Efficacy and safety of ketamine for the treatment of depressive symptoms in palliative care: a systematic review

Objectives: Ketamine has a fast onset of action that may offer a paradigm change for depression management at the end of life. We aimed to synthesize evidence regarding the safety and efficacy of ketamine in depression treatment within a broad palliative care concept. Methods: We searched seven databases and included studies on the safety and efficacy of ketamine for depression treatment in patients diagnosed with any life-threatening disease. We also conducted a narrative review of the evidence. Results: Among 2,252 screened titles and abstracts, we included 32 studies in our final synthesis: 14 case reports, two case series, two quasi-experimental studies, and seven randomized clinical trials (RCTs), as well as data from three unpublished clinical trials and seven cases from four larger case series. Most case reports reported a robust effect; however, the larger studies reported conflicting findings. Five RCTs reported positive outcomes; however, four of them were focused on a perioperative setting. Two negative studies did not primarily focus on depression and did not apply severity cutoffs. Conclusion: Although ketamine is generally safe and potentially useful, its efficacy in palliative care settings remains unclear. It may be a reasonable alternative for perioperative depression in oncological patients.

The association of hearing loss with depressive symptoms and cognitive function among older people: Results from the Brazilian Longitudinal Study of Aging.

OBJECTIVES: Hearing loss, depression, and cognitive decline are common among older people. We investigated the association of hearing loss with depressive symptoms and cognitive function in a nationally representative sample of people aged 50+ in Brazil. METHODS: Data from the Brazilian Longitudinal Study of Aging (ELSI-Brazil) included information on self-reported hearing loss, hearing aid use (effective or not effective), depressive symptoms (CES-D-8), and a global cognitive score (composed of immediate and late recall, verbal fluency, orientation and prospective memory) in a sample of 9412 individuals. Multiple linear regression was used to estimate the association of hearing loss and hearing aid use with both depressive symptoms and cognitive performance. The analyses were conducted with 7837 participants with complete data, and then repeated with data from the whole sample after multiple imputation. RESULTS: Compared to those without hearing loss, those with hearing loss were more likely to have a higher number of depressive symptoms (ß: 0.53 (0.40-0.67) p < 0.001) but not worse cognitive performance (ß: -0.01 (-0.03 to 0.19) p = 0.631). Among those with hearing loss, the use of hearing aid was neither associated with cognitive performance (ß: -0.08 (-0.19 to 0.03) p = 0.169) or depressive symptoms (ß: -0.42 (-0.98 to 0.14) p = 0.143); its effective use was associated with less depressive symptoms (ß: -0.62 (-1.23 to -0.01) p = 0.045) but not worse cognitive performance (ß: -0.15 (-0.030 to 0.03) p = 0.057). Sensitivity analyses revealed that hearing loss is associated with a worse performance in two non-amnestic cognitive domains. CONCLUSIONS: Hearing loss may negatively affect specific cognitive domains and depressive symptoms among older people, and the use of a hearing aid may mitigate the association with depressive symptoms.

Longitudinal invariance of psychotic experiences in children and adolescents: What do the data tell us?

BACKGROUND: Psychotic experiences are common in adults, adolescents, and children. While usually self-limited, they can indicate psychosis proneness when persistent. The Community Assessment of Psychic Experiences (CAPE) measures lifetime psychotic experiences in three dimensions. The 20-item subscale addressing positive symptoms (CAPE-positive) is the most widely used. No study investigated its measurement invariance across timepoints during childhood and adolescence. This step is required to conduct reliable comparisons in longitudinal studies with different age groups. METHODS: We used data from the Brazilian High-Risk Cohort, which enrolled 2511 individuals aged 6-12 years from public schools for the baseline evaluation. A 3-year follow-up assessment evaluated 1880 participants. Subjects were rated with the CAPE-positive and we performed, at each wave, a Multigroup Confirmatory Factor Analysis testing Exploratory and Confirmatory Factor Analysis models identified in a previous systematic review, to assess longitudinal invariance. RESULTS: A three-factor solution was the best fitting model, comprising Persecutory Ideation, Bizarre Experiences and Perceptual Abnormalities. The longitudinal invariance analysis of the best-fit model was unsatisfactory, achieving only the metric level of invariance. CONCLUSIONS: Our findings suggest that the CAPE-positive scale has good model fit indices for each evaluated time point individually (children and adolescents), but it is not invariant over time. Identifying which factors affect CAPE latent structure at different time points can improve our understanding of psychosis proneness and how to measure it.

