The fundamental right to equivalence of health care in prison settings encompasses the provision of medication to address mental health conditions. Considering the increased risk for self-harm among individuals dealing with depression, the limited effectiveness of conservative antidepressants is a major challenge in psychiatry. The high prevalence of suicidal tendencies within prison populations underscores the imperative for state-of-the-art pharmacological treatment to uphold adequate health care standards. Notably, the denial of access to effective medication could be deemed a violation of human rights of people living in prison according to international treaties, domestic law, and United Nations normative standards of detention. This article presents the authors\' perspective on the accessibility of ketamine treatment in prison settings, discussing psychiatric and legal considerations as well as current challenges in this context. Implementing novel psychopharmacological interventions may alleviate the distress experienced by individuals struggling with depressive symptoms and suicidality. At the same time, unprecedented treatment alternatives bring along potential issues, including limited understanding of long-term effects and the risk of abuse. Given the scarce data-availability, a pressing need exists for further research on the benefits and risks of ketamine treatment within prison populations.

BACKGROUND: Persistent depressive disorder (PDD) is prevalent and debilitating. For patients with PDD, psychiatric rehabilitation using self-management interventions is advised as the next therapeutic step after multiple unsuccessful treatment attempts. The \"Patient and Partner Education Program for All Chronic Diseases\" (PPEP4All) is a brief, structured self-management program that focuses on functional recovery for patients and their partners/caregivers. In chronic somatic disorder populations, PPEP4All has already been shown to be clinically effective. We examined whether PPEP4All adapted for PDD (PPEP4All-PDD, nine weekly group or individual sessions) is also clinically effective for adults/elderly with PDD and their partners/caregivers compared to care-as-usual (CAU) in specialized mental healthcare.
METHODS: In this mixed-method multicenter pragmatic randomized controlled trial, 70 patients with PDD and 14 partners/caregivers were allocated to either PPEP4All-PDD (patients, n = 37; partners/caregivers, n = 14) or CAU (patients, n = 33; partners/caregivers, not included) and completed questionnaires at 0, 3, 6, and 12 months regarding depressive symptoms, psychopathology, psychosocial burden, mental resilience, and happiness/well-being. Qualitative data were collected regarding treatment satisfaction. Data were analyzed using mixed model analyses and an intention-to-treat (ITT) approach.
RESULTS: There was no statistically significant difference in any outcome regarding clinical effectiveness between PPEP4All-PDD and CAU. Subgroup analysis for depressive symptoms did not show any interaction effect for any subgroup. Although 78% of participants recommended PPEP4All-PDD, there was no difference in treatment satisfaction between PPEP4All-PDD (score = 6.6; SD = 1.7) and CAU (score = 7.6; SD = 1.2), p = 0.06.
CONCLUSIONS: Although depressive symptoms did not improve relative to CAU, this only confirmed that treatment for patients with treatment-resistant PDD should move from symptom reduction to functional recovery. Also, functional recovery may be reflected in other outcomes than psychosocial burden, such as self-empowerment, in patients with treatment-resistant PDD. Future research on PPEP4All-PDD could focus on a longer-term program and/or online program that may also be offered earlier in the treatment process as an empowerment intervention.  TRIAL REGISTRATION: Netherlands Trial Register Identifier NL5818. Registered on 20 July 2016 https://clinicaltrialregister.nl/nl/trial/20302.

Emotional distress has been rising since before the COVID-19 pandemic and the public is told that depression is a major public health problem. For example, in 2017 depressive disorders were ranked as the third leading cause of \"years lost to disability\" and the World Health Organization now ranks depression as the single largest contributor to global disability. Although critical appraisals of the epidemiological data raise questions about the accuracy of population-based depression estimates, the dominance of the medical model and the marketing of psychotropics as \"magic bullets,\" have contributed to a dramatic rise in the prescription of psychiatric drugs. Unfortunately, the pharmaceutical industry\'s influence on psychiatric research and practice has resulted in over-estimates of the effectiveness of psychotropic medications and an under-reporting of harms. This is because the principles that govern commercial entities are incongruent with the principles that guide public health research and interventions. In order to conduct mental health research and develop interventions that are in the public\'s best interest, we need non-reductionist epistemological and empirical approaches that incorporate a biopsychosocial perspective. Taking depression as a case example, we argue that the socio-political factors associated with emotional distress must be identified and addressed. We describe the harms of industry influence on mental health research and show how the emphasis on \"scaling up\" the diagnosis and treatment of depression is an insufficient response from a public health perspective. Solutions for reform are offered.

