fallot. Many patients with tetralogy of Fallot have severe pulmonary regurgitation, which can lead to elevated central venous pressure. Patients with tetralogy of Fallot may be at risk of developing liver fibrosis.

Ten patients (24–56 years) with tetralogy of Fallot and pulmonary regurgitation were investigated for liver fibrosis. All patients were examined with magnetic resonance elastography of liver, hepatobiliary iminodiacetic acid scan, indocyanine green elimination by pulse spectrophotometry, elastography via FibroScan, abdominal ultrasound including liver elastography, and blood samples including liver markers.

Three out of ten patients had findings indicating possible liver fibrosis. Two of these had a liver biopsy performed, which revealed fibrosis stage 1 and 2, respectively. The same three patients had an estimated elevated central venous pressure in previous echocardiograms.

Mild liver fibrosis was present in selected patients with tetralogy of Fallot and may be related to elevated central venous pressure.

During the last decades, a renewed interest for negative symptoms (NS) was brought about by the increased awareness that they interfere severely with real-life functioning, particularly when they are primary and persistent.

In this guidance paper, we provide a systematic review of the evidence and elaborate several recommendations for the conceptualization and assessment of NS in clinical trials and practice.

Expert consensus and systematic reviews have provided guidance for the optimal assessment of primary and persistent negative symptoms; second-generation rating scales, which provide a better assessment of the experiential domains, are available; however, NS are still poorly assessed both in research and clinical settings.

This European Psychiatric Association (EPA) guidance recommends the use of persistent negative symptoms (PNS) construct in the context of clinical trials and highlights the need for further efforts to make the definition of PNS consistent across studies in order to exclude as much as possible secondary negative symptoms. We also encourage clinicians to use second-generation scales, at least to complement first-generation ones.

The EPA guidance further recommends the evidence-based exclusion of several items included in first-generation scales from any NS summary or factor score to improve NS measurement in research and clinical settings. Self-rated instruments are suggested to further complement observer-rated scales in NS assessment.

Several recommendations are provided for the identification of secondary negative symptoms in clinical settings.

The dissemination of this guidance paper may promote the development of national guidelines on negative symptom assessment and ultimately improve the care of people with schizophrenia.