Efficacy and safety of ketamine for the treatment of depressive symptoms in palliative care: A systematic review.

OBJECTIVES: Ketamine has a fast onset of action that may offer a paradigm change for depression management at the end of life. We aimed to synthesize evidence regarding the safety and efficacy of ketamine in depression treatment within a broad palliative care concept. METHODS: We searched seven databases and included studies on the safety and efficacy of ketamine for depression treatment in patients diagnosed with any life-threatening disease. We also conducted a narrative review of the evidence. RESULTS: Among 2,252 screened titles and abstracts, we included 32 studies in our final synthesis: 14 case reports, two case series, two quasi-experimental studies, and seven randomized clinical trials (RCTs), as well as data from three unpublished clinical trials and seven cases from four larger case series. Most case reports reported a robust effect; however, the larger studies reported conflicting findings. Five RCTs reported positive outcomes; however, four of them were focused on a perioperative setting. Two negative studies did not primarily focus on depression and did not apply severity cutoffs. CONCLUSIONS: Although ketamine is generally safe and potentially useful, its efficacy in palliative care settings remains unclear. It may be a reasonable alternative for perioperative depression in oncological patients.

Efficacy and Safety of Subcutaneous Esketamine in the Treatment of Suicidality in Major Depressive Disorder and Bipolar Depression.

BACKGROUND AND OBJECTIVE: Affective disorders account for most cases of suicide. The pharmacological arsenal to treat suicidality is limited and available agents take too long to take effect. A large body of evidence shows optimal results of ketamine for treating depression, but the evidence concerning suicidality has not been fully described. We report the first real-world study of severely depressed patients presenting with suicide ideation who were treated with repeated administration of subcutaneous esketamine. METHODS: We analyzed data from 70 acutely depressed subjects diagnosed with resistant major depressive disorder or bipolar depression. Subjects were administered subcutaneous esketamine once a week for 6 weeks. The primary efficacy endpoint, the change from baseline to 24-h post-administration 6 in the item 10 Montgomery-Åsberg Depression Rating Scale score, was analyzed using a mixed-effects repeated-measures model. RESULTS: There were significant effects for time on item 10 Montgomery-Åsberg Depression Rating Scale scores (p < 0.0001) but not for a time × diagnosis interaction (p = 0.164) from baseline to the end of the study. Efficacy of esketamine did not differ between groups (major depressive disorder vs bipolar depression) at any timepoint. Statistical significance on suicidality scores was observed from 24 h after the first administration (p < 0.001), and a further reduction was observed with repeated administrations. Esketamine was safe and well tolerated. Mean heart rate remained stable during the administrations and the blood pressure increase was self-limited. CONCLUSIONS: Repeated subcutaneous esketamine administration had significant anti-suicidality effects in both major depressive disorder and bipolar groups, with a rapid onset of action and a good tolerability profile. Large randomized controlled trials are warranted to confirm these preliminary findings.

Childhood individual and family modifiable risk factors for criminal conviction: a 7-year cohort study from Brazil.

Crime is a major public problem in low- and middle-income countries (LMICs) and its preventive measures could have great social impact. The extent to which multiple modifiable risk factors among children and families influence juvenile criminal conviction in an LMIC remains unexplored; however, it is necessary to identify prevention targets. This study examined the association between 22 modifiable individual and family exposures assessed in childhood (5-14 years, n = 2511) and criminal conviction at a 7-year follow-up (13-21 years, n = 1905, 76% retention rate) in a cohort of young people in Brazil. Population attributable risk fraction (PARF) was computed for significant risk factors. Criminal convictions were reported for 81 (4.3%) youths. Although most children living in poverty did not present criminal conviction (89%), poverty at baseline was the only modifiable risk factor significantly associated with crime (OR 4.14, 99.8% CI 1.38-12.46) with a PARF of 22.5% (95% CI 5.9-36.1%). It suggests that preventing children's exposure to poverty would reduce nearly a quarter of subsequent criminal convictions. These findings highlight the importance of poverty in criminal conviction, as it includes several deprivations and suggest that poverty eradication interventions during childhood may be crucial for reducing crime among Brazilian youth.