UNASSIGNED: This meta-analysis assessed whether atypical antipsychotics (AAPs) and esketamine nasal spray (ESK-NS), which are mechanistically distinct, differ in antidepressant outcomes.
UNASSIGNED: Data were extracted from 12 trials of ESK-NS or AAPs in depressed patients (4276) with inadequate response or resistance to conventional antidepressants. Montgomery-Åsberg Depression Rating Scale (MADRS) score reductions from baseline and response rates (≥50% reduction) were analyzed.
UNASSIGNED: At endpoint, the estimated MADRS score reduction of pooled ESK-NS arms was greater than pooled AAP arms (+9.16 points, p < 0.0001). The reduction also was greater in the pooled control arms of the ESK-NS trials than the pooled control arms of the AAP trials (+7.57 points, p < 0.0001). The mean difference in the reductions between pooled ESK-NS and control arms was 1.87 points greater than that between pooled AAP and control arms, but this difference was not significant (95% CI: -4.49, 0.74, p = 0.16). Relative to their respective control arms, the mean difference in response rates was 25% for the pooled ESK-NS and 9% for the pooled AAP arms; the mean response rate was 16% greater in the pooled ESK-NS studies than the pooled AAP studies (p = 0.0004). Comparisons against specific AAPs showed mean differences in the MADRS score reductions at 1 week between the experimental and control arms that were numerically larger in the ESK-NS trials than in the aripiprazole trials (mean difference of 1.71 points, p = 0.06) and the brexpiprazole trials (mean difference of 2.05 points, p = 0.02).
UNASSIGNED: The ESK-NS arms showed numerically larger MADRS score reductions at week-1 and endpoint, and a significantly larger response rate compared with AAP arms. Prospective studies involving direct comparisons are warranted to compare the relative efficacy between these treatment regimens.

[This corrects the article DOI: 10.3389/fpsyt.2021.764776.].

UNASSIGNED: Treatment resistant depression (TRD) affects 10-30% of patients with major depressive disorder. In 4-week trials, esketamine nasal spray (NS) was efficacious vs. placebo when both were initiated in addition to a new selective serotonin or serotonin norepinephrine reuptake inhibitor. However, comparison with an extended range of real-world treatments (RWT) is lacking.
UNASSIGNED: ICEBERG was an adjusted indirect treatment comparison using propensity score-based inverse probability weighting, performed on 6-month response and remission data from patients receiving esketamine NS plus oral antidepressant from the SUSTAIN-2 (NCT02497287; clinicaltrials.gov) study, compared with patients receiving other RWT from the European Observational TRD Cohort (EOTC; NCT03373253; clinicaltrials.gov) study. SUSTAIN-2 was a long-term open-label study of esketamine NS, while the EOTC was conducted at a time when esketamine NS was not available as RWT. Threshold and sensitivity analyses were conducted to assess how robust the primary analyses were.
UNASSIGNED: Patients receiving esketamine NS had a higher probability of 6-month response (49.7% [95% confidence interval (CI) 45.6-53.9]) and remission (33.6% [95% CI 29.7-37.6]) vs. patients receiving RWT (26.4% [95% CI 21.5-31.4] and 18.2% [95% CI 13.9-22.5], respectively), according to rescaled average treatment effect among treated estimates. Resulting adjusted odds ratios (OR) and relative risk (RR) favoured esketamine NS over RWT for 6-month response (OR 2.756 [95% CI 2.034-3.733], p < 0.0001; RR 1.882 [95% CI 1.534-2.310], p < 0.0001) and remission (OR 2.276 [95% CI 1.621-3.196], p < 0.0001; RR 1.847 [95% CI 1.418-2.406], p < 0.0001). Threshold analyses suggested that differences between the two studies were robust, and results were consistent across extensive sensitivity analyses.
UNASSIGNED: ICEBERG supports that, at 6 months, esketamine NS has a substantial and significant benefit over RWT for patients with TRD. While results may be affected by unobserved confounding factors, threshold analyses suggested these were unlikely to impact the study conclusions.To view an animated summary of this publication, please click on the Supplementary video.

