Esketamine for treatment resistant depression: a trick of smoke and mirrors?

Abstract In March 2019, the US Food and Drug Administration (FDA) approved a nasal spray formulation of esketamine for the treatment of resistant depression in adults. Esketamine is the S-enantiomer of ketamine, an FDA-approved anaesthetic, known to cause dissociation and, occasionally, hallucinations. While ketamine has not been approved for depression in the USA or in any other country, it has been used off-label in cases of severe depression. This commentary critically reviewed the evidence on esketamine submitted to the FDA, aiming to draw implications for clinical practice, research and regulatory science

Neonatal withdrawal syndrome following in utero exposure to antidepressants: a disproportionality analysis of VigiBase, the WHO spontaneous reporting database

Evidence on neonatal withdrawal syndrome following antidepressant intrauterine exposure is limited, particularly for antidepressants other than selective serotonin reuptake inhibitor (SSRIs)

Neonatal withdrawal syndrome following in utero exposure to antidepressants: a disproportionality analysis of VigiBase, the WHO spontaneous reporting database

Background: Evidence on neonatal withdrawal syndrome following antidepressant intrauterine exposure is limited, particularly for antidepressants other than selective serotonin reuptake inhibitor (SSRIs). Methods: In our case/non-case pharmacovigilance study, based on VigiBase®, the WHO database of suspected adverse drug reactions, we estimated reporting odds ratio (ROR) and the Bayesian information component (IC) with 95% confidence/credibility intervals (CI) as measures of disproportionate reporting of antidepressant-related neonatal withdrawal syndrome. Antidepressants were first compared to all other medications, then to methadone, and finally within each class of antidepressants: SSRIs, tricyclics (TCA) and other antidepressants. Antidepressants were ranked in terms of clinical priority, based on semiquantitative score ratings. Serious v. non-serious reports were compared. Results: A total of 406 reports of neonatal withdrawal syndrome in 379 neonates related to 15 antidepressants were included. Disproportionate reporting was detected for antidepressants as a group as compared to all other drugs (ROR: 6.18, 95% CI 5.45-7.01, IC: 2.07, 95% CI 1.92-2.21). Signals were found for TCAs (10.55, 95% CI 8.02-13.88), followed by other antidepressants (ROR: 5.90, 95% CI 4.74-7.36) and SSRIs (ROR: 4.68, 95% CI 4.04-5.42). Significant disproportionality emerged for all individual antidepressants except for bupropion, whereas no disproportionality for any antidepressant was detected v. methadone. Eleven antidepressants had a moderate clinical priority score and four had a weak one. Most frequent symptoms included respiratory symptoms (n = 106), irritability/agitation (n = 75), tremor (n = 52) and feeding problems (n = 40). Conclusions: Most antidepressants are associated with moderate signals of disproportionate reporting for neonatal withdrawal syndrome, which should be considered when prescribing an antidepressant during pregnancy, irrespective of class. Keywords: Abstinence syndrome; antidepressants; neonates; poor neonatal adaptation syndrome; pregnancy; withdrawal syndrome

O DESEMPENHO ECONÔMICO DE SIDERÓPOLIS PÓS PLANO REAL: UMA ANÁLISE A PARTIR DO VALOR ADICIONADO REAL E DA QUANTIDADE DE EMPREGOS

O valor adicionado real e o emprego são importantes meios para mensuração do desempenho de qualquer economia

Oral and long-acting antipsychotics for relapse prevention in schizophrenia-spectrum disorders: a network meta-analysis of 92 randomized trials including 22,645 participants

According to current evidence and guidelines, continued antipsychotic treatment is key for preventing relapse in people with schizophrenia-spectrum disorders, but evidence-based recommendations for the choice of the individual antipsychotic for maintenance treatment are lacking. Although oral antipsychotics are often prescribed first line for practical reasons, long-acting injectable antipsychotics (LAIs) are a valuable resource to tackle adherence issues since the earliest phase of disease. Medline, EMBASE, PsycINFO, CENTRAL and CINAHL databases and online registers were searched to identify randomized controlled trials comparing LAIs or oral antipsychotics head-to-head or against placebo, published until June 2021. Relative risks and standardized mean differences were pooled using random-effects pairwise and network meta-analysis. The primary outcomes were relapse and dropout due to adverse events. We used the Cochrane Risk of Bias tool to assess study quality, and the CINeMA approach to assess the confidence of pooled estimates. Of 100 eligible trials, 92 (N=22,645) provided usable data for meta-analyses. Regarding relapse prevention, the vast majority of the 31 included treatments outperformed placebo. Compared to placebo, “high” confidence in the results was found for (in descending order of effect magnitude) amisulpride-oral (OS), olanzapine-OS, aripiprazole-LAI, olanzapine-LAI, aripiprazole-OS, paliperidone-OS, and ziprasidone-OS. “Moderate” confidence in the results was found for paliperidone-LAI 1-monthly, iloperidone-OS, fluphenazine-OS, brexpiprazole-OS, paliperidone-LAI 1-monthly, asenapine-OS, haloperidol-OS, quetiapine-OS, cariprazine-OS, and lurasidone-OS. Regarding tolerability, none of the antipsychotics was significantly worse than placebo, but confidence was poor, with only aripiprazole (both LAI and OS) showing “moderate” confidence levels. Based on these findings, olanzapine, aripiprazole and paliperidone are the best choices for the maintenance treatment of schizophrenia-spectrum disorders, considering that both LAI and oral formulations of these antipsychotics are among the best-performing treatments and have the highest confidence of evidence for relapse prevention. This finding is of particular relevance for low- and middle-income countries and constrained-resource settings, where few medications may be selected. Results from this network meta-analysis can inform clinical guidelines and national and international drug regulation policies