Longitudinal invariance of the positive and negative syndrome scale negative dimension in antipsychotic naïve first-episode schizophrenia.

AIM: Construct stability over time is required for reliable inference, but evidence regarding the longitudinal invariance of negative symptoms is still limited. Thus, we examined the longitudinal invariance of the negative dimension using the positive and negative syndrome scale (PANSS) in an antipsychotic-naïve first-episode schizophrenia sample at baseline and after 10 weeks. METHODS: Our study was conducted at a specialized early intervention service. PANSS ratings were analysed for 138 patients, and two different models were specified and tested: a unidimensional and a two-correlated factor solution. RESULTS: The unidimensional model fulfilled criteria for longitudinal invariance, whilst the two-correlated did not. CONCLUSION: Our study provides support for the PANSS negative unidimensional model use to evaluate negative symptoms' longitudinal change following first-episode schizophrenia.

The probability of response after each subcutaneous injection of esketamine in treatment-resistant depression.

INTRODUCTION: The administration of multiple esketamine doses has shown efficacy for unipolar and bipolar treatment-resistant depression (TRD). Nevertheless, the probability of responding or not after each dose in the real-world remains unknown. This study aimed to estimate it throughout four doses of esketamine, administrated via subcutaneous (SC). MATERIAL AND METHODS: We conducted a retrospective analysis of a case series of 70 patients with TRD who received treatment from the esketamine assistance program at Federal University of Sao Paulo, between April 2017 and December 2018. The SC injections were administrated weekly at a dose of 0.5-1.0mg/kg, in conjunction with patients' psychotropic drugs. Response was defined as a decrease of at least 50% in the Montgomery-Åsberg Depression Rating Scale between baseline and 24h after dose. We used hidden Markov modeling in order to estimate de probability of response after each esketamine injection. RESULTS: The probability of a patient that was a "non-responder" to become a "responder" following a SC injection of esketamine was 17.30% and the probability that this patient remains a "non-responder" was 82.70%. The probability of a patient that was a "responder" to remain as a "responder" was 95%. CONCLUSIONS: Patients with TRD who had not responded after the first dose of esketamine, still had a chance of responding after the subsequent dose administrated via SC.

A Clinical Rationale for Assessing the Impact of Childhood Sexual Abuse on Adjunctive Subcutaneous Esketamine for Treatment-Resistant Depression.

Background: A history of child sexual abuse (CSA) is related to higher suicide rates and poor treatment outcomes in depressed adult patients. Twenty years after the first study investigating the effects of ketamine/esketamine on depression and suicide, there is a lack of data on the CSA effects on this emerging treatment. Here, we assess the impact of CSA on adjunctive subcutaneous (SC) esketamine for treatment-resistant depression (TRD). Methods: A directed acyclic graphic (DAG) was designed to identify clinical confounders between CSA and esketamine predictors of response. The confounders were applied in a statistical model to predict depression symptom trajectory in a sample of 67 TRD outpatients. Results: The patient sample had a relatively high prevalence rate of CSA (35.82%). Positive family history of first-degree relatives with alcohol use disorder and sex were clinical mediators of the effects of esketamine in a CSA adult population. Overall, the presence of at least one CSA event was unrelated to esketamine symptom reduction. Conclusions: Unlike responses to conventional antidepressants and psychotherapy, CSA does not appear to predict poor response to esketamine.

Comparative effectiveness of esketamine in the treatment of anhedonia in bipolar and unipolar depression.