UNASSIGNED: The efficacy of esketamine nasal spray (NS) as a rapid-acting agent for treatment resistant depression (TRD) was demonstrated in comparisons with placebo, when both were given in addition to a newly initiated selective serotonin reuptake inhibitor (SSRI)/serotonin norepinephrine reuptake inhibitor (SNRI). How esketamine NS compares with commonly used real-world (RW) polypharmacy treatment strategies is not known.
UNASSIGNED: ICEBERG was an adjusted indirect treatment comparison that analysed data from SUSTAIN-2 (NCT02497287; clinicaltrials.gov), a long-term, open-label study of esketamine NS plus SSRI/SNRI, and the European Observational TRD Cohort (EOTC; NCT03373253; clinicaltrials.gov), an observational study of routine clinical practice. Data were compared between patients receiving esketamine NS (SUSTAIN-2) and those from the EOTC treated with polypharmacy treatment strategies, either combination or augmentation. Analyses were adjusted for potential confounders, using rescaled average treatment effect among treated estimates. Threshold analyses were conducted to assess potential impact of unmeasured confounders on the robustness of analyses where esketamine NS was found to be significantly superior. Sensitivity analyses were used to understand the impact of analysis method selection and data handling.
UNASSIGNED: Esketamine NS treatment resulted in a higher probability of 6-month response (49.7% [95% confidence interval (CI) 45.6-53.9]) and remission (33.6% [95% CI 29.7-37.6]) versus RW polypharmacy (26.8% [95% CI 21.0-32.5] and 19.4%, [95% CI 14.2-24.6], respectively). Relative risk calculations showed esketamine NS was 1.859 (95% CI 1.474-2.345; p < 0.0001) times as likely to result in response and 1.735 (1.297-2.322; p = 0.0002) times as likely to result in remission versus RW polypharmacy at 6 months. Threshold and extensive sensitivity analyses supported that analyses of esketamine NS superiority were robust.
UNASSIGNED: ICEBERG supports esketamine NS being superior to current RW individualized polypharmacy strategies, including augmentation, with benefits extending beyond acute use, to improved chance of 6-month response and remission. While unobserved confounding factors may certainly impact results of an indirect comparison, threshold analysis supported a low likelihood of this affecting the conclusions.To view an animated summary of this publication, please click on the Supplementary video.

OBJECTIVE: To review the usefulness of esketamine for treatment-resistant depression.
METHODS: Pivotal trials of intranasal esketamine in treatment-resistant depression were synthesized as a narrative review.
RESULTS: Esketamine is postulated to act through antagonism of N-methyl-D-aspartate (NMDA) glutamate receptors, but opioidergic effects may also be involved. Unlike intravenous ketamine, esketamine is given intranasally (under clinical observation), usually in addition to an oral antidepressant. Trials compared esketamine plus antidepressant versus placebo plus antidepressant. At 4 weeks, remission was 37% higher with esketamine/antidepressant than placebo/antidepressant. Speed of response and improvement in suicidality were comparable. In stable remitters on esketamine/antidepressant, 45% relapsed when esketamine was withdrawn over the following 6 months (whereas 25% relapsed on esketamine/antidepressant). Response appears less likely in patients with multiple antidepressant failures. Adverse effects include dissociation, dizziness, nausea, sedation, and headache but no psychosis. Hypertension affected 13%, especially older patients. Dose frequency is twice-weekly for 4 weeks, then weekly/fortnightly thereafter. No abuse has been reported. Unsubsidised cost may be beyond the reach of many Australians.
CONCLUSIONS: Intranasal esketamine plus antidepressant has been approved by regulators as moderately effective and acceptably tolerable for treatment-resistant depression. Cost is a drawback. Use often needs to be long-term and vigilance for abuse is essential.