Which psychotherapy is effective in panic disorder? And which delivery formats are supported by the evidence? Study protocol for two systematic reviews and network meta-analyses

Introduction Panic disorder is among the most prevalent anxiety diseases. Although psychotherapy is recommended as first-line treatment for panic disorder, little is known about the relative efficacy of different types of psychotherapies. Moreover, there is little evidence concerning the effectiveness of different formats of major psychotherapeutic types, such as cognitive-behavioural therapy (CBT). In this protocol, we present an overarching project consisting of two systematic reviews and network meta-analyses (NMA) to shed light on which psychotherapy (NMA-1), and specifically, which CBT delivery format (NMA-2) should be considered most effective for adults suffering from panic disorder with or without agoraphobia. Methods and analyses Starting from a common pool of data, we will conduct two systematic reviews and NMA of randomised controlled trials examining panic disorder. A comprehensive search will be performed in electronic databases MEDLINE, Embase, PsycINFO and the Cochrane Register of Controlled Trials - CENTRAL from database inception to 1 January 2021 to identify relevant studies. A systematic approach to searching, screening, reviewing and data extraction will be applied. Titles, abstract and - whenever necessary - full texts will be examined independently by at least two reviewers. The quality of the included studies will be assessed using the revised Cochrane risk of bias tool V.2. The primary efficacy outcome will be anxiety symptoms at study endpoint. The primary acceptability outcome will be all-cause discontinuation, as measured by the proportion of patients who had discontinued treatment for any reason at endpoint. Data will be pooled using a random-effects model. Pairwise and NMA will be conducted. Ethics and dissemination No ethical approval is necessary for these two studies, as there will be no collection of primary data. The results will be disseminated through peer-reviewed publications and presentations at national and international conferences and meetings

Comparative efficacy and acceptability of psychotherapies for panic disorder with or without agoraphobia: Systematic review and network meta-Analysis of randomised controlled trials

Background Psychotherapies are the treatment of choice for panic disorder, but which should be considered as first-line treatment is yet to be substantiated by evidence. Aims To examine the most effective and accepted psychotherapy for the acute phase of panic disorder with or without agoraphobia via a network meta-Analysis. Method We conducted a systematic review and network meta-Analysis of randomised controlled trials (RCTs) to examine the most effective and accepted psychotherapy for the acute phase of panic disorder. We searched MEDLINE, Embase, PsycInfo and CENTRAL, from inception to 1 Jan 2021 for RCTs. Cochrane and PRISMA guidelines were used. Pairwise and network meta-Analyses were conducted using a random-effects model. Confidence in the evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). The protocol was published in a peer-reviewed journal and in PROSPERO (CRD42020206258). Results We included 136 RCTs in the systematic review. Taking into consideration efficacy (7352 participants), acceptability (6862 participants) and the CINeMA confidence in evidence appraisal, the best interventions in comparison with treatment as usual (TAU) were cognitive-behavioural therapy (CBT) (for efficacy: standardised mean differences s.m.d. =-0.67, 95% CI-0.95 to-0.39; CINeMA: moderate; for acceptability: relative risk RR = 1.21, 95% CI-0.94 to 1.56; CINeMA: moderate) and short-Term psychodynamic therapy (for efficacy: s.m.d. =-0.61, 95% CI-1.15 to-0.07; CINeMA: low; for acceptability: RR = 0.92, 95% CI 0.54-1.54; CINeMA: moderate). After removing RCTs at high risk of bias only CBT remained more efficacious than TAU. Conclusions CBT and short-Term psychodynamic therapy are reasonable first-line choices. Studies with high risk of bias tend to inflate the overall efficacy of treatments. Results from this systematic review and network meta-Analysis should inform clinicians and guidelines

Factors associated with first- versus second generation long-acting antipsychotics prescribed un-der ordinary clinical practice in Italy.

Background For many years, long-acting intramuscular (LAI) antipsychotics have been prescribed predominantly to chronic and severe patients, as a last resort when other treatments failed. Recently, a broader and earlier use of LAIs, particularly second-generation LAIs, has been emphasized. To date, few studies attempted to frame how this change in prescribing took place in real-world practice. Therefore, this study aimed to describe the clinical features of patients prescribed with LAIs, and to explore possible prescribing differences between first- and second-generations LAIs under ordinary clinical practice in Italy. Methods The STAR Network \u201cDepot\u201d Study is an observational, longitudinal, multicenter study involving 35 centers in Italy. In the cross-sectional phase, patients prescribed with LAIs were consecutively recruited and assessed over a period of 12 months. Descriptive statistics and multivariable logistic regression analyses were employed. Results Of the 451 recruited patients, 61% were males. The level of social and working functioning was heterogeneous, as was the severity of disease. Seventy-two per cent of the patients had a diagnosis of the schizophrenia spectrum. Seventy per cent were prescribed with second-generation antipsychotic (SGA) LAIs (mostly paliperidone, aripiprazole and risperidone). Compared to first-generation antipsychotic (FGA) LAIs, patients prescribed with SGA LAIs were more often younger; employed; with a diagnosis of the schizophrenia spectrum or bipolar disorder; with higher levels of affective symptoms; with fewer LAI prescriptions in the past. Discussion LAIs' prescribing practices appear to be more flexible as compared to the past, although this change is mostly restricted to SGA LAI