BACKGROUND: Anhedonia is a symptom associated with poorer outcomes in depression treatment, including resistance to treatment, higher functional impact and suicidality. Few drugs are known to adequately treat anhedonia in both unipolar and bipolar depression. The NMDA antagonist ketamine has been demonstrated to be effective in rapidly ameliorating anhedonia in depressive episodes. The main aim of present study is to evaluate the anti-anhedonic effect of esketamine, the S-enantiomer of ketamine recently approved for treatment-resistant depression, in unipolar and bipolar depression. METHODS: 70 patients with unipolar or bipolar depression were treated with 6 weekly subcutaneous esketamine infusions (0.5-1mg/kg). Anhedonia was measured through MADRS item 8 before and 24h after each infusion. RESULTS: A significant reduction in anhedonia severity was observed (p<0.0001) after 6 infusions. The effect was statistically significant 24h after the first infusion (p<0.001) in both unipolar and bipolar groups and increased with repeated infusions. Anti-anhedonic effect of esketamine did not differ between groups. LIMITATIONS: This is an open-label, real-world study. Lack of blinding and of a placebo arm may limit the interpretation of findings. CONCLUSION: Although preliminary, present findings suggest that repeated subcutaneous esketamine infusions are effective for the treatment of anhedonia in both unipolar and bipolar depressed patients. These results need to be confirmed through replication in larger double-blinded controlled trials.

The probability of response after each subcutaneous injection of esketamine in treatment-resistant depression.

INTRODUCTION: The administration of multiple esketamine doses has shown efficacy for unipolar and bipolar treatment-resistant depression (TRD). Nevertheless, the probability of responding or not after each dose in the real-world remains unknown. This study aimed to estimate it throughout four doses of esketamine, administrated via subcutaneous (SC). MATERIAL AND METHODS: We conducted a retrospective analysis of a case series of 70 patients with TRD who received treatment from the esketamine assistance program at Federal University of Sao Paulo, between April 2017 and December 2018. The SC injections were administrated weekly at a dose of 0.5-1.0mg/kg, in conjunction with patients' psychotropic drugs. Response was defined as a decrease of at least 50% in the Montgomery-Åsberg Depression Rating Scale between baseline and 24h after dose. We used hidden Markov modeling in order to estimate de probability of response after each esketamine injection. RESULTS: The probability of a patient that was a "non-responder" to become a "responder" following a SC injection of esketamine was 17.30% and the probability that this patient remains a "non-responder" was 82.70%. The probability of a patient that was a "responder" to remain as a "responder" was 95%. CONCLUSIONS: Patients with TRD who had not responded after the first dose of esketamine, still had a chance of responding after the subsequent dose administrated via SC.

Repeated subcutaneous esketamine administration for depressive symptoms and pain relief in a terminally ill cancer patient: A case report.

BACKGROUND: Depressive disorders are common among cancer patients. Ketamine can quickly relieve depression, and its subcutaneous administration appears to be as effective as and probably safer than its standard intravenous administration. Herein, we report a case verifying the antidepressant effect of a subcutaneous esketamine formulation. CASE PRESENTATION: A 65-year-old male with metastatic abdominal tumor reported sadness, weight loss, fatigue, hopelessness, insomnia, inattention, and reduced motivation. His scores on the visual analogical scale for pain and Montgomery-Asberg depression rating scale were 8/10 and 30/60, respectively. POSSIBLE COURSES OF ACTION: Monoaminergic antidepressants are effective, but their response is slow for end-of-life care. FORMULATION OF A PLAN: Esketamine was preferred because it possibly contributes to pain relief. It can repeatedly be infused intravenously, but was subcutaneously administered twice a week for safety reasons. OUTCOME: The patient showed continuous mood improvement, achieving depression remission on day 7. Pain relief was observed but without stability. His vital signs remained stable, and he remained calm, without major complaints. LESSONS FROM THE CASE: Repeated subcutaneous esketamine injections are possibly safe and effective in pain and depression relief in palliative care cancer patients. VIEW ON RESEARCH PROBLEMS, OBJECTIVES, OR QUESTIONS GENERATED BY THE CASE: Placebo-controlled studies with similar cases are needed to establish efficacy and safety.