UNASSIGNED: Many patients fail to respond to multiple antidepressant interventions, being defined as \"treatment-resistant depression\" (TRD) patients. TRD is usually associated with increased severity and chronicity of symptoms, increased risk of comorbidity, and higher suicide rates, which make the clinical management challenging. Efforts to distinguish between TRD patients and those who will respond to treatment have been unfruitful so far. Several studies have tried to identify the biological, psychopathological, and psychosocial correlates of depression, with particular attention to the inflammatory system. In this paper we aim to review available studies assessing the full range of biomarkers in TRD patients in order to reshape TRD definition and improve its diagnosis, treatment, and prognosis.
UNASSIGNED: We searched the most relevant medical databases and included studies reporting original data on possible biomarkers of TRD. The keywords \"treatment resistant depression\" or \"TRD\" matched with \"biomarker,\" \"inflammation,\" \"hormone,\" \"cytokine\" or \"biological marker\" were entered in PubMed, ISI Web of Knowledge and SCOPUS databases. Articles were included if they included a comparison with healthy controls (HC).
UNASSIGNED: Of the 1878 papers identified, 35 were included in the present study. Higher plasma levels of IL-6 and TNF-α were detected in TRD patients compared to HC. While only a few studies on cortisol have been found, four papers showed elevated levels of C-reactive protein among these patients and four articles focused on immunological cells. Altered kynurenine metabolism in TRD patients was reported in two studies, while contrasting results were found with regard to BDNF.
UNASSIGNED: Only a few biological alterations correlate with TRD. TNF-α seems to be the most relevant biomarker to discriminate TRD patients from both HC and treatment-responsive MDD patients. Moreover, several discrepancies among studies have been found, due to methodological differences and the lack of a standardized diagnostic definition of TRD.

UNASSIGNED: Among treatment-resistant depression (TRD), we identified anergic-anhedonic clinical presentations (TRAD) as putatively responsive to pro-dopaminergic strategies. Based on the literature, non-selective monoamine oxidase inhibitors (MAOI) and dopamine D2 receptor agonists (D2RAG) were sequentially introduced, frequently under the coverage of a mood stabilizer. This two-step therapeutic strategy will be referred to as the Dopaminergic Antidepressant Therapy Algorithm (DATA). We describe the short and long-term outcomes of TRAD managed according to DATA guidelines.
UNASSIGNED: Out of 52 outpatients with TRAD treated with DATA in a single expert center, 48 were included in the analysis [severity - QIDS (Quick Inventory of Depressive Symptomatology) = 16 ± 3; episode duration = 4.1 ± 2.7 years; Thase and Rush resistance stage = 2.9 ± 0.6; functioning - GAF (Global Assessment of Functioning) = 41 ± 8]. These were followed-up for a median (1st - 3rd quartile) of 4 (1-9) months before being prescribed the first dopaminergic treatment and remitters were followed up 21 (11-33) months after remission.
UNASSIGNED: At the end of DATA step 1, 25 patients were in remission (QIDS <6; 52% [38-66%]). After DATA step 2, 37 patients were in remission (77% [65-89%]) to whom 5 patients with a QIDS score = 6 could be added (88% [78-97%]). Many of these patients felt subjectively remitted (GAF = 74 ± 10). There was a significant benefit to combining MAOI with D2RAG which was maintained for at least 18 months in 30 patients (79% [62-95%]).
UNASSIGNED: These results support TRAD sensitivity to pro-dopaminergic interventions. However, some clinical heterogeneities remain in our sample and suggest some improvement in the description of dopamine-sensitive form(s).