Transgender Population under the Bioethics Perspective: a Panorama of the Curricula and Bioethics Courses of Medical Schools of the State of São Paulo / A População Transgênero sob o Olhar da Bioética: Um Panorama dos Currículos de Graduação e dos Cursos de Bioética das Escolas Médicas do Estado de São Paulo

Abstract: Introduction: Transgender people are subject to discrimination and illness due to social marginalization and lack of access to basic rights, especially health care. They suffer from the inadequacy of care directed to basic health demands, high incidence of diseases and non-fulfillment of specific demands. The vulnerability of these people reaches a disturbing level due to disrespectful attitudes that lead trans people to avoid seeking help. Understanding that medical education geared to the needs of marginalized populations is the basis for universal access and adequate care, it is essential that medical schools define contents and pedagogical strategies for vulnerable groups. The aim of this study was to investigate and discuss how (and if) the topic of transgender people healthcare is contemplated in the undergraduate curriculum of medical schools in the state of São Paulo. Method: Exploratory, descriptive-analytical study based on data collected from medical schools in São Paulo, conducted in two stages: 1st, documentary research on the inclusion of the topic of trans people health in the undergraduate curricula; 2nd, research with teachers of the Bioethics courses, where a questionnaire was applied to evaluate how and if the topic is approached as a programmatic content. The data obtained in the 1st stage were analyzed quantitatively and are presented as relative frequencies of the evaluated characteristics, while those of the 2nd stage were analyzed through the descriptive statistical method (closed questions) and content analysis (open questions). Results: We identified references to the trans topic in the formal curricula of only 2 of the 32 surveyed medical schools, with a total of 5 citations on the topic. Analyzing the questionnaires applied to teachers in the area of bioethics, we found reports of discussions on this topic in 5/12 (42%) schools. Although all participants consider the topic to be important, only 7/12 (58%) consider themselves prepared to address it. Conclusion: It is postulated that the evident lack of content aimed at trans health in medical schools can make it difficult to reduce transphobia and develop more dignified services within the healthcare network for these people. Based on the subsidies found in the Bioethics of Protection theoretical framework, we believe the medical curricula and Bioethics courses should create spaces to address this issue, using different and effectively transformative pedagogical practices, and respecting gender identity in all environments.

Resumo: Introdução: Pessoas transgênero constituem um grupo sujeito a situações de discriminação e adoecimento por causa da marginalização social e da falta de acesso a direitos básicos, em especial a saúde. Sofrem com a inadequação do atendimento voltado a demandas básicas de saúde, com a alta incidência de doenças e com o não atendimento de demandas específicas. A vulnerabilidade dessas pessoas atinge um nível preocupante em razão das atitudes desrespeitosas que as levam a não buscar ajuda. Como uma educação médica voltada às necessidades das populações marginalizadas constitui a base para a melhoria do acesso e para uma assistência adequada, é essencial que as escolas médicas definam conteúdos e estratégias pedagógicas destinados a grupos vulnerados. Com base nisso, este estudo se propôs a investigar e discutir como (e se) a temática da assistência à população trans está inserida no currículo de graduação das escolas médicas do estado de São Paulo. Método: Trata-se de um estudo exploratório, de natureza descritiva-analítico, realizado com base em dados coletados de escolas médicas paulistas. O estudo foi conduzido em duas etapas: 1. fez-se uma análise documental sobre a inserção da temática trans nos currículos de graduação e 2. adotou-se um questionário destinado aos professores dos cursos de Bioética com o objetivo de avaliar como e se o tema é abordado como conteúdo programático. Os dados obtidos na primeira etapa foram analisados quantitativamente e são apresentados por meio das frequências relativas das características avaliadas. Na segunda fase, examinaram-se os dados por meio do método estatístico descritivo (perguntas fechadas) e da análise de conteúdo (perguntas abertas). Resultados: Identificamos menções à temática trans nos currículos formais de apenas duas das 32 escolas médicas pesquisadas, com um total de cinco citações referentes ao tema. Na análise dos questionários aplicados aos docentes da área de bioética, encontramos relatos de discussões sobre esse tema em 5/12 (42%) das escolas. Apesar de todos os participantes afirmarem que a temática é importante, somente 7/12 (58%) se consideram preparados para abordá-la. Conclusões: Postula-se que a evidente falta de conteúdo formativo voltado à temática trans nas escolas médicas pode dificultar a busca por um atendimento mais digno dentro da rede de atenção à saúde e o combate à transfobia. A partir de subsídios encontrados no referencial teórico da bioética de proteção, acreditamos que os currículos médicos e os cursos de Bioética deveriam criar espaços para abordar essa temática, empregando diferentes práticas pedagógicas efetivamente transformadoras e respeitando a diversidade de gênero em todos os ambientes.